MX337178B

Piperidinone derivatives as mdm2 inhibitors for the treatment of cancer.

Abstract

The present invention provides MDM2 inhibitor compounds of Formula (I), wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

MX337178B, drawing sheet 1 — Sheet 1 of 2,543

Term

4.7 yearsleft in the term

Expires 3 June 2031.

Parties

Owner: AMGEN INC
Inventors: JOHNSON, MICHAEL, United States of America
LIU, JIWEN, United States of America
KAYSER, FRANK, Germany
CHEN, XIAOQI, United States of America
and 38 more inventorsShow fewer
YAN, XUELEI, China
MA, ZHIHUA, China
REW, YOSUP, Republic of Korea
JIAO, XIANYUN, China
FU, ZICE, China
DEIGNAN, JEFFREY, United States of America
FU, JIASHENG, Canada
SUN, DAQING, United States of America
HUANG, XIN, United States of America
YU, MING, China
GONZALEZ LOPEZ DE TURISO, FELIX, Spain
LAI, SUJEN, Taiwan Province of China
EKSTEROWICZ, JOHN, United States of America
FISHER, BENJAMIN, Canada
MCMINN, DUSTIN, United States of America
MCINTOSH, JOEL, United States of America
WANG, XIAODONG, United States of America
LI, ZHIHONG, United States of America
BARTBERGER, MICHAEL DAVID, United States of America
GONZÁLEZ BUENROSTRO, ANA, United States of America
BECK, HILARY PLAKE, United States of America
CONNORS, RICHARD VICTOR, Canada
DUQUETTE, JASON, United States of America
FOX, BRIAN MATTHEW, United States of America
GRIBBLE, MICHAEL WILLIAM, United States of America
GUSTIN, DARIN JAMES, United States of America
HEATH, JULIE ANNE, United States of America
KOPECKY, DAVID JOHN, United States of America
LI, YIHONG, United States of America
LOW, JONATHAN DANTE, United States of America
LUCAS, BRIAN STUART, United States of America
MCGEE, LAWRENCE, United States of America
MEDINA, JULIO CESAR, United States of America
MIHALIC, JEFFREY THOMAS, United States of America
OLSON, STEVEN HOWARD, United States of America
ROVETO, PHILIP MARLEY, United States of America
WANG, YINGEAI, China
ZHU, JIANG, China

Examination

Agent: MARIA ANGELICA PARDAVELL JUAREZ
Filing to grant: 3.2 years

Reach

Family: 149 members in 43 offices⁠IL18US13KR11EP8CA7HK6JP6TW6+35

Classification

CPC: C07D211/40C07D211/76C07D279/02C07D401/04C07D401/06C07D401/12+31 more
IPC: C07D211 40A61K31 4412A61P35 00C07D279 02C07D401 04C07D401 06+9 more

15 claims: 6 independent, 9 dependent

1
NOVEDAD DE LA INVENCION 1300 Habiendo descrito la presente invención, se considera como novedad, y por lo tanto se reclama como propiedad lo contenido en las siguientes:REIVINDICACIONES 1. Un compuesto de fórmula IE: o una sal farmacéuticamente aceptable del mismo, caracterizado porque: R e es H ó metilo ó etilo;R 1 es OH □τ.νττ-Α-η»—.η»Ί
2
El compuesto de conformidad con la reivindicación 1, o sal farmacéuticamente aceptable del mismo, caracterizado porque R e es metilo. 2'0
3
Un compuesto ó una sal farmacéuticamente aceptable ((S)-l-ciclopropil-2-(metilsulfonil)etil)-3-metil-2del mismo, caracterizado porque es seleccionado de:ácido 2-((3R,5R,6S)-5-(3-Clorofenil)-6-(4-clorofenil)-1oxopiperidin-3-il)acético;1302 ácido 2-((3R,5R,6S)-1-((S)-1-(tert-butilsulfonil)butan-2il)-5-(3-clorofenil)-6-(4-clorofenil)-3-metil-2-oxopiperidin- 3-il)acético;ácido 2-((3R,5R,6S)-5-(3-clorofenil)-6-(4-clorofenil)-1((S)-1-(isopropilsulfonil)butan-2-il)-3-metil-2-oxopiperidin- 3-il)acético;ácido 2-((3R,5R,6S)-5-(3-Clorofenil)-6-(4-clorofenil)-1((S)-1-(isopropilsulfonil)-3,3-dimetilbutan-2-il)-3-metil-2oxopiperidin-3-il)acético;ácido 2-((3R,5R,6S)-5-(3-Clorofenil)-6-(4-clorofenil)-1( (S)-1-(etilsulfonil)-3-metilbutan-2-il)-3-metil-2oxopiperidin-3-il)acético;ácido 2-((3R,5R,6S)-5-(3-Clorofenil)-6-(4-clorofenil)-1((S)-1-(etilsulfonil)butan-2-il)-3-metil-2-oxopiperidin-3il)acético;ácido 2-((3R,5R,6S)-5-(3-clorofenil)-6-(4-clorofenil)-1( (S)-l-ciclopropil-2-(N-fenilciclopropansulfonamido)etil)-3metil-2-oxopiperidin-3-il)acético;ó ácido 2-((3R,5R,6S)-5-(3-Clorofenil)-6-(4-clorofenil)-1((S)-1-((ciclopropilmetil)sulfonil)butan-2-il)-3-metil-2oxopiperidin-3-il)acético.
4
Una composición farmacéutica caracterizada porque comprende un compuesto de conformidad con cualquiera de las reivindicaciones 1 a 3, o una sal farmacéuticamente aceptable del mismo, un excipiente farmacéuticamente aceptable, diluyente o vehículo. 1303 INSTITUTO MEXICANO ft-'---C de la PROPIEDAD INDUSTRIAL
5
El compuesto de conformidad con la reivindicación 1, caracterizado porque el compuesto es ácido 2-((3R,5R,6S)- 5-(3-Clorofenil)-6-(4-Clorofenil)-1-((S)-1(isopropilsulfonil)-3-metilbutan-2-il)-3-metil-2oxopiperidin-3-il)acético.
6
El compuesto de conformidad con la reivindicación 1, caracterizado porque el compuesto es ácido 2-((3R,5R,6S)5-(3-Clorofenil)-6-(4-Clorofenil)-1-((S)-1(isopropilsulfonil)-3-metilbutan-2-il)-3-metil-2oxopiperidin-3-il)acético, o una sal farmacéuticamente aceptable del mismo.
7
Una composición farmacéutica caracterizada porque comprende el compuesto de conformidad con la reivindicación 5;y un excipiente, diluyente o vehículo farmacéuticamente aceptable.
8
Una composición farmacéutica caracterizada porque comprende el compuesto de conformidad con la reivindicación 6, o una sal farmacéuticamente aceptable del mismo, y un excipiente, diluyente o vehículo farmacéuticamente aceptable.
9
La composición farmacéutica de conformidad con cualquiera de las reivindicaciones 4, 7 y 8, caracterizada porque es una forma de dosificación sólida. 1304 INSTITUTO MEXICANO
10
La composición farmacéutica de conformidad con la reivindicación 9, caracterizada porque la forma de dosificación solida es una cápsula, tableta, polvo o gránulo.
11
La composición farmacéutica de conformidad con la reivindicación 1, caracterizada porque la forma de dosificación solida es una tableta.
12
La composición farmacéutica de conformidad con cualquiera de las reivindicaciones 9 a 11, en donde la forma de dosificación solida esta adaptada para ser administrada por via oral.
13
El uso del compuesto de conformidad con cualquiera de las reivindicaciones 1 a 3, 5 y 6 en la fabricación de un medicamento para el tratamiento de cáncer en un sujeto en necesidad del mismo, en donde el cáncer es seleccionado de sarcomas de tejido blando, cáncer en hueso como osteosarcoma, tumores de mama, cáncer de vejiga, Síndrome de Li-Fraumeni, tumores cerebrales, rabdomiosarcoma, carcinoma adenocortical, cáncer colorectal, cáncer de céulas no pequeñas de pulmón, y reivindicación 13 o 14, en donde el cáncer es identificado 1305 como p53 del tipo natural (p53 WT ) .
14
16. El uso de la composición de conformidad con cualquiera de las reivindicaciones 4 y 7 a 12 en la fabricación de un medicamento para el tratamiento de cáncer en un sujeto en necesidad del mismo, en donde el cáncer es seleccionado de sarcomas de tejido blando, cáncer en hueso como osteosarcoma, tumores de mama, cáncer de vejiga, Síndrome de Li-Fraumeni, tumores cerebrales, rabdomiosarcoma, carcinoma adenocortical, cáncer colorectal, cáncer de céulas no pequeñas de pulmón, y leucemia mielógena aguda (AML;por sus siglas en inglés)
15
17. El uso de la composición de conformidad con la reivindicación 16, en donde el tumor cerebral es glioblastoma. El uso de la composición de conformidad con la reivindicación 16 17, en donde el cáncer es identificado como p53 del tipo natural (p53 WT ) . 1306 INSTITUTO MEXICAN DB LA FKOWSI?/ .' INDUSTRIA

Independent claims15

15,239 paragraphs in 1,189 sections, as filed

(54) Title: PIPERIDINONE DERIVATIVES AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER.

(57) Summary

The present invention provides MDM2 Inhibitor compounds of Formula I, (see formula) wherein the variables are defined above, the compounds of which are useful as therapeutic agents, particularly for the treatment of cancers. The present Invention "Invention" also relates to pharmaceutical compositions containing an MDM2 Inhibitor.

(57) Abstract

The present ¡nventlon provides MDM2 inhibitor compounds of Formula (I), whereln the variables are deflned above, whlch compounds are useful as therapeutlc agents, partlcularly for the treatment of cancers. The present ventlon also relates to pharmaceutical composltons that contain an MDM2 Inhibitor.

Institute

Mexican Property

Industrial

PATENT TITLE NO. 337178

Holder (s) Address:

Denomination:

Classification:

Inventor (s) ___SE___ «RrálíÍA ΙΜΚΟΛΜί *

AMGEN INC.

i MP

I

One Amgen Center Drive, M / S 28-2-C, Thousand Oaks, California, 91320, USA

PIPERIDINONE DERIVATIVES AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER.

Int.CI.8: A61K31 / 4412; A61P35 / 00; C07D211 / 40; C07D279 / 02; C07D401 / 04; C07D401 / 06; C07D401 / 12; C07D407 / 04; C07D407 / 06; C07D409 / 04; C07D413 / 06; C07D417 / 06; C07D471 / 20; C07D498 / 08; C07D498 / 20

MICHAEL

DAVID BARTBERGER; ANA GONZÁLEZ BUENROSTRO;

HILARY PLAKE; JASON FOX; WILLIAM IANYUN IN LAI; LUKE; CESAR P REW; ; XUELEI

THAT SHE IBBL O; M

HONG

IHUA

DYNE

ILIP h

N; MlKW; JIANG ZHU

GUSTIN; JULIE ANNE N; FRANK KAYSER; DAVID JOH Ll; JIWEN LIU; JONATHAN DANTE LOW;

NCE MCGEE; JOEL MCINTOSH; DUSTIN MC AND THOMAS MIHALIC; STEVEN HOWARD OL ROVETO; DAQING SUN; XIAODONG WANG; YING

REQUEST

Date

PRIO

Numbers

MX / a / 2012/014 (14

Igency: Twenty years of VencAiient and reference patent becomes conforming to article 23 of MMHRMMMiniMi of pres

Date:

: June 3, undamento in articles 1, [, and 59 of the Industrial Property Law.

rights.

Who subscribes to this title does so based on the provisions of articles 6 sections III and 7 bis 2 of the Industrial Property Law (Official Gazette of the Federation (DOF) 06/27/1991, amended on 02 / 08/1994, 10/25/1996, 12/26/1997, 05/17/1999, 01/26/2004, 06/16/2005, 01/25/2006, 06/05/2009 / 06/01 / 2010, 06/18/2010, 06/28/2010, 01/27/2012 and 04/09/2012); articles 1, 3or fraction V subsection a), 4th and 12th fractions I and III of the Regulation of the Mexican Institute of Industrial Property (DOF 14/12/1999, amended on 07/01/2002, 07/15/2004, 07/28/2004 2004 and 7/09/2007); items 1or, 3°, 4°, 5or fraction V subsection a), 16 sections I and III and 30 of the Organic Statute of the Mexican Institute of Industrial Property (DOF 12/27/1999, amended on 10/10/2002, 07/29/2004, 08/04/2004 and 09/13/2007); 1st, 3or and 5th paragraph a) of the Agreement that delegates powers to the Deputy Directors General, Coordinator, Divisional Directors, Heads of Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Property ustrial JD OF 15/12/1999 , amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

Issue Date: February 15, 2016

NAHANNY CANAL REYES

Arenai No. 550. Floor *. Col Pueblo Santa María Tepepan, Xochimiico, CP 16020, Mexico City

Tel (55) 53 34 07 00 www.impiqob.mx

MX / 2016/13061

PIPERIDINONE DERIVATIVES AS INHIBITORS

------------------------ 1 -------------------------------------------—- 1 ------------: ------- INPUiTRlAL '

CANCER TREATMENT

FIELD OF THE INVENTION

The present invention relates to compounds that are MDM2 inhibitors that are useful as therapeutic agents, particularly for the treatment of cancers. The invention also relates to pharmaceutical compositions containing an MDM2 inhibitor.

BACKGROUND OF THE INVENTION

P53 is a tumor suppressor and transcription factor that responds to cell tension by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike normal cells, which have infrequent causes for p53 activation, tumor cells are under constant cellular stress from various attacks including hypoxia and activation of the pro-apoptotic oncogene.

In this way, there is a strong selective advantage for the inactivation of the p53 pathway in tumors, and it has been proposed that eliminating p53 function may be a prerequisite for tumor survival. In support of this notion, three groups of researchers have used models

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

of mice to demonstrate that the absence of p53 function is a continuous requirement for the maintenance of established tumors. When researchers restore p53 function for tumors with inactivated p53, the tumors return.

P53 is inactivated by mutation and / or loss in 50% of solid tumors and 10% of liquid tumors. Other key members of the p53 pathway are also genetically or epigenetically altered in cancer. MDM2, an oncoprotein, inhibits p53 function, and is activated by gene amplification in incidental ratios that are reported to be as high as 10%. MDM2, again, is inhibited by another tumor suppressor, pl4ARF. It has been suggested that alterations downstream of p53 may be responsible for at least partially inactivating the p53 pathway in p53 tumors.Wt (p53 wild type). In support of this concept, some p53 tumorsWt they appear to exhibit reduced apoptotic capacity, although their ability to experience cell cycle arrest remains intact. A cancer treatment strategy involves the use of small molecules that bind MDM2 and neutralize its interaction with p53. MDM2 inhibits p53 activity by three mechanisms: 1) acting as an E3 ubiquitin ligase to promote p53 degradation; 2) linked to and blocking the p53 transcriptional activation domain; and 3) export p53

from the nuclei to the cytoplasm. All of these three mechanisms would be blocked by neutralizing the MDM2-p53 interaction. In particular, this therapeutic strategy could be applied to tumors that are p53Wt, and studies with small molecule MDM2 inhibitors have provided promising reductions in tumor growth both in vitro and in vivo. In addition, in patients with p53-inactivated tumors, stabilization of wild-type p53 in normal tissues by inhibition of MDM2 may allow selective protection of normal tissues from mitotic poisonings.

The present invention relates to compounds capable of inhibiting the interaction between p53 and MDM2 and activating downstream effector genes of p53. As such, the compounds of the present invention could be useful in the treatment of cancers, bacterial infections, viral infections, ulcers, and inflammation. In particular, the compounds of the present invention are useful for treating solid tumors such as: breast, colon, lung, and prostate tumors; and liquid tumors such as lymphomas and leukemias. As used herein, MDM2 means a human MDM2 protein and p53 means a human p53 protein. It is noted that human MDM2 can also be referred to as HDM2 or hMDM2.

SUMMARY OF THE INVENTION

The present invention relates

piperidinone of Formula I.

enantiomers

diastereomers and pharmaceutically acceptable salts thereof, wherein

Q is a bond or can optionally be selected from O, NR7 And so)V, when n * is an integer from 1 to 6,

Z is C = O or S (= 0) 2

Rto is each presented independently selected from H, (C1-C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) alkyl (Ci-C3) z (alkoxy) (C1-C3) alkyl, or cyano;

Rb is H, halo,. (C1-C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl, (alkoxy) (C1-C3) alkyl, or cyano;

Rc and Rd are independently H, halo, (C1-C3) alkyl,

(C1-C3) alkyl, (halo) (C1-C3) alkyl, (halo) (C1-C3) alkoxy, (alkoxy) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl;

or Rc and Rd they can optionally combine to form a spiro-cycloalkyl or heterocycle ring system;

Rand is (a) H, or halo; or (b) alkyl (Ci-Cg), cycloalkyl (C3-Cg), heterocycle (C3cyano, halogen, hydroxyl,

-OR5,

NR7R8, heterocycloalkyl, any which can

<td>replace</td><td>optionally</td><td>with</td><td>1 0 more</td><td>groups</td><td>Rx how I know</td>

<td>allow for</td><td>valence.</td><td></td><td></td><td></td><td></td>

<td>0 Rand</td><td>and anyone</td><td>of</td><td>the groups</td><td>R '0</td><td>R can</td>

<td>combine</td><td>optionally</td><td>.for</td><td>To form a</td><td>system</td><td>ring</td>

spiro-cycloalkyl or heterocycle;

<td>0 Rd and anyone</td><td>of</td><td>the groups</td><td>R '0 R</td><td>they can</td>

<td>optionally combine</td><td>for</td><td>To form a</td><td>system of</td><td>ring</td>

cycloalkyl or fused heterocycle;

or Rd and Rand they may optionally combine to form a fused cycloalkyl or heterocycle system;

R 'and R each that occur respectively are independently H, halo, (C1-C3) alkyl, (C1-C3) alkoxy, (halo) (C1-C3) alkyl, (halo) alkoxy (G1-C3) , (alkoxy) alkyl (CiC3), (hydroxy) C1-C3 alkyl, -S-C1-C3 alkyl,

C (O) (C1-C3) alkyl, -NR7R8, or hydroxyl or R 'and R linked thereto

IMPÍ

MEXICAN INSTITUTE

OF EA INDUSTRIAL PROPERTY

carbon atom can optionally combine to form = 0;

or R 'and R linked to the same carbon atom can optionally combine to form a spiro-fused cycloalkyl or heterocycle · ring system

R1 is (a) -COOH, -C (O) OR10, -C (O) NH0H, -C (O) NH-NH2, -

C (O) NHS (O)2R10, -S (0) 2NHC (0) R10, -S (O) 2NR7R8, -NR7C (O) R10,

NR7C (O) 'OR5, -C (O) NR7R8, -NR7S (O) 2R10, O -NR7C (O) NR7R8, -S (O) vR10, or CN;

(b) heteroaryl or heterocycle either of which may optionally be independently substituted with one or more R groupsx as allowed by valence;

R2 is (a) -NR7R8, NR7C (O) OR10, NR7C (0) NR7R10, or -C (Rto) R5R6;

(b) aryl, heteroaryl, cycloalkyl, or heterocycle any of which can be optionally independently substituted with one or more R groupsx as allowed by valence; ·

R3 and R4 are independently aryl or heteroaryl, either of which may optionally be independently substituted · with one or more R groupsx as allowed by valence;

or any of R3 and Rto along with the carbon atom of the

IMPI

ring to which both are attached, or R4 and Rb together with the carbon atom of the ring to which both are attached they can optionally combine to form a spiro-fused bicyclic ring system selected from

where K is -O-, -NR7-, or -C (= O) NR7-,

R5, and R6 each presented, respectively, are independently selected from (a) H and CN; or (b) - (alkylene)t -OH, - (alkylene)t -OR9, - (alkylene)t

-MR9, - (alkylene) t -NR10Rn, - (alkylene) tC (O) R9,

- (alkylene) t ~ C (O) OR9, - (alkylene) t -OC (O) R9, - (alkylene) t -

INSTITUTC <-Í JA

OF.'"' '

INDUSTkiAS (O)VR9, - (alkylene) t-NHS (O) 2R10, - (alkylene) t ~ N (R11) S (O) 2R10,

- (alkylene) t_NR10C (O) R9, C (0) NR10Rn, NR10S (O) 2R9, S (O) 2NR10, and

NR10C (O) NR10R1: l; or (a) haloalkyl, haloalkoxy, alkyl-Ci-β, alkenyl-C2_ 6, alkynyl-C2-6, C3-cycloalkyl-ez (C3-cycloalkyl-

s) (C1-3alkyl), cycloalkenyl-Ci-sz aryl, aryl (Ci-3alkyl) heteroaryl, heteroaryl (Ci3alkyl), heterocycle and heterocycle (Ci-3alkyl), any of which can be substituted optionally independently with one or more R groupsx as allowed by valence;

R7, and R8 each occurring respectively are independently selected from H, haloalkyl- (Ci_6), cycloalkyl, alkenyl-C2_6, Ci-6-alkyl, C-alkynyl26z aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycle (alkyl

C1-10), (cycloalkyl-C3_8) (C1-3alkyl), any of which can be optionally substituted as valence with one or more Rx; or R7 and R8 can combine to form a C4-C8 heterocycle ring optionally substituted with one or more Rx;

R9 is haloalkyl, haloalkoxy, alkyl-Ci_6, alkenyl C2-6, alkynyl-C2-6, C3-8-cycloalkyl, (C3-8-cycloalkyl) (institute alkyl

PE LA PRO!

indu:

Ci_3), cycloalkenyl-C4-8, aryl, heteroaryl, and heterocycle any of which can optionally be independently substituted with one or more R groupsx as allowed by valence;

R10 and R11 each presented, respectively, are independently selected from alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, either of which may optionally be substituted as valency with one or more Rx;

or R10 and R11 they may combine to form one of the heterocyclic ring optionally substituted with one or more Rx;

Rx each occurring independently is deuterium, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, - (alkylene)t-OR *,

- (alkylene)t-S (0) VR *,

- (alkylene) t~ C (= 0) R *,

- (alkylene)t-C (-0) OR *,

- (alkylene) t-C (= S) OR *,

- (alkylene) tC (= S) NR1R11,

- (alkylene) t-N (R+) C (= S) NR+R '

- (alkylene) t-NR'R++,

- (alkylene) t_C (= S) R *,

- (alkylene) t ~ OC (= 0) R *,

- (alkylene) tC (= O) NR R11,

- (alkylene) t-N (R+) C (= 0) NR+R "",

- (alkylene) t-N (R+) C (= 0) R *,

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

- (alkylene) t-OC ~ (= O) NR+R++,

- (alkylene) t-N (R ') C (= S) R *,

- (alkylene) t-OC (= S) NR+R ”,

- (alkylene) t-N (R+) SO2R *,

- (alkylene) t-N (R ~) C (= 0) OR *,

- (alkylene) t-N (R ") SO2R *;

- (alkylene) t-SW2NR+R ~+,

- (alkylene) tN (R+) SO2NR+R ”,

- (alkylene) t-N (R+) C (= S) OR *, or where the groups alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,. and heterocycloalkyl can also be independently substituted • oxo, - (alkylene)t-0R *,

- (alkylene) t-NR+R-·,

- (alkylene) t-C (= S) R *,

- (alkylene)t-0C (= 0) R *, - (alkylene) tC (= 0) NR'R++,

- (alkylene) t-N (R+) C (= 0) NR+R ”,

- (alkylene) t-N (R1) C (= 0) R *,

- (alkylene) t-OC (= O) NR1R1: L,

- (alkylene) t-S02NR1R1,

- (alkylene) tN (R1) SO2NR1R

- (alkylene) t-N (R+) C (= S) OR *, or - with one or more halo, cyano,

- (alkylene) t-S (0) VR *,

- (alkylene) t-C (= 0) R *,

- (alkylene) t-C (= 0) OR *,

- (alkylene) t-C (= S) OR *,

- (alkylene) t-C (~ S) NR+R++',

- (alkylene) tN (R+) C (= S) NR+R,

- (alkylene) t-N (R) C (= S) R *,

- (alkylene)t-OC (= S) NR1R,

- (alkylene) t-N (R1) SO2R *,

- (alkylene) t-N (R) C (= 0) 0R *, (alkylene) t-N (R ”) SO2R *;

R * is haloalkyl, haloalkoxy, Ci-6-alkyl, C-alkenyl2_6, alkynyl-C2_6, cycloalkyl-C3_g, cycloalkenyl-C4_garil

heteroaryl, and heterocycle

R1 and R11 they are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl, or R+ and R+_ attached to the same nitrogen atom they can optionally combine to form a heterocycle ring system;

m is 1, 2 or 3 n and n * are each independently selected from 0 and integers from 1 to 6;

p is 0, 1, 2 or 3;

t each occurring is independently 0 or an integer from 1 to 6;

v each that occurs is independently 0, 1, or 2.

Preferred compounds within the scope of Formula I include compounds wherein R2 is -C (H) R5R6 or NR7R8, phenyl or pyridine, phenyl or pyridyl can optionally be substituted with one or more Rx as allowed by valence.

Preferred compounds within the scope of Formula I include compounds wherein R2 is R2 is selected from

, and any of which can optionally be substituted with one or more R groupsx as allowed by valence.

Preferred compounds within the scope of Formula I include compounds wherein R1 is

MEXICAN INSTITUTE OF THE PR.-OPISD / .O INDUSTRIAL '

OH or a heterocycle selected from

I Μ. ΡI

MEX'CANO INSTITUTE

OF THE PROPERTY • INDUSTRIAL

. 16

(most preferably selected from

a heterocycle

IMPI

INDUSTRY I.

Preferred compounds within the scope of

Formula I include compounds of Formula IA:

enantiomers, diastereomers and pharmaceutically acceptable salts thereof wherein q and p are each independently 0, 1, 2o

3. Preferred compounds of Formula IA include compounds containing R groups1 and R2 previously mentioned favorites.

Preferred compounds within the scope of

Formula I include compounds of the Formula

IMPI

INSTITUTE OF INDUSTRIAL PROPERTY

IB:

enantiomers, diastereomers and pharmaceutically acceptable salts thereof wherein q and p are each independently 0, 1, 2o

3. Preferred compounds of Formula IB include compounds containing R groups1 and R2 previously mentioned favorites.

Preferred compounds within the scope of

Formula I include compounds of Formula IC:

IC

MEXICAN INSTITUTE CE LAFROFÍEDAD. · INDUSTRIAL

enantiomers, diastereomers and pharmaceutically acceptable salts thereof wherein q and p are each independently 0, 1, 2o

3. Preferred compounds of Formula IC include compounds containing R groups1 and R2 preferred mentioned herein.

Preferred compounds within the scope of Formulas IA, IB and IC further include compounds wherein R2 is selected from

• 20

MF INSTITUTE / INDUSTRIAL PROPERTY CASH

, and any of which can optionally be substituted with one or more R groupsx as allowed by valence.

In another aspect, aspect A, the present invention provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Q is a bond or optionally can be selected from 0, NR7 or S (0)v, when n * is an integer from 1 to 6;

Z is C = 0 or S (= 0)2.

Rto each occurring is -i independent selected from H, (C1-C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl, (alkoxy) (C1-C3) alkyl, or cyano

Rb is H, halo, (C1-C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl (alkoxy) (C1-C3) alkyl, or cyano;

Rc and Rd are independently selected from H, halo, (C1-C3) alkoxy, (halo) (C1-C3) alkyl, (halo) (C1-C3) alkoxy, (hydroxy) (C1-C3) alkyl, or optionally to form

Rc and Rd a cycloalkyl or heterocycle spiro ring system can be combined;

(a) H or halo; or (b) (Ci-Cs) alkyl, (C3-C8) cycloalkyl, heterocycle (C3-

C8), cyano, halogen, hydroxyl, -OR5, NR7R8, or heterocycloalkyl, any of which can be optionally substituted with 1 or more R groupsx as allowed by valence, or Rand and any of the R 'or R groups can optionally combine to form a spiro-cycloalkyl or heterocycle ring system, or Rd and any of the R 'or R groups can optionally combine to form a fused heterocyclo or cycloalkyl ring system, or Rd and Rand can optionally combine to form a cycloalkyl or heterocycle ring system

merged; ,,: ........

R 'and R each presented, respectively, are independently H, halo, (C1-C3) alkyl, (C1-C3) alkoxy, (halo) (C1-C3) alkyl, (halo) (C1-C3) alkoxy , (alkoxy) alkyl (CiC3), (hydroxy) alkyl (Ci-C3), -S-alkyl (Ci-C3),

C (O) alkyl (Ci-C3), -NR7R8, or hydroxyl, or R 'and R linked to the same carbon atom can be optionally combined to form = 0, or R' and R · linked to the same carbon atom can be optionally combined to form a spiro-fused cycloalkyl or heterocycle ring system ;

R1 is (a) -COOH, -C (O) OR10, -C (O) NHOH, -C (O) NH-NH2,

C (O) NHS (O)2R10, -S (0) 2NHC (O) R10, -S (O) 2NR7R8, -NR7C (O) R10, NR7C (O) OR5, -C (O) NR7R8, -NR7S (O) 2R10, '-NR7C (O) NR7R8, -S (O) vR10, hydroxylalkyl, -cyclopropyl-COOH, or CN; or (b) heteroaryl or heterocycle, either of which can optionally be independently substituted with one or more R groupsx as allowed by valence;

R2 is (a) -NR7R8, NR7C (O) OR10, NR7C (O) NR7R10, O -C (Rto) R5R6; or (b) aryl, heteroaryl, cycloalkyl, or heterocycle, either of which may optionally be independently substituted with one or more R groups.x as allowed by valence;

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY or heteroaryl,

optionally as allowed

R3 and R4 are independently aryl any of which can be independently substituted with one or more R groupsx by the valence, or any of R3 and Rto along with the carbon atom of the ring to which both are attached, or R4 and Rb together with the carbon atom of the ring to which both are attached they can optionally combine to form a spiro-fused bicyclic ring system selected from

where K is -O-, -NR7-, or -C (= 0) NR7-;

R5 and R6 each presented, respectively, are independently selected from (a) H or CN;

. 26

(b) - (alkylene) t -OH, - (alkylene)t .......... ta 1 qui-íeno ·

-MR9, - (alkylene) t -NR1ORX1, - (alkylene) tC (O) R9,

- (alkylene)t -C (O) OR9, - (alkylene) t -OC (O) R9, - (alkylene) t S (O)VR9, - (alkylene) t-NHS (O) 2R10, - (alkylene) tN (Rxx) S (O) 2Rxo,

- (alkylene) t-S (O) 2NR1stR11, '-NR10C (O) R9, -C (O) NRXORXX,

NR10S (O) 2R9, S (O) 2NR10, or NRx° C (O) NRxoRxx; or (c) haloalkyl, haloalkoxy, Ci-6-alkyl, C-alkenyl2-6, alkynyl-C2-6z cycloalkyl-C3-8, (cycloalkyl-Cs-s) (Ci-alkyl cycloalkenyl-C4-8z aryl, aryl (Ci-3-alkyl), heteroaryl, heteroaryl (Ci-3-alkyl), heterocycle or heterocycle (Ci-3-alkyl), either of which may optionally be independently substituted with one or more groups Rx as allowed by valence;

R7 and R8 each occurring respectively are independently selected from H, cyano, -O Ci-6-alkyl, Ci-6-alkyl, haloalkyl- (Ci_6), cycloalkyl, alkenyl-C2-6, alkynyl-C2-6, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycle (Ci-10 alkyl), or (cycloalkylC3-8). (Ci-3-alkyl), any of which can optionally be substituted as valence with one or more Rx, or R7 and R8 can combine to form a heterocycle-C ring4-C8 optionally substituted with one or more Rx;

R9 it is haloalkyl ,. haloalkoxy, alkyl-Ci_6, alkenylC2_ 6, alkynyl-C2_6, cycloalkyl-C3-8, (cycloalkyl-C3IMPI

s) (alkylCi-3), cycloalkenyl-C4_8, aryl, heteroaryl, or heterocycle, any of which can optionally be independently substituted with one or more R groupsx as allowed by valence;

R10 and R11 each presented, respectively, are independently selected from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl, any of which may be optionally substituted as permitted by the valence with one or more Rx, or R10 and R11 they can combine to form a heterocycle ring optionally substituted with one or more Rx;

Rx each presented independently is deuterium, halo, cyano, nitro, ox, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, - (alkylene)t-0R *,

- (alkylene)t-S (0) VR,

- (alkylene)t-C (= 0) R *,

- (alkylene)t-C (= 0) OR *,

- (alkylene)t-C (= S) OR *,

- (alkylene) tC ^ SJNR ^

- (alkylene) t-N (R-) C (= S) NR'.R++,

- (alkylene) t-NR'R,

- (alkylene) t ~ C (= S) R *,

- (alkylene) t-0C (= 0) R *, - (alkylene) t-C (= 0) NR+R-',

- (alkylene) tN (R1) C (= O) NR1R1,

- (alkylene) t-N (Rj C (= 0) R *,

- (alkylene) t-OC (= O) NR'R++,

- (alkylene) t-SO2NR+R+,

- (alkylene)t-N (R+) C (= S) R *,

- (alkylene) t-0C (= S) NR+R ”,

- (alkylene) t-N (R ') SO2R *,

- (alkylene) t-N (R ") SO2NR'R++,

- (alkylene) t-N (R) C (= O) OR *,

- (alkylene) t-N (R) C (= S) OR *, or

- (alkylene) t-N (R) SO2R *, wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may also be independently substituted with one or more halo, cyano, oxo, - (alkylene ) t-OR *, - (alkylene) t-S (O) VR *,

- (alkylene) t-NR'R++,

- (alkylene)t-C (= S) R *,

- (alkylene) t-OC (= 0) R *,

- (alkylene) t-C (= 0) NR+R "",

- (alkylene) t-N (R1) C (= 0) NR1R1, -

- (alkylene) t~ N (R) C (= Ó) R *,

- (alkylene) t-0C (= Oj NR R11,

- (alkylene) t-SW2NR1R1,

- (alkylene) tN (R ') S02NR_R++,

- (alkylene) t-N (R) C (= S) 0R *, or -

- (alkylene) t-C (= 0) R *,

- (alkylene) t-C (= 0) OR *,

- (alkylene) t-C (= S) OR *,

- (alkylene)t-C (= S) NR1R, (alkylene) tN (R) C (= S) NR R11,

- (alkylene) t-N (R1) C (= S) R *, - (alkylene) t-0C (= S) NR1R, - (alkylene) tN (R ~) SO2R *,

- (alkylene) t-N (R ") C (= 0) 0R *, (alkylene) t-N (R ~) SO2R *;

R * is H, haloalkyl, haloalkoxy, Ci-6-alkyl, C-alkenyl2-6 <C2-alkynyl-6 <C-cycloalkyl3-8, cycloalkenyl-C4-8, aryl, heteroaryl, or heterocycle;

R and R++ they are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, arylalkyl,

MFXIGANO INSTITUTE OF INDUSTRIAL PROPERTY

ari 1o, heteroaryl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl, or R and R++ attached to the same nitrogen atom they can optionally combine to form a heterocycle ring system;

m is 1, 2 or 3;

n and n * are each independently selected from or an integer from 1 to 6;

p is 0, 1, 2 or 3;

t each occurring is independently 0 or an integer from 1 to 6; and v each that occurs is independently 0, 1 or 2.

In another aspect, aspect AA, the present invention provides compounds of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

MEXICAN INSTITUTE OF PROPERTY INJv λ.

Q is a link or optionally can be selected from 0,

NR7 bear)V, when n * is an integer from to 6;

Z is C = O or S (= O)2;

Rto each one presented is selected independently of

H, (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl

Rb is H, halo, (C1-.C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl

Rcy Rd are independently selected from H, halo, (C1-C3) alkyl, (C1-C3) alkoxy, (halo) (C1-C3) alkyl, (halo) (C1-C3) alkoxy, (alkoxy) (C1-C3) alkyl ), or (hydroxy) (C1-C3) alkyl, or Rc and Rd they can optionally combine to form a spiro-cycloalkyl or heterocycle ring system;

Rand is (a) H, or halo; or (b) alkyl (Ci-C8), cycloalkyl (C3-C8), heterocycle (C3C8), cyano, halogen, hydroxyl, -OR5, NR7R8, or heterocycloalkyl, any of which can be optionally substituted with 1 or more R groupsx as allowed by valence, or Rand and any of the R 'or R groups can optionally combine to form a spiro-cycloalkyl or heterocycle ring system, or Rd and any of the R 'or R groups can be optionally combined to

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY form a fused cycloalkyl or heterocycle ring system, or Rd and Rand they may optionally combine to form a fused cycloalkyl or heterocycle system;

R 'and R each presented, respectively, are independently H, halo, (C1-C3) alkyl, (C1-C3) alkoxy, (halo) (C1-C3) alkyl, (halo) (C1-C3) alkoxy , (alkoxy) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl,

-S-C1-C3-alkyl, C (O) -alkyl (Ci_C3), -NR7R8, or hydroxyl, or

R 'and R linked to the same carbon atom can be optionally combined' to form = 0, or R 'and R linked to the same carbon atom can be optionally combined to form a spiro-fused heteroalkyl or cycloalkyl ring system; .

R1 is · (a) -COOH, -C (O) OR10, —C (O) NHOH, -C (O) NH-NH2,

C (O) NHS (O)2R10, -S (O) 2NHC (O) R10, -S (O) 2NR7R8, -NR7C (O) R10, NR7C (O) OR5, -C (O) NR7R8, -NR7S (0) 2R10, -NR7C (O) NR7R8, -S (O) vR10, hydroxyalkyl, -cyclopropyl-COOH, or CN; or (b) heteroaryl or heterocycle, either of which can optionally be independently substituted with one or more R groupsx as allowed by valence;

R2 is (a) -NR7R8, NR7C (O) OR1 C, NR7C (O) NR7R10, or -C (Rto) R5R6; or

IMPI ^ J

MEXICAN INSTITUTE · '<

OF THE PROPERTY

INDUSTRIAL · (b) aryl, heteroaryl, cycloalkyl, or heterocycle, any of which may optionally be independently substituted with one or more R groupsx as allowed by valence;

R3 and R4 they are independently aryl or heteroaryl, either of which may optionally be independently substituted with one or more R groupsx as allowed by valence, or any of R3 and Rto along with the carbon atom of the ring to which both are attached, or R4 and Rb together with the carbon atom of the ring to which both are attached they can optionally combine to form a spiro-fused bicyclic ring system selected from

where K is -O-, -NR7-, or -C (= O) NR7-,

R5, and R6 each presented, respectively, are independently selected from (a) H or CN;

(b) - (alkylene)t-OH, - (alkylene)t -OR9, - (alkylene)t

-MR9, - (alkylene) t -NR1OR1: L, - (alkylene) tC (O) R9,

- (alkylene) t -C (O) OR9, - (alkylene) t -OC (O) R9, - (alkylene) t-

SW)VR9, - (alkylene) t-NHS (O) 2R10, - (alkylene) tN (R11) S (O) 2R10,

- (alkylene) t-S (O) 2NR10Ri: l, - (alkylene) t ~ N (R11) S (O) 2NR10R11,

NR10C (O) R9, —C (O) NR10R11, -NR10S (O) 2R9, S (O) 2NR10, or

NR10C (O) NR10R11; or (c) haloalkyl, haloalkoxy, Ci-6-alkyl, C-alkenyl2-6, alkynyl-C2_6, cycloalkyl-C3-8, · (cycloalkyl-Cs-g) (alkyl

C1-3), cycloalkenyl-C4-8, aryl, aryl (alkyl-Ci3) heteroaryl, heteroaryl (Ci-3-alkyl), heterocycle or heterocycle (Ci-3-alkyl), either of which may optionally be independently substituted With one or more R * groups as allowed by valence;

R7, and R8 each presented, respectively, are independently selected from H, cyano, -O Ci-6-alkyl, Ci- -alkyl6, haloalkyl- (Ci-6), cycloalkyl, alkenyl-C2-6, alkynyl-C2-6, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycle (C1-10alkyl), or (C3-8cycloalkyl) (C1-3alkyl), any of which

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

may optionally be substituted as valence with one or more Rx, or R7 and R8 can combine to form a heterocycle-C ring4-C8 optionally substituted with one or more Rx;

R9 is haloalkyl, haloalkoxy, Ci-6-alkyl, C-alkenyl2-

6, C2-6-alkynyl, cycloalkyl-C3-8, (cycloalkyl-C3

e) (Ci_alkyl3), cycloalkenyl-C4-8 / aryl, heteroaryl, heterocycle, or heterocycloalkyl, either of which may optionally be independently substituted with one or more R groupsx as allowed by valence;

FROM THE OWNER 'INDUSTRIAL'

- (alkylene)t-S (O) VR *,

- (alkylene) t~ C (= 0) R *,

- (alkylene)t-C (= 0) OR *,

- (alkylene)t-C (= S) OR *,

- (alkylene) t-C (= S) NR+R__, (alkylene) t-NR Rw,

- (alkylene) t_C (= S) R *,

- (alkylene)t-OC (= 0) R *, - (alkylene) t_C (= 0) NR+R__,

- (alkylene) t-N (R+) C (= 0) NR+R_+,

- (alkylene) t-N (R) C (, = S) NR_R++,

- (alkylene) t ~ N (R ') 0 (= 0) R *,

- (alkylene) t-N (R+) C (= S) R *,

- (alkylene) t-0C (= 0) NR R11,

- (alkylene)t-0C (= S) NR1R

- (alkylene) t-S02NR1R1,

- (alkylene)t-N (R) S02R *,

- (alkylene) tN (R) SO2NR R11,

- (alkylene)t-N (R) C (= O) ÓR *,

- (alkylene) tN (R) C (= S) OR *, or

- (alkylene) t-N (R) SO2R *, wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups can also be independently substituted with one or more halo, cyano, oxo, - (alkylene ) t~ 0R *, - (alkylene) t-S (0) VR *,

- (alkylene) t-NR'R++,

- (alkylene) t-C (= S) R *,

- (alkylene)t-0C (= 0) R *, - (alkylene)t-C (= 0) NRXR,

- (alkylene) t-N (R1) C (= 0) NR1R1,

- (alkylene) t-N (R-) C (= 0) R *,

- (alkylene) t-0C (= O) NR * R++,

- (alkylene) t-SW2NR+R '+,

- (alkylene) t-C (= 0) R *,

- (alkylene)t-C (= 0) OR *,

- (alkylene) t-C (= S) OR *,

- (alkylene) t-C (= S) NR ^ 'R,

- (alkylene) t-N (R ') C (= S) NR'R++,

- (alkylene) t-N (R+) C (= S) R *,

-. (alkylene) t-0C (= S) NR+R "",

- (alkylene) t-N (R) SO2R *,

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

- (alkylene)t-N (R) SC> 2NR ~ R++,

- (alkylene) t-N (R ~ j C (= 0) OR *,

- (alkylene)t-N (R) C (= S) OR *, or - (alkylene) t-N (R) SO2R *;

R * is haloalkyl, haloalkoxy, alkyl-Ci.5, alkenylC2_ 6, alkynyl-C2_6, cycloalkyl-Cg-g, cycloalkenyl-C4-8, aryl, heteroaryl, and heterocycle;

R and R11 they are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl, or R ~ and R++ attached to the same nitrogen atom they can optionally combine to form a heterocycle ring system;

m is 1, 2 or 3;

n and n * are each independently selected from 0 or an integer from 1 to 6;

weight, 1, 2 or 3;

every time I know. presents is independently 0 or an integer from 1 to 6; and v each that occurs is independently 0, 1 or 2.

In another embodiment, embodiment 2, of the compounds of aspect A or AA, or the pharmaceutically acceptable salts thereof, R2 is -C (H) R5R6, -NR7R8, phenyl or pyridine, wherein phenyl or pyridyl can optionally be substituted with one or more Rx as allowed by valence.

In another embodiment, embodiment 3, of the compounds of the

INSTITUTO MEXTAP-Z) \ DE LA

IN ^ IT ^ Al.

aspect A or AA, or the pharmaceutically_acceptable.es ... salts thereof, R2 is selected from

INSTITUTO MEX DE LA PRO?)

INDUSTRY

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

any of which can optionally be substituted with one or more R groupsx as allowed by valence.

In another embodiment, embodiment 4, the compounds of aspect A or AA have the structure of Formula IA

MEXICAN INSTITUTE

INDUSTRIAL EROPITY

IA or the pharmaceutically acceptable salts thereof, wherein q and p are each independently 0,

1, 2 or 3.

IB or the pharmaceutically acceptable salts thereof, where q and p are each independently 0,

1, 2 or 3.

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

In another embodiment, embodiment 6, the compounds of aspect A or AA have the structure of Formula IC

IC or the pharmaceutically acceptable salts thereof, where q and p are each independently 0, 1, 2 or 3.

In another aspect of embodiment 6 (embodiment 7), or the pharmaceutically acceptable salts thereof, R2 is selected from

OR

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

, any of which can optionally be substituted with one or more R groupsx as allowed by valence.

In another aspect of embodiment 6 (embodiment 8) or the pharmaceutically acceptable salts thereof,

R2 is selected from

any of which can optionally be substituted with one or more R groupsx as allowed by valence;

and R1 is

OH, or a heteroaryl or heterocycle selected from

ΪΜΡΙ (^

INSTITUTO MEXIC. '·, Or' ¿'i. OF PROPERTY Γ

In another aspect of modality 6 (modality ras ···· pharmaceutically acceptable salts thereof,

R2 is selected from

optionally replace with one or more

allow for valence; and

S

In another aspect of modality 6

ΪΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY (modality 10), pharmaceutically acceptable salts thereof,

any of which can optionally be substituted with one or more R groupsx how I know

MEXICAN INSTITUTE OF THE INDUSTRIAL FROKKUD

allow for valence; and

R1 is

a heteroaryl or heterocycle selected from

In another embodiment, embodiment 11, the compounds of aspect A have the structure of Formula ID

ID

A or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 11 (embodiment 12), or the pharmaceutically acceptable salts thereof, Re is H or

methyl or ethyl.

In another embodiment, embodiment 13, the compounds of aspect A have the structure of Formula IE

IE or the pharmaceutically acceptable salts thereof.

In another aspect of embodiment 13 (embodiment 14), or the pharmaceutically acceptable salts thereof, Re is H or methyl or ethyl.

In another aspect of embodiment 13 (embodiment 15), or the pharmaceutically acceptable salts thereof, wherein

R2 is selected from

ζ and

replace the valence; and optionally allow with one R groups as itself any

INSTITUTE i.

DS LA I ..

or a heteroaryl or heterocycle selected from

I

In another aspect of embodiment 13 (embodiment 16), or a pharmaceutically acceptable salt thereof,

R1 is

or a heteroaryl or heterocycle selected from

Rand it is methyl.

In another aspect of embodiment 13 (embodiment 17), or a pharmaceutically acceptable salt thereof:

R2 is

--- C — CH2—N — SO2—R10

R5R

H

--- C — CH2SO R

R5

C — CH2^ SO2—R9

C — CH2-SW2NRt0R11

H

--— C — CH2--- N (R11)SW2NR10R11

R5;

R5 is cyclopropyl, or Ci_alkyl6;

R9 it is haloalkyl, haloalkoxy, Ci-6-alkyl, C26-alkenyl, C2-6-alkynyl cycloalkyl-C3-8, (cycloalkyl-C3_e) (C1-3alkyl), cycloalkenyl-C4-8, aryl, heteroaryl, or heterocycloalkyl , or R9 is haloalkyl, haloalkoxy, C1-6alkyl, C2-6alkenyl, or C-alkynyl2-6z cycloalkyl-C3-8, (cycloalkyl-C3_8) (C1-3alkyl), cycloalkenyl-C4-8, aryl, heteroaryl, or heterocycle, any of which may optionally be independently substituted with one or more R groupsx as allowed by valence; and

R10 and R11 each presented respectively are independently selected from H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,

heterocycloalkyl, or cycloalkylalkyl, either of which may optionally be substituted as valency with one or more Rx, or R10 and R11 they can combine to form a heterocycle ring optionally substituted with one or more Rx.

In another aspect of embodiment 13 (embodiment 18), or a pharmaceutically acceptable salt thereof,

R1 is

and Rand it is methyl.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2 - ((3R, 5R, 6S) -1 - ((S) -l-tert-butoxy-l-oxobutan-2yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2- acid oxopiperidin-3yl) acetic;

2- ((3S, 5R, 6S) -1 - ((S) -l-tert-butoxy-l-oxobutan-2yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2- acid oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-ethoxy-l-oxobutan-2-yl) -2-oxopiperidin -3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-ethoxy-4-methyl-l-oxopentan-2-yl) acid -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-ethoxy-l-oxopentan-2-yl) -2-oxopiperidin -3-yl) acetic;

2 - ((3S, 5S, 6R) -5- (3-Chlorophenyl) -6- (4-chlorophenyl ·) -1 ((R) -l-ethoxy-l-oxopentan-2-yl) -2- acid oxopiperidin-3-yl) acetic;

VíT'a MEXICAN INSTITUTE—

DE LA FROñEDAD V · - · -. «*

INDUSTRIAL acid 2- ((3R, 5R, 6S) -1 - ((S) -2-tert-Butoxi-l-cyclopropyl-

2- oxoethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-

3- il) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-hydroxybutan-2-yl) -2-oxopiperidin-3-yl acid )acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-hydroxyethyl) -2-oxopiperidin-3yl) acetic acid ;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l- (cyclopropylmethoxy) butan-2-yl) -2-oxopiperidin- 3il) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-methoxybutan-2-yl) -2-oxopiperidin-3-yl acid )acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (2-methoxyethoxy) butan-2-yl) -2- acid oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1 - ((l-cyanocyclopropyl) methoxy) butan-2-yl) acid -2-oxopiperidin-3-yl) acetic;

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (cyclopropylmethoxy) butan-2-yl) -2-oxopiperidin- 3il) acetic;

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-methoxybutan-2-yl) -2-oxopiperidin-3-yl acid )acetic;

2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorofeml) -1 ((S) -1- (2-methoxyethoxy) butan-2-yl) -2- acid oxopiperidin-3yl) acetic;

2- ((3R, 5R, 6S) -l- ((S) -l- ((1carbamoylcyclopropyl) methoxy) butan-2-yl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -2 -oxopiperidin-3-yl) acetic (isomer 1);

'2 - ((3S, 5R, 6S) -l - ((S) -l - ((lcarbamoylcyclopropyl) methoxy) butan-2-yl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) - acid 2-oxopiperidin-3-yl) acetic (isomer 2);

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (2-hydroxy-2-methylpropoxy) butan-2-ii acid ) -2-oxopiperidin-

3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2oxo-1 - ((3S) -1,1, l-trifluoro-2-hydroxypentan-3 acid -il) piperidin-3yl) acetic (isomer 1);

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2oxo-1 - ((3S) -1,1, l-trifluoro-2-hydroxypentan-3 acid -yl) piperidin-3yl) acetic (isomer 2);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-morpholinobutan-2-yl) -2-oxopiperidin-3-yl acid )acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (ethylamino) butan-2-yl) -2-oxopiperidin- 3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxo-1 - ((S) -1- (2,2,2-trifluoroethylamino) butan- 2-yl) piperidin67

3-yl) acetic;

I jMLPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxo-1 - ((S) -1- (pyrrolidin-l-yl) butan-2- acid il) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxo-1 - ((S) -1- (2-oxopyrrolidin-l-yl) butan- 2-yl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (1,1-dioxidothiomorpholino) butan-2-yl) acid - 2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxo-1 - ((S) -1- (thiazol-2-ylamino) butan-2- acid il) piperidin-3yl) acetic;

2- ((3R, 5R, 6S) -1- ((S) -l-acetamidobutan-2-yl.) - 5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3-yl acid )acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (methylsulfonamido) butan-2-yl) -2-oxopiperidin- 3il) acetic; .

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyanopentan-3-yl) -2-oxopiperidin-3-yl acid )acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (methylsulfonyl) pentan-3-yl) -2-oxopiperidin- 3il) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -268 acid

οχο-1- ((S) -1- (pyridin-2-il) pentan-3-il) ρίρθΓΪΏΤΤΡΓ3 ^ · ““="^^" il) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (ethylamino) -l-oxobutan-2-yl) -2 acid -oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -1- (ethylamino) -l-oxobutan-2-yl) -2 acid -oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (5-methyl-l, 3,4-oxadiazol-2) -il) propyl) -2-oxopiperidin-

3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -1- (5-methyl-l, 3,4-oxadiazol-2) -il) propyl) -2-oxopiperidin-

3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclobutylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenylj-1 (2-ethylbutyl) -2-oxopiperidin-3-yl) acetic acid;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopentylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((2,2-dimethylcyclopentyl) methyl) -2-oxopiperidin-3-yl) acetic acid;

INSTITUTE ΜΕΧ'.Ο / ιΝΟ

OF INDUSTRIAL PROPERTY

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclohexylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2 - ((3S, 5R, 6S) -5- (3-chlorophenylj-6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxo-l-propylpiperidin-3-yl) acetic acid;

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclobutylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1isobutyl-2-oxopiperidin-3-yl) acetic acid;

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopentylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxo-1- (pentan-3-yl) piperidin-3-yl) acetic acid;

Methyl 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetate;

2- ((3R, 5R, 6S) -5- (3-cl.orophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamide;

Ethyl ethyl 2- (2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yljacetamido);

2- (2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2-oxopiperidin-3yl) acetamido) acetic acid;

' or MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetohydrazide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) -N-hydroxyacetamide ;

2 - ((2S, 3R, 5R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -5- (2 (methylsulfonamido) -2-oxoethyl) -6-oxopiperidin-l-yl) butanoate (S) -ethyl;

2 - ((2S, 3R, 5R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -5- (2 ((3-morpholinopropyl) amino) -2-oxoethyl) -6-oxopiperidin-lil ) (S) -ethyl butanoate;

(3R, 5R, 6S) -3 - ((lH-Tetrazol-5-yl) methyl) -5- (3-chlorophenyl)

6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one;

(3R, 5R, 6S) -3 - ((1,3,4-oxadiazol-2-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2 one ;

(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3 - ((5-methyl-l, 3,4-oxadiazol-2yl) methyl) piperidin -2-one;

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) -N (methylsulfonyl) acetamide ;.

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamide;

(3S, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl)

6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one;

(3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3 - ((5-methylisoxazol-3-yl) methyl) piperidin2-one;

2 - ((2'S, 3'R, 5'R) -6-chloro-3 '- (3-chlorophenyl) -1' (cyclopropylmethyl) -2,6'-dioxoespiro [indolin-3,2'-piperidin ] 5'-yl) acetic;

2 - ((2'R, 3'S, 5'S) -6-chloro-3 '- (3-chlorophenyl) -1' (cyclopropylmethyl) -2,6'-dioxoespiro [indolin-3,2'-piperidin] 10 acid 5'-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2yl) -1- (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2yl) -1- (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-ethoxy-l-oxobutan-2-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) -l-tert-butoxy-l-oxobutan-2yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 3-methyl-2-oxopiperidin20 3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((R) -l-tert-butoxy-l-oxobutan-2yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- acid methyl-2-oxopiperidine 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -13-yl) acetic acid;

IMPI

MEXICAN INSTITUTE

PS ΙΑ PROPERTY ((S) -1- (cyclopropylmethoxy) butan-2-yl) -3-methyl-2-oxopiperidine acid 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4 -chlorophenyl) -1 (cyclopropylmethyl) -2-oxo-3- (2- (pyrrolidin-1yl) ethyl) piperidin-3-yl) acetic;

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3- (2-morpholinoethyl) -2-oxopiperidin-3yl) acetic acid;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl) acetic acid ;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1cyclobutyl-3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1cyclopentyl-3-methyl-2-oxopiperidin-3-yl) acetic acid;

(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-3 ((5-oxo-4,5-dihydro-lH-l, 2,4-triazole -3-yl) methyl) -1- (pen.tan-3yl) piperidin-2-one;

5 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl) methyl ) -1,3,4 oxadiazol-2 (3H) -one;

IT KM ΤΗ 20 “'> <- MEXICAN INSTITUTE t' -TD3 PROPERTY <Ss® -Λ ·. ·: '' Industrial * «uh: __ (trifluoromethylsulfonyl) acetamide;

(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((3hydroxy-lH-pyrazol-5-yl) methyl) -3-methyl-l- (pentan- 3 yl) piperidin-2-one;

(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((3hydroxyisoxazol-5-yl) methyl) -3-methyl-l- (pentan-3-yl) piperidin2-one;

5 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl) methyl ) oxazolidin2,4-dione;

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl) methyl) -1,2,4 oxadiazol-5 (4H) -one;

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1isopropyl-3-methyl-2-oxopiperidin-3-yl) methyl) -1,2,4 -oxadiazol5 (4H) -one;

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl) methyl ) -1,2,4 thiadiazol-5 (4H) -one;

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1isopropyl-3-methyl-2-oxopiperidin-3-yl) methyl) -1,2,4 -thiadiazol5 (4H) -one;

IΜ ΡI η Λ MEXICAN INSTITUTE ' 4 OF THE PROPERTY

INDUSTRIAL (3R, 5R, 6S) -3 - ((lH-Tetrazol-5-yl) methyl) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one ;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3eti1-2-oxo-1- (pentan-3-yl) piperidin-3-yl) acetic acid ;

(3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-3 (methylsulfonylmethyl) -1- * (pentan-3-yl) piperidin-2-one;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (3-cyclopropyl-l, 2,4-oxadiazol-5) -yl) propyl) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -1- (3-cyclopropyl-l, 2,4-oxadiazol-5) acid -yl) propyl) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -l-morpholinobutan-2-yl) -2-oxopiperidin- 3il) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (2,2,2- trifluoroethylamino) butan-2yl) piperidin-3-yl) acetic;

2 - ((3R ,. 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (2,2-dimethylmorpholine) butan-2-yl) acid -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((2S) -1- (2,6-dimethylmorpholine) butan-2-yl) - 3-methyl-2-oxopiperidin-3-yl) acetic;

„IMPI / 5 MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (4- (cyclopropyl sulfonyl) piperazin-l-yl) butan -2-yl) -3methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) —1- (4- (methylsulfonyl) piperazin-l-yl ) butan-2-yl) 2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - (((S) -1- (4-acetylpiperazin-lil) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) acid -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (4- (cyclopropanobonyl) piperazin-l-yl) butan- 2-yl) -3meti1-2-oxopiperidin-3-i1) acetic;

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -l-morpholinobutan-2-yl) -2-oxopiperidin- 3yl) methyl) -1,2,4-oxadiazol-5 (4H) -one;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (5,5-dimethyl-2-oxooxazolidin-3-yl) acid ) butan-2-yl) -3-methyl-

2- oxopiperidin-3-yl) acetic;

2- ((3R, .5R, 6S) -1- ((S) -1- (tert-butylamino) -1oxobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) acid -3-methyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2R, 3S) -2,3-dihydroxycyclopentyl) -3-methyl-2 acid -oxopiperidin-

3- il) acetic;

• .τν.-πχ 76 IMPIAS

MEXICAN INSTITUTE

OF THE PROPERTY Vawirí.UUC'.í ·

INDUSTRIAL <!»<Saa2! Í £ - £> 'acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((IR, 2R, 3S) -2.3- dihydroxycyclopentyl) -3-methyl-2-oxopiperidin3-yl) acetic;

2 - ((3R, 3'S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l '- (2,2,2-trifluoroethyl) -1 acid , 3'bipiperidin-3-yl) acetic;

2 - ((3R, 3'R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l '- (2,2,2-trifluoroethyl) acid -1, 3 'bipiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l ((1S, 3S) -3-hydroxycyclopentyl) -3-methyl-2-oxopiperidin-3yl acid )acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((1S, 3R) -3-hydroxycyclopentyl) -3-methyl-2-oxopiperidin-3yl acid )acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenylj-3methyl-2-oxo-l - ((S) -tetrahydro-2H-pyran-3-yl) acid piperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -tetrahydro-2H-pyran-3-yl acid ) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pyrazin-2-yl) piperidin-3-yl) acetic acid ;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -377 acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pyrimidin-4-yl) piperidin-3-yl) acetic acid ;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (2-chloropyrimidin-4-yl) -3-methyl-2-oxopiperidin-3-yl acid )acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pyrimidin-2-yl) piperidin-3-yl) acetic acid ;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1- (3-methylpyridiii-2-yl) -2-oxopiperidin-3-yl acid) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1- (4-methylpyridin-2-yl) -2-oxopiperidin-3-yl acid) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (dicyclopropylmethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (dicyclopropylmethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

((3S, 4R / 6R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -1,1-dioxide-2- (2-propanyl) -1,2-thiazinan-6-yl) acetic acid;

((3S, 4R, 6S) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -1,1-dioxide-2- (2-propanyl) -1,2-thiazinan-6-yl) acetic acid;

((3S, 4R, 6R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6methyl-1, l-dioxide-2- (2-propanyl) -1,2-thiazinan-6- acid il) acetic;

((3S, 4R, 6S) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6methyl-1, l-dioxide-2- (2-propanyl) -1,2-thiazinan-6- acid il) acetic;

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

2-yl) -3-methyl-l - ((S) -l-morpholinobutan-2-yl) -2-oxopiperidin-3yl) acetic;

2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin5 2-yl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin -3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin2-yl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin-3 acid -il) acetic;

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin2-yl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin-3 acid -il) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) -l-tert-butoxy-l-oxobutan-2yl) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl ) -3-methyl-2oxopiperidin-3-yl) acetic; or acid 2 - ((3R, 5S, 6S) -1 - ((S) -l-tert-butoxy-l-oxobutan-2yl) -6- (4-chlorophenyl) -5- (4-chloropyridin-2- yl) -3-methyl-215 oxopiperidin-3-yl) acetic.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -120 ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin- 3-yl) acetic;

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) -2oxopiperidin- 3-yl) propanoic;

79 IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

2 - ((3R, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) (S) -tert-butyl butanoate;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (methylsulfonamido) butan-2-yl) -2 acid -pxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenylj-6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -5-oxohexan-3-yl) piperidin- 3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -5-hydroxy-5-methylhexan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - (((3S, 5S) -6,6,6-trifluoro -5-hydroxy-5methylhexan-3-yl) piperidin-3-yl) acetic (isomer 1);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((3S, 5R) -6,6, β-trifluoro acid -5-hydroxy-5methylhexan-3-yl) piperidin-3-yl) acetic (isomer 2);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (N-methylmethylsulfonamido) butan-2-yl) acid -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S) -5-cyclopropyl-6, 6, 6-trifluoro-5-hydroxyhexan- 3-yl) -3methi1-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- acid

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ((S) -6-hydroxy-6-methylheptan-3-yl) -3-methyl-2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -6, 6, 6-trifluoro-5 , 5-dihydroxyhexan-3yl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-1 - ((3S) -7,7,7-trifluoro-6 acid -hydroxy-6-methylheptan3-yl) piperidin-3-yl) acetic (isomer 1);

2 - ((3R, 5R, 68) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - (((3S) -7,7,7-trifluoro-6 acid -hydroxy-6-methylheptan3-yl) piperidin-3-yl) acetic (isomer 2);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -7-hydroxy-7-methyloctan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (N-methycyclopropanesulfonamido) butan-2-yl) acid -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (N-cyclopropylmethylsulfonamido) butan-2-yl) -3- acid methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- ((3S) -.6, 6, 6-trifluoro- 5-hydroxyhexan-3yl) piperidin-3-yl) acetic (isomer 1);

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- acid

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY methyl-2-oxo-l - ((3S) -6,6, β-trifluoro-5-hydroxyhexan-3yl) piperidin-3-yl) acetic (isomer 2);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S) -5-hydroxyhexan-3-yl) -3-methyl-2-oxopiperidin -3yl) acetic (isomer 1);

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S) -5-hydroxyhexan-3-yl) -3-methyl-2-oxopiperidin -3yl) acetic (isomer 2);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (N- (2,2 2,2trifluoroethyl) methylsulfonamido) butan-2-yl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (1, l-dioxideisothiazolidin-2-yl) butan-2 acid -yl) -3-methyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((3S, 4R) -5-hydroxy-4,5-dimethylhexan-3-yl) acid -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) - '5- (3-Chlorophenyl) -6- (4-chlorophenyl) -l ((3S, 4S) -5-hydroxy-4,5-dimethylhexan-3-yl acid ) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -5-cyano-5-methylhexan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic;

DE I λ F?

IND'Ji i UM'-ΛΖ acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -2 -oxopentan-3-yl) piperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2-hydroxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2-methoxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2R, 3S) -2-hydroxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3R) -2-hydroxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((2R, 3R) -2-hydroxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -2-hydroxy-2-methylpentan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((3S, 4S) -4-hydroxyhexan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -183 acid

((3S, 4R) -4-hydroxYhexan-3-Il) -R-meph1-2-nxnpiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-methoxybutan-2-yl) -3-methyl-2-oxopiperidin -3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (3S) -1,1,1-trifluoro-2- acid hydroxy-2-methylpentan-3yl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1- ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) ac.ethamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) -N- (methylsulfonyl) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) -N- (3-hydroxypropyl) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) -N- (2-hydroxyethyl) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) -N-hydroxyacetylamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-

MEXICAN INSTITUTE

OF THE INDUSTRIAL PROPILOAD

oxopiperidin-3-yl) -N-methoxyacetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) -N - ((R) -2,3-dihydroxypropii) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) -N - ((S) —2,3-dihydroxypropyl) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) -N-cyanoacetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl- l - ((S) -l- (N-methylcyclopropansulfonamido) butan-2-yl ) -2oxopiperidin-3-yl) -N- (2- (dimethylamino) ethyl) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) -N- (3,4-dihydroxybutyl) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (cyclopropansulfonamido) butañ-2-yl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

(S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (Nmethylcyclopropansulfonamido) butan-2- yl) -2-oxopiperidin-3yl) propanoic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -185 acid

IMPI * MEXICAN INSTITUTE

PROPERTY (3S) -2- (cyclopropansulfonamido) pentan-3-yl) -3-methyJJ2’¿-! A1'

oxopiperidin-3-yl) acetic (isomer 1);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (3S) -2- (cyclopropansulfonamido) peritan-3-yl) -3-methyl-2oxopiperidin -3-yl) acetic (isomer 2);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((2R, 3S) -2- (1-methylethylsulfonamido) pentan-3 acid -il) -2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) -1- (N-methylcyclopropansulfonamido) -l-oxobutan- 2yl) -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1 - ((S) -1- (neopentilamino) -l-oxobutan-2- yl) -2oxopiperidin-3-yl) acetic;

2 - {(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (4,4-dimethyl-4,5-dihydrooxazol-2) acid -yl) propyl) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (N- (2,2 , 2-trifluoroethyl) acetamido) butan-

2-yl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (1,1-dimethylethylsulfonamido) butan-2-yl) acid - 3-methy1-2 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -186 acid

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

((S) -1- (N, 2-dimethylpropan-2-ylsulfonamido) butan-2-yl) -3methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (1-methylethylsulfonamido) butan-2-yl) acid -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (N-ethylpropan-2-ylsulfonamido) butan-2-yl acid ) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-hydroxybutan-2-yl) -3-methyl-2-oxopiperidin -3yl) acetic;

2 - ((3R, 5R, 65) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (trifluoromethylsulfonamido) butan-2yl) acid piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (4-chlorophenylsulfonamido) butan-2-yl) -3- acid methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-1- ((S) -1- (4-methylphenylsulfonamido) butan-2-yl) acid -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -l ((S) -1- (2-chlorophenylsul'phonamido) butan-2-yl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -187 acid

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ((S) -1- (2-methylphenylsulfonamido) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenylj-1 ((S) -1- (4-methoxyphenylsulfonamido) butan-2-yl) -3-methyl acid -2 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (phenylsulfonamido) butan-2-yl) -3-methyl- acid 2-oxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (1-methylcyclopropanesulfonamido) buthan-2-yl) -3- acid methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (1,1-Dioxidebenzo [d] isothiazol-2 (3H) ) -yl) butan-2-yl) -3methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl.) -6- (4-chlorophenyl) -1 ((S) -1- (3,3-dimethyl-l, 1-dioxidebenzo [ d] isothiazol-2 (3H) yl) butan-2-yl) -3-methyl-2-oxop.iperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (pyridin-3-sulfonamido) acid butan-2yl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (4-cyanophenylsulfonamido) butan-2-yl) -3- acid methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -188 acid

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

((S) -1- (3-cyanophenylsulfonamido) butan-2-yl) -3-methyl-2 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-l - ((S) -1- (pyridin-2-sulfonamido) ) butan-2 yl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (N, 1-dimethylcyclopropanesulfonamido) butan-2-yl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

3 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) acid -2oxopiperidin-3-ii) propanoi.co;

3- ((3R, 5S, 6R) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl acid ) -2oxopiperidin-3-yl) propanoic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3ethyl-1 - ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) acid -2-oxopiperidin-3-yl) acetic;

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methoxy-1 - ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) acid -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -6-methyl-4-oxoheptan-3-yl) acid - 2-oxopiperidin-3 yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- acid

(ethylsulfonyl) p

il) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l ((S) -1- (isopropylsulfonyl) pentan-3-yl) -3-methyl- 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (cyclopropylmethylsulfonyl) pentan-3-yl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-l - ((S) -1- (2-oxopyrrolidin-l -il) butan-2yl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) -1 - ((IR, 4R) -2-oxa-5azabicyclo [2.2.1] heptan-5-yl) butan-2-yl acid) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1 - ((S) -3-methylmorpholine) butan- 2-yl) -2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R., 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1 - ((R) -3-methylmorpholino) butane -2-yl) -2 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (thiomorpholino-1,1-dioxide) butan-2-yl ) -3-methyl-2oxopiperidin-3-yl) acetic; ' 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -190 acid

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ((S) -1- (3,3-difluoroazetidin-l-yl) butan-2-yl) -3-methyl-2 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - (((2S) -1- (8-oxa-3azabicyclo [3.2.1] pctan-3-yl) butan-2-yl) -5- (3- acid) chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) —1— (3,3-dimethylmorpholine) butan-2-yl) - 3-methyl-2 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (3-hydroxy-3- (trifluoromethyl) azetidin-l- yl) butan-2 yl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- {(3JR acidZ 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) -1- (methyl (oxetan-3-yl) amino) butan-2-yl) -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (2-oxooxazolidin-3- il) butan-2yl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (2-oxopyridin-l ( 2H) -yl) butan-2yl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (2-oxo-5- (trifluoromethyl) pyridin-1 (2H) yl) butan-2-yl) piperidin-3-yl) acetic;

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-

methyl-1 - ((S) —1— (pyridin-3-yloxy) butan-2-yl) piperidin-2-one;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((1S) -1- (tetrahydrofuran-2-yl) acid propyl) piperidin3-yl) acetic (isomer 1);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((1S) -1- (tetrahydrofuran-2-yl) acid propyl) piperidin3-yl) acetic (isomer 2);

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((1S) -l-5-oxotetrahydrofuran-2yl) propyl acid ) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl.l) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((1S) -1- (tetrahydro-2H- piran-2yl) propyl) piperidin-3-yl) acetic (isomer 1);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((1S) -1- (tetrahydro-2H-pyran- 2yl) propyl) piperidin-3-yl) acetic (isomer 2);

2 - ((3R, 5R, 6S) -1 - ((R) -1- (benzo [d] thiazol-2yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, .6S) -1- ((S) -1- (benzo [d] thiazol-2yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (3-methylisoxazol-5-yl) propyl acid) -2-oxopiperidin92

3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((R) -1- (3-methylisoxazol-5-yl) propyl acid ) -2-oxopiperidin

3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (6-chloropyridin-2-yl) propyl) -3- methyl-2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -1- (6-chloropyridin-2-yl) propyl) -3- acid methyl-2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -1- (pyridin-2-yl) acid propyl) piperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -1- (pyridin-2-yl) acid propyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -1- (pyridin-2-yl) acid butyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -1- (pyridin-2-yl) acid butyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -2-cycloprppil-l- (pyridin-2-yl) ethyl) acid - 3-methyl-2-

oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -2-cyclopropyl-l- (pyridin-2-yl) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -l- (pyridin-3-yl) acid propyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -Ί- (pyridin-3-yl) acid propyl) piperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- ((S) -1- (pyrezin-2- il) propyl) piperidin-3yl) acetic;

2- ((3R, 5R, 6S) -.5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -1- (pyrazin-2-yl ) propyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (pyrimidin-2-yl) acid propyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -1- (pyrimidin-2-yl) acid propyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (6-methylpyridin-2-yl) propyl acid) -2-oxopiperidin-3-

il) acetic; __ 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((R) -1- (6-methylpyridin-2-yl) propyl acid ) -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (pyridin-4-yl) acid propyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -1- (pyridin-4-yl) acid propyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (6- (trifluoromethyl) pyridine -2yl) propyl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -1- (6- (trifluoromethyl) pyridine -2yl) propyl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - (((S) -1- (6-bromopyridin-2yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl acid -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((R) -1- (6-bromopyridin-2yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl acid -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (thiazol-2-ylj propyl ) piperidin-395

MSXICANp INSTITUTE OF INDUSTRIAL PROPERTY

il) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -1- (thiazol-2-yl) acid propyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (6- (2-hydroxypropan-2-.il) pyridine -2-yl) propyl) -3-methyl2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -1- (6- (2-hydroxypropan-2-yl) pyridine- 2-yl) propyl) -3-methyl2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l ((S) -1- (6-cyclopropylpyridin-2-yl) propyl) -3- methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -1- (6-cyclopropylpyridin-2-yl) propyl) -3- acid methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -3,3,3-trifluoro-1 acid - (pyridin-2yl) propyl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -3, 3, 3-trifluoro-l acid - (pyridin-2yl) propyl) piperidin-3-yl) acetic; , 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -2-methyl-l- (pyridin-2-yl) acid ) propyl) -2-oxopiperidin96

MEXICAN INSTITUTE OF INDUSTRIAL PftGPíEDAD

3-yl) acetic;

ΊΙΤΓΙΙΤΤΤΓΤ'ΊΤΓΙΒ (j ij acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((R) -2-methyl-l- (pyridin-2-yl) propyl) -2-oxopiperidin-

3-yl) acetic;

(3R, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-l- (pentan-3-yl ) piperidin-2-one;

(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((R) -2,3dihydroxypropyl) -1 - ((2S, 3S) -2-hydroxypentan-3 -il) -3methylpiperidin-2-one;

(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((S) -2,3dihydroxypropyl) -1 - ((2S, 3S) -2-hydroxypentan-3 -il) -3methylpiperidin-2-one;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-hydroxybutan-2-yl) -3-methyl-2-oxopiperidin -3yl) cyclopropancarboxylic;

2 - ((3R, 5R, 6S) -1 - ((S) -2- (tert-Butoxy) -1-cyclopropyl-2-oxoethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-ethoxy-2-oxoethyl) -3-methyl acid -2-oxopiperidin-

3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methyl-2-oxopiperidin -3yl) acetic; '

((IS, 2S) -l-cyclopropyl-2-hydroxybutyl) -3-methyl-2 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2R) -l-cyclopropyl-2-hydroxybutyl) -3-methyl-2oxopiperidin -3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenylj-6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-methylcyclopropanesulfonamido) ethyl) -3ethyl-2 acid -oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -2- (cyclopropanesulfonamido) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin -3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2- (ethylsulfonamido) ethyl) -3-ethyl- acid 2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-methylcyclopropanSulfonamido) ethyl) -3methyl- acid 2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2R) -l-cyclopropyl-2-hydroxy-propyl) -3-methyl acid -2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2S) -l-cyclopropyl-2-hydroxypropyl) -3-methyl-2oxopiperidin -3-yl) acetic;

,,, '-INSTITUTO MEXICANO Z, .J *} acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-σ1οψ £ ¥ & Ηϊί ((S) -l-cyclopropil -2- (1-methylethylsulfonamido) the "ll) -3oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -l-cyclopropyl-2- (N-methylcyclopropanesulfonamido) ethyl) -3methyl- acid 2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2-hydroxy-4-methylpentan-3-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -cyclopropyl (pyridin-2-yl) methyl) -3-methyl-2 acid -oxopiperidin-

3-yl) acetic; or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -cyclopropyl (pyridin-2-yl) methyl) -3-methyl- acid 2-oxopiperidin-

3-yl) acetic.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2- (1- (l-tert-Butoxy-l-oxobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-ethoxy-loxobutan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (l-ethOxy-4-methyl-l-oxopentan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

acid

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-ethoxy-1-oxopentan-2-yl) -2-oxopiperidin-3-yl) acetic;

2- (1- (2-tert-Butoxy-l-cyclopropyl-2-oxoethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1hydroxybutan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1cyclopropyl-2-hydroxyethyl) -2-oxopiperidin-3-yl) acetic acid;

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (110 (cyclopropylmethoxy) butan-2-yl) -2-oxopiperidin-3-yl) acetic;

methoxybutan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

methoxyethoxy) butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

acid

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- ((1-cyclopropyl) methoxy) butan-2-yl) -2-oxopiperidin-3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) —1— (1— (cyclopropylmethoxy) butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-methoxybutan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (2-methoxyethoxy) butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (1- (1- ((1-carbamoylcyclopropyl) methoxy) butan-2100 acid

INSTITUTO MEXICANO, Ul 1Λ rKUljtUKt · il) - 5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-D3-xlAL

il) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (2-hydroxy-2-methylpropoxy) butan-2-yl) -2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2-oxo-l (1,1,1-trifluoro-2-hydroxypentan-3-yl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-morpholinobutan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1 (ethylamino) butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-l- (1 (2,2,2-trifluoroethyl.amino) butan-2-yl) piperidin-3-yl acid ) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-l- (1 (pyrrolidin-l-yl) butan-2-yl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2-oxo-l- (1 (2-oxopyrrolidin-l-yl) butan-2-yl) piperidin-3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (1,1-dioxidothiomorpholinoj butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2-oxo-l- (1 (thiazol-2-ylamino) butan-2-yl) piperidin-3-yl) acetic acid;

2- (1- (l-Acetamidobutan-2-yl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1-

101 MEXICAN INSTITUTE

INDUSTRIAL PROPERTY (methylsulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1-cyanopentan-3-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1 (methylsulfonyl) pentan-3-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2-oxo-l- (1 (pyridin-2-yl) pentan-3-yl) pip'eridin-3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1 (ethylamino) -l-oxobutan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (5-methyl-1,3,4-oxadiazol-2-yl) propyl) -2-oxopiperidin-3yl) acetic acid ;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclobutylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2-ethylbutyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopentylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((2,2dimethylcyclopentyl) methyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 (cyclohexylmethyl) -2-oxopiperidin-3-yl) acetic acid;

<td></td><td>102- MEXICAN INSTITUTE 1OF PROPERTY See JLj · -, INDUSTRIAL</td>

<td>acid</td><td>2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-</td>

(cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-lpropylpiperidin-3-yl) acetic acid;

<td>acid</td><td>2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-</td>

(cyclobutylmethyl) -2-oxopiperidin-3-yl) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-isobutyl-2 oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopentylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chorophenyl) -6- (4-chlorophenyl) -2-oxo-í (pentan-3-yl) piperidin-3-yl) acetic acid;

Methyl 2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetate;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamide;

Ethyl 2- (2- (5- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamido) acetate;

2- (2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamido) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetohydrazide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenylj-1103

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

(cyclopropylmethyl) -2-oxopiperidin-3-yl) -N-hydroxyacetamide;

Ethyl ethyl 2- (3- (3-chlorophenyl) -2- (4-chlorophenyl) -5- (2 (methylsulfonamido) -2-oxoethyl) -6-oxopiperidin-l-yl) butanoate;

Ethyl ethyl 2- (3- (3-chloro-enyl) -2- (4-chlorophenyl) -5- (2- ((3-morpholinopropyl) amino) -2-oxoethyl) -6-oxopiperidin-yl) butanoate;

3 - ((lH-Tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4- chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one;

3 - ((1,3,4-oxadiazol-2-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one;

5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -

3 - ((5-methy1-1,3,4-oxadiazol-2-yl) methyl) piperidin-2-one;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) -N (methylsulfonyl) acetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamide;

3- ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4- chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one;

5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -

3 - ((5-methylisoxazol-3-yl) methyl) piperidin-2-one;

'2- (6-Chloro-3' - (3-chlorophenyl) -1 '(cyclopropylmethyl) -2,6' -dioxoespi.ro [indolin-3,2 '-piperidin] IMPI

104

2- (5- (3-chlorophenyl) -6- (5-chlorothiophene-i2-yl) -15'-yl) acetic;

(cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (5-chlorothiophene-2-yl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-ethoxy-loxobutan-2-ii) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (1- (l-tert-Butoxy-l-oxobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3 yl) acetic acid;

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1 (cyclopropylmethoxy) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylinethyl) -2-ΟΧΟ-3- (2- (pyrrolidin-yl) ethyl) piperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3- (2-morpholinoethyl) -2-oxopiperidin-3yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (pentan-3-yl) piperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-isopropyl105 acid

3-methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-cyclobutyl- acid

3-methyl-2-oxopiperidin-3-yl) acetic;

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 cyclopenti1-3-methi1-2-oxopiperidin-3-yl) acetic;

5- (3-chlorophenyl) -6- (4-cl.orophenyl) -3-methyl-3- ((5-oxo-4,5dihydro-lH-1, 2,4-triazol-3-yl) methyl) -1- (pentan-3yl) piperidin-2-one;

5 - ((5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l (pentan-3-yl) piperidin-3-yl) methyl) -1,3,4 -oxadiazol-2 (3H) -one;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l (pentan-3-yl) piperidin-3-yl) -N- (trifluoromethylsulfonyl) acetamide;

5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((3-hydroxy-lHpirazol-5-yl) methyl) -3-methyl-l- (pentan-3-yl) piperidin-2- ona;

5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((3-hydroxyisoxazol5-yl) methyl) -3-methyl-l- (pentan-3-yl) piperidin-2-one;

5 - ((5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l (pentan-3-yl) piperidin-3-yl) methyl) oxazolidin-2,4- diona;

3- ((5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl) methyl) -1,2, 4-oxadiazol-5 (4H) -one;

3 - ((5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3méj: il-2-oxopiperidin-3-yl) methyl) -1,2,4-oxadiazol-5 (4H ) -ona;

3 - ((5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methi1-2-oxo-l,

106

INDUS i ruAL - - (pentan-3-yl) piperidin-3-yl) methyl) -1,2,4-thiadiazol-5 (4H) -one, methyl-2-oxopiperidin-3-yl) methyl) -1 2,4-thiadiazol-5 (4H) -one;

3- ((lH-Tetrazol-5-.il) methyl) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxo- acid

1- (pentan-3-yl) piperidin-3-yl) acetic;

5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-3 (methylsulfonylmethyl) -1- (pentan-3-yl) piperidin-2-one;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) propyl) -3-methyl-2oxopiperidin-3 acid -il) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1morpholinobutan-2-yl) -2-.oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (2,2,2-trifluoroethylamino) butan-2-yl) piperidin-3yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (2,2dimethylmorpholino) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-chloroferiyl) -1- (1- (2,6dimethylmorpholino) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (4107

MEXICAN INSTITUTE

DS la HIOÍ · ItOAO

INDUSTRIAL

(cyclopropyl sulfonyl) piperazin-l-yl) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (4- (methylsulfonyl) piperazin-l-yl) butan-2-yl) -2-oxopiperidin3 acid -il) acetic;

2- (1- (1- (4-acetylpiperazin-l-yl) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic acid ;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (4 (cyclopropancarbonyl) piperazin-l-yl) butan-2-yl) -3-methyl-2-oxopiperidin-3 acid -il) acetic;

3 - ((5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1morpholinobutan-2-yl) -2-oxopiperidin-3-yl) methyl) -1,2,4 oxadiazole -5 (4H) -one;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -l- (l- (5,5dimethyl-2-oxooxazolidin-3-yl) butan-2-yl) -3-methyl-2oxopiperidin -3-yl) acetic;

2- (1- (1- (tert-butylamino) -l-oxobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2,3dihydroxycyclopentyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1 '- (2,2,2-trifluoroethyl) -1,3'-bipiperidin-3-yl acid) acetic;

hydroxycyclopentyl) -3-methyl-2-oxo'piperidin-3-yl) acetic;

108 acid

FP INSTITUTE M 2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (tetrahydro-2H-piran-3-yl) piperidin-3-yl acid) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (pyrazin-2-yl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1-methyl-lH-pyrazol-4-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-210 oxo-1- (pyrimidin-4-yl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2-chloropyrimidin-4-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (pyrimidin-2-yl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (3-methylpyridin-72-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (4-methylpyridin-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -ΙΣΟ (dicyclopropylmethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

(4- (3-chlorophenyl) -3- (4-chlorophenyl) -1, l-dioxide-2 (2-propanyl) -1,2-thiazinan-6-yl) acetic acid;

(4- (3-chlorophenyl) -3- (4-chlorophenyl) -6-methyl-l, 1-dioxide-2- (2-propanyl) -l, 2-thiazinan-6-yl) acetic acid;

ΙΜ, ΡΙ

109 MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL 2- (5- (3-Chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-1- (l-morpholinobutan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (5-chloropyridin-2-yl) -3methi1-2-oxo-l- (pentan-3-yl) piperidin-3-yl) acetic acid;

2- (1- (l-tert-butoxy-l-oxobutan-2-yl) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-2-oxopiperidin-3yl acid) acetic; or 2- (1- (l-tert-butoxy-l-oxobutan-2-yl) -6- (4-chlorophenyl) -5- (4-chloropyridin-2-yl) -3-methyl-2-oxopiperidin-3yl acid )acetic.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic acid;

5- (3-Chlorophenyl) -6- (4-chlorophenyl) -l- (l- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) propanoic acid;

Tertbutyl 2- (3- ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoate;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (methylsulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

. > >

110 acid

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (5-oxohexan-3-yl) piperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (5-hydroxy5-methylhexan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl) piperidin3 acid -il) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (N-methylmethylsulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (5cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl) -3-methyl-2oxopiperidin-3- acid il) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (6-hydroxy-

6- methylheptan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl) piperidin-3yl acid )acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (7,7,7-trifluoro-.6-hydroxy-6-methylheptan-3yl) piperidin- acid 3-i1) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -l- (7-hydroxy-

7- methyloctan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1111 acid)

IMGiü

INSTITUTO MlGrCAMO \ DE LA P? .O <- ;? 1OAD _ (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopi'P'é'ti ^ in - ^ = *

il) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N-cyclopropylmethylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (6,6,6-trifluoro-5-hydroxyhexan-3-yl) piperidin-3yl) acetic acid ;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (5hydroxyhexan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (N- (2,2,2-trifluoroethyl) methylsulfonamido) butan-2yl) piperidin acid -3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (1,1-Dioxideisothiazolidin-2-yl) butan-2-yl) -3-methyl-2-oxopiperidin3-yl acid )acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (5-hydroxy4,5-dimethylhexan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (5-cyano-5methylhexan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (2-oxopentan-3-yl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2hydroxipentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

112

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2-methoxipentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -l- (2hydroxipentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2-hydroxy2-methylpentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-CYOROPHENYL) -6- (4-CHLOPHENYL) -1- (4hydroxyhexan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-methoxybutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1,1,1-trifluoro-2-hydroxy-2-methylpentan-3yl) piperidin-3 acid -il) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) N- (methylsulfonyl ) acetamide ·;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) N- (3 -hydroxypropyl) acetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) 113

N- (2-hydroxyethyl) acetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) N-hydroxyacetamide ;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) N-methoxyacetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) N- (2 , 3-dihydroxypropyl) acetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) N-cyanoacetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) N- (2 - (dimethylamino) ethyl) acetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-yl) N- (3 , 4-dihydroxybutyl) acetamide;

2- (5-C3-Chlorophenyl) -6- (4-chlorophenyl) -l- (l (cyclopropanesulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-

'114

MEXICAN INSTITUTE

OF THE INDUSTRIAL PROPltDí-.D il) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) propanoic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2 (cyclopropansulfonamido) pentan-3-yl) -3-methyl-2-oxopiperidin3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (2 (1-methylethylsulfonamido) pentan-3-yl) -2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (N-methylcyclopropansulfonamido) -l-oxobutan-2-yl) -2oxopiperidin-3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (neopentylamino) -l-oxobutan-2-yl) -2-oxopiperidin-3yl) acetic acid; .

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (4,4dimethyl-4,5-dihydrooxazol-2-yl) propyl) -3-methyl-2-oxopiperidin-3 acid -il) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (N- (2,2,2-trifluoroethyl) ac. amido) butan-2yl acid ) piperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (1,1-dimethylethylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3- acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N, 2115

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY il) acetic;

dimethylpropan-2-ylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (1-methylethylsulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (Nethylpropan-2-ylsulfonamido) butan-2-yl) -3-methyl-210 oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) —1— (1— hydroxybutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Ciorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (trifluoromethylsulfonamido) butan-2-yl) piperidin-315 yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (4-chlorophenylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (120 (4-methylphenylsulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (2-chlorophenylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

116

MEXICAN INSTITUTE OF THE F'.O? IEÜA.D lUDbVftiúU.

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (2-methylphenylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (45 methoxyphenylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1 (phenylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -l- (l- (l-methylcyclopropansulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (1,1-dioxide-benzo [d] isothiazol-2 (3H) -yl) butan-2-yl) -3- acid methyl-2 oxopiperidin-3-yl) acetic; · 2 - (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (3,3dimethyl-1,1-dioxidebenzo [d] isothiazol-2 (3H) -yl) butan-2-yl) -3methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-220 oxo-1- (1- (pyridin-3-sulfonamido) butan-2-yl) piperidin-3yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (4-cyanophenylsulfonamido) .butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

117

acid

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- C cyanophenylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic;

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (pyridin-2-sulfonamido) butan-2-yl) piperidin-3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N, 1-dimethylcyclopropanesulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

3- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) propanoic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-l- (1 (N-methylcyclopropanesulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methoxy-l (1- (N-methylcyclopropanesulfonamido) buttan-2-yl) -2-oxopiperidin3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (6methyl-4-oxoheptan-3-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1 (ethylsulfonyl) pentan-3-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1mil

118

IMPI

MEXICAN INSTITUTE OF PROPERTY (isopropylsulfonyl) pentan-3-yl) -3-methyl-2-o.xopiper't! A5Ti?TO!-3

il) acetic;

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1 (cyclopropylmethylsulfonyl) pentan-3-yl) -3-methyl-25 oxopiperidin-3-yl) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (2-oxopyrrolidin-l-yl) butan-2-yl) piperidin-3yl acid) acetic;

2- (1- (1- (2-oxa-5-azabicyclo [2.2.1] heptan-510 yl) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (3-methylmorpholine) butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (115 (thiomorpholino-1,1-dioxide) butan-2-yl) -3-methyl-2-oxopiperidin3-yl acid) acetic; 2 - (5 - (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- (3,3-Difluoroazetidin-l-yl) butan-2-yl) -3-methyl-2-oxopiperidin- 3il) acetic;

2- (1- (1- (8-oxa-3-azabicyclo [3.2.1] octan-3yl) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (3,3-dimethylmorpholino) butan-2-yl) -3-methyl-2-oxopiperidin-3119 acid

MEXICAN INSTITUTE

D £ LA FKOFiEDAD INDUSTRIAL

il) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (3-hydroxy-3- (trifluoromethyl) azetidin-l-yl) butan-2-yl) -3-methyl2- acid oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (methyl (oxetan-3-yl) amino) butan-2-yl) -2-oxopiperidin- acid 3il) acetic;

'2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (2-oxooxazolidin-3-yl) butan-2-yl) piperidin-3yl acid )acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1— (2-oxopyridin-l (2H) -yl) butan-2-yl) piperidin acid -3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (2-oxo-5- (trifluoromethyl) pyridin-1 (2H) -yl) acid) butan-2yl) piperidin-3-yl) acetic;

3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (pyridin-3-yloxy) butan-2-yl) piperidin-2-one;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (tetrahydrofuran-2-yl) propyl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (5-oxotetrahydrofuran-2-yl) propyl) piperidin-3yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2120 acid.

IMPI

INST'TUTO M-Xs-ANO

Do THE PROPERTY OR INDUSTRiAl · oxo-1- (1- (tetrahydro-2H-pyran-2-yl) propyl) piperidin-3 yl) acetic;

2- (1- (1- (benzo [d] thiazol-2-yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1 (3-methylisoxazol-5-yl) propyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (6-chloropyridin-2-yl) propyl) -3-m'ethyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methi1-2oxo-1- (1- (pyridin-2-yl) propyl) piperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2 oxo-1- (1- (pyridin-2-yl) butyl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2cyclopropyl-1- (pyridin-2-yl) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (pyridin-3-yl) propyl) piperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl> -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (pyrazin-2-yl) propyl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (pyrimidin-2-yl) propyl) piperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1121 acid)

INSTITUTO MT.'NC.'NO D £ L?

(6-methylpyridin-2-yl) propyl) -2-oxopiperidin-3-yl) acetic;

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2 oxo-1- (1- (pyridin-4-yl) propyl) piperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (6- (trifluoromethyl) pyridin-2-yl) propyl) piperidin-3 yl acid) acetic;

2- (1- (1- (6-bromopyridin-2-yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3 yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (thiazol-2-yl) propyl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (6- (2hydroxypropan-2-yl) pyridin-2-yl) propyl) -3-methi1-2oxopiperidin- 3-yl) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (6-cyclopropylpyridin-2-yl) propyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (3,3,3-trifluoro-l- (pyridin-2-yl) propyl) piperidin- acid 3il) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (2methyl-1- (pyridin-2-yl) propyl) -2-oxopiperidin-3-yl) acetic acid ;

3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (pentan-3-yl) piperidin-2-one;

<td></td><td>122 institute OF THE 1 -f V INDlíS'iLuLAu ......</td>

5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2,3dihydroxypropyl) -1- (2-hydroxypentan-3-yl) -3-methylpiperidin-2one;

<td>acid</td><td>2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-</td>

hydroxybutan-2-yl) -3-methyl-2-oxopiperidin-3yl) cyclopropancarboxylic acid;

2- (1- (2- (tert-Butoxy) -l-cyclopropyl-2-oxoethyl) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3-yl) acetic acid;

<td>acid</td><td>2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-</td>

cyclopropyl-2-ethoxy-2-oxoethyl) -3-methyl-2-oxopiperidin-3yl) acetic;

<td>acid</td><td>2 - (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1-</td>

cyclopropyl-2-hydroxyethyl) -3-methyl-2-oxopiperidin-3yl) acetic;

<td>acid</td><td>2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-</td>

cyclopropyl-2-hydroxybutyl) -3-methyl-2-oxopiperidin-3yl) acetic;

<td>acid</td><td>2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-</td>

cyclopropyl-2- (N-methylcyclopropansulfonamido) ethyl) -3-ethyl-2oxopiperidin-3-yl) acetic;

<td>acid</td><td>2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2-</td>

(cyclopropansulfonamido) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin-3-yl) acetic;

<td>acid</td><td>2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1-</td>

123

cyclopropyl-2- (ethylsulfonamido) ethyl) -3-ethyl-2-oxopiperidin-3 yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) —1— (1— cyclopropyl-2- (N-methylcyclopropansulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1cyclopropyl-2-hydroxypropyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2 - (5 - (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1cyclopropyl-2- (1-methylethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1cyclopropyl-2- (N-methylcyclopropanesulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2-hydroxy-

4-methylpentan-3-ii) -3-methyl-2-oxopiperijdin-3-yl) acetic; or 2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropyl (pyridin-2-yl) methyl) -3-methyl-2-oxopiperidin-3yl) acetic acid.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) -2124 acid

oxopiperidin-3-yl) acetic; - 'acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (1, l-dioxideisothiazolidin-2-yl) butan -2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2-hydroxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -Ί ((2R, 3S) -2-hydroxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (1, l-dimethylethylsulfonamido) butan-2-yl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (N, 2-dimethylpropan-2-ylsulfonamido) butan-2 acid -il) -3methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (N, 1-dimethylcyclopropanesulfonamido) butan-2-yl) acid - 3-methyl-2-oxopiperidin-3-i1) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-methylcyclopropanesulfonamido) ethyl) -3methyl- acid 2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((1S, 2R) -l-cyclopropyl-'2-hydroxypropyl) -3-methyl- 2125 oxopiperidin-3-yl) acetic; or

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2S) -l-cyclopropyl-2-hydroxypropyl) -3-methyl-2oxopiperidin -3-yl) acetic.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N-methylcyclopropanesulfonamido) butan-2-yl) -2-oxopiperidin-3 yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (1,1-dioxideisothiazolidin-2-yl) butan-2-yl) -3-methyl-2-oxopiperidin-

3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (215 hydroxypentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2hydroxipentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (1,1-dimethylethylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-320 yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N, 2-dimethylpropan-2-ylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl acid )acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N, l126) acid

IMPI

MEXICAN INSTITUTE

FROM THE PROFiiOAD

INDUSTRIAL

dimethylcyclopropansulfonamido) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1cyclopropyl-2- (N-methylcyclopropanesulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid; or 2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1cyclopropyl-2-hydroxypropyl) -3-methyl-2-oxopiperidin-3yl) acetic acid.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (thiophene-2-sulfonamido) ethyl acid ) -3-methyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Clorofen.il) -1 ((S) -l-cyclopropyl-2- (N-methylthiophene-2-sulfonamido) ) ethyl) -3methyl-2-oxopiperidin-3 ^ yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (5-chlorothiophene-2-sulfonamido) -1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -1 - ((S) -2- (5-Chloro-N-methylthiophene-2-sulfonamido) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4Chlorophenyl) ) -3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1INSTITUTO MEXICANO

OF THE PROPERTY

INDUSTRIAL

127 ((S) -l-cyclopropyl-2- (N- (difluoromethyl) -? - τηΑί- · ί 1 prnpan-9ylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N- (difluoromethyl) ethylsulfonamido) ethyl acid) 3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N (difluoromethyl) cyclopropanesulfonamido) ethyl acid) - 3-methyl-2-oxopiperidin-3-yl) acetic;

1 - ((3R, 5R / 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (cyclopropanesulfonamido) -1-cyclopropylethyl) -3-methyl-2oxopiperidin -3-yl) cyclopropancarboxylic acid;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N- (2-fluorophenyl) ethylsulfonamido) acid) ethyl) 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N- (2fluorophenyl) methylsulfonamido) ethyl) acid) -3-methyl-2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-phenylcyclopropanesulfonamido) ethyl) -3methyl- acid 2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-phenylethylsulfonamido) ethyl) -3- acid methyl-2128

INSTITUTE

OF THE indust.

oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (ethylsulfonamido) ethyl) -3-methyl- acid 2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N- (3-fluorophenyl) ethylsulfonamido) acid) ethyl)

3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (N- (2-cyanophenyl) methylsulfonamido) -1-cyclopropylethyl ) 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (propylsulfonamido) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-phenylmethylsulfonamido) ethyl) -3- acid methyl-

2- oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (N- (3-cyanophenyl) methylsulfonamido) -1-cyclopropylethyl ) -

3- methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N- (pyridin-3-yl) acid methylsulfonamido) ethyl) 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N- (thiophene-2-

129

MEXICAN INSTITUTE

INDUSTRIAL PROPERTY (methyl) methylsulfonamido) ethyl) ^ 3-methyl-2-oxopiperidin-3

il) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N- (3methoxybenzyl) methylsulfonamido) ethyl) acid) -3-methyl-2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (phenylmethylsulfonamido) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (pyridin-2-ylmethylsulfonamido) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (pyridin-3-ylmethylsulfonamido) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N- (pyridin-2-yl) acid methylsulfonamido) ethyl) 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (methylsulfonamido) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-ethylmethylsulfonamido) ethyl) -3- acid methyl-2-oxopiperidin-3-yl) acetic;

130

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-isopropylmethylsulfonamido) ethyl) -3methi1- 2-oxopiperidin-3- ^ 1) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (1-methylethylsulfonamido) ethyl) -3- acid ethyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (cyclobutanesulfonamido) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin -3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (cyclopentansulfonamido) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin -3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-l - ((S) -3-methyl-l- (N-methylcyclopropansulfonamido) butan2- yl) -2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (cyclopropansulfonamido) -3-methylbutan-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenylj-6- (4-Chlorophenyl) -1 ((S) -1- (ethylsulfonamido) -3-methylbutan-2-yl) -3- acid methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (cyclobutansulfonamido) butan-2-yl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

131

IMPT.S

INSTITUTE l?Ύ ANO fcjí'—. Ufe ι γ Μ £ · acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (N-ethylcyclobutansulfonamido) butan-2 -yl) -3-methyl-2 oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (phenylsulfonyl) butan-2- acid il) piperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-1 - ((S) -1- (methylsulfonyl) butan-2-yl) - 2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxo-l - ((S) -1- (propylsulfonyl) butan-2 acid -il) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (isobutyl sulphonyl) butan-2-yl) -3-methyl- acid 2-oxopiperidin3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1 - ((cyclopropylmethyl) sulfonyl) butan-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1 - ((cyclobutylmethyl) sulfonyl) butan-2-yl) -3 -methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (cyclopentylsulfonyl) butan-2-yl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

132

ΠΌυ5'ία'.Λ1 »· * acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -1- (oxetane -3-ylsulfonyl) butan-2-ίΐ) -2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -.5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -1 - (((3-methyloxetan-3-yl) ) acetic methyl) sulfonyl) butan-2yl) -2-oxopiperidin-3-yl ');

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-2-oxo-l - ((S) -1 - ((tetrahydro-2H-pyran) -4yl) sulfonyl) butan-2-yl) piperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1 - ((2-hydroxy-2-methylpropyl) sulfonyl) butan- 2-yl) -3methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -l - ((S) -l - ((R) -secbutylsulfonyl) butan-2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) acid 3-methyl-2-oxopiperidin-3-yl) acetic;

'2 - ((3R, 5R, 6S) -l- ((S) -l- ((S) -secbutyl sulphonyl) butan-2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) acid ) 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (cyclopentylsulfonyl) -1-cyclopropylethyl) -3-methyl-2oxopiperidin -3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2 - (((3-methyloxetan-3yl) methyl) ) sulfonyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

I

133

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (phenylsulfonyl) ethyl) -3-methyl-2oxopiperidin -3-yl) acetic ;.

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (o-tolylsulfonyl) ethyl) -3- methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2 - ((2-Chlorophenyl) sulfonyl) -1-cyclopropylethyl) - 3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2 - ((4-Chlorophenyl) sulfonyl) -1-cyclopropylethyl) - 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (('4-fluorophenyl) sulfonyl) ethyl acid ) -3-methyl2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (pyridin-4-ylsulfonyl) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -l - ((S) -2 - ((2-Chloro-4fluorophenyl) sulfonyl) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6 (4-Chlorophenyl) ) -3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- ((cyclopropylmethyl) sulfonyl) ethyl) acid) -3-methyl-2-oxopiperidin-3-yl) acetic;

INSTITUTE

FROM LA? K (

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Cl © r

134

((S) -l-cyclopropyl-2- ((2,2,2-trifluoroethyl) sTrifonllTet-iH— methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2 - ((trifluoromethyl) sulfonyl) ethyl) -3 acid -methyl

2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (phenylsulfonyl) ethyl) -3-ethyl- 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2 - ((2-Chlorophenyl) sulfonyl) -l-cyclopropylethyl) - 3-ethyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2 - ((2-fluorophenyl) sulfonyl) ethyl) acid) -3-ethyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2 - ((3-fluorophenyl) sulfonyl) ethyl) acid) -3-ethyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- ((4-fluorophenyl) sulfonyl) ethyl acid) -3-ethyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (propylsulfonyl) ethyl) -3-ethyl- acid 2oxopiperidin-3-yl) acetic;

acid

135

2- ((3R, 5R, 6S) -1- ((S) -2- (Butylsulfonih-l ^ cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-ethyl-2oxopiperidin- 3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -15 ((S) -l-cyclopropyl-2- (isopentyl sulfonyl) ethyl) -3-ethyl- acid 2oxopiperidin-3-yl) acetic; · 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (cyclopentyl sulfonyl) -1 -cyclopropylethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -l ((S) -2- (cyclohexylsulfonyl) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin -3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (methylsulfonyl) ethyl) -3-ethyl- acid 215 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -3-methyl-l - ((2,2,2 -trifluoroethyl) sulfonyl) butan2-yl) -2-oxopiperidin-3-yl) acetic;

acid

2 - ((3R, 5R, 6S) -1 - ((S) -1- (tert-Butylsulfonyl) -320 methylbutan-2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) - 3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -3-methyl-l- (methylsulfonyl) butan-2- acid yl) -2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenylj-1136

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

((S) -1- (ethylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (cyclopropyl sulfonyl) butan-2-yl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (isopropylsulfonyl) butan-2-yl) -3-methyl- acid 2-oxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) -1- (tert-butylsulfonyl) butan2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (cyclobutyl sulphonyl) butan-2-yl) -3-methyl- 2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3ethyl-1 - ((S) -1- (ethylsulfonyl) butan-2-yl) -2 acid -oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3ethyl-1 - ((S) -1- (isopropylsulfonyl) butan-2-yl) -2 acid -oxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) -1- (tert-butylsulfonyl) butan2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-ethyl acid -2-oxopiperidin-3-yl) acetic;

137

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (cyclobutyl sulphonyl) butan-2-yl) -3-ethyl-2 -oxopiperidin3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorpphenyl) -1 ((S) -1- (cyclopropyl sulfonyl) butan-2-yl) -3-ethyl- 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (ethylsulfonyl) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic; 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- ( isopropylsulfonyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, $ R, 6S) -1 - ((S) -2- (tert-Butyl sulfonyl) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (cyclobutyl sulfonyl) -1-cyclopropylethyl) -3-methyl-2oxopiperidin -3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (cyclopropyl sulfonyl) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (methylsulfonyl) ethyl) -3-methyl- 2oxopiperidin-3-yl) acetic;

138

IMPI

INSTITUTO M5X1CAM £ D £ LA PROPíLmAV INDUSTRIAL

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 _ ((S) -l-cyclopropyl-2- (tert-pentylsulfonyl) ethyl) -3- acid methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2 - ((2,4-difluorophenyl) sulfonyl) acid ethyl) -3methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (ethylsulfonyl) ethyl) -3-ethyl- acid 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (isopropylsulfonyl) ethyl) -3-ethyl- acid 2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -1 - ((S) -2- (tert-Butyl sulfonyl) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-ethyl- 2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (cyclopropyl sulfonyl) ethyl) -3-ethyl- acid 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (ethylsulfonyl) -3-methylbutan-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) - 1— (isopropylsulfonyl) -3-methylbutan-2-yl) -3 acid -inethyl-2oxopiperidin-3-yl) acetic;

139

2 - ((3R, 5R, 6S) -5- (3-Chlorpphenyl) -6- (4-Chlorophenyl) -1 ((S) -3,3-dimethyl-l- (methylsulfonyl) butan-2-yl ) -3-methyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (ethylsulfonyl) -3,3-dimethylbutan-2-yl) acid -3-methyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-ClOrophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (isopropylsulfonyl) -3,3-dimethylbutan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (pentan-3-ylsulfonyl) acid) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid; 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) - 1 - ((S) -isopropylsulfinyl) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1 - ((R) -isopropylsulfinyl) butan-2-yl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic; more polar isomer;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((2S, 3S) -2- (methylsulfonyl) pentan-3-yl) acid -2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((2R, 3S) -2- (methylsulfonyl) pentan-3-yl) acid -2-oxopiperidin-3-yl) acetic;

4 π MEXICAN INSTITUTE · * w OF THE PROPERTY

INDUSTRIAL 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((2S, 3S) -2- (ethylsulfonyl) pentan-3-yl) -3 -methyl-2-oxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -15 ((2R, 3S) -2- (ethylsulfonyl) pentan-3-yl) -3- methyl-2-oxopiperidin3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenylj-6- (4-Chlorophenyl) -3methyl-1 - ((S) -1- (N- (oxetane-3-yl) sulfamoyl) acid) butan-2-yl) -2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -1- (N - ((3-Methyloxetan-3- yl) methyl) sulfamoyl) butan2-yl) -2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -1- (N- (oxetane-3-ylmethyl) sulfamoyl ) butan-2-yl) -215 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) -2- (N- (tert-Butyl) sulfamoyl) acid -

1- Cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-

2- oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenylj-6- (4-Chlorophenyl) -120 ((S) -l-cyclopropyl-2- (N-methylsulfamoyl) ethyl) -3-methyl acid -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N, N-dimethylsulfamoyl) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

141

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-isopropylsulfamoyl) ethyl) -3- acid methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (morph'olinosulfonyl) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (piperidin-l-ylsulfonyl) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (pyrrolidin-1-ylsulfonyl) ethyl) acid - 3-methyl2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -1 - ((S) -2- (Azetidin-1-ylsulfonyl) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3- methyl-2-oxopiperidin-3-yl) acetic; ' 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2 - ((N, N-dimethylsulfamoyl) amino) acid) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2 - ((N, N-dimethylsulfamoyl) (methyl) amino ) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (3-methyl-2,5-dioxoimidazolidin) acid -l1

yl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

142 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (3,4,4-trimethyl-2-acid) , 5-dioxoimidazolidin-yl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (4,4-dimethyl-2,5-acid) -di0Xoimidazolidin-yl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (3-isopropyl-2,2-dioxide) acid -4-oxo-3,4dihydro-lH-benzo [c] [1,2,6] thiadiazin-l-yl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (2-oxo-2,3-dihydro) acid -lH-benzo [d] imidazole-

1-yl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chloro-4-fluorophenyl) -6- (4Clorophenyl) -l-isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic acid;

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4Clorophenyl) -l-isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic acid;

2 - ((3S, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4Clorophenyl) -l-isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic acid;

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -1- (ethylsulfonamido) butan-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4- acid

143

IMPIS '

MEXICAN INSTITUTE Vg-'fcpr 'OF INDUSTRIAL PROPERTY

Chlorophenyl) -3-methyl-l - ((S) -1-ÍN-mati 1ptílsulfonamido) butan-2 il) -2-oxopiperidin-3-ilj acetic;

2- ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4Clorophenyl) -3-methyl-l - ((S) -1- (methylsulfonyl) butan-2- yl) -2 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -1- (ethylsulfonyl) butan-2-yl) -3 acid -methyl-2 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3 ~ Chloro-5-fluorophenyl) -6- (4Chlorophenyl) -1 - ((S) -1- (cyclopropyl sulfonyl) butan-2-yl) -3methyl acid -2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -l - ((S) -l- (tert-Butyl sulfonyl) butan2-yl) -5- (3-chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -3-methyl-2oxopiperidin-3-yl) acetic; 2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -1- (isopropylsulfonyl) butan-2-yl) acid 3-methyl-

2- oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin-

3- yl) -l - ((S) -1- (cyclopropylsulfonyl) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -1 - ((S) -1- (tert-Butylsulfonyl) butan2-yl) -6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) acid -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin144 acid

3-yl) -1- ((S) -1- (cyclopropansulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin3-yl) -3-methyl-l - ((S) -1- (N-methylcyclopropanesulfonamido) butan2- yl) -2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin2-yl) -1 - ((S) -1- (ethylsulfonyl) butan-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -1 - ((S) -morpholin-2-yl) acid propyl) -2-oxopiperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -1 - ((R) -morpholin-2-yl) acid propyl) -2-oxopiperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((R) -1 - ((S) -morpholin-2-yl) acid propyl) -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((R) -1 - ((R) -morpholin-2-yl) acid propyl) -2-oxopiperidin-3yl) acetic;

or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) - acid

145

IMTI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

3-methyl-l- ((R) -1- ((S.) -morpholin-2-yl) propyl) -2-oxopiperidin-3 yl) acetic;

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) -3- (2morpholinoethyl) -2-oxopiperidin-3-yl) acetic;

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3 (2- (1,1-dioxidothiomorpholino) ethyl) -1 - ((S) -1 acid - (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic;

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) -2- acid oxo-3- (2 (pyrrolidin-l-yl) ethyl) piperidin-3-yl) acetic;

2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3 (2- (dimethylamino) ethyl) -1- ((S) -1- (N-methylcyclopropansulfonamido) ) butan-2-yl) -2-oxopiperidin-3yl) acetic;

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -

1- (N-methylcyclopropansulfonamido) butan-2-yl) -3- (2morpholinoethyl) -2-oxopiperidin-3-yl) acetamide;

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -

1- (N-methylcyclopropansulfonamido) butan-2-yl) -3- (2-morpholinoethyl) -2-oxopiperidin-3-yl) acetamide;

(IR, 3S, 6S, 7R) -7- (3-Chlorophenyl) -6- (4-Chlorophenyl) -5 ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -4-oxo -5-

IMPI

146 azaspiro [2.5] octan-l-carboxylic; _______ (3S, 6S, 7R) -7- (3-Chlorophenyl) -6- (4-Chlorophenyl) -5 ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) -4-oxo- 5azaspiro [2.5] octan-1-carboxylic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((2S, 3S) -1,2-dihydroxipentan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((2R, 3S) -1,2-dihydroxipentan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((2R, 3S) -1,2-dihydroxipentan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((2S, 3S) -1,2-dihydroxipentan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((1S, 2S) -l-cyclopropyl-l-hydroxybutan-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -l ((IR, 2S) -l-cyclopropyl-l-hydroxybutane-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1isopropyl-6-methyl-2-oxopiperidin-.3-yl) acetic acid;

147 ΙΜΡΙ €?> ^

MEXICAN INSTITUTE Kf

PROPERTY 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-C? L)IgWeniT ^ T ^ isopropyl-6-methyl-2-oxopiperidin-3-yl) acetic;

(3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -1 (1, l-dioxideisothiazo.lidin-2-yl) butan-2-yl ) -3 - ((6methoxypyridin-2-yl) methyl) piperidin-2-one;

(3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -1 (1, l-Dioxideisothiazolidin-2-yl) butan-2-yl) - 3 - ((6methoxypyridin-2-yl) methyl) piperidin-2-one;

(3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -1 (1, l-Dioxideisothiazolidin-2-yl) butan-2-yl) - 3 - ((6hydroxypyridin-2-yl ·) methyl) piperidin-2-one;

(3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -1 (1, l-Dioxideisothiazolidin-2-yl) butan-2-yl) - 3 - ((6hydroxypyridin-2-yl) methyl) piperidin-2-one;

(3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - ((Sj-1 (1, l-Dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6methoxypyridin-2-yl) methyl) - '3-methylpiperidin-2-one;

(3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -1 (1, l-Dioxideisothiazolidin-2-yl) butan-2-yl) - 3 - ((6methoxypyridin-2-yl) methyl) -3-methylpiperidin-2-one;

(3S, 5R, 6S) -5- (3-Ciorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -1 (1, l-dioxideisothiazolidin-2-yl) butan-2-yl) - 3 - ((6hydroxypyridin-2-yl) methyl) -3-methylpiperidin-2-one;

(3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - ((S) -114 8

i. .tv'A Á JL \ 'INSTITUTO mexicz.no VZ -

OF U. PROPERTY V * = *. INDUSTRIAL (1, l-Dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6hydroxypyridin-2-yl) methyl) -3-methylpiperidin-2-one;

cyclopropyl-2- (ethylsulfonyl) ethyl) -3- (3-hydroxy-2-oxopropyl) 3-methylpiperidin-2-one;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 (diethylamino) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 (dimethylamino) -3-methyl-2-oxopiperidin-3-yl) acetic acid; or (2S, 3S, 5S, 6R, 7aR, lOaS.) -6- (3-Chlorophenyl) -5- (4Chlorophenyl) -3-ethyl-2,7a-dimethylhexahydrofide [2,3b] oxazolo [3,2- a] pyridin-9 (5H) -one.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (thiophene-2-sulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (N-methylthio.en-2-sulfonamido) ethyl) -3-methyl-2oxopiperidin-3-yl acid )acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2- (5-chlorothiophene-2-sulfonamido) -1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

149

IMPI

MEXICAN INSTITUTE

FROM PROPERTY, 2- (1- (2- (5-Chloro-N-methylthiophene-2-sulToriamido *) 'acid;<[·

cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

cyclopropyl-2- (N- (difluoromethyl) -2-methylpropan-2ylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

cyclopropyl-2- (N- (difluoromethyl) ethylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (N- (difluoromethyl) cyclopropansulfonamido) ethyl) 3-methyl-2-oxopiperidin-3-yl) acetic acid ;

1 - (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (cyclopropanesulfonamido) -1-cyclopropylethyl) -3-methyl-215 oxopiperidin-3-yl) cyclopropancarboxylic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N- (2-fluorophenyl) ethylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-C10phenyl) -1- (120 cyclopropyl-2- (N- (2-fluorophenyl) methylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3-yl acid ) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Glorophenyl) -1- (1-cyclopropyl-2- (N-phenylcyclopropanesulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

150

MFXTCA'lÓ X 'INSTITUTE -

DE LÁ PROf iú; XO l: · · -.....

INDUSTRIAL J 2 - (5— (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 cyclopropyl-2- (N-phenylethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid ;.

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 cyclopropyl-2- (ethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 cyclopropyl-2- (N- (3-fluorophenyl) ethylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3-yl acid )acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2- (N- (2 cyanophenyl) methylsulfonamido) -1-cyclopropylethyl) -3-methyl-2oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 cyclopropyl-2- (propylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 cyclopropyl-2- (N-phenylmethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2- (N- (3 cyanophenyl) methylsulfonamido) -1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 cyclopropyl-2- (N- (pyridin-3-yl) methylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3 acid -il) acetic;

MEXÍCZiNO INSTITUTE

OF THE PROPERTY

INDUSTRIAL

151 acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- cyclopropyl-2- (N- (thiophene-2-yl.methyl) methylsulfonamido) ethyl) -3methyl-2-oxopiperidin -3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N- (3-methoxybenzyl) methylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3-yl acid) acetic;

2 - (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (phenylmethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (pyridin-2-ylmethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (pyridin-3-ylmethylsulfonamido) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N- (pyridin-2-yl) methylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3- acid il) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (methylsulfonamido) ethyl) -3-methyl-2-oxopiperidin3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N-ethylmethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

acid

152

MEXICAN INSTITUTE

DELAK.OrtíiWAO INDUSTRIAL

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N-isopropylmethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -l- (15-cyclopropyl-2- (1-methylethylsulfonamido) ethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic acid; ' 2 - (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (cyclobutanesulfonamido) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (cyclopentansulfonamido) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (3methyl-1- (N-methylcyclopropansulfonamido) butan-2-yl) -215 oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (cyclopropansulfonamido) -3-methylbutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (120 (ethylsulfonamido) -3-methylbutan-2-yl) -3-methyl-2-oxopiperidin3-yl) acetic acid;

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (cyclobutansulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic;

153 acid

MEXICAN INSTITUTE, <

FROM THE VJKsr-TaXjS® PROFKDAD. INDUSTRIAL

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1— (N— ethylcyclobutansulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-25 oxo-1- (1- (phenylsulfonyl) butan-2-yl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (1 (methylsulfonyl) butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2oxo-1- (1- (propylsulfonyl) butan-2-yl) piperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (isobutyl sulphonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 ((cyclopropylmethyl) sulfonyl) butan-2-yl) -3-methyl-215 oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 ((cyclobutylmethyl) sulfonyl) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (120 (cyclopentylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (l (oxetan-3-ylsulfonyl) butan-2-yl) -2-oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (1INSTITUTO MEXICANO)

OF THE PROPERTY

INDUSTRIAL (((3-methyloxetan-3-yl) methyl) sulfonyl) butan-2-yl) -219

154 oxopiperidin-3-yl) acetic;

acid

2- (5- (3-Chlorophenyl) -6- (4-Glorophenyl) -3-methyl-2oxo-1- (1 - ((tetrahydro-2H-pyran-4-yl) sulfonyl) butan-2yl) piperidin- 3-yl) acetic;

hydroxy-2-methyIpropi1) sulfonyl) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

acid

2- (1- (1 - (- sec-butylsulfonyl) butan-2-yl) -5- (3

Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic;

(cyclopentylsulfonyl) -l'-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

cyclopropyl-2 - (((3-methyloxetan-3-yl) methyl) sulfonyl) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic acid;

cyclopropyl-2- (phenylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

acid

2- (5- (-3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 - ((2-

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

Chlorophenyl) sulfonyl) -1-cyclopropylethyl) -3-methyl-2155

oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 - ((4Clorophenyl) sulfonyl) -l-, cyclopropylethyl) -3-methyl-25 oxopiperidin-3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2 - ((4-fluorophenyl) sulfonyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (ΙΙΟ cyclopropyl-2- (pyridin-4-ylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (1- (2 - ((2-Chloro-4-fluorophenyl) sulfonyl) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2oxopiperidin-3-yl )acetic;

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) —1— (1— cyclopropyl-2 - ((cyclopropylmethyl) sulfonyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- ((2,2,2-trifluoroethyl) sulfonyl) ethyl) -3-methyl-220 oxopiperidin -3-yl) acetic; · 2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2 - ((trifluoromethyl) sulfonyl) ethyl) -3-methyl-2oxopiperidin- 3-ii) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-

i> cl / *. ζηυηΐιλ · »υ

INDUSTRIAL cyclopropyl-2- (phenylsulfonyl) ethyl) -3-ethyl-2-oxopiperidin156 yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2- ((2Clorophenyl) sulfonyl) -1-cyclopropylethyl) -3-ethyl-25 oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2 - (((2-fluorophenyl) sulfonyl) ethyl) -3-ethyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (ΙΙΟ cyclopropyl-2 - (((3-fluorophenyl) sulfonyl) ethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2 - ((4-fluorophenyl) sulfonyl) ethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (propylsulfonyl) ethyl) -3-ethyl-2-oxopiperidin-3yl) acetic acid;

2- (1- (2- (Butylsulfonyl) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-ethyl-2-oxopiperidin-3 yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (isopentylsulfonyl) ethyl) -3-ethyl-2-oxopiperidin3-i1) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 acid 157 IMPI 'MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL (cyclopentylsulfonyl) -1-cyclopropylethyl) -3-ethyl-2-

oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (cyclohexylsulfonyl) -1-cyclopropylethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (methylsul'phonyl) ethyl) -3-ethyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (3methyl-1- ((2,2,2-trifluoroethyl) sulfonyl) butan-2-yl) acid - 2oxopiperidin-3-yl) acetic;

2- (1- (1- (tert-Butylsulfonyl) -3-methylbutan-2-yl) -5 (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (3methyl-1- (methylsulfonyl) butan-2-yl) -2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -i- (1 (ethylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (cyclopropylsulfonyl) butan-2-yl) -3-ynyethyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1IMPI

(isopropylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3158 yl) acetic;

acid

2- (1- (1- (tert-butylsulfonyl) butan-2-yl) -5- (3Clorophenyl) -6- (4-Chlorophenyl.l) -3-methyl-2-oxopiperidin-3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (cyclobuti1sulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-ethyl-l- (1 (ethylsulfonyl) butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-ethyl-l- (1 (isopropylsulfonyl) butan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (1 - (1- (tert-Butylsulfonyl) butan-2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-ethyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (cyclobutyl sulphonyl) butan-2-yl) -3-ethyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (cyclopropyl sulfonyl) butan-2-yl) -3-ethyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (ethylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

IMPI

159 acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 cyclopropyl-2- (isopropylsulfonyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic;

2- (1- (2- (tert-Butyl sulfonyl) -1-cyclopropylethyl) -5 (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (cyclobutyl sulfonyl) -1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (cyclopropyl sulfonyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (methylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (tert-pentylsulfonyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlo.phenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2 - ((2,4-difluorophenyl) sulfonyl) ethyl) -3-methyl-2-oxopiperidin-3- acid il) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (ethylsulfonyl) ethyl) -3-ethyl-2-oxopiperidin-3yl) acetic acid;

^ TvssssscssxrZSSÜ

160

MEXICAN INSTITUTE

DE The profísdaí? INDUSTRIAL acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1MMWMOiaSBgrjggX »» ^ »».!,, - ^ .... 1.7¾¾ cyclopropyl-2- (isopropylsulfonyl) ethyl) - 3-ethyl-2-oxopiperidin

3-yl) acetic;

2- (1 - ((2- (tert-Butylsulfonyl) -1-cyclopropylethyl) acid -

5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-ethyl-2-oxopiperidin-3- yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 cyclopropyl-2- (cyclopropyl sulfonyl) ethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (ethylsulfonyl) -3-methylbutan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (isopropylsulfonyl) -3-methylbutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (3,3— dimethyl-1- (methylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin3-yl acid )acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (ethylsulfonyl) -3,3-dimethylbutan-2-yl) -3-methyl-2-oxopiperidin3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (isopropylsulfonyl) -3,3-dimethylbutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid ;

161 acid

IMPI

Mexican Institute of Industrial Property

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 cyclopropyl-2- (pentan-3-ylsulfonyl) ethyl) -3-methyl-2-acid (isopropylsulfinyl) butan-2-yl ) -3-methyl-2-oxopipéridin-3 yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (2 (methylsulfonyl) pentan-3-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (ethylsulfonyl) pentan-3-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (1 (N- (oxetan-3-yl) sulfamoyl) butan-2-yl) -2-oxopiperidin -3 yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (1 (N- ((3-methyloxetan-3-yl) methyl) sulfamoyl) butan-2-yl acid ) -2oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (1 (N- (oxetan-3-ylmethyl) sulfamoyl) butan-2-yl) -2-oxopiperidin -3yl) acetic;

2- (1- (2- (N- (tert-Butyl) sulfamoyl) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 acid

IMPI

162 cyclopropyl-2- (N-methylsulfamoyl) ethyl) -3-methyl-2-oxopiperidin3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N, N-dimethylsulfamoyl) ethyl) -3-methyl-25 oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N-isopropylsulfamoyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (ΙΙΟ cyclopropyl-2- (morpholinosu'lf ynyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (piperidin-1-ylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (pyrrolidin-1-ylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (1- (2- (Azetidin-1-ylsulfonyl) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-220 oxopiperidin-3-yl) acetic acid; ' 2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2 - ((N, N-dimethylsulfamoyl) amino) ethyl) -3-methyl-2oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-

163

OF THE C 'INDUSTRIAL' PROPERTY 2 cyclopropyl-2 - ((N, N-dimethylsulfamoyl) (methyl) amino) ethyl) -3methyl-2-oxopiperidin-3-.il) acetic; * ”* 2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (3-methyl-2,5-dioxoimidazolidin-l-yl) ethyl) -3methyl- acid 2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (3,4,4-trimethyl-2,5-dioxoimidazolidin-lyl) ethyl) -3-methyl acid -2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (4,4-dimethyl-2,5-dioxoimidazolidin-l-yl) ethyl) 3-methyl- acid 2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (3-isopropyl-2,2-dioxide-4-oxo-3,4-dihydro-lHbenzo) acid [ c] [1,2,6] thiadiazin-l-yl) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (2-oxO-2,3-dihydro-lH-benzo [d] imidazol-1yl) ethyl acid) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chloro-4-fluorophenyl) -6- (4-Chlorophenyl) -1isopropyl-3-methyl-2-oxopiperidin-.3-yl) acetic acid;

2- (5- (3-Chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -1isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -1 (1- (ethylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3- acid

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

il) acetic;

2- (5- (3-Chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -3methyl-1- (1- (N-methylethylsulfonamido) butan-2-yl) -2oxopiperidin-3-yl) acetic acid ;

2- (5- (3-Chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -3methyl-1- (1- (methylsulfonyl) butan-2-yl) -2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -1 (1- (ethylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -1 (1- (cyclopropyl sulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (1- (1— (tert-Butylsulfonyl) butan-2-yl) -5- (3-chloro-5-fluorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxopiperidin3-yl) acetic acid ;

2- (5- (3-CYOR-5-Fluorophenyl) -6- (4-Chlorophenyl) -1 (1- (isopropylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) -1- (1 (cyclopropyl sulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (1- (1- (tert-Butylsulfonyl) butan-2-yl) -6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) -3-methyl-2-oxopiperidin-3- acid

MEXICZiNO INSTITUTE

OF INDUSTRIAL PROPERTY

165 il) acetic; —---- 2- (6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) -1- (1 (cyclopropanesulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin acid -3yl) acetic;

2- (6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) -3methyl-1- (1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (5-chloropyridin-2-yl) -1- (1 (ethylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (1 (morpholin-2-yl) propyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- (N-methylcyclopropansulfonamido) butan-2-yl) -3- (2-morpholinoethyl) 2-oxopiperidin-3-yl) acid acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3- (2- (1,1-dioxydothiomorpholino) ethyl) -1- (1- (N-methylcyclopropanesulfonamido) butan-2-yl) -2- acid oxopiperidin-3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxo-3- (2 (pyrrolidin-1-i1) acid ethyl) piperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3- (2 (dimethylamino) ethyl) -1- (1- (N166

methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic;

2- (5- (3-Chlorophenyl ·) -6- (4-Chlorophenyl) -1- (1— (N— methylcyclopropansulfonamido) butan-2-yl) -3- (2-morpholinoethyl) 2-oxopiperidin-3- il) acetamide;

7- (3-Chlorophenyl) -6- (4-Chlorophenyl) -5- (1- (N-methylcyclopropanesulfonamido) butan-2-yl) -4-oxo-5azaspiro [2.5] octan-l-carboxylic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1,2dihi.droxipentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-l-hydroxybutane-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid; 2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1-isopropyl acid · -

6-methi1-2-oxopiperidin-3-yl) acetic;

5- (3-Chlorophenylj-6- (4-Chlorophenyl) -1- (1- (1,1— dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6-methoxypyridin-2yl) methyl) piperidin-2-one;

5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- (1,1-Dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6-hydroxypyridin-2yl) methyl) piperidin -2-one ;.

5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- (1,1-Dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6-methoxypyridin-2yl) methyl) - 3-methylpiperidin-2-one;

167

I My PI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- (1,1 dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6-hydroxypyridin-2 yl) methyl ) -3-methylpiperidin-2-one;

(5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (l-cyclopropyl-2 (ethylsulfonyl) ethyl) -3- (3-hydroxy-2-oxopropyl) -3methylpiperidin-2-one;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 (diethylamino) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 (dimethylamino) -3-methyl-2-oxopiperidin-3-yl) acetic acid; or

6- (3-Chlorophenyl) -5- (4-Chlorophenyl) -3-ethyl-2,7-dimethylhexahydrofide [2,3-b] oxazolo [3,2-a] pyridin-9 (5H) -one.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (methylsulfonyl) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (isopropylsulfonyl) -3-methylbutan-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) —1— (tert-butylsulfonyl) butan2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl -2-oxopiperidin-3-yl) acetic;

acid

X1VA1. l

MEXICAN INSTITUTE \;

OF PROPERTY \ nz INDUSTRl. · '.!. - -L--2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1168 ysi

í 4 · ((S) -1- (isopropylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-

3-yl). acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (isopropylsulfonyl) -3,3-dimethylbutan-2-yl) -3-methyl-2 oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (ethylsulfonyl) -3-methylbutan-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2 - {(3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (ethylsulfonyl) butan-2-yl) -3-methyl- acid 2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-phenylcyclopropanesulfonamido) ethyl) -3methyl- acid 2-oxopiperidin-3-yl) acetic; or 2 - ((3R, 5Rj6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) —1 - ((cyclopropylmethyl) sulfonyl) butan-2-yl) -3- methyl-2oxopiperidin-3-yl) acetic.

In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from:

2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1-cyclopropyl-2- (methylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3 yl) acetic acid;

169 MEXICAN INSTITUTE

OF THE PROPERTY < 1 INDUSTRIAL 2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 (isopropylsulfonyl) -3-methylbutan-2-yl) -3-methyl-2oxopiperidin-3-yl acid) acetic;

2 - (- 1 - (- 1- (tert-butylsulfonyl) butan-2-yl) -5- (3Clorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 (isopropylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (-5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 (isopropylsulfonyl) -3,3-dimethylbutan-2-yl) -3-methyl-2oxopiperidin-3-yl acid )acetic;

2- (-5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 (ethylsulfonyl) -3-methylbutan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid ;

2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 (ethylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1-cyclopropyl-2- (N-phenylcyclopropansulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 ((cyclopropylmethyl) sulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid ;

170 acid mercan institute or V “t. , r

2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 cyclopropyl-2- (methylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3 yl) acetic;

acid

2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 (isopropylsulfonyl) -3-methylbutan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic; or 2 - (- 1 - (- 1- (tert-butylsulfonyl) butan-2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxopiperidin-3 yl) acetic acid .

The present invention provides pharmaceutical compositions comprising a compound of any one of the above aspects or embodiments, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, diluent, or carrier.

The present invention also provides the method of treating cancer in a subject in need of treatment, the method comprising administering to the subject an effective dosage amount of a compound according to any one of the aspects or modalities above, or a salt pharmaceutically acceptable thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term H means a single hydrogen atom.

This radical can be linked, for example, to an oxygen atom

171

IMPI

to form a hydroxyl radical.

Where the term alkyl is used, either 1 alone or dehtW from other terms such as haloalkyl or alkylamino, encompasses linear or branched radicals having one to about twelve carbon atoms. The most preferred alkyl radicals are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The term "alkylene or alkylene" encompasses divalent alkyl radicals such as methylenyl or ethylenyl. The term lower alkyl substituted with R2 does not include an acetal portion. The term "alkyl" further includes alkyl radicals where one or more carbon atoms in the chain is replaced with a heteroatom selected from oxygen, nitrogen, or sulfur.

The term alkenyl encompasses linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. The most preferred alkenyl radicals are lower alkenyl radicals having two to about six carbon atoms. The most preferred lower alkenyl radicals are

INSTITUTE Ni E Xi C AI * · * O 'i®- *

172

OF INDUSTRIAL PROPERTY carbon radicals.

ethenyl, which have two to about four atoms of

Examples of alkenyl radicals include propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The terms alkenyl and lower alkenyl encompass radicals having both cis and trans orientations, or alternatively E and Z orientations.

The term "alkynyl" means linear or branched radicals having at least one carbon-carbon triple bond and having two to about twelve carbon atoms. The most preferred alkynyl radicals are lower alkynyl radicals having two to about six carbon atoms. Most preferred are lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include propargyl, and butynyl, and the like.

The alkyl, alkylene, alkenyl, and alkynyl radicals can optionally be substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocycle and the like.

The term halo means halogens such as fluorine, chlorine, bromine, or iodine atoms.

The term haloalkyl encompasses radicals where any one or more of the alkyl carbon atoms is

IMPI above. They cover

specifically replace with halo like

173 monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals are defined including perhaloalkyl.

A monohaloalkyl radical, for example, can have either an iodine, bromine, chlorine, or fluoro atom within the radical. The dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms or a combination of different halo radicals.

Lower haloalkyl encompasses radicals having 1 to 6 carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term perfluoroalkyl means alkyl radicals having all of the hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.

The term hydroxyalkyl encompasses linear or branched alkyl radicals having one to about ten carbon atoms, any of which can be substituted with one or more hydroxyl radicals. Radicals

174

iNjmvT? msí¡> í: .j M ca t-tcs ·: '

More preferred hydroxyalkyl are lower hydroxyalkyl radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.

The term alkoxy encompasses linear or branched oxy-containing radicals each having alkyl moieties of one to about ten carbon atoms. The most preferred alkoxy radicals are lower alkoxy radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals can also be substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide haloalkoxy radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.

The term aryl, alone or in combination, means a carbocyclic aromatic system containing one or two

institute r. and? i

FROM THE PBOL'IST '>

INDUSTIi. ”.

175

rings, where such rings can be joined together in a fused manner. The term aryl encompasses aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. The most preferred aryl is phenyl. An aryl group can have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino, and the like. Phenyl substituted with -O-CH2-OR- forms the aryl benzodioxolyl substituent.

The term heterocyclyl (or heterocycle) encompasses ring radicals containing saturated, partially saturated, and unsaturated heteroatoms, where heteroatoms can be selected from nitrogen, sulfur, and oxygen.

Rings containing -0-0 -, - OS- or

-H.H-. The heterocyclyl group can have up to substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino.

Examples of saturated heterocyclic radicals include saturated 3- to 6-membered heteromonocyclic groups containing 1 to '4 nitrogen atoms [eg, pyrrolidinyl,' imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3- to 6-membered heteromonocyclic group containing 1 to 2 atoms of

176 oxygen and 1

MP

NrXIC INSTITUTE '

OF THE PROFÍEI

INDUSTuIAi up to 3 nitrogen atoms [eg

morpholinyl];

saturated 3- to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

Examples of unsaturated heterocyclic radicals, also called heteroaryl radicals, include unsaturated 5- to 6-membered heteromonocyclyl group containing 1 to nitrogen atoms, eg pyrrolyl, imidazolyl, pyrazolyl,

2-pyridyl, 3-pyridyl,

4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [eg 4H-1,2,4-triazolyl,

1H-1,2,3-triazolyl, 2H-

1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, eg, pyranyl, 2-furyl, 3-furyl, etc .; 5- to 6-membered unsaturated heteromonocyclic group containing a sulfur atom, eg 2-thienyl, 3-thienyl, etc .; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, eg oxazolyl, isoxazolyl, oxadiazolyl [eg 1,2,4-oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,5-oxadiazolyl]; heteromonocyclic group of

177

up to 6-membered unsaturated containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, eg thiazolyl, thiadiazolyl [eg 1,2,4-thiadiazolyl,

1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term heterocyclyl, (or heterocycle) also encompasses radicals where heterocyclic radicals are fused / condensed with aryl radicals:

unsaturated condensed heterocyclic group containing 1 to nitrogen atoms, for example>

indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [eg, tetrazolo [1,5-b] pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [eg, benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg, benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated, and unsaturated fused heterocyclic group containing 1 to 2 'sulfur or oxygen atoms [eg, benzofuryl, benzothienyl, 2,3-dihydro-benzo [1,4] dioxinyl, and dihydrobenzofuryl]. Preferred heterocyclic radicals include fused or unfused radicals of five to ten members. Examples of more preferred heteroaryl radicals include

178 · 'F · / quinolyl, thiazolyl, heteroaryl

IMPI P>

INSTITUTO IC 'i V eturc ·>

isoquinolyl, imidazolyl, pyridyl, thienyl, oxazolyl, furyl, and pyrazinyl. Other preferred radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl , piperidinyl and pyrazinyl.

Particular examples of non-nitrogen containing heteroaryl include pyranyl, 2-furyl, 3-furyl, 2-thienyl,

3-thienyl, benzofuryl, and benzothienyl, and the like.

Particular examples of saturated and partially saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl,

2,3-dihydro-benzo [1,4] dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,

1,2,3,4-tetrahydro-quinolyl,

2,3,4,4a, 9,9a-hexahydrq-lH-3-aza-fluorenyl, 5,6,7-trihydro1,2,4-triazolo [3,4-a] isoquinolyl,

3,4-dihydro-2Hbenzo [1,4] oxazinyl, benzo [1,4] dioxanil, 2,3-dihydro-lH-lÁ'benzo [d] isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl, and the like .

IMPIf>: INSTITUTE: no V '. <·

DELA thus covers the

179

The term heterocycle follows ring systems:

180

ΙΜΡΙΓ-. MEXICAN INSTITUTE OF THE PRO? I £ D / .D INDUSTRIAL

181

The term sulfonyl,

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

terms such as if used alone or linked to other alkylsulfonyl, respectively means divalent radicals -SO2-,

The terms sulfamyl, aminosulfonyl and sulfonamidyl, means a sulfonyl radical substituted with an amine radical, which forms a sulfonamide (-SO2NH2).

The term "alkylaminosulfonyl" includes Nalkylaminosulfonyl where sulfamyl radicals are independently substituted with one or two alkyl radicals. The most preferred alkylaminosulfonyl radicals are lower alkylaminosulfonyl radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, and N-ethylaminosulfonyl.

The terms carboxy or carboxy, if used alone or with other terms, such as carboxyalkyl, mean CO2H.

182

The term carbonyl, if used

alone or with other terms, such as aminocarbonyl, means - (C = O) -.

The term aminocarbonyl means an amide group of the formula C (= O) NH2 ·

The terms N-alkylaminocarbonyl and N, N-diakylaminocarbonyl mean aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. Most preferred are lower alkylaminocarbonyl having lower alkyl radicals as described above linked to an aminocarbonyl radical.

The terms N-arylaminocarbonyl and N-alkyl-Narylaminocarbonyl mean aminocarbonyl radicals substituted, respectively, with an aryl radical, or an alkyl and an aryl radical.

The terms heterocyclylalkylenyl and heterocyclylalkyl encompass heterocyclic-substituted alkyl radicals. The most preferred heterocyclylalkyl radicals are 5- or 6-membered heteroarylalkyl radicals having alkyl moieties of one to six carbon atoms and a 5- or 6-membered heteroaryl radical. Even more preferred are lower heteroarylalkylenyl radicals having alkyl moieties of one to three carbon atoms. Examples include radicals such as

pyridylmethyl and thienylmethyl. ___

The term aralkyl encompasses aryl-substituted alkyl radicals. Preferable aralkyl radicals are lower aralkyl radicals having aryl radicals bonded to alkyl radicals having one to six carbon atoms. Even more preferred are portion-bonded phenylakylenyl, alkyl having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, and phenylethyl. The aryl in aralkyl 10 can be further substituted with halo, alkyl, alkoxy, halcoalkyl and haloalkoxy.

The term "alkylthio" encompasses radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, bonded to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms. An example of alkylthio is methylthio, (CH3S-).

The term haloalkylthio encompasses radicals containing a haloalkyl radical, of one to ten carbon atoms, bonded to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of haloalkylthio is trifluo'romethylthio.

The term "alkylamino" encompasses N-alkylamino and N, N-

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY are independently

184 dialkylamino where amino groups substituted with an · alkyl radical and with two alkyl radicals, respectively. The most preferred alkylamino radicals are lower alkylamino radicals having one or two alkyl radicals of one to six carbon atoms, bonded to one nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Appropriate alkylamino radicals can be mono or dialkylamino such as Nmethylamino, N-ethylamino, N, N-dimethylamino, and N, N-diethylamino, and the like.

The term arylamino means amino groups, which have been replaced with one or two aryl radicals, such as N-phenylamino. The arylamino radicals can also be substituted at the aryl ring portion of the radical.

The term heteroarylamino means amino groups, which have been replaced with one or two heteroaryl radicals, such as N-thienylamino. Heteroarylamino radicals can further be substituted at the heteroaryl ring portion of the radical.

The term aralkylamino means amino groups, which have been replaced with one or two aralkyl radicals. Most preferred are phenyl-alkylamino-Ci-C3 radicals, such as N-benzylamino. Aralkylamino radicals can also

185

IΜ ΡI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL be replaced in the aryl ring portion.

The terms N-alkyl-N-arylamino and Nyaralkyl-Nalkylamino mean amino groups, which have been independently substituted with an aralkyl and one alkyl radical, or an aryl and one alkyl radical, respectively, to an amino group.

The term aminoalkyl encompasses linear or branched alkyl radicals having one to about ten carbon atoms, any of which can be substituted with one or more amino radicals. The most preferred aminoalkyl radicals are lower aminoalkyl radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl. Even more preferred are the lower amino alkyl radicals having one to three carbon atoms.

The term "alkylaminoalkyl" encompasses alkyl radicals substituted with alkylamino radicals. The most preferred alkylaminoalkyl radicals are lower alkylaminoalkyl radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Appropriate alkylaminoalkyl radicals can be mono or dialkyl

186

IMPI

INSTITUTO MEXICANO V '' OF INDUSTRIAL PROPERTY substituted, such as N-methylaminomethyl, N, N-dimethylaminoethyl, and N, N-diethylaminomethyl, and the like.

The term "alkylaminoalkoxy" encompasses alkoxy radicals substituted with alkylamino radicals.

The most preferred alkylaminoalkoxy radicals are lower alkylaminoalkoxy radicals having alkoxy radicals of from one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Appropriate alkylaminoalkoxy radicals can be mono or substituted dialkyl, such as

N-methylaminoethoxy,

N, N-dimethylaminoethoxy, and N, N-diethylaminoethoxy, and the like.

The term "alkylaminoalkoxyalkoxy" encompasses alkoxy radicals substituted with alkylaminoalkoxy radicals. The most preferred alkylaminoalkoxyalkoxy radicals are lower alkylaminoalkoxyalkoxy radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms. Appropriate alkylaminoalkoxyalkoxy radicals can be mono or substituted dialkyl, such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N,N_ dimethylaminoethoxyethoxy, · and N, N-diethylaminomethoxymethoxy, and the like.

187

The term carboxyalkyl encompasses linear or branched alkyl radicals having one to about ten carbon atoms, any of which can be substituted with one or more carboxy radicals. The most preferred carboxy alkyl radicals are lower carboxy alkyl radicals having one to six carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, and carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having one to three CH2 groups,

The term halosulfonyl encompasses sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl.

The term arylthio encompasses aryl radicals of six to ten carbon atoms, bonded to one divalent sulfur atom. An example of arylthio is phenylthio.

The term aralkylthio encompasses aralkyl radicals as described above, linked to a divalent sulfur atom. Most preferred are phenyl-alkylthio-Ci-C3 radicals. An example of aralkylthio is benzylthio.

The term aryloxy encompasses optionally substituted aryl radicals, as defined above, linked to an oxygen atom. Examples of such radicals include phenoxy.

IMPI

188 encompasses aralkyl radicals that

The term aralkoxy contain oxy bonded through an oxygen atom to other radicals. The most preferred aralkoxy radicals are lower aralkoxy radicals having optionally substituted phenyl radicals linked to the lower alkoxy radical as described above.

The term heteroaryloxy encompasses optionally substituted heteroaryl radicals, as defined above, linked to an oxygen atom.

The term heteroarylalkoxy encompasses heteroarylalkyl radicals containing oxy bonded through one oxygen atom to other radicals. The most preferred heteroarylalkyl radicals are lower heteroarylalkyl radicals having optionally substituted heteroaryl radicals linked to the lower alkoxy radical as described above.

The term cycloalkyl includes saturated carbocyclic groups. Preferred cycloalkyl groups include C3-C6 rings.

The most preferred compounds include, cyclopentyl, cyclopropyl, and cyclohexyl.

The term cycloalkylalkyl encompasses cycloalkyl substituted alkyl radicals. Preferred cycloalkylalkyl radicals are lower cycloalkylalkyl radicals having radicals

189

cycloalkyl linked to alkyl radicals having one to six carbon atoms. Even more preferred are 5- to 6-membered cycloalkylalkyl linked to alkyl moieties having one to three carbon atoms. Examples of such radicals include cyclohexylmethyl. The cycloalkyl in the radicals can be further substituted with halo, alkyl, alkoxy and hydroxy.

The term cycloalkenyl includes carbocyclic groups having one or more carbon-carbon double bonds that include cycloalkylodienyl compounds. Preferred cycloalkenyl groups include C3-C6 rings. The most preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cycloheptadienyl.

The term it includes is intended to be open, including the indicated component but not excluding other elements.

A group or atom that replaces a hydrogen atom is also called a substituent.

Any particular molecule or group can have one or more substituents that depend on the number of hydrogen atoms that can be replaced.

The symbol - represents a covalent bond and also

190

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

can be used in one radical group to indicate the point of attachment to another group. Ep chemical structures, the symbol is commonly used to represent a methyl group in a molecule.

The term "therapeutically effective amount" means an amount of a compound that alleviates, attenuates, or eliminates one or more symptoms of a particular disease or condition, or prevents or delays the onset of one or more symptoms of a particular disease or condition.

The terms patient and subject can be used interchangeably and mean animals, such as dogs, cats, cows, horses, sheep, and humans. The particular patients are mammals. The term patient includes both male and female subjects.

The term "pharmaceutically acceptable" means that the referenced substance, such as a compound of Formula I, or a salt of a compound of Formula I, or a formulation containing a compound of Formula I, or a particular excipient, is suitable for administration to a patient.

Terms treating, treating or treating and the like include preventive (eg, prophylactic) and palliative treatment.

The term excipient means any additive,

191

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY carrier, diluent, adjuvant, or other pharmaceutically acceptable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and / or administration to a patient.

The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. Furthermore, the compounds or compositions can be administered all at once, such as by bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, such as, for example, using transdermal supply. It is also noted that the dose of the compound can be varied over time.

Furthermore, the compounds of the present invention can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds. The other pharmaceutically active compounds may be intended to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is receiving or is receiving multiple pharmaceutically active compounds, the compounds may

192

OF THE PROPERTY Ltto- *

INDUSTRIAL administered simultaneously, or sequentially. For example, in the case of tablets, the active compounds may be in one tablet or in separate tablets, which may be administered once or sequentially in any order. · In addition, it must be recognized that the compositions can be different shapes. For example, one or more compounds can be supplied by means of a tablet, while another is administered by injection or orally as a syrup. All combinations, delivery methods and administration sequences are contemplated.

The term cancer means a physiological condition in mammals that is characterized by irregular cell growth. The general classes of cancers include carcinomas, lymphomas, sarcomas, and blastomas.

The compounds of the present invention can be used to treat cancer. Cancer treatment methods comprise administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be used to treat tumors. The . methods of treating a tumor include administering to a patient who needs it

193 a therapeutically effective amount of a compound of Formula I, IA, IB, IC, ID. or IE, or a pharmaceutically acceptable salt thereof.

The invention also relates to the use of a compound of the present invention in the manufacture of a medicament for the treatment of a condition such as cancer.

Cancers that can be treated with compounds of the present invention include, without limitation, carcinomas such as cancer of the bladder, breast, colon, rectum, kidney, liver, lung (small cell lung cancer, and non-cell lung cancer small), 'esophagus, gallbladder, ovaries, pancreas, stomach, cervical, thyroid, prostate, and skin (including squamous cell carcinoma); Hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and Burkett lymphoma) ; hematopoietic tumors of. myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, eg, soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma,

194

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY schwanomas); and other seminoma, neuroblastoma, glioma, and teratocarcinoma tumors (including melanoma, osteosarcoma, xenoderoma pigmentosum, ceratoctantoma, follicular thyroid cancer, and Kaposi's sarcoma). Other cancers that can be treated with a compound of the present invention include endometrial cancer, head and neck cancer, glioblastoma, malignant ascites, and hematopoietic cancers.

Particular cancers that can be treated by the compounds of the present invention include soft tissue sarcomas, bone cancers such as osteosarcoma, breast tumors, bladder cancer, Li-Fraumeni syndrome, brain tumors, rhabdomyosarcoma, adrenocortical carcinoma, colorectal cancer , non-small cell lung cancer, and acute mylogenous leukemia (AML).

In a particular embodiment of the invention that relates to the treatment of cancers, the cancer is identified as p53-type (p53Wt). In another particular modality, the cancer is identified as p53Wt and CDKN2A mutant. In another aspect, the present invention provides a diagnosis to determine which patients should be administered a compound of the present invention. For example, a sample of the patient's cancer cells can be taken and analyzed to determine the status of the cancer cells with respect to p53 and / or CDKN2A.

In one respect,

195

you have cancer that is p53Wt it will be selected for treatment in patients who have cancer that is mutated with respect to p53. In another aspect, a patient who has cancer that is both p53Wt since it has a mutant CDNK2A protein, it is selected on a patient that does not have these characteristics. The collection of cancer cells for analysis is well known to those skilled in the art. The term p53Wt means a protein encoded by genomic DNA sequence no. NC 000017 version 9 (7512445..7531642) (GenBank); a protein encoded by the cDNA sequence no. NM_000546 (GenBank); or a protein that has the GenBank sequence no. NP 000037.3. The term CDNK2A mutant means a CDNK2A protein that is not wild type. The term wild-type CDKN2A means a protein encoded by genomic DNA sequence no. 9: 21957751-21984490 (Enseml ID); a protein encoded by cDNA sequence no. NM_000077 (GenBank) or NM_058195 9 GenBank); or a protein that has the GenBank sequence no. NP_000068 or NP_478102.

The compounds of the present invention can also be used to treat hyperproliferative disorders such as thyroid hyperplasia (especially Grave's disease), and cysts (such as ovarian stromal hypervascularity,

196 characterized by

Stein-Leventhal)).

The compounds of the present invention can also be used to treat the following diseases or conditions:

asthma, chronic obstructive pulmonary disease (COPD), emphysema, psoriasis, contact dermatitis, conjunctivitis, allergic rhinitis, systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, multiple sclerosis, rheumatoid arthritis, disease inflammatory bowel, Alzheimer's disease, atherosclerosis and Huntington's disease.

The compounds of the present invention can also be used to treat inflammatory diseases, hypoxia, ulcers, viral infections, bacterial infections, and bacterial sepsis.

The compounds of the. Formula I, IA, IB, IC, ID or IE, or the pharmaceutically acceptable salts thereof, can also be administered in combination with one or more additional pharmaceutically active compounds / agents. In a particular embodiment, the additional pharmaceutically active agent is an agent that can be used to treat cancer. For example, an additional pharmaceutically active agent may be selected from antineoplastic agents, antiangiogenic agents, chemotherapeutic agents, and peptide agents .4 i

197

for cancer therapy. In yet another embodiment, the selected antineoplastic agents are antibiotic type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon type agents, kinase inhibitors, combination agents thereof.

compounds / agents pharmaceutically being organic chemical molecules

Be small miscellaneous active and note that additional ones may be traditional or may be macromolecules such as proteins, antibodies, peptidobodies, DNA, RNA or fragments of such macromolecules

Examples of specific pharmaceutically active agents that can be used in which the present fluorouracil can be used in combination;

cisplatin;

Treatment of cancers and with one or more compounds of the invention include: methotrexate; tamoxifen;

5-fluorouracil; hydroxyurea; mercaptopurine;

carboplatin;

daunorubicin; doxorubicin;

etoposide; vinblastine; vincristine; pacitaxel; thioguanine;

idarubicin;

dactinomycin;

imatinib;

gemcitabine;

altretamine;

asparaginase;

bleomycin;

Capecitabine;

carmustine;

solution of

NaCl ac. cladysat .;

cyclophosphamine;

irinotecan;

fludarabine;

mythosmycin; mitoxane; mitoxantrone;

topotecan;

vinorelbine;

adriamycin; mitram; imiquimod;

alemtuzmab;

exemestane; bevacizumab; cetuximab; azacitidine;

cytarabine;

decarazine;

docetaxel; idarubicin; ifosfamide;

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

198 clofarabine; decitabine; desatinib;

dexrazoxane; docetaxel;

btiiii my go ίιιι1, ii i, 1: 111.¾¾ epirubicin; oxaliplatin; erlotinib; raloxifene; fulvestrant;

letrozole; gefitinib; . gemtuzumab; trastuzumab; gefitinib; ixabepilone; lapatin.ib; lenalidomide; aminolevulinic acid; temozolomide; nelarabine; sorafenib; nilotinib; pegaspargasa; pemetrexed; rituximab; dasatinib; thalidomide; bexarotene; temsirolimus; bortezomib; vorinostat; Capecitabine; Zoledronic acid; anastrozole; sunitinib; aprepitant and nelarabine, or a pharmaceutically acceptable salt thereof.

Additional pharmaceutically active agents that can be used in the treatment of cancers and that can be used in combination with one or more compounds of the present invention include: vascular endothelial growth factor (VEGF) inhibitors, hepatocyte growth factor / dispersion factor (HGF / SF) inhibitors, angiopoietin 1 and / or 2 inhibitors, necrosis factor-related apoptosis-inducing agonists Tumor (TRAIL), Recombinant Human Apo2 Ligand (TRAIL), Insulin-like Growth Factor 1 Receptor (IGFR-1) Inhibitors, cFMS Inhibitors, HER 2 Inhibitors, C-Met Inhibitors, Aurora Kinase Inhibitors, CDK 4 and / or 6 inhibitors, and B-raf inhibitor.

Additional pharmaceutically active agents that can also be used in the treatment of cancers and that can

199

used in combination with one or more compounds of the present invention include antibody drug conjugates (ADCs) therefore an antibody that binds to a protein, preferably in a cancer cell, is conjugated using a ligation with a chemical compound that is deleterious for the cancer cell. Examples of chemical compounds that are harmful to a cancer cell include maytansinoid derivatives and auristatin derivatives.

Still further, additional pharmaceutically active agents that can be used in the treatment of cancers and that can be used in combination with one or more compounds of the present invention include: epoetin alfa; darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim;

<td>denosumab;</td><td colspan="2">ancestim;</td><td>AMG</td><td> 102;</td><td>AMG 319;</td><td>AMG</td><td>38 6; AMG</td><td> 479</td>

<td>(Ganitumab)</td><td>; AMG</td><td> 511,</td><td>AMG</td><td> 900,</td><td>AMG 655</td><td colspan="2">(Conatumumab);</td><td>AMG</td>

<td>745; AMG</td><td> 951;</td><td>and</td><td>AMG</td><td> 706</td><td>(Motesan</td><td>ib),</td><td>or one</td><td>Salt</td>

<td colspan="2">pharmaceutically</td><td colspan="2">acceptable</td><td colspan="2">thereof.</td><td></td><td></td><td></td>

In another aspect, the present invention relates to the use of the compounds of the present invention in combination with one or more pharmaceutical agent that is an inhibitor of a protein in the phosphatidylinositol 3-kinase (PI3K) pathway. Combinations of the compounds of the present invention together with protein inhibitors in the PI3K pathway have shown synergy in assays of

IMPI

200

<td>increase</td><td>of</td><td>cell of</td><td colspan="3">cancer, including apoptosis</td>

<td>empowered</td><td>and</td><td>extermination</td><td>mobile.</td><td>The examples</td><td>of</td>

<td>proteins in</td><td>the</td><td>trajectory</td><td>PI3K include</td><td>PI3K, mTOR and</td><td>PKB</td>

(also known as Akt). The PI3K protein exists in several isoforms including a, β, δ, or γ. It is contemplated that a PI3K inhibitor that can be used in combination with a compound of the present invention can be selective for one or more isoforms. By selective means that the compounds inhibit one or more isoforms more than other isoforms. Selectivity is a concept well known to those in the art and can be measured with well known in vitro activity or cell based assays. The preferred selectivity includes greater than 2 times, preferably 10 times, or more preferably 100 times greater than the selectivity for one or more isoforms over the other isoforms.

In one aspect, the PI3K inhibitors that can be used in combination with prese compounds is a selective PI3K a inhibitor.

In another aspect the compound is a selective PI3K inhibitor

δ.

Examples of PI3K inhibitors that can be used in combination with one or more compounds of the present invention include those described in the following: PCT published application no. W02010 / 151791; PCT published application no.

<td>WO2010 / 151737;</td><td>PCT published application no. W02010 / 151735;</td>

201

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY published application PCT no. W02010151740; published request

PCT no. WO2008 / 118455; PCT published application no.

WO2008 / 118454; PCT published application no. WO2008 / 118468;

published application, from USA no. US20100331293; US published application no. US20100331306; published request for

USA does not. US20090023761; US published application no.

<td>US20090030002;</td><td>request</td><td>published</td><td>from USA</td><td>not.</td>

<td>US20090137581;</td><td>request</td><td>published</td><td>from USA</td><td>not.</td>

<td>US2009 / 0054405;</td><td>request</td><td>posted from</td><td>USA does not.</td><td>US</td>

<td> 2009/0163489;</td><td>request</td><td>posted from</td><td>USA does not.</td><td>US</td>

<td> 2010/0273764;</td><td>Request</td><td>posted from</td><td>USA does not.</td><td>US</td>

2011/0092504; or PCT published application no. W02010 / 108074.

Preferred PI3K inhibitors for use in combination with compounds of the present invention include:

or a pharmaceutically acceptable salt thereof.

Also preferred is a compound of Formula Ha below, or a pharmaceutically acceptable salt thereof,

where X1 it is fluorine or hydrogen; AND1 it is hydrogen or methyl; and Z1 it is hydrogen or methyl.

Compounds that inhibit both PI3K and mTOR (double inhibitors) are known.

In yet another respect, the.

IMPI

203 The present invention provides the use of dual PI3K and mTOR inhibitors for use in combination with a compound of the present invention.

mTOR is a protein in the PI3K path. It is another aspect of the present invention to use an mTOR inhibitor in combination with one or more compounds of the present invention. MTOR inhibitors that can be used in combination with the compounds of the present invention include those described in the following documents: PCT published application no. WO2010 / 132598 or PCT published application no. W02010 / 096314.

PKB (Akt) is also a protein in the PI3K pathway. It is another aspect of the present invention to use an mTOR inhibitor in combination with one or more compounds of the present invention. PKB inhibitors that can be used in combination with the compounds of the present invention include those described in the following documents: US Patent no. 7,354,944; US patent no. 7,700,636; US patent no. 7,919,514; US patent

not. 7,514,566; US patent application publication no.

US 2009/0270445 Al; US patent no. 7,919,504; US patent no. 7,897,619; · or PCT published application ño. WO

2010/083246 Al.

The compounds of the present invention can be used in

204 · Combination with CDK4 and / or 6 inhibitors.

MEXIOAN INSTITUTE OF INDUSTRIAL PROPERTY

CDK and / or 6 inhibitors that can be used in combination with the compounds of the present invention include those- described in the following documents: PCT published application no. WO

2009/085185 or US Patent Application Publication

not. US2011 / 0097305.

The compounds of the present invention can also be used in combination with pharmaceutically active agents that treat nausea. Examples of agents that can be used to treat nausea include: 'dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or a pharmaceutically acceptable salt thereof.

Furthermore, the compounds of the present invention can be used in combination with other agents that can be used to treat cancer such as acemannan; aclarubicin; aldesleukin; alitretinoin; amifostine; amrubicin; amsacrine; anagrelide; arglabin; arsenic trioxide; BAM 002 (Novels); bi.calutamide; broxuridine; celmoleucine; cetrorelix; cladribine; clotrimazole; DA 3030 (Dong-Aj; daclizumab; denileucine diftitox; deslorelin; dilazep; docosanol; doxercalciferol; doxifluridine; bromocriptine; cytarabine; HIT diclofenac; alpha interferon; tretinoin; edelfosine; edrecolomab; eflornithine; emitefur; epirubicin; epoetin beta; etoposide phosphate; exisulind;

205 foteiriustina;

MHZiCAiL Z INSTITUTE ·

D; LAFRC-? ·?:;. ·. *} 'Fadrozol; finasteride; fludarabine phosphate; formmestan;

gallium nitrate; gemtuzumab zogamycin;

gimeracil / oteracil / tegafur combination;

glycopine;

goserelin;

heptaplatin; human chorionic gonadotropin;

human fetal alpha fetoprotein; Ibandronic acid;

alpha interferon; natural interferon alpha; interferon alfa2; interferon alfa-2a; interferon alfa-2b; interferon alfaNi; interferon alfa-n3; interferon alfacon-1;

natural interferon alpha; interferon beta; interferon beta-la;

interferon beta-lb; natural interferon gamma;

interferon gamma-la;

interferon gamma-lb; beta interleukin;

yobenguano;

irsogladin; lanreotide; LC 9018 (Yakult);

leflunomide; lenograstim; lentinan sulfate;

letrozole;

leukocyte alpha interferon; leuprorelin; levamisole + fluorouracil;

liarozole;

lobaplatin;

lonidamine;

lovastatin;

masoprocol;

melarsoprol;

metoclopramide;

mifepristone;

miltefosine;

mirimostim; Misaligned double-stranded RNA;

mitoguazone;

mitolactol;

mitoxantrone;

molgramostim;

nafarelin;

naloxone pentazocine;

nartograstim;

nedaplatin; nilutamide; noscapine; novel erythropoiesis stimulating protein;

NSC

631570 octreotide;

oprelvecina; osaterone; paclitaxel;

pamidronic acid;

peginterferon alfa-2b; pentosan sodium polysulfate; pentostatin; picibanil; pyrarubicin; antibody

206

polyclonal antithomyocyte

M'a! CA..O INSTITUTE

OF THE PR.O ?. .-r-.D industrial rabbit; polyethylene

glycol interferon alpha-2a;

porfimer sodium; raltitrexed;

rasburicase; rhenium etidronate Re 186; retinamide RII;

<td>romurtida;</td><td>samarium (153 Sm) lexidronam; sargramostim;</td>

<td>sizofirán;</td><td>sobuzoxane; sonermin; strontium chloride 89;</td>

<td>suramine;</td><td>tasonermin; tazarotene; tegafur; temoporfin;</td>

teniposide; tetrachlorodecaoxide; timalfasin; alpha thyrotropin; toremifen; tositumomab-iodide 131; treosulfan;

tretinoin; trilostane trimetrexate; triptorelin; natural tumor necrosis factor alpha; ubenimex bladder cancer vaccine; Maruyama vaccine;

melanoma lysate vaccine; valrubicin; verteporfin; virulizin zinostatin estimalmer; abarelix; AE 941 (Aeterna); ambamustine;

antisense oligonucleotide; bcl-2 (Genta); APC 8015 (Dendreon); dexaminoglutethimide; diaziguone; EL 532 (Elan); EM 800 (Endorecherche); eniluracil; ethanidazole; fenretinide; filgrastim SD01 (Amgen); galocitabine; gastrin '17 immunogen; HLA-B7 gene therapy (Vical); granulocyte macrophage colony stimulating factor; histamine dichloride; ibritumomab tiuxetan; ilomastat; IM 862 (Cytran); interleukin 2; iproxifene; LDI 200 (Milkhaus); leridistim; lintuzumab; CA 125 monoclonal antibody (MAb) (Biomira); Cancer MAb (Japan Pharmaceutical Development); HER-2 and Fe MAb (Medarex); 105AD7 MAb

207

idiotypical (CRC Technology); Idiotypical CEA MAb

LYM-l-iodide

131

MAb (Techniclone); polymorphic epithelial mucin-yttrium

MAb (Antisome); marimastat; menogaril;

mitumomab;

motexafin gadolinium; MX 6 (Galderma), · nolatrexed;

protein • 30; pegvisomant;

porphyromycin;

prinomastat;

RL

0903 satraplatin;

sodium phenylacetate;

sparphosic acid;

SRL 172 (SR

Pharma). ;

ITS

5416

TA 077 (Tanabe);

tetrathiomolybdate; t.aliblastin; thrombopoietin; tin ethyl etiopurpurin; tirapazamina; cancer vaccine (Biomira); melanoma vaccine (New York University); Melanoma Vaccine (Sloan Kettering Institute); Oncolysate Melanoma Vaccine (New York Medical College); Cellular Used Vaccine for Viral Melanoma (Royal Newcastle Hospital); or waltzpodar. It is noted that the agents recited above can also be administered as pharmaceutically acceptable salts when appropriate.

The compounds of the present invention can also be used in combination, with radiation therapy, hormonal therapy, surgery and immunotherapy, the therapies of which are well known to those skilled in the art.

Since one aspect of the present invention contemplates treating the disease / conditions with a combination of pharmaceutically active compounds that can

208

administered separately, the invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit comprises. two separate pharmaceutical compositions: the compound of the present invention, and a second pharmaceutical compound. The kit comprises a container containing the separate compositions such as a divided bottle or a divided foil package.

Additional examples of containers include syringes, boxes, and bags. Typically, the kit comprises instructions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (eg oral and parenteral), administered at different dosage intervals, or when the titration of the individual components of the combination is desired by the prescribing doctor or veterinarian.

An example of such a kit is the so-called blister packaging (bubbles). Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, 'and the like). Blister packs generally consist of a sheet of a relatively rigid material covered with aluminum foil of a

209 'preferably transparent plastic material. During the packaging process, gaps form in the plastic foil. The voids are the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the voids and the sheet of relatively stiff material is sealed against the plastic foil on the side of the foil that is opposite the direction in which the voids were formed.

As a result, the tablets or capsules are sealed in the gaps between the plastic foil and the foil. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure to the gaps thereby forming an opening in the sheet at the gap site. The tablet or capsule can then be removed through the opening.

It may be desirable to provide a memory aid in the kit, for example, in the form of consecutive numbers to the tablets or capsules therefore the numbers correspond to the days of the regimen at which the tablets or capsules should be specifically ingested. Another example of such a memory aid is a calendar printed on the card, for example, as follows First Week, Monday, Tuesday, ... etc ... Second Week, Monday, Tuesday, ... etc. Other variations of i

Ί memory aids will be easily apparent. A daily dose can be a single tablet or capsule or several pills or capsules a. be taken on any given day. Also the daily dose of the compound of the present invention can

210

MEXICAN INSTITUTE

PROPERTY V v —D JlíDc INDUSTRIAL Xa M 'consist of one tablet or capsule, while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory helper will reflect this and assist in the correct administration of the active agents

In another specific embodiment of the invention, there is provided a dispenser designed to dispense daily doses one at a time in the order of the intended use. Preferably, the dispenser is equipped with a memory aid, so that it further facilitates compliance with the regimen. An example of such a memory aid is a counter mechanism that indicates the number of daily doses that have been dispensed. Another example of such a memory aid is a battery micro-chip memory paired with a liquid crystal reader, or an audible reminder signal that, for example, reads the date the last daily dose was taken and / or reminds you when to take the next dose.

The compounds of the present invention and other pharmaceutically active compounds, if desired, can

211

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

administered to a patient either orally, rectally, parenterally,

I use intravenously (for

intraperitoneally, intracisternally, intravaginally, intravesicularly, locally (eg, powders, ointments, or drops), or as a mouth or nasal spray. All methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.

Appropriate compositions for parenteral injection may comprise sterile aqueous or nonaqueous solutions, dispersions, suspensions, or physiologically acceptable emulsions, and sterile powders for reconstitution in sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), appropriate mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants.

212 impW such as emulsifiers, preservatives, humectants ^ „. ^CT¡«» And dispersants. Contamination by microorganisms can be prevented by adding various antibacterial and antifungal agents, · for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents that retard absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert regular carrier (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or diluents, such as starches, lactose, sucrose , mannitol, and silicic acid;

(b) binders, such as, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, such as

-A213

MEXIC INSTITUTE / .I

OS LA PROF'i'A INDUStíu.

paraffin;

(f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate;

(h) adsorbents,. such as kaolin and bentonite;

(i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, and tablets, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coated and others well known in the art. They can also contain opacifying agents, and can also be of such composition that they release the active compound (s) in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The

214 active compounds may also be

in microencapsulated form, if appropriate, with one or more of the above mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents as per. example ethyl alcohol alcohol

isopropyl, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germ oil , olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and sorbitan fatty acid esters, or mixtures of these substances, and the like.

In addition to inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavors, and perfume agents. Suspensions, in addition to the active compound, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols,

215

polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, or mixtures of these substances, the like.

Compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with appropriate non-irritating carrier excipients such as cocoa butter, polyethylene glycol, or a suppository wax, which are solid at ordinary room temperature, but liquids at body temperature, and therefore melt in the rectum or vaginal cavity and release the active compound.

Dosage forms for topical administration of the compound of the present invention include ointments, powders, sprays, and inhalants. The active compound or suitable compounds are mixed in a sterile condition with a physiologically acceptable carrier, and any of preservatives, buffer solutions, or propellants that

The compounds. of the present invention can be administered to a patient at dosage levels where required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of the invention.

216

range from about 0.1 to about 3,000 mg ppr ... day. For a normal adult who has a body weight of about 7 0 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight is typically sufficient. The specific dosage and dosage range that can be used depends on a number of factors, including the patient's requirements, the severity of the condition or disease to be treated, and the pharmacological activity of the compound to be administered. Determination of optimal dosage ranges and ranges for a particular patient is within ordinary skill in the art.

The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides, or prodrugs. The term salts refers to inorganic and organic salts of the compounds of the present invention. Salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts include bromohydrate, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate salts,

217

stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate, and the like. Salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium. , tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See for

<td colspan="2">example,</td><td>SM Berge,</td><td>et al.,</td><td colspan="2">Pharmaceutical Salts, J Pharm</td>

<td></td><td>The</td><td>examples of</td><td>esters</td><td>pharmaceutically acceptable</td><td>of</td>

<td>the</td><td colspan="2">compounds of the</td><td>Present</td><td>invention include esters</td><td>of</td>

Ci-C alkyl8. Acceptable esters also include C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl. C1-C4 alkyl esters are commonly used. The esters of compounds of the present invention can be prepared according to methods that are well known in the art.

Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary Ci-Cg alkyl amines, and Ci-C dialkyl amines.8 high schools. In the case of amines

218

Secondary, the amine may also be in the form of a 5 o heterocycloalkyl group. 6-member containing at least one nitrogen atom. Amides derived from ammonia, C1-C3 primary alkyl amines and C1-C2 dialkyl secondary amines are commonly used. The amides of the compounds of the present invention can be prepared according to methods well known to those skilled in the art.

The term prodrug means compounds that are transformed in vivo to provide the compound of the present invention. Transformation can occur by various mechanisms, such as through hydrolysis in the blood. A discussion of the. use of prodrugs is provided by T. Higuchi and W. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

To illustrate, if the compound of the invention contains a carboxylic acid functional group, a prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a- group such as alkyl (Ci ~

Cg, (C2-CI2) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having from 4 to carbon atoms, 1-methyl-l (alkanoyloxy) ethyl

219 carbon,

INSTITUTE M DE LA Pl'.G

-INP'JSi RIAL atoms to carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-l (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl ) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, Nalkylamino (Ci-C2) alkyl (C2-C3) (such as βdimethylaminoethyl), carbamoyl (C1-C2) -alkyl, N, Ndialkylcarbamoyl (C1-C2) -alkyl (C1-C2) and piperidino-, pyrrolidino- or morpholino (C2-3) alkyl

Similarly, if the compound of the present invention comprises an alcohol functional group, the prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as alkanoyloxymethyl (Cx-Cg), 1 (alkanoyloxy (C1-C6)) ethyl , 1-methyl-l- (alkanoyloxy (όχΟβ)) ethyl, alkoxycarbonyloxymethyl (Ci-Cg), Nalkoxycarbonylaminomethyl (C1-C6), succinoyl, alkanoyl (Οχ-Οβ), oi-aminoalkanoyl (C1-C4), arylacyl and α -aminoacyl, or aaminoacyl-a-aminoacyl, where each α-aminoacyl group is independently selected from naturally occurring amino acids L, -P (O) (OH) 2Z -P (0) (Oalkyl (Οχ-Οβ)) 2 or

220

glycosyl (the radical that results from the removal of the hydroxyl group from the hemiacetal form of a carbohydrate).

The compounds of the present invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, are contemplated to form part of the present invention. Furthermore, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both the cis and trans forms (designated S and E, respectively), as well as mixtures, are contemplated.

Stereoisomer mixtures, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical-chemical differences by known methods such as chromatography and / or fractional crystallization. The enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an optically appropriate compound (eg, an alcohol), separating the diastereomers, and converting (eg hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some compounds may be atropisomers (eg, substituted biaryls).

221

The compounds of the present

INSTITUTO .MEXICANO

OF THE PRO? ISTY C k ~ - ~ A7 £ jW

INDUSTRIAL invention may exist in non-solvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like. The present invention contemplates and encompasses both solvated and unsolvated forms.

It is also possible that the compounds of the present invention may exist in different tautomeric forms.

All tautomers of the compounds of the present invention are contemplated. For example, all tautomeric forms of the tetrazole portion are included in this invention. Also, for example, all keto-enol or imine-enamine forms of the compounds are included in this invention.

Those skilled in the art will recognize that the names of the compounds and structures contained herein can be based on a particular tautomer of a compound. Although the name or structure may be used only for a particular tautomer, all tautomers are intended to be encompassed by the present invention, unless stated otherwise.

The present invention is also intended to encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques,

222 such as through metabolism

IMPI

MEXICAN INSTITUTE K-úrr3 ¡. . , DE LA F ^ QFIECAO, <r '<

fermentation, wuge.ati

Similar. It is also contemplated that the —rr) inpnp..R'nr of the present invention can be synthesized using a combination of in vitro and in vivo techniques.

The present invention also includes isotopically labeled compounds, which are identical to those

<td>recited</td><td>in the present but</td><td>the</td><td>done</td><td>of which one</td><td>or more</td>

<td>atoms are</td><td>replace with an atom</td><td>than</td><td>has</td><td colspan="2">an atomic mass</td>

<td>or mass</td><td>weighted different from</td><td>the</td><td>mass</td><td>atomic or</td><td>mass</td>

<td>weighted</td><td>usually found</td><td>in</td><td>the</td><td>nature.</td><td>The</td>

Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H 3H

<td>appearance,</td><td>the</td><td>Present</td><td>invention</td><td>I know</td><td colspan="2">refers to compounds</td><td>in</td>

<td>where one</td><td>or</td><td>more atoms</td><td colspan="2">hydrogens</td><td>are replaced with</td><td colspan="2">atoms</td>

deuterium (2H).

Compounds of the present invention that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those in which radioactive isotopes such as3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays.

IMPI

223 .

Tritiated isotopes, i.e. 3H 14C, are particularly · preferred for their ease '^' of1Preparation and detection. Also, substitution with heavier isotopes such as deuterium, i.e.2H, may provide certain therapeutic advantages resulting from increased metabolic stability, eg, increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. The isotopically labeled compounds of this invention can generally be prepared by replacing an already available isotopically labeled reagent with a non-isotopically labeled reagent.

The compounds of the present invention can exist in various solid states including crystalline states and as an amorphous state. The different crystalline states, also called polymorphs, and the amorphous states of the current compounds are contemplated as part of this invention.

In synthesizing the compounds of the present invention, it may be desirable to use certain starting groups. The term starting groups (LG) generally refers to. groups that move through a nucleophile. Such starting groups are known in the art. Examples of starting groups include, but are not limited to, halides (eg, I, Br,

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

224

F, Cl), sulfonates (eg mesylate

sulfides (eg, SCH3), N-hydroxysuccinimide, N-hydroxybenzotriazole, and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (eg, alkoxides, amides, carbanions), and the like.

All patents, published patent applications and other publications recited herein are hereby incorporated by reference.

The examples presented below illustrate specific embodiments of the present invention. These examples are intended to be representative and are not intended to limit the scope of the claims in any way. Unless noted otherwise, when a percentage is used herein relative to a solid, the percentage is by weight relative to the reference solid composition. When a percentage is used herein with respect to a liquid, the percentage is by volume with respect to the reference solution.

The specters 1H-NMR were typically acquired on a Bruker Advance III 500 spectrometer system (Bruker, Bilerica, MA) operating at a frequency 1500.13 MHz H, equipped with a Bruker 5 mm PABBI probe with a z axis gradient; or on a Bruker Avance II 400 spectrometer that operates at

BE *

225 a frequency X400.23 MHz H,

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY equipped with a probe

Bruker 5 mm PABBO with a gradient typically dissolved in 500 pL of either DMSO-d6 or CD3OD for analysis

NMR. Chemical changes1H also refer to DMSO-d residual solvent signals6 a δ

2.50 and CD3OD at δ

3.30.

Major peaks are tabulated and typically include:

proton number, multiplicity (s, singlet; d, doublet;

dd, double of doublets; t, triplet; q, quartet; m, multiplet; br s, broad singlet) and coupling constants in Hertz.

Electron ionization mass spectra (El) were typically recorded on an Agilent Technologies 6140 Quadrupole CL / MS mass spectrometer. Mass spectrometry results are reported as the ratio of mass to charge, sometimes followed by the relative abundance of each ion (in parentheses). The starting materials in the Examples below typically are either

<td>available</td><td colspan="2">from sources</td><td>commercial</td><td colspan="2">such as Sigma-</td>

<td>Aldrich, St.</td><td>Louis,</td><td>MO, 0</td><td>through</td><td>Procedure of</td><td>the</td>

<td>literature.</td><td></td><td></td><td></td><td></td><td></td>

<td>They can</td><td>wear</td><td>the</td><td>following</td><td>abbreviations in</td><td>the</td>

Present:

226

About

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td>+ go or pos. ion</td><td>. positive ion</td>

<td>Ac</td><td>Acetyl</td>

<td>Ac20</td><td>Acetic anhydride</td>

<td>Ac</td><td>Aqueous</td>

<td>AcOH</td><td>Acetic acid</td>

<td>Bn</td><td>Benzyl</td>

<td>Boc</td><td>tert-butyloxycarbonyl</td>

<td>BSA</td><td>Bovine serum albumin</td>

<td>Bu</td><td>Butyl</td>

<td>Bz</td><td>Benzoyl</td>

<td>Caled or Calc'd</td><td>Calculated</td>

<td>Conc.</td><td>Concentrated</td>

<td>CSA</td><td>Camphor-10-sulfonic acid</td>

<td>DBU</td><td>1,8-diazabicyclo [5.4.0] undec-</td>

<td>DCE</td><td>dichloroethane</td>

<td>DCM</td><td>Dichloromethane</td>

<td>DEA</td><td>Diethylamine</td>

Persodynane Dess1,1,1-triacetoxy-l, 1-dihydro-l, 2Martin; benziodoxol-3- ^ reagent (IL · ') - ona

Dess-Martin

<td>DIEA-O DIPEA</td><td>227 IMPIfrT'ía MEXICAN INSTITUTE- V OF PROPERTY 1 or - * Industrial Diisopropylethylamine -></td>

<td>DMAP</td><td> 4-dimethylaminopyridine</td>

<td>DME</td><td>1,2-dimethoxyethane</td>

<td>DMF</td><td>N, N-dimethylformamide</td>

<td>DMSO</td><td>Dimethyl sulfoxide</td>

<td>dr</td><td>Diastereomeric relationship</td>

<td>DTT</td><td>dithiothreitol</td>

<td>DVB</td><td>Divinylbenzene</td>

<td>EDC</td><td>N-Ethyl-N '- (3- dimethylaminopropyl) carbodiimide</td>

<td>eq</td><td>Equivalent</td>

<td>ESI O ES</td><td>Electronium ionization</td>

<td>Et</td><td>Ethyl</td>

<td>Et2OR</td><td>Diethyl ether</td>

<td>Et3N</td><td>Triethylamine</td>

<td>EtOAc</td><td>Ethyl acetate</td>

<td>EtOH</td><td>Ethyl alcohol</td>

<td>h</td><td>hours)</td>

<td>HEY YOU</td><td>O- (7-) hexafluorophosphate azabenzotriazole-l-il) -Ν, Ν, Ν ', N'- 'tetramethyluronium</td>

<td>HBTU</td><td>O-benzotriazol-Ν, Ν, Ν ', N'-tetramethyl-</td>

<td></td><td>228 IMPI ^^ MEXICAN INSTITUTE V OF PROPERTY V '' '- industrial uronium-hexafluorophosphate</td>

<td>HMPA</td><td>hexamethylphosphoramide</td>

<td>HOAt</td><td>l-hydroxy-7-azabenzotriazole</td>

<td>HOBt</td><td>hydroxybenzotriazole</td>

<td>HPLC</td><td>High pressure liquid chromatography</td>

<td>IPA or iPrOH</td><td>Isopropyl alcohol Chromium (IV) oxide solution and</td>

<td>Jones reagent</td><td>sulfuric acid in water</td>

<td>KHMDS</td><td>Potassium hexamethyldisilazide</td>

<td>KOAc</td><td>Potassium acetate Liquid chromatography spectrometry</td>

<td>CLEM, CL-EM or CL / EM</td><td>of dough</td>

<td>LDA</td><td>Lithium diisopropylamide</td>

<td>LHMDS or LiHMDS</td><td>Lithium hexamethyldisilazide lithium tri-sec-butylborohydride</td>

<td>L-Selectride®</td><td>(Sigma-Aldrich, St. Louis)</td>

<td>M</td><td>Molar (mol L1)</td>

<td>m / z</td><td>mass divided by load</td>

<td>mCPBA</td><td>M-Chloroperoxybenzoic acid</td>

<td>I</td><td>Methyl</td>

<td>MeCN</td><td>Acetonitrile</td>

Mel

Iodomethane

<td></td><td>229 IMPIDO MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY</td>

<td>MeOH</td><td>Methyl alcohol</td>

<td>Mg</td><td>milligram (s)</td>

<td>min</td><td>minute (s)</td>

<td>mL</td><td>milliliter (s)</td>

<td>EM</td><td>Mass spectrometry</td>

<td>MsCl</td><td>Methanesulfonyl chloride</td>

<td>MTBE or MtBE</td><td>Methyl tert-butyl ether</td>

<td>m / z</td><td>Mass to load ratio</td>

<td>NaHMDS</td><td>Sodium hexamethyldisilazide</td>

<td>NaOtBu</td><td>sodium tert-butoxide</td>

<td>NBS</td><td>N-bromosuccinimide</td>

<td>nBuLi</td><td>n-butyl lithium</td>

<td>NMO</td><td>N-methylmorpholin-N-oxide</td>

<td>NMP</td><td>l-methyl-2-pyrrolidinone</td>

<td>NMR</td><td>Nuclear magnetic resonance sodium tri-sec-butylborohydride</td>

<td>N-Selectride®</td><td>(Sigma-Aldrich, St. Louis) Saline buffer solution</td>

<td>PBS</td><td>phosphate</td>

<td>PMB</td><td>Paramethoxybenzyl</td>

<td>Pr</td><td>Propyl</td>

<td>ppm</td><td>parts per million</td>

IMPI

rae

RP-HPLC or RPHPLC

230 racemic

Reverse phase high pressure liquid chromatography

<td>TA or ta</td><td>Room temperature</td>

sat. or sat'd or satd Saturated

<td>CFS</td><td>Supercritical Fluid Chromatography</td>

<td>TBAF</td><td>Tetrabutylammonium fluoride</td>

<td>TBDMS</td><td>Tert-butyldimethylsilyl</td>

<td>TBDMS-C1</td><td>Tert-Butyldimethylsilyl chloride</td>

<td>TBDPS</td><td>tert-butyldiphenylsilyl (2,2,6,6-tetramethylpiperidin-l-</td>

<td>TEMPO</td><td>il) oxydyl</td>

<td>tert ot</td><td>tertiary</td>

<td>TFA</td><td>Trifluoroacetic acid</td>

<td>THF</td><td>Tetrahydrofuran</td>

<td>TIPS</td><td>triisopropylsilyl</td>

<td>TLC</td><td>Thin strip chromatography</td>

<td>TMS</td><td>trimethylsilyl or trimethylsilane</td>

<td>TPAP</td><td>Tetrapropylammonium perruthenate</td>

<td>tR</td><td>Holding time</td>

<td>tBuOH</td><td>Tert-butyl alcohol</td>

<td>v / v</td><td>Volume by volume</td>

EXAMPLES

231

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

General Synthetic Schemes

The compounds of the present invention can generally be prepared by starting with commercially available starting materials and using techniques known to those of skill in the art. Some appropriate reaction schemes for preparing compounds of the present invention are summarized below. Further exemplification is found in the specified examples provided.

Reaction scheme 1

NaHMDS;

OR

O t-BuOK

2. NaBH4

As shown in Reaction Scheme 1, the compounds of the present invention wherein Rto and Rb Both are

H, can be prepared by reacting an appropriately substituted aryl acetic acid 1 and an aryl acid

232 n

j carboxylic 2 in an organic solvent

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL k- ~ or solvent mixture (including aqueous mixtures) in the presence of a base, such as LHMDs or KHMDS to provide, after work, the compound of Formula 3. Treatment of 3 with methyl acrylate in the presence of a base, such as tBuOK results in the formation of a 4,5-substituted 5-oxopentanoate, which can be reduced with a reducing reagent such as NaBH4 or LiBEt3H in an appropriate solvent such as THF, diethyl ether or dimethoxyethane to produce racemic compound 4. 5 may again be obtained from 4 by converting the alcohol to a toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate, followed by reaction with sodium azide in a appropriate solvent such as, for example, DMF, DME or acetone. Azide can be reduced to a primary amine by a number of reducing agents including NaBH4, H2 and a catalyst, triphenylphosphine and trimethylphosphine, which again, during treatment with a base, such as LiOH, K2CO3 or

NaHCOa in an aqueous mixture with an organic solvent

appropriate, such as THE, will cycle piperidin-2-one 6

The individual racemic enantiomers can be separated by chiral HPLC using, for example, a Chiralcel® column.

OD-H 20 mm ID χ .250 mm (Daicel Chemical Industries LTD,

Fort Lee, NJ) using 40% ispropyl alcohol / hexane as the eluant.

Reaction scheme 2

233

reaction 2, the

As shown in the Scheme, piperidin-2-one 6 can be further modified, for example by arylating or renting nitrogen by methods well known to those of ordinary skill in the art. For example, by reacting 6 with an alkyl halide in the presence of a base such as sodium hydride in a solvent such as

DME, DMF, or THF will perform this transformation. 7 can be further alkylated by treatment with a base such as lithium diisopropylamide or lithium hexamethyldisilazide in an appropriate solvent such as THF, followed by reaction with an alkylating agent, such as an alkyl halide, alkyl methanesulfonate, or alkyl toluenesulfonate to give intermediate 8. If desired, the sequence may be repeated to give the compounds of general formula 9. LG is a starting group.

As shown in Reaction Scheme 3, the nitrogen bound group can potentially be removed to give intermediate 16. For example by treating a derivative of

234

2,4-dimethoxybenzyl with TFA is performed

Transformations are well documented

INb.ITUTO MEXICANO

OF THE I'ROFiEDAD

INDUSTRIAL

such a transformation.

example, PGM Wuts and TW Greene, Greene's protective groups in organic synthesis, 4to ed., John Wiley & Sons, New York, (2007)). Re-subjecting Compound 16 to alkylation conditions similar to those described above gives 17.

Reaction scheme 3

As further shown in the

Reaction scheme 3, if one of the alkyl groups contains a double bond, this

235

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

double bond can be converted to a carboxylic acid 11 by a number of methods known to those of ordinary skill in the art. For example, by reacting 10 with a periodate solution containing KMnO4 or RuC13 (See, eg, RU Lemieux, E. von Rudloff, Can. J. Chem., 38, 1703, (1955)) this transformation will be performed. The carboxylic acid 11 can, again, be converted to other groups such as an amide or hydrazide by methods well known to those of. ordinary skill in the technique. For example, carboxylic acid 11 can be condensation activated with a variety of coupling reagents, including hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (HOSu), for example, using dicyclohexylcarbodimide (DCC) or a similar carbodiimide reagent or a wide variety of reagents such as those developed for formation of peptide bonds. The conditions for such reactions are well known to those of ordinary skill in the art. The activated intermediate, an HOBt or HOSu ester, for example, can then be condensed with a wide variety of nucleophiles such as amines or alcohols.

Reaction Scheme 3 shows the conversion of the compound from. Formula 11 into an amide 12 by this sequence. Using ammonia as the nucleophile, the

236 compound 13.

IMPI ^

INSTITUTE S '.'-' XIO'.r-Ό V. '. 4- -.-; - = of the property V The dehydration of amide 13 to W ^ ñirtrilrr ^ can be performed by a variety of · uiéLudub. Phosphorous pentoxide is a common dehydrating reagent for this reaction, but many others are known to those of skill in the art (see, for example, R.

Larock;

Comprehensive Organic

Transformations, 2gives ed., John

Wiley &

Sons,

New York, pp.

1983, (1999)).

The nitrile can, again, be converted to other groups such as a tetrazole by reacting the nitrile with an azide, such as sodium azide, lithium azide OR such as DMF or water.

Scheme

such solvent

As it is shown in

Reaction scheme

they can also be used to produce heterocyclic derivatives,

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY such as, for example, [1,3,4] -oxadiazoles 18, [1,2,4] -

oxadiazol-5 (4H) -onas 19, and [1,2,4] -oxadiazoles 20 by methods

<td>well known</td><td colspan="2">for those</td><td>of ability</td><td>ordinary</td><td>in</td><td>the</td>

<td>technique. By</td><td>example,</td><td>to the</td><td>convert the</td><td>acid 11</td><td>in</td><td>a</td>

<td>diacylhydrazide,</td><td>Following</td><td>by</td><td>treatment</td><td>with a</td><td>base</td><td>to</td>

Elevated temperature will provide 18. In another example 11 it is converted to a nitrile as described in Reaction Scheme 3, which is treated with hydroxylamine. The reaction with

1,1'-carbonyldiimidazole in the presence of a base, such as DBU, generates 19. In yet another example, 11 reacts with an N-hydroxycarboxamidine derivative in the presence of 1,1'carbonyldiimidazole, followed by treatment with tetrabutylammonium fluoride to give 20.

As shown in Reaction Scheme 5, the compound of the Formula can also be dehydroxylated to yield 21. Osmium tetroxide in the presence of a second oxidizing agent such as

4-methylmorpholin-4-oxide in an appropriate solvent will perform such a transformation. 21 can be converted by reaction with acetone or

2,2dimethoxypropane in the presence of an acid, such as methanesulfonic acid, p-toluenesulfonic acid camphor sulfonic acid.

Compound 22 can then be N-arylated or

N-rented by a variety of methods well known to those of ordinary skill in the art, such as al

239 treat 22 with an alkylhalide,

MEXICAN INSTITUTE —μ5,5ι

FROM THE PROPERTY tWaO® INDUSTRIAL alkylmethanesulfonate or alkyl toluenesulfonate in the presence of a base such as butyllithium or sodium hydride in a solvent such as DME,

DMF or THF. When treating 23 with an acid such as

HC1 or H2SO4 in the presence of water will give diol 24, which can be cleaved to aldehyde 25 by a variety of oxidizing periodic acid or lead tetraacetate agents, such as (see, for example,

Haines, AH Methods for the Oxidation of Organic Compounds, Vol 2 .; p 277, Academic Press, NY, (1988)). Aldehyde 25 can be converted to acid 26 by strong oxidizing agents including CrC> 3 or a periodate solution containing RUCI3.

240

Reaction scheme 6 Ph'r% y

I ^ 'C! + R3

X = -C (O) -, SO2E1 Reaction Scheme 6 illustrates an alternative method for the preparation of intermediate compounds of general structure 35. This intermediate can be used to make additional compounds in this invention. Here, a (4S, 5S) -2-allyl-2-chloro-3,4-dimethyl-5-phenyl-l, 3,2oxazasilolidine of the general formula 28 is formed by the reaction of 27 (prepared as described in J. Am. Chem. Soc. 124, 7920, (2002) with an alkene in the presence of Grubb catalyst. The reaction with imine 29, which is prepared by the reaction of 2- (aminomethyl) phenol with an aldehyde using

conditions well known to those

241 Those skilled in the art will provide Compound 30 (See also J. Am.

Chem. Soc. 129, 14552, (2007)). Intermediate 30 can again be converted to compound 31 by reacting consecutively with acetic anhydride in the presence of a base such as triethylamine, toluenesulfonic acid, and oxalyl chloride in the presence of propylene glycol as described in Org. Letters, 11, 433, (2009), for example. Homoalyl amine 31 can optionally be further modified, for example by arylating or alkylating nitrogen by methods well known to those of ordinary skill in the art. For example, reaction of 31 with a ketone or aldehyde in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride in a solvent such as DME, DMF, or THF will effect this transformation. 32 can be added or sulfonylated under conditions well known to those of ordinary skill in the art to provide 33. 33 can be cyclized to 34 by a ring-closed metathesis reaction (RCM). Suitable catalysts for such transformations are known to those of skill in the art (see, for example, (a) Grubbs, RH Handbook of Metathesis; Wiley-VCH: Weinheim, (2003); (b) Angew. Chem., Int . Ed., 42, 1900, (2003)) e

242

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY including Grubbs catalysts of Ito generation and Grubbs of

2gives generation. Catalytic hydrogenation of 34 using, for example, a palladium, platinum or iridium catalyst in a solvent such as DCM, THF, methanol, or an aqueous mixture containing an alcohol or THF as a co-solvent, for example, is used to reduce double bond, those produced by compound 35.

243

IMPI

MEXICAN INSTITUTE DS INDUSTRIAL PROPERTY

Reaction scheme 7

The compounds of the present invention can also

244

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

prepare by using the lactone route illustrated in

Reaction scheme 7.

Aryl benzyl ketones 3, commercially available or prepared by condensation

Dieckmann or by coupling an aryl methyl ketone 41 with a bromoaryl compound 42, can be condensed with acrylate esters 43 including methacrylate, ethacrylate, etc., to form the keto ester 44. Stereoselective reduction occurs with sodium borohydride in methanol to form racemic 45 as a mixture of epimers in the R positionand. Alternatively, this reduction can be carried out by means of dynamic kinetic resolution (see, Chen, et. Al., Organic Process Research & Development, 2007, 11, 616-623 and references contained therein) to give enantioenriched 46, also as a mixture of epimers at the R position. In this process, the isopropyl esters are produced by transesterification. Hydrolysis for carboxylic acid 47 followed by 'lactonization provides racemic or enantioenriched lactone 48 as a mixture of diastereomers at the R position.and. Diastereomers as a mixture can be enolized with strong base such as LiHMDS or LDA to give a common enolate which is alkylated with allyl bromide to provide lactone 49 as a simple diastereomer. (see Example 261 Stage E). Condensation of racemic lactone 49 with enantiopure amino alcohols 50

245

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY results in diastereomeric hydroxylamides 51 that can be converted to oxazolines 52, oxazolinium salts 53 or hydroxylactams 54. The separation of diastereomers can generally occur in any of these intermediates by normal phase chromatography on silica. Alternatively, condensation of enantioenriched lactone 49 with enantioenriched amino alcohols 50 leads to the increased enantiopurity of the resulting 51,

52, 53 or 54. For example

94% ee lactone combined with 98% ee of amino alcohol results in the main diastereomer of '99.94% ee.

Hydroxylactam 54 (Rs= Et, cPr) has been prepared by alternative procedures (see Example 91 Step B; and Example 252 Step A) and used as an intermediate for many of the compounds of the present invention (equivalent to lactam 10 of Reaction Scheme 3). Using the lactone procedure, the additional examples (R5= iPr [Example 261, Step H], tBu, etc.) can be prepared. Additionally, amino alcohols containing two adjacent stereocenters (i.e., R6 no H) can be incorporated into this route. Oxazolinium salt 53 is also a versatile intermediate. It can intercept with various nucleophiles such as azide, thiols, or sulphinate salts to form lactams 56, leading to amines, amides, sulfonamides, and sulfones. The allyl group of oxazolinium salt

246 with minimal complications from the primary or secondary alcohol center that is paired in the oxazoline ring.

The resulting orthoamide 57 releases the lactam carboxylate under conditions of medium hydrolysis. In this way, lactone '49 [R3= pClPh, R4= mClPh,

Rand= Me] (2S, 3S) -3-aminopentan-2-ol [WO2007 / 110649A2]. The corresponding oxazoline 52 [R3= pClPh, R4= mClPh, Rand= I R5= Et,

R6= Me] by dehydration under Dean-Stark conditions in toluene with ammonium molybdate as a catalyst.

Treatment with .triphilic anhydride in dichloromethane with lutidine a

-50 ° C gave the oxazolinium salt [R3= pClPh,

R4= mClPh, Rand= I R5= Et,

R6= Me]. Oxidation with KMnO4 in dichloromethane / water is facilitated by tetrabutylammonium chloride given after work and hydrolysis with solution of sodium bicarbonate in isopropyl acetate at ° C, compound 58 [R3= pClPh,

R4= mClPh, Rand= I R5= Et, R6= Me] identical to the material prepared in Example 152.

247

EXAMPLE 1

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -l-tert-butoxy-l-oxobutan-2-yl) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -2 -oxopiperidin-3-yl) acetic

Stage A. 2- (3-Chlorophenyl) -1- (4-chlorophenyl) ethanone

To a solution of 2 -. (3-chlorophenyl) acetic acid (lOg,

58.6 mmol) in THF (58 ml) 117 mL of a 1M solution of sodium bis- (trimethylsilyl) amide in THF was added slowly over 1 h at -78 ° C. After stirring at -78 ° C for 40 min, a solution of methyl 4-chlorobenzoate (10g, 58.6mmol) in THF (35ml) was added over a period of 10 min. The reaction was stirred at -78 ° C for 3 hr, then allowed to warm to 25 ° C, and stirred for an additional 2 hr to completion. The reaction was quenched with saturated aqueous NH solution4C1 and most of the THF was removed under reduced pressure. The residue was extracted with ethyl acetate (2 χ

-." or. ι · τζ — s

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

248

<td>lOOml).</td><td>The</td><td>organic layers</td><td>combined</td><td>They were washed</td><td>with</td>

<td>solution</td><td colspan="2">saturated with NaCl,</td><td>they dried up</td><td>about Na2SO4,</td><td>I know</td>

<td>leaked</td><td>and</td><td>the product of</td><td>filtration</td><td>concentrated.</td><td>The</td>

<td>product</td><td>I know</td><td>recrystallized</td><td>from</td><td>ether / pentane</td><td>for</td>

provide the title compound as a white solid.

Stage B. 4- (3-Chlorophenyl) -5- (4-Chlorophenyl) -5-

To a solution of 52.lg (197 mmol) of 2- (3-chlorophenyl) -

1- (4-Chlorophenyl) Ethanone (Example 1, Step A) and Methyl Acrylate (19.5 ml, 216 mmol) in 360 mL of THF 20mL of a 1M solution of potassium tert-butoxide in THF was added slowly at 0 ° C for a period of 20 min (temp. Of the reaction solution maintained <10 ° C). The reaction was allowed to warm to room temperature. After stirring at rt for 1h, the reaction was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel

249 (eluent: 15% EtOAc / hexanes). provided title as a colorless liquid. R is CH3.

the compound of

Stage C.

4- (3-Chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy pentanoate of (4S, 5S) -Methyl and 4- (3-Chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy pentanoate of

To a solution of

75.1 g (213 mmol) 4- (3-chlorophenyl) -

Methyl 5- (4-chlorophenyl) -5-oxopentanoate (Example 1, Step

B) in MeOH (0.71 L, c = 0.3 M) at 0 ° C, sodium borohydride (8058 mg, 213 mmol) was added in several small portions.

After stirring at 0 ° C for 30 min, the reaction mixture was quenched with H2Or ice-cold, concentrated under reduced pressure, and extracted with EtOAc. The combined organic layers were washed (saturated aqueous solution of

NaCl), dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (eluent: 20-30% EtOAc / hexanes, gradient elution) provided a racemic mixture of the title compounds as a colorless liquid.

Stage D.

250

(4S, 5R) -Methyl and 5-azido-4- (3-chlorophenyl) -5- (4-chlorophenyl) pentanoate 5-azido-4- (3-chlorophenyl) -5- (4 chlorophenyl) pentanoate 5S) -Methyl

To a solution of 63.lg (179 mmol) of 4- (3-chlorophenyl) 5- (4-chlorophenyl) -5-hydroxy pentanoate of (4S, 5S) -methyl and 4 (3-chlorophenyl) -5- ( (4R, 5R) -methyl 4-chlorophenyl) -5-hydroxypentanoate (Example 1, Step C) and triethylamine (49.8 mL, 357 mmol) in DCM (600 mL, 0.3 M) methanesulfonyl chloride (18 mL, 232 mmol) at 0 ° C dropwise over a period of 10 min. The reaction was stirred at 0 ° C for 40 min and monitored by TLC for completion. The reaction was then quenched with ice-cold water, extracted (3 x DCM), and washed with saturated aqueous NaCl solution. The combined organic layers were dried (Na2SW4), and concentrated under reduced pressure.

The above synthesized crude mesylate was dissolved in DMF (350 mL, 0.5 M) and sodium azida (58 g, 893 mmol) was added in various portions. The mixture was heated to 100 ° C and after stirring at 100 ° C for 30 min, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers are

251

MEXICAN INSTITUTE

PROPERTY V 'INDUSTRIAL' washed (saturated aqueous NaCl solution), dried over

Na2SC> 4, filtered and the filter product concentrated.

Purification of the residue by flash chromatography on silica gel (eluent:

at 20% EtOAc / hexanes, elution title compound as a colorless liquid.

Stage E. (5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) piperidine-2-one

To a solution of 45.9 g (121 mmol) of methyl 5-azido-4- (3-chlorophenyl) -5- (4-chlorophenyl) pentanoate (Example 1, Step D) in THF / H2Or (4: 1, 375 mL) 152 mL of a 1M solution of trimethylphosphine in THF (152 mmol) was added. After stirring for 1 h a. At 25 ° C, most of the THF was removed under reduced pressure. The residue was basified (ice cold 2M LiOH) and the product was extracted with methylene chloride. The combined organic layers were washed with saturated NaCl solution, dried over Na2SW4, filtered, and the filtration product was concentrated under reduced pressure to provide a white solid.

252

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

This solid was dissolved in lbl saturated aqueous MeOH / NaHCO3. .i, —uj »tr.-éaccagt (4: 1, 2.4 L, c = 0.05 M) and the reaction was heated to reflux for 3 h. The excess organic solvent was removed under reduced pressure, the residue was diluted with water and extracted (2 χ 10% MeOH / DCM). The combined organic layers were washed with saturated NaCI solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure to provide trans5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one as a mixture of stereoisomers. The individual stereoisomers were separated by chiral HPLC (flow ratio: 18 ml / min on a Chiralcel® OD-H 20 mm ID χ 250 mm, 5 mic column (Daicel Inc., Fort Lee, NJ), using 40% alcohol. isopropyl / hexane as the eluant) to give the title compound (tR = 8.2 min) as a white solid.

[to]D = + 158 (T = 23 ^ 4 ° C, c = 1.12, MeOH); XH NMR (400 MHz, C LORO FORMO-d) 8 ppm 7.21 (2 H, d, J = 8.2 Hz), 7.09-7.19 (3 H; m), 7.04-7.01 (1 H, m), 6.97 (2 H, d, J = 8.2 Hz), 6.80-6.77 (1 H, mj, 5.83 (1 H, s, br), 4.51 (1 H, d, J = 9.8 Hz), 2.94-2.77 (1 H, mj , 2.74-2.60 (2 H, m), 2.34-2.20 (1 H, m), 2.17-2.08 (lH, m); MS (ESI) 320.0 [M + H] + .

The enantiomer of the title compound, (5S, 6R) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one, was also obtained by the above method: tR = 12.4 min; [to]D = -1.56 (T =

253

23.4 ° C, c = 1.13, MeOH).

Stage F. (2S) -2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -

Tert-Butyl 6-oxo-l-piperidinyl) butanoate and (2R) -2 ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6-oxo-lpiperidinyl) butanoate tert-butyl

To a solution of 13.5 g (42.2 mmol) of (5R, 6S) -5, 6bis (4-chlorophenyl) piperidin-2-one (Example 1, Step E) in 140 mL of DMF was added 4.22 g (105 mmol) of a 60% sodium hydride dispersion in mineral oil at 0 ° C. After stirring for 20 min, tert-butyl 2-bromobutanoate (28.2 g, 126 mmol) was added at 0 ° C and the resulting solution was stirred at 25 ° C for 1.5 h until completion of the reaction. Then saturated aqueous NH solution4C1 was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated NaCl solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20 to 50% EtOAc / hexanes, elution

254

JL 1Λ x. Iu .ii.

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

gradient) provided (2S) -2 - ((2S, 3R) -3- (3-chlorophenyl) -2 (4-chlorophenyl) -6-oxo-l-piperidinyl) tert-butyl butanoate as the minor isomer of faster elution:

XH NMR (4 00 MHz, CHLOROFORM-d) δ ppm 7.22 (2 H, d, J =

8.2 Hz), 7.20-7.10 (2 H, m), 7.08 (2 H, t, J = 8.2 Hz) 6.99-

6.96 (1 H, m), 6.77-6.73 (1 H, m), 4.48 (1 H, d, J = 9.4 Hz),

3.24 (1 H, t, J = 7.0 Hz), 3.04-2.94 (1 H, m), 2.72-2.58 (2

H, m), 2.25-2.00 (3 H, m), 1.93-1.82 (1 H, m), 1.45 (9 H, s),

0.98 (3H, t, J = 7.4 Hz); MS (ESI) 4 62.1 [M + H]+ .

The additional elution provides (2R) -2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6-oxo-l-piperidinyl) tert-butyl butanoate as the major isomer of elution slower.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J =

2.99 (1 H, m), 2.70-2.64 (2 H, m), 2.28-2.18 (2 H, m), 2.082.02 (1 H, m), 1.48 (9 H, s), 0.57 (3 H , t, J = 7.4 Hz); MS (ESI) 462.1 [M + H]+.

Step G. (2S) -2 - ((3S, .5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) tert-Butyl butanoate and (2S) -2- ((3R, 5R, 6S) -3-al'yl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

2-oxopiperidin-l-yl) tert-Butyl butanoate

255

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

To a solution of 1.45 g (3.14 mmol) of (2S) —2— ((2S, 3R) -

Tert-Butyl 3- (3-chlorophenyl) -2- (4-chlorophenyl) -6-oxo-l piperidinyl) butanoate (Example 1, Step F) and allyl bromide (0.326 mL, 3.76 mmol) in 12.5 mL of THF was added dropwise at -78 ° C 3.3 mL of a 1M solution of lithium bis (trimethylsilyl) -amide in THF (3.3 mmol). After stirring at -78 ° C for 3 hr, the reaction was quenched with ethyl solution.

aqueous saturated NH4C1, was extracted with acetate

The combined organic layers were washed with saturated NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure.

Purification of the residue by flash chromatography on silica gel (50g

SiO2, eluent: 5 provided 20% EtOAc / hexanes, gradient elution) (2S) -2 - ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) - Tert-butyl 2-oxopiperidin-l-yl) butanoate as the fastest eluting major isomer.

XH NMR (400 MHz, CHLOROFORM-d} δ ppm 7.27-7.24 (2 H, m),

7.21-7.12 (2 H, m), 7.11-7.00 (3 H, m), 6.93-6.87 (1 H, m),> · '

256

5.90-5.77 (1 H, m), 5.19-5.09 (2 Η, m)

4.64 (1 Η,

8.6

Hz), 3.21-3.10 (2 H, m), 2.80-2.71 (1 H, m), 2.70-2.63 (1 Η,

The additional elution provides tert-butyl (2S) -2 - ((3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-lyl) butanoate as the lower isomer, slower elution.

XH

NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2 H, d, J =

8.2

Hz), 6.77-6.72 (1, 7.01-6.95 (3 H, m), 7.19-7.07 (2 H, m)

Stage H. Acid 2- ((3R, 5R, 6S) -1 - ((S) -l-tert-Butoxi-loxobutan ^ -il) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 2oxopiperidin-3-yl) acetic

257

MEXICAN INSTITUTE V>

OF FSOPILOAD VI

INDUSTRIAL '' * · <*

To a rapidly stirred solution of 842 mg (1.67 mmol) of (2S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -2-oxopiperidin -l-yl) tert-butyl butanoate (Example 1, Step G) in a mixture of 7 mL of water, 5 mL of acetonitrile and 5 mL of CCI4, sodium periodate (1.43 g, 6.70 mmol) was added, followed by hydrate ruthenium (III) chloride (37.8 mg, 0.168 mmol). After vigorously stirring for 18 hr, the reaction was acidified (10% citric acid) and diluted with EtOAc. The reaction mixture was filtered through celite and the filter product was extracted with EtOAc. The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (GeminiTM Prep C18 5pm column, Phenomenex, Torrance, CA; eluent: 60 to 80% acetonitrile + 0.1% TFA in water + 0.1% TFA-, gradient elution) to give the compound of the title as a white solid.

TH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.35 (2 H, d, J =

258

EXAMPLE 2

Acid 2- ((3S, 5R, 6S) -1- ((S) -l-tert-;Butoxy-l-oxobutan-2-yl) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3-yl) acetic

The title compound was prepared from 2 - ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxopiperidin-l-yl) butanoate of (S ) -tert-butyl (Example 1, Step G) by the procedure described in Example 1, Step H.

TH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.27-7.26 (2 H, m),

7.12-7.16 (1 H, m), 7.13-7.10 (1 H, m), 7.02-6.94 (3 H, m),

6.74-6.71 (1 H, m), - 4.51 (1 H, d, J = 10.8 Hz), 3.18-3.08 (2

H, m), 3.06-2.96 (2 H, m), 2.47 (1 H, dd, J = 15.4, 3.2 Hzj,

259

2.35-2.25 (1 H, m), 2., 24-2.12 (2 Η, m), 1.52-1.57 (1 Η, m),

1.51 (9 Η, s), 0.56 (3 Η, t, J = 7.5 Hz); MS (ESI) 520.2 [M. + H]+, 518.0 [Μ - H] ~.

The following, Examples 3 to 6 were prepared as described in Example 1, substituting tert-butyl 2-bromobutanoate in step F, with the appropriate amount of ethyl 2-bromobutanoate, 2-bromo-3-methylpentanoate, 2 -ethyl bromopentanoate, and ethyl 2-bromo-2-cyclopropylacetate, respectively.

EXAMPLE 3

CI

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) - l-ethoxy-l-oxobutan-2-yl) -2- oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42-7.33 (3 H, m),

7.32-7.28 (3 H, m), 7.27-7.24 (2 H, m), 4.91 (1 H, d, J = 3.5 Hz), 4.23-4.10 (2 H, m), 3.54 (1 H, dd, J = 8.6, 3.5 Hz), 3.22-3.16 (1 H, m), 2 / 84-2.73 (3 H, m), 2.38-2.30 (2 H, m),

2.05-1.97 (1 H, m), 1.60-1.50 (1 H, m), · 1.27 (3 H, t, J = 7.4 Hz), 0.70 (3 H, t, J = 7.4 Hz); MS (ESI) 491.8 [M + H]+,

489.9 [M - H] ~.

MEXICAN INSTITUTE OF THE. INDUSTRIAL IBOHEDAD

260

EXAMPLE 4

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -l-ethoxy-4-methyl-l-oxopentan-2-yl acid ) -2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) opm 0.34 (d, J = 6.7 Hz, 3

H), 0.77 (d, J = 6.7 Hz, 3 H), 1.13 (m, 1 H), 1.28 (t, J = 7.1

Hz, 3H), 1.30 - 1.44 (m, 1H), 1.98 (m, 1H), 2.32 - 2.47 (m, 2H), 2.75 (m, 1H), 2.79 - 2.86 (m, 2H ), 3.14 - 3.19 (m, 1H), 3.66 (dd, <7 = 9.2, 2.4 Hz, 1H), 4.11 - 4.24 (m, 2H), 4.95 (m, 1H), 7.23 - 7.34 ( m, 5H), 7.36 - 7.41 (m, 3H), MS (ESI)

520.2 [M + H] 1 . 518.0 [MH] '.

EXAMPLE 5

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- ethoxy-l-oxopentan-2-yl) -2-oxopiperidin-3-yl) acetic and Acid

2- ((3S, 5S, 6R) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -1-

261

uv-iiu w esi ·.

ethoxy-l-oxopentan-2-yl) -2-oxopiperidin-3-yl) acetic

The compounds described in Example 5 were derived from racemic piperidinone which was prepared in Example 1,

Stage E.

XH NMR (400 MHz, OLOROFORM-d) δ ppm 7.40-7.37 (3 H, m),

7.31-7.27 (3 H, m), 7.27-7.24 (2 H, m), 4.92 (1 H, d, J = 3.5 Hz), 4.20-4.10 (2 H, m), 3.60 (1 H, dd, J = 8.6, 3.5 Hz),

3.20-3.15 (1H, m), 2.83-2.72 (3H, m), 2.40-2.30 (2H, m),

2.03-1.97 (1 H, m), 1.44-1.37 (l H, m), 1.27 (3H, t, J = 7.2

Hz), 1.26-1.17 (1 H, m), 0.92-0.80 (1 H, m), 0.54-0.78 (3 H, t, J = 7.4 Hz); MS (ESI) 506.0 [Μ + H]1, 504.0 [Μ - H].

EXAMPLE 6

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2-ethoxy-2-oxoethyl) -2-oxopiperidin -3-yl) acetic

<td></td><td></td><td>XH NMR (400 MHz,</td><td>CHLOROFORM-d) δ</td><td>ppm</td><td> 0.08</td><td> (1</td><td>H, m), 0.34</td>

262 (1 Η, ____________ DO I LOVE

DE ΕΛ ΡδΟ? ·, AGE t INDUSTRIAL

INSTITUTE ME

Η, m),

7.15-7.25 (7 Η, m); MS (ESI)

504.1 [Μ + Η].

EXAMPLE 7

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) - l-hydroxybutan-2-yl) -2-oxopiperid.in- 3-yl) acetic

To a solution of 300mg (0.61 mmol) of Acid 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1-ethoxy-l- oxobutan-2-yl) -2-oxopiperidin-3-yl) acetic (Example 3) in 12 mL of Et2Or, lithium tetrahydroborate (39.8 mg, 1.8 3 mmol) was added at 0 ° C. After stirring for 20 min, methanol (37.0 pl, 914 pmol) was added at 0 ° C and the resulting solution was stirred at 25 ° C for 2 h. The reaction was quenched (10% citric acid), extracted (2 * EtOAc) and washed (1 x saturated aqueous NaCl solution). The combined organic layers were washed with saturated NaCl solution, dried over Na?SW4, filtered and the filter product concentrated under reduced pressure. Purification by reverse phase preparative HPLC (GeminiTM Prep C18 5pm column, Phenomenex, Torrance, CA; eluent: 35

263

at 75% acetonitrile + 0.1% TFA in water + 0.1% TFA, gradient elution) provided the title compound as a white foam.

XH NMR (400 MHz, CHLORINE FORM-d) δρρίπ 7.42-7.37 (3 H, m),

EXAMPLE 8

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) l-cyclopropyl-2-hydroxyethyl) -2-oxopiperidin-3-yl acid )acetic

The title compound was prepared from Acid 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l— cyclopropyl-2-ethoxy -2-oxoethyl) -2-oxopiperidin-3-yl) acetic (Example 6) as described in Example 7.

XH NMR (400 MHz, CHLOROFORM-d) 'δ ppm 0.23 (m, 1 H), 0.36

264

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 1- (cyclopropylmethoxy) butan-2-yl) -2-oxopiperidin- 3-yl) acetic

Stage Ά. (S) -Ethyl 2-((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6oxopiperidin-l-yl) butanoate

To a solution of 15 g (46.8 mmol) of ((5R, 6S) -5- (3Clorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 1, Step

E) in 140 mL of DMF, 3.75 g (94 mmol) of a

265

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY dispersion of 60% sodium hydride in mineral oil at 0 C. After stirring for 20 min, ethyl 2-bromobutanoate (17.2 mL, 117 mmol) was added at 0 ° C and the resulting solution was Stirred at 25 ° C for 12 h until completion of the reaction. Then saturated aqueous NH solution4C1 was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 30% EtOAc / hexanes, gradient elution) provided the title compound as the fastest eluting isomer.

Stage B.

(S) -Ethyl 2-((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4- chlorophenyl) -2-oxopiperidin-l-yl) butanoate

CI

To a solution of 0.62g (1.4 mmol) of 2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6-oxopiperidin-l-yl) butanoate of (S) -ethyl ( Example 9, Step A) and allyl bromide (0.14 ml, 1.7 mmol) in THF (6.0 mL, 0.25 M) was added

266 bis (trimethylsilyl)-lithium amide

IMPI

MEXICAN INSTITUTE v OF VINDUSTR1AL PROPERTY ** (1M solution in THF, 1.5

mi, 1.5 mmol) at -78 ° C.

The reaction was allowed to warm

RT, then went off (NH4C1 saturated aqueous) and extracted with

EtOAc. The combined organic layers were washed with water and saturated NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure.

Purification of the residue by flash chromatography on silica gel (15 a

20%

EtOAc / Hex, gradient elution) provided the title compound as the slowest eluting isomer as a colorless oil.

Step C. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) piperidin-2-one

To a 256 mg (0.54 mmol) solution of 2 - ((3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-lil) butanoate of -ethyl (Example 9, Step B) in Et2Or (5.5 mL) lithium borohydride of 90% purity (17.6 mg, 0.809 mmol) was added at 0 ° C. After stirring at 0 ° C for 10 min, the reaction was quenched (ice cold citric acid

267

OF INDUSTRIAL PROPERTY

OF THE PROPERTY ixinncTniA)

10%), extracted (2 χ EtOAc) and washed (saturated aqueous NaCl solution). The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Purification by chromatography on silica gel (eluent 30% to 50% EtOAc / Hexanes, gradient elution) provided the title compound.

Stage D. (3S, 5R, 6S) -3-ali.l-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (cyclopropylmethoxy) butan-2yl) piperidin-2 -ona

OR.

To a solution of (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) piperidin-2- ona (98 mg, 0.227 mmol) in DMF (1.10 mL) 60% sodium hydride in mineral oil (27.2 mg, 0.680 mmol) was added at 0 ° C. After stirring at 0 ° C for 2 min, (bromethyl) cyclopropane (47.3 pL, 0.680 mmol) was added. The mixture was stirred at 0 ° C for 2 h and then warmed to

IMPI

268

Then the reaction was stirred at

t. from one day to the next. The reaction was quenched (NH4C1 saturated aqueous), extracted (2 χ EtOAc) and washed (saturated aqueous NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography on silica gel (10% to 20% EtOAc / Hexanes gradient) provided (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1- ( (Rj-1- (cyclopropylmethoxy) butan-2yl) piperidin-2-one as the least polar isomer and the title compound as the most polar stereoisomer.

Stage E. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (cyclopropylmethoxy) butan-2-yl) -2oxopiperidin- 3-yl) acetic

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (cyclopropylmethoxy) butan-2-yl) piperidin-2-one was converted to carboxylic acid by a similar procedure to that described in Example 1, Step H.

269

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

I purification by preparatory reverse phase HPLC (column

GeminiTM Prep C18 5pm, Phenomenex, Torrance, CA; eluent: 50 to 80% acetonitrile + 0.1% TFA in water + 0.1% TFA, gradient elution) provided the title compound as a white solid.

XH

NMR (400 MHz,

CHLOROFORM-d) 5ppm 7.39 (2 H, d, J =

8.2

Hz)

H

m), 7.33-7.28 (3H,

m), 7.23 (2

H, d,

8.2 Hz), 5.09 (1

4.17-4.07 (1

H

3.47-3.40 (2H,

3.23-3.15 (m, 2

H),

3.12-3.08 (1

H

2.85 (1

H, dd,

15.8,

8.8 Hz),

2.66-2.55 (2

H

2.22-2.12 (1

H

2.07-1.99 (LH, m)

H

m),

1.62-1.54 (1

H

1.07-1.00 (1 H, m),

0.65 (3H, t,

7.4

Hz)

0.600.52 (2 H, m), 0.24-0.18 (2

H, m); MS (ESI) 504.1 [M

H] ~, 502.1 [Μ - H].

The following Examples 10 to 12 were prepared from ((S) -l-hydroxybutane-2-yl) piperidin-2-one (Example 9, Step C) by procedures similar to those described in

Example

Stages

E, when 'replacing (bromomethyl) cyclopropane in stage

D for the appropriate amount (bromomethyl) cyclopropancarbonitrile, respectively of methyl iodide, 2-methoxyethyl bromide, and 1270

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td>Example</td><td>R</td>

EXAMPLE. 10

Acid 2- ((3R, 5R, 6S) ~ 5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-methoxybutan-2-yl) -2-oxopiperidin-3-yl )acetic

IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52-7.48 (1 Ή, m),

271

[M + H]+, 462.1 [Μ - Ή] '.

(1 H, m), 2.64-2.55 (2 Η, m), (1 Η, m), 1.90-1.81 (1 Η, m), t, J = 7.4 Hz); MS (ESI) 464.0

EXAMPLE 11

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (2-methoxyethoxy) butan-2-yl) -2- oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41-7.35 (3 H, m), 7.28-7.26 (2 H, m), 7.25-7.21 (3 H, m), 5.09 (1 H, d, J = 2.7 Hz), 4.17-4.10 (1 H, m), 3.74-3.65 (1 H, m), 3.60-3.52 (3 H,

m), 3.44 (1 H, dd, J = 10.4, 3.3 Hz), 3.35 (3 H, s), 3.253.15 (1 H, m), 3.12-3.07 (1 H, m), 2.91-2.80 ( 1 H, m), 2.71-

2.58 (2 H, m), 2.21-2.12 (1 H, m), 2.05-1.89 (2 H, m), 1.611.52 (1 H, m), 0.64 (3 H, t, J = 7.6 Hz); MS (ESI) 508.1 [M +

H] ', 506.0 [Μ - H].

272

EXAMPLE 12

CN

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- ((l-cyanocyclopropyl) methoxy) butan-2-yl) acid -2-oxopiperidin-3yl) acetic XH NMR (400 MHZ, CHLOROFORM-d) δ ppm 7.43-7.30 (3 H, m),

MS (ESI) 529.2 [Μ + H]-, 527.0

Examples 13-15 were prepared from (3R, 5R, 6S) 3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) —1— cyclopropyl-2- hydroxyethyl) piperidin-2-one in a process similar to that described in Example 9, Step D and E.

<td>Example</td><td>R1</td>

EXAMPLE 13

2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (cyclopropylmethoxy) butan-2-yl) -2-oxopiperidin- 3-yl) acetic

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, d, J =

8.6 Hz), 7.22-7.18 (1 H, m), 7.15-7.11 (1 H, m), 7.08-7.04 (1

H, m), 6.96 (2 H, d, J = 8.6 Hz), 6.77-6.73 (1 H, m), 4.69 (1

H, d, J = 10.2 Hz), 4.03 (1 H, t, J = 9.8 Hz), 3.42-3.33 (2

H, m), 3.28-3.22 (1 H, m), 3., 10-2.90 (4H, m), 2.50 (1 H, dd,

J = 15.3, 3.1 Hz), 2.20-2.10 (1 H, m), 2.01-2.01 (1 H, m),

I. 92-1.80 (1 H, m), 1.65-1.53 (1 H, m), 1.16-1.08 (1 H, m),

0.66-0.60 (2 H, m), 0.53 (3 H, t, J = 7.6 Hz), 0.28-0.24 (2

H, m); MS (ESI) 504.1 [M + H]_, 502.1 [M-H]_.

EXAMPLE 14

274

Acid 2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-methoxybutan-2-yl) -2-oxopiperidin-3 ~ yl )acetic

IH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 (t, J = 7.53 Hz,

H), 1.49 - 1.60 (m, 1H), 1.77 - 1.91 (m, 1H), 2.02 - 2.15 (m, 2H), 2.51 (dd, J = 15.26, 3.33 Hz, 1H), 2.89 - 2.99 (m, 1H), 2.99 - 3.09 (m, 2H), 3.09 - 3.17 (m, 1H), 3.29 (dd,

J = 9.68, 4.21 Hz, 1 H), 3.34 (s, 3 H), 3.90 (t, J = 9.49 Hz, 1

H), 4.57 (d, J = 9.98 Hz, 1 H), 6.75 (d, J = 7.43 Hz, 1 H), 6.97 (d, J = 8.41 Hz, 2 H), 7.00 (t, J = 1.76 Hz , 1 H), 7.14 (t,

J = 7.73 Hz, 1 H), 7.17 - 7.22 (m, 1 H), 7.25 (d, J = 8.41 Hz, 2

H).

EXAMPLE 15

Acid 2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S)

1- (2-methoxyethoxy) butan-2-yl) -2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J =

8.2 Hz), 7.21-7.16 (1 H, m), 7.14-7.09 (1 H, m), 7.05-7.03 (1

H, m), 6.97 (2 H, d, J = 8.2 Hz), 6.75-6.71 (1 H, m), 4.66 (1

H, d, J = 10.6 Hz), 4.09 (1 .H, t, J = 9.8 Hz), 3.70-3.55 (4

H, m), 3.47 (3 H, s), 3.44 (1 H, dd, J = 9.8, 4.3 Hz), 3.052.90 (4 H, m), 2.53 (1 H, dd, J = 15.1, 2.5 Hz), 2.28-2.15 (1

H, m), 2.05-1.97 (1 H, m), 1.92-1.82 (1 H, m), 1.65-1.55 (1, 0.50 (3 H, t, J = 7.6 Hz); MS (ESI) 508.1 [ M + H]+,

H, m) ή

275

506.0 [Μ - Η]-.

EXAMPLE. 16

Acid

2 - ((3R, 5R, 6S) -1 - ((S) -1 - ((1 carbamoylcyclopropyl) methoxy) butan-2-yl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -2 -oxopiperidin-3-yl) acetic

A solution of 10mg (0.02 mmol) of Acid 2 - ((3R, 5R, 6S)

5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l- ((1-cyclopropyl) methoxy) butan-2-yl) -2-oxopiperidin-3yl) acetic (Example 11) and Potassium hydroxide (3.2 mg, 0.06 mmol) in t-BuOH (189 pL) was stirred at 85 ° C for 24 h. The reaction was acidified (10% citric acid) and extracted (2 x EtOAc). The combined organic layers were washed with saturated NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Preparatory HPLC purification of

<td>reverse phase</td><td>(GeminiTM Prep C18 5pm column, Phenomenex,</td>

<td>Torrance, CA;</td><td>eluent: 35 to 75% acetonitrile + 0.1% TFA in</td>

<td>water + 0.1%</td><td>TFA, gradient elution) provided the</td>

276

ΪΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

title compound.

<td></td><td>XH NMR</td><td> (400</td><td>MHz, CHLOROFORM-d) opm</td><td> 0.</td><td>67 (m, 5H), 1.34</td>

The additional elution provides Example 17.

Acid 2 - ((3S, 5R, 6S) -1 - ((S) -1 - ((1carbamoylcyclopropyl) methoxy) butan-2-yl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -2 -oxopiperidin-3-yl) acetic

<td>XH NMR i</td><td colspan="5">(400 MHz, CHLOROFORM-d) δ ppm 7.26-7.21 (2 H,</td><td>m),</td>

H, m), 1.65-1.55 (1 Η, m),

277

1.43-1.35 (2 Η,

m), 0.85-0.73 (2

H, m), 0.63-0.52 (3 H, m); MS (ESI) 547.2 [M + H]+, 545.0 [M

- H].

EXAMPLE 18

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (2-hydroxy-2-methylpropoxy) butan-2 -il) -2-oxopiperidin

3-yl) acetic

Step A. 2 - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) butoxy) acetate ethyl

To a solution of-203mg (0.47mmol) of (3S, 5R, 6S) -Ξ-βϋΙδ- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -l-hydroxybutan-2yl) piperidin-2-one (Example 9, Step B) and acetate dimer

IMPI

rhodium (II)

278 (10.4 mg, 0.047 mmol) in CH2C12 (1.90 mL) ethyl diazoacetate (286 pL, 2.35 mmol) was added dropwise at 25 ° C. After stirring at 25 ° C for 14h, the reaction was concentrated under reduced pressure and purified by chromatography on silica gel (20% to 30% EtOAc / Hexanes, gradient elution) to provide the title compound as a colorless liquid :

Step B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (2-hydroxy-2-methylpropoxy) butan-2yl ) piperidin-2-one

To a solution of 2 - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-lyl) butoxy) acetate Ethyl (69.0 mg, 0.133 mmol) in THF (2.22 mL), methylmagnesium bromide, 1.4M in Toluene / THF, (0.38 mL, 0.532 mmol) was added at 0 ° C. After stirring at 25 ° C for 3 hr, the reaction was quenched (saturated aqueous NH4CI), and extracted with EtOAc. The combined organic layers were washed with saturated NaCl solution, dried over

IMPI

279

Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification by chromatography on silica gel (20% to 50% EtOAc / Hexanes, gradient elution) provided the title compound as a colorless liquid.

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (2-hydroxy-2-methylpropoxy) butan-2 -il) -2oxopiperidin-3-yl) acetic

To a rapidly stirred solution of (3S, 5R, 6S) -3-allyl5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (2-hydroxy-2methylpropoxy) butan- 2-yl) piperidin-2-one (51.0 mg, 0.101 mmol) in a mixture of water (361 pL), acetonitrile (241. pL), and CC14 (241 pL) sodium periodate (86 mg, 0.404 mmol) was added, followed by ruthenium (III) chloride hydrate (2.28 mg,

10.1 pmol). After vigorously stirring for 18 hr, the reaction was acidified (10% citric acid) and diluted (EtOAc). The mixture was filtered through Celite® (JT Baker, Phillipsberg, NJ, JT Baker, Phillipsberg, NJ, diatomaceous earth) and the filter product was extracted with EtOAc. The combined organic layers were laid with saturated NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Reverse phase preparative HPLC purification (column

IMPI

280

GeminiTM Prep C18 5μπν,

Phenomenex, Torrance, CA; eluent: 50 to 7 6% acetonitrile + 0.1% TFA in water + 0.1% TFA, gradient elution) provided the title compound as a white solid.

<td></td><td>ΧΗ</td><td>NMR</td><td> (400 1</td><td>MHz, CHLOROFORM-d) δ</td><td>ppm 0.64</td><td>- 0.74 (t,</td>

EXAMPLE 19

★ unknown absolute stereochemistry

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2-oxo1 - ((3S) -1,1, l-trifluoro-2-hydroxypentan-3 -il) piperidin-3yl) acetic (Isomer 1)

281

Stage Ά. (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -2-oxopiperidin-l-yl) butanal

OR.

CI

To a solution of oxalyl dichloride (166 pL, 1.87 mmol) in DCM (4.16 mL) at -60 ° C was added a solution of DMSO (222 pL, 3.12 mmol) in DCM (4.16 mL) under N2. After about 20 min, a 540mg (1.25mmol) solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxybutan-2-yl) piperidin-2-one (Example 9, Step B) in 4.2mL DCM was added, and the resulting solution was stirred for 15 min. Triethylamine (872 pL, 6.24 mmol) was then added. After stirring at -60 ° C for 5 min, the reaction was allowed to warm to rt, and 5 mL of water was added. The solution was extracted (2 * DCM), washed (saturated aqueous NaCl solution), dried (MgSO4) and concentrated under reduced pressure to give the crude title compound containing 20% of the starting material (SM).

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-clOrophenyl) -6- (4-chlorophenyl) -1- ((3S) -1,1, l-'trifluoro-2-hydroxipentan-3yl ) piperidin-2-one

282

★ unknown absolute stereochemistry

A solution of (S) -2- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) butanal (80 mg, 0.186 mmol) and trimethyl (trifluoromethyl) silane (82 pL, 0.558 mmol) in THF (929 pL) was treated at 0 ° C with 1M tetrabutylammonium fluoride in THF (93 pL, 0.093 mmol). After stirring for 1 hr, three additional equivalents of trimethyl (trifluoromethyl) silane (82 pL, 0.558 mmol) and 1 M-tetrabutylammonium fluoride in THF (93 pL, 0.093 mmol) were added to the reaction at 0 ° C and the reaction stirred for 14h. The reaction mixture was diluted (EtOÁc), washed (1 χ H2O and 1 χ aqueous saturated NaCl solution), dried (Na2SW4), and concentrated under reduced pressure. Reverse phase preparative HPLC purification (GeminiTM Prep C18 5pm column, Phenomenex, Torrance, CA; eluent: 60 to 90% acetonitrile + 0.1% TFA in water + 0.1% TFA, gradient elution) provided two compounds that are diastereomers in secondary alcohol.

.10

Stage C.

Acid

IMPI ^

MEXICAN INSTITUTE% t

D £ THE PROPERTY Zí

INDUSTRIAL.[

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4- *

283

chlorophenyl) -2-oxo-l - ((3S) -1,1,1-trifluoro-2-hydroxypentan-3 The title compound was prepared from yl) piperidin-2-one by a procedure similar to that described in Example 18, Stage C.

H),

2.32

H),

<td colspan="4">Έ NMR (400 MHz, CHLOROFORM-d) δ ppm 0.53 (t, d = 7.5 Hz</td>

H);

MS (ESI) 518.0 f

(m, [M + H]1. 516.0 [MH] '.

7.37 - 7.46

EXAMPLE

★ unknown absolute stereochemistry

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2-oxo20 acid

284

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY il) acetic (Isomer 2)

To a rapidly stirred solution of 6.3 mg (0.013 mmol) of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1- ((3S) -1.1 , 1-trifluoro-2-hydroxypentan-3-yl) piperidin-2-one (Example 19, Step B, the diastereomer not used by Example 19 Step B)) (6.30 mg, 0.013 mmol) in a mixture of

CC14 (71.9 pL) sodium periodate (10.7 mg, 0.050 mmol) was added, followed by ruthenium (III) chloride hydrate (0.284 mg,

1.26 pmol).

After vigorously shaking for 18 h, the reaction was 10% citric) and diluted (EtOAc). The reaction mixture (JT

Baker,

Phillipsberg,

NJ,

JT

Baker, Phillipsberg,

NJ, diatomaceous earth).

The filtration product was extracted (2 x combined organic layers were washed with saturated NaCl solution, dried over NazSOo, filtered and the filtration product was concentrated under reduced pressure, Reverse phase preparative HPLC purification

Torrance, CA;

(GeminiTM Prep C18 5pm column, Phenomenex, eluent: 45 to 70% acetonitrile + 0.1% TFA in XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.44-0.72 (m, 3Η);

water + 0.1%

TFA, gradient elution) provided the title compound as a white solid.

2.89-3.05 m, 3 H), 3.10-3.18 (m, 2 H),

285

4.02-4.16 (m, 1H),

4.56 (d, J = 7.8 Hz, 1H), 6.84-6.93 (m, 1H)

7.01-7.04 (m,

H), 7.08-7.14 (m, 2 H), 7.17-7.20 (m, 2 H), 7.32-7.38 (m, 2

H); MS (ESI) 518.0 [Μ + H]. 516.0 [Μ - H].

EXAMPLE 21

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-morpholinobutan-2-yl) -2-oxopiperidin-3-yl )acetic

Stage A. 2 - ((3R, 5R, 6S) -3- (2-tert-butoxy-2-oxoethyl) -5- (315 chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl ) butanoate

To a stirred solution of 1.14g (2.3 mmol) of acid 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1-ethoxy- oxobutan-2-yl) -2-oxopiperidin-3-yl) acetic (Example 3) in

286

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

DCM (21.0 mL) Sulfuric acid (0.247 mL, 4.63 mmol) was added followed by Isobutylene (4.42 mL, 46.3 mmol) at -78 ° C. The reaction vessel was sealed and the mixture slowly warmed to rt and stirred vigorously for 3 days. After cooling to -78 ° C, the tube was opened and the reaction quenched with NaHCO3 Aqueous saturated to pH 8. The organic solvent was removed under reduced pressure, and the remaining mixture was extracted (2 x EtOAc). The combined organic layers were washed with saturated NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: 20 to 35% EtOAc / hexanes) to provide the title compound as a foam.

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -2-oxopiperidin-3yl) tert-butyl acetate

.0 Cl r Ί1

To a solution of 2 - ((3R, 5R, 6S) -3- (2-tert-butoxy-2oxoethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l287 yl) butanoate

MEXICAN INSTITUTE \ 'C> J DE LA FROPIEDAD' INDUSTRIAL.

de (S) -ethyl (1.94 'g, 3.54 mmol, Example 21,

Stage A) in

Et2Or lithium borohydride (0.154 g, 7.07 mmol) at 0 ° C. After stirring at ° C for 30 min, the reaction was quenched (citric acid at

10% ice-cold), extracted (2 x EtOAc) and washed (saturated aqueous NaCl solution).

The combined organic layers were washed with saturated solution of

NaCl, dried over

Na2SW4, filtered and the filter product concentrated under reduced pressure.

Chromatography purification

EtOAc / Hexanes, on silica gel (50% to 100% gradient elution) provided the title compound.

Stage C. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxo-1 - ((S) -l-oxobutan-2-yl) piperidin-3 -il) tertbutyl acetate.

To a solution of oxalyl chloride (0.261 mL, 2.99 mmol) in DCM (5.87 mL) at -60 ° C was added a solution of DMSO (0.512 mL, 5.98 mmol) in DCM (5.87 mL) under N2. After stirring for 20 min, a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -2-oxopiperidin-3-yl) tert-butyl acetate (1.01 g, 1.99 mmol, Example 21, Step B) in DCM (5.87 mL) was added, and the resulting solution was stirred for 15 min. To this solution

IMPI cno MEXICAN INSTITUTE

PROPERTY ZOO

INDUSTRIAL triethylamine (1.3.9 mL, 9.97 mmol) was added. After stirring at -60 ° C for 5 min, the reaction was allowed to warm to rt, and quenched (H2O). The solution was extracted (3 χ DCM) and washed (H2O and saturated aqueous NaCI solution). The combined organic layers were washed with saturated NaCI solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure to give the title compound.

Stage D. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-morpholinobutan-2-yl) -2-oxopiperidin-3 -il) tert-butyl acetate

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-l - ((S) -l-oxobutan-2-yl) piperidin- 3il) tert-butyl acetate (0.050 g, 0.099 mmol, Example 21, Step C) and morpholine (0.013 mL, 0.149 mmol) in DCE (1.0 mL) sodium triacetoxyhydroborate (0.063 g, 0.297 mmol) was added at 0 ° C. After stirring at 25 ° C for 18 hr, the reaction was quenched by adding NaHCO3 chilled saturated aqueous

IMPI

289 i

with ice and extracted (2 x DCM) and

The combined organic layers were washed (1 x saturated aqueous NaCl solution) and concentrated under reduced pressure. This was used in the next step without further purification.

Stage E. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-morpholinobutan-2-yl) -2-oxopiperidin-3yl )acetic

To a round bottom flask with 2 - ((3R, 5R, 6Sj-5- (3chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-morpholinobutan-2-yl) -2oxopiperidin-3 -yl) tert-butyl acetate (0.057g, 0.099mmol; Example 21, Step D) in DCM (lmL) TFA (1,129g, 9.90mmol) was added at 0'C. The ice bath was removed and the mixture The mixture was stirred at rt for 3 h and the solvent was removed. Reverse phase preparative HPLC purification (GeminiTM Prep C18 5pm column, Phenomenex, Torrance, CA; eluent: 10 to 90% acetonitrile + 0.1% TFA in water + 0.1% TFA, elution of

<td colspan="2">gradient)</td><td colspan="2">provided the compound</td><td colspan="4">of the title like a dust</td>

<td>White.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>XH</td><td>NMR</td><td> (400</td><td>MHz, CHLOROFORM-d)</td><td>δ ppm 0.99</td><td>(m, 3</td><td>H),</td><td> 1.60</td>

(ESI) 519.1 [M + H]+. 517.2 [MH] ”

290

INSTITUTO N DE LA íKO?

IND'JI

Examples 22 to that described by a 27 were prepared in a similar process as Example 21, by substituting morpholine in

H

<td> 24</td><td>toand</td>

EXAMPLE 22

291

Acid

2 - ((3RS, 5RS, 6SR) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((SR) -1- (ethylamino) butan-2-yl) -2-oxopiperidin-3 -il) acetic

<td colspan="3">XH NMR (4 00</td><td colspan="2">MHz, CHLOROFORM-d]</td><td colspan="2">i δ ppm 0.91-1.1Ξ</td><td>! (t,</td><td>J =</td>

EXAMPLE 23

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo1 - ((S) -1- (2,2,2-trifluoroethylamino) butan- 2-yl) piperidin-3yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (t, J = 7.3

EXAMPLE 24

292

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo

1- ((S) -1- (pyrrolidin-l-yl) butan-2-yl) piperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93 (m., 3 H),

H); MS (ESI) 503.2 [M + H]+, 501.1 [M - H] ~.

EXAMPLE 25

Acid 2 - ((3RS, 5RS, 6SR) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxo-1- ((SR) -1- (2-oxopyrrolidin-l-yl) butan- 2-yl) piperidin-3yl) acetic (prepared from the racemic intermediate.)

Ethyl 4-aminobutanoate hydrochloride was used in the amine. After reductive amination the intermediate was cyclic by heating to 120 ° C in acetic acid and toluene to provide the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93 (m., 3 H),

1.67 (m, 1H), 1.82 (m, 1H), 2.07-2.20 (m., 5H), 2.44-2.46 (m, 3H), 2.71-3.06 (m, 3H) ·., 3.20 -3.30 (m, 2H), 3.40-3.55 (m, 3H), 3.69 (m, 1H), 4.70 (m, 1H), 6.99-7.04 (m, 1H)

7.12-7.16 (m, 3H) 7.24-7.27 (m, 2H) 7.35 (m, 2H); MS (ESI)

517.2 [Μ + H].

293

EXAMPLE 26

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (1,1-dioxidothiomorpholino) butan-2-yl) - 2-oxopiperidin-3yl) acetic

NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 (m., 3 H) 1.71 (m, 2 H) 1.83-1.98 (m, 1 H) 2.37 (m, 1 H) 2.58 (m, 1 H) 2,632 .83 (m, 2H) 3.04-3.15 (m, 3H), 3.25-3.35 (m., 6H) 3.433.64 (m, 2H) 4.88 (m, .1H) 7.09 (m., 1H) 7.19 (m, 1H) 7.29 (m, 2H) 7.34-7.50 (m, 4H); MS (ESI) 567.1 [Μ + H]1, 565.2 [Μ - H].

EXAMPLE 27

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo

1- ((S) -1- (thiazol-2-ylamino) butan-2-yl) piperidin-3-yl) acetic XH NMR (500 MHz, ACETONITRILE-d3) δ ppm 0.58 (t, J = 7.2

EXAMPLE 28

294

MEXICAN INSTITUTE - '-ja

PE PROPERTY

INDUSTRIAL -----

2- ((3RS, 5RS, 6SR) -1 - ((SR) -l-acetamidobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3-yl) acid acetic (racemic)

Stage A. (3SR, 5RS, 6SR) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((SR) -1- (4-methoxybenzylamino) butan-2-yl) piperidin -2-one

To a solution of 7 9mg (0.184mmol) of (SR) -2 ((3SR, 5RS, 6SR) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxopiperidin-l-yl ) butanal (racemate of Example 19, Step A) and

4-methoxybenzylamine (35.7 pL, 0.275 mmol) in 1.8 mL of dichloroethane Sodium triacetoxyborohydrate (117 mg, 0.551 mmol) was added at 0 ° C in several portions. After stirring at 25 ° C for 18 hr, the reaction was quenched by adding NaHCO3 Ice-cold saturated aqueous solution was extracted (2 * DCM) and the combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Chromatography purification

295

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

snapshot on silica (0% to 3% MeOH / DCM with NH41% aqueous OH) provided the title compound as a yellow film.

Stage B.

(3SR, 5RS, 6SR) -3-allyl-l - ((SR) -l-aminobutan-2yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one

To a solution of (3SR, 5RS, 6SR) -3-allyl-5- (3-chlorophenyl) 6- (4-chlorophenyl) -1 - ((SR) -1- (4-methoxybenzylamino) butan-2yl) piperidin -2-one (88 mg, 0.160 mmol) in acetonitrile (1899 pL) and water (380 pL) ceric ammonium nitrate (350 mg, 0.638 mmol) was added at 25 ° C. The reaction was monitored by CLEM and

HPLC and upon completion diluted with NaOH 0.5

Aqueous M and EtOAc and the resulting emulsion was filtered through a pad

Phillipsberg,

NJ,

JT

Baker,

Phillipsberg, NJ, land

The filter product was extracted with ethyl acetate and the combined organic layers were washed with saturated solution of

NaCl, dried over Na2SO4, were filtered and the filter product was concentrated under reduced pressure to provide the crude product which was used in subsequent steps without further purification.

Stage C.

N - ((SR) -2 - ((3SR, 5RS, 6SR) -3-allyl-5- (3 chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) butyl)

296

MEXJC INSTITUTE? OF PROHEL

INDUSTRIAL acetamide

To a solution of 53 mg (0.123 mmol) of (3SR, 5RS, 6SR) -3alyl-1 - ((RS) -l-aminobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Step B) in DMF (307 pL) acetic anhydride (116 pL, 1,229 mmol) was added at 25 ° C. After stirring at 25 ° C for 14h the reaction was quenched (H2O) and extracted (2 x EtOAc). The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered, and the filtration product was concentrated under reduced pressure. Reverse phase HPLC separation (50 to 80% AcCN / H2Or in 25 min, 2 injections, tR = 15,683 min) provided the title compound as a yellow solid.

Stage D. Acid 2- ((3RS, 5RS, 6SR) -1 - ((SR) -l-acetamidobutan-2yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3 -il) acetic

Oxidation of N - ((SR) -2 - ((3SR, 5RS, 6SR) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) butyl) acetamide The title compound was carried out as described in Example 1, Step H to give the title compound as a white solid.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.80 (t, J = 7.4

Hz, 3H,) 1.62-1.75 (m, 1H), 1.84-1.97 (m, 2H), 2.07 (s, 3

297

Η), 7.22-7.30 (m, 2 Η), · 7.32-7.38 (m, 4 Η); MS (ESI) 491.0 [Μ + Η] ', 489.1 [Μ - Η].

EXAMPLE 29

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (methylsulfonamido) butan-2-yl) -2-oxopiperidin- 3-yl) acetic

Step A. N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) butyl) methanesulfonamide

To a 69 mg (0.16 mmol) solution of (3S, 5R, 6S) -3alyl-1 - ((S) -l-aminobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) Piperidin-2-one (Example 28, Step B of the non-racemic precursor described in Example 19, Step A) In 1.6 mL DCM methanesulfonyl chloride (13.7 pL, 0.175 mmol) and pyridine (38.7 pL, 0.478 mmol) were added successively at 0 ° C.

298

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Mexican institute

After stirring at ta¿ for 14h the me ^ é ^ us ^^ was acidified with acid. aqueous citrus and attracted (2 ~ x DCM). The combined organic layers were washed with saturated NaCl solution, dried over Na2SÜ4, filtered, and the filter product was concentrated under reduced pressure. Reverse phase HPLC purification (40 to 90% MeCN / H2Or in 45 min, 2 injections, tR = 25.94 min) provided the title compound as a yellow solid.

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenylj-6- (4-chlorophenyl) -1 - ((S) —1— (methylsulfonamido) butan-2-yl) -2oxopiperidin-3 acid -il) acetic

The title compound was prepared as described in Example 28, Step D, using N- ((S) -2 - ((3S, 5R, 6S) -3-allyl-

5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) butyl) methanesulfonamide (Step A).

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.67 (t, <J = 7.6

IMPI

299

EXAMPLE 30

Mexican Institute of Industrial Property

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyanopentan-3-yl) -2-oxopiperidin-3-yl )acetic

Stage Ά. 2- ((3R, 5R, .6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyanopent-l-en-3-yl) -2-oxopiperidin -3-yl) tert-butyl acetate

To a solution of diethyl cyanomethylphosphonate (62.4 pL, 0.396 mmol) and DMPU (239 pL, 1.98 mmol) in THF (661 pL),

<td>added</td><td>hydride</td><td>of</td><td>sodium</td><td>at 60%</td><td>to</td><td colspan="2">an oil suspension</td>

<td>mineral</td><td> (11.89</td><td>mg,</td><td> 0.297</td><td>mmol)</td><td>to</td><td>0 ° C. The mixture is</td><td>waved</td>

<td>during</td><td>30 min</td><td>, and</td><td>then</td><td colspan="2">it was</td><td>with a solution</td><td>lOOmg</td>

<td> (0.2</td><td>mmol)</td><td></td><td>of</td><td>2- ((3R,</td><td>5R,</td><td>6S) -5- (3-chlorophenyl)</td><td> -6-(4-</td>

tert-butyl chlorophenyl) -2-oxo-l - ((R) -l-oxobutan-2-yl) piperidin-3yl) acetate (Example 21, Step C) in THF (661 pL). After stirring for 12 hr, the reaction was quenched with water, extracted (2 x EtOAc), and the combined organic layers were washed with saturated NaCl solution, dried over Na2SW4, filtered and the filtration product

<td> 300</td><td>IMPI INSTITUTO MSXiCANO vtX DE LA PROffsUAD ¡NuUSTSJAL ---</td>

<td>it was concentrated under reduced pressure.</td><td>The purification of the</td>

Residue by flash chromatography on silica gel (10 to 20% EtOAc / Hex, 'gradient elution) provided the title compound as a mixture of the E and Z isomers.

MS (ESI) 527.2 [Μ + H].

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyanopentan-3-yl) -2-oxopiperidin-3yl) tert-butyl acetate

To a 56 mg (0.106 mmol) solution of 2 - ((3R, 5R, 6S) 5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyanopent-l- en-3yl) -2-oxopiperidin-3-yl) tert-butyl acetate (Example 30, Step A) in 3.5 mL EtOH) 10% palladium on activated carbon (11.30 mg, 10.62 pmol) was added. Then the reaction mixture was subjected to regular hydrogenation with hydrogen. After stirring under an atmosphere at rt for 2 h, the catalyst was filtered using a short plug of silica gel. The stopper was washed several times with EtOAc. The combined filter products were concentrated under reduced pressure to provide the crude title compound as a colorless film which was used in the subsequent reaction without further purification. MS (ESI) 529.2 [M + H] +.

Stage C.

301

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -l-cyanopentan-3-yl) -2-oxopiperidin-3 yl) acetic

To a 57 mg (0.11 mmol) solution of 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyanopentan-3- yl) -2 oxopiperidin-3-yl) tert-butyl acetate (Example 30, Step B) in DCM (359 pL) trifluoroacetic acid (415 pL, 5.38 mmol) was added at 0 ° C. After stirring at 25 C for 2 h, the solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure three times. Separation of the crude product by reverse phase HPLC (45 to 70% AcCN / H2Or in 30 min, time runs, tR = 18.52 min) provided the title compound as a white solid.

<td colspan="2">XH NMR (</td><td> 400</td><td colspan="3">MHz, CHLOROFORM-d) δ ppm 7.37 (2</td><td>H, d, J .. =</td>

Examples 31 and 32 were prepared in a process similar to that described by Example '30, Using the phosphonates

appropriately substituted in Stage A:

302

EXAMPLE 31

2- ((3R, 5R, 6S) -5- (3-chlorophenyl.) -6- (4-chlorophenyl) -1- ((S) 1- (methylsulfonyl) pentan-3-yl) -2-oxopiperidin -3-il ·) acetic rH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.71 (t, J = 8.0 Hz,

EXAMPLE 32

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo1 - ((S) -1- (pyridin-2-yl) pentan-3- acid il) piperidin-3-yl) acetic lV λ.

303 XH NMR (400 MHz,

CHLOROFORM-d) δ ppm 0.89 (t, J =

EXAMPLE 33

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S)

1- (ethylamino) -l-oxobutan-2-yl) -2-oxopiperidin-3-yl) acetic and

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) 1- (ethylamino) -l-oxobutan-2-yl) -2 -oxopiperidin-3-yl) acetic

Stage A. (R) -2 - (((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -2-oxopiperidin-l-yl) butanoic acid

To a solution of 320 mg (0.64 mmol) of (2S) —2— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxopiperidin-l- il) tert-butyl butanoate

304

IMPIOS

MEXICAN INSTITUTE OF PROPERTY Vympggjatfjijy INDUSTRIAL ---- (Example 1, Stage

G) in DCM (3184 pL) trifluoroacetic acid (2453 pL, 31.8 mmol) was added at 0 ° C. After stirring at 25 ° C for 3 h, the solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure 3 times to provide the title compound as a pale yellow foam which was used in the subsequent reaction without further purification.

Stage B. (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -2-oxopiperidin-l-yl) -N-ethylbutanamide

A 107mg (0.24 mmol) solution of (S) —2— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxopiperidin-l-yl ) butanoic (Example 33, Step A) and ethylamine (31.4 pL, 0.479 mmol) in DCM (539 pL) and DMF (59.9 pL) were treated at 0 ° C with Nl ((ethylimino) methylene) -N3, N3 hydrochloride -dimethylpropane-l, 3-diamine (138 mg, 0.719 mmol), 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (98 mg, 0.719 mmol), and sodium bicarbonate (60.4 mg, 0.719 mmol), successively. Then the reaction was stirred at 25 ° C for 12 h. The reaction was diluted (aqueous HCI IN), extracted (2 χ EtOAc), the combined organic layers were washed with saturated aqueous solutions of NaCl and NaHCOa, dried over Na2SO4, filtered and the product of

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL filtration concentrated - under pressure

305 reduced. Purification by chromatography on silica gel (30% to 40%

EtOAc / Hexanes, at gradient elution) provided the title compound as a mixture of diastereomers (dr =

5: 1) as a white solid: MS (ESI) 473.2 [M + H]+.

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (ethylamino) -l-oxobutan-2-yl) -2oxopiperidin-3-yl) acetic and Acid 2 - ((3R, 5R, 6S) -5- (3Clorophenyl) -6- (4-chlorophenyl) -1 - ((R) -1- (ethylamino) -1- oxobutan-

2-yl) -2-oxopiperidin-3-yl) acetic

2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 2-oxopiperidin-l-yl) -N-ethylbutanamide (Example 33, Step B) converted to acid as described in Example 1, Step H to give the title compound as a mixture of diastereomers (dr = 5: 1).

NMR (400 MHz, CHLOROFORM-d) δ ppm 0.81 (t, J = 7.8

Hz, 3 Η), 1.10 (t, J = 7.2 Hz, 3 H), 1.65-1.75 (m, 1 H), 1.87 (m, 1 H), 2.24-2.41 (m, 2 H), 2.57-2.66 (m, 1H), 2.70 (dd,

7.38 (m, 5H); MS (ESI) 491.0 [Μ + H]1. 489.1 [Μ - H].

'306

EXAMPLE 34

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (5-methyl-l, 3, 4-oxadiazol-2) acid -yl) propyl) -2-oxopiperidin-3yl) acetic and 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -1- ( 5-methyl-l, 3,4-oxadiazol-2-yl) propyl) -2oxopiperidin-3-yl) acetic

Step A. (S) -Ν'-acetyl-2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-lil) butanohydrazide

A solution of. (S) —2— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) butanoic acid 95 mg (0.213 mmol) (Example 33, Step A) and acetic hydrazide (23.65 mg,. 0.319 mmol) in DCM (479 pL) and DMF (53.2 pL) were treated at 0 ° C with Nl ((ethylimino) methylene) -N3, N3 hydrochloride -dimethylpropane-l, 3-diamine (122 mg, 0.638 mmol), 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (87 mg, 0.638 mmol), and sodium bicarbonate (53.6 mg, 0.638 mmol) at 0 ° C, successively. Then the reaction was stirred at 25 ° C for

307

h. The reaction was diluted with

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

1N aqueous HC1 and extracted (2

x EtOAc). The combined organic layers were washed with saturated aqueous solutions of

NaCl and NaHCO3, dried on Na2SW4, filtered and the filter product concentrated under reduced pressure.

Purification by chromatography on silica gel (60% a

80% EtOAc / Hexanes, gradient elution) provided the title compound as a colorless film. MS (ESI) 502.1 [M + H]+.

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (5-methyl-l, 3,4-oxadiazole) -2il) propyl) piperidin-2-one

A 58 mg (0.115 mmol) solution of (S) -Ν'-acetyl-2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxopiperidin -l-yl) butanohydrazide (Example 34, Step A) and Burgess's reagent (110 mg, 0.462 mmol) in dichloroethane (1154 pL) was heated in the microwave at 120 ° C for 30 min. Then the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with saturated aqueous solutions of

NaCl and

NaHCO3, dried on Na2SW4, filtered and the filtration product was concentrated under reduced reverse phase pressure (55 to 90% MeCN / H2Or in

Separation by HPLC min, 29 mg title injection as a

colorless film. MS (ESI) 484.1 [M + H] \

308

IMPI

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1- (5-methyl-l, 3, 4-oxadiazole) -2-yl) propyl) -2oxopiperidin-3-yl) acetic (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1 - (5-methyl-l, 3,4-oxadiazol-2-yl) propyl) piperidin-2-one (Example 34, Step B) was acidified as described in Example 1, Step H to give the compound of the title as a mixture of diastereomers (dr = 10: 1).

XH NMR (400 MHz, CHLOROFORM-d) δρριη 0.81 (t, J = 7.8 Hz,

H), 1.93-2.04 (m, 2H), 2.25 (m, 1H), 2.26 (s, 3H), 2.332.44 (m, 1H), 2.83-2.94 (m, 3H), 3.12 (d, J = 2.3 Hz, 1

H), 5.08-5.18 (m, 1H), 5.60 (br; s., 1H), 7.07 (d, J = 8.2 Hz, 2H), 7.18-7.23 (m, 1H), 7.26 ( m, 1H), 7.28 (m, 1H), 7.30-7.35 (m, 3H); MS (ESI) 502.1 [M + H] ", 500.0 [MH] ~.

EXAMPLE 35

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid

309

Stage A.

(5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) piperidin-2-one

To a solution of 1.5 g (4.7 mmol) of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 1, Step E) in 9.4 mL of DMF was added hydride sodium (60% suspension in mineral oil, .244 mg, 6.1 mmol) at 0 ° C. The reaction was stirred at 0 ° C for 20 min and then treated with cyclopropylmethyl bromide (759 pl, 5621 pmol). After stirring at 25 ° C for '5 h, the reaction was quenched (NH4C1 saturated aqueous), extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl and NaHCO3 solutions, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (30 to 50% EtOAc / hexanes, gradient elution) provided the title compound as a colorless foam.

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmet.il) piperidin-2-one

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

310

To a solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one (1481 mg, 3957 pmol; Example 35, Step A) and bromide allyl. (360 µΐ, 4155 µπιοί) in THF (16 mL, 0.25 M) Lithium bis (trimethylsilyl) amide (1M solution in THF, 4352 µΐ, 4352 µπιοί) was added dropwise at -78 ° C. After stirring at -78 ° C for 3 hr, the reaction was quenched (NH4C1 saturated aqueous), extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. . The purification of the residue by flash chromatography (SiO2, 20-30% EtOAc / Hex, gradient elution) provided the title compound as a mixture of stereoisomers.

The individual stereoisomers were separated by HPLC on a Chiralcel OD column (eluent: 25% iPA / hexanes).

Stage C. · 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -11

311

INSTITUTO M1XCAUO PE INDUSTRIAL PROPERTY (cyclopropylmethyl) piperidin-2-one (Example 35, Step B) was acidified as described in Example 1, Step H to give the title compound as a white solid.

XH NMR. (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.46 (1 H, m),

7.40 (2 H, d, J =

8.6 Hz), 7.31-7.35 (2

H, m), 7.22-7.26 (1 (1

H

H, (1 H, s), 4.24 d, J = 8.6 Hz), 5.17

Examples 36 to 40 similar

They were prepared in a process to that described by the example

35, by substituting (bromomethyl) cyclopropane in the

Stage

A for the appropriate amount of alkyl bromide or alkyl iodide

OR

<td>Example</td><td>R1</td>

312 '

EXAMPLE 36

2- ((3R, .5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclobutylmethyl) -2-oxopiperidin-3-yl) acetic acid XH NMR (400 MHz, CDCl-3) δ ppm 1.62 - 1.74 (m, 1H), 1.75

- 1.84 (m, 2H), 1.84 - 2.01 (m, 2H), 2.03 - 2.17 (m, 2H),

2.18 - 2.29 (m, 1H), 2.53 (dd, J = 13.69 and 7.24 Hz, 1H),

2.57 - 2.63 (m, 1H), 2.63 - 2.70 (m, 1H), 2.69 - 2.76 (m, 1

H), 2.76 - 2.85 (m, 1 H), 3.04 - 3.17 (m, 1 H), 4.25 (dd, J =

13.69 and 7.63 Hz, 1 H), 4.76 - 4.89 (m, 1 H), 7.07 - 7.17 (m,

H), 7.22 (d, J = 8.61 Hz, 2H), 7.27 - 7.31 (m, 3H), 7.39 (d, J = 8.61 Hz, 2H). MS (ESI) 446.2 [Μ + H]

EXAMPLE'37

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2-ethylbutyl) -2-oxopiperidin-3-yl) acetic acid XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37 (2 H, d, J =

8.4 Hz), 7.27 (2 H, m), 7.18 (IH, S), 7.15 (2H, d, J = 8.4

313

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

m), 0.89 (3 H, t, J = 8.0 Hz), 0.55 (3 H, t,. J = 8 Hz); MS (ESI) 448.1 [M - H] ~.

EXAMPLE 38

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopentylmethyl) -2-oxopiperidin-3-yl) acetic acid 10 XH NMR (400 MHz, C LORO FORMO-d) δ ppm 7.42 (2 H, d, J =

8.4 Hz), 7.31 (2 H, m), 7.24 (1 H, s), 7.20 (2 H, d, J = 8.4

Hz), 7.11 (1 H, m), 4.93 (1 H, s), 3.87 (1 H, m), 3.16 (1 H,

m), 2.81 (1 H, dd, J = 16.4, 7.8 Hz), 2.68 (1 H, dd, J = 16.4,

3.9 Hz), 2.57 (1 H, m), 2.12 (1 H, m), 2.00 (1 H, m), 1.90- 15 1.65 (6H, m), 1.55-1.40 (2H, m); MS (ESI) 446.0 [Μ - H].

EXAMPLE 39

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((2,2-dimethylcyclopentyl) methyl) -2-oxopiperidin-3-yl) acetic acid XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41 (2 H, d, J =

8.2 Hz), 7.39 (1 H, m), 7.35-7.27 (3 H, m), 7.13 (2 H, d, J =

8.2 Hz), 4.93 (1 H, s), 4.45 (1 H, m), 3.20 (2 H, m), 3.00 (1

H, dd, J = 16.8, 8.0 Hz), 2.51 (1 H, dd, J = 16.8, 3.3 Hz),

2.10 (IH, m), 1.90 (1 H, m), 1.65-1.35 (5 H, m), 0.88 (3 H,

MEXICAN INSTITUTE

OF THE PROPERTY

INlJUSTÍÍa *.

s), 0.53 (3H, s); MS (.ESI) 474.1 [Μ - H] '.

314

EXAMPLE 40

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclohexylmethyl) -2-oxopiperidin-3-yl) acetic acid

<td>XH NMR (400 MHz,</td><td colspan="2">CHLOROFORM-d) δ ppm 7.41</td><td>(2 H, 'd,</td><td>J =</td>

MS (ESI) 460.4 [Μ— H] '.

EXAMPLE 41

Acid

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic (3R, 5R, 6S) -3 -allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) piperidine-2-one (Example 35, Step B) was converted to acid as described in Example 1, Step H for give the title compound as a white solid.

315

1ΜΡΙ

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J =

8.2 Hz), 7.23-7.19 (1 H, m), 7.17-7.12 (1 H, t, J = 7.4 Hz), 7.01 (1 H, s), 6.86 (2 H, d, J = 8.2 Hz), 6.74 (1 H, d, J = 7.4 Hz), 4.63 (1 H, d, J = 10.2 Hz), 3.92 (1 H, dd, J = 14.1, 6.3 Hz), 3.12-2.92 (3 H, m) , 2.60 (1 H, dd, <7 = 15.5, 3.3 Hz), 2.34 (1 H, dd, J = 14.1, 7.4 Hz), 2.29-2.08 (2 H, m), 0.95-0.85 (1 H, m ), 0.55 - 0.47 (1 H, m), 0.46 - 0.39 (1 H, m), 0.15 - (-) 0.02 (2 H, m); MS (ESI) 432.0 [M + H]+, 429.9 [MH]-.

EXAMPLE 42

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxol-propylpiperidin-3-yl) acetic acid

Stage Ά.

(3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one ..

A 100 mL flame dried round bottom flask equipped with a magnetic stir bar was charged with (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one

316

ΙΜΡΙ

MEXICAN INSTITUTE t - '** --- OF YOUR OWN 1Γ »£ * ¿j?

(1.32 g, 4.12 mmol) (Example 1, Step E) and anhydrous THF (41.2 ml). This solution was cooled to 0 ° C under argon and BuLi (3.30 mL, 8.24 mmol) was added. After 10 minutes allyl bromide (0.357 mL, 4.12 mmol) was added. After an additional 45 minutes the reaction was quenched by the addition of NH4C1 saturated aqueous and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organic compounds were accumulated, washed with saturated aqueous NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil. Purification using a Combiflash Companion (flash column chromatography, Teledyne Isco, Lincoln, NE) with a 120 g SiO column2 and eluting with 10 to 100% EtOAc / hexanes provided the title compound.

XH NMR (400 MHz, CDC13) Ó ppm 2.07 (m, 1H), 2.15 (m, 1H),

2.45 (m, 1H), 2.69 (m, 1H), 2.80 (m, 1H), 2.88 (m, 1H), 4.49 (d, J = 10.3 Hz, 1H), 5.13 (m, 2H), 5.82 (br s, 1H), 5.84 (m, 1H), 6.77 (m, 1H), 6.95 (d, J = 8.4 Hz, 2H), 7.01 (m, ÍH),

7.12 (t, J = 7.7 Hz, 1H), 7.18 (m, 1H), 7.21 (d, J = 8.6 Hz,

2H).

INSTITUTO MEXICANO DZ LA PROPIEDAD INDUSTRIAL

317

Stage B. (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-propylpiperidin-2-one.

To a solution of (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) piperidin-2-one (Example 42, Step A) (70 mg, 0.19 mmol) in 430 pL DMF spdio hydride (60% suspension in mineral oil · / 20 mg, 0.51 mmol) was added at 0 ° C. The reaction was stirred- at 0 ° C for 15 min and then treated with 1-bromopropane (53 pL, 0.58 mmol). After stirring at 25 ° C for 4 hr, the reaction was quenched with saturated aqueous NaHCO3 and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl and NaHCO3 solutions, dried over Na2SO4, filtered, and the filtration product was concentrated under reduced pressure. Purification of the residue by prep plate on silica gel (25% EtOAc / hexanes) provided the title compound as a colorless solid.

Stage C. 2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-l-propylpiperidin-3-yl) acetic acid

The title compound was obtained from

318

(3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1propylpiperidin-2-one (Example 42, Step B) by a procedure similar to that described in Example 1 , Step H. Purification by prep plate on silica gel (5% MeOH / DCM) provided the title compound as a white solid.

XH NMR (400 MHz, CDC13) δ ppm 0.78 (t, J = 7.34 Hz, 3 H)

1.33 - 1.45 (m, 1 H) 1.45 - 1.57 (m, 1 H) 2.05 - 2.21 (m, 2

H) 2.48 (ddd, J = 13.89, 9.39 and 5.09 Hz, 1 H) 2.60 (dd, J =

15.94 and 4.79 Hz, 1 H) 2.96 (dd, J = 16.04 and 7.43 Hz, 1 H) 10 2.97 - 3.02 (m, 1H) 3.02 - 3.12. (m, 1H) 3.75 (ddd, J =

13.69, 9.68 and 6.36 Hz, 1 H) 4.41- (d, J = 10.17 Hz, 1 H) 6.66

- 6.76 (m, 1H) 6.87 (d, J = 8.41 Hz, 2H) 6.97 (t, J = 1.66

Hz, 1 H) 7.12 (t, J = 7.83 Hz, 1 H) 7.16 - 7.20 (m, 1 H) 7.23 (d, J = 8.41 Hz, 2 H). MS (ESI) 420.2 [Μ + H] '.

EXAMPLE 43

Acid

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclobutylmethyl) -2-oxopiperidin-3-yl) acetic

N

IMPI

319

Step A. (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclobutylmethyl) piperidin-2-one.

To a solution of (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) piperidin-2-one (Example 42, Step A) (70 mg, 0.19 mmol) in 430 pL DMF sodium hydride (60% suspension in mineral oil, 20 mg, 0.51 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 min and after treatment with (bromomethyl) cyclobutane (66 pL, 0.58 mmol) the reaction mixture was heated to 70 ° C for 15 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCC> 3 and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCI and NaHCO3 solutions, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by prep plate on silica gel (25% EtOAc / hexanes) provided the title compound as a colorless solid.

320

Stage Β.

Acid

INdl 1l ui U MhÁKANU

OF INDUSTRIAL PROPERTY

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclobutylmethyl) -2-oxopiperidin-3-yl) acetic

The title compounds were prepared from (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclobutylmethyl) piperidin-2-one (Example 43, Step A ) as described in Example 1 Step H and purified by reverse phase HPLC on an Eclipse column (45-60% acetonitrile / water, gradient elution) to provide the title compound as a white solid.

XH NMR (400 MHz, CDC13) δ ppm 1.52 - 1.69 (m, 2H), 1.72

- 1.90 (m, 2H), 1.91 - 2.09 (m, 3H), 2.14 (t, J = 12.52 Hz,

EXAMPLE 44

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1isobutyl-2-oxopiperidin-3-yl) acetic acid.

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

321

Stage A. (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-isobutylpiperidin-2-one

To a solution of (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) piperidin-2-one (Example 42, Step A) (78 mg, 0.22 mmol) in 480 pL DMF potassium tert-butoxide (40mg, 0.54mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 min and then treated with l-bromo-2-methylpropane (82 pL, 0.76 mmol). After stirring at 25 ° C for 4 hr, the reaction was quenched with saturated aqueous NaHCO3 and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl and NaHCO solutions3, dried on Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by silica gel prep plate (25% EtOAc / hexanes) provided the title compound as a

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4322 colorless solid.

Stage B. Chlorophenyl) -l-isobutyl-2-oxopiperidin-3-yl) acetic acid.

The title compound was prepared from isobutylpiperidin-2-one (Example

44,

Step A) as described in Example 1, Step H to provide a white solid.

XH NMR (400 MHz, CDC13) δ ppm

0.83 (d, J = 6.65

Hz, 3 Η),

0.85 (d, J = 6.85 Hz, 3 Η), 1.93

J = 8.39 and 6.66 Hz, 1 (m, 1 Η), 2.60 (dd, J =

15.85 and 4.30

3.03 (m,

Hz, 1 Η), 2.90

EXAMPLE 45

Acid

323

IMPI

Stage A.

(3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopentylmethyl) piperidin-2-one

The title compound was prepared from (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin2-one (Example 42, Step A) and (bromomethyl) cyclopentane as described in Example 44, Step A. Purification of the residue by prep plate on silica gel (25% EtOAc / hexanes) provided the title compound as a colorless solid.

Stage B. 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopentylmethyl) -2-oxopiperidin-3-yl) acetic acid.

The title compound was prepared from (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopentylmethyl) piperidin-2-one (Example 45, Stage A) as

Stage H to provide a

KOBiG »

324

MEXICAN INSTITUTE

DS INDUSTRIAL PROPERTY is described in Example 1 white solid.

EXAMPLE 46

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo acid

1- (pentan-3-yl) piperidin-3-yl) acetic

Stage

TO.

chlorophenyl) -1- (pentan-3-yl) piperidin-2-one

325

To a solution of (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) piperidiri-2-one (Example 42, Step A) (440 mg, 1,221 mmol) in 3-Bromopentane (3196 pL, 25.6 mmol) under nitrogen at rt a dispersion of 60% sodium hydride in mineral oil (244 mg, 6.11 mmol) was added. The evolution of the gas was observed. The reaction was stirred at room temperature for 10 min and then heated to 120 ° C under N2 for 19 h. The reaction mixture was cooled to room temperature and quenched with NH4CI sat. The layers were separated and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title compound (375 mg, 71% yield) as a mixture of diastereomers.

Stage B. 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-1- (pentan-3-yl) piperidin-3-i1) acetic acid

The title compound was prepared from (5R, 6S) 3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-l- (pentan-3yl) piperidin-2-one (Example 46, Step A) as described in

326

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

Example 1 Stage H.

Reverse phase preparative HPLC purification (eluent: 0 to 100% MeCN + 0.1% TFA in water +

0.1% TFA, for 20 minutes) provided the compound of the

Title.

<td></td><td>XHR!</td><td>MN (400 M</td><td colspan="2">Hz, CHLOROFORM-d)</td><td>δ ppm</td><td>0.55 (t,</td><td>J =</td><td> 7.53</td>

<td>from M</td><td>handles</td><td>(ESI) m / z</td><td> = 448</td><td>[M + H]+.</td><td></td><td></td><td></td><td></td>

EXAMPLE 47

Methyl 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl)

To a suspension of 250mg (0.578 mmol) of 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic (Example 35) in MeOH (3 mL) thionyl chloride (78.0 µΐ, 1070) was added

IMPI

327 MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL pmol) drop by drop at 0 ° C. After stirring at 25 ° C for

14h, the reaction was diluted (EtOAc), basified (NaHCO3 sat), extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4, filtered, and the filtration product was concentrated under reduced pressure to provide the title compound as a colorless liquid.

<td>XH NMR (400</td><td>MHz, CHLOROFORM-d) δ</td><td>PPm</td><td> 7.53-7.49</td><td> (1</td><td>H</td><td>m)</td>

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamide

In a sealed tube, 60mg (134 pmol) of 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2oxopiperidin-3-yl) acetate Methyl (Example 47) and 4.8 mL of a solution of ammonia in methanol (7N, 3.4mmol) were stirred at ° C for 5 days. Then NaCN (3 mg) was added and the resulting solution was stirred at 50 ° C for 3 days. NH removed3 and excess MeOH under reduced pressure. The

328 r

MEXICAN INSTITUTE £ 4 ^ * ·· ^ -, OF THE PROPERTY

INDUSTRIAL reverse phase HPLC separation (10 to 90% AcCN / H2Or in 45 min) provided the title compound as a white solid.

<td></td><td></td><td>XH NMR</td><td colspan="3">(400 MHz, CHLOROFORM-d)</td><td>δ</td><td>ppm</td><td> 7.52-7</td><td> .45 (1</td><td>H</td><td>m),</td>

m); MS (ESI) 430.9 [Μ + H]_.

EXAMPLE 49

Ethyl ethyl 2- (2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamido)

329

INSTITUTO MEX'CA NO V> DE LA PROF-¡EDAD INDUSTRIAL

A 40mg solution. (93 pmol) 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2oxopiperidin-3-yl) acetic acid (Example 35) and Ethyl 2-aminoacetate hydrochloride (14 mg, 102 pmol) in DMF (0.31 mL) was treated at 0 ° C with NI - ((ethylimino) methylene) -N3, N3dimethylpropane-1,3-diamine hydrochloride (27 mg, 139 pmol ), 3H [1,2,3] triazolo [4,5-b] pyridin-3-ol (19 mg, 139 pmol), and sodium acid carbonate (23 mg, 278 pmol), successively. After stirring at 25 ° C for 12 hr, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were successively washed with 10% aqueous citric acid, saturated aqueous NaHCC solution> 3, and saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO240% to 60% EtOAc / Hexanes, gradient elution) provided the title compound as a colorless film.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.47 (1 H, m),

7.35 (2 H, d, J = 8.6 Hz), 7.32-7.28 (2 H, m), 7.26-7.24 (1 H, m), 7.16 (2 H, d, J = 8.2 Hz), 6.89 (1 H , br, s), 5.11 (1 H, s), 4.27-4.18 (3 H, m), 4.11-3.98 (2 H, m), 3.20-3.15 (1 H, d, J = 1.6 Hz), 2.83 -2.72 (1 H, m), 2, 63-2.55 (2 H, m),

2.32-2.16 (2 H, m), 1.95-1.87 (1 H, m), 1.29 (3 H, t, J = 7.0

330

OF INDUSTRIAL PROPERTY

Hz), 1.22-1.12 (1 H, m), 0.72-0.62 (1 H, m), 0.60-0.52 (1 H,

m), 0.30-0.18 (2H, m); MS (ESI) 516.8 [M + H]+ .

EXAMPLE 50

2- (2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamido) acetic acid

To a 38mg (73 pmol) solution of 2- (2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2-oxopiperidin-3-yl ) acetamido) ethyl acetate (Example 49) in 0.75mL MeOH / THF / H2Or (2/2/1) a 2M solution of lithium hydroxide in water (70 pl, 141 pmol) was added at 25 ° C and the mixture was stirred for 10 h. The reaction was acidified (IN aq. HCI) and extracted with DCM (2X). The combined organic layers were washed successively with 10% aqueous citric acid solution and saturated aqueous NaCl solution, dried over Na2SC> 4, filtered and the filter product was concentrated under reduced pressure. Purification of the residue by reverse phase HPLC (10 to 90% AcCN / H2Or with 0.1% TFA in 45 min) provided the title compound as a white solid.

331

δ ppm 7.37-7.34 (1 H, m), XH NMR (400 MHz,

CHLOROFORM-d)

7.35 (2 H, d, J = 8.2 Hz), 7.27-7.25 (1 H, m), 7.23-7.19 (1

H, m), 7.17-7.14 (1 H, m), 7.08 (2 H, d, J = 8.2 Hz), 5.00 (1

EXAMPLE 51

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetohydrazide

To a solution of 120mg (0.27 mmol) of 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2oxopiperidin-3-yl) acetate Methyl (Example 47) in EtOH was added or hydrazine, monohydrate (135 µΐ, 2688 pmolj. After refluxing for 14h, the reaction was concentrated, diluted (H2O) and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4were filtered and the filter product was

332 concentrated low

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

reduced pressure. Purification of the residue by flash chromatography on silica gel (5% MeOH / CH2Cl2, gradient elution) provided the title compound as a white solid.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52-7.46 (1 H, m),

0.59-0.52 (1H, m), 0.30-0.18 (2H, m); MS (ESI) 445.9 [M +

EXAMPLE 52

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) -N-hydroxyacetamide

A 30mg (0.07 mmol) solution of 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid (Example 35) in DMF (0.5 mL, c = 0.14 'M) was treated with Ni333 hydrochloride

((ethylimino) methylene) -N3, N3-dimethylpropane-l, 3-diamine (0.03 g, 0.1 mmol), 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (0.02 g,

0.1 mmol), hydroxylamine hydrochloride (0.006 ml, 0.1 mmol) and sodium acid carbonate (0.02 g, 0.2 mmol) successively. After stirring at 25 ° C for 12 hr, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed successively with saturated aqueous NaHCO solution3 and saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10 to 90% AcCN / H2O with 0.1% TFA in 45 min) to give the title compound as a white solid.

<td colspan="2">XH NMR</td><td> (400</td><td>MHz, CHLOROFORM-d)</td><td>δ</td><td>ppm 7</td><td> . 45</td><td>(1 HOUR,</td><td>s)</td>

2.30 (2 H, dd, J = 14.1, 7.8 Hz), 1.91 (1 H, br. S.), 1.15 (1

H, d, J = 2.0 Hz), 0.77-0.65 (1 H, m), 0.65-0.51 (1 H, m),

0.37-0.14 (2H, m).

INSTITUTO MEXb.Ar de LA PROPitDAÜ

INDUSTRIAL f5

334

2 - ((2S, 3R, 5R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -5- (2 (methylsulfonamido) -2-oxoethyl) -6-oxopiperidin-l-yl) butanoate (S) -ethyl

Methanesulfonamide (0.02 g, 0.2 mmol), N-ethyl-Nisopropylpropan-2-amine (0.05 ml, 0.3 mmol), di (lH-imidazole-

1- yl) methanone (0.04 g, 0.2 mmol) and 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -l-ethoxy- l-oxobutan-2-yl) -

2- oxopiperidin-3-yl) acetic (Example 3, 0.030 g, 0.06 mmol) were combined in 2mL of THF. After stirring at 25 ° C for 12 h, saturated NH solution4C1 was added and the reaction mixture was extracted with EtOAc. The combined organic layers were successively washed with saturated aqueous NaHCO solution3 and saturated aqueous NaCl solution, dried over Na2SO4, filtered, and the filtration product was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10 to 90% AcCN / H2Or with 0.1% TFA in 45 min) to give the title compound as a white solid.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.45-7.33 (3 H, m),

335

INDUSTRIAL

7.33-7.21 (5 H, m), 4.88 (1 H, d, J = 3.9 Hz), 4.27-4.10 (2 H, m), 3.48 (1 H, dd, J = 8.8, 3.3 Hz), 3.3 o "73" h? ——- and— ™

H, dd, J = 4.Ί, 0.8 Hz), 3.04-2.74 (2 H, m), 2.72-2.59 (1 H, m), 2.48-2.28 (2 H, m), 2.03 (1 H, s ), 1.63-1.46 (1 H, m),

I. 28 (3 H, t, J = 7.2 Hz), 0.69 (3 H, t, J = 7.4 Hz).

EXAMPLE 54

2- ((2S, 3R, 5R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -5- (2 - ((3morpholinopropyl) amino) -2-oxoethyl) -6-oxopiperidin-lil) (S) -ethyl butanoate

The title compound was prepared as described in Example 49, using 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) - acid.

6- (4-Chlorophenyl) -1 - ((R) -l-ethoxy-l-oxobutan-2-yl) -2oxopiperidin-3-yl) acetic (Example 3) as the starting material.

XH NMR (400 MHz, CHLOROFORM-d} δ ppm 7.34 (2 H, d, J =

8.6 Hz), 7.30-7.16 (5 H, m), 7.11-7.03 (1 H, m), 4.73 (1 H, d, J = 5.5 Hz), 4.14 (2 H, q, J = 7.3 Hz), 4.09-3.92 (4 H, m), 3.67-3.51 (2 H, m) ', 3.50-3.40 (1 H, m), 3.39-3.30 (2 H, m), 3.25 (1 H, dd, J = 8.8, 3.3 Hz), 3.22-3.12 (2 H, m), 2.98-

336

2.50 (5H, m),. 2.33-2.03 (5 Η, m), 1.52-1.37 (0 Η, m), 1.26 (3 Η, t, J = 7.2 Ηζ), 0.60 (3 Η, t, J = 7.4 Ηζ).

(3R, 5R, 6S) -3 - ((lH-Tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one

Stage A. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetonitrile

A 136mg (0.315mmmol) solution of 2 - ((3R, 5R, 6S) -5 (3-cl.orophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2oxopiperidin-3-yl) acetamide (Example 48) and triethylamine (220 pl, 1576 pmol) in 5mL THF was treated with trifluoroacetic anhydride (lll pl, 788 pmol) at 0 ° C. After stirring at 0 ° C for '2 h, the reaction was quenched (saturated NH4CI), extracted (2

EtOAc) and washed (solution

IMP

337 saturated aqueous NaCl). The combined organic layer was dried (Na2SW4) and concentrated under reduced pressure.

After stirring at 0 ° C for 2 h, the saturated NH solution4C1 was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. The purification of the residue by flash chromatography (SiO2, 20-25% EtOAc / Hexanes) provided the title compound which was used without further purification.

Step B. (3R, 5R, 6S) -3 - ((lH-Tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2one

To a solution of 136mg (0.33mmol) of 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2oxopiperidin-3-yl) acetonitrile ( Example 55, Step A) In 1.8 mL of DMF, ammonium chloride (176 mg, 3290 pmol) and sodium azide (214 mg, 32 90 pmol) were added. The resulting mixture was stirred at 90 ° C for 4 days. Then, the reaction was acidified (10% aqueous citric acid) and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4, leaked and the

338 Filtration product was concentrated under reduced pressure. The iMPir?

MEXICAN INSTITUTE \

OF PROPERTY t _

INDUSTRIAL '«CLÚ

<td>HPLC separation</td><td>reverse phase</td><td>(60-90% AcCN / H2OR</td><td>in 30</td>

<td>min) provided the</td><td>composed of</td><td>title like a</td><td>solid</td>

<td>White.</td><td></td><td></td><td></td>

<td>XH NMR (400 MHz,</td><td>CHLOROFORM-d) δ</td><td>ppm 7.51-7.48 (1</td><td>H, s),</td>

7.35 (2 H, d, J = 8.2 Hz), 7.32-7.28 (2 H, m), 7.25-7.21 (1 H, m), 6.86 (2 H, d, J 8.2 Hz), 5.14 (1 H, s), 4.23 (1 Ή, dd, J = 14.1, 6.7 Hz), 3.40 (1 H, dd, J = 15.3, 3.1 Hz), 3.28-3.20 (1 H, m), 3.15 (1 H, dd, J = 15.1, 8.0 Hz), 2.60 -

2.52 (1 H, m), 2.33 (1 H, dd, J = 14.1, 8.2 Hz), 2.26-2.18 (2

H, br. s.), 2.04-1.93 (1 H, m), 1.25-1.15 (1 H, m), 0.77-0.70 (1 H, m), 0.68-0.59 (1 H, m), 0.36-0.24 (2 H , m); MS (ESI)

456.0 [Μ + H], 453.9 [Μ - H].

(3R, 5R, 6S) -3 - ((1,3,4-oxadiazol-2-yl) methyl) -5- (3-chlorophenyl) -

6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one

To a 20mg (45 pmol) solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2339

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

oxopiperidin-3-yl) acetohydrazide (Example 51 1 in 0.2 τηΤ, typ toluene ethyl formimidate hydrochloride (6.4 mg, 58 μιηοΐ) was added. The reaction mixture was heated to reflux for 14h and then the reaction was concentrated under reduced pressure Reverse phase HPLC separation (10 to 90% ACCN / H2O in 40 min) provided the title compound as a colorless film.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.35 (1 H, s),

456.0 [M + H] + .

EXAMPLE 57

(cyclopropylmethyl) -3 - ((5-methyl-l, 3,4-oxadiazol-2yl) methyl) piperidin-2-one (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4- chlorophenyl) -1340

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

To a 40mg (90 pinol) solution of 2 - ((3R, 5R, 6S) -5- (3chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2oxopiperidin-3-yl) acetohydrazide (Example 51) in 0.2 · mL of toluene, acetimidate hydrochloride mg, 116 pmolj was added. The reaction mixture was heated to reflux for 14h and then the reaction was concentrated under reduced pressure.

Reverse phase HPLC separation (10 to 90% AcCN / H2Or in 45 min) provided the title compound as a colorless film.

TH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.47-7.45 (1 H, sj,

7.38 (2 H, d, J = 8.6 Hz), 7.33-7.29 (2 H, m), 7.24-7.19 (1

H, m), 7.15 (2 H, d, J = 8.6 Hz), 5.12-5.10 (1 H, mj, 4.18 (1

H, dd, J = 14.1, 6.7 Hz), 3.38-3.23 (2 H, m), 3.22-3.18 (1 H,

H].

EXAMPLE 58

IMPI

341

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) -N (methylsulfonyl) acetamide.

To a solution of 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2-oxopiperidin-3yl) acetic acid (Example 41) (83 mg, 0.192 mmol), methanesulfonamide (22.59 mg, 0.230 mmol) and 4-dimethylaminopyridine (1.057 mg, .00865 mmol) in DCM (2 mL), diisopropylethylamine (80 pL, 0.461 mmol) was added. The reaction mixture was stirred at room temperature for one minute before adding bromo-tris-pyrrolidinophosphonium hexafluorophosphate (125mg, 0.269mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with HCI IN and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with HCI IN, NaOH IN, saturated aqueous NaCl solution and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (column: Gemini-NX Ci8 5um;

Phenomonex, Torrance, CA; eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes) to result in the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm -0.06 - 0.04 (m, 1

H) 0.06 - 0.16 (m, 1 H) 0.43 (dd, J = 8.51 and 4.60 Hz, 1 H) 0.47 - 0.60 (m, 1 H) 0.88 (d, J = 6.26 Hz, 1 H) 2.09 - 2.18

342 (m, 1 Η) 2.29 (dt, J = 14.04 and 6.77 Hz,

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

<td>H) 7.00</td><td>(d, J</td><td>= 1.76 Hz,</td><td>1 H) 7.1</td><td> 0-7</td><td> .26</td><td>(m, 4H). Esp</td><td>ectro</td>

<td>of masses</td><td>(ESI)</td><td>m / z = 509</td><td>[M + 'H] + .</td><td></td><td></td><td></td><td></td>

EXAMPLE 59

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamide.

NH2

Stage A. Methyl methyl 2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl)

To a solution of 2 - ((3S, 5R, 6S) -5- (3-chlorophenylj6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2-oxopiperidin-3IMPI

343 yl) acetic (Example 41) (500 mg, 1,156 mmol) in 10% MeOH in

DCM (10 mL) (trimethylsilyl) diazomethane (2.0 M in diethyl ether) (1 mL) was added. The yellow reaction mixture was stirred at room temperature for 30 min. The reaction was concentrated under reduced pressure and purified by flash chromatography on silica gel (eluent: 0 to

50% EtOAc in hexanes) to give the title compound as a clear oil.

Stage B.

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -1- (cyclopropylmethyl) -2-oxopiperidin-3yl) acetamide.

A sealed tube was loaded with methyl 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2-oxopiperidin-3-yl) (Example 59 , Step A) (109 mg, 0.244 mmol), ammonia, 7N solution in methanol (2 ml, 14.00 mmol) and sodium cyanide (1,197 mg, 0.024 mmol). The tube was sealed and heated to 50 ° C. The pressure reached 35 kilopascals after 1 hour. The reaction was stirred at 50'C for 18h. The reaction was cooled to rt and bubbled

344 anhydrous ammonia (gas) through the solution for minutes at room temperature.

The hill heated up

50 ° C over cooled to ambient.

° C during

IMPIí reaction mixture

h. The reaction was bubbled with anhydrous ammonia (gas) solution for twenty minutes at a temperature. Reaction mixture was closed and heated up to 50 days.

The crude reaction was concentrated under reduced pressure and purified in reverse (column: Gemini-NX Ci8 5um;

Phase preparatory HPLC

Phenomonex, Torrance, CA;

eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes) to result in the title compound.

ΤΗ NMR (4 00 MHz, CHLOROFORM-d) δ ppm 0.04 - 0.15 (m, 1

H) 0.06 - 0.15 (m, 1 H) 0.36 - 0.45 (m, 1 H) 0.46 - 0.56 (m,

H) 0.79 - 0.93 (m, 1 H) 2.11 - 2.20 (m, 1 H) 2.29 (dt, J = 13.99, 6.90 Hz, 1 H) 2.64 - 2.73 (m, 1 H) 2.75 - 2.83 (m, 1 H) 2.96 - 3.13 (m, 2H) 3.91 (dd, J = 14.09, 6.46 Hz, 1H) 4.63 (d, J = 9.98 Hz, 1H) 6.41 (br. S., 1H) 6.75 (dt , J = 7.58, 1.59 Hz, 2 H) 6.83 - 6.90 (m, 2 H) 7.01 (t, J = 1.96 Hz, 1 H) 7.10-

7.26 (m, 4H). Mass Spectrum (ESI) m / z = 431 [M + H]+.

EXAMPLE-60 (3S, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

Step A. (3S, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one

A 100 mL round bottom flask was placed under vacuum and heated with a heat gun to ensure dryness. The flask was allowed to cool to room temperature and a 500 mg (1.56 mmol) solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 1, Step E) in THF (12 mL) under argon was added and cooled to 0 ° C. Butyllithium (1.6M in hexanes, 2440 pL, 3.90 mmol) was added followed by 5-chloromethyl-lH-tetrazole (185 mg, 1,561 mmol) and the reaction mixture was stirred for 15 minutes at 0 ° C. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The aqueous layer was acidified with 1M HC1. The aqueous layer was extracted with ethyl acetate (2 x 30 mL) and the combined organic layers were washed with saturated aqueous NaCl solution, dried

346

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

on sodium sulfate, and concentrated under reduced pressure -------. The residue was purified by reverse phase preparative HPLC (column:

Gemini-NX Ci8 5um;

Phenomonex,

Torrance, CA;

eluent: 0 to 100% MeCN + 0.1%

TFA in water +

0.1% TFA, for 25 minutes) to result in the title compound.

Step B. (3S, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2one

A solution of (3S, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) 5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 60, Step A) (65 mg, 0.162 mmol) in DMF (1.6 mL) was cooled to 0 ° C and sodium tert-butoxide (31.1 mg, 0.323 mmol) was added. The reaction mixture was stirred at 0 ° C for ten minutes before adding (bromomethyl) cyclopropane (78 pL, 0.808 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours, quenched with saturated ammonium chloride, and diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the organic layers were combined, washed with 1M LiCl, saturated aqueous NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (column: Gemini-NX

INSTITUTE · :DEL 'DELA

INDUSTRIAL k

347 column Cie 5um; Phenomonex, Torrance, CA; eluent: 0 to 100%

MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes) to result in the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm -0.08 - 0.02 (m, 1

H) 0.11 (dt, J = 9.44 and 4.77 Hz, 1 H) 0.38 - 0.46 (m, 1 H)

0.50 (td, J = 8.31 and 4.50.Hz, 1 H) 0.78 - 0.89 (m, 1 H) 2.18

- 2.28 (m, 2H) 2.31 - 2.41 (m, 1H) 2.96 - 3.07 (m, 2H)

3.29 (dd, J = 14.87 and 7.82 Hz, 1 H) 3.47 - 3.56 (m, 1 H) 3.89 (dd, J = 14.09 and 6.46 Hz, 1 H) 4.58 (d, J = 9.98 Hz, 1 H)

6.71 - 6.76 (m, 1 H) 6.80 - 6.87 (m, 2 H) 6.98 (d, J = 1.76 Hz, 1 H) 7.12 - 7.18 (m, 1 H) 7.19 - 7.25 (m, 3 H). Mass Spectrum (ESI) m / z = 456 [Μ + H].

EXAMPLE 61 (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3 - ((5-methylisoxazol-3-yl) methyl) piperidin2-one

The title compound was prepared from (5R, 6S) 5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 1,

348

MEXICAN INSTITUTE

FROM THE PROIIL ^ j:

INDUSTRIAL

Step E), 3- (bromomethyl) ~ 5-methyliswcage'Í7 · '· ........... and (bromomethyl) cyclopropane as described in Example 60.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm -0.05 - 0.04 (m, 1

H) 0.05 - 0.14 (m, 1 H) 0.32 - 0.41 (m, 1 H) 0.42 - 0.51 (m, 5 1 H) 0.79 - 0.94 (m, 1 H) 2.04 - 2.09 (m, 2 H) 2.28 (dd, J =

14.28 and 7.24 Hz, 1 H) 2.37 (d, J = 0.59 Hz, 3 H) 2.86 - 3.04 (m, 3 H) 3.33 - 3.41 (m, 1 H) 3.93 (dd, J = 14.18 and 6.55 Hz,

H) 4.56 (d, J = 9.98 Hz, 1 H) 5.92 (d, J = 0.78 Hz, 1 H)

6.70 (dt, J = 7.58 and 1.30 Hz, 1 H) 6.80 - 6.86 (m, 2 H) 6.95 10 (t, J = 1.76 Hz, 1 H) 7.06 - 7.11 (m, 1 H) 7.13 - 7.17 (m, 1

H) 7.17 - 7.23 (m, 2H). Mass Spectrum (ESI) m / z = 469 [Μ + H]1 .

EXAMPLE 62 (rae) Acid 2 - ((2'S, 3'R, 5'R) -6-chloro-3 '- (3-chlorophenyl) -1' (cyclopropylmethyl) -2,6'-dioxoespiro [indolin-3 , 2'-piperidin] -

Stage A. 1- (3-Chlorophenyl) pent-4-en-l-ona

349

OR.

To a solution of 3-chlorobenzoyl chloride (7 ml, 54.7 mmol) in THF (60 mL) was added copper (I) iodide (0.521 g, 2.73 mmol). The thick mixture was cooled to -10 ° C and 3-butenylmagnesium bromide (0.5M in THF) (112 ml, 55.8 mmol) was added dropwise via cannula over 30 min. The reaction mixture was stirred at -10 ° C for 1 hr and then warmed to room temperature. The reaction mixture was concentrated to 25 mL and diluted with 100 mL DCM and 100 mL 1M HC1. The layers were separated and the organic layer was filtered. The filter product was washed with saturated NaHCO3, dried over Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 50% DCM in hexanes) to give the title compound.

Stage B. 6-chloro-3- (1- (3-chlorophenyl) pent-4-enyliden) indolin

2-one

It combines a mixture of 1- (3-chlorophenyl) pent-4-en-l-one (Example

62, Step A) (14.86 g, 76 mmol) and 6-chloroindolin-2-one (12.79 g, 7 6 mmol) in toluene (50 mL) at room temperature pyrrolidine (6.31 mL, 76 mmol) was added. The thick mixture was heated to reflux with a Dean Stark trap for 6 h. The reaction mixture was cooled to room temperature and

concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 10 to 20% EtOAc in hexanes) to give the title compound.

Stage C.

6-chloro-3- (1- (3-chlorophenyl) pent-4-enyl) indolin-220 one

To a mix

6-chloro-3- (1- (3-chlorophenyl) pent-4-enylidene) indolin-2-one (Example 62, Step

B) (12.81 g, 37.2 mmol) in MeOH (200 mL) at room temperature, borohydride was added slowly

351

44.7 mmol). The evolution of the gas was observed. The yellow reaction mixture was stirred at room temperature for 30 min. Additional sodium borohydride (1,689 g, 44.7 mmol) was added slowly and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was emptied into water (200 mL). A precipitate formed and the mixture was sonicated for 15 min then filtered. The filtration product was concentrated under reduced pressure to 36 mL and then extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure to provide the title compound.

Stage D. 3-bromo-6-chloro-3- (1- (3-chlorophenyl) pent-4enyl) indolin-2-one

To a solution of 6-chloro-3- (1- (3-chlorophenyl) pent-4enyl) indolin-2-one (Example 62, Step C (13.0 g, 37.5 mmol) in THF (200 mL) (previously degassed with Ar) at -78 ° C under Ar, NI, NI, Ñ2, N2-tetramethylethane-l, 2-diamine (11.79 mL, 79 mmol) (previously degassed with Ar) was added and

butyllithium (1.6 M in hexanes) (49.3 mL, 79 mmol) (previously degassed with Ar) by means of addition funnel. The light brown reaction mixture was stirred at -78 pcs for 30 min., Wrapped in metal foil, and 1bromopyrrolidine-2,5-dione (6.68 g, 37.5 mmol) was recrystallized from THF (50 mL) (previously degassed with Ar ) was added via cannula. After addition the reaction was immediately quenched with monobasic saturated potassium phosphate and warmed to room temperature. The mixture was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 10% EtOAc in hexanes) to give the title compound as a 1: 1.7 ratio of diastereomers.

Stage E. 4- (3-Bromo-6-chloro-2-oxoindolin-3-yl) -4- (3-chlorophenyl) butanoic acid

To a rapidly stirred solution of 3-bromo-6-chloro-3 (1- (3-chlorophenyl) pent-4-enyl) indolin-2-one (Example 62, Step

353

H2O / CCl4/ MeCN (1.5 / 1/1)

D) (7.74 g,

18.21 mmol) in (80mL / 50mL / 50 mL)

mmol) and ruthenium (III) chloride hydrate (0.205 g, 0.910 mmol). The reaction mixture was vigorously stirred for 30 min and the reaction was observed on TLC. The reaction mixture was acidified (10% citric acid) and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCI solution, dried over Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 30 to 70% EtOAc in hexanes) to give the title compound.

Stage F.

Methyl 4- (3-bromo-6-chloro-2-oxoindolin-3-yl) -4- (3- chlorophenyl) butanoate

To a solution of 4- (3-bromo-6-chloro-2-oxoindolin3-yl) -4- (3-chlorophenyl) butanoic acid (Example 62, Step E) (5.38 g, 12.14 mmol) in MeOH (120 mL ) at room temperature a drop of concentrated sulfuric acid was added. The reaction mixture was stirred at room temperature for 18 hr and then concentrated under reduced pressure. The residue was purified

354 by instant chromatography on

ΛΛ.Λ.ΛΛ TO THE MEXICAN INSTITUTE Γ, 'DE LA PROPIEDAD V ——

INDUSTRIAL silica (eluent:

to 50% EtOAc in hexanes) to give the title compound.

Step G. (rae) 4 - ((S) -6-chloro-3- (cyclopropylmethylamino) -2oxoindolin-3-yl) -4- (3-chlorophenyl) butanoate of (S) -methyl and (rae) 4- ((S) -6-Chloro-3- (cyclopropylmethylamino) -2-oxoindolin3-yl) -4- (3-chlorophenyl) butanoate (R) -methyl

A solution of methyl 4- (3-bromo-6-chloro-2-oxoindolin-3-yl) -4 (3-chlorophenyl) butanoate (Example 62, Step F) (110 mg, 0.241 mmol) in DCE (4 mL) was heated under reflux. Cesium carbonate (157 mg, 0.481 mmol) and cyclopropylmethylamine hydrochloride (25.9 mg, 0.241 mmol) in DCE (1 mL) were added in one portion. The reaction mixture was heated under reflux for 5 h and then cooled to room temperature.

Washed

.1 1

INSTITUTO MEÍ ^ -V'O DE LA PÍT- i— ΛΟ de celite yi ce?

and chromatized «crraf la '355

The reaction mixture was filtered through with DCM. The filtration product separated the diastereomeric pairs instantaneously on silica gel (eluent: 20 to 60% Et <DAc in hexanes) to give the title compounds. The more polar isomeric ring is used in Example 62, Stage H.

Stage H. (rae) (2 'S, 3'R) -6-chloro-3' - (3-chlorophenl_ 1) -1 '(cyclopropylmethyl) spiro [indolin-3,2' -piperidin] -2.6 '-dioná

A solution . (R) -methyl (R) -methyl (rae) 4 - ((S) -6-chloro-3 (cyclopropylmethylamino) -2-oxoindolin-3-yl) -4- (3-chlorophenyl) butanoate (Example 62, Step G, further isomer polar) in DCM washed with NaHCOa sat, dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved with distilled xylene (5 mL), and the reaction mixture was heated to 135 ° C for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 20 to 60% EtOAc in hexanes) to give the title compound.

356

Stage I.

(rae)

INSTITUTE

OF THE PZOPJEDAD V «. • iNDUSTfJAL (21S, 3'R) -6-chloro-3 '- (3-chlorophenyl) (cyclopropylmethyl) -1 - ((2 (trimethylsilyl) ethoxy) methyl) spiro [indolin-3,2'-piperidin] 2,6' -diona

To a solution of (rae) (2'S, 3'R) -6-chloro-3'- (3chlorophenyl) -1 '- (cyclopropylmethyl) spiro [indolin-3,2' piperidin] -2,6'-dione ( Example 62, Step H) (114 mg, 0.274 mmol) in DMF (2 mL) at 0 ° C A dispersion of 60% sodium hydride in mineral oil (10.98 mg, 0.274 mmol) was added followed by (2- (chloromethoxy ) ethyl) trimethylsilane (48.4 pL, 0.274 mmol). The reaction mixture was stirred at 0 ° C for 30 min and then warmed to room temperature and stirred at room temperature for 24 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with 1M LiCl, saturated aqueous NaCl solution, dried over Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 50% EtOAc in

JL íap! / ^andL

35W

357 hexanes) to give the title compound.

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Stage J.

(rae) (2'S, 3'R, 5'S) -5'-allyl-6-chloro-3 '- (3chlorophenyl) -1' - (cyclopropylmethyl) -1 - ((25 (trimethylsilyl) ethoxy) methyl) spiro [ indolin-3,2'-piperidin] 2,6'-dione

To a solution of (rae) (2 'S, 3' R) -6-chloro-3 '- ΟοΙοτοίβηϋ) -1' - (cyclopropylmethyl) -1- ((215 (trimethylsilyl) ethoxy) methyl) spiro [indolin- 3,2'-piperidin] 2,6'-dione (Example 62, Stage I) (97mg, 0.178mmol) in THF (1mL) at -78 ° C under Ar Freshly prepared LDA (1.0M in THF) was added (178 pL, 0.178 mmol). The color of the reaction turned yellowish orange. The reaction was stirred at -78-20 ° C for 30 min then distilled allyl bromide (15.39 pL,

0.178 mmol) was added. The reaction was stirred at -78 ° C for min then warmed to 0 ° C. The reaction died down with

NH4C1 saturated and warmed to room temperature. The mixture was diluted with EtOAc and the layers were separated. The layer

I.. (MEXICAN TUTO

OF THE PROPERTY

INDUSTRIAL

358 organic dried over Na2SW4 and concentrated under reduced pressure.

The residue was purified by flash chromatography on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title compound.

Step K. (rae) Acid 2 - ((2'S, 3'R, 5'R) -6-chloro-3 '- (3chlorophenyl) -1' - (cyclopropylmethyl) -2,6'-dioxo-1- ( (2 (trimethylsilyl) ethoxy) methyl) spiro [indolin-3,2'-piperidin] -5'il) acetic

To a rapidly stirred solution of (rae) (2 'S, 3' R, 5 'S) -5'-allyl-6-chloro-3' - (3-chlorophenyl) -1 '(cyclopropylmethyl) -1- ( (2 (trimethylsilyl) ethoxy) methyl) spiro [indolin-3,2'-piperidin] 2,6'-dione (Example 62, Step J) (46 mg, 0.079 mmol) in

HaO / CClí / MeCN (0.75ml / .5 mL / .5 mL) added sodium periodate (67.2 mg, 0.314 mmol) and ruthenium (III) chloride hydrate (1,771 mg, 7.85 pinol). The reaction mixture was vigorously stirred for 19 h 'and then acidified (acid

IMPI

359 10% citric) and filtered through a celite plug and washed with EtOAc

The filter-product was transferred to a separatory funnel and extracted with EtOAc. The organic layer was dried over Na2SW4 and concentrated under reduced pressure to provide the title compound.

Stage L. (rae) Acid 2 - ((2'S, 3'R, 5'R) -6-chloro-3 '- (3 chlorophenyl) -1' - (cyclopropylmethyl) -1- (hydroxymethyl) -2.6 'dioxoespiro [indolin-3,2'-piperidin] -5'-yl) acetic

To a solution of (rae) acid 2 - ((2'S, 3'R, 5'R) -6-chloro3'- (3-chlorophenyl) -1 '- (cyclopropylmethyl) -2,6'-dioxo-1- ((2 (trimethylsilyl) ethoxy) methyl) spiro. [Indolin-3,2 '-piperidin] -5' yl) acetic (Example 62, Step K) (47 mg, 0.078 mmol) in DCM (0.8 mL) at temperature environment 0.2 mL of TFA was added. The reaction mixture was stirred at room temperature for 19 h before concentrating under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes) to give the title compound.

360

MEXICAN INSTITUTE \ OF PROPERTY V '' «L · .....

INDUSTRIAL

Stage M. (rae) Acid 2 - ((2 ^, 3 ^, 5 ^) - 6-010 ^ -3 ^ (3chlorophenyl) -1 '- (cyclopropylmethyl) -2,6'-dioxoespiro [indolin3,2' -piperidin] -5'-yl) acetic

To a solution of (rae) acid 2 - ((2'S, 3'R, 5'R) -6-chloro3'- (3-chlorophenyl) -1 '- (cyclopropylmethyl) -1- (hydroxymethyl) 2,6' -dioxoespiro [indolin-3,2'-piperidin] -5'-yl) acetic (Example 62, Step L) (12.6 mg, 0.025 mmol) in MeOH (1 mL) at room temperature DIEA (8.74 pL, 0.050) was added mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction was quenched with 10% citric acid and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (column: Gemini-NX Cig 5um column; Phenomonex, Torrance, CA; eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA) to give the title compound .

XH NMR (400 MHz, ACETONITRILQ-d3) δ ppm -0.25 - -0.18 (1

IMPI

MEXICAN INSTITUTE

6.91 (2 H, m) 7.08 (1 H, t, J = 7.8 Hz)

361

7.11 - 7.20 (2 H, m)

7.49 (1 H, d, J = 8.2 Hz) 8.29 (1 H, br s). Spectrum

Masses (ESI) m / z = 473 [Μ + H] 1.

EXAMPLE 63

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2-yl)

1- (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic

Stage A.

2- (3-Chlorophenyl) -1- (5-chlorothiophene-2-yl) ethanone

Silica gel 60 (21 g, 350 mmol) was added to a 500 mL round bottom flask and the flask was heated with a heat gun under high vacuum for 30 min. The system was cooled to room temperature and phosphorous pentoxide (8.75 mL, 148 mmol) was added. The mixture was stirred at 110 ° C (oil bath) under high vacuum for 120 min. The mixture was allowed to cool to room temperature. Acid 3362

chlorophenylacetic (15.6 g, 91 mmol), 2-chlorothiophene (33.8 mL,

366 mmol) and DCE (50 mL) were added. The reaction mixture was stirred under reflux for 4 hours. CLEM analysis showed that the reaction was complete.

The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with ether (300 mL) and filtered. The organic solution was concentrated under reduced pressure. The residue was triturated with hexane to result in the title compound as a colorless white solid. The hexane mother liquor was concentrated and purified by flash chromatography (SiO20.030% EtOAc / Hex, gradient elution) provided another batch of the title compound as a light yellow solid. Mass Spectrum (ESI) m / z = 271 (M + l).

Stage B. rae. 4- (3-chlorophenyl) -5- (5-chlorothiophene * -2-yl) -

Methyl 5-oxopentanoate

CI

To a solution of 7.35g (27.1 mmol) of 2- (3-chlorophenyl) 1- (5-chlorothiophene-2-yl) ethanone (Example 63, Step A) and acrylic acid methyl ester (2.81 mL, 31.2 mmol ) in DCM (60 mL) 1,8-diazabicyclo [5.4.0] undec-7-ene (4.05 mL, was added,

27.1 mmol) in DCM (10 mL) slowly at 0 ° C for 20 min.

Then the

363 Reaction was allowed to warm to room temperature. After stirring at 25 ° C for two days, the reaction mixture was diluted with DCM and washed with 2N HCI, water, and saturated aqueous NaCl solution. The organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light yellow oil. The crude material was absorbed on top of a plug of silica gel and purified by chromatography through a prepackaged column of silica gel (220 g), eluting with a gradient from 0% to 30% EtOAc in hexane, to providing the title compound as a light yellow oil. Mass Spectrum (ESI) m / z = 357 (M + l).

Stage C.

rae (4S, 5S) (4R, 5R) methyl 4- (3-chlorophenyl)

5- (5-chlorothiophene-2-yl) -5-hydroxypentanoate

To a solution of methyl 8.20g (22.95 mmol) of 4- (3-chlorophenyl) -5- (5-chlorothiophene-2-yl) -5-oxopentanoate (Example 63, Step B) in MeOH (100 mL) was added sodium borohydrate (0.809 mL, 22.95 mmol) in portions at 0 ° C. Then the reaction was stirred at 0 ° C for 30min. CLEM analysis showed that the reaction was complete. Water with ice

<td></td><td>364 MEXICAN INSTITUTE OF PROPERTY V -'- í-tiZ</td>

<td>added</td><td>INDUSTRIAL ---- to turn off the reaction. The reaction mixture is</td>

<td>concentrated</td><td>under reduced pressure to bouquet most</td>

<td>MeOH. The</td><td>The residue was extracted with DCM (3 X 100 mL). The layers</td>

<td>organic</td><td>Combinations were washed with saturated aqueous solution</td>

<td>of NaCl,</td><td>they dried on Na2SW4, and concentrated low</td>

reduced pressure. The purification of the residue by flash chromatography. (TLC, SiO2, 20-30% EtOAc / hexanes, gradient elution) provided the title compound as a colorless oil.

Stage D.

rae.

(4S, 5R) (4R, 5S) -methyl-5 ~ azido-4- (3-chlorophenyl) -5- (5-chlorothiophene-2-yl) pentanoate

To a solution of 1.18 g (3.28 mmol) of

(4S, 5S) (4R, 5R) -Racemic methyl (Example 63, Step C) in toluene (10 mL) 1,8-diazabicyclo [5.4.0] undec-7-ene (0.639 mL, 4.27 mmol) was added over 5 min at 0 ° C with stirring. To the above solution, diphenylphosphoryl azide (0.852 mL, 3.94 mmol) was added dropwise over a period of 8 min. The reaction mixture was stirred at 0 ° C to rt for 14 hours and monitored by LCMS analysis. The reaction mixture was diluted (NH4C1 aqueous saturated),

365

^ (3 x

EtOAc), and washed (2 x saturated aqueous NaCl solution)

The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. The crude material was dissolved in a small amount of DCM for chromatography. The insoluble material was removed by filtration and the solution was absorbed on top of a silica gel stopper and purified by chromatography through a Redi-Sep column pre-packed with silica gel (40 g), eluting with a gradient of 0 % to 60% EtOAc in hexane, to provide the racemic title compound as a colorless oil.

Mass Spectrum (ESI) m / z = 406 (M + 23).

Stage E.

(5R, 6S) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2yl) piperidin-2-one

To a solution of 7.8 g (20.3 mmol) of 5-azido-4- (3 chlorophenyl) -5- (5-chlorothiophene-2-yl) pentanoate of (4S, 5R) (4R,

Racemic 5S) -methyl (Example 63, Step D) in THF / H2Or (4/1, 75 mL) trimethylphosphine, a 1.0M solution in tetrahydrofuran (24.36 mL, 24.36 mmol) was added. After shaking

366 iMPiee

MEXICAN INSTITUTE ¥ 2 ^ · ^ * r FROM INDUSTRIAL PROPERTY for 1 h at 23 ° C, CLEM analysis showed the reaction.

was complete. Most of the THF was removed under reduced pressure and the residue was basified (LiOH

Ice-cold 2M) and the product was extracted (3 x DCM) and washed (2 χ aqueous saturated solution of

NaCl).

The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide a crude mixture of amines as a yellow solid.

The crude amine from the above was dissolved in saturated aqueous MeOH / NaHCO3 (4/1, mL, c = 0.04

M) and the reaction was refluxed for

h. After the CLEM analysis showed that the reaction was complete, the excess solvent was removed under reduced pressure, the residue was diluted

10% MeOH / DCM), and washed (1 χ aqueous saturated solution of

NaCl).

The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the crude title compound.

The crude material was absorbed onto a plug of silica gel and purified by chromatography through a column prepacked with silica gel (220 g), eluting with a gradient of 20% to 100% EtOAc in CH2CI2, to provide the racemic title compound as a white solid.

The individual enantiomers of racemic (5R, 6S) (5S, 6R) -5 (3-chlorophenyl) -6- (5-chlorothiophene-2-yl) piperidin-2-one

367 were separated by chiral CFS in a

250 x 30 mm column

Chiralcel AS-H with 50 g / min MeOH (+ 20 mM NH3) + 50 g / min C02 at Thar 350 SFC (Thar Technologies, Inc., Pittsburg, PA). Outlet pressure = 100 bar; Temp. = 46 ° C; Wavelength = 245 nm. Run time = 20 min .; cycle time = 17 min. The title compound (5R, 6S) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2-yl) piperidin-2-one was obtained as the fastest eluting isomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18 - 7.24 (2 H,

m), 7.10 (1 H, m), 6.93 - 6.95 (1 H, m) 6.23 (1 H, d, J = 4 Hz), 6.42 (1 H, d, J = 4 .Hz), 6.09 (1 H, s), 4.73 (1 H, d, J = 8 Hz), 2.87 - 2.94 (1 H, m), 2.60 - 2.65 (2 H, m), 2.05 -

2.25 (2H, m); Mass Spectrum (ESI) m / z = 326 (M + l); [to]D = + 165.8 (T = 24.7 ° C, c = 0.104, CHC13)

The enantiomer of the title compound, (5S, 6R) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2-yl) piperidin-2-one was also obtained as the slowest eluting isomer.

[to]D = - 158 (T = 24.8 ° C, c = 0.104, CHC13)

Stage F. rae. (.5R, 6S) (5S, 6R) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2-yl) -1- (cyclopropylmethyl) piperidin-2-one

368

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

The title compound was prepared from racemic (5R, 6S), (5S, 6R) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2-yl) piperidin-2 one (Example 63, Step E) as described in Example 35, Step A.

XH NMR (400 MHz, CHLOROFORM-d) at ppm 7.34 (1H, br s),

7.25 - 7.30 (2 H, m), 7.13 - 7.17 (1 H, m), 6.74 (1 H, d, J =

Hz), 6.56 (1 H, d, J = 4 Hz), 5.06 (1 H, d, J = 4 Hz), 4.13

- 4.19 (1H, m), 3.19 - 3.23 (1 H, m), 2.46 - 2.60 (3H, m),

2.23 - 2.29 (1 H, m), 2.01 - 2.10 (1 H, m), 1.05 - 1.13 (1 H,

m), 0.59 - 0.66 (1 H, -m), 0.49 - 0.56 (1 H, m), 0.27 - 0.33 (1 H, m), 0.18 - 0.24 (1 H, m). Mass Spectrum (ESI) m / z = 380 (M + l).

Stage G. (3R, 5R, 6S) (3S, 5S, 6R) -3-A1Í1-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one and (3S , 5R, 6S) (3R, 5S, 6R) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one

369

The compounds of the. Titer were prepared from racemic ((5R, 6S) (5S, 6R) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2-ylj-1 (cyclopropylmethyl) piperidin-2-one (Example 63 , Step F) as described in Example 1, Step G and obtained as a mixture of stereoisomers The individual racemic stereoisomers were separated by chromatography on silica gel.

The title compound (3R, 5R, 6S) (3S, 5S, 6R) -3-allyl-5 (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) piperidin-2-one was obtained as the fastest elution isomer (least polar isomer) by chromatography on silica gel.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.16 - 7.23 (2 H,

(1 H, m), 2.05-2.11 (1 H, m), 1.89 - 1.99 (1 H, m), 0.88 0.98 (1 H, m), 0.49 - 0.56 (1 H, m), 0.39 - 0.46 ( 1 H, m),

0.19 - 0.25 (1 H, m), 0.07 -0.13 (1 H, m). Mass Spectrum

370

(ESI) m / z = 420 (M + l).

The title compound (3S ', 5R, 6S) (3R, 5S, 6R) -3-allyl-5-

(3-Chlorophenyl) -6- (4-Chlorophenyl) -1 (cyclopropylmethyl) piperidin-2-one was obtained as the slowest eluting isomer on silica gel chromatography.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42 (1 H, br s)

726 -7.31 (1 H, m), 7.19 - 7.23 (1 H, m), 6.79 (1 H, d, J = 4

Hz), 6.60 (1 H, d, J = 4 Hz), 5.70 - 5.80 (IH, m), 5.065.15 (3 H, m), 4.18 - 4.23 (1 H, m), 3.26 - 3.29 (1 H, m), 10 2.62 - 2.68 (1 H, m), 2.41 - 2.51 (2H, m), 2.31 - 2.38 (1 H,

m), 2.15 - 2.22 (1 H, m), 1.92 - 1.98 (1 H, m), 1.11 - 1.21 (1 H, m), 0.63 - 0.69 (1 H, m), 0.54 - 0.60 (1 H, m), 0.240.34 (2 H, m). Mass Spectrum (ESI) m / z = 420 (M + l).

Stage H. Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2-yl) -1- (cyclopropylmethyl) -2-oxopiperidin-3yl) acetic

The title compound was prepared from (3R, 5R, 6S) (3S, 5S, 6R) -3-allyl-5- (3-chlorophenyl) -6- (4371

MEXICAN INSTITUTE

OF THE PLOFIEO..D

Industrial

racemic chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one (Example 63, Step G) as described in Example 1, Step

H and resolved by chiral SFC on a CHRALCEL® OJ column (Daicel, Fort Lee, NJ). Obtained as the slowest eluting isomer.

<td></td><td>XH NMR</td><td> (4(</td><td>30 MHz, CHLOROFORM-d)</td><td>δ</td><td>ppm 7.45</td><td> (1</td><td>H</td><td>br s)</td>

0.34 - 0.40 (1 H, m), 0.27 -0.33 (1 H, m). Mass Spectrum (ESI) m / z = 438 (M + l).

• 15

EXAMPLE 64

2- ((3S, 5R, 6.S) -5- (3-chlorophenyl) -6- (5-chlorothiophene-2-yl) 1- (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid

The title compound was prepared from (3R, 5R, 6S) (3S, 5S, 6R) -3-allyl-5- (3-chlorophenyl) -6- (4372

racemic chlorophenyl) -1- (cyclopropylmethyl) piperidin-2-one (Example 63, Step G) as described in Example 1, Step H and resolved by chiral SFC on an AD column. Obtained as the slowest elution isomer on an AD CHIRALCEL® column (Daicel, Fort Lee, NJ).

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.17 - 7.24 (2H,

m), 7.09 - 7.10 (1 H, m), 6.90 - 6.92 (1H, m), 6.62 (1 H, d,

J = 4Hz), 6.35 (1 H, d, 7 = 4 Hz), 4.80 (1 H, d, J = 12 Hz),

3.94 - 3.99 (1 H, m), 3.1.1 - 3.18 (1 H, m), 2.99 - 3.16 (1H,

m), 2.54 - 2.66 (2H, m),. 2.09 - 2.22 (2 H, m), 0.87 - 0.98 (1 H, m), 0.50 - 0.57 (1 H, m), 0.40 - 0.47 (1 H, m), 0.18 0.24 (1 H, m), 0.07 -0.13 (1H, m). Mass Spectrum (ESI) m / z = 438 (M + l).

EXAMPLE 65 χ- '° γ ° ο

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-ethoxy-l-oxobutan-2-yl) -3-methyl acid -2-oxopiperidin-3-yl) acetic

Stage A.

2 - ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4373

(S) -ethyl and 2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxopiperidin chlorophenyl) -2-oxopiperidin-l-yl) butanoate -l-yl) (S) -ethyl butanoate

To a solution of 362 mg (833 pinol) of 2 - ((2S, 3R) —3— (3— chlorophenyl) -2- (4-chlorophenyl) -6-oxopiperidin-l-yl) butanoate of (S) - Ethyl (Example 9, Step A) and allyl bromide (87 pl, 1000 pinol) in THF (3.30 mL, 0.25 M) were added dropwise lithium bis (trimethylsilyl) amide (1M solution in THF; 875 pl, 875 pmol) at -78 ° C. After stirring at -78 ° C for 3 hr, the reaction was quenched (NH4Saturated aqueous C1), extracted (2 χ EtOAc). The combined organic layers were washed with water and saturated aqueous NaCI solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. The purification of the residue by chromatography (12 g of SiO2, 15-20% EtOAc / Hex, gradient elution) provided the title compounds as a mixture of stereoisomers.

Stage B. 2 - ((2S) - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoate ethyl and

374

MEXICAN INSTITUTE

FROM THE PRO ?! INDUSTRIAL AGE

(2S) -Ethyl 2-((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoate

To a solution of 0.66 g (1.39 mmol) of 2 - ((5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-lil) butanoate of (S ) -ethyl (Example 65, Step A; mixture of diastereomers) and iodomethane (0.592g, 4.17 mmol) in 15mL of

THF LHMDS (1.0M solution in THF; 4.17 mL, 4.17 mmol) was added at RT. After stirring for 12h, the reaction was quenched (NH4Saturated aqueous C1), extracted (2 χ EtOAc). The combined organic layers were washed with water and saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by reverse phase preparative HPLC (GeminiTM Prep C18 5um column, Phenomenex, Torrance, CA; eluent: 10 to 90% acetonitrile + 0.1% TFA in water + 0.1% TFA, gradient elution) gave the title compound as a mixture -of stereoisomers.

375

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Stage D. Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-ethoxy-l-oxobutan-2-yl) -3-methyl-2oxopiperidin -3-yl) acetic

To a rapidly stirred 0.28g (0.573mmol) solution of 2 - ((5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 10

(2S) -ethyl 3-methyl-2-oxopiperidin-l-yl) butanoate

<td>(Example 65,</td><td>Stage B;</td><td>mixture</td><td>of</td><td colspan="2">diastereomers)</td><td>in</td>

<td>H2O / CCl4/ MeCN</td><td> (4.0/2.0/2.0,</td><td>8.OmL)</td><td>I know</td><td>added</td><td>periodate</td><td>of</td>

<td colspan="2">sodium (0.490 g, 2.29 mmol),</td><td>Following</td><td>by</td><td>hydrate</td><td>chloride</td><td>of</td>

ruthenium (III) (0.013 g, 0.057 mmol). After shaking15 Vigorously for 12 hr, the reaction was acidified (10% citric acid) and diluted with EtOAc. Insoluble material was removed by filtration through a pad of Celite® (JT Baker, Phillipsberg, NJ, diatomaceous earth). The filter product was removed (2 x EtOAc). The combined organic layers were washed with water and saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure.

The residue was purified by preparative reverse phase HPLC

376

(GeminiTM Prep C18 column

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

5um, Phenomenex, Torrance, CA;

<td>eluent:</td><td>10 to 90% acetonitrile + 0.1% TFA in water + 0.1% TFA,</td>

gradient elution) to give the title compound as the first elution isomer as a white powder.

<td>XH NMR</td><td> (400</td><td>MHz,</td><td>CHLOROFORM-d)</td><td>δ</td><td>ppm</td><td>0.59 (t,</td><td>J = 7.6</td><td>Hz,</td>

[M + H]1 . 504.1 [MH]-.

EXAMPLE 66

Acid 2- ((3S, 5R, 6S) -Ir ((S) -l-tert-butoxy-l-oxobutan-2-yl) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -3- methyl-2-oxopiperidin-320 yl) acetic:

Step A. 2 - ((Sj-tert-Butyl) -Butyl (2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6oxopiperidin-l-yl)

377

The title compound was synthesized as described in Example 9, Step A, by replacing ethyl 2-bromobutanoate with t-butyl 2-bromobutanoate. Purification by flash chromatography on silica gel (30% EtOAc / Hexanosj provided the title compound as the fastest eluting component as a white foam.

Stage B.

(2S) -tert-butyl 2-((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) 5-methyl-6-oxopiperidin-l-yl) butanoate

To a solution of 11.2 g (24.2 mmol) of 2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6-oxopiperidin-l-yl) butanoate of (S) -tert- butyl (Example 66, Step A) and iodomethane (1,813 mL,

9.1 mmol) in THF (120.0 mL) was added to lithium bis (trimethylsilyl) amide, (1M solution in THF; 26.6 mL, 26.6 mmol) at -78 ° C. The reaction was allowed to warm

IMPI

MEXICAN INSTITUTE OF PROPERTY

AT, then quenched (saturated aqueous NH4CI) and ext'E

378

fx EtOAc). The combined organic layers were washed with water '"i"" ~ And saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. The residue was absorbed on top of a plug of silica gel and purified by chromatography on silica gel, eluting with a gradient from 10% to 30% EtOAc in hexane, to provide the title compound as a mixture of stereoisomers.

Stage C.

(2S) tert-butyl chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoate

To a solution of 10.2 g (21.4 mmol) of 2 - ((2S, 3R) -3- (320 yl) (2S) -tert-butyl butanoate (Example 66, Step B, mixture of diastereomers) and allyl bromide (7.24 mL, 86 mmol) in

THF (210 mL) LHMDS was added, (1.0M solution in THF; 64.2 mL,

64.2 mmol) a

RT Allow to stir at RT for 5 min. Then the reaction mixture was heated at 50 ° C for 3h. Solution

379

IMPI

NH MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY4Aqueous saturated C1 was added and the mixture was extracted with

CH2CI2. The combined organic layers were washed with water and saturated aqueous NaCl solution, dried over MgSO4, filtered and the filtration product was concentrated under reduced pressure. The residue was purified by chromatography, eluting with a gradient from 0% to 20% EtOAc in hexane, to provide the title compound as a mixture of C-3 stereoisomers.

Stage D. Acid 2 - ((3S, 5R, 6S) -1 - ((S) -1-tert-butoxy-l-

oxobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxopiperidin-3-yl) acetic

(2S) -tert-butyl 2-((5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoate (Example 66, Step C, mixture of diastereomers) was converted to acid by a procedure similar to that described in

Example 65, Step D. The crude product was purified by reverse phase preparative HPLC (GeminiTM Prep C18 5um column,

Phenomenex, Torrance, CA; eluent: 10 to 90% acetonitrile

M? V ICANO INSTITUTE

OF THE PROPERTY

INDUSTRIAL

380 + 0.1% TFA in water + 0.1% TFA, gradient elution) to give, the title compound as the first elution isomer

<td>XH NMR</td><td> (400</td><td>MHz,</td><td>CHLOROFORM-d) δ ppm</td><td> 0.54</td><td>(t, J = 7</td><td>.5 Hz,</td>

H), 4.58 (d, J = 10.5 Hz, 1 H), 6.76 (m, 1 H) 6.97 - 7.06 (m, 3

H) 7.08 - 7.20 (m, 2H) 7.25 (s, 2H); MS (ESI) 534.1 [M + H] ”.

532.0 [MH] '.

The additional elution provided Example 67.

EXAMPLE 67

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -l-tert-butoxy-l-oxobutan-2-yl) -5-

(3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (t, <J = 7.5 Hz,

381

7.29

Η), 6.90 - 6.98 (m, 1 Η),

534.1 [Μ + Η] '. 532.0 [Μ — Η] '.

7.05

ΙΜΡΙ ^

INSTITUTO MEXICAt.OV -

OF THE INDUSTRIAL PROPERTY 1 (m, 6H); MS (ESI)

EXAMPLE 68

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (cyclopropylmethoxy) butan-2-yl) -3-methyl- acid 2-oxopiperidin-3yl) acetic

Stage A. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -115 hydroxybutane-2-yl) piperidin-2-one

to ORa solution of 3 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6-oxopiperidin-l-yl) butanoate of (S) -ethyl (Example 9) , Step A) in 45 mL of Et2Or, lithium tetrahydroborate (0.334 g, 13.81 mmol) was added at 0 ° C. After stirring at 0 ° C for 50 min, the reaction was

382 put out

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL Ssg*to...

(ice-cold 10% citric acid) and extracted (2 x

EtOAc). The combined organic layers were washed with water and saturated NaCl · aqueous solution, dried over

MgSOo and filtered under reduced pressure.

gel snapshot

EtOAc / Hexanes, elution .de of the title.

Stage B.

filtration product concentrated

Purification by silica chromatography (eluent: 30% to 60% gradient) provided the compound ((S) -1- (cyclopropylmethoxy) butan-2-yl) piperidin-2-one

To a solution of 1.48g (3.77 mmol) of (5R, 6S) -5- (3 chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-220 yl) piperidin-2- one (Example bromomethylcyclopropane (0.828 mL, added sodium t-butoxide (0.544

68,

Stage

7.54 mmol) in g, 5.66 mmol)

TO)

DMF (20mL) o ° c.

I know

The mixture was stirred at 0 ° C for 2.

then warmed up

Then the reaction was stirred for 14h. The reaction was quenched with saturated NH aqueous solution4C1 and it

383

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

extracted with EtOAc.

The combined organic layers were washed with water and saturated aqueous NaCl solution were dried over

MgSO4, filtered and the filter product concentrated under reduced pressure. Purification by flash chromatography 5 on silica gel (eluent: 20% -40%

EtOAc / Hexanes, gradient elution) provided the title compound as a colorless oil.

Stage C.

(5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -ΙΙΟ ((S) -1- (cyclopropylmethoxy) butan-2-yl) -3-methylpiperidin-2-one ♦

To a solution of 0.325g (0.73 mmol) of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 (cyclopropylmethoxy) butan-2-yl) piperidine- 2-one (Example 68, Step B) and iodomethane (0.055 mL, 0.874 mmol) in THF (7.0 mL) was added lithium bis (trimethylsilyl) amide (1M solution in THF, 0.8 mL, 0.8 mmol) at -78 ° C. The reaction was allowed to warm to RT, then quenched with saturated NH aqueous solution.4C1 and extracted with EtOAc. The combined organic layers were washed with water and saturated aqueous solution of

MEXICAN INSTITUTE OF PROPERTY

384

NaCl, dried over MgSO4, were filtered and the pFSSIÍdto ^ S ^ filtration was concentrated under reduced pressure? You uidlélldl1Crude was absorbed on top of a plug of silica gel and purified by chromatography on silica gel, eluting with a gradient from 10% to 30% EtOAc in hexane, to provide the title compound as a mixture of C-3 stereoisomers , as indicated by *.

Step D. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (ocyclopropylmethoxy) butan-2-yl) -3methylpiperidin- 2-one

CI

CI

To a solution of 0.2 g (0.434 mmol) of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 (cyclopropylmethoxy) butan-2-yl) -3 -methylpiperidin-2-one (Example 68, Step C, mixture of diastereomers) and allyl bromide (0.147 mL, 1.737 mmol) in THF (5 mL) LHMDS was added, (1.0M solution in THF, 1.3 mL, 1.3 mmol ) at RT. Allow to stir at RT for 5min. Then the reaction mixture was heated at 50 ° C for 3h. The reaction mixture was diluted

385

IMPI6P

INSTITUTO MEXICANO 'with NH4CI satd. and it was extracted with

PROPERTY _ INDUSTRIAL,. ---- .--- CH2CI2. The combined organic layers were washed with water and saturated aqueous solution of

NaCl, dried over MgSO4, filtered and the filter product concentrated under reduced pressure. The crude material was purified by chromatography, eluting with a gradient from 0% to 20% EtOAc. In hexane, to provide the title compound as a colorless oil.

Stage E. Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (410 chlorophenyl) -1 - ((S) -1- (cyclopropylmethoxy) butan-2-yl) -3-methyl-

2-oxopiperidin-3-yl) acetic (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (cyclopropylmethoxy) butan- 2-yl) -3-methylpiperidin-2-one (Example 68, Step E) was converted to acid by a procedure similar to that described in Example 1, Step H,

to provide the title compound.

<td></td><td colspan="2">XH NMR (400</td><td>MHz, SMELL</td><td>.0 FORM -d)</td><td>δ ppm 0.20</td><td> -</td><td> 0.33</td><td> (</td><td>m, 2</td>

H), 3.24 - 3.40 (m, 3H), 3.95 (t, J = 9.8 Hz, 1H), 4.69 (d,

J = 10.0 Hz, 1H), 6.72 - 6.80 (m, 1H), 6.94 - 7.07 (m, 3H),

7.07-7.21 (m, 2H), 7.25 (d, J = 8.61 Hz, 2H);

EXAMPLE 69

386

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-OXO-3- (2- (pyrrolidin-1yl) ethyl) piperidin -3-yl) acetic

Stage Ά. (5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3- (2— (triisopropylsilyloxy) ethyl) piperidin2-one

To a solution of 3.70 g (8.9 mmol) of a mixture of C-3 diastereomers of (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -1- (cyclopropylmethyl) piperidin -2-onaoxopentanoate (Example 35,

Step -B) and 20.7 g (63 mmol) of (2-iodoethoxy) triisopropylsilane in degassed, dry THF (60

IMPI fPVJk

MEXICAN INSTITUTE \ $

PROPERTY V - r

INDUSTRIAL --— a 1M mL solution) 54.5 mL (54.5 mmol) of

THF

387 Lithium bis (trimethylsilyl) amide in syringe for 6 min. After orange it was warmed up to 40 ° C and additional. The reaction was ambient, quenched with chloride, extracted with EtOAc (3X). Chilled them slowly for half a min, stirred until aqueous ammonia organic layers dried over Na2SW4, filtered and the product was concentrated. Purification of the residue by the solution for 2.25 h saturated temperature, and combined with filtration (gradient chromatography) provided the title compound (C-3 epimer mixture) as a light yellow oil.

(triisopropylsilyloxy) ethyl) piperidin-3-yl) acetaldehyde

To a solution of 1.28 g (2.08 mmol) of (5R, 6S) -3-allyl (triisopropylsilyloxy) ethyl) piperidin-2-one (Example 69, Step

A, mixture of diastereomers) in THF (50 mL)

388 and water (17.5 mL) a catalytic amount of osmium tetroxide was added.

After 25 min, 1.34 g (6.25 mmol) of sodium periodate was added. The resulting light brown thick mixture was stirred for 19 h and was then filtered through a filter funnel.

The filter product was partially concentrated under reduced pressure, then diluted with water and extracted with ethyl acetate (2X). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried

about Na2SO4 was filtered and the filter product was concentrated. The crude title compound (mixture of epimers

C-3) was used directly in the next step.

Step C. Synthesis of (5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -1- (cyclopropylmethyl) -3- (2- (pyrrolidin-l-yl) ethyl) -

3- (2- (triisopropylsilyloxy) ethyl) piperidin-2-one

A mixture of 1.02 g (1.66 mmol) of 2 - ((5R, 6S) -5- (3389

IMPIAS

MEXICAN INSTITUTE OF PROPERTY chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2 "" Ϊ / 5ΪΒ ^ 3-Τ2 (triisopropylsilyloxy) ethyl) piperidin-3-yl) acetaldellldo crude

(Example 69, Step B, mixture of diastereomers), 0.55 mL (6.6 mmol) of pyrrolidine, 880 mg (4.15 mmol) of sodium triacetoxyborohydride and 285 pL (4.98 mmol) of acetic acid was suspended in a mixture of 1.2 -dichloroethane (36 mL) and DMF (12 mL). After stirring at room temperature for 20 hr, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with DCM (3X). The combined organic layers 10 were dried over Na2SO4, leaked and

the filter product was concentrated. The crude title compound (C-3 epimer mixture) was used directly in the next step.

Step D. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3- (2-hydroxyethyl) -3- (2- (pyrrolidin-1yl) ethyl) piperidin-2-one

To an ice-cold solution of 1.12 g (1.66 mmol) of

390

(5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3- (2- (pyrrolidin-l-yl) ethyl) -3- (2-

Crude (triisopropylsilyloxy) ethyl) piperidin-2-one (Example 69,

Step C, mixture of diastereomers) in THF (55 mL) is added

8.3 mL (8.3 mmol) of a 1M solution of TBAF in THF. After stirring at room temperature for 1.5 hr, the reaction mixture was quenched with water and extracted with EtOAc (3X). The combined organic layers were dried (Na2SW4), and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (3-

30% MeOH / DCM, gradient elution) provided the title compound (C-3 epimer mixture) as a light yellow oil.

Stage E. Acid

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -1- (cyclopropylmethyl) -2-oxo-3- (2- (pyrrolidin-lil) ethyl) piperidin-3 -il) acetic

An ice-cold solution of 2.05 g (20.5 mmol) of

Chromium (VI) oxide in water (4 mL) was treated with 1.75 mL (32.7 mmol) of sulfuric acid by syringe. The mixture will be used. In a separate flask, 105 mg (0.21 mmol) of (5R, 6S) 5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -3- (2hydroxyethyl) -3- (2- (Pyrrolidin-l-yl) ethyl) piperidin-2-one diluted with additional water (4 mL) and stored at 0 ° C before

D, mixture of diastereomers) dissolved

391

IMPI (Example 69, Stage and then treated with Jones reagent (see

above) slowly ambient. After resulting reaction was with water and by means of 30 min, the mixture was heated to 55 ° C by concentrated low pressure was extracted with acetate pipette at dark red solution temperature

17.5 h reduced, additional ethyl. The was then diluted (4X). The organic layers were put on

Na2SW4, filtered and the filter product concentrated. Purification of the residue by pm

HPLC prep. reverse phase (Sunfire column

Prep Cis OBD 10

<td>(Waters, Milford,</td><td colspan="4">MA), gradient elution from MeCN</td><td>to the</td><td> 40%</td>

<td>water up to MeCN</td><td>at 55</td><td>>% in water</td><td>during a</td><td colspan="2">period</td><td>of</td>

<td>minutes where</td><td>both of them</td><td>solvents</td><td>they contain</td><td>TFA</td><td>to the</td><td> 0.</td>

en provided the title compound (single enantiomer) as a white solid. [Note that the desired C-3 (3S) epimer is the least polar epimer and completely elutes the second].

XH

NMR (400 MHz, CDC13) δ ppm 11.11 (1 H, br

s), 7.187.24 (2

H

7.08-7.18 (2H, m), 6.99 (1H, br

s), 6.77

6.87 (3

H

m),

4.7 Hz),

3.72-3.86

H, m),

3.61

H, br

m), (2

H

s),

2.75-2.97 (4 H, m), 2.20-2.35 (2 H, m), 1.99-2.22 (7

H

392

EXAMPLE 70

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3- (2-morpholinoethyl) -2-oxopiperidin-3yl) acetic acid

Stage A. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3- (2-hydroxyethyl) -3- (2morpholinoethyl) piperidin-2-one

A 94 mg (0.15 mmol) mixture of 2 - ((5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -2-OXO-3- (2 (triisopropylsilyloxy) ethyl) piperidin-3-yl) crude acetaldehyde

393

WICK> 7

MEXICAN INSTITUTE '' -ύ <

FROM PROPERTY (Example 69, Step B, mixture of diastereomers), 66 pL (0776 mmol) of morpholine, mg (06 mmol) of sodium triacetoxyborohydride and 30 pL (0.53 mmol) of acetic acid and DMF for (2 suspended in mL). After h, the aqueous sodium organic layers were filtered and the mixture mixture of 1,2-dichloroethane (6 mL) was stirred at room temperature, reaction was quenched with saturated bicarbonate and combined product was extracted with DCM, dried over

Na2SO4, filtration concentrated.

purification of the residue by preparative HPLC of

I know

The phase

reverse (SunFire ™ Prep C columni8 OBD 10 pm (Waters, Milford,

MA), gradient elution of 50% MeCN in water to MeCN at

90% in water over a period of 30 minutes, where both solvents contain 0.1% TFA) provided the title compound (mixture of C-3 epimers) together with the corresponding TIPS ether (mixture of C-3 epimers) and trifluoroacetate corresponding (mixture of C-3j epimers as a colorless oil.

This mixture was dissolved in THF (5 mL) and treated with 0.76 mL (0.76 mmol) of a 1M solution of TBAF in THF. After stirring at room temperature for 3.5 hr, the reaction mixture was quenched with water and extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4), and concentrated under reduced pressure. The purification of the

394

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Residue by flash chromatography on silica gel (835% MeOH / DCM, gradient elution) provided the title compound (C-3 epimer mixture) as a white solid.

Stage B. 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -3- (2-morpholinoethyl) -2oxopiperidin-3-yl) acetic acid

An ice-cold solution of 403 mg (4.03 mmol) of chromium (VI) oxide in water (1 mL) was treated with 343 pL (6.44 mmol) of sulfuric acid by syringe. The solution is

diluted with additional water (1 mL) and stored at 0 ° C before use. In a separate flask, (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopropylmethyl) -3- (2-hydroxyethyl) -3- (2morpholinoethyl) piperidin-2-one ( Example 70, Step A, mixture of diastereomers) was dissolved in acetone (5 mL) and then treated with Jones reagent (see above) slowly by pipetting at room temperature. After 30 min, the resulting dark red solution was heated at 55 ° C for 17 h

additional.

The reaction was concentrated under reduced pressure, then diluted with water and extracted with ethyl acetate (3X). The organic layers were put on Na2SW4, filtered and the filter product concentrated. Purification of the residue by HPLC prep. reverse phase (SunFire ™ Prep Cig OBD 10 pm column (Waters, Milford, MA),

395

IMPI ^

MEXICAN PROPERTY INSTRUMENT 40% MeCN gradient elution in water up to 60%

in water over a period of minutes, where both solvents contain

0.1% TFA) provided the compound of the

title (single enantiomer) as a white solid.

[Note that the epimer (3S)

Desired C-3 is the least polar epimer and completely elutes the second].

, 6.95XH NMR (400 MHz, CDC13) δ ppm

12.05 (1 H, br s)

<td> 0.33-0.55</td><td> (2</td><td>H, m),</td><td>-0.10-0.15 (2 H,</td><td>m).</td><td>Spectrum</td><td>of</td><td>Masses</td>

(ESI) m / z = 545 (M + l).

EXAMPLE

Methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl) acetic acid

Stage A.

dimethoxybenzyl) piperidin-2-one.

396

Thionyl chloride (116 mL, 1586 mmol) was added dropwise over 1 hour to a cloudy solution of dimethoxyphenyl) methanol (97.00 g, 577 mmol) and pyridine

1153 mmol) in Et2Or anhydrous (1153 mL) at 0 ° C (2.4 (93 mL, under nitrogen with mechanical stirring. After reaction, it was emptied into 2 L of ice separated.

ice compounds (1.2

NaHCO3 ac.

of the ether added and hour water and the

The aqueous layer was extracted with Et2Or (2 x mix layers

L) and organic accumulated, washed with water from them with

L), cold 5: 1 aqueous saturated NaCl / sat solution was dried (MgSOJ, filtered and most of the mixture was removed in vacuo at 12 ° C.

concentrated 12

Benzene ° C until (300 mL) remains

100 mL of benzene to provide a solution of

120 (chloromethyl) -2,4-dimethoxybenzene.

80g (250mmol) of (5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) piperidin-2-one. (Example I add in portions over 20 minutes to a mixture of NaH (19.98 g,

500 mmol) in anhydrous DMF (400 mL) at 0 ° C under nitrogen.

397

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

After the addition was complete the ice bath was stirred and the mixture was stirred at rt for 1 hour before the solution was cooled to 0 ° C. to the cooled solution was added

a solution of 1- (chloromethyl) -2,4-dimethoxybenzene (107 g,

575 mmol) in benzene and the reaction mixture was allowed to warm to rt. After 16 hours the reaction mixture was poured into ice water (2 L) and extracted with EtOAc (3 x 1 L). The organic compounds were accumulated, washed with water (3 x 1 L), saturated aqueous NaCl solution (1 L), dried (MgSO.), Filtered, and concentrated in vacuo for column purification, columns providing a in the combiflash

Teledyne Isco,

330 g in bars and with 35-40-45-50-55% very pale yellow.

Solvent was stirred in to provide the thick yellow oil. The

XL (flash chromatography

Lincoln, NE) when using a 1.5 kg column

EtOAc / hexanes provided a four and elute oil

This was dissolved in vacuum benzene and dried under vacuum for title compound as one and a day foam

Stage B. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2,4dimethoxybenzyl) -3-methylpiperidin-2-one.

IMPI

398

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

A solution

(5R, 6S) -5- (3-chlorophenyl) -6- (471, Step A) (140.34 g, 298 mmol) degassed by bubbling argon piperidin-2-one (Example in anhydrous THF (994 mL) through of the solution for 20 iodomethane adding minutes while cooling to -78 ° C.

the

373 mmol) was added followed by

LHMDS (328 mL reaction mixture, 328 mmol) for 15 min.

stirred during

Minutes at -78 ° C and then the reaction was removed from the cooling bath and stirred at rt for 12 hours. The reaction was quenched by the addition of saturated aqueous NH4C1 and the layers were separated.

The aqueous layer was extracted with EtOAc (2 x 500 mL) and the organic compounds were accumulated, washed with saturated aqueous solution of

NaCl, dried (MgSO4), filtered and concentrated in vacuo to provide an orange oil

Purification (wet loaded with a small amount of,

DCM) when using the Combiflash Companion XL (flash column chromatography, Teledyne Isco, Lincoln, NE) with a

399

MEXICAN INSTITUTE

OF THE PRO? Ir.UO INDUSTRIAL

1.5 kg SiO column2 and eluting with 4 L each of 15-2025-30-35% EtOAc / hexanes afforded the title compound /

as a thick very pale yellow oil and a 3.7: 1 mixture of C-3 diastereomers.

Step C. (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (2,4-dimethoxybenzyl) -3-methylpiperidin-2-one.

A solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1- (2,4-dimethoxybenzyl) -3-methylpiperidin-2-one (Example 71, Step B, mixture of C-3 diastereomers) (117.0 g,

242 mmol) in anhydrous THF (966 mL) was degassed by bubbling argon through the solution for 20 minutes

allyl (105 mL,

1208 mmol)

LHMDS (725 mL,

725 mmol) reaction heated to 40 reaction mixture cooled to rt and quenched by addition of

NH4Aqueous saturated C1 was added followed by for 20 minutes.

'C under argon during

<td> •</td><td>Bromide</td><td>of</td>

<td>the</td><td>addition</td><td>of</td>

<td>The</td><td>mixture</td><td>of</td>

<td> 5</td><td>hours.</td><td>The</td>

<td colspan="2">reaction</td><td>I know</td>

layers were separated. The aqueous layer was extracted with EtOAc (2 x

400 saturated solution

INSTITUTE «SECANO

DE LA-Pí'.INDUSTRIAL PROPERTY -

L) and organic compounds accumulated, washed with _________. .

dried (MgSO4), aqueous NaCl (1 L), were filtered and concentrated in vacuo to provide a

g). Purification when using the system

Biotage (Charlotte, NC) with a column

1.5 kg YES2 and eluting with 10-30% EtOAc / hexanes provided the title compound as a very pale yellow oil as a 3.7: 1 mixture of (3S) :( 3R) diastereomers.

Stage D. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one.

A solution of (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl) -3-methylpiperidin-2-one (Example 71, Step C , mixture of diastereomers) (105.87 g, 202 mmol) in TFA (778 mL, 1.01E + 04 mmol) was heated at 50 ° C for 2 hours before concentrating the reaction mixture in vacuo. The residue was azeotroped with hexanes to remove all the TFA. The dark purple oil containing some residue was taken up in a minimal amount of DCM, filtered and washed freely with DCM. The filter product is

401

INSTITUTO MEX.r

-DCP '

OF UHCKtDAD

INDUSTFJAL TSa concentrated in vacuo to provide a dark purple oil

Purification (wet packed with a minimum amount of

DCM) when using the Biotage Isolera (Biotage, Charlotte, NC) with a column

1.5 kg and eluting with 25-40% EtOAc / hexanes provided the title compound as a white solid.

XH NMR (500 MHz, CDC13) δ ppm

Step E. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (pentan-3-yl) piperidin-2-one

To a suspension of 1.81 g (4.8 mmol) of (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one (Example 71, Step D ) in, 3-bromopentane (17.6 mL) is added

967 mg (60% by weight in mineral oil, 24.2 mmol) of sodium hydride. The resulting thick white milky mixture is

402

MEXICAN INSTITUTE DS LA PROÍilD'I) INDUSTRIAL

heated at 120 ° C for 20 h, and Inpgn mag i-hrmnponi-ann (5.1 mL) was added. After an additional 24 hr at 120 ° C, the reaction was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3X) and the combined organic layers were dried over Na2SO4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (2 to 26% EtOAc / hexanes, gradient elution) provided the title compound as a white solid.

Step F. Synthesis of Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -

6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin-3yl) acetic

To a solution of 725 mg (1.63 mmol) of (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (pentan-3yl) piperidin- 2-one (Example 3, Step A) in a mixture of acetonitrile (4 mL), carbon tetrachloride (4 mL) and water (5.9 mL) 1.40 g (6.53 mmol) of sodium periodate is added followed by 44 mg ( 0.20 mmol) of ruthenium (III) chloride hydrate. The dark brown biphasic mixture was vigorously stirred at room temperature for 21 h, and then acidified with 1N HCI. The mixture was diluted with EtOAc and filtered through a pad of Celite® (JT Baker,

403

MEXICAN INSTITUTE

Dt THE PROPERTY

INDUSTRIAL

Phillipsberg, NJ, diatomaceous earth). After filtering, the layers were separated and the aqueous layer was extracted with EtOAc (IX). The combined organic layers were washed with saturated aqueous sodium chloride (IX), then dried over Na2SO4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (0 to MeOH / DCM 25%, gradient elution) provided the title compound as a white solid.

XH NMR (400 MHz, CDC13) δ ppm 7.06-7.27 (5 H, m), 6.907.01 (2 H, m), 6.68 (d, 1 H, J = 7.8 Hz), 4.34 (1 H, d, J =

10.4 Hz), 3.00-3.15 (2 H, m), 2.63-2.79 (2 H, m), 2.15-2.27 (1 H, m), 1.85-2.03 (3 H, m), 1.51 (s, 3 H ), 1.38-1.51 (2 H,

m), 0.95 (3 H, t, J = 7.4 Hz), 0.50 (3 H, t, J = 7.4 Hz).

Mass Spectrum (ESI) m / z = 462 '(M + l).

They were prepared in a process similar to that of bromopentane in alkylhalide.

Examples 72 described

Example 71, by substituting 3Eta appropriate amount of

<td>Example</td><td>R1</td>

EXAMPLE 72

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid

<td></td><td></td><td>1 HOUR</td><td>NMR (400</td><td>MHz,</td><td colspan="3">CHLOROFORM-d)</td><td>δ ppm 7.</td><td>.29 (2 H, d,</td><td>J =</td>

EXAMPLE 73

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic acid

405

<td></td><td colspan="2">1H NMR (400</td><td>MHz,</td><td>CHLOROFORM-d) δ</td><td>ppm 7.27</td><td> (2</td><td>H, d,</td><td>IJ =</td>

EXAMPLE 74

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1cyclobutyl-3-methyl-2-oxopiperidin-3-yl) acetic acid

<td></td><td></td><td>1 HOUR</td><td>NMR</td><td>(4C</td><td>10 MHz,</td><td>CHLOROFORM-</td><td>-d) δ ppm 7.15-7.26</td><td>(3 H, m),</td>

EXAMPLE 75

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-cyclopentyl-3-methyl-2-oxopiperidin-3-yl) acetic acid

<td></td><td>1H NMR (400 MHz,</td><td>CHLOROFORM-d) δ</td><td>ppm 7.28 (2</td><td>H</td><td>d</td><td></td><td> =</td>

406

m), 2.62 (1 H, d, J = 15.7 Hz), 1.75-2.13 (7 H, m), 1.26-1.45 (3 H, m), 1.33 (3 H, s); MS (ESI) 460.1 [M + H]+.

EXAMPLE 76 (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-3- ^ ((5oxo-4,5-dihydro-lH-l, 2,4 -triazol-3-yl) methyl) -1- (pentan-3yl) piperidin-2-one

Stage A. 2- (2 - ((3R, 5R / 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) 3-methyl-2-oxo-l- (pentan-3-yl) piperidin -3yl) acetyl) hydrazinecarboxamide

Cl.

To a solution of 320 mg (0.69 mmol) of acid 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo1- (pentan-3 -il) piperidin-3-yl) acetic (Example 71, Step F) and

921 mg (2.42 mmol) of HOBt in DMF (13 mL) 0.58 mL was added

407

I

INSTITUTO MSXICAHO D2 THE INDUSTRIAL PROPERTY

(4.15 mmol) of triethylamine. After ambient for 40 min, semicarbazide hydrochloride is added. Shake at temperature

270 mg (2.42 mmol) of resulting dark red solution was stirred at room temperature for 2.5 h, and then concentrated under reduced pressure. Purification of the residue by HPLC prep. reverse phase (Sunfire ™ Prep Cié OBD 10 pm column (Waters, Milford, MA), gradient elution from 40% MeCN in water to .90% MeCN in water over a period of 30 minutes, where both solvents contain TFA 0.1%) provided the title compound as a light yellow solid.

Stage B. (3R, 5R, 6S) -5- (3-chlorophenylj-6- (4-chlorophenyl) -3methyl-3 - ((5-oxo-4,5-dihydrorlH-l, 2,4-triazole- 3-yl) methyl) -1 (pentan-3-yl) piperidin-2-one

259 mg (0.50 mmol) 2- (2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan-3- il) piperidin-3yl) acetyl) hydrazinecarboxamide (Example 76, Step A) was suspended in 2N aqueous sodium hydroxide (16 mL) and heated under reflux for 3.25 h. During cooling to room temperature, the mixture was acidified with conc. HC1. Until strongly acidic and then extracted with EtOAc (3X). The combined organic layers were dried over Na2SW4, filtered and the filter product concentrated.

Gradient elution from 40% MeCN in water to 75% MeCN in water over a period of 30 minutes, where both solvents contain 0.1% TFA) provided the title compound as a white solid.

NMR (400 MHz, CDC13) δ ppm 10.36 (1 H, br s), 9.35 (1 H, br s), 7.20-7.27 (3 H, m), 7.05-7.17 (2 H, m), 6.86-6.95 (2 H, m) , 6.68 (1 H, d, J = 7.8 Hz), 4.34 (1 H, d, J = 10.5 Hz), 2.90-3.09 (3 H, m), 2.68-2.76 (1 H, m), 2.21 (1 H, t, J = 13.8 Hz), 2.05 (1 H, dd, J = 13.9 Hz, 2.9 Hz) 1.85-1.99 (2 H, m), 1.37-1.52 (2 H, m), 1.36 (3. H , s), 0.94 (3 H, t, J =

7.4 Hz), 0.50 (3 H, t, J = 7.5 Hz). Mass Spectrum (ESI) m / z = 501 (M + l), 523 (M + 23).

5- (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenylj -3-methyl-2oxo-1- (pentan-3-yl) piperidin-3-yl) methyl) -1,3,4-oxadiazol2 <3H) -one

A 56 mg (0.19 mmol) solution of triphosgene in DCM

409

MEXICAN INSTITUTE OF PROEffiTY

INDUSTRIAL '• sJS— (1 mL) was added dropwise to a 62 mg (0.13 mmol) solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl ) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl) acetohydrazide (obtained as a by-product in Example 76, Step B) and 170 pL (0.98 mmol) of diisopropylethylamine in DCM (4 mL). The resulting light yellow solution was stirred at room temperature for 18 h, then quenched with saturated aqueous sodium bicarbonate, and extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4, filtered and the filter product concentrated. Purification of the residue by preparative reverse phase HPLC (Sunfire ™ Prep C column18 10 pm OBD, (Wat.ers, Milford, MA) gradient elution from 4 0% MeCN in water to 7 5% MeCN in water over a period of 30 minutes, where both solvents contain 0.1% TFA) provided the title compound as a white solid.

XH NMR (400 MHz, CDC13) δ ppm 9.68 (1 H, br s), 7.08-7.27 (4 H, m), 6.90-7.01 (3 H, m), 6.70 (1 H, d, J = 7.4 Hz), 4.35 (1 H, d, J = 10.4 Hz), 3.01-3.15 (3 H, m), 2.70-2.79 (1 H,

Mass Spectrum (ESI) m / .z = 502 (M + l).

IMPI

410

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-l- (pentan-3-yl) piperidin-3-yl) -N (trifluoromethylsulfonyl) acetamide

To a solution of 47 mg (0.10 mmol) of 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo1- (pentan-3 -yl) piperidin-3-yl) acetic (Example 71, Step F) in DMF (4 mL) 64 mg (0.34 mmol) of EDC, 48 mg (0.36 mmol) of HOBt, and a catalytic amount of DMAP were added. After 30 min, 45.5 mg (0.30 mmol) of trifluoromethanesulfonamide was added. The resulting light yellow solution was stirred at room temperature for 3 h, and then concentrated under reduced pressure. Purification of the residue by HPLC prep. reverse phase (Sunfire ™ Prep Cié OBD 10 pm column (Waters, Milford, MA), gradient elution from 50% MeCN in water to 90% MeCN in water over a period of 30 minutes, where both solvents contain TFA at 0.1%) provided the title compound as a white solid.

3H NMR (400 MHz, CDC13) δ ppm 7.25-7.32 (3 H, m), 7.16-

7.20 (1 H, m), 7.11 (t, 1 .H, J = 7.8 Hz), 6.92-7.00 (2 H, m),

411

(d, 1 H, J = 15.7 Hz), 2.97-3.06 (1 H, m), 2./3-2.83 (! Ή? m), 2.68 (1 H, d, J = 15.7 Hz), 2.26 ( 1 H, t, J = 13.8 Hz),

1.86-2.08 (3 H, m), 1.52 (3 H, s), 1.39-1.52 (2 H, m), 0.95 (3 H, t, J = 7.4 Hz), 0.50 (3 H, t, J = 7.4 Hz). Mass Spectrum (ESI) m / z = 593 (M + l), 615 (M + 23).

EXAMPLE 79

O =

Cl (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((3-hydroxyH-pyrazol-5-yl) methyl) -3-methyl-l- (pentan -3-yl) piperidin-2-one

Stage A. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl ) acetaldehyde

To a 240 mg (0.54 mmol) solution of (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-cl.orophenyl) -3-methyl-l- (pentan-3yl) piperidin-2-one (Example 71, Stage E) in THF (8 mL) and water

412

osmium. After 1.25 h, 323 mg "TIT51 'mmol) of sodium periodate was added. The resulting light brown thick mixture was stirred at room temperature for 18.5 h, and then filtered through a filter funnel. The filter product was partially concentrated under reduced pressure, then diluted with water and extracted with ethyl acetate (2X). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Ña2SO4, filtered and the filter product concentrated. The crude title compound was used directly in the next step.

Stage B. 4 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl ) -3-ethyl oxobutanoate

To a suspension of 160 mg (0.36 mmol) of 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (pentan-3- il) piperidin-3-yl) acetaldehyde (Example 79,

MEXb-'ij'X INSTITUTE , N OF THE INDUsIUAL PROFU DAD

413

Step A) and 20.4 mg (0.11. Mmol) of tin (II) chloride in

DCM (6 mL) 104 pL (1.00 mmol) of ethyl diazoacetate was added via syringe over 3 min. The resulting thick yellow mixture was stirred at room temperature for

14.25 h, then quenched with 1N HC1 and extracted with EtOAc (2X). The combined organic layers were washed with 1N HC1 (IX), then dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by HPLC prep. reverse phase (Sunfire ™ column

Prep Co. 10 pm OBD (Waters, Milford, MA), gradient elution from 55% MeCN in water to 85% MeCN in water over a period of 30 minutes, where both solvents contain 0.1% TFA) provided the compound of the title as a light yellow oil.

Step C. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) 3- ((3-hydroxy-lH-pyrazol-5-yl) methyl) -3-methyl-l - (pentan-3il) piperidin-2-one

To a 42 mg (0.08 mmol) solution of 4 - ((3R, 5R, 6S) 5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan3- il) ethyl piperidin-3-yl) -3-oxobutanoate (Example 79,

Step B) In ethanol (4 mL) 36 pL (0.48 mmol) hydrazine monodrate (64-65 wt% hydrazine) was added. The resulting colorless solution was heated at 65 ° C for 3.5

414

INSTITUTO MEXIlAMO Y 4 ''

PE LA PROSWA'O V INDUSTRIAL —'- reduced pressure. H, then concentrated under purification of the residue by prep HPLC. phase reversed (Sunfire Prep Cig OBD 10 pm column, gradient elution from

MeCN at

45% in water up to MéCN at

80% in water over a period of 30 minutes, where both solvents contain 0.1% TFA) provided the title compound as a white solid.

XH NMR (400 MHz,

CDC13) δ ppm 7.23-7.30 (3 H, m),

7.187.22 (1H,

7.12

7.7

Hz) (2

m) t

J r

1.36

m),

H

H,, 6.90-6.96

522

Spectrum

500 (M + l), de Masas (ESI) m / z (M + 23).

EXAMPLE 80

hydroxyisoxazol-5-yl) methyl) -3-methyl-l- (pentan-3-

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

415 il) piperidin-2-one

To a thick ice-cold mixture of 65 mg (0.12 mmol) of 4 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methi1-2-oxo-1 - (Ethyl (pentan-3-yl) piperidin-3-yl) -3-oxobutanoate (0.77 (Example 79, Step B) in water (2 mL) 53.5 mg mmol) of hydroxylamine hydrochloride and 62 mg (1.55) were added mmol) of sodium hydroxide. After 5 min, added

THF (1 mL) and MeOH (1 mL). The resulting cloudy light yellow solution was stirred at 0 ° C for 20 min, then warmed to room temperature and stirred for an additional 6 h.

The reaction was acidified by dropwise addition of conc. HC1. until strongly acidic, then diluted with water and extracted with EtOAc (4X).

The combined organic layers were dried over Na2SW4, filtered and the filter product concentrated.

The purification of the residue by

HPLC prep.

reverse phase (Sunfire ™ column

Prep Cíe OBD 10 μιη (Waters, Milford,

MA), gradient elution from 55% MeCN in water to 85% MeCN in water over a period of 30 minutes, where both solvents contain 0.1% TFA) provided the title compound as a white solid.

NMR (400 MHz, CDC13) δ ppm 7.20-7.27 (3 H, m), 7.14-

7.20 (1 (3 H, m), 6.70 (1 H, d, J = 7.4 Hz), 4.33 (1 H, dd, <J = 10.5

416

1nst'SIaíBB2 OF industrial

Hz, 3.4 Hz), 3.59-3.78 (2 H, m), 3.13-3.23 (1 H, m), 3.07 (1

0.51 (3 H, dt, J = 7.5 Hz, 3.6 Hz). Mass Spectrum (ESI) m / z = 501 (M + l).

EXAMPLE 81

5 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (pentan-3-yl) piperidin-3-yl) methyl ) oxazolidin-2,4-dione

Stage A. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 (2,3-dihydroxypropyl) -3-methyl-l- (pentan-3-yl) piperidin -2-one

To a solution of 298 mg (0.67 mmol) of (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (pentan-3417

ΜΕΧΊΟΑ.ΝΟ INSTITUTE OF INDUSTRIAL PROPERTY

il) piperidin-2-one (Example 71, Step E) in a mixture of acetone (11.5 mL) and water (4 mL) a catalytic amount of osmium tetroxide is added. After 4 min, 275 mg ( 2.35 mmol) of N-methylmorpholine-N-oxide. The resulting brown solution was stirred at room temperature for 3.5 hr, and then partitioned between water and DCM (3X). The combined organic layers were dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (1 to 20% MeOH / DCM, gradient elution) provided the title compound (mixture of alcohol epimers) as a yellow oil.

Stage B. 3 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin-3- acid il) -2hydroxypropanoic

CI

OR

co2h

A mix of . (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2,3-dihydroxypropyl) -3-methyl1- (pentan-3-yl) 142 mg (0.30 mmol) piperidin-2-one (Example 81, Step A) and 28 mg (0.18 mmol) of TEMPO in a mixture of acetonitrile (6 mL) and

418

MEXICAN INSTITUTE γ <_ DE LA PROPINAD \ _

INDUSTRIAL> * «u ^ sodium hydroxide-sodium phosphate buffer solution (pH 6.7, 4.5 mL) at 35 ° C was treated simultaneously with a solution of 105 mg (1./16 mmol) of sodium chlorite in water ( 1.2 mL) and a solution of 106 pL (0.07 mmol) of bleaching solution (ca. 0.7 N) in water (0.6 mL) for 10 min. The resulting dark orange solution was stirred at 35 ° C for

1.75 h, and then partitioned between 1N HCI and EtOAc (3X). The combined organic layers were dried over Na2SO4, filtered and the filter product concentrated. Purification of the residue by HPLC prep. reverse phase (Sunfire ™ Prep Ci column8 10 pm OBD (Waters, Milford, MA), gradient elution from 60% MeCN in water to 80% MeCN in water over a period of 30 minutes, where both solvents contain 0.1% TFA) provided the title compound ( mixture of alcohol epimers) as a white solid.

Stage C. 3 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl ) -N- (2,4dimethoxybenzyl) -2-hydroxypropanamide

To a solution of 43 mg (0.09

419

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY mmol) of acid 3-

((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo

1- (pentan-3-yl) piperidin-3-yl) -2-hydroxypropanoic (Example

81, Step B) in DMF (5 mL) 67 mg (0.18 mmol) of HATU, 58.5 mg (0.35 mmol) of 2,4-dimethoxybenzylamine and 36 pL (0.26 mmol) of triethylamine were added. The resulting yellow solution was stirred at room temperature for 1.1 hr, and then partitioned between saturated aqueous sodium bicarbonate and EtOAc (2X). The combined organic layers were dried over Na2SW4, filtered and the filter product concentrated. The crude title compound (mixture of alcohol epimers) was used directly in the next step.

Step D. (S) -3- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin -3-yl) -2hydroxypropanamide and (R) -3 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan- 3-yl) piperidin-3-yl) -2hydroxypropanamide

A 56 mg (0.09 mmol) solution of 3 - ((3R, 5R, 6S) -5- (3420

chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan-3yl) piperidin-3-yl) -N- (2,4-dimethoxybenzyl) -2hydroxypropanamide (Example 81, Step C ) in trifluoroacetic acid (2.3 mL) was heated at 50 ° C for 2.5 h, and then concentrated under reduced pressure. Purification of the residue by HPLC prep. Reverse phase '(Sunfire ™ Prep Cis OBD 10 pm column (Waters, Milford, MA), gradient elution from 50% MeCN in water to 75% MeCN in water over a period of 30 minutes, where both solvents contain TFA 0.1%) provided two title compounds (in each stereochemical case the alcohol stereocenter is arbitrarily assigned) each as a light green solid.

Step E. 5 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin-3yl) methyl) oxazolidin-2,4-dione

To a 10.3 mg (0.02 mmol) solution of (S) —3 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo1- ( pentan-3-yl) piperidin-3-yl) -2-hydroxypropanamide (Example 81, Step D) in MeOH (2.5 mL) 0.50 mL (1.22 mmol) of sodium ethoxide (21 wt% solution in ethanol) was added ) and

1.20 mL (9.90 mmol) of diethyl carbonate. The resulting mixture was heated under reflux for 15 min, and then concentrated under reduced pressure. The residue was divided between

421

0.5 M HCI and EtOAc

IMPIAS

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ---- (3X). The combined organic layers were dried over Na2SO4, filtered and the filter product concentrated. Purification of the residue by HPLC prep. reverse phase (Sunfire ™ Prep Ci column8 10 pm OBD (Waters, 5 Milford, MA), gradient elution from 60% MeCN in water to 80% MeCN in water over a period of 30 minutes, where both solvents contain 0.1% TFA) provided the title compound (mixture of ether epimers) as a white solid.

θ rH NMR (400 MHz, CDCI3, mixture of epimers) δ ppm 8.90 (T

H, br s, major epimer), 8.83

7.15-7.20

J = 10.0 Hz)

2.67-2.79 .94-7.02 (2 minor epimer), 1.44 (1 H, br s, epimer (1

H, (1 minor),

H, m), 7.11

m), 6.71 (1

H, m,

Hz, 8.6 Hz, epimer

H, m), 1.35-1.45 (s, 3H, epimer (1 (1H,

H, d, minor epimer),

H, m), dt, J =

J = 7.6

J = 10.4 Hz), greater) 2.41

1.82-2.31

1.45 (3 H, major), 0.94 (3 H, t, (6 s,

7.4 Hz), 0.52 (3 H, t, J = 7.5 Hz).

m / z = 517 (M + l), 539 (M + 23).

EXAMPLE'82

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (pentan-3-yl) piperidin-3-yl) methyl ) -1,2,4-oxadiazolIMPI

422

5 (4Η) -ona

Stage A. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3 yl) piperidin-3-yl) acetamide

To an ice-cold solution of 1.15 g (2.49 mmol) of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yljpiperidin-3-yl) acetic (Example 71, Step F) in THF (12.5 mL) was added 383 pL (3.48 mmol) of N-methylmorpholine and 392 pL (2.98 mmol) of isobutyl chloroformate. The resulting thick opaque white mixture was stirred at 0 ° C for 2 h, and then 336 pL (28% ammonia in water, 4.97 mmol) of ammonium hydroxide was added. After an additional 3 hr at 0 ° C, the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc (3X). The combined organic layers were dried over Na2SW4, filtered and the filter product concentrated. The crude compound

423

DS

INSTITUI DS l of the title was used directly in the following e-

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl ) acetonitrile

O =

To an ice-cold solution of 1.15 g (2.49 mmol) of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- ( pentan-3-yl) piperidin-3-yl) acetamide (Example 82, Step A) in THF (21 mL) 1.73 mL (12.4 mmol) of triethylamine and 865 pL (6.22 mmol) of TFA were added. The resulting cinnamon solution was stirred at 0 ° C for 2.75 h, then warmed to room temperature and stirred for an additional 2 h. The reaction was recooled to 0 ° C, quenched with 1N citric acid, and then extracted with EtOAc (3X). The combined organic layers were dried over Na2SÓ4, filtered and the filter product concentrated. The combined organic layers were washed with saturated aqueous sodium chloride (IX), then dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (5 to 35% EtOAc / hexanes, gradient elution) provided the title compound as a white solid.

424

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Stage C. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl ) -Ν'hydroxyacetymidamide

To a suspension of 1.49 g (20.6 mmol) of hydroxylamine hydrochloride in DMSO · (10 mL) was added 2.88 mL (20.6 mmol) of triethylamine. The thick mixture was stirred for 5 min and then filtered twice through cotton wool, rinsing with THF, to remove the solids. The filtration product was partially concentrated under reduced pressure to remove THF, and then added to a flask containing 915 mg (2.06 mmol) of 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 - (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin-3yl) acetonitrile (Example 82, Step B). The resulting yellow solution was heated at 75 ° C for 22 hr, and then partitioned between water and EtOAc. The organic layer was dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (1 to 7% MeOH / DCM, gradient elution)

425

provided the title compound as a white solid.

Stage D. 3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pentan-3-yl) piperidin-3- il) methyl) -1,2,4 oxadiazol-5 (4H) -one

To a solution of 385 mg (0.81 mmol) of 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pentan- 3il) piperidin-3-yl) -Ν'-hydroxyacethimidamide (Example 82, Step

C) in dioxane (12.5 mL) 211 pL (1.41 mmol) of

DBU and 262 mg (1.62 mmol) of

1,1'-carbonyldiimidazole.

The resulting colorless solution was heated at 100 ° C for min, and then quenched with water and extracted with EtOAc.

The organic layer was then dried washed with saturated aqueous sodium chloride, and over Na2SW4, filtered and the filter product concentrated. Purification of the residue by HPLC

<td>prep. of</td><td colspan="3">reverse phase (Sunfire ™ Prep column</td><td>C18</td><td>OBD</td><td> 10</td>

<td>(Waters,</td><td>Mlford,</td><td>MA), elution of</td><td>gradient of</td><td>MeCN</td><td>to the</td><td> 55%</td>

<td colspan="2">water up to MeCN</td><td>80% in water</td><td>during a</td><td colspan="2">period</td><td>of</td>

<td>minutes,</td><td>where</td><td>both solvents</td><td>they contain</td><td>TFA</td><td>to the</td><td> 0.</td>

pm in the title as a white solid provided the compound

1%)

426 ΤΗ NMR (400 MHz, CDC13)

Mass Spectrum (ESI) m / z = 502 (M + l), 524 (M + 23).

EXAMPLE 83

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-isopropyl3-methyl-2-oxopiperidin-3-yl) methyl) -1,2,4 -oxadiazole-5 (4H) -one

The title compound was prepared by methods similar to those described in Example 82.

ΤΗ NMR (400 MHz, CDC13) δ ppm 10.38 (1 H, br s), 7,247.32 (2 H, m), 7.18-7.23 (m, 1 H), 7.15 (1 H, dt, J = 7.8 Hz,

3.6 Hz), 7.04 (1 H, br s), 6.90 (2 H, d, J = 5.4 Hz), 6.76 (1

H, d, J = 7.1 Hz), 4.52 (1 H, dd, J = 8.6 Hz, 3.2 Hz), 3.40427

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

3.50 (1 H, m), 3.09 (1 H, dd, J = 15.3 Hz, 2.8 Hz), 2.99-3.06 (1 H, m), 2.78 (1 H, dd, J = 15.3 Hz, 3.1 Hz), 2.18 (1 H, dt, J = 11.9 Hz, 3.2 Hz), 2.05-2.13 (1 H, m), 1.22-1.27 (m, 9

H). Mass Spectrum (ESI) m / z = 474 (M + l).

EXAMPLE 84

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (pentan-3-yl) piperidin-3-yl) methyl ) -1,2,4-thiadiazol5 (4H) -one

To a 83 mg (0.17 mmol) solution of 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-clo.phenyl) -3-methyl-2-oxo-l- ( pentan-3yl) piperidin-3-yl) -Ν'-hydroxyacethimidamide (Example 82, Step C) in THF (4 mL) was added 50 mg (0.28 mmol) of 1,1-thiocarbonyldiimidazole. The resulting yellow solution was stirred at room temperature for 1 hr, then quenched with water and extracted with EtOAc. The organic layer was dried over Na2SW4, · was filtered, and the filter product was concentrated. The residue was dissolved in THF (4.5 mL), and 69 pL (0.56 mmol) of boron trifluoride etherate was added via syringe. The resulting light yellow solution was stirred at room temperature for 2.5 h, then quenched with water and extracted with EtOAc. The organic layer was dried over .Na2SO4, was filtered, and the filter product was concentrated. Purification of the residue by HPLC prep. reverse phase (Sunfire Prep Ci column8 OBD 10 pm, elution of

428

gradient from 55% MeCN in water to 85% MeCN in water over a 35 minute period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.

XH NMR (400 MHz, CDC13) δ ppm 10.94 (1 H, br s), 7.20-

7.27 (3 H, m), 7.13-7.18 (1 H, m), 7.09 (1 H, t, J = 7.7 Hz), 6.85-6.95 (2 H, m), 6.66 (1 H, d, J = 7.6 Hz), 4.34 (1 H, d, J = 10.2 Hz), 3.09 (1 H, d, J = 14.8 Hz), 2.87-3.01 (2 H, m), 2.68-2.77 (1 H, m), 2.25 (1 H, t, J = 13.5 Hz), 2.04-2.13 (1 H, m), 1.87-2.04 (2 H, m), 1.39-1.51 (2 H, m), 1.38 (3 H, s) , 0.95 (3 H, t, J = 7.4 Hz), 0.50 (3 H, t, J = 7.4 Hz). Mass Spectrum (ESI) 'm / z = 518 (M + l), 540 (M + 23).

EXAMPLE 85

429

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-isopropyl3-methyl-2-oxopiperidin-3-yl) methyl) -1,2,4 -thiadiazole-5 (4H) -one

The title compound was prepared by methods similar to those described in Example 84.

XH NMR (400 MHz, CDC13) δ ppm 10.89 (1 H, br s), 7.24-

7.30 (2 H, m), 7.18-7.22 (m, 1 H), 7.15 (1 H, t, J = 7.8 Hz), 7.04 (1 H, br s), 6.86 (2 H, d, J = 8.3 Hz), 6.77 (1 H, d, J = 7.8 Hz), 4.53 (1 H, d, J = 8.3 Hz), 3.41-3.50 (1 H, m), 2.90-3.04 (3 H, m), 2.05 -2.19 (2 H, m), 1.27 (6 H, dd, J =

6.6 Hz, 6.6 Hz), 1.23 (s, 3H). Mass Spectrum (ESI) m / z = 490 (M + l), 512 (M + 23).

EXAMPLE 86

(3R, 5R, 6S) -3 - ((lH-Tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4430

chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one

The title compound was prepared from 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3 methyl-2-oxopiperidin-3-yl acid ) acetic (Example 73) as described in Example 51.

XH NMR (400 MHz, CDC13) δ ppm 1.20 (s, 3H), 1.27 (d, J =

6.9 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H), 2.20 (m, 2H), 3.08 (m,

1H), 3.41 (d, J = 15.7 Hz, 1H), 3.47 (m, 1H), 3.50 (d, J =

15.6 Hz, 1H), 4.52 (d, J = 8.8 Hz, 1H), 6.78 (m, 3H), 7.06 (m, 1H), 7.16 (m, 1H), 7.23 (m, 3H). Mass Spectrum (ESI) m / z 458.0 [M + H]+.

EXAMPLE 87

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl2-oxo-l- (pentan-3-yl) piperidin-3-yl) acetic acid

Step A. (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3ethyl-1- (pentan-3-yl) piperidin-2-one.

431

To a solution of (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) piperidin-2-one (Example 42, Step

1,221 mmol.) In 3-bromopentane (3196 pL, 25.6

A) (440 mg, mmol) under nitrogen to ta was added a dispersion of 60% sodium hydride in mineral oil (244 mg, 6.11 mmol).

The evolution of the gas was observed.

The reaction was stirred at room temperature for 10 min and then heated to 120 ° C under N2 for 19 h. The reaction mixture was cooled to room temperature and quenched with NH4C1 saturated. The layers were separated and the organic layer was dried over Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent:

up to 25% EtOAc in hexanes) to give the title compound as a mixture of diastereomers.

Step B. (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3ethyl-1- (pentan-3-yl) piperidin-2-one.

ZsBSSBXSKffl ·

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

432

A (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (pentan-3-yl) piperidin-2-one (Example 87, Step A) (125 mg 0.290 mmol) toluene (15 mL) was added and the mixture was concentrated under reduced pressure. This stage was repeated three times. Inhibitor-free THF (1 mL) was added and the mixture was cooled to -78 ° C. Freshly prepared LDA (1.0M in THF) (290 pL, 0.290 mmol) was added and the reaction turned to a golden yellow color. The reaction was warmed to 0 ° C for 30 min and the color reaction turned orange. The reaction was cooled to -78 ° C and ethyl iodide (281 pL, 3.49 mmol) was added. The reaction mixture was warmed to 0 ° C and stirred for 30 min. The reaction was quenched with NH4C1 saturated, warmed to room temperature, diluted with EtOAc and the layers separated. The organic layer was dried over Na2SW4 : and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 10% EtOAc in hexanes) to give the title compound as a mixture of diastereomers

1:1.

433

Stage

INSTITUTO mexica.no>

FROM THE V.-YAl · property :. J i, INDUSTRIAL

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6-lor-chlorophenyl) -3-ethyl-2-oxo-l- (pentan-3-yl) piperidin-3 yl) acetic acid

The title compound was prepared from (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-l (pentan-3-yl) piperidin-2 -one (Example 87, Step Bj as described in Example 42, Step C. Purification by preparative reverse phase HPLC (eluent: 0 to 100% MeCN

<td>+ TFA to</td><td> 0.1%</td><td>in water + 0.1% TFA) provided</td><td>the</td>

<td>compound</td><td>of the</td><td>title as the first diastereomer</td><td>of</td>

<td>elution.</td><td></td><td></td><td></td>

<td>XH NMR</td><td> (50 0</td><td>MHz, CHLOROFORM-d) δ ppm 0.50 (3 H, t,</td><td>J =</td>

7.5 Hz) 0.95 (3 H, t, J = 7.5 Hz), 1.00 (3 H, t, J = 7.5 Hz) 1.29 - 1.45 (2 H, m) 1.45 - 1.53 (1 H, m) 1.84- 2.01 ( 4

H, m) 2.30 (1 H, t, J = 13.8 Hz) 2.72 - 2.80 (2 H, m) 3.03

- 3.11 (2 H, m) 4.34 (1 H, d, J = 10.3 Hz) 6.69 (1 H, d, J = 7.6 Hz) 6.95 (2 H, 'br s) 7.05 - 7.20 (2 H, m) 7.087.17 (2H, m) 7.22-7.25 (1H, m). Mass Spectrum (ESI) m / z = 476 [Μ + H] '.

EXAMPLE 88 (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-3 (methylsulfonylmethyl) -1- (pentan-3-yl) piperidin-2-one

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

434

Step A. 5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl) -3-methyl-2-oxopiperidine-3-carboxylate of (5R, 6S) -methyl.

LHMDS (5.42 mL, 5.42 mmol) was added to a solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2,4dimethoxybenzyl) -3-methylpiperidin-2- ona (Example 71, Step B) (1.75 g, 3.61 mmol) in anhydrous THF (14.45 mL) at rt under argon. After 5 minutes dimethyl dicarbonate (1,159 mL, 10.84 mmol) was added. After 4 hours TLC indicated that a significant amount of product had formed but some of the starting material remained. Additional LHMDS (5.42 mL, 5.42 mmol) was added followed by dimethyl dicarbonate (1,159 mL, 10.84 mmol). After 2.5 hours the reaction was quenched by the addition of NH4C1 saturated aqueous and

435

the layers were separated. The aqueous layer was extracted with EtOAc twice and the organic compounds were accumulated, washed with saturated aqueous NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a yellow oil. Purification using a 120 g S1O2 column and eluting with 25 to 40% EtOAc / hexanes provided the title compound as a colorless oil as a mixture of isomers.

Stage B. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2,4dimethoxybenzyl) -3- (hydroxymethyl) -3-methylpiperidin-2-one

2M lithium borohydride (1,078 mL, 2,157 mmol) was added to a solution of (5R, 6S) -methyl 5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl) -3- methyl-2-oxopiperidine-3carboxylate (Example 88, Step A) (1.17 g, 2,157 mmol) in anhydrous THF (21.57 mL) and anhydrous ether (20 mL) at 0 ° C under nitrogen. The reaction was quenched after 58 hours with the addition of NH4C1 saturated aqueous and the layers were separated.

IMPI

436

The aqueous layer was extracted with EtOAc twice and the organic compounds were accumulated, washed with saturated aqueous NaCl solution. dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil.

Purification using an 80 g SiO column2 and eluting with 35 to 65% EtOAc / hexanes provided the title compound as a ~ 30: 1 mixture of isomers.

Step C. ((5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl) -3-methyl2-oxo piperidin-3-yl) methyl 4-methylbenzenesulfonate

DMAP (0.015 g, 0.120 mmol) was added to a solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2,4dimethoxybenzyl) -3- (hydroxymethyl) - 3-methylpiperidin-2-one (Example 88, Step B) (0.616 g, 1,197 mmol) and tosyl chloride (0.457 g, 2,395 mmol) in pyridine (5.99 mL) at rt The reaction mixture was heated to 100 ° C for 5 hours before removing the solvent in vacuo to provide an oil

437

cream. Purification using a column d¿> RQ g Ha

S1O2 and eluting with 25 to 55% EtOAc / hexanes provided the title compound as a colorless oil as a 33: 1 mixture of isomers.

Stage D. (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (2,4-dimethoxybenzyl) -3-methyl-3- (methylthiomethyl) piperidin-2-one

Sodium thiomethoxide (0.193 g., 2.7 6 mmol) was added to a solution of 4-methylbenzenesulfonate ((5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2,4- dimethoxybenzyl) -3-methyl2-oxopiperidin-3-yl) methyl (Example 88, Step C) (0.738 g, 1104 mmol) in anhydrous DMF (5.52 mL) at rt under nitrogen. The reaction mixture was heated at 50 ° C for 8 hours before cooling to rt, diluted with water, and extracted with ether three times. The organic compounds accumulated, washed with water three times, saturated aqueous NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil. Purification by using a

438

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

g column of

SiQ2 and eluting with 15 to 40% EtOAc / hexanes provided the title compound as a colorless foam.

Stage E. (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-3- (methylthiomethyl) piperidin-2-one

A solution of (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2,4-dimethoxybenzyl) -3-methyl-3 (methylthiomethyl) piperidin-2-one (Example 88, Step D) (0.406 g, 0.746 mmol) in TFA (6.00 mL) was heated at 50 ° C under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo to provide a purple oil. Purification using a 40 g SiO column2 and eluting with 35 to 60% EtOAc / hexanes provided the title compound as a white solid.

Step F. (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-3- (methylthiomethyl) · -! - (pentan-3-yl) piperidin-2-one

IMPI

MEXICAN INSTITUTE of property

INDUSTRIAL

NaH (0.076 g, 1,900 mmol) was added to a solution of (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-3 (methylthiomethyl) piperidin-2- one (Example 88, step E) (0.150 g, 0.380 mmol) in 3-bromopentane (1.42 mL, 11.41 mmol) at rt under nitrogen. The reaction mixture was heated at 120 ° C for 24 hours, cooled to rt, diluted with water, and extracted with DCM three times. The organic compounds accumulated, washed with saturated aqueous NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a yellow oil.

Purification using a 24 g S1O2 column and eluting with

15%

EtOAc / hexanes provided the title compound as a colorless syrup.

Stage G. (3S / 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-3- (methylsulfonylmethyl) -1- (pentan-3-yl) piperidin-2-one

N

440

3-Chloroperbenzoic Acid (0.054 g

MEXICAN INSTITUTE OF THE

INDUSTRIAL

0.242 mmol) was added to a solution of (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-3- (methylthiomethyl) -1- (pentan-3yl) piperidin -2-one (Example 88, · Stage F) (0.045 g, 0.097 mmol) in DCM (0.969 mL) at 0 ° C. The reaction mixture was stirred at rt for Ί hour, washed with saturated NaHCC> 3, saturated aqueous NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil. Purification using a 4g column of S1O2 ISCO and eluting with 25 to 75% EtOAc / hexanes provided the title compound as colorless glass.

XH NMR (500 MHz, CDC13) δ ppm 0.49 (t, J = 7.6 Hz, 3H),

0.95 (t, J = 7.5 Hz, 3H), 1.39 (m, 1H), 1.54 (s, 3H), 1.56

<td> 7.10</td><td>(m, 2H),</td><td>7.20 (m,</td><td>2H)</td><td>Spect</td><td>ro</td><td>of Masses (ESI)</td><td>m / z</td>

496.2 [M + H]_.

EXAMPLE 89

Acid 2- ((3R, 5R, 6SJ-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (3-cyclopropyl-l, 2,4-oxadiazol-5- yl) propyl) -3-methyl-2-oxopiperidin-3-yl) acetic.

441

Step A. 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoic acid.

HO.

LiOH (0.267 g, 11.13 mmol) in water (2.6 mL) was added to a solution of methyl 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoate (Example 65, Step B) (0.528 g, 1,113 mmol) in MeOH (7.5 mL) at rt. The reaction mixture was heated at 80 ° C for 14 hours, cooled to rt and acidified to pH = 1 with 3M HCI. The mixture was extracted with EtOAc three times and the organic compounds were accumulated, washed with saturated aqueous NaCI solution, dried (MgSO4), filtered and concentrated in vacuo to provide a white solid. Purification using a 40 g column of SIO2 and eluting with 35-60% EtOAc / hexanes provided the title compound as

IMPI

442 a mixture of isomers. .......

Step B. N '- (2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lyl) butanoyloxy) cyclopropancarboximidamide nh2

1,1'-Carbonyldiimidazole (0.104 g, 0.639 mmol) was added to a solution of 2 - ((3S, 5R, 6Sj-3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- methyl-2-oxopiperidin-lyl) butanoic (Example 89, Step A) (0.196 g, 0.426 mmol) in dichloromethane (1.7.03 mL) at rt and stirred for 22 hours before adding n-hydroxycyclopropancarboxamidine (0.064 g, 0.639 mmol) After 6 hours the reaction mixture was adsorbed on silica and purified using a 12 g SiO column2 ISCO and elute with 35 to 60% EtOAc / hexanes to provide a 2: 1 mixture of isomers.

Stage C. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (3-cyclopropyl-l, 2,4-oxadiazole) -5I Μ Ρ I

443 yl) propyl) -3-methylpiperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -1- ( 3-cyclopropyl-l, 2,4-oxadiazol-5-yl) propyl) -3-methylpiperidin-2-one

A solution of tetrabutylammonium fluoride (1.0M in

THF, 1,880 mL, 1,880 mmol) was added to a solution of N '- (2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- methyl-

2- oxopiperidin-l-yl) butanoyloxy) cyclopropancarboximidamide (Example 89, Step B) (0.204 g, 0.376 mmol) in THF (3.76 mL) at rt. After 2 hours the reaction mixture was concentrated in vacuo and purified using an 24 g column of SIO2 eluting with 25% Et20 / hexanes to provide (3S, 5R, 6S) -

3- allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (3cyclopropyl-1,2,4-oxadiazol-5-yl) propyl) -3-methylpiperidin -2 one.

Additional elution provided (3S, 5R, 6Sj-3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) —1 - ((R) —1— (3-cyclopropyl-l, 2,4-oxadiazol-5 -il) propyl) -3-methylpiperidin-2-one.

<td colspan="2"></td><td colspan="2"> 444</td><td>ΊΜΡΙ MCXíCANO INSTITUTE OF INDUSTRIAL PROPERTY</td><td></td>

<td>Stage</td><td>D.</td><td>Acid</td><td>2 - ((3R, 5R, 6S) -5-</td><td>(3-chlorophenyl)</td><td> -6-(4-</td>

chlorophenyl) -1 - ((S) -1- (3-cyclopropyl-l, 2,4-oxadiazol-5yl) propyl) -3-methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) —1 - ((S) —1— (3-cyclopropyl -l, 2,4-oxadiazol-5-yl) propyl) -3-methylpiperidin2-one (Example 89, Step C), as described in Example 42 Step C. Purification using a 4 g column of SiO2 and eluting with 35 to 100% EtOAc / hexanes provided the title compound as a colorless film.

XH NMR (500 MHz, CDC13) δ ppm 0.84 (t, J = 7.5 Hz, 3H), 0.89 (m, 2 Η), 1.01 (m, 2H), 1.25 (m, IH), 1.43 (s, 3H), 1.95

<td> 7.10</td><td>(t,</td><td>J =</td><td>7.9 Hz, IH), 7</td><td> . 16</td><td>(m, 3H).</td><td>Spectrum</td><td>of masses</td>

EXAMPLE'90

445

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) 1- (3-cyclopropyl-l, 2,4-oxadiazol-5 -il) propyl) -3-methyl-2oxopiperidin-3-yl) acetic.

The title compound. was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -1 (3-cyclopropyl-l, 2, 4-oxadiazol-5-yl) propyl.) -3-methylpiperidin2-one (Example 89, Step C) as described in Example 42, Step C.

XH NMR (400 MHz, CDC13) δ ppm 0.85-1.05 (m, 3H) 1.09 (t,

J = 7.6 Hz, 3H), 1.44 (s, 3H), 2.01 (m, 1H), 2.19 (m, 1H), 2.26 (m, 3H), 2.83 (d, J = 14.7 Hz, 1H), 2.91 ( d, J = 14.7 Hz, 2H), 3.32 (m, 1H), 3.95 (t, J = 7.2 Hz, 1H), 4.57 (d, J = 10.4 Hz, 1H), 6.73 (m, 1H), '6.98 (m, 1H), 7.09 (t, J = 7.8

Hz, 1H), 7.16 (m, 2H), 7.20 (m, 3H). Mass Spectrum (ESI) m / z 542.2 [M + H]+.

446

EXAMPLE 91

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -l-morpholinobutan-2-yl) -2-oxopiperidin- 3il) acetic

Step A. 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) methyl butanoate

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methylpiperidin-2-one (Example 71, Step D) (4.00 g, 10.7 mmol) in .45 mL of DMF a dispersion of 60% sodium hydride in mineral oil (1.71 g, 42.7 mmol) was added at 0 ° C. After stirring for 20 min, methyl 2-bromobutanoate (6.15 mL, 53.4 mmol) was added at 0 ° C and the resulting solution was stirred at 25 ° C for 12 h until completion of the reaction. Then NH4CI solution

447

IME

MKuCAT INSTITUTE

DELAPW.'Pifc? · NDUSTP.IA'aqueous saturated was added, and the mixture was extracted with ethyl acetate. The combined organic layers "were washed with water and saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 0 to 100% MTBE / hexanes, gradient elution), followed by separation of individual stereoisomers by chiral SFC (flow ratio: 65 mL / min on a ChiralPak column ®AD-H (Diacel Inc., Fort Lee, NJ) when using 3: 1 heptanes / IPA (0.1% DEA) / CO2 as the eluant) provided the title compound as the fastest eluting isomer.

XH NMR (400 MHz, 'CHLOROFORM-d) δ ppm 7.23 (2 H, d, J =

8.4 Hz), 7.06 - 7.17 (2 H, m), 7.00 (3 H, t, J = 1.8 Hz),

6.77 (1 H, d, J = 7.6 Hz), 5.79 - 5.94 (1 H, m), 5.20 (1 H, d, J = 4.7 Hz), 5.17 (1 H, s), 4.56 (1 H, d , J = 10.8 Hz),

3.73 (3 H, s), 3.25 - 3.37 (1 H, m), 3.18 (1 H, dd, J = 7.6

Hz, 4.9 Hz), 2.61 (2 H, d, J = 7.4 Hz), 2.20 -2.34 (1 H, m),

2.09 - 2.19 (1 H, m), 1.99 (1 H, d, J- 3.1 Hz), 1.57 - 1.72 (1 H, m), 1.24 (3 H, s), 0.61 (3 H, t, J = 7.5 Hz); Mass Spectrum (ESI) m / z = 474.1 [M + H]+.

Additional elution provided:

(R) -Methyl 2-((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoate

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

as the slower eluting isomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (2 H, d, J = 8.0 Hz), 6.99 - 7.19 (4 H, m), 6.95, (1 H, t, J = 1.8 Hz),

6.71 (1 H, d, J = 7.6 Hz), 5.81 - 5.95 (1 H, m), 5.19 (1 H, d, J = 2.7 Hz), 5.16 (1 H, d, J = 1.0 Hz), 4.4 8 (1 H, d, J =

10.6 Hz), 3.67 (3 H, s), 3.24 - 3.32 (1 H, m), 3.20 (1 H, dd, J = 7.8 Hz, 6.1 Hz), 2.61 - 2.72 (1 H, m), 2.49 - 2.60 (1 H, m), 1.91 - 2.21 (4 H, m), 1.27 (3 H, s), 1.00 (3 H, t, J =

7.5 Hz); MS (ESI) m / z = 474.1 [M + H]+.

Stage B.

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((R) -l-hydroxybutan-2-yl) -3-methylpiperidin-2one

To a solution of 2- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoate of

449

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ^ ¾¾. ^ 1x3 ^ (S) -methyl and 2- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) (R) methyl butanoate (1.73 g, 3.64 mmol) (mixture of stereoisomers from Example 91, Step A) in 27 mL of Et2 <3 and 9 mL of THF, a solution of lithium tetrahydroborate in THF (0.238 mL,

7.28 mmol) at 0 ° C. The resulting solution was stirred at 25 ° C for 2h. The reaction was quenched (10% citric acid), extracted (2 * EtOAc) and washed (1 * NaCl aqueous saturated solution). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0-60% EtOAc in hexanes) to give the title compound as the fastest eluting isomer.

XH NMR (4 00 MHz, CHLOROFORM-d) δ ppm 0.99 (t, J = 7.4

<td>H),</td><td>7.23 (d, J</td><td>= 8.6 Hz, 2</td><td>H); Spect</td><td>ro of</td><td>Masses (ESI)</td><td>m / z =</td>

Additional elution provided:

450

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-ο1οηοίθηΠΡ1- ((SFÍ hydroxybutan-2-yl) -3-methylpiperidin-2-one '.

HO.

Cl as the slowest eluting isomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.68 (t, J = 7.5

Hz, 3H), 1.27 (s, 3H), 1.38 - 1.52 (m, 1H), 1.90 - 2.08 (m, 4H), 2.61 (d, J = ΊΛ Hz, 2H), 3.10 - 3.25 (m, 2H),

3.59 - 3.68 (m, 2H), 4.4'6 (d, d = 10.2 Hz, 1 Η), 5.18 (dd, J = 13.7, 1.8 Hz, 2H), 5.79 - 5.93 (m, 1H), 6.72 (d, J = 7.6

Hz, 1H), 6.93 - 7.04 (m, 2H), 7.09 - 7.13 (m, 1H), 7.15 -

7.20 (m, 1H), 7.24 (d, J = 8.6Hz, 2H); Mass Spectrum (ESI) m / z = 446 (M + l).

Stage C. (S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-Í) butanal

To a solution of 218 mg (0.49 mmol) of (3S, 5R, 6S) -33

I

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

451 allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1-hydroxybutane

2-yl) -3-methylpiperidin-2-one (Example 91, Step B) in a mixture of water (13.20 pL ·, 0.733 mmol) and DCM (4883 pL) 1,1,1-tris (acetoxy ) -1,1-dihydro-l, 2-benziodoxol-3 (lH) one (Persodinano Dess Martín) (311 mg, 0.733 mmol) at room temperature. The reaction was monitored by. LCMS, and several small portions of additional periodynan were added until the reaction was complete. The reaction was quenched (2 mL, 1 M Na2S2O3), extracted (2 x DCM), and the combined organic layers were washed with sat. NaHCC> 3 (2X), sat. NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20 to 35% EtOAc / hexanes, gradient elution) provided the title compound.

Stage D. (3S, 5R, 6S) -3A1Í1-5- (3-chlorophenylj-6- (4-chlorophenyl) -3-methyl-l - ((S) -l-morpholinobutan-2-yl) piperidin-2-

To a solution of 100 mg (0.225 mmol) of (S) —2— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl2- oxopiperidin-l-yl) butanal (Example 91, Step C) in DCE (2420 pL) morpholine (200 pL, 2,297 mmol), acetic acid (1,288 pL, 0.023 mmol) and sodium triacetoxyborohydride (95 mg, 0.450 mmol) were added . The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM (2x10 mL). The combined organic layers were washed with sat NaCl solution, dried over Na ^ SOo, filtered, and the filtration product was concentrated under reduced pressure to result in the crude title compound as an oil.

Stage E. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -l-morpholinobutan-2-yl) -2oxopiperidin- 3-yl) acetaldehyde.

453

To a round bottom flask loaded with (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl.) -6- (4-chlorophenyl) -3-methyl-l- ((S) -1morpholinobutane-2- il) piperidin-2-one (Example 91, Step D) (125 mg, 0.242 mmol) THF (2 mL) was added. Approximately 1 mL of water was added dropwise until the solution was made and turned cloudy with gentle stirring. t-BuOH (0.350 mL) was added dropwise until the solution became homogeneous. NMO (42.6 mg, 0.364 mmol) was added followed by osmium theroxide, 4% by weight, in water (1 drop from a Pasteur glass pipette). The reaction mixture was stirred at room temperature for 16 hours. An additional drop of osmium tetroxide, 4% by weight, in water was added. After 5 hours, two additional drops of osmium tetroxide, 4% by weight, in water were added and the reaction mixture was stirred at room temperature for an additional 16 hours. Sodium periodate (145 mg, 0.679 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and water (10 mL), and filtered. The aqueous layer of the product

454

saturated aqueous NaCl, dried over sodium sulfate, filtered, and the filter product was concentrated under reduced pressure to provide the title compound.

Stage F. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -l-morpholinobutan-2-yl) -2oxopiperidin -3-yl) acetic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -l-morpholinobutan-2-yl) -2oxopiperidin -3-yl) acetaldehyde (Example 91, Step E) (125 mg, 0.242 mmol) in acetone (2 mL) 3 mL of a mixture of CrC> 3 in water (2 mL) was added and H2SO4 (1 mL) was concentrated ). The reaction mixture was stirred at room temperature for 2 hours and then diluted with water (10 mL) and ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (10 mL). The combined organic layers were concentrated under reduced pressure. The residue

455

FROM INDUSTRIAL PROPERTY was purified by reverse phase preparative HPLC (column: Gemini-NX column Cie 5um; Phenomonex, Torrance, CA; eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA) to provide the compound of the title.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.57 (t, J = 7.53

Hz, 1H) 1.26 (s, 1H) 1.39 (s, 3H) 1.54 - 1.70 (m, 1H)

1.72 - 1.89 (m, 1 H) 2.02 - 2.27 (m, 3 H) 2.49 (br. S., 2 H) 2.69 (br. S., 2 H) 2.82 (m, 2 H) 3.02 (br. S ., 2 H) 3.13 -

3.30 (m, 2H) 3.74 - 3.93 (m, 4H) 4.47 - 4.72 (m, 1H) 6.75 (d, J = 7.82Hz, 1H) 6.96 (t, J = 1.86Hz, 1H) 7.01 (br.

s., 1H) 7.04 - 7.17 '(m, 3H) 7.22 (d, J = 8.41 Hz, 2H).

Mass Spectrum (ESI) m / z = 533 [M + H]+.

Examples 92-94 were prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1cyclopropyl-2-hydroxyethyl ) piperidin-2-one by procedures similar to those described in Example 91, by substituting step D for morpholine for the appropriate amount of amine

R

OR

456

EXAMPLE '92

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (2,2,2- trifluoroethylamino) butan-2yl) piperidin-3-yl) acetic

<td></td><td>XH NMR</td><td>(400 MHz,</td><td colspan="2">CHLOROFORM-d) δ pp</td><td>m 0.5</td><td>6 (t, J = 7.43 Hz,</td>

<td>(d,</td><td>J = 8.22</td><td>Hz, 2H).</td><td colspan="2">Mass Spectrum</td><td>(ESI)</td><td>m / z = 545 [M +</td>

EXAMPLE 93

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (2,2-dimethylmorpholine) butan-2-yl) acid - 3-methyl-2-oxopiperidin-3IMPI

457 il) acetic.

<td colspan="4">XH NMR (400 MHz, CHLOROFORM-d) δ ρρπΠΤ</td><td></td><td>or,</td><td>J</td><td> = 7.34</td>

<td>Hz, 2H),</td><td colspan="2">Mass Spectrum (ES</td><td>I) m / z = 561</td><td>[M +</td><td>H]</td><td> -</td><td></td>

EXAMPLE 94

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((2S) -1- (2,6-dimethylmorpholine) butan-2-yl) - 3-methyl-2oxopiperidin-3-yl) acetic

The crude product was purified by reverse phase preparative HPLC (column: Gemini-NX Cis 5um; Phenomonex,

Torrance, CA; eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA) to provide a 4: 1 ratio of diastereomers of diastereomers of undetermined configuration at the positions indicated by *.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (br. S., 1 H) 1.24 (d, J = 6.06 Hz, 6 H) 1.35 - 1.49 (m, 4 H) 2.02 - 2.44 (m, 4 H) 2.68 (s, 1H) 2.79 - 2.89 (m, 2H) 3.20 - 3.32 (m, 2

3.80 - 4.00 (m, 2 Η) 4.10 (br. S., 3

458

H) 6.89

4.41 - 4.58 (m, 1H) 4.91 - 5.10 (m,

6.98 (m, 2H) 6.99

7.15 (m, 4H) 7.20

7.30 (m, 2H). Mass Spectrum (ESI) m / z = 561 [Μ + H].

EXAMPLE 95

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (4- (cyclopropyl sulfonyl) piperazin-l-yl) butan-2-yl) -3-methyl-

2- oxopiperidin-3-yl) acetic

Stage A. 4- ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) tert-butyl butyl) piperazin-1-carboxylate.

The title compound was prepared from (S) -2-

. _ - MEXICAN INSTITUTE

459 OF THE PROPERTY

INDUSTRIAL

((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl

2-oxopiperidin-l-yl) butanal (Example 91, Step C) and tert-butyl piperazine-l-carboxylate according to the procedure described in Example 91 Step D

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (piperazin-l-yl) butan -2il) piperidin-2-one

To a solution of 4 - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) tert-butyl butyl) piperazine-l-carboxylate (Example 95, Step A) (187 mg, 0.304 mmol in DCM (2.4 mL) TFA (600 pL, 7.79 mmol) was added The reaction mixture was stirred at room temperature for 16 hours before concentrating under reduced pressure. The residue was taken up in DCM (15 mL) and washed with saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to result in

the title compound as a white foam.

460

Step C. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (4- (cyclopropyl sulfonyl) piperazin-l-yl ) butan-2-yl) -3methylpiperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (piperazin-l-yl) Butan-2yl) piperidin-2-one (Example 95, Step B) (60 mg, 0.117 mmol) in DCE (1.2 mL) cyclopropansulfonyl chloride (23.76 pL, 0.233 mmol) was added followed by diisopropylethylamine (40.6 pL, 0.233 mmol) ). The reaction mixture was stirred at room temperature for 16 hours, diluted with water (10 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 x 10 mL). The combined organic layers were washed with saturated NaCI solution (10 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to result in the title compound as a solid.

461

IMPIfT ^

MEXICAN INSTITUTE '1

OF THE RROI'IEDAD Lí

INDUSTRIAL-Stage D. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl)

1- ((S) -1- (4- (cyclopropyl sulfonyl) piperazin-l-yl) butan-2-yl) -3methyl-2-oxopiperidin-3-yl) acetic

To a 10 mL round bottom flask charged with (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- ( 4 (cyclopropyl sulfonyl) piperazin-l-yl) butan-2-yl) -3methylpiperidin-2-one (Example 23, Step C) (85.1 mg, 0.138 mmol) THF (—800 uL) was added followed by water (~ 600 uL, until the reaction remains cloudy with gentle stirring) followed by tBuOH (-200 uL, until the reaction becomes translucent). NMO (24.17 mg, 0.206 mmol) was added followed by 5 drops of osmium tetroxide, 4% by weight, in water (33.6 pL, 0.138 mmol) by means of a pasteur pipette. The reaction was stirred at rt overnight before Jones reagent (0.154 mL) was added. The reaction was stirred at room temperature for 2 hours, diluted with water (15 mL), and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (3 x 20 mL), saturated sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and the filtration product concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA, for 20 min) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.92 - 1.25 (m, 10 H)

462

1.43 (s, 3 Η) 1.85 (br. S ,,

H) 2.08 (d, J = 13.50 Hz, 1 H)

-1 - ni - J - r, ----------- «ΙιΜΤϋχ-, ΙιιίιΠ, ^, Γ, - ,, - ι ^ ί, ύ ·

2.16 - 2.30 (m, 1H) 2.40 (d, J = 5.87 Hz, 2H) 2.52 (br. S., 2

Mass Spectrum (ESI) m / z = 636 [Μ + H].

EXAMPLE 96

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l ((S) -1- (4- (methylsulfonyl) piperazin-l- il) butan-2-yl) -2oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, GSjS-allyl-S- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- ((S) -1 (piperazine-l -il) butan-2-yl) piperidin-2-one (Example 95, Step B) and methanesulfonyl chloride as described in Example 95, Steps C and D.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (br. S., 3 H)

1.42 (s, 3H) 1.85 (br. S., 2H) 2.00 - 2.13 (m, 1H) 2.14 -

.463

2.28 (m, 1H) 2.56 (br. S., 3H) 2.66 - 2.77 (m, 3H) 2.85 (d, J

<td>Spectrum</td><td>of</td><td>Masses</td><td>(ESI) m / z = 610</td><td>[M</td><td> +</td><td>H] + .</td><td></td><td></td><td></td><td></td>

EXAMPLE 97

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -1- (4-acetylpiperazin-l-yl) butan-2yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic

Stage A. (3S, 5R, 6S) -I - ((S) -1- (4-acetylpiperazin-l-yl) buthan-2yl) -3-allyl-5- (3-chlorophenyl) -6- (4 -chlorophenyl) -3-methylpiperidin-2 one.

CI

464

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-l - ((S) -1- (piperazin-l-yl ) butan-2yl) piperidin-2-one (Example 95, Step B) (80 mg, 0.155 mmol) in DCE (1.5 mL) acetyl chloride (22.1 pL, 0.31 mmol) was added followed by diisopropylethylamine (54.1 pL, 0.311 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to provide the title compound.

Stage B. Acid 2 - ((3R, 5R, 6S) -1 - ((S) -1- (4-acetylpiperazin-lil) butan-2-yl) -5- (3-chlorophenyl) -6- (4 -chlorophenyl) -3-methyl-2oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) 1- ((S) -1- (4-acetylpiperazin-l-yl) butan-2-yl) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one (Example 97, Step A) as described in Example 95, Step D. The residue was purified by reverse phase preparative HPLC (column: Gemini-NX Cis 5um; Phenomonex, Torrance, CA; eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94 - 1.18 (m, 3 H)

1.42 (s, 3H) 1.77 - 1.98 (m, 1H) 2.12 (s, 4H) 2.23 (s, 2H)

2.48 - 2.63 (m, 3H) 2.67 (s, 3H) 2.84 (br. S., 3H) 3.16 -

3.35 (m, 2H) 3.83 - 4.05 (m, 3H) 4.43 - 4.61 (m, 1H) 6.62 -

465

6.75 (m, 1 Η) 6.97 (s, 2 Η) 7.07 (d,

7.17 (m, 3H). Mass Spectrum (ESI) m / z - 574 [Μ + H].

EXAMPLE 98

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 (4- (cyclopropancarbonyl) piperazin-l-yl) butan- 2-yl) -3-methyl-2oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) 3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1 (piperazin -l-yl) butan-2-yl) piperidin-2-one (Example 95, Step B) and cyclopropancarbonyl chloride as described in Example 97.

'Η NMR (400 MHz, CHLOROFORM-d) δ ppm 0.79 - 0.91 (m, 6H)

1.02 (br. S., 6 H) 1.43 (s, 3 H) 1.65 - 1.75 (m, 2 H) 2.11 (br.

s., 2 H) 2.17 - 2.30 (m, 2 H) 2.51 (br. s., 3 H) 2.65 (s, 2H)

2.80 - 2.88 (m, 2H) .3.29 (t, J = 11.44 Hz, 2H) 6.98 (s, 2H)

7.06 (t, J = 7.83 Hz, 2 H) 7.10 - 7.16 (m, 2 H) 7.19 - 7.26 (m, 2 H). Mass Spectrum (ESI) m / z = 600 [Μ + H].

466

EXAMPLE 99

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) l-morpholinobutan-2-yl) -2-oxopiperidin -3-yl) methyl) -1,2,4-

The title compound was prepared from 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) —1— morpholinobutan -2-yl) -2-oxopiperidin-3-yl) acetic (Example 91) using a procedure similar to that described in Example 82. The crude product was purified by flash chromatography on silica gel (eluent: 0 to 10% MeOH in DCM) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.56 (t, J = 7.34 Hz, 3 H) 1.29 (br. S., 1 H) 1.30 - 1.38 (m, 3 H) 1.57 (ddd, J = 13.99 , 7.53 and 3.91 Hz, 1 H) 1.81 (dt, J = 14.48 and 7.43 Hz, 1H)

2.09 (dd, J = 13.99 and 3'.03 Hz, 1 H) 2.18 (d, J = 9.98 Hz, 1H)

2.22 - 2.32 (m, 1 H) 2.46 (d, J = 3.72 Hz, 2 H) 2.66 (br. S., 2 H) 2.90 (d, J = 15.06 Hz, 1 H) 2.95 - 3.21 (m, 4 H) 3.74 - 3.89 (m, 4 H) 4.59 (d, J = 10.17 Hz, 1 H) 6.72 (d, J = 7.63 Hz, 1H)

6.84 - 6.99 (m, 3H) 7.08 - 7.13 (m, 1H) 7.14 - 7.18 (m, 1H)

467 mri

MEXICAN INSTITUTE

D2 PROPERTY

INDUSTRIAL

7.23 (d, J = 8.22 Hz, 2H). Mass Spectrum (ESI) m / z [Μ + Η]+.

EXAMPLE 100

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1 (5,5-dimethyl-2-oxooxazolidin-3-yl ) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic.

1- ((S) -1- (2-hydroxy-2-methylpropylamino) butan-2-yl) -3methylpiperidin-2-one.

The title compound was prepared as described in

Example 91, Step D and using and using l-amino-2-methylpropan-2-

ol (Tyger Scientific,

Inc., Ewing, NJ).

IMPI

468

Stage B.

3- ((S) -2- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butyl ) -5.5-

Ά a 42 mg (0.081 mmol) solution of (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (2-hydroxy -2-methylpropylamino) butan-2-yl) -3-methylpiperidin-2-one (Example 100, Step A) in dioxane (2705 pL) carbonyldiimidazole (132 mg, 0.812 mmol) was added. The reaction was heated to 100 ° for 6h. Purification of the residue by reverse phase HPLC (Sunfire ™ Prep Cie OBD 10 pm column (Waters, Milford, MA) (eluent: 60 to 85% MeCN / water (0.1% TFA), gradient elution) provided the title compound .

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (5,5-dimethyl-2-oxooxazolidin-3 -il) butan2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic.

To a rapidly stirred solution of 20 mg (0.037 mmol) of 3 - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (410

469

To JLVL. .eleven. K MEXICAN INSTITUTE OF FAOPIWA »INDUSTRIAL chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butyl) -5,5 dimethyloxazolidin-2-one of CC14 (210 pL), MeCN (Example 100, Stage B) in a mixture (210 pL), and water (315 pL) mg, 0.147 mmol) was added, followed by catalytic ruthenium (III) chloride hydrate (4.15 mg, 0.018 mmol).

When celite material reaction was completed.

with insoluble acid

It was extracted by monitoring CLEM, citric acidified and removed to acetate and diluted with chloroform.

by filtration through

The ethyl one and the combined organic layer were washed with saturated NaCl, dried, filtered and the filtration product was emptied. Purification (Sunfire ™ Prep column (eluent:

to 80% of the residue by HPLC of

Company OBD 10 pm (Waters, on Na2SW4, concentrated in reverse phase

Milford, MA)

MeCN / water (0.1% TFA), gradient elution) provided the title compound as a white powder.

<td>1H</td><td>NMR (500</td><td>MHz,</td><td>CHLOROFO.RMO-d)</td><td>δ ppm 0</td><td> .55</td><td>(t</td><td></td><td> =7.21</td><td>Hz,</td>

(M + l).

7.20 (m, 1H). Mass Spectrum (ESI) m / z = 561

470

EXAMPLE 101

Acid

2 - ((3R, 5R, 6S) -1 - ((S) -1- (tert-butylamino) -1 oxobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 3-methyl-2oxopiperidin-3-yl) acetic.

Stage A. 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoic acid

2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl was added to a 15 ml round bottom flask ) (S) -tert-butyl butanoate (420 mg, 0.813 mmol) (Example 1, Step F) and anisole (444 pL, 4.07 mmol), followed by TFA (4066 pL) which had been pre-cooled to 0 ° C. The reaction mixture was stirred at 0 ° C for 1h, diluted with 50ml of ether, and the combined organic products were washed with 20ml of water, NaHCO3 / sat. of NaCl until neutral, then dried over Na2SW4, leaked and '471

the filter product was concentrated. Purification of the residue by flash chromatography on silica gel (eluent: 0 to 20% EtOAc / hexanes, gradient elution) provided the title compound.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (1 H, s), 7.07 7.19 (2 H, m), 7.00 (3 H, br. S.), 6.76 (1 H, d, J = 7.4 Hz),

5.77 - 5.93 (1 H, m), 5.15 - 5.25 (2 H, m), 4.58 (1 H, d,

J = 10.8 Hz), 3.35 (1 H, br. S.), 3.23 - 3.33 (1 H, m), 2.62 (2

H, d, J = 7.2 Hz), 2.27 (1 H, dquin, J = 14.6, 7.5, 7.5, 7.5, 7.5 Hz), 2.14 (1 H, t, J = 13.5 Hz), 1.99 (1 H, dd , J = 13.7, 2.9 Hz),

I. 50 - 1.64 (1 H, m), 1.29 (3 H, s), 0.66 (3 H, t, J = 7.4 Hz).

Stage B. 2 - ((5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 3-methyl-2-oxopiperidin-l-yl) -N-tert-butylbutanamide

To a solution of 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) butanoic acid (81 mg, 0.17 .6 mmol) (Example 101, Step A) in dry DMF (880 pL) with 3eq TEA (73.6 pL, 0.528 mmol) at 0or 2 eq of HATU (134 mg, 0.352 mmol) were added. The reaction

472

IMPI

INITTITT MtXICANO

PSIAÍROPIEDAD

ÍN'DÍÁSTRLAL. Stirred at 0or for 5 min, followed by addition of t-butyl amine (25.7 mg, 0.352 mmol). Stirred for 30 min at 0 °, quenched with NaHCC> 3 sat. and extracted to EtOAc. The combined organic layers were washed with saturated NaCI solution, dried over Na2SW4, filtered and the filter product concentrated. · Purification of the residue by flash chromatography on silica gel (eluent: 030% EtOAc / hexanes, gradient elution) provided the title compound as a mixture of stereoisomers.

Stage C. Acid 2 - ((3R, 5R, 6S) -1 - ((S) -1- (tert-butylamino) -1oxobutan-2-yl) -5- (3-chlorophenyl) -6- (4- chlorophenyl) -3-methyl-2oxopiperidin-3-yl) acetic.

The title compound was prepared from (5R, 6S) - 5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) piperidin-2-one (Example 101, Step B) as described in Example 1, Step H. The crude product was purified by reverse phase preparative HPLC (Sunfire ™ Prep Ci column8 10 pm OBD (Waters, Milford, MA) (eluent: 55% acetonitrile, water, 0.1% TFA, gradient elution).

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.71 (t, J = 7.46 Hz, 3 Η), 1.32 (s, 9 Η), 1.40 (s, 3 Η), 1.60 - 1.71 (m, 1 Η) , 2.07 - 2.25 (m, 3 Η), 2.86 (d, J = 2.20 Hz, 2 Η), 3.16 (ddd, <7 = 12.65, 9.60, 3.42 Hz, 1 Η), 3.67 (dd, 7 = 8.80, 5.62 Hz, 1

473

MEXI INSTITUTE

FROM THE ΡΓ.ΟΓΗ-ΟΛΕ?

INDUSTÍGAL

J = 7.58 Hz, 1H), 6.97

Η), 4.70 (d, J = 9.78 Hz, 1 H),

6.78 (d, (s, 1H), 6.98 - 7.05 (m, 3H), 7.11 (t, J = 7.83 Hz, 1H),

7.14 - 7.19 (m, 1H), 7.21 (d, J = 8.56 Hz, 2H). Spectrum

Masses (ESI) m / z = 533 (M + l).

EXAMPLE 102

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2S, 3R) -2,3-dihydroxycyclopentyl) -3-methyl-2 acid -oxopiperidin3-yl) acetic

Stage Ά. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 (2,3-dihydroxypropyl) -3-methylpiperidin-2-one.

To a solution of 4g (10.69 mmol) of (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2one (Example 71, Step D) in 100 mL of THF water (60mL) was added followed by 4-methylmorpholine 4-oxide (1878g, 16.03mmol). The cloudy reaction mixture became clear

within min and oxide of

474

MEXICAN INSTITUTE OF PROPERTY / O osmio , Ν? ντ · Φ · Ι aqueous) (0.340 mL, 0.053 mmol) and the mixture ofreatTCTOTr remained clear. The reaction mixture was stirred at room temperature for 18h. Osmium (VIII) oxide (4% aq) (0.1 mL) was added and the reaction mixture was stirred at room temperature for 24 h. Saturated NaCl solution was added and the mixture was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and the filter product concentrated to give the title compound as a 1: 1 ratio of diastereomers.

Step B. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -3 -methylpiperidin-2-one

To a solution of (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2,3-dihydroxypropyl) -3-methylpiperidin-2-one (Example 102, Step .A ) (4,900 g, 12.00 mmol) and 2,2-dimethoxypropane (14.76 mL, 120 mmol) in N, N-dimethylformamide (34 mL) at room temperature CSA (0.279 g, 1,200 mmol) was added and the reaction mixture was allowed to stir for 1 hr at room temperature. The reaction was quenched with

475 sodium bicarbonate (100 mL) and EtOAc (100 mL). The layers were separated and the organic layer was washed three times with saturated sodium carbonate (100 mL). The aqueous layers were combined and extracted with EtOAc (200 mL). The organic layers were combined, washed with saturated aqueous NaCl solution, dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.

Stage C. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopent-2-enyl) -3 - ((2,2-dimethyl-l, 3- dioxolan-4-yl) methyl) 3-methylpiperidin-2-one ci

At (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -3- Methylpiperidin-2one (Example 102, Step B) (0.909g, 2.027mmol) Toluene (15mL) was added and the mixture was concentrated under reduced pressure. This stage was repeated three times. Inhibitor-free THF (20 mL) was added and the solution was cooled to 78 ° C. Butyllithium in pentane (2.0M) (1,014 mL, 2,027 mmol) was added dropwise and the reaction mixture remained colorless. The reaction mixture was warmed to 0 ° C and he

476

MEXICAN INSTITUTE

PROPERTY reaction color turned yellowINDW / -

nBuLi in pentane (2.0M) drop added to CfótcF

reaction mixture remained bright yellow. The reaction mixture was cooled to -78 ° C and freshly made 3-bromocyclopent-l-ene (0.4 g, 2.72 mmol) in THF (2 mL) was added dropwise. The reaction mixture was wrapped in metal laminate and warmed to 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hr and then at rt for 2 days. The reaction was quenched with NH4C1 saturated and extracted with EtOAc. The organic layer was dried over Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 100% EtOAc in hexanes) to give the title compound as a colorless film.

Stage D. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopent-2-enyl) -3- (2,3-dihydroxypropyl) -3-methylpiperidin2- one

To a solution of (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-

JE- JL »£ _g_ X

MEXfC'NO INSTITUTE

OF THE PROPERTY

INDUSTRIAL

477 chlorophenyl) -1- (cyclopent-2-enyl) -3- ((2, P-dimethyl-l, 3dioxolan-4-yl) methyl) -3-methylpiperidin-2-one (Example

28,

Step C) (310 mg, 0.603 mmol) in THF (3 mL) at room temperature, aqueous HCI (1M) (3013 pL, 3.01 mmol) was added. The reaction mixture was stirred at room temperature for 19

h. The reaction mixture was diluted with EtOAc and the layers were separated. The organic layer was washed with NaHCO3 saturated, saturated aqueous NaCl solution and dried over Na2SW4 and concentrated under reduced pressure to provide the title compound.

Stage E.

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl)

1- (cyclopent-2-enyl) -3-methyl-2-oxopiperidin-3yl) acetaldehyde

To a solution of (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -1- (cyclopent-2-enyl) -3- (2,3-dihydroxypropyl) -3methylpiperidin-2- Ona (Example 102, Step D) (286 mg, 0.603 mmol) in THF (3 mL) and water (3 mL), sodium periodate (258 mg, 1,206 mmol) was added at room temperature. The τ KA T /

Ivi. .L.

478 suspension was stirred at room temperature for 1 h X —— inBTTi-T was then diluted with EtOAc and the layers separated. The organic layer was washed with

Na2S2Saturated O3 and saturated aqueous NaCl solution and dried over Na2SW4 and concentrated under reduced pressure to provide the title compound.

Stage F. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopent-2-enyl) -3-methyl-2-oxopiperidin-3yl) acetic acid

Al 2 - ((3R, 5R, 6SJ-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopent-2-enyl) -3-methyl-2-oxopiperidin-3-yl) acetaldehyde ( Example 102, Step E) (267 mg, 0.604 mmol) in acetone (4 mL) Freshly prepared Jones reagent (0.5 mL) was added at rt The reaction mixture was stirred at room temperature for 15 min Before dilution with EtOAc and washed with water and saturated aqueous NaCl solution. The organic layer was dried over Na2SW4 and concentrated under reduced pressure. The residue was purified by

479

Flash chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes) to give the title compound as a colorless film as a 3.6: 1 mixture of diastereomers.

Stage G. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((IS, 2S, 3'R) -2,3-dihydroxycyclopentyl) -3 -methyl-

2- oxopiperidin-3-yl) acetic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -1- (cyclopent-2-enyl) -3-methyl-2-oxopiperidin-

3- yl) acetic (Example 102, Step F) (94 mg, 0.205 mmol) in THF (1.0 mL), water (0.25 mL) and tBuOH (0.2 mL) were added at room temperature. NMO (36.0 mg, 0.308 mmol) was added followed by osmium tetroxide (4% aq) (1,303 pL, 0.205 pmol). The reaction mixture was stirred at room temperature for 24h. Water (10 mL) was added and the mixture was extracted with DCM twice. The organic layers were combined and dried over Na2SO4 and concentrated under reduced pressure. The residue, containing a mixture of three stereoisomers, was purified by reverse phase preparative HPLC (eluent: 30 to 50% MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes) to provide the title compound as the first isomer of elution.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21 - 1.36 (3 H,

MEXICAN INSTITUTE

OF THE FRO / IEDAD

INDUSTRIAL

480

<td>H</td><td>m), 6</td><td> .93 - 7.12</td><td>(4 H, m)</td><td> , 7.12</td><td> - 7.25</td><td> (3</td><td>H, m). Spectrum</td>

<td>of</td><td>Masses</td><td>(ESI) m / z</td><td>= 492 [M</td><td>+ H].</td><td></td><td></td><td></td>

The additional elution provided as the last elution isomer Example 103.

EXAMPLE 103

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((IR, 2R, 3S) -2,3-dihydroxycyclopentyl) -3-methyl-2 acid -oxopiperidin3-yl) acetic

Cl XH NMR (400 MHz, 'CHLOROFORM-d) δ ppm 1.19 - 1.38 (1 H,

7.19 (3H, m) 7.23 (3H, d, J = 8.6Hz). Mass Spectrum

481 (ESI) m / z = 492 [Μ + H] 1 .

EXAMPLE 104

Acid 2 - ((3R, 3'S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l '- (2,2,2-trifluoroethyl) -1 , 3'bipiperidin-3-yl) acetic or 2 - ((3R, 3'R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l '- (2,2,2trifluoroethyl) -1,3'-bipiperidin-3-yl) acetic

chlorophenyl) -1- (1,5-dioxopentan-2-yl) -3-methyl-2-oxopiperidin3-yl) acetic.

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -1- (2,3-dihydroxycyclopentyl) -3-methyl-2-oxopiperidin-3-yl acid ) acetic (Example 102, Step F) (110 mg,

482

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

0.223 mmol) in THF (3 mL) and water (3 mL) sodium periodate (134 mg, 0.626 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 45 min and diluted with EtOAc and the layers were separated. The organic layer was washed with saturated aqueous Na solution2S2OR3, saturated aqueous NaCl solution, dried over Na2SW4 and concentrated under reduced pressure to provide the title compound.

Stage B. Acid 2 - ((3R, 3'S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-meth 1-2-cyx-1 '- (2,2, 2-trif luoroethyl) -1,3'bipiperidin-3-yl) acetic or Acid 2 - ((3R, 3'R, 5R, 6S) -5- (3Clorophenyl) -6- (4-chlorophenyl) -3- methyl-2-oxo-l '- (2,2,2trifluoroethyl) -1,3' -bip> iperidin-3-yl) acetic (Isomer 1)

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) —1— (1,5-dioxopentan-2-yl) -3-methyl-2oxopiperidin -3-yl) acetic (Example 104, Step A) (55 mg, 0.112 mmol) in DCE (1 mL) 2,2,2-trifluoroethanamine (9.24 pL, 0.118 mmol) and sodium. Triacetoxyborohydride (76 mg) were added 0.359 mmol) at room temperature. The cloudy reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with DCM, and washed with saturated aqueous solution of

483

INSTITUTE ΜΓ / Τ.-ζ wr. · I --- F xi

D £ LA PRCM2LV.D '' '' í

INDUSTUiAL

NaHCCh and saturated aqueous NaCI solution. The layers were separated and the aqueous layer was extracted three times with DCM. The organic layers were combined, dried over Na2SW4 and concentrated under reduced pressure.

The residue was purified by HPLC

40% MeCN + TFA to reverse phase high school (eluent

0.1% in water + 0.1% TFA, for 20 minutes) and concentrated in vacuo to provide the first elution diastereomer. The residue was dissolved in DCM (1 mL) and HC1 in ether (1M) (1 mL) was added and the solvent was removed under reduced pressure to provide the hydrochloride salt of one of the title compounds as the first isomer of elution .

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.73 - 1.00 (4 H,

m), 1.13 - 1.53 (6 H, m), 1.58 - 1.84 (2 H, m), 1.98 - 2.13 (1 H, m), 2.24 - 2.44 (1 H, m), 2.67 - 2.99 (3 H, m), 3.17 3.32 (1 H, m), 4.22 (2 H, t, J = 6.0 Hz), 6.65 - 6.91 (1 H, m), 7.00 (1 H, d, J = 0.6 Hz), 7.05 - 7.24 (4H, m), 7.48 -

7.59 (1H, m), 7.63 - 7.79 (1H, m). Mass Spectrum (ESI) m / z = 557 [Μ + H].

Elution and additional concentration in vacuo provided Example 105.

EXAMPLE 105

Acid

484

- mtMggcan* '|[ 11

2 - ((3R, 3'S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-l '- (2,2,2-trif'luoroethyl) -1, 3 '-bipiperidin-3yl) acetic or 2- ((3R, 3'R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxo -l '- (2,2,2-trifluoroethyl) -1,3' bipiperidin-3-yl) acetic (Isomer 2)

(1 mL) was added and the reduced to provide the solvent salt

DCM (1 mL) and HC1 in ether (1M) were removed under hydrochloride pressure of one of the title compounds as the second elution isomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.73 - 1.08 (7 H, m), 1.13 - 1.50 (7 H, m), 1.69 (6 H, d, J = 6.1 Hz), 7.54 (4 H, dd, J = 5.7 and 3.3 Hz), 7.72 (4 H, dd, J = 5.7 and 3.3 Hz). Mass Spectrum (ESI) m / z = 557 [M + H]+.

485

MFI1

EXAMPLE 106

INSTITUTE 7777 OF THE Κ <· .'νΖ

INDuST

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 3S) -3-hydroxycyclopentyl) -3-methyl-2-oxopiperidin-3 il) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4oxopiperidin-3-yl) acetic acid

* unknown stereochemistry

Stage A.

(cyclopent-2-enyl) piperidin-2-one.

To a solution of 3.25 g (10.16 mmol) of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 1, Step

E) in DMF (150 mL) at 0 ° C, a dispersion of 60% sodium hydride in mineral oil (1,016 g,

25.4 mmol). The evolution of the gas was observed. The cloudy reaction mixture was stirred at 0 ° C for 20 min before adding 3486

bromocyclopent-l-ene (4.48 g, 30.5 mmol). The cloudy reaction mixture was warmed to room temperature and stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NH solution4C1 was diluted with EtOAc and the layers were separated. The organic layer was washed with 1M LiCl, saturated aqueous NaCl solution, dried over

Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 25 to 100% EtOAc in hexanes) to give the title compound as a 5: 2 mixture of diastereomers.

Stage B. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (3hydroxycyclopentyl) piperidin-2-one

To a solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cycloperit-2-enyl) piperidin-2-one (Example 106, Step A) (394 mg, 1,020 mmol) in THF (10 mL) borane-tetrahydrofuran complex (l.Om in THF) (1020 pL, 1,020 mmol) was added. The evolution of the gas was observed. The reaction was stirred at room temperature for 30 min. before reaction it turned cloudy and

487 add NaOH

Mix room temperature for 1 hr.

The reaction mixture was extracted with EtOAc. The organic layers were washed with saturated aqueous NaCl solution and dried over Na2SO4.

The residue was purified by flash chromatography on silica gel (eluent:

up to 100% EtOAc in hexanes) to give the title compound as a mixture of diastereomers.

Stage C. '(5R, 6S) -1 - ((IS, 3S) -3 - ((tertButildimethylsilyl) oxy) cyclopentyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one or ( 2S, 3R) -1 - ((IS, 3R) -3 - ((tertButildimethylsilyl) oxy) cyclopentyl) -3- (3-chlorophenyl) -2- (4-chlorophenyl) piperidine

To a solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1- (3-hydroxycyclopentyl) piperidin-2-one (Example

106, Step B) (175 mg, 0.433 mmol) in DMF (4 mL) a

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL room temperature added TBDMS-C1 (71.8 mg, 0.476

488

and imidazole (29.5 mg, 0.4333 mmol). The reaction mixture was stirred at room temperature for 18h. Additional imidazole (29.5 mg, 0.433 mmol) and TBDMS-C1 (71.8 mg, 0.476 mmol) were added. The reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc, washed with 1M aqueous LiCl, 1M 'HC1 and saturated aqueous Na2CO solution. Dried - organic layer over Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent:

up to 100% EtOAc in hexanes) to give the title compound as the main single isomer.

Stage

(5R, 6S) -1 - ((IS, 3Sj-3- (tertButildimethylsilyloxy.) Cyclopentyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one or (2S, 3R) -1 - ((IS, 3R) -3 ((tert-Butyldimethylsilyl) oxy) cyclopentyl) -3- (3-chlorophenyl) -2 (4-chlorophenyl) -5-methylpiperidine

Cl * unknown stereochemistry

489

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

(5R, 6S) -1 - ((1S, 3S) -3 - ((tertButildimethylsilyl) oxy) cyclopentyl) -5- (3-chlorophenyl) -6- (4 chlorophenyl) piperidin-2-one or (2S, 3Rj -1 - ((1S, 3R) -3 - ((tertButyldimethylsilyl) oxy) cyclopentyl) -3- (3-chlorophenyl) -2- (4 chlorophenyl) piperidine of the above (Example 106, Step C) (104 mg, 0.201 mmol) toluene (15 mL) was added and the mixture was concentrated under reduced pressure This step was repeated three times. The residue was dissolved in inhibitor-free THF (2 mL) that had previously been degassed with Ar and the mixture was cooled to 0 ° C under Ar. Methyl iodide (13.79 pL, 0.221 mmol) was added followed by LHMDS (previously degassed with Ar) (1.0M in THF) (221 pL, 0.221 mmol). The reaction mixture was warmed to room temperature and stirred under Ar for 24 h. Additional LHMDS (1.0 M in THF) (221 pL, 0.221 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NH solution4C1 and extracted with EtOAc. The organic layers were dried over Na2SW4, filtered, and the filter product concentrated in vacuo to provide the title compound.

Step E. (5R, 6S) -3-Allyl-l - ((1S, 3S) -3 - ((tertbutyldimethylsilyl) oxy) cyclopentyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin -2-one · o (2S, 3R) -5-Alil-l490

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

((1S, 3R) -3- ((tert-butyldimethylsilyl) .oxy) cyclopentyl) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -5-methylpiperidine

* unknown stereochemistry

A (5R, 6S) -l - ((1S, 3S) -3- (tertButyldimethylsilyloxy) cyclopentyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one or (2S, 3R ) -1 - ((1S, 3R) -3 ((tert-Butyldimethylsilyl) oxy) cyclopentyl) -3- (3-chlorophenyl) -2 (4-chlorophenyl) -5-methylpiperidine of the above (Example 106, Step D ) (107 mg, 0.201 mmol) toluene (15 mL) was added and the mixture was concentrated under reduced pressure. This stage was repeated three times. The residue was dissolved in inhibitor-free THF (2 mL) that had previously been degassed with Ar and the mixture was cooled to 0 ° C under Ar. Distilled allyl bromide (87 pL, 1,004 mmol) and LHMDS (1M in THF) (502 pL, 0.502 mmol) were added and the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hr before heating the reaction mixture at 50 ° C under Ar overnight. The reaction mixture was cooled to room temperature and allyl bromide was added

491

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

additional (87 pL, 1,004 mmol) and LHMDS (1.0 M in THF) (502 pL,

0.502 mmol) and the reaction mixture was heated to 60 ° C

<td>for 6</td><td>h under Ar.</td><td>The</td><td>mix of</td><td colspan="2">reaction got cold</td><td>until</td>

<td colspan="2">ambient temperature and</td><td>the</td><td>reaction</td><td>It was</td><td colspan="2">quenched with solution</td>

<td>saturated</td><td>from NH4C1 and</td><td>I know</td><td>extracted 0</td><td>with</td><td>EtOAc. The</td><td>layers</td>

<td>organic</td><td>they dried up .</td><td colspan="2">about Na2SO</td><td>and</td><td>they concentrated</td><td>ba j 0</td>

<td>Pressure</td><td>reduced.</td><td colspan="3">The residue</td><td>was purified</td><td>by</td>

<td colspan="3">instant chromatography</td><td>on gel</td><td>of</td><td>silica (eluent</td><td>: 0 to</td>

20% MTBE in hexanes.) To give the title compound as a mixture of diastereomers.

Stage F.

2 - ((5R, 6S) -1 - (((IS, 3S) -3- (tertButyldimethylsilyloxy) cyclopentyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3 -yl) acetic or 2 ((5R, 6S) -l - ((lS, 3R) -3 - ((tertButyldimethylsilyl) oxy) cyclopentyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- methylpiperidin-3-yl) acetic

* unknown stereochemistry

The title compound was prepared from (5R, 6S) 492

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

3-Alil-l - ((1S, 3S) -3 - ((tert-

butyldimethylsilyl) oxy) cyclopentyl) -5- (3-chlorbtenyl) -6- (4-: chlorophenyl) -3-methylpiperidin-2-one or (2S, 3R) -5-Allyl-l ((1S, 3R) -3 - ((tert-butyldimethylsilyl) oxy) cyclopentyl) -3- (3 chlorophenyl) -2 - (4-chlorophenyl) -5-methylpiperidine of the above (Example 106, Step E) as described in Example 95,

Stage D.

Stage G. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((1S, 3S) -3-hydroxycyclopentyl) -3-methyl-2oxopiperidin-3 -yl) acetic or 2 - ((3R, 5R, 6S) -5- (3Clorophenyl) -6- (4-chlorophenyl) -1 - ((1S, 3R) -3-hydroxycyclopentyl) -3-methyl-2-oxopiperidin -3-yl) acetic

To a solution of 2- ((5R, 6S.) - 1- ((1S, 3S) -3- (tertButildimethylsilyloxy) cyclopentyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl- 2-oxopiperidin-3-yl) acetic or 2 ((5R, 6S) -1 - ((1S, 3R) -3 - ((tertButildimethylsilyl) oxy) cyclopentyl) -5- (3-chlorophenyl) -6- ( 4-chlorophenyl) -3-methylpiperidin-3-yl) acetic from the above

<td colspan="2">(Example 106, Stage F)</td><td> (31</td><td colspan="2">mg, 0.052</td><td>mmol)</td><td>in</td><td>THF</td><td>(1.0 mL)</td>

<td>added</td><td>TBAF 1.0M</td><td>in</td><td>THF</td><td> (2 62</td><td>pL,</td><td> 0.</td><td> 262</td><td>mmol) a</td>

<td>temperature</td><td>environment.</td><td>The</td><td colspan="2">mix of</td><td colspan="3">reaction is</td><td>waved to</td>

<td>temperature</td><td>environment</td><td colspan="2">during 19</td><td colspan="2">h before</td><td>of</td><td colspan="2">To concentrate</td>

under reduced pressure. The residue was purified by HPLC

493

IMPI

MEXICAN INSTITUTE

OF THE FROPÍcDAD. INDUSTRIAL

reverse phase preparative (eluent: 45 to 75% MeCN + 0.1% TFA in water + 0.1% TFA) to give the title compound.

<td></td><td>XH NMR (400 MHz,</td><td>CHLOROFORM-d ')</td><td>δ</td><td>ppm 1.31 (3H,</td><td>s</td><td> ),</td>

7.00 (2 H, m), 7.0 9 (1 'H, t, J = 1.9 Hz), 7.15-7.26 (2 H,

m), 7.30 (2 H, d, J = 8.6 Hz). Mass Spectrum (ESI) m / z =

476 [M + H]+.

EXAMPLE 107

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-l - ((S) -tetrahydro-2H-pyran-3- yl) piperidin-3 yl) acetic or 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl.) - 6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((R) -tetrahydro-2H-pyran-3-

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-

methyl-2-oxo-l - ((S) -tetrahydro-2H-piran-3-yl) piperiSTfr- ^ T494 yl) acetic acid or 2 - ((3R, 5R, 6S) -5- (3

chlorophenyl) -3-methyl-2-oxo-l - ((R) -tetrahydro-2H-pyran-3yl) piperidin-3-yl) acetic

* unassigned stereochemistry

Stage A.

2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6oxopiperidin-l-yl) pentanodia1

To a solution of. 454 mg (1,175 mmol) of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (cyclopent-2-enyl) piperidin2-one (Example 104, Step A) in THF (6 mL) water was added dropwise (3.5 mL) and tBuOH (0.2 mL). 4-Methylmorpholine 4-oxide (207 mg, 1,763 mmol) was added followed by

<td colspan="2">osmium oxide</td><td>(VIII) at</td><td> 4%</td><td colspan="3">aqueous (37.3 pL, 5.88 pinol).</td>

<td>Mix</td><td>of</td><td>reaction</td><td>I know</td><td>waved</td><td>at temperature</td><td>environment</td>

<td>for 18</td><td>h.</td><td>Periodate</td><td>of</td><td>sodium</td><td>(704 mg, 3.29</td><td>mmol)</td>

IMPI

495 added and the reaction mixture at room temperature for 90 min.

cloudy stirred to

Water (4 mL) was added and the mixture was filtered and washed with EtOAc.

The filter product was diluted with EtOAc and the layers were separated. The combined organic layers were washed with Na2S2Saturated O3, saturated aqueous NaCl solution, dried over Na2SO4 and concentrated in vacuo to provide the title compound.

Stage B. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1,5dihydroxipentan-2-yl) piperidin-2-one

To a solution of

2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4 chlorophenyl) -6-oxopiperidin-l-yl) pentanedial (Example 107, Step A) (492 mg, 1,176 mmol) in MeOH ( 11 mL) sodium borohydride (89 mg, 2,352 mmol) was added at room temperature. The evolution of the gas was observed. The reaction mixture was stirred at room temperature for 15 min and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes and then

496

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

10% MeOH in DCM) to give the title compound.

Stage C. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (tetrahydro-2H-piran-3-yl) piperidin-2-one

To a solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1,5-dihydroxipentan-2-yl) piperidin-2-one (Example 107, Step B) ( 192 mg, 0.455 mmol) in THF (5 mL) at room temperature, triphenylphosphine (119 mg, 0.455 mmol) was added followed by dropwise addition of diisopropyl azodicarboxylate (89 pL, 0.455 mmol). The reaction mixture turned light yellow during the addition and then became colorless within 5 min. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaCl solution. The organic layer was dried over Na2SW4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 0 to 100% EtOAc in hexanes) to give the title compound as a mixture of diastereomers.

497

Stage D.

(5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1- (tetrahydro-2H-piran-3-yl) piperidin-2-one

The title compound was prepared from (5R, 6S) 5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (tetrahydro-2H-pyran-3yl) piperidin-2-one (Example 107, Step C) as described in Example 71, Step B.

Step E. (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1- (tetrahydro-2H-pyran-3-yl) piperidin-2-one

The title compound was prepared as a mixture of stereoisomers from (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (tetrahydro-2H-pyran-3-yl ) piperidin-2one (Example 107, Step D) as described in Example 71

Stage C.

498

Stage

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -tetrahydro-2H-piran-32H-piran -3-yl) piperidin-3-yl) acetic

The title compound was prepared from (5R, 6S) -

3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (tetrahydro-2H-pyran-3-yl) piperidin-2-one (Example 107, Step

E) as previously described in Example 42, Step

The residue was purified by preparative reverse phase HPLC (eluent: 0 to 100% MeCN + 0.1% TFA in water +

TFA at

0.1%) to give the title compound as a simple, but not assigned, stereoisomer.

XH

1.49 ppm 1.40

NMR (400 MHz, CHLOROFORM-d) δ

(4 H, m).

[Μ + H] 1.

EXAMPLE 108

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-1- (pyrazin-2-yl) piperidin-3-yl) acetic acid

IMPI

MEXi'-ANO INSTITUTE

499

from LA FKurítu'pY INDUSTRIAL

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (pyrazin-2-yl) piperidin-2-one

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2-one (Example 71, Step D) (100mg, 0.27mmol), 2- Iodopyrazine (170 pL, 0.80 mmol) and cesium carbonate (220 mg, 0.67 mmol) were dissolved in 2.7 mL of 1,4-dioxane. The reaction vessel was flushed with argon, copper (I) iodide (5.1 mg, 27 pmolj and TMEDA (11 pL, 80 pmol) were added, and the reaction mixture was allowed to stir at 110 ° C for 15 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted (2 x 'EtOAc). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. . Purification of the residue by flash chromatography on silica gel (0 to 50% de / Vi

500

ΙΜΡΙΓ

MEXICAN INSTITUTE>

FROM property V

INDUSTRIAL '««

EtOAc / hexanes) provided the title compound as a colorless solid.

Step B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) 3-methyl-2-oxo-l- (pyrazin-2-yl) piperidin-3 acid -il) acetic.

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1- (pyrazin-2-yl) piperidin- 2-one (Example 108, Step A) as described in Example 42 Step C to provide a white solid.

XH NMR (400 MHz, MeOD) δ ppm 1.42 (s, 3 H), 2.30 - 2.39

EXAMPLE 109

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1- (l-methyl-lH-pyrazol-4-yl) -2-oxopiperidin- 3il) acetic.

V

IMPI

501

MEXICAN INSTITUTE OF INDUSTÍUAL

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l- (l-methyl-lH-pyrazol-4-yl) piperidin-2-one.

(3S, 5R, 6S) -3-allyl-5-, (3-chlorophenyl) -6- (4-chlorophenyl) -3 methylpiperidin-2-one (Example 71, Step D) (90 mg, 0.24 mmol), l-methyl-4- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2yl) -lH-pyrazole (125 mg, 0.60 mmol), diacetoxicobre (44 mg, 0.24 mmol) and N, N-dimethylpyridin-4-amine (88 mg, 0.72 mmol) was dissolved in 1.2 mL of toluene. Sodium bis (trimethylsilyl) amide (4 80 pL, 0.48 mmol) was added and the reaction apparatus was coupled with a reflux condenser and allowed to stir at 115 ° C for 13 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and the filter product was concentrated under

502

Flash chromatography (0 to 60% EtOAc / hexanes) provided the title compound as a colorless solid.

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (l-methyl-lH-pyrazol-4-yl) -2oxopiperidin acid -3-yl) acetic.

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl (Example 108,

Step A) as described in Example

42, Step C to provide a white solid.

XH NMR (400 MHz, MeOD)

H), 2.25 - 2.33 (m, 1H), 2.31 -2.44 (m, 1H), 2.60 (d, J = 12.91 Hz, 1H),

3.01 (d, J = 13.30 Hz, 1 H), 3.47 - 3.59 (m, 1 H), 3.68 (s, 3

Η), 5.06 (d, J = 10.37 Hz, 1 H), 6.95 - 7.05 (m, 3 H), 7.09 (d, J = 8.41 Hz, 2 H), 7.12 - 7.20 (m, 3 H), 7.24 (s, 1H),

7.49 (s, 1H). MS (ESI) 472.2 [M + H]+.

EXAMPLE 110

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pyrimidin-4-yl) piperidin-3-yl) acetic acid .

503

Step A, 1- (Pyrimidin-4-yloxy) -ΙΗ-benzo [d] [1,2,3] triazole

To a solution of pyrimidin-4-ol (350 mg, 3.6 mmol) and hexafluorophosphate (V) 'of (ΙΗ-benzo [d] [1,2,3] triazol-1-yloxy) tris (dimethylamino) phosphonium (1.9 g, 4.4 mmol) in 24 mL of acetonitrile, 2,3,4,6,7,8,9,10-octahydropyrimido [1,2ajazepine (820 pL, 5.5 mmol) was added dropwise at room temperature. After the reaction mixture was stirred for 1 hour, the reaction solvent was removed under reduced pressure. Purification of the residue by flash chromatography (0 to 70% EtOAc / hexanes) provided the title compound as a light yellow solid.

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (pyrimidin-4-yl) piperidin-2-one

504

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methylpiperidin-2-one (Example 71., Step D) (100 mg, 0.27 mmol) in 1.3 mL DMSO sodium hydride (60% suspension in mineral oil, 13 mg, 0.32 mmol) was added at room temperature. . The reaction mixture was stirred for 5 minutes, and was treated with 1- (pyrimidin-4-yloxy) -1Hbenzo [d] [1,2,3] triazol '(Example 110, Step A) (170 mg, 0.80 mmol ). The reaction mixture was stirred at 110 ° C for 13 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl solution, dried over NaSOO, filtered, and the filtration product was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 45% EtOAc / hexanes) provided the title compound as a colorless solid.

Stage C. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- (pyrimidin-4-yl) piperidin-3-yl ) acetaldehyde

IMPI

MEXICAN INSTITUTE OF THE INDUS * KIAL PROtlíDAD

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l- (pyrimidin-4-yl) piperidin-2-one ( Example 110, Step B) (60 mg, 0.13 mmol) in a mixture of tetrahydrofuran (2.7 mL) and water (880 pL), osmium tetroxide (1.7 mg, 6.6 pmol) was added. After 5 minutes, sodium periodate (89 mg, 0.46 mmol) was added and the reaction mixture was stirred for 14 hours. The reaction mixture was filtered through Celite® (JT, Baker, Phillipsberg, NJ, diatomaceous earth) and washed with EtOAc and water. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and the filter product was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 75% EtOAc / hexanes, gradient elution) provided the title compound as a colorless solid.

Stage D. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-2-oxo-l- (pyrimidin-4-yl) piperidin-3-yl) acetic.

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- (pyrimidin-4-yl) piperidine-3-

506

IMPI

MEXICAN INSTITUTE AND PROPERTY

INDUSTÍU-Av il) acetaldehyde (Example 110, Stage C) (25 mg, 55 pmol) in a mixture of 2-methylpropan-2-ol (1.0 mL) and 2-methyl-2-butene (55 pL, 2.0 M solution in THF, 0.11 mmol) was added a solution of sodium chlorite (37 mg, 0.55 mmol) and sodium acid phosphate (4.8 mg, 50 pmol) in 550 pL of water at room temperature. The reaction mixture was stirred for 1 hour before it was quenched with water and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by silica gel prep plate (10% MeOH / DCM) provided the title compound as a colorless solid.

EXAMPLE lll

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (2-chloropyrimidin-4-yl) -3-methyl-2-oxopiperidin-3-yl )acetic.

'507

INSTITUTO MEXICANO DS LA FROÍIEDAD INDUSTRIAL

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2-chloropyrimidin-4-yl) -3-methylpiperidin-2-one.

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methylpiperidin-2-one (Example 71, Step D) (100 mg, 0.27 mmol) in 1.1 mL of DMSO sodium hydride (60% suspension in mineral oil, 32 mg, 0.80 mmol) was added at room temperature. The reaction mixture was stirred for 15 minutes, and was treated with 2,4-dichloropyrimidine (200 mg, 1.3 mmol). The reaction mixture was stirred at 60 ° C for 5 hours. The reaction mixture was cooled to room temperature and quenched with water and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCI solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. The purification of the

508

Residue per silica gel prep plate (50% EtOAc / hexanes) provided the title compound as a colorless solid.

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (2-chloropyrimidin-4-yl) -3-methyl-2-oxopiperidin-3yl ) acetaldehyde

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2-chloropyrimidin-4-yl) -3-methylpiperidin -2-one (Example 111, Step A) as described in Example 110, Step C to provide a white solid.

Stage C. Acid · 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2-chloropyrimidin-4-yl) -3-methyl-2-oxopiperidin-

3-yl) acetic.

The title compound was prepared from 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (2-chloropyrimidin-4-yl) -3-methyl-2 -oxopiperidin-3-yl) acetaldehyde (Example 111, Step B) as described in Example 110

509

IMPI

Mexican Institute of Industrial Property

Stage D to provide a white foam. -_

H), 8.39 (d, J = 5.7 Hz, 1 H). MS (ESI) 504.0 [M + H]+.

EXAMPLE 112

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-2-oxo-l- (pyrimidin-2-yl) piperidin-3-yl acid )acetic.

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2-one (Example 71, Step D) and 2-chloropyrimidine as described in Example lll, followed by conversion to the acid as described in Example 71, Step F.

XH NMR (500 MHz, CDC13) δ ppm 1.49 (s, 3 Η), 2.34 - 2.40 (m, 2H), 2.94 (d, J = 14.18 Hz, 1 Η), 3.10 (d, J = 13.45 Hz, 1 H), 3.50 (td, J = 10.88 and 3.91 Hz, 1 Η), 5.46 (d, J = 10.27

Hz, 1 Η), 6.89 (d, J = 7.34 Hz, 1 H), 6.93 - 7.01 (m, 5 H),

7.11 (t, J = 8.19 Hz, 1 H), 7.14 - 7.18 (m, 2 H), 8.56 (d, J = 4.9 Hz, 2 H). MS (ESI) 470.2 [M + H].

EXAMPLE 113

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1- (3-methylpyridin-2-yl) -2-oxopiperidin-3-yl) acid acetic.

510

CI

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l- (3-methyl-5-nitropyridin-2-yl) piperidin-2-one

CI

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2-one (Example 71, Step D) and 2-chloro-3-methyl5-nitropyridine as described in Example 111, Step A to provide a light yellow solid.

511

MEXICAN INSTITUTE

INDUSTRIAL

Stage B. (3S, 5R, 6S) -3-allyl-l- (5-amino-3-methylpyridin ^ 2 ^ yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin -2-one

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1- (3-methyl-5-nitropyridin-2-yl) piperidin-2-one (Example 113, Step A) (120 mg, 0.23 mmol) and tin (II) chloride dihydrate (260 mg, 1.1 mmol) were dissolved in 2.3 mL of ethyl acetate. The reaction apparatus was coupled with a reflux condenser and stirred at 90 ° C for 4 hours. The reaction mixture was cooled to room temperature, quenched with 1M NaOH and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCI solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 90% EtOAc / Hex, gradient elution) provided the title compound as a colorless solid.

Step C. (3S, .5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (3-methylpyridine-2-yl) piperidin-2-one

512

To a solution of (3S, 5R, 6S) -3-allyl-l- (5-amino-3methylpyridin-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2- Ona (Example 113, Step B) (89 mg, 0.185 mmol) in 1,4-dioxane (4.0 mL) and acetic acid (0.50 mL) 3.0M HC1 (730 pL, 2.2 mmol) was added at 0 ° C. After the reaction was stirred for 5 minutes, hydrogen peroxide (6% aqueous weight, 95 pL, 0.185 mmol) was added dropwise, followed by sodium nitrite (46 mg, 0.74 mmol). The reaction mixture was stirred for 2 hours at 0 ° C. The reaction mixture was warmed to room temperature, quenched with 1M NaOH and extracted (2 x EtOAc). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 55% EtOAc / Hex, gradient elution) provided the title compound as a colorless solid.

Stage D. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1- (3-methylpyridin-2-yl) -2-oxopiperidin-3- il) acetaldehyde

513

INSTITUTE Mt)

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1- (3-methylpyridin-2-yl) piperidin-2-one (Example 113, Step C) as described in Example 110, Step C to provide a white solid.

Stage E. 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (3-methylpyridin-2-yl) -2-oxopiperidin-3yl acid )acetic

The title compound was prepared from 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (3methylpyridin-2-yl) -2 -oxopiperidin-3-yl) acetaldehyde (Example 113, Step D) as described in Example 110 Step D to provide a white foam.

XH NMR (500 MHz, CDC13) δ ppm 1.54 (s, 3H), 2.12 (s, 3

H), 2.29 (dd, J = 14.31 and 3.06 Hz, 1 H), 2.50 (t, J = 13.82

Hz, 1 H), 2.92 - 3.01 (m, 1 H), 3.07 - 3.17 (m, 1 H), 3.56 3.67 (m, 1 H), 5.51 (d, J = 11.00 Hz, 1 H), 6.90 - 7.02 (m, 5H), 7.05 - 7.15 (m, 4H), 7.45 (d, J = 7.09Hz, 1H), 8.30 (d, J = 3.67Hz, 1H). MS (ESI) 483.2 [Μ + H]1.

EXAMPLE 114

514

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1- (4-methylpyridin-2-yl) -2-o'xopiperidin-3- acid il) acetic.

Step A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (410 chlorophenyl) -3-methyl-l- (4-methylpyridin-2-yl) piperidin-2-one

15

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2-one (Example 71, Step D) and 2-chloro-4-methyl-

5-nitropyridine as described in Example 113 Steps AC to provide a white solid.

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (4-methylpyridin-2-yl) -2-oxopiperidin-3yl acid )acetic.

515

IMPI

Mexican Institute of Industrial Property

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-l- (4-methylpyridin-2-yl) piperidin2-one ( Example 114, Step A) (73 mg, 0.16 mmol) in 780 pL tetrahydrofuran, water (1.0 mL) was added, followed by 2-methylpropan-2-ol (100 pL) at room temperature. The reaction mixture was treated with 4-methylmorpholine 4-oxide (28mg, 0.24mmol), followed by osmium tetroxide (2.0mg,

7.8 pmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with a solution

1.25 M Jones reagent (190 pL, 0.24 mmol) at room temperature and stirred at room temperature for 1 hour.

The reaction was quenched with water and extracted (3 x EtOAc).

The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by HPLC on an Eclipse column (Agilent Technologies, Santa, Clara, CA) (20 to 80% acetonitrile / water, gradient elution) provided the title compound as a colorless solid.

XH NMR (500 MHz, CDC13) δ ppm 1.49 (s, 3 Η), 2.23 (s, 3 Η), 2.28 (dd, J = 14.2 and 3.2 Hz, 1 Η), 2.42 (t, J = 13.45 Hz, 1 H), 2.96 (m , 1 Η), 3.04 (m „1 Η), 3.39 (ddd, J = 12.9, 10.2 and 3.1 Hz, 1 H), 5.57 (d, J = 10.3 Hz, 1 Η), 6.81 (d, J = 5.1

516

Hz, 1 Η), 6.86 - 6.92 (m, 3 Η), 6.99

7.08 - 7.13 (m, 2 Η), 7.13 - 7.18 (m,

I

INSTITUTE

OF THE TNDUSlRIAL FLOUnLpO

Η), 8.13 (d, (d, J = 8.1 Hz

EXAMPLE 115

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (dicyclopropylmethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid

Step A. (Z) -2 - ((4-chlorobenzylideneamino) methyl) phenol

CI

To a stirred suspension of 2- (aminomethyl) phenol, (4.0 g, 32.5 mmol) in ethanol (65 mL), 4-chlorobenzaldehyde (3.86 mL, 32.8 mmol) was added. The resulting reaction mixture was stirred at rt for 3h. The solvent was removed and 100 ml of toluene were added and concentrated in vacuo twice. The resulting imine was dried under vacuum overnight and was used in the next step without further purification.

XH NMR (500 MHz, DMSO-de) δ ppm 9.47 (1 H, br. S.), 8.44

517 : χ:

Stage Β.

2 - (((IS, 2R) -2- (3-chlorophenyl) -1- (4chlorophenyl) but-3-enylamino) methyl) phenol

To a solution of 1.42 g (5.3 mmol) (4S, 5S) -2-allyl-2-chloro-3,4-dimethyl-5-phenyl- [1,3,2] -oxazasilolidine (prepared according to J.Am. Chem.Soc. 124, 7920, 2002) and l-chloro-3vinylbenzene (1.69 g, 12.21 mmol) in DCM (12 mL) and DCE (12 mL) 0.173 g (0.2 mmol) of 1,3-bis- was added (2,4,6trimethylphenyl) -2- (imidazolidinylidene) (dichlorophenylmethylene) (tricyclohexylphosphine) ruthenium (Grubb Catalyst 2to.

generation). The resulting mixture was degassed twice and then heated to reflux for 8h. The reaction mixture was cooled to room temperature. The imine, from the above (Step A) (1.0 g, 4.07 mmol) was added. The reaction mixture was heated to reflux for 14h, then cooled to rt and quenched by adding 8 ml of ethanol. The

518

IMPI

INSTITUTO MJXte.'c \, __ F. Dayk Reaction mixture was diluted with ethyl acetate (120 ml) and washed with water (30 ml) and saturated NaCl solution (30 ml). The combined organic layers were dried over MgSO4, filtered and the filter product concentrated. The residue was purified by chromatography on silica gel, (eluent: hexane / ethyl acetate 90 / 10-65 / 35) to give the title compound.

XH NMR (500 MHz, ACETONITRILE-d3) δ ppm 7.52 (2 H, d,

Step C. 2 - ((N - ((IS, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-3-enyl) acetamido) methyl) phenyl acetate

To a solution of l.lg (2.76 mmol) of 2 - (((IS, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-3-enylamino) methyl) phenol (Example 115, Step B ). and triethylamine (0.85 mL, 6.08 mmol) in

519 A mixture of THF (5.0 mL) and DCM (5.0 mL) acetic anhydride (0.55 mL, 5.80 mmol) was added at 0 ° C. The reaction temperature was slowly allowed to rise to room temperature and the mixture was stirred at room temperature overnight. When the CLEM indicated completion of the reaction, 100 ml of ethyl acetate was added and the combined organic products were washed consecutively with water (30 ml), citric acid (30 ml, 1M), NaHCO solution3 (30 ml) and saturated NaCl solution (30 ml), dried over MgSO4, filtered and the filter product concentrated to give the title compound. The crude product was used without further purification.

<td></td><td>XH NMR</td><td> (400</td><td>MHz,</td><td>CL</td><td colspan="2">OROFORM-d)</td><td>δ</td><td>ppm 7.05 - 7.14 (4H,</td>

482.0.

Step D. N - ((1S, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-3-enyl) acetamide

520

A solution of 1.05g (2.18mmol) of 2 - ((Νί (IS, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-3enyl) acetamido) methyl) phenyl acetate (Example 115 , Step C) and toluenesulfonic acid monohydrate (1.66 g, 8.71 mmol) in toluene (15.0 mL) was heated to reflux for about 2 h. 120 ml of ethyl acetate were added, and the combined organic products were washed consecutively with NaHCO solution3 and saturated NaCl solution, dried over MgSO4, filtered and the filtration product was concentrated. The crude mixture was purified by preparative HPLC to give the title compound.

TH NMR (500 MHz, CHLORINE FORM-d) δ ppm 7 | .O8 - 7.15 (2 H, m), 7.02 - 7.08 (2 H, m), 6.92 (3 H, t, J = 8.6, Hz), 6.81 (1 H, dd, J = 3.5, 2.1 Hz), '5.83 - 6.07 (2 H, m), 5.04 - 5.21 (3 H, m), 3.48 (1 H, t, J = 9.3 Hz), 1.97 (3 H, s). MS (ESI) [M + H]+, 334.0.

Stage E. (IS, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-

3-en-l-amine

IMPI • MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

To a mixture of 4.1g (12.2-7 mmol) of N - ((1S, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl.l) but-3-enyl) acetamide (Example

115, Step D) and pyridine (1.20 mL, 14.72 mmol) in THF (35.0 mL) 1.2 mL (13.5mmol) of oxalyl chloride was added at 0 ° C. The resulting light yellow suspension was stirred at 0 ° C for 1.5 h. 1,2-dihydroxypropane (1.80 mL, 24.53 mmol) was added in one portion and the reaction warmed to rt. The mixture was treated with ethanol (16.0 mL) followed by 6N HC1 (16.0 mL). The reaction mixture was heated at 55 ° C for 10 min and then cooled back to rt When the CLEM indicated that most of the SM was consumed, 200 ml of ethyl acetate were added, and the organic layer was washed consecutively with NaHCO solution3 and saturated NaCl solution, dried over MgSO4, filtered and the filter product concentrated. The crude mixture was purified by flash chromatography on silica gel to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 (3 H, d, J = 8.4 Hz), 7.03 - 7.17 (3 H, m), 6.96 (1 H, s), 6.79 (1 H, ddd, J = 6.2, 2.2, 2.0 Hz), 5.98 (1 H, dt, J = 16.8, 9.8 Hz), 5.39 (1 H, d, J = 16.8 Hz), 5.24 (1 H, d, J = 10.2 Hz) , 4.14 (1 H, d,

522

3 = 11.2 Hz)

292.1.

3.76 (1 H, t,

J = 10.2 Hz).

MS (ESI) [M + H] “,

Step F. (IS, 2.R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) -N (dicyclopropylmethyl) but-3-en-l-amino

To a solution of 2.0g (6.84 mmol) of (lS, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-3-en-l-amine (Example 115, Step E), dicyclopropyl ketone ( 7.54 mL, 68.4 mmol), and acetic acid (1.96 mL, 34.2 mmol) in methanol (25.0 mL) Sodium cyanoborohydride (1.44 mL, 27.4 mmol) was added at rt. The resulting mixture was stirred at 50 ° C for 2 days. Acetic acid (1.5 ml) and sodium cyanoborohydride (0.6 g) were added again, and heating continued overnight. 200 ml of ethyl acetate were added, and the organic layer was washed consecutively with K2CO3 solution and saturated NaCI solution, dried over K2CO3, filtered and the filtration product concentrated under reduced pressure at 60 ° C. The mixture was purified by flash chromatography on silica gel (eluent: DCM / MeOH, 95/5) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.

523

H, d, <7 = 10.8 Hz), 4.06 (1 H, t, J = 10.0 Hz), 1.79 (1 H, t,

[M + H]1, 386.0.

Step G. N - ((1S, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-3enyl) -N- (dicyclopropylmethyl) acrylamide

To a solution of 2. Ig (5.44 mmol) of (1S, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) -N- (dicyclopropylmethyl) but-3-en1-amine (Example 115, Step F ) and triethylamine (1.89 mL, 13.59 mmol) in THF (30.0 mL), acryloyl chloride (0.66 mL, 8.15 mmol) was added at 0 ° C. The resulting reaction mixture was stirred at rt for 2h. When CLEM indicated completion of the reaction, 100 ml of ethyl acetate was added and the combined organic products were washed consecutively

τ'.τύτο Mexican

OF THE VROPIEDAP INDU-í KiA-

524

NaHC03 (10 ml) and saturated NaCl solution (30 ml), dried over MgSO4, filtered and the filter product concentrated. The crude product was purified by flash chromatography on silica gel (eluent: hexane / ethyl acetate, 90/10 to 20/80) to give the title compound.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.28 (3 H, br. S.),

6.94 - 7.17 (5 H, m), 6.87 (1 H, br. S.), 6.42 (1 H, m.),

6.20 (2 H, ddd, J = 16.9, 9.8, 9.5 Hz), 5.58 (1 H, d, J = 10.3

Hz), 5.18 (1 H, d, J = 16.9 Hz), 5.06 (2 H, dd, J = 10.3, 1.3

Hz), 2.72 (1 H, br. S.), 1.19 - 1.41 (1 H, m), 0.77-1.00 (2

H, m), 0.63 (3 H, d, J = 5.6 Hz), 0.50 (1 H, br. S.), 0.43 (1

H, d, <7 = 4.6 Hz), 0.20 (1 H, br. S.), -0.28 (1 H, br. S.). MS (ESI) [M + H] ·, 440.0.

Stage H. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (dicyclopropylmethyl) -5,6-dihydropyridin-2 (IH) -one

To a solution of 2 .lg (4.77 mmol) of N - ((lS, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-3-enyl) -N525

MSIÍICA INSTITUTE

OF THE PROP1ED INDUSTiL

(dicyclopropylmethyl) acrylamide (Example 115, Step G) in 50 mL of DCE 160 mg of 1,3-bis- (2,4,6-trimethylphenyl) was added -

2- (imidazolidinylidene) (dichlorophenylmethylene) (tricyclohexylphosphine) ruthenium (2nd generation Grubb catalyst). The resulting mixture was degassed twice and then heated to 70 ° C for 18h. Another 160 mg of Grubb's Catalyst, 2nd. generation were added at that time and heating continued for another 18h. The reaction mixture was cooled to room temperature. The solvent was removed and the residue was purified by chromatography on silica gel (eluent: hexane / ethyl acetate, 90/10 to 20/80) to give the title compound.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.13 - 7.36 (8 H, m),

6.42 (1 H, d, J = 9.8 Hz), 6.27 (1 H, ddd, l> 9.8, 6.1, 1.3 Hz),

4.91 (1 H, s), 3.67 (1 H, d, J = 6.1 Hz), 3.28 - 3.44 (1 H, m), 0.42 (1 H, ddd, J = 8.9, 4.6, 4.5 Hz), 0.26 - 0.37 (3 H, m), 0.12 - 0.26 (3 H, m), -0.07 - 0.02 (1 H, m), -0.24--0.12 (1 H, m), -0.34 - -0.24 (1 H, m). MS (ESI) [M + H]+, 412.1.

Stage I. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (dicyclopropylmethyl) piperidin-2-one

526

A solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (dicyclopropylmethyl) -5,6-dihydropyridin-2 (IH) one (Example 115, Step H; 0.826g, 2,003 mmol) and (1,5-cyclooctadiene) (pyridine) (tricyclohexylphosphine) iridium (i) (0.129 g, 0.160 mmol) hexafluorophosphate in DCM (60.0 ml) was saturated with hydrogen cpn. The resulting mixture was stirred at rt under a hydrogen atmosphere for 2 h, then another 66.0 mg of hexafluorophosphate (1,5cyclooctadiene) (pyridine) (tricyclohexylphosphine) iridium (i) was added. Stirring under hydrogen atmosphere was continued until CLEM indicated complete saturation of the double bond. The solvent was removed and the crude mixture was purified by chromatography on silica gel (eluting with ethyl acetate: hexane, 10:90) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.11 - 7.32 (7 H, m), 6.98 - 7.11 (1 H, m), 4.96 (1 H, d, J = 4.7 Hz), 3.26 (1 H,

INSTITUTE

OF THE INDUSTRIAL PROPERTY

-0.04 (1

527

m), 0.05 (1 H, dt, J = 9.7, 4.8, Hz), -0.19

MS (ESI) [M + H]+, 414.0..

Step J. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (dicyclopropylmethyl) -3 (R, S) -methylpiperidin-2-one

The title compound was prepared from (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (dicyclopropylmethyl) piperidin-2-one (Example 115, Step I) as described in Example 68, Step C. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate: hexane, 10:90) to give the title compound as a colorless oil.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.16 (2 H, d, <J = 8.6 Hz), 7.00 - 7.14 (6 H, m), 4.95 (1 H, d, J = 2.2 Hz), 3.21 (one

H, br. s.), 2.85 - 2.99 (1 H, m), 2.40 (1 H, dt, <7 = 10.3, 7.1 Hz), 1.68 - 1.87 (2 H, m), 1.21 (3 H, s), 1.04 - 1.17 (1H,

m), 0.86 (1 H, d, <7 = 4.2 Hz),. 0.35 - 0.51 (1 H, m), 0.12 0.28 (4 H, m), -0.04 - 0.12 (2 H, m), -0.34 - -0.15 (1 H, m).

Stage K.

528

MEXICAN INSTITUTE OF INDUSTRIAL FROHEDAD

(3S / 3R, 5R, 65) -3-allyl-5- (3-chlorophenyl) -6- (4chlorophenyl) -1- (dicyclopropylmethyl) -3-methylpiperidin-2-one

The title compound was obtained as a mixture of stereoisomers using a procedure similar to that described in Example 68, Step D ..

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.06 - 7.23 (4 H,

m), 6.91 - 7.06 (3 H, m), 6.69 - 6.86 (1 H, m), 5.79 - 5.98 (1 H, m), 5.03 - 5.26 (2 H, m), 4.81 (1 H, d, ^ 9.6 Hz), 3.03

- 3.22 (1 H, m), 2.49 - 2.18 (2 H, m), 1.88 - 2.01 (2 H, m),

Stage L.

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1- (dicyclopropylmethyl) -3-methyl-2-oxopiperidin-3 yl) acetic acid

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

A mixture of (3S / 3R, 5R, 6S) -3-allyl-5 (3-chlorophenyl) -6- (4-chlorophenyl) -1- (dicyclopropylmethyl) -3methylpiperidin-2-one diastereomers (Example 115 , Step K) was converted to a diastereomeric mixture of the acids by a similar procedure to that described in Example 71, Step F. The individual stereoisomers were separated by prep HPLC. phase reversed (Sunfire ™ Prep Cig OBD 10 pm column (Waters, Milford, MA), gradient elution from 40% MeCN in water to 80% MeCN in water, over a period of 30 min, where both solvents contained 0.1 % TFA) to give the title compound as the fastest eluting isomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.98 (1 H, dd, <J = 7.6, 6.5 Hz), 7.00 - 7.29 (7 H, m), 6.86 (1 H, d, J = 7.4

Hz), 4.93 (1 H, d, J = 8.2 Hz), 4.33 (1 H, d, J = 5.1 Hz), 3.09 -

3.15 (1 H, m), 3.03 (1 H, d, J = 15.1 Hz), 2.69 - 2.80 (1 H,

m), 2.08 - 2.17 (2 H, m), 1.35 (3 H, s), 1.14 - 1.21 (1 H,

m), 0.53 - 0.73 (2 H, m), 0.41 - 0.51 (2 H, m), 0.27 - 0.40 (2 H, m), 0.02 - 0.21 (3 H, m). MS (ESI) [M + H] ', 486.2.

Additional elution and concentration in vacuo provided Example 116.

IMPI

530

EXAMPLE 116

Acid 2 - ((3S,

5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (dicyclopropylmethyl) -3-methyl-2-oxopiperidin-3-yl) acetic

The title compound of process 115 was obtained as the slowest eluting isomer.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.10 - 7.33 (6 H,

m), 6.95 - 7.03 (2 H, m), 6.7 3 - .6.83 (1 H, m), 4.80 (1 H, d,

7 = 9.8 Hz), 3.18 - 3.23 (1 H, m), 2.84 (1 H, t, <7 = 13.4 Hz),

EXAMPLE 117

((3S, 4R, 6R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -1,1-dioxide-2- (2-propanil) -1,2-thiazine-6-yl) acetic acid

Stage

TO.

531

(E) -N - ((1S, 2R) -2- (3-chlorophenyl) -1- (4chlorophenyl) but-3-enyl) -2-phenylethenesulfonamide

To a solution of 5.33 g (18.24 mmol) of (1S, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-3-en-l-amine (Example 115, Step E) in DCM (45.0 mL) N, Ndiisopropylethylamine (4.8 mL, 27.5 mmol) was added, followed by trans-beta-styrenesulfonyl chloride (4.17 g, 20.58 mmol). The resulting solution was stirred at room temperature under an atmosphere of N2. After stirring for 3.25 hours, the reaction was diluted with water and extracted with DCM. The combined organic layers were washed with saturated aqueous NaCI solution, dried over Na2SW4, filtered and the filter product concentrated. Purification by flash chromatography on silica gel (0 to 40% EtOAc in gradient

hexanes) provided the compound of the

532

I! ' ('' '7 ^ i- \

MEXICAN INSTITUTE

OF PROPERTY V - -, /

INDUSTRIAL Li -.- title as a yellow solid.

<td></td><td>XH NMR</td><td> (500</td><td>MHz, chlorine:</td><td>FORM-d) δ</td><td> 7.30</td><td> - 7.41</td><td>(m,</td><td>3H),</td>

MS (ESI) 480.0 [M + Na] '.

Stage B. · (3S, 4R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -3,4dihydro-2H-l, 2-thiazine

CI

To a degassed solution of 7.29 g (15.90 mmol) of (E) -N - ((IS, 2R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) but-3-enyl) -

2-phenylethenesulfonamide (Example 117, Step A) in a 1: 1 mixture of DCM (350 mL) and DCE (350 mL) first generation Grubbs (1.20 g, 1,434 mmol) was added. The resulting solution was stirred at 70 ° C for 20 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. Purification by flash chromatography on silica gel (0 to 2% of

533

JL

INSTITUTO MF.X DELATO?

INDUSTRIAL

Gradient MeOH from DCM) provided the title compound.

<td></td><td>XH</td><td>NMR (500 MHz, CLC</td><td>• ROFORM-d)</td><td>δ 7.20 -</td><td> 7.29</td><td>(m,</td><td>J =</td>

Stage

(3S, 4R) thiazinan

A solution of

yl) -3- (4-chlorophenyl) -1.2 (11.69 mmol) de (3S, 4R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -3, 4-dihydro-2H-l, 2 -thiazine (Example 117, Step B). in dichloromethane (63.0 mL) was purged with argon three times, and then catalyst was added

Crabtree (835.2 mg, 1,027 mmol) to the reaction mixture. The reaction was flushed again with argon, and then a hydrogen atmosphere was placed over the reaction.

The solution was stirred at room temperature for 15 hours, at which point the reaction was concentrated to an oil. Purification

534

by flash chromatography on silica gel ^ tF ^ aMia ··· ^ ·?

Gradient MeOH from DCM) provided the titer "SUU Util titer" as a tan solid.

XH NMR (500 MHz, CHLOROFORM-d) δ 7.16 - 7.22 (m, 2H),

7.08 - 7.14 (m, 2H), 6.99 - 7.07 (m, 3H), 6.82 - 6.88 (m,

1H), 4.67 (dd, J = 5.01, 10.88 Hz, 1H), 4.55 (d, J = 4.65 Hz,

1H), 3.25 - 3.39 (m, 2Hj, 2.89 - 3.04 (m, 1H), 2.67 (dddd, J = 6.60, 10.39, 12.50, 14.52 Hz, 1H), 2.39 (qd, J = 3.67,

14.43 Hz, 1H). MS (ESI) 378.0 [M + Na]+.

Stage D. (3S, 4R) -4 - (- 3-chlorophenyl) -3- (4-chlorophenyl) -2- (2propanil) -1,2-thiazinan

Cl ci

To a solution of 1.21 g (3.40 mmol) of (3S, 4R) -4- (3chlorophenyl) -3- (4-chlorophenyl) -1, 2-thiazinan (Example 117, Step C) in DMF (8.5 mL) Cesium carbonate (4.31 g, 13.23 mmol) was added, followed by 2-iodopropane (2.9 mL, 29.0 mmol). The resulting mixture was heated at 85 ° C for 23 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate./ The combined organic layers were washed

<td></td><td> 535</td><td>IMPIí MEXICAN INSTITUTE \ DI LA PSOF'ED * V INDUSTRIAL</td><td>* '· -'L--</td><td></td>

<td>with solution</td><td>saturated with NaCl, dried</td><td>about Na2SW4,</td><td>I know</td><td></td>

<td>filtered and</td><td>the filtration product is</td><td>concentrated.</td><td>The</td><td></td>

<td>purification</td><td>by instant chromatography</td><td>on gel</td><td>of</td><td></td>

<td>silica (0 to</td><td>2% MeOH in DCM gradient)</td><td>provided</td><td>the</td><td></td>

title compound as a white solid.

XH NMR (500 MHz, CHLOROFORM-d) δ 7.13 - 7.19 (m, 3H),

7.04 - 7.12 (m, 3H), 7.00 (t, J = 1.83 Hz, IH), 6.75 (d, J =

7.58 Hz, IH), 4.51 (d, J = 10.76 Hz, IH), 3.81 (td, J = 6.94,

13.75 Hz, IH), 3.40 - 3.49 (m, 1H), 3.25 - 3.39 (m, 2H), 2.53 (ddt, J = 6.85, 11.49, 13.45 Hz, IH), 2.23 (tdd, J = 2.96, 6.54, 13.94 Hz, IH), 1.36 (d, J = 6.85 Hz, 3H), 1.07 (d, J = 7.09 Hz, 3H). MS (ESI) 420.0 [M + Na]+.

Stage E. (3S, 4R / 6R / 6S) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -2 (2-propanil) -6- (2-propen-l-yl) -1, 2-thiazinan

To a degassed solution of 211.7 mg (0.531 mmol) of (3S, 4R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -2- (2-propanil) -1,2 thiazinan (Example 117, Step D) in THF (2.5 mL) allyl iodide (0.25 mL, 2.74 mmol) was added. The resulting solution was heated to 50 ° C. After 10 minutes, a solution 1

IMPI

Lithium bis (trimethylsilyl) -amide M in THF (0.86 mL, 0.860

536 mmol) was added dropwise, over one minute. After heating at 50 ° C for 20 hours, the reaction was cooled to room temperature, quenched with water (2 mL), and then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0 to 100% DCM in hexane gradient) provided the title compound as a white solid. TheXH NMR showed a 91: 9 mixture of allyl R / S epimers.

A degassed solution of 98.6 mg (0.225 mmol) of the epimeric mixture in THF (5 mL) was heated to 60 ° C. After 10 minutes, a 1M solution of lithium bis (trimethylsilyl) -amide in THF (1.0 mL, 1.00 mmol) was added. The resulting solution was then stirred at 60 ° C for 45 minutes, at which point methanol (275.0 pL, 6.80 mmol) was then added. The solution was heated for another 45 minutes at 60 ° C. With cooling to room temperature, the reaction was quenched with methanol (5 mL), then concentrated under reduced pressure. The material was purified by preparative reverse phase HPLC using an Agilent Eclipse Plus C18 column (Agílent Technologies, Santa, Clara, CA), 0.1% TFA in MeN / H2Or, 30% to 95% gradient over 25 minutes to provide the title compound as a white solid. TheXH NMR showed a ~ 2: 1 mixture of epimers.

The individual stereoisomers are

537 separated by SFC (Chiralcel® AD-H column (Diacel, Fort Lee NJ), 30 mm ID χ

250 mm, when using 12 g / min of a 20 mM NH solution3 in isopropyl alcohol and 68 g / min of CO2 as the eluent) to give (3S, 4R, 6S) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -2- (2propanil) -6- (2-propen-l-yl) -1, 2-thiazinan (tR = 1.62 min) as a white solid.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.16 - 7.21 (m, 1 H), 7.06 - 7.15 (m, 5 H), 7.00 (t, J = 1.59 Hz, 1 H), 6.72 (d, J = 7.58 Hz, 1H), 5.71 - 5.88 (m, 1H), 5.11 - 5.24 (m, 2H),

(3S, 4R, 6R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -2- (2-propanil) -6- (2-propen-l-yl) -1,2-thiazinan was also obtained (tR = 1.87 min) as a white solid.

XH NMR (500 MHz, 'CHLOROFORM-d) δ ppm 7.16 (d, J = 8.31

IMPI

538

3.26 (ddd, 7 = 12.65, 10.82, 3.42 Hz, 1 Ή),

2.84 - 2.98 (m, 1

2.19 (m, 1. H), 1.36 (d,

H), 2.21 - 2.33 (m, 2 H), 2.04

7 = 6.85 Hz, 3H), 1.13 (d, 7 = 6.85 Hz, 3H). MS (ESI) 460.0 [M + Na]1 .

Stage F.

((3S, 4R, 6R) -4- (3-chlorophenyl) -3- (4 chlorophenyl) -1, l-dioxide-2- (2-propanil) -1,2-thiazinano-6 yl) acetic acid

The title compound was obtained from (3S, 4R, 6S) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -2- (2-propanil) -

6- (2-propen-l-yl) -1,2-thiazinan · (Example 117, Step E) by a procedure similar to that described in Example 71, Step F. Purification by preparative reverse phase HPLC using a Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, CA), 0.1% TFA in MeCN / H2Or, gradient 30% to 95% over 25 minutes, provided the title compound as a white solid.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.12 - 7.19 (m, 3

H), 7.04 - 7.12 (m, 3H), 6.99 (br. S., 1H), 6.73 (d, 7 = 7.58 Hz, 1H), 4.38 (d, 7 = 11.00 Hz, 1H), 3.91 - 4.05 (m, 1H),

3.84 (br. S., 1 H), 3.39 - 3.49 (m, 1 H),

539

3.24 (d, <7 = 1.7.12

Hz, 1H), 2.88 (dd,> 17.12, 10.27 Hz, 1H), 2.66 - 2.79 (m,

H), 2.02 (d, <7 = 12.72 Hz, 1 Η), 1.32 - 1.40 (m, 3 Η), 1.03 (d, J = 6.85 Hz, 3 H). MS (ESI) 478.0 [M + Na]+.

EXAMPLE 118

((3S, 4R, 6Sj-4- (3-chlorophenyl) -3- (4-chlorophenyl) -1,1-dioxide-2- (2-propanil) -1,2-thiazinano-6-yl) acetic acid

The title compound was prepared from (3S, 4R, 6R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -2- (2-propanil) 6- (2-propen-l-yl ) -1,2-thiazinan (Example 117, Step E) as described in Example 117, Step F.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.07 (d, J = 6.85 Hz, 2 H), 6.94 - 7.05 (m, 4 H), 6.90 (br. S., 1 H), 6.65 (d, J = 7.34 Hz, 1H), 4.48 (d,> 11.00 Hz, 1H), 3.70 - 3.79 (m, 1H), 3.48 - 3.57 (m, 1H), 3.22 - 3.32 (m, 1H) , 3.10 (dd, ¿T = 17.12, 4.65

540

EXAMPLE 119

MEXICAN INSTITUTE D = INDUSTRIAL PROPERTY

Acid ((3S, 4R, 6R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6-methyl-

1, l-Dioxide-2- (2-Propanyl) -1,2-Thiazinan-6-yl) acetic

Step A. Synthesis of (3S, 4R / 6S) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6-methyl-2- (2-propanil) -6- (2-propen-l-yl) -1,2 thiazinan

To a degassed solution of diisopropylamine (300 pL, 2,123 mmol) in THF (1.0 ml) was added dropwise at -78 ° C n-butyllithium, 2.5 M in hexanes (800 pL, 2,000 mmol). After stirring the solution at -78 ° C for 10 min, the reaction was warmed to room temperature. In a separate flask, a degassed solution of 111.9 mg (0.255 mmol) of (3S, 4R, 6R) -4- (3 -chlorophenyl) -3- (4-chlorophenyl) -2- (2propanil) -6- (2-propen-l-yl) -1,2-thiazinan (Example 117, Step E) and methyl iodide (0.6 ml, 9.62 mmol) in THF (1.0 ml) was heated to 50 ° C. After

LDA was added drop by drop to the

another flask, and stirring continued for 14 hours at 50 ° C.

With cooling to room temperature, the reaction was quenched with water (3 mL), then concentrated under reduced pressure. Preparative reverse phase HPLC purification using an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, CA), 0.1% TFA in CH3CN / H2O, 60% to 80% gradient over 25 minutes provided the title compound like a white solid.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.18 (br. S., 2 Η),

7.03 - 7.14 (m, 4 Η), 6.96 (d, J = 1.71 Hz, 1 Η), 6.72 (d,

H), 1.34 (d, J = 6.85 Hz, 3 Η), 1.11 (d, J = 6.85 Hz, 3 H). MS (ESI) 474.1 [M + Na]+ .

Stage B. ((3S, 4R / 6R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6-methyl-l, l-di-oxide-2- (2-propanil) -1,2 acid -tiazinano6-yl) acetic • 542

OR

The title compound was prepared from (3S, 4R, 6S) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6-methyl-2- (2propanil) -6- (2-propen- l-yl) -1,2-thiazinan (Example 119, Stage

A) as described in Example 1, Step F.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.08 (d, J = 7.34 Hz, 2 H), 6.92 - 7.03 (m, 4 H), 6.87 (br, s., 1 H), 6.63 (d, J = 7.34 Hz, 1 H), 4.41 (d, J = 11.00 Hz, 1 H), 3.41 - 3.52 (m, 1

H), 3.29 - 3.36 (m, 1H), 3.25 (d, J = 14.92 Hz, 1H), 2.93 (d,

J = 15.16 Hz, 1 H), 2.21 -2.36 (m, 2 H), 1.51 (s, 3 H), 1.23 (d, J = 6.60 Hz, 3 H), 1.05- (d, J = 6.60 Hz, 3 H). MS (ESI) 492.1 [M + Na]+.

EXAMPLE 120

Acid ((3S, 4R, 6S) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6-methyl-

1, l-Dioxide-2- (2-Propanyl) -1,2-Thiazinan-6-yl) acetic

CI

Stage A.

(3S, 4R, 6R) -4- (3-chlorophenyl) -3- (4-chloroferp 1)

543

methyl-2- (2-propanyl) -1,2-thiazinan cy

To a degassed solution of 239.9 mg (0.602 mmol) of (3S, 4R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -2- (2-propanil) -1,2 thiazinan (Example 117, Step D) in THF (2.0 mL) iodomethane (60.0 µΐ, 0.960 mmol) was added, followed by dropwise addition of a 1M solution of lithium bis (trimethylsilyl) -amide in THF (640.0 µΐ, 0.640 mmol). After stirring at room temperature for 17 hours, the reaction was quenched with MeOH (3 mL), then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0 to 70% DCM in hexane gradient) provided the compound of the

<td>title like a solid</td><td>White. TheΧΗ</td><td>NMR</td><td>than</td><td>He showed</td><td>6% of</td>

<td>6S epimer was also</td><td>isolated.</td><td></td><td></td><td></td><td></td>

<td>XH NMR (500 MHz,</td><td>CHLOROFORM-d) δ</td><td>ppm</td><td> 7.14</td><td> - 7.18</td><td>(m, 2</td>

3.39 - 3.51 (m, 1 Η), 3.23 - 3.39 (m, 1 Η), 2.14 - 2.27 (m, 2

H), 1.42 (d, J = 6.85 Hz, 3 Η), 1.34 - 1.38 (m, 3 Η), 1.13 (d,

J = 6.85 Hz, 3H). MS (ESI) 434.0 [M + Na]1 .

Stage B.

IMPI

MEXICAN INSTITUTE 'OBLA TÑDUsmAL PROPERTY

544

methyl-2- (2-propanyl) -6- (2-propen-l-yl) -1,2-thiazinan

To a degassed solution of 174.7 mg (0.424 mmol) of (3S, 4R, 6R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6-methyl-2- (2propanil) -1,2- Thiazinan (Example 120, Step A) in THF (1.5 mL) allyl iodide (0.55 mL, 6.02 mmol) was added. The resulting solution was heated to 60 ° C for 10 minutes, then a 1M solution of lithium bis (trimethylsilyl) -amide in THF (2.0 mL, 2.00 mmol) was added dropwise, over one minute. After heating at 60 ° C for 17 hours, the reaction was cooled to room temperature, quenched with water (2 mL), and then concentrated under reduced pressure. Preparative reverse phase HPLC purification using an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa, Clara, CA), 0.1% TFA in MeCN / H2O, 40% to 95% gradient over 25 minutes, provided the compound of the title as a white solid.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.15 - 7.20 (m, 2

Η), 7.03 - 7.13 (m, 4H), 6.97 (s, 1H), 6.73 (d, <7 = 7.34 Hz, 1H), 5.72 - 5.89 (m, 1H), 5.22 (d, J = 4.65 Hz, 1H), 5.19

IMPI

MEXICAN INSTITUTE

OF THE FROFRDAD

INDUSTRIAL

545

Stage C. ((3S, 4R, 6S) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6-methyl-l, l-dioxide-2- (2-propanyl) -1,2-thiazinano6 acid -il) acetic

The title compound was prepared from (3S, 4R, 6R) -4- (3-chlorophenyl) -3- (4-chlorophenyl) -6-methyl-2- (2propanil) -6- (2-propen- l-yl) -1,2-thiazinan (Example 120, Stage

B) as described in Example 1, Step F.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.15 - 7.23 (m, 2

H), 7.03 - 7.14 (m, 4 H), 6.97 (br. S. ', 1 H), 6.73 (d, J = 6.60

Hz, 1 H), 4.47 (d, <7 = 10.5.2 Hz, 1 H), 3.59 - 3.73 (m ,. 1 H),

3.42 (t, <7 = 11.74 Hz, IH), 2.95 - 3.03 (m, 1 H), 2.84 - 2.93 (m, 1 H), 2.47 (t, <7 = 13.08 Hz, 1 H), 2.28 (d , <7 = 13.94 Hz, 1

H), 1.79 (br. S., 3H), 1.30 - 1.39 (m, 3H), 1.02 - 1.14 (m, 3H). MS (ESI) 492.1 [M + Na]+.

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -

546

EXAMPLE 121

3-methyl-l - ((S) -1-morpholinobutan-2-yl) -2-oxopiperidin-3-yl) acetic

Step A. Methyl 5-chloropicolinate

To a solution of 5-chloropyridin-2-carboxylic acid (309 g, 1.96 mol) in anhydrous MeOH (2 L), 15 thionyl chloride (299.7 mL, 4.12 mol, 2.1 eq) was slowly added at room temperature (the cloudy solution a light brown solution was made during the addition of thionyl chloride). After the addition was complete, the reaction mixture was heated to

50 ° C and stirred at this temperature overnight. The solvent and excess thionyl chloride were removed under reduced pressure and the crude product formed azeotrope with toluene twice. The resulting solid was transferred to a filter funnel and washed with saturated aqueous NaHCC> 3 until

547 the filtration product was basic.

Dissolved in dichloromethane (2L) and washed with saturated aqueous ÑaHCÓ3 'The organic compounds were dried over sodium sulfate, filtered, and the filtration product was concentrated to provide the title compound as a colorless white solid.

Stage B. 2- (3-Chlorophenyl) -1- (5-chloropyridin-2-yl) ethanone.

To a solution of 3-chlorophenylacetic acid (326.5 g,

1.91 mol, 0.95 eq) in THF (1.82 L) at -78 ° C NaHMDS (1M solution in THF, 3.82 L, 3.82 mol, 2 eq) was added slowly over 2 h 4 5 min while maintaining the temperature below - 65 ° C. After the addition was complete, the reaction mixture was stirred for 30 min at -78 ° C. A solution of methyl 5-chloropicholinate (326.5 g, 1.91 mol, Example 121, Step A) in THF (0.9 L) was added to the above solution at -78 ° C for 30 min. The reaction was stirred for another 1h and then allowed to warm to room temperature overnight. The reaction mixture was slowly transferred into a saturated aqueous solution of ammonium chloride (4 L), extracted with ethyl acetate ¡NSTITUTC, '' £ L? F3. d (2 x 8 L), and then the combined organic layers were dried

548 about Na2SW4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (eluent: DCM) provided the title compound as a white solid.

Step C. Methyl 4- (3-chlorophenyl) -5- (5-chloropyridin-2-yl) -5-oxopentanoate

To a solution of 368.5 g (1.39 mol) of 2— (3— chlorophenyl) -1- (5-chloropyridin-2-yl) ethanone (Example 121, Step B) in dioxane (1.5 L) at 80 ° C was added DBU (207 mL,

1.39 mole, 1 eq), followed by dropwise addition of methyl acrylate (124.7 mL, 1.39 mol, 1 eq) at 80 ° C. The reaction was stirred at 80 ° C for 1 hr 30 min and then allowed to cool to room temperature. It was quenched with 2M aqueous HC1 solution (56.5 eq) and then basified to pH 7 with NaHCO3 saturated aqueous. The aqueous layer was extracted with EtOAc (2 X 4L). The combined organic layers were dried over Na2SW4, filtered and the filter product evaporated. Purification by chromatography. snapshot on silica gel (eluent: 40 to 100% DCM / hexanes) provided the

549

MEXICAN INSTITUTE

Say THE PROPERTY

INDUSTRIAL

title compound as a yellow liquid.

Step D. 4- (3-Chlorophenyl) -5- (5-chloropyridin-2-yl) -5-hydroxy pentanoate of (4R, 5R) methyl and 4- (3-chlorophenyl) -5- (5-chloropyridin-2- (4S, 5S) -methyl yl) -5-hydroxypentanoate

To a solution of 2- (3-chlorophenyl) -1- (5-chloropyridin-2yl) ethanone (459.5 g, 1.3 mol, Example 121, Step C) in anhydrous MeOH (1.5 L) was added portionwise sodium borohydride ( 14.8 g, 0.392 mol, 0.3 eq) at 0-5 ° C. The reaction was stirred at the same temperature for 30 min then quenched with ice water. Methanol was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate (3X2 L). The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 10 to 70% EtOAc / hexanes, gradient elution) provided the title compound as a yellow liquid.

Stage E.

5-azido-4- (3-chlorophenyl) -5- (5-chloropyridin-2550

yl) (4R, 58) -methyl and 5-azido-4- (3-chlorophenyl) -5 (5-chloropyridin-2-yl) (4S, 5R) -methyl pentanoate

To a solution of 4- (3-chlorophenyl) -5- (5-chloropyridin-2yl) -5-hydroxypentanoate of (4R, 5R) -methyl (432 g, 1.22 mol, Example 121, Step D) and triethylamine (340 mL, 2.4 mol, 2 eq) in DCM (2.4 L) methanesulfonyl chloride (123.21 mL, 1.59 mol, 1.3 eq) was added dropwise at 0-5 ° C. The reaction was stirred at 0-5 ° C for 30 min, then slowly quenched with ice water and extracted with DCM (2 X 2 L). The combined organic layers were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and the filter product concentrated under reduced pressure.

The crude mesylate thus obtained was dissolved in DMF (1.5 L) and sodium azide (300 g, 4.6 mol, 3.8 eq) was added to it. The reaction mixture was heated to 90 ° C (internal temperature) for 2h. It was allowed to cool down to room temperature. The reaction mixture was diluted with water (2 L) and extracted with ethyl acetate (2X4 L). The combined organic layers were washed with saturated NaCl solution (2 L), dried over Na2SO4, filtered and the filter product concentrated

under reduced pressure. Raw azide was brought directly to

551 the next stage without further purification.

Stage F.

(5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin-2yl) piperidin-2-one

OR

The

Crude (4R, 5S) -methyl methyl 5-azido-4- (3-chlorophenyl) -5- (5-chloropyridin-2 yl) pentanoate (463 g, 1.22 mol, Example 121, Step E) was dissolved in 2.5 L THF / water (4: 1). Trimethyl phosphine (1 M 'in THF, 1.46 L, 1.46 mol, 1.2 eqj was added slowly at 0-5 ° C. The reaction was stirred for 30 min and then basified with 2.0 M aqueous solution of LiOH to pH 12. The reaction mixture was stirred for another 30 min, and extracted into ethyl acetate (2 X 5 L). The combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure.

Purification of the residue by flash chromatography on silica gel (eluent: 20-90% EtOAc / hexanes, gradient elution) followed by recrystallization from EtOAc / hexanes afforded trans

5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) piperidin-2-one as

552

a mixture of stereoisomers. The individual stereoisomers were separated by chiral HPLC (flow ratio: 100 ml / min on a Chiralcel® column1 OD-H 10 cm ID χ 50 cm, 20 mic (Daicel Chemical Industries LTD), using 25% isopropyl alcohol / hexane as the eluant) to give the title compound (tR = 17-25 min, earliest peak elution) as a white solid.

XH NMR (300 MHz, CDC13) δ 8.49 (d, J = 2.34 Hz, IH),

7.52 (dd, J = 2.35 and 8.21 Hz, IH), 7.20-7.17 (m, 2H), 7.07 (s, IH), 6.93-6.88 (m, 2H), 6.11 (s, IH), 4.70 (d , J = 9.31 Hz, IH), 3.20-3.13 (m, IH), 2.61 (q, J = 5.21 and 8.2 Hz, 2H), 2.26-2.04 (m, 2H). Mass Spectrum (ESI) m / z = 321 (M + l).

Stage G. 2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (5-chloropyridin-2yl) -6-oxopiperidin-l-yl) butanoate of (S) -Ethyl

CI

Ά an ice-cold solution of 9.93 g (30.9 mmol) of (5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2yl) piperidin-2-one (Example 121, Step F) in DMF (65 mL) 2.47 g (60% wt. Mineral oil, 61.8 mmol) of

min, then warmed up

553 sodium hydride. Stirred at 0 ° C for room temperature and stirred for an additional 12 min.

The reaction re-cooled to

0 ° C and 11.4 mL (77 mmol) of

Ethyl 2-bromobutyrate was added slowly via syringe over 10 min. The resulting orange suspension was warmed to room temperature and stirred for

4.75 h, and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3X), and the combined organic layers were washed with water (2X) and saturated aqueous NaCl solution (IX). The organic layer was dried over Na2SO4 was filtered and the filter product was concentrated. Purification of the residue by flash chromatography on silica gel (38 to 40% EtOAc / hexanes, gradient elution) provided the title compound as a light yellow solid.

Stage H. (5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -1 ((S) -l-hydroxybutan-2-yl) piperidin-2-one

To an ice-cold solution of 3.95 g (10.0 mmol)

(S) -Ethyl 2-((2S, 3R) -3- (3-chlorophenyl) -2- (5-chloropyridin-2-yl) -6554 oxopiperidin-l-yl) butanoate (Example 121, Step G) in ether (100 mL) 486 mg (90%, 20.1 mmol) of lithium borohydride was added. The resulting light yellow suspension was stirred at 0 ° C for 3 hr, and then warmed to room temperature and stirred for an additional 3 hr. The reaction was recooled to 0 ° C and quenched by careful addition of HCI IN until the bubbling was quenched. The mixture was extracted with EtOAc (3X), and the combined organic layers were washed with saturated aqueous sodium chloride (IX). The organic layer was dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (1 to 7% MeOH / DCM, gradient elution) provided the title compound as a white solid.

Stage I. (5R, 6S) -1 - ((S) -1- (tert-butyldiphenylsilyloxy) butan-

2-yl) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) piperidin-2-one

To a solution of 2.03 g (5.2 mmol) of (5R, 6S) -5- (3-chlorophenyl) -6- (5-chloro.pyridin-2-yl) -1- ((S) -1-hydroxybutan-

555

2-yl) piperidin-2-one (Example 121, Step rf) and 877 mg (12.9 mmol) of imidazole in DMF (32 mL) 1.9 mL (7.3 mmol) of 'tert-butyldiphenylsilyl chloride was added. The resulting light yellow solution was stirred at room temperature for 4.5 h. The reaction was partitioned between water and EtOAc (2X), and then the combined organic layers were dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (0 to 4% MeOH / DCM, gradient elution) provided the title compound as a white solid.

Step J. (5R, 6S) -1 - ((S) -1- (tert-butyldiphenylsilyloxy) butan2-yl) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3methylpiperidin- 2-one

Cl n

TBDPSO

To a -78 ° C solution of 3.19 g (5.05 mmol) of (5R, 6S) -

1- ((S) -1- (tert-butyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) piperidin-2-one (Example 121, Stage I) and 347 pL (5.55 mmol) of methyl iodide in dry, degassed THF (40 mL) was added 6.82 mL (6.82 mmol) of

556 a 1M solution of lithium bis (trimethylsilyl) amide in THF slowly by syringe for 2 min. The yellow solution was warmed to 0 ° C and stirred for 1.5 h, and then warmed to room temperature and stirred for an additional 15 min. The reaction was quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (0-15% MeOH / DCM, gradient elution) provided the title compound (C-3 epimer mixture) as a white solid.

Step K. (5R, 6S) -3-allyl-l - ((S) -l - ((tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (5-chloropyridin-2- il) -3-methylpiperidin-2-one

TBDPSO

CI

To a solution of 2.95 g (4.57 mmol) of (5R, 6S) -1 - ((S) -

1- (tert-butyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6 (5-chloropyridin-2-yl) -3-methylpiperidin-2-one (Example 121,

Step J) and 7.91 mL (91.0 mmol) of allyl bromide in THF

dry, degassed (22 mL) 68.6 mL (68.6 mmol) of γ was added!

557 a 1M solution of lithium bis (trimethylsilyl) amide in THF slowly by syringe for 6 min at room temperature. After 10 min, the orange solution was warmed to 50 ° C and stirred for 24 h. At this time,

11.4 mL (11.4 mmol) of a 1M solution of lithium bis (trimethylsilyl) amide in THF and 790 pL (0.79 mmol) of allyl bromide were added.

An additional 6.25 hr at 50 ° C, room temperature and quenched saturated. The mixture was extracted organic combined dried

The reaction was stirred for and then quenched with aqueous ammonium chloride with EtOAc (3X), and the layers over Na2SW4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (2 to 25% EtOAc / hexanes, gradient elution) provided the title compound (C-3 epimer mixture) as a light yellow solid.

Stage L. (5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (5chloropyridin-2-yl) -1 - ((S) -l-hydroxybutan-2-yl) -3methylpiperidin-2 -ona

558

To an ice-cold solution of 1.30 g (1.90 mmol) of (5R, 6S) -3-allyl-l - ((S) -1- (tert-butyldiphenylsilyloxy) butan-

2-yl) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3methylpiperidin-2-one (Example 121, Step K) in THF (55 mL) 11.37 mL (11.37 mmol) was added ) of a 1M solution of TBAF in THF. The orange solution was warmed to room temperature and stirred for 3.75 h. The reaction was partitioned between 1M HC1 and EtOAc (2X), and then the combined organic layers were washed with water (2X). The organic layer was dried over Na2SO4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (0 to 10% MeOH / DCM, gradient elution) provided the title compound as a light yellow solid.

Step M. (S) -2- ((5R, 6S) -3-AÜ1-5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-2-oxopiperidin-l-yl) butanal

559 '

-MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY (5R, 6S) -3-alylΆ a solution of · 197 mg (0.44 mmol)

5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -1 - ((S) -1hydroxybutan-2-yl) -3-methylpiperidin-2-one (Example 121, Step L) in DCM (6 mL) 12 pL (0.66 mmol) of water and 280 mg (0.66 mmol) of Dess-Martin periodate were added. The resulting light yellow suspension was warmed to room temperature and stirred for 50 min. The reaction was quenched with saturated aqueous sodium thiosulfate, diluted with water, and extracted with DCM (2X). . The combined organic layers were washed with saturated aqueous sodium bicarbonate (IX) and saturated aqueous sodium chloride (IX), and then dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by flash chromatography on silica gel (0 to 7% MeOH / DCM, gradient elution) provided the title compound as a light yellow solid.

Step N. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-l - ((S) -l-morpholinobutan-2yl) piperidin-2-one

560

The title compound was prepared from (S) —2— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -

3-methyl-2-oxopiperidin-l-yl) butanal (Example 121, Step M) as described in Example 91, Step A. Purification of the crude product by flash chromatography on silica gel (3 to 10% MeOH / DCM, gradient elution) provided the title compound as a white solid.

Stage O. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2 yl) -3-methyl-l - ((S) -l-morpholinobutan-2- il) -2-oxopiperidin-3yl) acetaldehyde

To a 42 mg (0.08 mmol) solution of (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-l ((S) -l-morpholinobutan-2-yl) piperidin-2-one (Example 121, Step N) in THF (6 mL) and water (2 mL), a catalytic amount of osmium tetroxide was added. After 3 min, 87 mg

561 Temperature through a (0.41 mmol) of sodium periodate resulting white suspension was stirred for 4.25 hr, and then a porous funnel was filtered. The filtration product was partially concentrated under reduced pressure, and then diluted with a mixture of water and saturated aqueous sodium chloride and extracted with ethyl acetate (2X). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by preparative reverse phase HPLC (Sunfire ™ Prep Cig OBD 10 μιη column (Waters, <Milford, MAj, gradient elution from 35% MeCN in water to 75% MeCN in water over a period of 35 min, where both solvents contain 0.1% TFA provided the title compound as a white solid.

Stage P.

Acid2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-

chloropyridin-2-yl) -3-methyl-l - ((S) -l-morpholinobutan-2-yl) -220 oxopiperidin-3-yl) acetic

Ά a solution of 16 mg (0.03 mmol) of

562

2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-l - ((S) -1 morpholinobutan-2-yl) -2 -oxopiperidin-3-yl) acetaldehyde (Example 121, Step O) and 1.0 mL (9.4 mmol) of 2-methyl-2butene in t-BuOH (3 mL), a solution of 28 mg (0.31 mmol) of chlorite was added. sodium and 4.6 mg (0.03 mmol) of sodium diacid phosphate dihydrate in water (1.6 mL). The resulting mixture was stirred at room temperature for 2 h, then quenched with 1M HCI and extracted with EtOAc (3X). The combined organic layers were dried over Na2SO4, filtered and the filter product concentrated. Purification of the residue by preparative reverse phase HPLC (Sunfire ™ Prep Cig OBD 10 pm column (Waters, Milford, MA), gradient elution of 35% MeCN in water to 60% MeCN in water over a period of 35 min, where both solvents contain 0.1% TFA provided the title compound as a white solid.

XH NMR (400 MHz, CD3OD) δ ppm 8.69 (1 H, d, J = 2.4 Hz),

7.65 (1 H, dd, J = 8.3 Hz, 2.5 Hz), 7.14-7.22 (2 H, m), 7.01-7.08 (2 H, rn), 6.88-6.95 (1 H, m), 4.85-4.90 ( 1 H, buried d), 3.94-4.09 (4 H, m), 3.42-3.53 (1 H, m), 3.07-3.24 (2 H, m), 2.88-3.01 (2 H, m), 2.73 (1 H, d, J = 13.7 Hz),

2.38 (1 H, t, J = 13.9 Hz), '2.10 (1 H, dd, J = 13.9 Hz. 3.5

Hz), 1.80-1.92 (1 H, m), 1.41 (3 H, s), 1.39-1.47 (2 H, m),

1.13 (3 H, dd, J = 6.5 Hz, 4.9 Hz), 0.93-1.05 (3 s

Mass Spectrum (ESI) m / z = 534 (M + l). _~

563

EXAMPLE 122

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -

3-methyl-2-oxo-l- (pentan-3-yl) piperidin-3-yl) acetic

Stage A. (5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin-2-yl) -1 (pentan-3-yl) piperidin-2-one

To a degassed solution of (5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) piperidin-2-one (1.00 g,

3.11 mmol, Example 121, Step F), 3-bromopentane (6.0 ml,

48.1 mmol) and tetrabutylammonium iodide (3.45 g, 9.34 mmol) in dry DMF (5.2 ml) 1.25 g (31 mmol) of a 60% sodium hydride dispersion in mineral oil was added at 0 ° C. The reaction was heated to 90 ° for 8h. Saturated aqueous NaHCOs / NaCl solution was added and the mixture was

564

extracted with ethyl acetate. The organic layers were washed with water and saturated NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 25 to 50% EtOAc / hexanes that had been bubbled with NH gas3, gradient elution) provided the title compound.

Stage B. (5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (5chloropyridin-2-yl) -3-methyl-l- (pentan-3-yl) piperidin-2-one

The title compound was prepared from (5R, 6S) 5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -1- (pentan-3yl) piperidine-2-one (Example 122 , Step A) by a procedure similar to that described in Example 121, Steps J and K and obtained as a mixture of epimers at C-3.

Step C. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-2-oxo-l- (pentan-3-yl) acid piperidin-3íl) acetic

-i

The title compound was obtained from (5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-l (pentan-3-yl) piperidin -2-one (149 mg, 0.335 mmol, mixture of C-3 stereoisomers, Example 122, Step B) by a procedure similar to that described in Example 71, Step F. Purification by preparative reverse phase HPLC (eluent: 50% MeCN / water (0.1% TFA), isocratic elution) using a Sunfire ™ C18 OBD column, 10 uM, (30 x 150 mm), Waters Corp (Milford, MA ) provided the title compound as the important, more polar isomer.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.53 (t, <7 = 7.46 Hz,

Hz, 1 Η), 2.22 (t, <7 = 13.57 Hz, 1 Η), 2.72 (d, <7 = 15.89 Hz, 1

Η), 2.88 - 2.99 (m, 1 Η), 3.35 (d, <7 = 15.89 Hz, 1 Η), 3.43 (ddd, <7 = 13.14, 9.72, 3.06 Hz, 1 Η), 4.50 (d, < 7 = 9.78 Hz, 1 Η),

6.76 (dt, <7 = 7.58, 1.22 Hz, 1 Η), 6.84 (d, <7 = 8.07 Hz, 1 Η),

6.98 (t, <7 = 1.83 Hz, 1 Η), 7.14 (t, <7 = 7.70 Hz, 1 Η), 7.53 (dd, <7 = 8.07, 2.45 Hz, 1 Η), 8.60 (d, <7 = 2.20 Hz, 1H). Spectrum

566

Masses (ESI) m / z = 463 (M + l).

Mbxicang INSTITUTE

OF THE PROPERTY . INDUSTRIAL

EXAMPLE 123

2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin-2yl) -3-methyl-2-oxo-l- (pentan-3-yl) piperidin-3 acid -il) acetic.

The title compound was obtained in Example 122,

Stage C as the minor, less polar isomer.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.51 (t, 7 = 7.46 Hz,

<td colspan="2">7 = 2.45 Hz, 1H).</td><td colspan="2">Mass Spectrum (ESI) m / z = 463</td><td colspan="2">(M + l</td><td> ) ·</td>

EXAMPLE 124

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -l-tert-butoxy-l-oxobutan-2-yl) -5 (3-chlorophenyl) -6- (5-chloropyridin-2- il) -3-methyl-2oxopiperidin-3-yl) acetic

567

Stage A. (5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2yl) -1- (2,4-dimethoxybenzyl) piperidin-2-one

To a 6.72g (20.92 mmol) solution of (5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) piperidin-2-one (Example 121, Step F) in DMF ( ~ 0.5M) at 0 ° C a 60% sodium hydride dispersion in mineral oil (2.51 g, 62.8 mmol) was added slowly. The reaction was stirred at 0 ° C for 30 min, followed by addition of 1- (chloromethyl) -2,4-dimethoxybenzene (7.81, g, 41.8 mmol). On completion, the reaction was quenched at 0 ° C with a small excess of acetic acid (4.79 mL, 84 mmol). It was neutralized with a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The organic layer was dried over Na2SC> 4, and the filter product was filtered as a concentrate under reduced pressure to produce a reddish oil. Purification by flash chromatography on silica gel (eluent: 0 to 30% ethyl acetate / DCM, gradient elution) provided the title compound as a pale yellow oil.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.81 - 1.93 (m, 1

568

(m, 1H), 7.18 (d, J = 8.31 Hz, 1H), 7.61 (dd, J = 8.31, 2.45

Hz, 1H), 8.5.6 (d, <7 = 2.45Hz, 1H). Mass Spectrum (ESI) m / z = 471 (M + l).

chloropyridin-2-yl) -1- (2,4-dimethoxybenzyl) -3-methylpiperidin-2one and (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (5-chloropyridin- 2yl) -1- (2,4-dimethoxybenzyl) -3-methylpiperidin-2-one

Stage B.

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (5569

title from

The (5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -1- (2,, 4-dimethoxybenzyl) piperidin-2-one compound was prepared (Example 124, Step A ) by a procedure similar to those described in Example 121, Steps J and K and was obtained as a mixture of epimers at C3.

Stage C. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (5chloropyridin-2-yl) -3-methylpiperidin-2-one (5R, 6S) -3-allyl- 5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -

1- (2,4-Dimethoxybenzyl) -3-methylpiperidin-2-one (3.6g, 6.85mmol, C-3 epimer mixture, Example 124, Step B) was dissolved in TFA (26.4mL, 343mmol) and the Reaction was heated to 70 ° for 1.5h. It was then cooled to room temperature and the TFA was removed by concentration under reduced pressure. The product formed azeotropes with heptanes, dissolved in DCM, and the organic layer was washed with saturated aqueous NaHCCh solution and saturated NaCl solution. Purification by flash chromatography on silica gel (eluent: 35 to 45% EtOAc / hexanes that had been bubbled with NH3, gradient elution)

570

title compound as the most polar isomer as a white solid: (Rf in 75% EtOAc / Hexanes = 0.44).

IH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.67 - 0.84 (m, 1

H), 1.10 - 1.25 (m, 3H), 1.60 (br. S., 1H), 1.85 - 2.04 (m,

<td>Spectrum</td><td>of</td><td>Masses</td><td>(ESI</td><td>). m / z = 375 (M + lj.</td><td></td><td></td><td></td>

Step D. 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-2-oxopiperidin-l-yl) butanoate (S) tert-Butyl

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (5-chloropyridin-2-yl) -3-methylpiperidin-2-one (77 mg, 0.205 mmol, Example 124, Step C) in DMF i (0.3 mL) slowly added 9.5 mg (0.24 mmol) of a hydride dispersion of

60% sodium in mineral oil followed by 2-bromobutanoate

571 tert-butyl (92 mg, 0.410 immole). The reaction was stirred at room temperature overnight, quenched with MeOH / HOAc, diluted with EtOAc and water, and extracted to

EtOAc. The organic compounds were dried over Na2SW4, filtered and the filter product concentrated. Reverse phase preparative HPLC purification (Sunfire ™ Prep C18 OBD 10 pm column (Waters, Milford, NA) (eluent: 70% acetonitrile, water, 0.1% TFA) provided the title compound, as well as its stereoisomer, (R ) -tert-butyl 2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) 3-methyl-2-oxopiperidin-l-yl) butanoate.

Stage E. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2yl) -3-methyl-2-oxo-3- (2-oxoethyl) piperidin-l -il) (S) -tert-butyl butanoate

The example was prepared from 2 - ((3S, 5R, 6S) -3-allyl5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-2oxopiperidin-l-yljbutanoate of (S) -tert-butyl (Example 124,

Step D) as described in Example 121, Step o. Ta

572 «IL,. 'ζ cnm *; r, V.

Purification of the residue by reverse phase preparative HPLC (Sunfire ™ Prep C18 OBD 10 pm column (Waters, Milford, MA) (eluent: 55 to 75% acetonitrile, water, 0.1% TFA, gradient elution) provided the title compound as a white solid after freeze drying.

Stage F. Acid 2 - ((3R, 5R, 6S) -1 - ((S) -1-tert-butoxy-loxobutan-2-yl) -5- (3-chlorophenyl) -6- (5-chloropyridin- 2-yl) -3methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) -3-methyl-

2-oxo-3- (2-oxoethyl) piperidin-l-yl) butanoate (S) -tert-butyl (Example 124, Step E) as described in Example 121, Step P.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.46 (t, J = 7.46 Hz,

(dd, J = 7.70, 4.28 Hz, 1 H)

3.01 - 3.09

573

(m, 1H), 3.61 (ddd,

J = 13.02, 9.84, 3.55Hz, 1H), 4.73 (d, J = 10.27Hz, 1H), 6.83 (d, J = 7.58Hz, 1H), 6.94 (d, J = 8.31Hz, 1H ), 7.03 (s, 1H),

7.11 (t, J = 7.70 Hz, 1 H), 7.14 - 7.18 (m, 1 H), 7.56 (dd, J = 8.31, 2.45 Hz, 1 H), 8.61 (d, J = 2.45 Hz, 1 H) . Spectrum

Masses (ESI) m / z = 535 (M + l).

EXAMPLE 125

Acid 2 - ((3R, 5S, 6S) -1 - ((S) -l-tert-butoxy-l-oxobutan-2-yl) -6 (4-chlorophenyl) -5- (4-chloropyridin-2- il) -3-methyl-2oxopiperidin-3-yl) acetic

Stage A. 1- (4-Chlorophenyl) -2- (4-chloropyridin-2-yl) ethanone

To a solution of 4-chloro-2-methylpyridine (23.07 g, 181 mmol) and methyl 4-chlorobenzoate (30.8 g, 181 mmol) in dry THF (500 mL) at 0 ° C was added 1M LiHMDS in THF (63.5 g, 380 mmol) slowly by means of a dropping funnel. When

574 he was

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY completed, the reaction was quenched with solution

NaHCO3, concentrated under reduced pressure, and extracted with ethyl acetate.

The combined organic products were dried over

Na2SO4, were filtered and the filter product was concentrated under reduced pressure to provide the title compound.

Stage B. 5- (4-Chlorophenyl) -4- (4-chloropyridin-2-yl) -5 (4R, 5R) -methyl and 5- (4-chlorophenyl) -4- (4-chloropyridin-2-yl) hydroxypentanoate (4S, 5S) -methyl -5-hydroxypentanoate

To a solution of 1- (4-chlorophenyl) -2- (4-chloropyridin-2yl) ethanone (42.0 g, 158 mmol) and DBU (28.5 mL, 189 mmol, Example 125, Step A) in dioxane (316 mL) at 80 ° C methyl acrylate (15.73 mL, 174 mmol) was added dropwise. The reaction was stirred at 80 ° C for 30 min, during which time more methyl acrylate. (2.86 mL, 31 mmol) was added. When the reaction was complete, it was cooled to 0 ° C. Methanol (500 mL) was added slowly, the reaction cooled to 0 ° C and NaBH4 (5.97 g, 158 mmol) was added slowly. The solution was concentrated under reduced pressure, and divided

between ethyl acetate and NaOH IN.

The

575 concentrated under reduced pressure.

Purification by flash chromatography on silica gel (eluent:

EtOAc / hexanes (which had been bubbled with NH3, gradient elution) provided the title compound.

Stage C.

(4S, 5S) -methyl and 5-azido-5- (4-chlorophenyl) -4 (4-chloropyridin- 5-azido-5- (4-chlorophenyl) -4- (4-chloropyridin-2 yl) pentanoate 2-yl) of (4R, 5R) -methyl

The title compound mixture was prepared from

Methyl 5- (4-chlorophenyl) -4- (4-chloropyridin-2-yl) -5 hydroxypentanoate (Example 125, Step B) as

Stage D.

(5S, 6S) -6- (4-chlorophenyl) -5- (4-chloropyridin-2 yl) piperidin-2-one described in Example 121, Step E, using 2.0 eq of NaN3 to

100 ° C. The residue was purified by flash chromatography on silica gel (eluent: 15 to 45% ethyl acetate / hexanes, gradient elution).

IMPI

MEXICAN INSTITUTE>,

OF THE PROPERTY \ - -__

INDUSTRIAL

The title compound mixture was prepared from (4S, 5S) -methyl 5-azido-5- (4-chlorophenyl) -4- (4-chloropyridin-2-yl) pentanoate (racemic compound mixture) ( Example 125, Step C) as described in Example 121, Step F. The crude product was first purified by flash chromatography on silica gel (eluent: 5 to 40% ethyl acetate / DCM, gradient elution), then the individual stereoisomers were separated by chiral HPLC (250 x mm AS-H column with 50 g / min IPA (0.2% DEA) + 50 g / min CO2 in Thar 350 SFC (Thar Technologies, Pittsburg, PA)) to give the title compound as the fastest eluting stereoisomer.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.60 (br. S., 3 H), 2.07 (dddd, 7 = 13.60, 5.84, 2.93, 2.81 Hz, 2 H), 2.30 - 2.46

(d, J = 5.38 Hz, 2 H), Mass Spectrum (ESI) m / z = 321 (M + l), (tR = 7.1 min at 40% iPrOH / Hexanes on analytical column

577

Chiracel OD)

Step E. (5S, 6S) -6- (4-chlorophenyl) -5- (4-chloropyridin-2-yl) -1 (2,4-dimethoxybenzyl) piperidin-2-one or (5R, 6R) -6 - (4chlorophenyl) -5- (4-chloropyridin-2-yl) -1- (2,4dimethoxybenzyl) piperidin-2-one

The title compound mixture was prepared from (5S, 6S) -6- (4-chlorophenyl) -5- (4-chloropyridin-2-yl) piperidin2-one or (5R, 6R) -6- (4 -c. chlorophenyl) -5- (4-chloropyridin-2yl) piperidin-2-one (Example 125, Step D and 1- (chloromethyl) 2,4-dimethoxybenzene using a procedure similar to that described in Example 124, Step TO.

Step F. (3S, 5S, 6S) -3-allyl-6- (4-chlorophenyl) -5- (4-chloropyridin-2-yl) -1- (2,4-dimethoxybenzyl) -3-methylpiperidin-2one and ( 3R, 5S, 6S) -3-allyl-6- (4-chlorophenyl) -5- (4-chloropyridin-2yl) -1- (2,4-dimethoxybenzyl) -3-methylpiperidin-2-one

'578

The title compound was prepared as a mixture of stereoisomers from (5S, 6S) -6- (4-chlorophenyl) -5- (4-chloropyridin-2-yl) -1- (2,4-dimethoxybenzyl) -3- methylpiperidin-2one (Example 125, Step E) using a procedure similar to that described in Example 121, Steps J and K.

Stage G. (5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin-2yl) piperidin-2-one

The title compound was prepared as a mixture of stereoisomers in. position C3. from (5S, 6S) -6- (4-chlorophenyl) -5- (4-chloropyridin-2-yl) -1- (2,4-dimethoxybenzyl) -3methylpiperidin-2-one (Example '125, Step F) in a procedure similar to that described in Example 124, Step C, dried by purification on silica gel, except that the reaction was warmed to temperature

579 environmental more than 70 °

MeOH / DCM.

eluents were 0 to 3% wiarrma »and the

Step H. 2- ((3S, 5S, 6S) -3-allyl-6- (4-chlorophenyl) -5- (4-chloropyridin-2-yl) -3-methyl-2-oxopiperidin-l-yl) butanoate tert-butyl and 2- ((3R, 5S, 6S) -3-allyl-6- (4-chlorophenyl) -5- (4-chloropyridin-2-yl) -3-methyl-2-oxopiperidin-l-yl) butanoate tert-butyl

To a 100 mg solution, (0.266 mmol) of (5S, 6S) -3alyl-6- (4-chlorophenyl) -5- (4-chloropyridin-2-yl) -3methylpiperidin-2-one (Example 125, Step G .; mixture, of stereoisomers) in dry DMF (533 pL) at room temperature, a dispersion of 60% sodium hydride in mineral oil (15.99 mg, 0.400 mmol) was added. The mixture was sonicated at 40 ° C for 10 min, followed by addition of tert-butyl 2bromobutanoate (119 mg, 0.533 mmol). It was stirred at room temperature for 24h, then an additional 2 eq of NaH was added, and it was stirred overnight. The reaction was quenched with a small amount of 10% HOAc in MeOH,

580

TO MEXICAN 0 £ INDUSTRIAL PROPERTY diluted with EtOAc and water and extracted to EtOAc x 3 τ, / ηο. combined organic products were dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by preparatory RP-HPLC (Sunfire ™ Prep C18 OBD 10 pm column (Waters, Milford, MA, gradient elution from 55% MeCN in water to 7.5% MeCN in water over a period of 35 min, where both solvents containing 0.1% TFA) produced a mixture of 4 epimers including the title compound and the other 3 epimers. After HPLC, the product-containing fractions were concentrated under reduced pressure, and extracted into ethyl acetate. The combined organic products were dried over Na2SO4, filtered and the filter product concentrated.

Stage I. Acid 2 - ((3R, 5S, 6S) -1 - ((S) -1-tert-butoxy-loxobutan-2-yl) -6- (4-chlorophenyl) -5- (4-chloropyridin- 2-yl) -3methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from (5R, 6S)

5- (3-chlorophenyl) -6- (5-chloropyridin-2-yl) piperidin-2-one

581

(Example 125, Step H) as described in Example 121, Steps O and P. Purification of the residue by reverse phase HPLC (Sunfire ™ Prep C18 OBD 10 pm column (Waters, Milford, MA) (eluent: 55% MeCN / water (0.1% TFA) provided the title compound as a white solid.

<td>1H NMR (500</td><td>MHz, CHLOROFORM-d) δ ppm 0.56</td><td>(t, 7 = 7.46 Hz</td>

H). Mass Spectrum (ESI) m / z = 535 (M + l).

EXAMPLE 126

Acid 2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-

3 — il) acetic

Stage A.

2 - ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4582

(S) -Methyl chlorophenyl) -2-oxopiperidin-l-yl) butanoate

To a solution of 1.3 g (3.61 mmol) of (3R, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 42, Step A) in DMF (14.43 mL) at 0 ° C a dispersion of 60% sodium hydride in mineral oil (0.361 g, 9.02 mmol) was added. The gray suspension was stirred at 0 ° C for 30 minutes. Then methyl 2-bromobutanoate (1,246 mL, 10.83 mmol) was added. The mixture was warmed to room temperature and stirred at room temperature for 1 h. The mixture was quenched with NH4C1 saturated. The mixture was extracted with ethyl acetate. The organic layer was washed with water, 1M LiCl (2x), and a saturated, aqueous NaCl solution. The organic layer was dried over Na2SW4 they were filtered and the filter product was concentrated under reduced pressure. The residue was purified, by flash chromatography on silica gel (80 g column; eluent: 10 to 35% EtOAc in hexanes) to give the title compound as the most important, least polar diasteromer.

Stage B.

583

INSTITUTE

FROM INDUSTRIAL Chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) piperidin-2-one

To a solution of 710 mg (1,542 mmol) of (S) -methyl 2 ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxopiperidin-l- il) butanoate (Example 126, Step A) in Et2Or (15 mL) lithium borohydride (67.2 mg, 3.08 mmol) was added at 0 ° C. The evolution of the gas was observed. The resulting white suspension was stirred at 0 ° C for 60 min. The mixture was quenched with ice cold 1M HC1. The evolution of the gas was observed. The mixture was warmed to room temperature and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SW4, was filtered, and the filter product was concentrated under reduced pressure.

The residue was purified by flash chromatography on silica gel (column 24 g; eluent: 20 to 40% EtOAc in hexanes) to give the title compound.

Stage C. (S) -2 - ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) butanal

IΜ Ρ _ί

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

584

To a mixture of 2.00 g (4.63 mmol) (3R, 5R, 6S) -3-allyl-5 (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutane-2yl) piperidin-2-one (Example 126, Stage B) in water (0.125 g,

6.94 mmol) and DCM (50 mL) Dess-Martin periodicin (2.94 g, 6.94 mmol) was added at room temperature. After

10.

Stir for 1 hr (SM was not detected by TLC), the reaction was quenched by the addition of 10 ml of Na2S2C> 3 0.5 M, extracted with DCM, and washed with saturated aqueous NaHCC solution> 3 and saturated aqueous solution of NaCl. The combined organic layers were dried over Na2SO4, leaked and the product 15 Filtration was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (80 g SiO2.5-20% EtOAc / hexanes) provided the title compound as a white foam.

Stage D. (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (methylamino) butan-2-yl) piperidin-2-one

585

To a solution of 1.67 g (3.88 mmol) of (S) —2— ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxopiperidin-l- il) butanal (Example 126, Step C) and acid

<td colspan="2">acetic (6.60</td><td>mL, 116</td><td>mmol)</td><td>at DCE</td><td>(40 mL) was added</td>

<td>methylamine</td><td>2M</td><td>in THF</td><td colspan="2">(19.40 mL, 38.8</td><td>mmol) and triacetoxy</td>

<td>hydroborate</td><td>of</td><td>sodium</td><td>(3.29 g,</td><td> 15.52</td><td>mmol) at temperature</td>

<td>environment.</td><td>The</td><td>reaction</td><td>stirred</td><td>during</td><td>2 days. The reaction</td>

was turned off with NaHCO3 saturated, extracted with EtOAc, and the combined organic layers were washed with NaOH IN and saturated aqueous NaCI solution, dried over Na2SW4 and concentrated under reduced pressure to provide the title compound as a pale yellow oil, which was used without further purification in the next step.

Step E. N- (2 - ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide

To one

126, stage

D (1.67 pyridine

586 solution

free amine made Example

3.75 mmol) mL) was added in DCE (15

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY mL,

75.0 mmol) cyclopropansulfonyl chloride

40 ° C. The reaction was timed, cyclopropansulfonyl (3.85 mL, 37.5 mmol) was added successively to stirred at 40 ° C for 14h. After that eq. pyridine and 10 eq. of additional chloride. The reaction was stirred at 40 ° C for 14h. The reaction was acidified with citric acid to

10% and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCC solution> 3 and saturated aqueous NaCl solution, dried over Na2SO4, and concentrated under reduced pressure. Purification by chromatography on silica gel (SiO2, 25 g; eluent: 20% to 40% EtOAc / Hexanes) provided the title compound as a white foam.

Step F. Acid 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -1- (N-methylcyclopropanesulfonamido) butan-2yl) -2 -oxopiperidin-3-yl) acetic

The

N- (2 - ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4587 chlorophenyl) -2-oxopiperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide (Example 126, Step D) was converted to acid by a procedure similar to that described in Example 1, Step H, to provide the crude title compound. The crude material was absorbed on top of a plug of silica gel and purified by chromatography, eluting with 60% to 80% EtOAc in hexane, to provide a colorless oil. This was purified by preparative reverse phase HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to provide the title compound as the second peak elution from reverse phase HPLC) as a white solid after freeze drying.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.51 (t, <7 = 7.53 Hz,

<td>Masses</td><td>(ESI)</td><td>m / z = 567.2 (M + l).</td><td></td><td></td><td></td>

Acid 2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S j -

588

EXAMPLE 127

1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-

3-yl) propanoic

Step A. (3R, 5R, 6S) -3-allyl-l - ((S) -l - ((tertbutyldiphenylsilyl) oxy) buthan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one

To a solution of 615 mg (1,422 mmol) of (3R, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1-hydroxybutan-

2-yl) piperidin-2-one (Example 126, Step B) in DMF (4741 pL) at 0 ° C lH-imidazole (97 mg, 1,422 mmol) was added followed by tert-butylchlorodiphenyls'ilane (473 pL, 1,849 mmol). Mix

589

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY then warmed up to

stirred at temperature quenched with NH4C1 sat. The was stirred at 0 ° C for 15 min and room temperature. The ambient mixture for 30 min and then mixing was extracted with EtOAc and the organic layer was washed with water, 1M LiCl, and saturated aqueous NaCl solution. The mixture was dried over Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (column 24 g; eluent: 0 to 30% EtOAc in hexanes) to give the title compound.

Stage B. Acid 2 - ((3S, 5R, 6S) -1 - ((S) -1 - ((tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3-yl) acetic

To a solution of (3R, 5R, 6S) -3-allyl-l - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl ·) -6- (4-chlorophenyl) piperidin -2-one (816 mg, 1,216 mmol; Example 127, Step A) in water / acetonitrile / CCl4 (7 mL / 5 mL / 5 mL) at room temperature sodium periodate (1041 mg,

4.87 mmol) e

ruthenium chloride hydrate (27.4 mg, 0.122

590 mmol). The mixture was vigorously stirred at room temperature for 3 h. The mixture was diluted with EtOAc and acidified with 1M HCI. Saturated aqueous NaCl solution was added and the mixture was filtered to remove the emulsion. The layers of the filter product were separated. The organic layer was dried over .Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (column 24 g; eluent: 0 to 50% EtOAc. In hexanes) to give the title compound.

Stage C.

2- ((3S, 5R, 6S) -1 - ((S) -1- ((tert butyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2- oxopiperidin-3-yl) methyl acetate

To a solution of 2 - ((3S, 5R, 6S) -1 - ((S) -1- (tert butyldiphenylsilyloxy) butan.-2-yl) -5- (3-chlorophenylj -6- (4-chlorophenyl) - acid 2-oxopiperidin-3-yl) acetic (741 mg, 1,076 mmol;

591

ΙΜΡΪ

INDUSTÍjAL in 10 ml of a 10% solution of

Example 127

Step B) In DCM at room temperature TMS-dlazomethane (2.0M in ether) (807 pL, 1,614 mmol) was added. Gas evolution was observed and the yellow mixture was stirred at room temperature for 45 min. More TMS-diazomethane (2.0M in ether) (807 pL, 1.614 mmol) was added and the reaction was stirred at room temperature for 45 min. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (column 24 g; eluent: 0 to 30% EtOAc in hexanes) to give the title compound.

* unknown stereochemistry

2- ((3S, 5R, 6S) -l- ((S) -l - (- (tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2- oxopiperidin-3-yl) methyl acetate (Example

127,

Stage C) formed an azeotrope with

592 toluene 3x and then dissolved in THF (14 mL). under Ar and the mixture was cooled to ° C. HMPA (236 pL, 1,356 mmol) and LHMDS (1.0M in THF) (1356 pL, 1,356 mmol) were added under Ar at -78 ° C. The mixture was stirred at -78 ° C for 30 min. The color of the mixture turned light yellow. Then iodomethane (110 pL, 1,763 mmol) was added and the reaction mixture was allowed to warm slowly to room temperature. · The mixture was quenched with NH4C1 saturated and the layers were separated. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2 x 50 g stacked Style I VersaPak, Spherical, Supelco, Bellenfonte, PA; eluent: 20 to 30% MtBE in hexanes) to give the title compound as the major diastereomer less polar. The retention time of the least polar diastereomer is 0.871 min (80-100% MeCN + 0.1% TFA in water + 0.1% TFA, for 1 minute). The retention time of the most polar diastereomer is 0.841 min (80 to 100% MeCN + 0.1% TFA in water + 0.1% TFA, for 1 minute).

Stage E. 2- ((3S, 5R-, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) 1- ((S) -l-hydroxybutan-2-yl) -2-oxopiperidin- 3-yl) methyl propanoate

MEXICAN INSTITUTE Γ

OF PROPERTY - · »Λ,

INDUSTRIAL

593

* unknown stereochemistry

Ά a solution of 2 - ((3S, 5R, 6S) -1 - ((S) -1 - ((tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3-yl) methyl propanoate (285 mg, 0.398 mmol) (the least polar isomer of stage D) in THF (1988 pL) TBAF (1.0M, in THF) was added (1590 pL, 1,590 mmol). The mixture was stirred at room temperature for 16h. The mixture was quenched with 1M HC1 and diluted with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (11 g VersaPak I-style, Spherical, Supelco, Bellenfonte, PA; eluent: 50 to 75% MtBE in hexanes) to give the title compound.

Step F. 2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) - Methyl 2oxopiperidin-3-yl) propanoate

IMPI

594

* unknown stereochemistry

A flask, containing a solution of 2 - ((3S, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) 2 methyl methyl-oxopiperidin-3-yl) propanoate (195 mg, 0.408 mmol; Example 127, Step E.) and N-methylcyclopropansulfonamide (165 mg, 1,223 mmol) in toluene (2038 pL) was evacuated and refilled with Ar (5 x). Then cyanomethylene tributylphosphoran (321 pL, 1,223 mmol) was added. The slightly brownish orange mixture was heated to 70 ° C for 2 h. More Nmethylcyclopropansulfonamide (134 mg, 0.991 mmol) was added and the mixture was heated to 70 ° C for 2 h. The mixture was heated to reflux overnight, and then cooled to room temperature. The mixture was diluted with EtOAc and saturated aqueous NaCI solution. The layers were separated. The organic layer was dried over Na2SW4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (column 4 g eluant: 0 to 100% EtOAc in hexanes) to give the compound>.

IMPIir

INSTITUTO ME'XÍCANO V

FROM THE PP.OTiEüAD V'u .....

INDUSTRIAL

595 Title.

Step G. Acid 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2yl) -2- oxopiperidin-3-yl) propanoic

To a solution of 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2yl) -2- methyl oxopiperidin-3-yl) propanoate (56 mg, 0.094 mmol; Example 127, Step F) in MeOH / THF / H2Or (1 mL / Ι mL / 2 mL) LiOH (3M in water) (157 pL, 0.470 mmol) was added at room temperature. The suspension was heated to ~ 100 ° C for 3 h. The mixture was cooled to room temperature, acidified with 1M HCI, and extracted with EtOAc (2x). The organic layers were combined, dried over Na2SO4, filtered and the filter product concentrated under reduced pressure. The colorless film was purified by reverse phase preparative HPLC (eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (t, J = 6.65

Hz, 3H), 0.95 - 1.07 (m, 2H), 1.20-1.26 (m, 5H), 1.40 (dd, J = 10.96, 7.24Hz, 1H), 1.52 - 1.66 (m, 1H) , 1.851.93 (m, 1 Hj, 1.96-2.00 (m, 1 H), 2.22-2.36 (m, 2 H), 2.70

- 2.79 (m, 1H), 2.88 '- 3.07 (m, 6H), 3.13 (quin, J = 7.19

596

Hz, 1 Η), 4.67 (d, <7 = 10.56 Hz, 1 H), 6.89-6.92 (m, 1 H),

6.94 - 7.01 (m, 3H), 7.14 - 7.18 (m, 2H), 7.25 (d, J = 8.41

Hz, 2H); Mass Spectrum (ESI) m / z = 603 (M + 23), 581 (M + l).

EXAMPLE 128

2- ((3R, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-l -il) (S) tert-butyl butanoate

Stage Ά.

(S) -tert-butyl chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lyl) butanoate

A solution of 2 - ((3R, 5R, 6S) -1 - ((S) -1-tertbutoxy-l-oxobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) acid -3-methyl-2-oxopiperidin-3-yl) acetic (230 mg, 0.430 mmol;

597

Example 67) in DMF (4.3 mL) was treated with N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride (165 mg, 0.8 6 mmol), l-hydroxy-7-azabenzotriazole (117 mg, 0.86 mmol) and NaHCO3 (72.3 mg, 0.861 mmol) successively. After stirring at rt for 0.5 h, 7M ammonia in methanol (6.2 mL, 4.30 mmol) was added dropwise and the reaction was stirred overnight. Then the reaction was diluted (water), extracted (2> <EtOAc), and washed (lxNaHCO3 saturated and 2x saturated aqueous NaCl solution). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification by RP-HPLC (45 to 70% MeCN / H2O (0.1% TFA), at gradient elution) provided the title compound as a white solid.

Step B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 (cyanomethylj-3-methyl-2-oxopiperidin-l-yl) butanoate of (S ) tert-butyl

<td></td><td>I MF 7 5 QQ INSTITUTO ME Y'A 2 V 'UJ ° DZ LA PROV - \ or - INDUSTRIAL</td>

<td>A solution</td><td>2 - ((3R, 5R, 6S) -3- (2-amino-2-oxoethyl) -5-</td>

(S) -tert-Butyl (3) chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) butanoate (105mg, 0.197mmol; Example

128, Step A) and triethylamine (137 pL, 0.984 mmol) in THF (3.3 mL) was treated with 2,2,2-trifluoro acetic anhydride (69.8 pL, 0.492 mmol) at 0 ° C. After stirring at 0 ° C for 3 hr, the reaction was quenched (10% citric acid), extracted (2xEtOAc) and washed (saturated aqueous NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 20 to 50% EtOAc / Hex, gradient elution) provided the title compound as a colorless foam.

Stage C. 2 - ((3R, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin -lil) (S) -tert-butyl butanoate

To a solution of 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (cyanomethyl) -3-methyl-2-oxopiperidin-lil) butanoate of (S) -tert-butyl (101 mg,

0.196 mmol; Example

128, Stage B) in DMF (0.50 mL) sodium azide (127 mg, 1.96 mmol) and NH were added4C1 (105mg, 1.96mmol)

The resulting mixture was stirred at 90 ° C for days

Then the reaction was quenched (10% aqueous citric acid), extracted

599

IMPI

MEXICAN INSTITUTE

INDUSTRIAL DBLAFROFisDAD (2xEtOAc), and washed (3x aqueous saturated NaCl solution).

The combined organic layer was dried (Na2SW4) and concentrated under reduced pressure. Purification by RP-HPLC (60 to 85%

ACCN / H2O, gradient elution) provided the title compound as a white solid.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 - 7.26 (2 H, m),

7.09 - 7.19 (2 H, m), 7.01 (1 H, t, J = 1.9 Hz), 6.92 (2 H, d, J = 8.6 Hz), 6.75 - 6.80 (1 H, m), 4.60 (1 H , d, J = 10.8 Hz),

3.44 - 3.63 (2 H, m), 3.27 (1 H, br. S.), 3.15 (1 H, dd, J = 10 8.3, 3.4 Hz), 2.29 - 2.42 (2 H, m), 2.24 (1 H, d, J = 3.3 Hz),

1.49 - 1.52 (8 H, m), 1.34 - 1.40 (1 H, m), 1.32 (3 H, s), 0.55 (3 H, t, J = 7.4 Hz); MS (ESI) 558.1 [M + H]+, 556.2 [MH].

EXAMPLE .129

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (methylsulfonamido) butan-2-yl) -2 acid -oxopiperidin-

3-yl) acetic

600

Stage

TO.

(3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -1 - ((4-methoxybenzyl) amino) butan-2-yl) -3methylpiperidin-2-one

To a solution of (S) -2 - ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) butanal (300 mg, 0.675 mmol; Example 91, Step C) and (4methoxyphenyl) methanamine (131 pL, 1.01 mmol) in DCE (4.5 mL) sodium triacetoxyborohydride (429 mg, 2.03 mmol) was added at 0 ° C in various portions. After stirring at 25 ° C for 18 hr, the reaction was quenched by adding ice-cold saturated aqueous NaHCC> 3 and extracted (2 * DCM). The combined organic layers were washed (saturated aqueous NaCl solution) and concentrated under reduced pressure to provide the title compound as a yellow film. The product was used in the next step without further purification.

Step B. (S) -2 - ((3S, 5R, 6S) -3-Alyl • 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl- Stage B. 2,2,2-Trifluoroacetate 2-oxopiperidin-l601 il) butan-l-ammonium

To a solution of (3S> 5R, 6S) -3-allyl-5- (3-chlorophenyl)

6- (4-chlorophenyl) -1 - ((S) -1- (4-methoxybenzylamino) butan-2-yl)

3-rnetylpiperidin-2-one (370 mg, 0.654 mmol; Example 129, Step A) in acetonitrile (8.0 mL) and water (1.6 mL), ceric ammonium nitrate (2.87 g, 5.23 mmol) was added at 25 ° C.

After stirring at rt for 2 days, the reaction was quenched (saturated aqueous NaCl solution), extracted (3xEtOAc), and washed (saturated aqueous NaCl solution).

The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by RPHPLC (35 to 70% MeCN / H2O (0.1% TFA), gradient elution) provided the title compound as a pale yellow powder.

Stage C. N- ((S) -2 - ((3S, 5R, 6S) -3-A111-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lyl) butyl ) methanesulfonamide

602

2,2,2-Trifluoroacetate (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3- chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin -l-il) butan-

1-ammonium (74 mg, 0.14 mmol; Example 129, Step B) was dissolved in DCM at 0 ° C and 2N lithium hydroxide (0.34 mL, 0.68 mmol) was 10 added and the resulting solution was stirred for 5 min at 0 ° C.

The solution was extracted (2xDCM), washed (saturated aqueous NaCl solution), dried (Na2SW4), and concentrated under reduced pressure to give the free amine. To a solution of the free amine of the above in DMF (0.34 mL) was added methanesulfonyl chloride (53 pL, 0.68 mmol) and pyridine (66 pL, 0.820 mmol) successively at 0 ° C. After stirring at 25 ° C overnight, the reaction was acidified (10% citric acid) and extracted (2 * EtOAc) and washed (saturated aqueous solution of

NaCl). The combined organic layers were dried (Na2SW4), and concentrated under reduced pressure. Purification by RP-HPLC (45 to 80% MeCN / H2O (0.1% TFA), gradient elution) provided the title compound as a white powder.

Stage D.

Acid

IM

INSTITUTO λί PE LA FROrirD INDUSTR.

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl)

603 chlorophenyl) -3-methyl-l - ((S) -1- (methylsulfonamido) butan-2-yl) -2 oxopiperidin-3-yl) acetic

To a rapidly stirring solution of N - ((S) —2— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxopiperidin -l-yl) butyl) methanesulfonamide (34 mg, 0.064 mmol; Example 91, Step C) in a mixture of water (0.55 mL), acetonitrile (0.37 mL), and CC14 (0.37 mL) was added. sodium periodate (55 mg, 0.26 mmol) and ruthenium (III) chloride hydrate (1.5 mg, 6.5 pmol). After vigorously stirring for 20 h, the reaction was acidified (10% citric acid) and diluted with EtOAc. Insoluble material was removed by filtration through a pad of Celite® (JT Baker,

Phillipsberg, NJ, diatomaceous earth). The filtration product was extracted (2 * EtOAc) and washed (saturated aqueous NaCI solution). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification by RP-HPLC (40 to 70% MeCN / H2O (0.1% TFA), a gradient elution) provided the computation of the title as a white foam.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, d, J =

8.2 Hz), 7.10 - 7.18 (2 H, m), 7.00 - 7.10 (2 H, m), 6.97 (1

604

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

s), 2.96 (1 H, s), 2.77 (1 H, s), 2.36 (1 H, y), 1/19.,. ,, 2. ,,, 06 (1 H, m), 1.77 - 1.92 (1 H, m), 1.52 - 1.59 (1 H, m), 1.50 (3

H, s), 0.58 (3 H, t, J = 7.3Hz); MS (ESI) 541.0 [M + H], 539.0 [MH :.

EXAMPLE 130

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -5-oxohexan-3-yl) piperidin -3-yl) acetic

Step A. (S) -3 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) pentanal

OR

(Methoxymethyl) triphenylphosphonium chloride was dried at 80 ° C under vacuum for 3 h. To a solution of the dry (methoxymethyl) triphenylphosphonium chloride (1.96 g, 5.71 mmol) in THF (10 mL) was added 0.5 M KHMDS in toluene (10.2 mL, 5.08

605

mmol) a

MEX INSTITUTE

-78 ° C. The color of the solution was iwi blood color. After stirring to O0^ They last a solution of (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-l- il) butanal (Example 91, Step C; 564 mg, 1.27 mmol) in THF (10.1 mL) was added at 0 ° C dropwise. After stirring at rt overnight, the reaction was quenched (ÑH4CI sat. Solution), extracted (2xEtOAc), and washed (saturated aqueous NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography on silica gel (SIO2, 40 g, 15% and 20% EtOAc / Hexanes) provided the vinyl ether (3S, 5R, 6S) -3 allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S, E) -1-methoxypent-l-en-3-yl) -3-methylpiperidin-2-one.

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S, E) - l-methoxypent-l-en-3 -il) -3-methylpiperidine-2-one previously prepared in acetonitrile (7.8 mL), 3N hydrochloric acid (4.4 mL, 13 mmol) was added and the resulting solution was stirred at rt for 1.5 h. Then, the reaction was extracted (2 * EtOAc), and washed (saturated aqueous NaCl solution). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure to provide the title compound as a pale yellow film.

Stage

606

MEXICAN INSTITUTE V —'í '- OF PROPERTY V *' -? industrial (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S) -5-hydroxyhexan-3-yl) -3-methylpiperidin-2 one

To a solution

il) pentanal (540 mg, 1.18 mmol; Example 130, Step Aj in THF added bromide (2.52 mL, 3.53 methyl magnesium 1.4M in toluene and mmol) at 0 ° C. The reaction was then allowed to warm to rt and stirred for 3 h The reaction was quenched (saturated N'H solution4C1), it was extracted (2 * EtOAc), and it was washed (saturated aqueous solution of

NaCl). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure to provide the crude title compound as a mixture of diastereomers.

Stage

il) acetic

The title compound was obtained from hydroxyhexan-3-yl) -3-methylpiperidin-2-one (90 mg, 0.19

607 mmol;

Example 130 Step B) as' described in Example 71,

Stage

F like a white foam.

m), XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 - 7.27 (2 H,

7.06 - 7.17 (4 H, m), 7.00 (1 H, t, J = 1.8 Hz), 6.81 (1

H, s), 4.92 (1 H, d, J = 10.8 Hz), 3.54 - 3.63 (1 H, m), 3.07 (3 H, d, J = 15.7 Hz), 2.67- (1 H, d, J = 15.8 Hz), 2.50 2.60 (1 H, m), 2.19 (3 H, s), 2.12 (1 H, s), 1.97 - 2.07 (1

H, m), 1.88 - 1.96 (1 H, m), 1.39 (3 H, s), 1.21 - 1.32 (1 H,

m), 0.37 (3H, t, J = 7.5 Hz); MS (ESI) 490.0 [M + H]1, 488.0 [MH].

EXAMPLE 131

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 5-hydroxy-5-methylhexan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic

chlorophenyl) -3-methyl-l - ((S) -5-oxohexan-3-yl) piperidin-2-one

Stage A.

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4608

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -5hydroxyhexan-3-yl ) -3-methylpiperidin-2-one (100 mg, 0.21 mmol; Example 130, Step B) by a procedure similar to that described in Example 129, Step C.

♦

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -5-hydroxy-5-methylhexan-3-yl) -3methylpiperidin -2-one

To a solution of (3S / 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) -5-oxohexan-3-yl) piperidin-2-one (90 mg, 0.19 mmol; Example 131, Step A) in THF (1.9 mL) 1.4M methylmagnesium bromide in toluene and THF (75:25) (408 pL, 0.571 mmol) were added at 0 ° C. Then the reaction was left

609

I

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

warm to rt and stirred for 4 h. The reaction was quenched (saturated NH4CI solution)., Extracted (2> <EtOAc), and

washed (saturated aqueous NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure and purification of the residue by chromatography on silica gel (12g SiO2, 30% and 35% EtOAc / Hex) provided the title compound as a colorless foam.

Stage C.

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -5-hydroxy-5-methylhexan-3-yl) -3-methyl acid -2-

oxopiperidin-3-yl) acetic

The title compound was obtained from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -5hydroxy-5-methylhexan- 3-yl) -3-methylpiperidin-2-one (73 * mg,

0.15 mmol; Example 131, Step B) by a procedure similar to that described in Example 71, Step F as a white foam.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, d, J =

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-

610

EXAMPLE 132 methyl-2-oxo-l - ((3S) -6,6,6-trifluoro-5-hydroxy-5-methylhexan-3yl) piperidin-3-yl) acetic (Isomer 1)

* unknown stereochemistry

Stage A.

(3S, 5R, 6S) -3-ali1-5- (3-chlorophenyl) -6- (4chlorophenyl) -3-methyl-l - ((3S, 5S) -6,6,6-trifluoro-5-hydroxy -5 methylhexan-3-yl) piperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((3S , 5R) -6,6,6 trifluoro-5-hydroxy-5-methylohexan-3-yl) piperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-l - ((S) -5-oxohexan-3-yl) piperidin-

2-one (120 mg, 0.254 mmol; Example 131, Step A) in THF (2.5 mL) trimethyl (trifluoromethyl) silane (113 pL,

611

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

0.7 62 mmol) at 0 ° C and the reaction was stirred for 5 min.

Then 1M TBAF in THF (381 pL, 0.381 mmol) was added slowly at 0 ° C. After stirring at 0 ° C for 20 min, the reaction was allowed to warm to rt After stirring at rt for 40 min the reaction was quenched (NH4C1 saturated aqueous), extracted (2xDCM), and washed (2xsat.

NaHCO3 and the saturated aqueous NaCI solution). The combined organic layers were dried (Na2SW4) and conc was entered under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 13% and 24% of

EtOAc / Hex) provided a less polar isomer and a more polar isomer.

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl15 1 - ((3S) -6,6,6-trifluoro-5-hydroxy- 5-methylhexan-3yl) piperidin-2-one (least polar isomer).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J =

8.2 Hz), 7.15 - 7.20 (1 H, m), 7.07 - 7.14 (1 H, m), 6.88 -

7.06 (3H, m), 6.69 (1H, d, 3 = 7.4Hz), 5.77 - 5.92 (1H, 20 m), 5.09 - 5.23 (2 H,, m), 4.44 - 4.59 (1 H, m), 3.13 (1 H, br. s.), 2.62 (2 H, d, J = 7.4 Hz), 1.84 - 2.05 (3H, m),

1.64 - 1.82 (2 H, m), 1.33 (3 H, s), 1.25 - 1.31 (5 H, m),

0.72-0.94 (3H, m) .; MS (ESI) 542.0 [M + H]1.

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

612

1 - ((3S) -6,6,6-trifluoro-5-hydroxy-5-methylhexan-3 yl) piperidin-2-one (most polar isomer).

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 - 7.27 (2 H, 0 m), 7.14 - 7.20 (1 H, m), 7..09 - 7.14 (1 H, m), 6.90 - 7.08 (3 H, m), 6.70 (1 H, d, J = 7.4 Hz), 5.86 (1 H, dd, J = 17.4,

9.6 Hz), 5.12 - 5.22 (2 H, m), 4.44 - 4.56 (1 H, m), 3.06 -

3.21 (1 H, m), 1.83 - 2.03 (2 H, m), 1.53 - 1.82 (3 H, m),

1.37 - 1.49 (1 H, m), 1.29 (3 H, s), 1.23 (3 H, d, J = 14.5 10 Hz), 0.62 - 0.94 (3H, m); MS (ESI) 542.0 [M + H]+.

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxo-l - ((3S) -6,6,6 -trifluoro-5-hydroxy

5-methylhexan-3-yl) piperidin-3-yl) acetic (isomer 1)

The title compound was obtained from the least polar isomer of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((3S) - 6,6,6-trifluoro-5-hydroxy-5methylhexan-3-yl) piperidin-2-one prepared in Step A by a procedure similar to that described in Example 71, Step F as a white foam.

XH NMR (400 MHz, CHLORFORM-d) δ ppm 7.24 - 7.27 (2 H, m), 7.14 - 7.19 (1 H, m), 6.96 - 7.12 (3 H, m), 6.93 (1 H, t, J = 1.7 Hz), 6.68 (1 H, d, J = 7.6 Hz), 4.58 - 4.67 (1 H, m),

2.98 - 3.14 (2 H, m), 2.71 - 2.81 (1 H, m), 2.17 (1 H, s),

IMPI

2.02 (2H, s),

Η, s), 0.19 613

1.52 - 1.70 (1 Η, m)

1.48 (3H, s), 1.34 (5

0.93 (3H, m); MS (ESI) 558.0 [M + H], 560.0 [MH].

EXAMPLE 133

Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- methyl-2-oxo-l- ((3S) -6, 6, β-tri ' f luoro-5-hydroxy-5-methylhexan-3yl) piperidin-3-yl) acetic (Isomer 2)

* unknown stereochemistry

The title compound was obtained from the most polar isomer of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((3S) - 6,6,6-trifluoro-5-hydroxy-5methylhexan-3-yl) piperidin-2-one (48 mg, 0.088 mmol; Example 132, Step A) by a procedure similar to that described in Example 71, Step F as a white foam.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, br. S.),

6.96 - 7.19 (4 H, m), 6.93 (1 H, t, J = 1.8 Hz), 6.69 (1 H, d, J = 7.6 Hz), 4.60 - 4.70 (1 H, m), 3.01 ( 2 H, s), 2.75 (1

H, d, J = 15.1 Hz), 2.11 - 2.21 (1 H, m), 2.02 (2 H, s), 1.77

IMPI r Τ Λ MEXICAN INSTITUTE

O 1 4 OF PROPERTY

INDUSTRIAL

- 1.93 (1 H, m), 1.48 (6 H, s), 1.35 (3 H, br. S.), 0.39 —M — gggjlfil IILIT'jJ »..» · <ΐ1|> ιι~ Μίιι\*

0.71 (3H, m); MS (ESI) 560.0 [M + H]+, 558.0 [MH] ~.

EXAMPLE 134

Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- methyl-1 - ((S) -1- (N-methylmethylsulfonamido) butan-2-yl ) -2oxopiperidin-3-yl) acetic

Step A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (415 chlorophenyl) -3-methyl-l - ((S) -1- (methylamino) butan-2yl) piperidin-2-one

To a solution of (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) butanal (70 mg, 0.16 mmol; Example 91, Step C) and acid

IMPI (2.6 mL) was added

1.58 mmol) and

0.47 mmol) at rt

615 acetic (271 pL, 4.73 mmol) in C1CH2CH2C1-methylamine 2M in THF (788 pL, sodium triacetoxyborohydride (100 mg,

After stirring at rt for 3 h, the reaction quenched 5 (NaHCO3'saturated aqueous), extracted (2 * EtOAc), and washed (saturated aqueous NaCl solution). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure to provide the crude title compound as a pale yellow film. The product was used in the next step without further purification.

Stage B. N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) butyl) -Nmethylmethanesulfonamide

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) -1- (methylamino) butan-2yl ) piperidin-2-one (72 mg, 0.16 mmol; Example 134 Step A) in

DMF (0.40 mL) methanesulfonyl chloride (61 pL,

0.79 mmol) and pyridine (76 pL, 0.95 mmol) successively at 0 reaction was acidified (10% citric acid) and extracted

616

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY (2xEtOAc).

(solution concentrated

The combined organic layers were saturated with aqueous NaCl), dried (Na2SO4) washed under reduced pressure. Separation by RP-HPLC (50 to 85% MeCN / H2O (0.1% TFA) (gradient elution) provided the title compound as a pale yellow film.

Stage C.

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-

chlorophenyl) -3-methyl-l - ((S) -1- (N-methylmethylsulfonamido) butan2-yl) -2-oxopiperidin-3-yl) acetic

The title compound was prepared from N— (<S) —2— (Example

134, Stage B) described

in Example AB, Stage G (1 H

13.9 dd,

H, s

<td>XH NMR (400</td><td>MHz,</td><td colspan="2">CHLOROFORM-d) δ ppm 7.21 - 7.27 (2 H,</td>

553.0 [Μ-H]- .

H, s), 0.50 (3 H, t, J = 7.5 Hz); MS (ESI) 555.1 [M + H] ~,

Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-

617

EXAMPLE 135

MEXICAN INSTITUTE DS INDUSTRIAL PROPERTY ((3S) -5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl) -3methyl-2-oxopiperidin-3-yl) acetic

* unknown stereochemistry

Stage

TO.

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4methylpiperidin-2-one

To a solution

(S) -3- ((3S, 5R, 6S) -3-allyl-5- (3 yl) pentanal (160 mg, 0.349 mmol; Example 130, Step A) In THF (3.5 mL) cyclopropylmagnesium bromide was added 0.5 M in THF (2.09 mL, 1.05 mmol) at 0 ° C.

The reaction was then allowed to warm to rt and stirred for 3.5 h. The reaction

PREVENT £> £ THE PSOPíbZ-Λί) quenched (NH saturated solution4C1), extracted (2xEtOAc), and from NaCl). The organic layers washed (combined solution was reduced for mixing of two

618 saturated aqueous dried (Na2SW4) provide the and concentrated under pressure the title compound as a diastereomers. The . crude product was used in the next step without further purification

1 - ((S) -l-cyclopropyl-l-oxopentan-3-yl) -3-methylpiperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6methylpiperidin-2-one previously prepared in Step A (175 mg,

0.350 mmol) and water (9.5 pL, 0.52 mmol) in DCM (3.9 mL), added periodan

Dess-Martin (222 mg,

0.524 mmol) at rt

After stirring at rt for 40 min, the reaction was quenched (Na2S2OR3 it was extracted (2 * DCM), and washed (2χ NaHCO3 sat. and saturated aqueous NaCl solution). Organic layers reduced. The purification of the residue by combined chromatography was dried (Na2SW4) and concentrated under pressure

619

IMPI

INSTITUTO MEXICANO DE LA-PROPALAD INDCST & ÍAL silica gel (12 g S1O2, 15% and 25% EtOAc / Hex) provided

the title compound as a colorless film.

Step C. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (45 chlorophenyl) -1 - ((3S, 5S) -5-cyclopropyl-6,6,6-trifluoro -5hydroxyhexan-3-yl) -3-methylpiperidin-2-one and (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S, 5R) -5cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl) -3methylpiperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-l-oxopentan-3-yl) -3-methylpiperidin-2-one previously prepared in Step B (132 mg, 0.265 mmol) in THF (2.6 mL), trimethyl (trifluoromethyl) silane (117 pL, 0.794 mmol) was added at 0 ° C and the reaction was stirred for 5 min. Then 1M tetrabutylammonium fluoride in THF (397 pL, 0.397 mmol) was added slowly at 0 ° C. Then the reaction was allowed to warm to ta After stirring for 3 hr, additional trimethyl (trifluoromethyl) silane (234 pL, 1.59 mmol)

620

IMPI

MEXICAN INSTITUTE

INDUSTRIAL PROPERTY - * and 1M tetrabutylammonium fluoride in THF (794 pL, 0.794 mmol) were added at 0 ° C

After stirring and the reaction was allowed to warm to rt

at rt for 15 h, the reaction was quenched (saturated aqueous NaCl solution), extracted (2 * EtOAc), and washed (saturated aqueous NaCl solution). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure.

Purification of the residue by chromatography on silica gel (12 g SiO2,

6% and 13% of

EtOAc / Hex) provided one of the title compounds as the least polar isomer and another of the title compounds as the most polar isomer, successively.

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S) 5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan- 3-yl) -315 methylpiperidin-2-one (least polar isomer) XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J =

8.2 Hz), 7.15 - 7.20 (1 H, m), 7.07 - 7.14 (1 H, m), 6.88 -

7.06 (3 H, m), 6.69 (1 H, d, J = 7.4 Hz), 5.77 - 5.92 (1 H,

m), 5.09 - 5.23 (2 H, m), 4.4 4 - 4.59 (1 H, m), 3.13 (1 H, 20 br. s.), 2.62 (2 H, d, J = 7.4 Hz), 1.84 - 2.05 (3 H, m),

1.64 - 1.82 (2 H, m), 1.33 (3 H, s), 1.25 - 1.31 (5 H, m),

0.72-0.94 (3H, m); MS (ESI) 568.2 [M + H]+.

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S) -

621

5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl) -3methylpiperidin-2-one (most polar isomer) XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 - 7.27 (2 H,

Hz), 0.62 - 0.94 (3H,

Stage D.

Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4hydroxyhexan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from methylpiperidin-2-one (Example 135, polar) by a similar procedure

71, Stage F.

XH NMR (400 MHz, CHLOROFORM-d)

Step C, the described δ ppm 7.00 more product in the Example

7.04 (2H,, 6.67

6.84 (3 H, m), 6.46 (1 H, d, J = 7.6 Hz), 4.29 - 4.45 (1 H, m), 2.76

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

622

EXAMPLE 136

2- ((3R / 5R, 6S) '- 5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -6-hydroxy-6-methylheptan-3-yl) -3- acid methyl-2-oxopiperidin3-yl) acetic

Step A. (S) -4- ((3S, 5R, 6S.) - 3-allyl-5- (3-chlorophenyl) -6 -. (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) hexanal

The title compound was prepared from (S) -3 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl2-oxopiperidin-l -il) pentanal (106 mg, 0.231 mmol; Example

623

FROM OWN 'D' vv

130, Step A) by a procedure similar to deá ^ M ^

Example 130, Stage A. '

Step B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) - - ((3S) -6-hydroxyheptan-3-yl) -3-methylpiperidin- 2-one

HO

OR

The title compound was prepared from (S) —4— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

2-oxopiperidin-l-yl) hexane.l (84 mg, 0.18 mmol; Example 136, Step A) by a procedure similar to that described in Example 130, Step B as a colorless film. The crude product was used in the next step without further purification

Step C. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -6-oxoheptan-3-yl) piperidin- 2-one

OR.

IMPI

The title compound was prepared from a

624 (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -6-hydroxyheptan-3-yl) -3-methylpiperidin-2one mixture prepared in Step B by a procedure similar to that described in Example 129, Step C.

Step D. (3S, .5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -6-hydroxy-6-methylheptan-3-yl) - 3methylpiperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) -6-oxoheptan-3-yl) Piperidin-2-one previously prepared in Step C (78 mg, 0.16 mmol) in THF (1.6 mL), 1.4M methylmagnesium bromide in toluene and THF (75:25) (344 pL, 0.481 mmol) were added at 0 ° C. The reaction was then allowed to warm to rt and stirred for 2 h. The reaction was quenched (saturated NH solution4C1), extracted (2 * EtOAc), and washed (saturated aqueous NaCl solution). The combined organic layer was dried (Na2SW4) and concentrated under reduced pressure. The purification of the residue by chromatography on

625 Silica gel

title compound as a colorless foam.

Stage E. 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -6-hydroxy-6-me.thylheptan-3-yl) acid -3-methyl-2oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -6hydroxy-6-methylheptan- 3-yl) -3-methylpiperidin-2-one (Example 136, Step D) by a procedure similar to that described in

<td colspan="6">Example 71, Stage F.</td>

<td></td><td>XH NMR (400</td><td>MHz, CHLOROFORM-d)</td><td>δ</td><td>ppm</td><td>7.25 (2 H, d, J =</td>

m), 1.37 - 1.56 (7 H, m), 1.22 (6 H, d, J = 5.5 Hz), 0.55 (3

H, t, J = 7.5 Hz); MS (ESI) 520.2 [M + H]+, 518.0 [MH] ".

EXAMPLE 137

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-l - ((S) -6,6,6-trifluoro- 5,5-dihydroxyhexan-3yl) piperidin-3-yl) acetic

626

Ί.Α,

ΙΜΡΙ (^ 5

MEXICAN INSTITUTE

DELA PkOPlEC. '. D *

INDUS i R.1aL ^ Sg *,.

Step A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - (((3S) -6,6,6-trifluoro-5- hydroxyhexan-3yl) piperidin-2-one

To a solution of (S) -3 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) pentanal (100 mg, 0.218 mmol; Example 130, Step A) in THF (2.2 mL) trimethyl (trifluoromethyl) silane (97 pL, 0.66 mmol) was added at 0 ° C and the reaction stirred for 5 min. Then 1M TBAF in THF (327 pL, 0.327 mmol) was added slowly at 0 ° C. After stirring at 0 ° C for 40 min, the reaction was quenched (saturated aqueous NaCl solution), extracted (? XEtOAc), and washed (saturated aqueous NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure.

The purification of the residue by chromatography on

627

Silica gel (12 g S1O2, 13% and 23% EtOAc / Hex) provided the title compound as a mixture of two diastereomers.

Step B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -6,6,6-trifluoro-5, 5dihydroxyhexan-3-yl) piperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) -6,6,6-trifluoro- 5-hydroxyhexan-

3-yl) piperidin-2-one previously prepared in Step A (100mg, 0.189mmol) in DCM (2.1mL) added water (17pL, 0.95mmol) and persodinan Dess-Martin (161mg, 0.378mmol) at rt and the resulting solution was stirred overnight. The reaction was quenched (1M aq. Na2S2Ü3), extracted (2 * DCM), and washed (2xsat. NaHCO3 and saturated aqueous NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a colorless film. The product was used in the next step without further purification.

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-

628

chlorophenyl) -3-methyl-2-oxo-l - ((S) -6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl) piperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl) piperidin-2one (Example 137, Step B) by a procedure similar to that described in Example .71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29 (2 H, br. S.),

EXAMPLE 138

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((3S) -7,7,7-trifluoro-6 -hydroxy-6-methylheptan-

3-yl) piperidin-3-yl) acetic (Isomer 1)

629

* unknown stereochemistry

Step A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- ('(3S, 6R) -7,7,7-trifluoro -6-hydroxy-6-methylheptan-3-yl) piperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- ( (3S, 6S) -7,7,7trif luoro-6-hydroxy-6-methylheptan-3-yl) piperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) -6-oxoheptan-3-yl) piperidin-2one (169 mg, 0.347 mmol; Example 136, Step C) in THF (3.5 mL) trimethyl (trifluoromethyl) silane (154 pL, 1.04 mmol) was added at 0 ° C and the reaction stirred for 5 min. Then 1M TBAF in THF (521 pL, 0.521 mmol) was added slowly at 0 ° C.

Then the reaction was allowed to warm to rt After

630 Stirring at rt for 1.5 was extracted (2 * EtOAc), and washed (water and saturated aqueous NaCl solution). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (40 g SiO2, 13%, 23% and 33% EtOAc / Hex) provided one of the title compounds as the least polar isomer and another of the title compounds as the most polar isomer, successively (3S, 5R, 6S) -3- allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((3S) -7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl) piperidin-2-one (least polar isomer) XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (2 H, d, J =

8.2 Hz), 7.07, - 7.20 (2 H, m), 6.91 (3 H, t, J = 1.8 Hz),

6.65 - 6.74 (1 H, m), 5.82 - 5.97 (1 H, m), 5.13 - 5.24 (2 H, m), 4.33 (1 H, d, 7 = 10.6 Hz), 3.7 8 - 3.99 (1 H , m), 3.10 -

3.26 (1 H, m), 2.64 (2 H, dd, 7 = 7.4, 4.5 Hz), 1.91 - 2.04 (2 H, m), 1.68 - 1.78 (1 H, m), 1.62 (3 H, t, J = 7.3 Hz),

1.33 - 1.46 (1 H, m), 1.29 (4 H, s), 1.25 (3 H, s), 0.94 1.13 (1 H, m), 0.84 (3 H, t, J = 7.3 Hz); MS (ESI) 556.2 [M + H]+ .

V (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-cryophonyl) 3-mefeéjy

631

MEX1C INSTITUTE OF INDUSTRIAL PROPERTY

1 - ((3S) -7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl) piperidin-2-one (most polar isomer) XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2 H, d, J =

8.4 Hz), 7.08 - 7.20 (2 H, m), 6.89 - 7.01 (3 H, m), 6.68 -

6.75 (1 H, m), 5.84 (1 H, s), 5.13 - 5.23 (2 H, m), 4.28 (1 H, d, 7 = 10.4 Hz), 3.09 - 3.22 (2 H, m), 2.62 (2 H, d, J = 7.2 Hz), 1.90 - 2.05 (2 H, m), 1.73 - 1.84 (2 H, m), 1.53 - 1.66 (3 H, m), 1.35 -1.48 (1 H, m ), 1.31 (3H, s), 1.24 - 1.29 (4H, m), 0.66 (3H, t, 7 = 7.4Hz); MS (ESI) 556.2 [M + H]+,

Stage B. Acid · 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((3S) -7,7,7 -trifluoro-6-hydroxy6-methylheptan-3-yl) piperidin-3-yl) acetic (Isomer 1)

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((3S) -7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl) piperidin-2-one (Example 138, Step A, less polar product) by a procedure similar to that described in Example 71, Step F.

'h NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2 H, d, J =

8.0 Hz), 7.14 - 7.19 (1 H, m), 7.07 - 7.13 (1 H, m), 7.01 (2

H, br. s.), 6.92 (1 H, t, J = 1.7 Hz), 6.69 (1 H, d, J = 7.6

Hz), 5.57 - 5.68 (1 H, m), 4.38 (1 H, d, 7 = 10.4 Hz), 3.52

632

EXAMPLE 139

Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-1 - ((3S) -7,7,7-trifluoro-6 -hydroxy-6-methylheptan3-yl) piperidin-3-yl) acetic (Isomer 2)

★ unknown stereochemistry

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((3S) -7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl) piperidin-2-one (Example 138, Step A, more polar product) by a procedure similar to that described in Example 71,

Stage F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, s), 7.16

633

J = 4.1

7.21 (1 H, m), 7.09 - 7.15 (1 Η, m), 7.01 (2 Ή, d

Ηζ), 6.93 (1 Η, t, J = 1.7 Ηζ), 6.72 (1 Η, d, J = 7.6 Ηζ),

5.66 - 5.74 (1 Η, m), 4.34 (1 Η, d, J = 10.2 Ηζ), 3.09 - 3.27 (2 Η, m), 2.98 (1 Η, d, J = 14.5 Ηζ), 2.74 (1 Η , d, J = 14.5 Ηζ), 2.14 - 2.24 (1 Η ,, m), 2.02 - 2.08 (1 Η, m), 1.81 (2 Η, dd, J = 14.3, 7.2 Ηζ), 1.52 - 1.70 (3 Η, m), 1.50 (3 Η, s),

1.29 - 1.38 (1 Η, m), 1.27 (3 Η, s), 0.64 (3 Η, t, J = 7.3 Hz); MS (ESI) 574.2 [M + H]+, 572.0 [MH]-.

EXAMPLE 140

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

7-hydroxy-7-methyloctan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

CI

Step A. (S) -5- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) heptanal

634

The title compound was prepared from (S) —4— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

2-oxopiperidin-l-yl) hexanal (147 mg, 0.311 mmol; Example 136, Step A) by a procedure similar to that described in Example 130, Step A.

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

1 - ((3S) -7-hydroxyoctan-3-yl) -3-methylpiperidin-2-one

To a solution of (S) -5 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) heptanal previously prepared In Step A (138 mg, 0.284 mmol) in THF (2.8 mL), 1.4M methylmagnesium bromide in toluene and THF (75:25) (608 pL, 0.851 mmol) were added at 0 ° C.

635

The reaction was then allowed to warm to rt and stirred for 2 h. The reaction was quenched (saturated NH solution4C1), extracted (2 * EtOAc), and- washed (saturated aqueous NaCl solution). The combined organic layer was dried (Na2SW4) and concentrated under reduced pressure to provide the title compound as a colorless film.

Step C. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 3-methyl-l - ((S) -7-oxooctan-3-yl) piperidin -2-one

CI

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -7hydroxyoctan-3-yl) -3-methylpiperidin-2-one previously prepared in Step B (143 mg, 0.285 mmol) by a procedure similar to that described in Example 131, Step A as a white solid.

Stage D. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

1 - ((S) -7-hydroxy-7-methyloctan-3-yl) -3-methylpiperidin-2-one

gWTWW

636

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) -7-oxooctan-3-yl) Piperidin-2-one previously prepared in Step C (122mg, 0.244mmol) in THF (2.4mL) 1.4M methylmagnesium bromide in toluene and THF (75:25) (522pL, 0.731mmol) was added at 0 C. The reaction was then allowed to warm to rt and stirred for 2 h. The reaction was quenched (saturated NH solution4C1), extracted (2xEtOAc), and washed (saturated aqueous NaCI solution). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure and purification of the residue by chromatography on silica gel (12g SiO2, 30% and 40% EtOAc / Hex) provided the title compound as a colorless foam.

Stage E. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -7-hydroxy-7-methyloctan-3-yl) -3 -methyl-2oxopiperidin-3-yl) acetic

The title compound was prepared from

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -7637 hydroxy-7-methyloctan-3-yl) -3-methylpiperidin -2-one (Example

140, Stage

D) by a procedure similar to that described in

Example 71,

Stage F.

CHLOROFORM-d) XH NMR (400 MHz, δ ppm 7.23 (2 H, d, J

[M + H], 532.2 [MH].

EXAMPLE 141

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) acid -2oxopiperidin-3-yl) acetic

CI

CQO MEXICAN INSTITUTE ÜJO D2 PROPERTY

INDUSTRIAL

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1- (methylamino) butan-2-yl) piperidin-2-one (Example 134, Step A) by procedures similar to those described in Example 134, Steps B and C, substituting the methanesulfonyl in Step B by the appropriate amount of cyclopropyl sulfonyl chloride. '

<td></td><td>XH NMR (400</td><td>MHz,</td><td>CHLOROFORM-d</td><td>j 8 ppm 7.24 (2 H,</td><td>br. s</td><td></td>

H, dd, J = 8.0, 3.9Hz), 0.51 (3 H, t, J = 7.4 Hz); EM (ESI)

581.0 [M + H]+, 579.0 [MH]-.

EXAMPLE '142

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -

1- (N-cyclopropylmethylsulfonamido) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic

639

IMPI

go to

S) -2 The title compound a ((3S, 5R, 6S) -3-allyl-5- (3-chloro'phenyl) -6- (4-chlorophenyl) -3-methyl- was prepared.

2-oxopiperidin-l-yl) butanal (Example 91, Step C) by procedures similar to. those described in Example 134, Step A-C, substituting methylamine in Step A for the appropriate amount of cyclopropylamine.

XH NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.22 - 7.27 (2 H,

m), 7.11 - 7.18 (2 H, mj, 6.81 - 7.06 (4 H, m), 4.81 (1 H, d,

J = 10.6 Hz), 4.25 - 4.41 (1 H, m), 3.08 (2 H, d, J = 15.5

Hz), 2.95 (3 H, s), 2.81 - 2.90 (1 H, m), 2.73 - 2.80 (1 H, m), 2.67 (1 H, d, J = 15.5 Hz), 2.52 (2 H, s ), 1.95 - 2.14 (1

H, m), 1.77 - 1.88 (1 H, m), 1.53 (4 H, s), 0.70 - 0.92 (3 H,

m), 0.59 - 0.69 (1 H, m), 0.50 (3 H, t, J = 7.5 Hz); EM (ESI)

581.0 [M + H] ', 579.0 [MH]-.·

EXAMPLE 143

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - (((3S) -6,6,6-trifluoro-5 -hydroxyhexan-3IMPL

il) piperidin-3-yl) acetic (Isomer 1)

* unknown stereochemistry

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 3-methyl-l - ((3S, 5S) -6,6,6-trifluorO -5-hydroxyhexan-3yl) piperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4chlorophenyl) -3-methyl-l - ('(3S, 5R) -6, 6, 6-trifluoro-5hydroxyhexan-3-yl) piperidin-2-one

To a solution of (S) -3 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) pentanal (139 mg, 0.303, mmol; Example 130, Step A) in THF (3.0 mL) trimethyl (trifluoromethyl) silane (134 pL, 0.910 mmol) was added at 0 ° C and the reaction was stirred for 5 min. Then 1M TBAF in THF (455 pL, 0.455 mmol) was slowly added at 0.641

IMPI iKicTTTirrn αχτχ'ΓΑΝΟ

MEXICAN INSTITUTE

CE INDUSTRIAL PROPERTY

° C. Then, the reaction was allowed to warm to rt. After stirring at rt for 1.5 h, the reaction was quenched (saturated aqueous NaCl solution), extracted (2 * EtOAc), and washed (saturated aqueous NaCl solution). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (24 g SiO2, 6% and 16% EtOAc / Hex) provided one of the title compounds as the least polar isomer and another of the title compounds as the most polar isomer, successively.

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((3S) -6,6,6-trifluoro-5-hydroxyhexan-3-yl) piperidin-2-one (less polar isomer) XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.15 - 7.26 (3 H, m), 7.11 (1 H, t, J = 7.7 Hz), 6.93 (3 H, t, J = 1.9 Hz),

6.68 (1 H, dt, J = 7.6, 1.5 Hz), 5.83 - 5.95 (1 H, m), 5.17 -

5.26 (2 H, m), 4.38 (1 H, d, J = 10.4 Hz), 3.69 - 3.81 (1 H, m), 3.11 - 3.22 (1 H, m), 2.66 (2 H, d, J = 7.6 Hz), 1.92 -

2.12 (3 H, m), 1.72 - 1.89 (1 H, m), 1.49 - 1.60 (1 H, m),

1.25 - 1.37 (5H, m), 1.00 (1H, 'none), 0.92 - 1.07 (3H, m); EM (ESI) 528.1 [MIH] '.-

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

642

1 - ((3S) -6,6,6-trifluoro-5-hydroxyhexan-3-yl) piperidin-2-one (most polar isomer) XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, dd, J =

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((3S, 5S) -6.6, 6-trifluoro-5-hydroxyhexan-3-yl) piperidin-3-yl) acetic (Isomer 1)

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((3S) -6,6,6-trifluoro-5-hydroxyhexan-3-yl) piperidin-2-one (Step A, less polar product) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.06 - 7.27 (6 H,

m), 6.94 (1 H, t, J = 1.7 Hz),, 6.68 (1 H, d, J = 7.6 Hz),

4.58 - 5.15 (3 H, m), 4.42 (2 H, d, J = 10.4 Hz), 3.88 - 4.01 (1 H, m), 3.19 - 3.28 (1 H, m), 2.86 (2 H, d, J = 12.7 Hz),

643

2.03 - 2.24 (2

H, m), 1.71 - 1.89 (1 H, m), 1.54 - 1.66 (3 H,

s), 1.26 - 1.40 (1 H, m), 0.97 (3 H, br.

EM (ESI)

546.0 [M4-H]+, 544.0 [MH]-.

Acid

EXAMPLE 144 methyl-2-oxo-l- ((3S) -6,6,6-trifluoro-5-hydroxyhexan-3yl) piperidin-3-yl) acetic (Isomer 2)

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((3S) -6,6,6-trifluoro-5-hydroxyhexan-3-yl) piperidin-2-one

(Example 143, Step A; more polar product) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 - 7.27 (2 H, m),

7.08 - 7.20 (2 H, m), 6.93 - 7.08 (3 H, m), 6.70 (1 H, dt, J =

7.7, 1.4 Hz), 4.49 (1 H, d, J = 10.4 Hz), 3.88 - 4.01 (1 H, m),

644

ΙΜΡΙ

ÍNS ^ rUTC · MiXICáNO

OF THE INDUSTRIAL FR0PÍ2DAD

J = 14.3, 7.2 Hz), 1.52 - 1.70 (2 H, m), 1.48 (3 H, s), 0.7¿

H, t, J = 7.5 Hz); MS (ESI) 546.0 [M + H]1, 544.0 [MH].

EXAMPLE 145

Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S) -5-hydroxyhexan-3-yl) -3-methyl-2-oxopiperidin- 3 yl) acetic (Isomer 1)

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) acid

6- (4-Chlorophenyl) -3-methyl-2-ox.ol- ((S) -5-oxohexan-3yl) piperidin-3-yl) acetic (24 mg, 0.049 mmol; Example 130) in

<td>ether</td><td>(0.40 mL) and MeOH (0.10 mL)</td><td>I know</td><td>added</td><td>borohydride</td><td>of</td>

<td>sodium</td><td>(9.26 mg, 0.245 mmol) to 0</td><td>° C.</td><td>Then</td><td>the reaction</td><td>I know</td>

<td>left</td><td>warm up to ta. Then</td><td>of</td><td>shake</td><td colspan="2">a ta during</td>

lh, the reaction was quenched (10% citric acid) and extracted (2 * EtOAc). The combined organic layer was washed (saturated aqueous NaCl solution), dried (Na2SW4), and concentrated under reduced pressure. Purification by RP-HPLC (30 to 70% MeCN / H2 <0 (0.1% TFA), at gradient elution) provided the title compound as the most polar isomer.

645

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7 99 -7

7.07 - 7.19 (2H, m), 6 '. 95 - 7.06 (3 H, m), 6.71 (1 H, dt, J =

7.6, 1.6 Hz), 4.57 (1 H, d, J = 10.2 Hz), 3.77 - 3.89 (1 H, m),

2.99 - 3.15 (2 H, m), 2.69 (1 H, d, J = 14.9 Hz), 2.23 (1 H, t,

J = 13.6 Hz), 1.81-1.99 (2 H, m), 1.52 - 1.64 (1 H, m), 1.47 (3 H, s), 1.39 (1 H, d, J = 2.0 Hz), 1.19 (3 H, d, J = 6.3 Hz),

0.60 (3H, t, J = 7.4 Hz); MS (ESI) 492.1 [M + H]+, 490.0 [MH].

EXAMPLE 146

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S) -5-hydroxyhexan-3-yl) -3-methyl-2-oxopiperidin -3yl) acetic (Isomer 2)

The additional elution from Example 145 provided the title compound as the least polar isomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.04 -7.27 (5 H, m),

6.91 - 7.04 (2 H, m), 6.70 (1 H, dt, J = 7.7, 1.5 Hz), 4.47 (1

646

1.59 - 1.71 (2 H, m), 1.50 (3 Η, s),

6.8 Hz), 1.08 - 1.21 (2 Η, m), 0.99

1.26 (1 Η, dd, J = 16.8, ι · ιι »· ι ·» · ^ - ·· n · i ·· -11 111 '~ ι ~ ι ~ πτι' m-nrrn—

1.07 (3H, m), 0.89 (3H, br. S.); MS (ESI) 492.1 [M + H]+, 490.0 [MH].

EXAMPLE 147

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

2-oxo-l - ((S) -1- (N- (2,2,2-trifluoroethyl) methylsulfonamido) butan-

2-yl) piperidin-3-yl) acetic

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l - ((S) -1 - ((2,2,2-trifIuoroethyl) amino) butan-2- yl) piperidin-2-one

To a solution of (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l647

il) butanal (104 mg, 0.234 mmol; Example 130, Step A) in CICH2CH2CI (3.9 mL) 2,2,2-trifluoroethylamine (74 pL, 0.94 mmol) and sodium triacetoxyborohydride (248 mg, 1.17 mmol) were added to rt After stirring at rt overnight, the reaction was quenched (saturated aqueous NaHCC> 3), extracted (2xEtOAc), and washed (saturated aqueous NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a white solid. The product was used in the next step without further purification.

Stage B. N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) butyl) -N- (2,2,2trifluoroethyl) methanesulfonamide

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) -1- (2,2,2-trifluoroethylamine) ) butan-2-yl) piperidin-2-one previously prepared in Step A (60.9 mg, 0.115 mmol) in DCE (770 pL) was added

DMAP (70.5 mg, 0.577 mmol) and methanesulfonyl chloride (35.9

After shaking!

648 pL, 0.462 mmol) successively at rt.

rt for 3 h, pyridine (46.7 pL, 0.577 mmol), methanesulfonyl chloride (35.9 pL, 0.462 mmol), and DCE (0.77 mL) were added and the resulting solution was stirred for 15 h. The reaction was quenched (saturated NH4CI), and extracted (3 * DCM). The combined organic layers were washed (water and saturated aqueous NaCl solution), dried (Na2SW4), and concentrated under reduced pressure. Separation by RP-HPLC (10 to 90% MeCN / H2O (0.1% TFA), at gradient elution) provided the title compound as a yellow solid.

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-2-oxo-l - ((S) -1- (N- (2,2,2- trifluoroethyl) methylsulfonamido) butan-2-yl) piperidin-3-yl) acetic

The title compound was prepared from N - ((S) —2— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl -

2-oxopiperidin-l-yl) butyl) -N- (2,2,2-trifluoroethyl) methanesulfonamide (Step B) by a procedure similar to that described in Example 71, Step F.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 - 7.28 (2 H,

m), 7.11 - 7.20 (2 H, m), 6.74 - 7.10 (4 H, m), 4.65 (1 H, d, J = 10.8 Hz), 4.32 - 4.50 (1 H, m), 4.11 (1 H , d, J = 7.8 Hz), 3.4 8 - 3.65 (1 H, m), 2.94 - 3.19 (6 H, m), 2.79 - 2.92 (1 H, m), 2.75 (1 H, d, J = 14.7 Hz), 2.42 (1 H, t, J = 13.9

649

7.4 Hz); MS (ESI) 623.0 [M + H]+, 621.0 [MH] 7

EXAMPLE 148

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (1, l-Dioxideisothiazolidin-2-yl) butan-2-yl) -3-methyl-2- oxopiperidin-3-yl) acetic

Stage A. N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopipéridin-l-yl ) butyl) -3chloropropane-l-sulfonamide

(3S, 5R, 6S) -3-Allyl-l - ((S) -1aminobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 2,2,2-trifluoroacetate - 3-methylpiperidin-2-one (76 mg, 0.14 mmol; Example 129, Step

650

B) dissolved in

DCM, basified (1 N LiOH), extracted

IMPIAS)

INSTITUTO .MEXICANO D £ LA FaOPI £ DA-D. INDUSTRIAL.

(3xDCM), and washed (saturated aqueous NaCl solution)

The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure to provide the free amine. To a solution of the free amine in DCE (0.68 mL) pyridine (55 pL, 0.68 mmol) and 3-chloropropane-l-sulfonyl chloride (96 mg, 0.54 mmol) were added successively at rt. The reaction was stirred at rt for 5h. Then additional pyridine (55 pL, 0.68 mmol) and 3-chloropropane-l sulfonyl chloride (96 mg, 0.54 mmol) were added. After stirring overnight, the reaction was quenched (10% citric acid), extracted (3 * EtOAc), and washed (saturated aqueous NaHCO3 and saturated aqueous NaCl solution). The combined organic layers were dried (Na2SW4), and concentrated under reduced pressure. Separation by RPHPLC (10 to 90% MéCN / H2O (0.1% TFA), gradient elution) provided the title compound as a yellow solid.

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

1 - ((S) -1- (1, l-dioxypisothiazolidin-2-yl) butan-2-yl) -3- methylpiperidin-2-one

651

N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3A a solution of chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) Butyl) -3-chloropropane-l-sulfonamide previously prepared in Step A (36.1 mg, 0.062 mmol) in DMF (1.2 mL) DBU (46.4 pL, 0.308 mmol) was added at rt After stirring at rt for one day to Another, the reaction was quenched (10% citric acid), extracted (3xEtOAc), and washed (NaHCO3 saturated aqueous and saturated aqueous NaCl solution). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure to provide the title compound as a light brown film.

Stage

C. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -1- (1, l-dioxideisothiazolidin-2-yl) butan -2 yl) -3-methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 (1, l- Dioxideisothiazolidin-2-yl) butan-2-yl) -3-methylpiperidin-

2-one (Stage B)) by a procedure similar to that described in XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.27 (2 H, d, J = 8.0

652

MEXICAN INSTITUTE V

DS LA Ρ 'ί.Ο -? {£ ί? ΛΏ i INDUSTRIAL Example 71, Stage F.

t, J = 7.5 Hz); MS (ESI) 567.1 [M + H]1, 565.0 [MH].

EXAMPLE 149

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((3S, 4R) -5-hydroxy-4,5-dimethylhexan-3-yl) -3-methyl-2oxopiperidin-3-yl) acetic · o Acid 2 - ((3R, 5R, 6S) -5- (3Clorophenyl) -6- (4-chlorophenyl) -1 - ((3S, 4S) -5 -hydroxy-4,5-dimethylhexan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

Stage A. (3S, 5R, .6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l - ((S) -2-oxopentan-3-yl) piperidin-2-one

To a mmol solution) in

DCM (1.5 mL) (93 pL,

1.30 mmol) shake

'653

de in for 2 min, oxalyl dichloride (78 pL, 0.87

DCM a ° C a DMSO solution (1.5 mL) was added under N2. After solution of (3S, 5R, 6S) -3-allyl-5 (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S) -2-hydroxypentan-3yl) -3-methylpiperidin-2 -one prepared in solution of Example 151, Step resulting solution

Then triethylamine

C (200 mg, 0.434

<td>mmol) in DCM (1.5 mL)</td><td>was added and</td><td>the</td>

<td>i stirred for 15</td><td>min. to -60</td><td>° C.</td>

<td>(305 pL, 2.17 mmol)</td><td>added to</td><td>the</td>

<td>i. After shaking</td><td>a ta during</td><td> 20</td>

min, reaction was quenched (water), extracted (2> <EtOAc), and washed (2x saturated aqueous NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash combi (SiO2, 24 g, 20% and 30% EtOAc / Hexanes) provided the title compound as a colorless foam.

Stage B.

((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((Sj-l-methoxy-2-methylpent-l-en-3-yl) - 3methylpiperidin-2-one

654

(Methoxymethyl) triphenylphosphonium chloride was dried at 80 ° C under vacuum for 2 h. To a solution of the dry (methoxymethyl) triphenylphosphonium chloride (673 mg, 1.96 mmol) in THF (3.5 mL) was added 0.5 M KHMDS in toluene (3.49 mL, 1.75 mmol) at -78 ° C. The solution resulted in a blood red color. After the addition, the reaction was stirred at 0 ° C for 30 min and a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl -l - ((S) -2-oxopentan-3-yl) piperidin-2one previously prepared in Step B (200 mg, 0.436 mmol) in THF (3.5 mL) was added dropwise at 0 ° C. The reaction was allowed to warm to rt and stirred for 1.5 h. Then the reaction was quenched (saturated NH solution4C1), extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash combi (SiO2, 24 g, 15% and 20% EtOAc / Hexanes) provided the title compound as a colorless film.

655

Stage C.

chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2-met'iTpéntanaÍ and (2R, 3S) -3 - ((3S, 5R / 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2-methylpentanal

OR

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -l-methoxy-2-methylpent-l-en- 3-yl) -3methylpiperidin-2-one previously prepared in Step B (179 mg, 0.368 mmol) in acetonitrile (3.7 mL) 3N hydrochloric acid (1.5 mL, 4.5 mmol) was added at rt After stirring at rt for 1.5 h, the reaction was extracted (2 * EtOAc), and washed (2> <brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure and provided the title compounds as a mixture of stereoisomers (dr = 7: 3) as a pale yellow film.

Stage D. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l - ((3S, 4R) -4-methyl-5-oxohexan-3-yl) piperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((3S, 4S) -4-methyl-5-oxohexan-3-yl) piperidin-2-one

656

To a solution of. (2S, 3S) -3- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2methylpentanal and (2R, 3S) -3 - ((3S, 5R, 6Sj-3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2methylpentanal in Stage C (177 mg, 0.375 mmol) in THF (3,076 ml) methylmagnesium bromide was added

1.4 M in toluene and THF (75:25) (0.803 ml, 1.12 mmol) at 0 ° C.

The reaction was then allowed to warm to rt and stirred for 2 h. The reaction was quenched (saturated solution

NH4CI), extracted (2xEtOAc), and washed (brine). The combined organic layer was dried (Na2SW4) and concentrated under reduced pressure to provide a crude secondary alcohol product. To a solution of the crude secondary alcohol product (183 mg, 0.375 mmol) in DCM (4.2 mL) was added water (14. pL, 0.75 mmol) and Dress-Martin periodicin (196 mg, 0.462 mmol) successively. After stirring at rt overnight, the reaction was quenched (Na2S21M aqueous O3), extracted (2xDCM), and washed (2xsat. NaHCO3 and 1xsalmuera). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. The

657

purification of the residue by chromatography on silica gel (24 g SiO2, 13%, 27% and 37% EtOAc / Hex) provided one less polar and one more polar isomer, successively.

Less polar isomer: ΧΗ NMR (400 MHz, CHLOROFORM-d) δ

<td></td><td>Isoi</td><td colspan="2">mere more polar: XH NMR (400 MHz,</td><td colspan="2">CHLOROFORM-d)</td><td>δ</td><td>ppm</td>

7.22 - 7.27 (2 H, m)., 7.01 - 7.17 (4 H, m), 6.89 - 6.95 (1 H,

m), 6.71 (1 H, dt, J = 7.5, 1.3 Hz), 5.81 - 5.93 (1 H, m),

5.17 - 5.25 (2 H, m), 4.32 (1 H, 'd, J = 10.8 Hz), 3.50 (1 H, br.s.), 3.23 - 3.32 (1 H, m), 3.06 (1 H, br. s.), 2.60 -

2.66 (2 H, m), 2.13-2.20 (3 H, m), 1.91 - 2.01 (2 H, m),

1.64 - 1.70 (2 H, m), 1.28 - 1.32 (3 H, m), 1.13 (3 H, d, J =

7.0 Hz), 0.34 (3 H, t, J = 7.5 Hz); MS (ESI) 486.1 [M + H]+.

Stage E. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

1- ((3S, 4R) -5-hydroxy-4,5-dimethylhexan-3-yl) -3-methylpiperidin-

2- one or (3S, 5R, 6S) -3-Α1Ϊ1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

IΜ PI

INSTITUTE Μ “.λΙΟΛΙ ·: 0 DE LA PKOíIEvAD

INDUSTRIAL

1 - ((3S, 4S) -5-hydroxy-4,5-dimethylhexan-3-yl) -3-methylpiperidin658

2-one

A solution of the less polar isomer previously prepared in Example 149, step D (96 mg, 0.20 mmol) in THF (2.0 mL) was added 1.4M methylmagnesium bromide in toluene and THF (75:25) (423 pL, 0.592 mmol ) at 0 ° C.

Then the reaction was allowed to warm to rt and stirred overnight

The reaction is from NH4C1), extracted (2 * EtOAc), washed (brine).

The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure.

The purification of the residue by combi-flash (12 g

S1O2, 30% EtOAc / Hex) provided the title compound as a single isomer.

Stage F. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S, 4R) -5-hydroxy-4,5-dimethylhexan-3- yl) -3methyl-2-oxopiperidin-3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S, 4S) - 5-hydroxy-4,5-dimethylhexan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

659

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S, 4R) -5-hydroxy-4 , 5-dimethylhexan-3-yl) -3-methylpiperidin-2one or (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S, 4S ) -5-hydroxy-4,5-dimethylhexan-3-yl) -3-methylpiperidin-2one (Example 149, Step E) by a procedure similar to that described in Example 129, Step D.

XH NMR (400 MHz, CHLOROFORM-d} δ ppm 7.01 - 7.27 (6 H,

EXAMPLE 150

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -5cyano-5-methylhexan-3-yl) -3-methyl- 2-oxopiperidin-3-yl) acetic

660

Stage A. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 (2,3-dihydroxypropyl) -3-methyl-2-oxopiperidin-l-yl (2S) -methyl butanoate

To a solution of 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoate of (S ) methyl (1.06 g, 2.23 mmol; Example 91, Step A) and 4-methylmorpholine 4-oxide (393 mg, 3.35 mmol) in DCM (15,800 mL) added osmium oxide (VIII) bound to the polymer, 1% DVB ( 56.8 mg, 2,234 pmol). After it was vigorously stirred at ta

<td>during 2</td><td colspan="2">days, osmium oxide · (VIII)</td><td>bound</td><td>to the</td><td>polymer</td>

<td>additional,</td><td>1% DVB (56.8 mg,</td><td>2.23 pmol)</td><td>added and</td><td>the</td><td>solution</td>

<td>resulting</td><td>vigorously</td><td>waved ta</td><td>during</td><td> 2</td><td>days. The</td>

resin was filtered and washed (DCM). The combined organic layers were washed (saturated aqueous NaCI solution),

IMPIO 'rMRTrruTG MEXICAN M - ** dried (Na2SW4), and concentrated under reduced pressure. ' The

661 Title.

Step B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl (2S) -methyl) -3-methyl-2-oxopiperidin-l-yl) butanoate

To a solution of. (S) 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2,3-dihydroxypropyl) -3-methyl-2-oxopiperidin-lyl) butanoate -methyl previously prepared in Step A (749 mg, 1.47 mmol) in DCM (8.2 mL) p-toluenesulfonic acid monohydrate (14.0 mg, 0.074 mmol) and 2,2-dimethoxypropane (8.15 mL, 66.3 mmol) were added. After stirring at rt for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved (EtOAc and saturated aqueous NaHCO3) and extracted (3 * EtOAc). The combined organic layers were washed (saturated aqueous NaCl solution), dried (Na2SW4), and concentrated under reduced pressure. Purification by chromatography on silica gel (SiO2, 40 g, 27% and 37% of

662

MEXICAN INSTITUTE

<td>EtOAc / Hexanes)</td><td>OF THE PROPERTY INDUSTRIAL provided the title compound as a</td>

colorless film.

Step C. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -35 ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -1 - ((S) -1-hydroxybutan-

2-yl) -3-methylpiperidin-2-one

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl ) -3-methyl-

(2S) -methyl 2-oxopiperidin-l-yl) butanoate previously prepared in Step B (734 mg, 1.34 mmol) in ether (12.2 mL), lithium borohydride (58.3 mg, 2.68 mmol) was added at 0 ° C . After stirring at 0 ° C for 30 min, the reaction was quenched (10% ice cold citric acid) was extracted (2 * EtOAc) and reduced, and provided the title compound as a colorless film. The product was used in the next step without further purification.

washed (saturated aqueous NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under pressure

IMPI or 6 J MEXICAN INSTITUTE

OF THE PRO? 'AGE

INDUSTRIAL

Stage D. (2S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2,2-dimethyl-1,3-dloxolan-4- il) methyl) -3-methyl-

2-oxopiperidin-l-yl) butanal

The title compound was prepared from (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2,2-dimethyl-

1,3-dioxolan-4-yl) methyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methylpiperidine-2-one (Example 150, Step C) by a procedure similar to that described in Example 91, Stage C.

Step E. (4S) -4- ((3R, 5R, .6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2,2-dimethyl-l, 3-dioxolan-4 -il) methyl) -3-methyl-

2-oxopiperidin-l-yl) hex-2-ene nitrile

To a solution of diethyl cyanomethylphosphonate (126 pL, 0.799 mmol) and DMPU (481 pL, 3.99 mmol) in THF (1.33 mL) was added 60% sodium hydride in mineral oil (24.0 mg,

0.599 mmol) at 0 ° C. 'The mixture was stirred for 30 min

664 It was then treated with a solution of (2S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2,2-dimethyl-l, 3- dioxolan-4yl) methyl) -3-methyl-2-oxopiperidin-l-yl) butanal previously prepared in Step D (207 mg, 0.399 mmol) in THF (1.33 mL). After stirring for 4 h, the reaction was quenched with aqueous

NaCl). The combined organic layers were dried (Na2SW4) were concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (24 g SIO2, 30 to 40% EtOAc / Hex) (gradient elution) provided the title compound as a colorless liquid.

Stage F.

(4S) -4 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -3 - ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -3-methyl-

2-oxopiperidin-l-yl) hexanonitrile

To a solution of (4S) -4 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3 - ((2,2-dimethyl-l, 3-dioxolan- 4-yl) methyl) -3methyl-2-oxopiperidin-l-yl) hex-2-enenitrile previously prepared in

IMPI

O 65 MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL Stage E (208 mg, 0.384 mmol) in EtOH (12.8 mL) 10% palladium on activated carbon (40.9 mg, 0.038 mmol) was added. Then the reaction mixture was subjected to regular hydrogenation with hydrogen (0.774 mg, 0.384 mmol). After stirring at rt for 1.5 h, the catalyst was filtered using a short plug of silica gel and washed (EtOAc). The combined organic solutions were concentrated under reduced pressure. Combi flash purification (flash column chromatography, Teledyne Isco, Lincoln, NE) (SiO2, 24 g, 35% and 40% EtOAc / Hexanes) provided the title compound as a colorless film.

Step G. (4S) -4 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2,2-dimethyl-l, 3-dioxolan-4- il) methyl) -3-methyl-

2-oxopiperidin-l-yl) .- 2,2-dimethylhexanonitrile

To a solution of (4S) -4 - ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3 - ((2, .2-dimethyl-l, 3-dioxolan -4-yl) methyl) -3methyl-2-oxopiperidin-l-yl) hexanonitrile prepared in Step

F (120 mg, 0.221 mmol) in THF (1.10 mL) was added

666

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY 2M lithium diisopropylamide (552 pL, 1.10 mmol) at -78 ° C. After stirring for 5 min at -78 ° C, iodomethane (94 pL, 1.51 mmol) was added and the resulting solution was stirred at -78 ° C for 30 min. The reaction was then allowed to warm to rt and stirred overnight. The reaction was quenched (saturated aqueous NH4CI) and extracted (2xEtOAc) and the combined organic layers were washed (saturated aqueous NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Purification by chromatography on silica gel (SiO2, 30% and 40% EtOAc / hex) provided a mixture of dimethylated product and monomethylated product, which was re-subjected to methylation conditions

described below.

To a solution of the crude product from the previous reaction in THF (1.10 mL) was added 2M lithium diisopropylamide in heptane / THF / ethylbenzene (552 pL, 1.10 mmol) at -78 ° C. After stirring for 5 min at -78 ° C, iodomethane (94 pL, 1.51 mmol) was added and the resulting solution was stirred at -78 ° C for 30 min. The reaction was then allowed to warm to rt and stirred overnight. The reaction was quenched (NH4Saturated aqueous C1) and extracted (2xEtOAc) and the combined organic layers were washed (saturated aqueous NaCl solution), dried (Na2SW4), and concentrated under reduced pressure. Purification by RP-HPLC (60 to 90% MeCN / H2O (0.1% TFA),

gradient elution) provided the title compound.

667

Stage H. (4S) -4 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2,3-dihydroxypropyl) -3-methyl-2-oxopiperidin- lil) -2,2-dimethylhexanonitrile

To a solution of (4S) -4 - ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3 - ((2,2-dimethyl-l, 3-dioxolan- 4-yl) methyl) -3methyl-2-oxopiperidin-l-yl) -2,2-dimethylhexanonitrile previously prepared in Step G (77 mg, 0.135 mmol) in THF (2.69 mL) 3N hydrochloric acid was added in water ( 1.35 pL, 4.04 mmol) at rt After stirring at rt for 4 h, the reaction was diluted (sat. Aq. NaCl) and extracted (2xEtOAc). The combined organic layers were washed (saturated aqueous NaCl solution), dried (Na2SO4), and concentrated under reduced pressure to provide the title compound as a colorless foam.

Stage I. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -5-cyano-5-methylhexan-3-yl) - 3-methyl-2IMPI

668 oxopiperidin-3-yl) acetic

The title compound was prepared from (4S) —4— ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2,3 dihydroxypropyl) -3 -methyl-2-oxopiperidin-l-yl) -2,2 dimethylhexanonitrile previously prepared in Step H by a procedure similar to that described in Example 71, Step F.

<td></td><td></td><td>XH</td><td>NMR (400 MHz,</td><td colspan="3">CHLOROFORM-d.) Δ ppm 7.27 (2 H,</td><td>s)</td><td> , 7.00</td>

EXAMPLE 151

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3- methyl-2-oxo-l - ((S) -2-oxopentan-3-yl) piperidin-3-yl) acetic

Stage A.

(3S, 5R, 6S) -3-Á1Í1-5- (3-chlorophenyl) -6- (4669 chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methylpiperidin-2 one

To a solution of 1004 g (1.47 mol) of (3S, 5R, 6S) -3alyl-1 - ((S) - 1— ((tert-butyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one (Example 185, Step E) in THF (3.0 L) 2.50 L (2.50 mol) of a 1M solution of TBAF in THF was added over a period of 10 min. The orange solution was stirred at room temperature for 4 h. The reaction was quenched with HC1 IN (3 L) and extracted with EtOAc (3X). The combined organic layers were washed with a mixture of water and 3: 1 saturated aqueous sodium chloride (4X) and then saturated aqueous sodium chloride (IX). The organic layer was dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by chromatography (Biotage® Snap ™ column; Biotage, LLC, Charlotte, NC), 10 to 50% EtOAc / hexanes, where EtOAc contains 2% MeCN, gradient elution) provided the title compound as a white foam.

ΓΜΡΙ

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL (S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl)

670

Stage B.

(4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanal

To a solution of 428 g (959 mmol) of (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxybutan-2-yl) -3-methylpiperidin-2-one (Example 151, Step A) in dichloromethane (4.55 L) 25.9 mL (1.44 mol) of water was added. A solution of 610 g (1.44 mol) of Dess-Martin periodicin in dichloromethane (4.55 L) was added slowly over a period of 25 min in order to maintain an internal reaction temperature not to exceed 25 ° C. The white suspension was stirred for 2.5 h and then quenched by the slow and careful addition of saturated aqueous sodium thiosulfate (5.2 L) in order to maintain an internal reaction temperature below 30 ° C. Water was added and the mixture was extracted with dichloromethane (3X). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (4X) and then saturated aqueous sodium chloride (IX), dried over Na2SO¿, filtered, and the filtration product concentrated to an oily yellow solid. A mixture of ethyl

671

IMPI

M.fX'CANO INSTITUTE

D £ LA PRC '? (INDUSTRIAL cDaD

<td>ether and DCM</td><td>added,</td><td>and</td><td>leaked</td><td>by</td><td>full</td><td>the</td>

<td>solids</td><td colspan="2">precipitates.</td><td>The</td><td colspan="2">process</td><td>of</td>

<td colspan="2">precipitation / filtration</td><td>I know .</td><td>he repeated.</td><td>The</td><td>product</td><td>of</td>

<td>filtration</td><td>: concentrated</td><td colspan="2">to provide</td><td>the</td><td>compound</td><td>of the</td>

<td>title like</td><td>a solid</td><td>White</td><td colspan="2">The product</td><td>raw it</td><td>use</td>

directly into the next stage.

Stage C. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

1 - ((3S) -2-hydroxypentan-3-yl) -3-methylpiperidin-2-one

To a 0 ° C solution of 399 g (899 mmol) of (S) —2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) - 3-methyl-2-oxopiperidin-l-yl) butanal (Example 151, Step B) in THF (9 L) 1.93 L (2.70 mol) of a 1.4 M solution of methylmagnesium bromide in toluene / tetrahydrofuran was added slowly during a period of 30 min in order to maintain an internal reaction temperature below 6 ° C. The yellow solution was warmed to room temperature and stirred for 1.5 h. At this time the reaction was cooled to 0 ° C and quenched by the slow and careful addition of saturated aqueous ammonium chloride (4.6 L) in order to maintain a

internal reaction temperature below 15 ° C. The mixture is

672 Warmed to room temperature, ethyl acetate was added, and the layers were separated. The aqueous layer was extracted with EtOAc (2X). The combined organic layers were washed with water (IX) and then saturated aqueous sodium chloride (IX), dried over

Na2SO4, filtered and the filter product concentrated to a yellow oil. Purification of the residue by chromatography on silica (Biotage® Snap ™ column; Biotage, LLC, Charlotte, NC), 5% acetone / 5% EtOAc / 90% hexanes ranging up to 5% acetone / 29% EtOAc / 66% hexanes ) provided the title compound as a white solid.

Stage D. Acid .2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -2-oxopentan-3 -il) piperidin-

3-yl) acetic

Ruthenium (III) chloride hydrate (1,404 g, 6.23 mmol) was added to a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((3S) -2-hydroxypentan-3-yl) -3methylpiperidin-2-one (Example 151, Step C) (130.30 g, 283 mmol) and NaIO4 (61.5 g) in EtOAc (630 mL), CH3CN (630 mL), and water (935 mL) at 18 ° C. The NaIO4 Remaining (307.5 g) was added in five portions over 2.5 hours while maintaining the temperature below 2-6 'C. 15 minutes after the final addition of NaIO4 the cooling bath was removed and the '673

minute mix.

The reaction was stirred at room temperature for 50. The tan reaction mixture was filtered using a Büchner funnel and washed with EtOAc (500 mL) and CH3CN (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc twice. Organic compounds accumulated, washed with 10% aqueous NaHSO3 (3 x 1 L), brine (1 L), dried (Na2SW4), decanted and concentrated in vacuo to provide a green oil. The material was dissolved in a minimal amount of DCM and purified using two columns of

1.5 kg Biotage® Snap ™ (Biotage ,. LLC, Charlotte, NC) and eluting with 10-50% (15% .MeOH / acetone) / hexanes to provide a light pink foam (109.67 g).

XH NMR (400 MHz, CHLOROFORM-d) 6ppm 7.25 (2 H, d, J =

8.2 Hz), 6.93 - 7.18 (5 H, m), 6.73 - 6.80 (1 H, m), 4.47 (1

EXAMPLE 152

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2-hydroxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic

To a solution of 3.86 g (8.13 mmol) of acid 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-

1 - ((S) -2-oxopentan-3-yl) piperidin-3-yl) acetic (Example 151) in THF (102 mL) a 1M solution of sodium tri-secbutylborohydride (N-Selectride®, Aldrich) was added , St. Louis, MO) in THF (16.26 mL, 16.26 mmol) at -78 ° C dropwise over a period of 5 min. After stirring at -78 ° C for 30 min, the reaction was allowed to warm to rt The reaction was stirred at rt for 2 h, the reaction was quenched (saturated NH4CI solution), extracted (3 * EtOAc) and washed (3 * aqueous HCI IN ice cold and 3 * aqueous saturated sodium chloride). The combined organic layers were dried over Na2SO4, filtered, and the filter product was concentrated under reduced pressure. The crude material was purified by chromatography on a Biotage Isolera Instant Purification System (Biotage, Charlotte, NC) (2 columns x 1500 g, using a gradient from 10-30% (15% MeOH / acetone) in hexanes. The purified material it was then recrystallized from hexane / acetone 3: 1 (8 mL / g) to provide the compound

IMPI XH NMR (500 MHz, DMSO-d6) δ ppm 0.30 (t, J = 7.6 Hz, 3

675 of the title.

H), 7.17-7.27 (m, 4H), 7.33 (d, 7 = 8.4 Hz, 2H), 12.42 (br s, 1H); MS (ESI) 478.2 [M + H], 476.2 [MH]. [to]D = + 110 ° (T = 23 ° C, MeOH, c = 0.51).

Alternatively the title compound can be prepared from (3S, 5R, 6R) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one as prepared in Example 261 step F.

To a 10 mL round-bottom reaction flask was added (3S, 5R, 6Rj-3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyltetrahydro-2H-pyran-2-one ( 750 mg, 1,998 mmol), (2S, 3S) -3-aminopentan-2-ol hydrochloride (837 mg, 6.00 mmol, reference: 7. Org Chem., 2003, 68 (26), 9948), and triethylamine ( 1966 μΐ, 13.99 mmol.) The vessel was coupled with a reflux condenser and heated to 85 to 95 ° C for 2d.The reaction was cooled to rt. and diluted with ethyl acetate and washed with HCI IN (2 X 20 mL) and brine.

The organic layer was dried over. Mg.S04/ leaked, and

676

INSTITUTE Μ.ΞΧ ~

concentrated.

DE LA FRO ' T . z , INDUSW ..., __

Purification by column chromatography using 40 to 50% ethyl acetate in hexanes resulted in (S) -2 - ((2R, 3R) -2- (3-chlorophenyl) -3- (4-chlorophenyl) -3 hydroxypropyl) -N - ((2S, 3S) -2-hydroxypentan-3-yl) -2-methylpent-

4-enamide.

<td></td><td> 7.14</td><td> -7.08</td><td>(series of m,</td><td>2H), 6.97</td><td>(m, 2H), 6.88</td><td>(br d, J = 6.9</td>

ppm. LC / MS (M + H) = 478.2.

To a solution of (S) -2 - ((2R, 3R) -2- (3-chlorophenyl) -3- (4chlorophenyl) -3-hydroxypropyl) -N - ((2S, 3S) -2-hydroxypentan-3yl ) -2-methylpent-4-enamide (127 mg, 0.265 mmol) in toluene (5309 μΐ) Ammonium molybdate ((NH4) 2Mo04) (5.20 mg,

0.027 mmol) and heated to reflux under DeanStark conditions overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, and

677 IMPI θ '' MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL washed with NaHCC> 3 saturated and brine. The organic compounds were dried over MgSO4, filtered and concentrated. Purification by column chromatography using 20 to 40% ethyl acetate in hexanes resulted in (IR, 2R, 4S) -2- (3-chlorophenyl) -1- (4-chlorophenyl) -4 - ((4S, 5S) -4 -ethyl-5-methyl-4,5-dihydrooxazol-2-yl) -4-methylhept-6.-en-l-ol.

ΤΗ NMR (500 MHz, DMSO-d6) 5 7.25 (m, 2H), 7.12 (m, 2H),

7.07 (br s, IH), 7.05 (m, 2H), 6.96 (br d, J = 6.8 Hz, IH),

5.53 (ddt, J = 17.4, 10.3, 7.4 Hz, IH), 5.42 (d, J = 4.2Hz,

IH), 4.95 (m, 2H), 4.66 (t, J = 4.9 Hz, IH), 3.56 (dq, J =

7.6, 6.1 Hz, IH), 3.12 (q, J = 7.1 Hz, IH), 2.90 (ddd, (9.5,

5.1, 2.3Hz, IH), 2.20 (m, 2H), 1.93 (dd, J = 13.7, 7.8 Hz, IH), 1.75 (dd, J = 14.3, 2.2 Hz, IH), 1.11 (m, IH), 1.10 (d,

J = 6.4 Hz, 3H), 0.98 (m, IH), 0.97 (s, 3H), 0.75 (t, J = 7.6 Hz, 3H) ppm. LC / MS (M + H) = 460.2.

To a solution of (IR, 2R, 4S) -2- (3-chlorophenyl) -1- (4-chlorophenyl) -4 - ((4S, 5S) -4-ethyl-5-methyl-4,5-dihydrooxazol-2 yl) -4-methylhept-6-en-l-ol (80 mg, 0.174 mmol) in CH2C12 (1737 pl) at -50 ° C was added

2,6-lutidine (46.4 pl, 0.400 mmol) followed by solution of 1M trifluoromethanesulfonic anhydride in methylene chloride (191 pl, 0.191 mmol). The reaction was stirred at

-50 ° C for trifluoromethanesulfonic anhydride, 1 M in chloride of min and then treated with an additional 25 uL of

678 methylene, then 2 mL of CuSO4 heated to rt and extracted organic dried over MgSO4, will be saturated. The reaction was filtered and concentrated with dichloromethane.

Purification by column chromatography using 40 to acetone in hexanes resulted in triflate of (2S, 3S, 5S, 6R, 8S) -

8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io.

<td></td><td>XH</td><td>NMR (</td><td colspan="2">500 MHz, DMSO-d6)</td><td colspan="2">δ 7.55-7.05 (series of</td><td>m,</td><td>8H),</td>

<td> 2.0</td><td>Hz,</td><td>IH),</td><td> 5.18</td><td>(quintet, J</td><td>= 6.1 Hz, IH),</td><td> 4.10</td><td>(td</td><td>, J =</td>

IH) ppm. LC / MS (M + = 442.2).

To a solution of. (2S, 3S, 5S, 6R, 8S) -8-allyl-6 (3-chlorophenyl) -5- (4-chlorophenyl) -3-ethyl-2,8-dimethyl- triflate

2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io (60 mg, 0.101 mmol) in 1 mL dichloromethane at 0 ° C tetran-butylammonium chloride (2.81 mg) was added , 10.13 pmol) and acetic acid (116 pl, 2,025 mmol). KMnO was added to this4 (32.0 mg, 0.203 mmol) in

mL water followed by a 1 mL rinse of water.

679 Additional equivalents of acetic acid were added followed by 16 mg KMnO4 additional in 1 mL water. This is

<td>repeated once</td><td>plus. A total</td><td>of 4</td><td>eq</td><td>from KMnO4</td><td>and</td><td>40 eq.</td><td>of</td>

<td>acetic acid is</td><td>added.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="2">The reaction was quenched</td><td>with 1</td><td>mL</td><td colspan="2">from solution</td><td colspan="2">saturated</td>

<td>welcome2S2OR3 and</td><td colspan="2">diluted with acetate</td><td>of</td><td>ethyl.</td><td>The</td><td>layers</td><td>I know</td>

separated and the organic phase was washed once with brine, dried over MgSO4, filtered and concentrated to give (2S, 3S, 5S, 6R, 7aR) -6- (3-chlorophenyl) -5- (4chlorophenyl) -3-ethyl-2,7a-dimethylhexahydrofuro [2,3b] oxazolo [ 3,2-a] pyridin-9 (5H) -one crude. This crude residue was redissolved in 2 mL of isopropyl acetate and treated with 2 mL of NaHCO3 saturated and heated to 70 ° C. After 2h, the reaction was cooled to 0 ° C and treated with 10% acetic acid to a pH of about

3. The reaction was diluted with ethyl acetate and washed once with 10% acetic acid solution, dried over MgSO4, filtered, and concentrated. Purification by column chromatography using 10 to 50% of (15% MeOH / acetone) in hexanes resulted in 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) - acid. 1 - ((2S, 3S) -2-hydroxipentan-

3-yl) -3-methyI-2-oxOpiperidin-3-yl) acetic.

EXAMPLE 153

680 ·

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2-methoxypentan-3-yl) -3-methyl-2 -oxopiperidin-3yl) acetic

Stage A. 2 - ((3RZ5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2-hydroxypentan-3-yl) -3-methyl-2-oxopiperidin-3yl) acetate methyl

260 ma (0.543 mmol) 2Cl acid

To a solution of ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((2S, 3S) -2hydroxipentan-3-yl) -3-methyl-2 -oxopiperidin-3-yl) acetic (Example 152) In 5 mL of THF 60% sodium hydride (217 mg, 5.43 mmol) was added at 0 ° C. After stirring to 0pC for 20 min, iodomethane (271 uL, 4.35 mmol) was added. The reaction was allowed to warm to room temperature, and

IMPI

'681 was stirred for an additional 3 hr until completion. The reaction was quenched with saturated aqueous NH4CI solution, extracted with EtOAc (2 x 25 mL). They were washed with saturated NaCI, filtered and the product of providing the compound of the combined organic layers was dried over MgSO4, filtration concentrated for title.

Stage B. 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2-methoxypentan-3-yl) -3-methyl -2-oxopiperidin-3yl) methyl acetate

To a 50 mg (0.102 mmol) solution of 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((2S, 3S) -2-hydroxypentan- Methyl 3yl) -3-methyl-2-oxopiperidin-3-yl) acetate (Example 153, Step A) In 0.3 mL of DMF 60% sodium hydride (20.31 mg, 0.508 mmol) was added at 25 ° C. After stirring at 25 ° C for 20 min, iodomethane (25.4 uL, 0.406 mmol) was added. The reaction was stirred for an additional 30 min and quenched with saturated aqueous NH solution4C1, was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with NaCI

IMPI

saturated, dried over

MgSO4, were filtered and the product of

682 Filtration was concentrated.

Purification of the residue by flash chromatography on silica gel (eluent:

up to 60% of

EtOAc / hexanes) provided the title compound.

Stage

chlorophenyl) -1 - ((2S, 3S) -2-methoxipentan-3-yl) -3-methyl-2 oxopiperidin-3-yl) acetic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((2S, 3S) -2-meto.xipentan-3-ylj-3- methyl-2-oxopiperidin-3-yl) methyl acetate (34 mg, 0.067 mmol; Example 153, Step B) in THF / MeOH / H2Or (1/1/1, 0.48 mL) 2M lithium hydroxide (67 uL, 0.134 mmol) was added at rt.

After stirring at rt for 4 h, the reaction was quenched with saturated aqueous NH solution4C1 and extracted (2 * DCM) and the combined organic layers were washed (1 * aqueous saturated NaCl solution) and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 70 to 100% EtOAc / hexanes) provided the. title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.38 (t, J = 8.0 Hz, 3

H), 1.05 (d, J = 4.0 Hz, 1H), 1.48 (s, 3H), 1.65 (m, 1H),

1.75 (m, 1H), 2.00 (dd, J = 12.0, '4 Hz, 1H), 2.21 (m, 1H),

683

2. 48 (m, 1 Η), 2.70 (d, J = 16.0 Hz, 1 H)

IMPI

MACANO INSTITUTE

Dt LA PFCnIE-JAD INDUSTRIAL

3.06-3.15 (m, 2H),

3.41 (s, 3H), 3.94 '(m, 1H), 4.63 (d, J = 12.0 Hz, 1H), 6.75 (d, J

8.0 Hz, 1H), 6.90-7.05 (m, 3H), 7.05-7.15 (m, 2H),

7.25 (d, J = 8.0 Hz, 2H); MS (ESI) 492.1 [M + H]+.

EXAMPLE 154

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2R, 3S) -2-hydroxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic

A solution of acid, 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -l-oxobutan-2 -yl) piperidin-3yl) acetic (71 mg, 0.154 mmol) (Example 210, Step A) in THF (2 mL) was bubbled with argon for 5 minutes. The mixture was cooled to 0 ° C and methylmagnesium chloride, 3.0 M solution in tetrahydrofuran (0.113 ml, 0.339 mmol) was added at such a rate that the internal temperature did not reach above 4 ° C. The mixture was stirred at 0 ° C for 45 minutes. The mixture was quenched with saturated aqueous NH solution4C1 and extracted with EtOAc. The combined organic layers were dried over Na2SO4were filtered and the filter product was

684 The residue was purified by flash chromatography on silica gel (2 x 4 g stacked columns, eluent: 5 to 15% isopropanol / hexanes) to give the title compound as the most polar diastereomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 (t, J = 7.63 Hz, 3 H), 1.18 (d, J = 6.65 Hz, 3 Η), 1.44 (s, 3 Η), 1.63 - 1.77 ( m, 1 H), 1.99 - 2.18 (m, 3 Η), 2.61 - 2.71 (m, 1 Η), 2.81 (d,

J = 14.28 Hz, 1 H), 2.92 (d, J = 14.48 Hz, 1 Η), 3.24 (td, J = 10.22,

5.77 Hz, 1 Η), 4.11 - 4.22 (m, 1 Η), 4.45 (d, <J = 10.17 Hz, 1 Η),

6.74 (dt, J = 7.53, 1.61 Hz, 1 Η), 6.93 - 7.05 (m, 3 Η), 7.07 -

7.14 (m, 1H), 7.15 - 7.20 (m, 1 Η), 7.24 - 7.31 (m, 2H). Mass Spectrum (ESI) m / e = 478.1 (M + l).

EXAMPLE '155

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3R) -2-hydroxypentan-3-yl) -3-methyl-2 acid -oxopiperidin-3yl) acetic (isomer 1)

* stereochemistry was not confirmed

685

Stage A.

(R) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-

chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanal

The title compound was prepared from (3S, 5R, 6S) '- 3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) - ^ 1- ((R) -1hydroxybutan-2- yl) -3-methylpiperidin-2-one by a procedure similar to that described in Example 91, Step B. The product was used in the next step without further purification.

1— ((3R) -2-hydroxipentan-3-yl) -3-methylpiperidin-2-one

The title compound was prepared from (R) -2-

2-oxopiperidin-l-yl) butanal (Example 155, Step A) as described in Example 149, Step A. Purification by ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

686 flash chromatography (SiO2, 40 g,

EtOAc / hexanes) provided the title compound as a mixture of two diastereomers at the newly formed stereocenter.

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxo-l - ((R) -2-oxopentan-3 -il) piperidin-

3-yl) acetic

from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((3R) -

2-hydroxypentan-3-yl) -3-methylpiperidin-2-one (0.210 g, 0.456 mmol; Example 155, Step B) by a procedure similar to that described in Example 71, Step F.

Stage D. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((2S, 3R) -2-hydroxypentan-3-yl) -3-methyl acid -2oxopiperidin-3-yl) acetic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((R) -2-oxopentan) acid -3687

il) piperidin-3-yl) acetic (0.150 g, 0.315 mmol, Example 155,

Step C) In THF / MeOH (3/1, 4 mL) sodium borohydride (0.060 g, 1,574 mmol) was added at room temperature. After stirring at room temperature for 1 h, the reaction was acidified with saturated aqueous NH Cl solution and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCI solution, dried over MgSO4, filtered and the filter product concentrated under reduced pressure. The crude material was purified by preparative reverse phase HPLC (eluent: 10-90% acetonitrile, water, 0.1% TFA, gradient elution) to give a mixture of two isomers (dr = 93: 7). Individual stereoisomers were separated by chiral HPLC (250 x 30 mm CHIRALPAK® IC column (CHIRAL TECHNOLOGIES, INC., West Chester, PA, USA) with 46 g / min isopropylamine + (20 μΜ NH3) + 84 g / min CO2 in Thar 350 SFC (Thar Technologies, Inc., Pittsburg, PA)) to give the title compound as the fastest eluting stereoisomer.

XH NMR (400 MHz, CHLOROFORM-d) δρριη 0.61 (d, J = 6.65 Hz,

IMPI

688

Η),

7.20-7.32 (m, 2 Η). EM (ESI)

478.0 [Μ + H].

The additional elution provided Example 156.

EXAMPLE 156

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l ((2R, 3R) -2-hydroxypentan-3-yl) -3-methyl-2 -oxopiperidin-3yl) acetic

* stereochemistry was not confirmed

Example 155, Step D; slower elution isomer of chiral HPLC.

XH NMR (400 MHz, CHLOROFORM-d) opm 0.81 (d, J = 6.46 Hz,

H), 1.01 (t, J = 7.43 Hz, 3 Η), 1.47 (s, 3 Η), 1.64 (m, 1 Η), 1.82 - 1.95 (m, 1 Η), 2.13 - 2.25 (m, 2 Η ), 2.73 - 2.84 (m, 2H), 2.93 (d, 7 = 14.87 Hz, 1 Η), 3.37 (m, 1 Η), 3.93 (m, 1 Η), 4.45 (d, 7 = 10.56 Hz, 1 Η), 6.72 (d, 7 = 7.43 Hz, 1 Η), 6.96 (m, 1 Η), 7.02 - 7.17 (m, 4 Η), 7.21 (m, 2 H); Mass Spectrum (ESI) m / z = 478.0 (M + l).

689

EXAMPLE 157

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

2-hydroxy-2-methylpentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

1 - ((S) -2-hydroxy-2-methylpentan-3-yl) -3-methylpiperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) -2-oxopentan-3-yl) piperidin-2one (0.100 g, 0.218 mmol; Example 149, Step B) in THF, (4 mL) a solution of methylmagnesium bromide, 1.4M in toluene (0.104 g, 0.873 mmol) was added at 0 ° C. The reaction was allowed to warm to room temperature. After stirring at room temperature for 4h, another 1 eq. of MeMgBr was added and stirred for another 2h. The reaction was quenched with saturated NH solution4C1, and extracted with EtOAc. The

690

Combined organic layers were washed with saturated aqueous NaCl solution, dried - over MgSO4, filtered and the filter product concentrated under reduced pressure. The crude material was absorbed on top of a plug of silica gel and purified by chromatography on silica gel, eluting with 40% EtOAc / hexanes, to provide the title compound as a light yellow oil.

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -2-hydroxy-2-methylpentan-3-yl) -3 acid -methyl-2oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -2hydroxy-2-methylpentan- 3-yl) -3-methylpiperidin-2-one (Example 157, Step A) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.37 (t, 7 = 7.63 Hz, 3

H) 1.10 (s, 3 H) 1.35 (s, 3 H) 1.50 (s, 3 H) 1.68 (ddd, 7 = 15.21,

7.78, 4.01 Hz, 1H) 2.10 - 2.31 (m, 3H) 2.44 - 2.55 (m, 1H)

2.78 - 2.95 (m, 2H) 3.24 - 3.37 (m, 1H) 4.40 (d, 7 = 10.56 Hz, 1

H) 6.73 (dt, 7 = 7.53, 1.52 Hz, 1 H) 6.95 (m, 1 H) 7.01 - 7.21 (m,

H) 7.21 - 7.38 (m, 2H). MS (ESI) 492.2 [Μ + H].

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1691

EXAMPLE 158 ((3S, 4S) -4-hydroxyhexan-3-yl) -3-methyl-2-oxopiperidin-3 yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenylj- 6- (4-chlorophenyl) -1 - ((3S, 4R) -4-hydroxyhexan-3-yl) -3-methyl-2oxopiperidin-3-yl) acetic

Stage A.

(3S, 5R, 6S) -3-Α1Ϊ1-5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -4-hydroxyhexan-3-yl) -3-methylpiperidin-2one

The title compound was prepared from (S) -2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl2-oxopiperidin-l -yl) butanal (Example 91, Step C) and ethylmagnesium bromide as described in Example 149, Step A.

The raw material was used in the next stage without

IMPI

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4692 further purification

Stage B.

chlorophenyl) -3-methyl-2-oxo-l - ((S) -4-oxohexan-3-yl) piperidin-3yl) acetic

The title compound 'was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -4hydroxyhexan-3-yl ) -3-methylpiperidin-2-one (Example 158, Step

A) as described in Example 71, Step F.

Stage C. Acid. 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S) -4-hydroxyhexan-3-yl) -3-methyl-2oxopiperidin-3-yl )acetic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2-oxo-l - (((S) -4-oxohexan -3yl) piperidin-3-yl) acetic (0.038 g, 0.077 mmol; Example 158, Step B) In a mixture of THF and methanol (4: 1, 5 mL) sodium borohydride (9 mg, 0.24 mmol) was added at Ó ° C. Then the reaction was allowed to warm to room temperature. Then

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY stirring at room temperature for 1.5 h, another 2 eq. of sodium borohydride were added and stirred for another 0.5h. The reaction was acidified (10% citric acid) and extracted (2 * EtOAc). The combined organic layers were washed (saturated aqueous NaCl solution), dried (MgSO4), and concentrated under reduced pressure. The crude material was purified by preparative reverse phase HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to give the title compound as the first elution fraction as a white solid after lyophilization.

<td colspan="2">XH NMR</td><td colspan="3">(400 MHz, CHLOROFORM-d)</td><td>δ ppm</td><td colspan="2">0.55 (t, <7 = 7.53</td><td>Hz,</td>

EXAMPLE 159

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) l-methoxybutan-2-yl) -3-methyl-2-oxopiperidin -3-yl) acetic

694

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

Stage A. (3S, 5R, 6S) -3-ali'l-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

1 - ((S) -l-methoxybutan-2-yl) -3-methylpiperidin-2-one

To a 50 mg (0.112 mmol) solution of (3S, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1-hydroxybutan-

2-yl) -3-methylpiperidin-2-one (Example 91, Step B) In 0.5 mL of THF 60% sodium hydride (8.96 mg, 0.244 mmol) was added at 0 ° C. After stirring at 0 ° C for 30 min, iodomethane (14.01 uL, 0.244 mmol) was added. The reaction was allowed to warm to 25 ° C, and was stirred for an additional 2 hr until complete. The reaction was quenched with saturated aqueous NH solution4C1, extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with saturated NaCI solution, dried over MgSO4, leaked and the

filtration product is

695 concentrated

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY to provide title compound.

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-methoxybutan-2-yl) -3-methyl-2oxopiperidin acid -3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -

3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-methoxybutan-2 yl) -3-methylpiperidin-2-one (Example 159, Step A) by a procedure similar to that described in Example 71, Step F. The residue was purified by reverse phase preparative HPLC (MeCN in water with 0.1% TFA, gradient elution) to give the title compound as a white solid.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (t, J = 8.0

Hz, 3H), 1.42 (s, 3H), 1.50 (m, 1H), 1.93 (m, 1H), 2.02 (dd, J = 12.0, 4.0 Hz,. 1H), 2.18 (dd, J = 12.0, 12.0 Hz, 1 H), 2.71 (d, J = 16.0 Ηζ, Ι H), 3.05 (d, J = 12.0 Hz, 1 H),

2.90-3.10 (m, 2H), 3.31 (dd, J = 8.0, 4.0Hz, 1H), 3.38 (s, 3H), 3.93 (t, J = 12.0Hz, 1H), 4.61 (d, J = 8.0 Hz, 1H),

6.78 (d, J = 8.0 Hz, IH), 7.01 (d, J = 8.0 Hz, 2 H), 7.05 (s, 1 H), 7.12 (t, J = 8.0 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1H),

7.26 (d, J = 8.0 Hz, 2H); MS (ESI) 478.0 [M + H]+.

IMPI

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3696

EXAMPLE 160 methyl-2-oxo-l - ((3S) -1,1, l-trifluoro-2-hydroxy-2-methylpentan-

3-yl) piperidin-3-yl) acetic

* unknown stereochemistry

Stage A. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l - ((3S) -1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl) piperidin-2-one

* unknown stereochemistry

A solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -2-oxopentan-3-yl) piperidin- 2-one (30 mg, 0.065 mmol; Example 149, Step B) and trimethyl (trifluoromethyl) silane (48.5 pL, 0.327 mmol) in THF (0.5 mL) was treated with fluoride solution of

697

MEXfCAMO INSTITUTE

OF INDUSTRIAL PROPERTY

1M tetrabutylammonium in THF (196 pL, 0.196 mmol) at 0 ° C. After stirring for 2 hr, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and saturated NaCl solution, dried over Na2SO4, filtered and the filter product concentrated. The residue was purified by flash chromatography on silica gel (eluent: 10 to 20% EtOAc / Hexane, gradient elution) to provide the title compound as the main product.

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-o.x or -l- ((3S) -1,1, l-trifluoro-2-hydroxy-

2-methylpentan-3-yl) piperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((3S) -1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl) piperidin-2-one (Example 160, Step A) by a procedure similar to that described in Example 71, Stage F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.33 (t, J = 8.0

Hz, 3H), 1.47 (s, 3H), 1.52 (s, 3H), 1.70 (m, 1H), 2.10-

2.25 (m, 3H), 2.89 (d, J = 8.0 Hz, 2H), 2.95 (t, J = 8.0, 1H), 3.43 (m, IH), 4.40. (D, J = 12.0 Hz, 1H), 6.75 (d, J- 8.0Hz, 1H), 6.95 (m, 1H), 7.08-7.20 (m, 3H), 7.26-7.40 (m, 3H); MS (ESI) 545.2 [M + H]+.

EXAMPLE 161

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl ) -2 oxopiperidin-3-yl) acetamide

A solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) —1— (N— methylcyclopropanesulfonamido) butan- 2-yl) -2-oxopiperidin-3yl) acetic (0.055 g, 0.095 mmol; Example 141) in DMF (2.0 mL) was treated with HBTU (0.072 g, 0.189 mmol), N hydrochloride1((ethylimino) methylene) -N3, N3-dimethylpropane-l, 3-diamine (0.036 g, 0.189 mmol) and sodium acid carbonate (0.016 g, 0.189 mmol) successively. Let it stir for 0.5h. 7.0M ammonia in methanol (0.135 mL, 0.946 mmol) was added dropwise. After stirring at room temperature for 18 h, the reaction was diluted with water, extracted (2 χ EtOAc), and washed (1x Saturated NaHCO3, and 2 χ saturated aqueous NaCl solution). The combined organic layers were dried over Na2SW4, filtered and the filter product was concentrated under reduced pressure. The residue was purified by HPLC

699 reverse phase preparatory (eluent: 10 to acetonitrile, aaem.eMSKi'i'.ssíssES ··. • s.-TAar.'üSKa ·· * · * water, 0.1% TFA, gradient elution) to give the compound of the title as a white solid after freeze drying.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.52 (t, <7 = 7.53 Hz,

<td> <7=7.82</td><td>Hz,</td><td>4 H)</td><td>7.42 (br.</td><td>s.,</td><td>1 HOUR); Spectrum</td><td>of Masses (ESI)</td>

m / z = 58 0 ·. 2 (M + l).

EXAMPLE 162

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl ) -2oxopiperidin-3-yl) -N- (methylsulfonyl) acetamide

A solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) - acid

IMPI

700

6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (N • i methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic (0.045 g, 0.0.77 mmol) (Example 141) in THF (2.0 mL) was treated with methanesulfonamide (0.029 g,

0.310 mmol),

Netyl-N-isopropylpropan-2-amine (0.050 g,

0.387 mmol) and

1,1'-carbonyldiimidazole (0.050 g <

0.310 mmol), successively

The mixture was heated to reflux for h, quenched with saturated NH solution4C1 and extracted with EtOAc. The combined organic layers were dried over

MgSO4, filtered and the filter product concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to give the title compound, as a white solid after lyophilization.

<td>XH</td><td>NMR (400 MHz,</td><td colspan="3">'CHLOROFORM-d) δ ppm 0</td><td> .52</td><td>(t, J =</td><td> 7.53</td>

Examples 163

170 were prepared from Acid 2701 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l ((S) -1- (N-methylcyclopropansulfonamido) butan -2-yl) -2oxopiperidin-3-yl) acetic (Example 141) using the following general procedure using the appropriate amine, unless otherwise indicated.

A mixture of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S) -1- (N-methylcyclopropanesulfonamido) butan-2 -il) -2-oxopiperidin-3yl) acetic (0.020 g, 0.034 mmol; Example 141), the corresponding amine (1.2eq.), N-ethyl-N-isopropylpropan-2-amine (3.3eq.) and hexafluorophosphate of (ΙΗ-benzo [d] [1,2,3] triazole-

1-yloxy) tripyrrolidin-l-ylphosphonium (V) (1.05eq.) In 2 ml of DCM was stirred at room temperature for 5h. The solvent was removed under reduced pressure, and the residue was purified by reverse phase HPLC (40-90% water / acetonitrile gradient with 0.1% TFA). The desired fractions were then collected and concentrated to give the pure product.

IMPI

702

<td>Example</td><td>R</td><td>Used amine</td>

<td> 163</td><td></td><td>3-Aminopropan-1-ol</td>

<td> 164</td><td></td><td>2-Aminoethanol</td>

<td> 165</td><td>γΟΗ</td><td>Hydroxylamine</td>

<td> 166</td><td>/ O</td><td>O-Methylhydroxylamine</td>

<td> 167</td><td>OH / xA, O</td><td>(R) -3-Aminopropane- 1,2-diol</td>

<td> 168</td><td>OH / JxzO</td><td>(S) -3-Aminopropane- 1,2-diol</td>

<td> 169</td><td>γθΝ</td><td>Monosodium cyanamide</td>

<td> 170</td><td>/ vY one</td><td>N1, N1-Dimethyl ethane- 1,2-diamine</td>

EXAMPLE 163

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl ) -2 oxopiperidin-3-yl) -N- (3-hydroxypropyl) acetamide XH NMR (400 MHz, MeOH-cW opm 0.54 (t, J = 7.63 Hz, 3 H),

1.00-1.19 (m, 4H), 1.39 (s, 3H), 1.65-2.13 (m, 5H), 2,252.36 (m, IH), 2.48- 2.61 (m, 2H), 2.81-2.95 (go, 6H), 3.25703

IMPI

MEXICAN INSTITUTE

D £ THE PROPERTY

INDUSTRIAL

3.43 (m, 3H), 3.61 (t, J = 6.26 Hz, 1H), 4.13-4.26 (br, IH),

4.44 (s, 1H), 4.82 (d, J = 10.76 Hz, 1H), 6.97-7.07 (m, 2

H), 7.11 - 7.22 (m, 4H), 7.27-7.347 (m, 2H). Spectrum

Masses (ESI) m / z = 638.2 (M + l) '.

EXAMPLE 164

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2r

H)

XH NMR (400

3.53-3.64 (m, 2

2.49-2.58 (m, 2H)

1.92 (m, 1H),

4.79 (d, J = 10.76 H

0.95-1.15 (m, 4H),

H), 7.24- 7.32 (m,

<td>2 H). Spectrum</td><td>of masses</td><td colspan="2">(ESI) m / z =</td><td colspan="2"> 624.4</td>

(M + l).

EXAMPLE 165

2- ((3R, 5R, 6S) -5- (3-chlor.phenyl) -6- (4-chlorophenyl) -3-methyl-l ((S) -1- (N-methylcyclopropansulfonamido) butan-2- yl) -2oxopiperidin-3-yl) -N-hydroxyacetamide XH NMR (4 00 MHz, MeOH-d4) opm 0.53 (t, J = 7.53 Hz, 3 H),

1.00 - 1.16 (m, 4H), 1.38 (s, 3H), 1.70 (ddd, J = 14.23,

704

7.78

2.09

H),

H)

H),, 2.77

INSTITUTE t / .W-CANO .88 (ddd, J = 14.28, 8.51, 7.WW; ΓΗΤ7

2.17-2.22 (m, IH),

2.88 (m, 2

H), 2.92 (s, 3

4.20 (br

H), 4.82

Hz,

H), 7.01 - 7.09 (m, 2

Η),. 7.13

7.22 (m,

H), 7.30 (d,

J = 8.02 Hz, 2H). Mass Spectrum (ESI) m / z =

618 (M + l).

EXAMPLE 166

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) -N-methoxyacetamide XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (t, J = 7.53 Hz, 3 H), 0.96 - 1.07 (m, 2 H), 1.17 - 1.28 (m, 2 H), 1.43 (s, 3 H), 1.55-1.65 (m, 1H), 1.87 - 2.00 (m, IH), 2.07 -2.13 (dd, J = 13.79, 2.64 Hz, 1H), 2.28 - 2.42 (m, 2H), 2.63 -2.77 (m, 3

H), 2.88 (br, 4H), 3.26 (ddd, J = 13.89, 10.66, 3.03 Hz, 1H),

3.82 (s, 3H), 4.25 (br, 1H), 4.77 (d, J = 10.76 Hz, 1H),

6.88 -6.92 (m, 1H), 6.99- 7.05 (m, 2H), 7.10 - 7.14 (m, 2

H), 7.18 - 7.30 (m, 3H). Mass Spectrum (ESI) m / z = 632 (M + l).

EXAMPLE 167

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2705 ^ τιτυτο

DE LA ΓΕ, ΟΗΕΜΑυ oxopiperidin-3-yl) -N - ((R) -2,3-dihydroxypropyl) ace? Amide.

<td colspan="2">XH NMR (500</td><td>MHz,</td><td colspan="2">CHLOROFORM-d) δ ppm 0.51 Jt, J = 6.</td><td>6 Hz,</td>

EXAMPLE 168

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) -2oxopiperidin-3-yl) -N - ((S) -2,3-dihydroxypropyl) acetamide

<td></td><td>XH</td><td>NMR (500 MHz,</td><td>CLO</td><td>ROFORM-d)</td><td>δ ppm 0.</td><td> 43 -</td><td>0.58 (m, 3</td>

706

Η), 6.90 (d, J = 5.1 Hz, 1 H) 6.92 -

7.16 (m, 2 Η), 7.20 - 7.26 (m, 2 H).

EXAMPLE 169

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -

1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3- yl) -N-cyanoacetamide

A mixture of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (NmethylcyclopropansulfonamidQ) butan-2-yl acid ) -2-oxopiperidin-3yl) acetic (0.030 g, 0.052 mmol; Example 141),

N, N'dicyclohexylcarbodiimide (10.64 mg, 0.052 mmol) and Nhydroxysuccinimide (5.94 mg,

0.052 mmol) in 3 mL of

THF was stirred while cooling with an ice bath for 3h. The reaction mixture was filtered and the filter product was added dropwise to a solution of monosodium cyanamide (10.90 mg, 0.170 mmol) in 2 mL of water at an ice bath temperature. The reaction mixture was stirred at room temperature for 12h. Solvents were removed and the residue was purified by reverse phase HPLC (40-90% water / acetonitrile gradient with 0.1% TFA). The desired fractions were then collected and concentrated to give the title compound.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.52 (t, J = 7.6 Hz, 3

707

INSTITUTE ΜΚ,r „FROM THE E-kOrlEUAD

INDUSTRIAL

1.17 -1.30 (m, 2H), 1.49 - 1.53 (m,

EXAMPLE 170

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -

1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3 yl) -N- (2- (dimethylamino) ethyl) acetamide XH NMR (400 MHz, MeOH-d4) δ ppm 0.52 (t, <7 = 7.53 Hz, 3 Η),

1.01 - 1.21 (m, 4 Η), 1.47 (s, 3 H) 1.62 - 1.85 (m, 2 Η), 1.90 (dd, 7 = 13.50, 3.13 Hz, 1H), 2.42 (t, <7 = 13.69 Hz , 1 Η), 2.51 2.62 (m, 2 Η), 2.80 - 2.91 (m, 3 H, 2.93 (s, 3 Η), 3.03 (s,

Η), 3.38 - 3.50 (m, 2 Η), 3.29 - 3.39 (m, 2H), 3.84 (ddd, 7 = 15.01, 7.38, 4.79 Hz, 1 H), · 4.21 (dd, 7 = 13.89, 10.56 Hz , one

H), 4.80 (d, 7 = 10.76 Hz, 1 Η), 7.00 - 7.12 (m, 2 H) 7.15 -

7.25 (m, 4H) 7.33 (d, 7 = 6.85 Hz, 2H). Mass Spectrum (ESI) m / z = 651.2 (M + l)

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-clorofeiIll) -3-llltiLll-l " 1

708

EXAMPLE 171 ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2 oxopiperidin-3-yl) -N- (3,4-dihydroxybutyl) acetamide

To a solution of N- (but-3-enyl) -2 - ((3R, 5R, 6S) -5- (3 chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetamide (0.030 g, 0.047 mmol; Example 170) in 1 mL of THF / H2Or (4: 1) osmium (VIII) oxide (0.030 mL, 2,363 pmol) was added, followed by 4-methylmorpholine 4-oxide (8.31 mg, 0.071 mmol). The reaction mixture was stirred at room temperature for 12h. Solvents were removed and the residue was purified by reverse phase HPLC (40-90% water / acetonitrile gradient with 0.1% TFA). The desired fractions were then collected and concentrated to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d). opm 0.51 (t, 3 Η), 1.00 (t, J = 7.24 Hz, 2 Η), 1.21 (d, J = 4.11 Hz, 2 Η), 1.42 (br. s., 3

709

Η), 1.61 (br. S., 2 .Η), 1.75-2.10 (m, 2 Η) 2.26 - 2.44 (m, 2

Η) 2.52 - 2.80 (m, 7 Η) 2.88 (s, 3 Η), 3.21 (br. S., 2 Η),

3.45 - 3.85 (m, 4 Η), 4.23 (br. S., 1 Η), 4.76 (d, 7 = 10.56 Hz, 1 H), 6.90 (br. S., 1 Η), 6.95 - 7.04 (m , 2 H), 7.07 - 7.15 (m, 3 H) 7.23 (d, 7 = 7.04 Hz, 2 H). Mass Spectrum (ESI) m / z = 668 (M + l).

EXAMPLE 172

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 (cyclopropansulfonamido) butan-2-yl) -3-methyl- 2-oxopiperidin-3yl) acetic

HN

The title compound was prepared by a similar procedure to that described in Example 129, using the equivalent amount of cyclopropansulfonyl chloride in place of methanesulfonyl chloride in Step C. Purification of the residue by preparative reverse phase HPLC (eluent: 10 at 90% acetonitrile, water, 0.1% TFA, gradient elution) provided the title compound as a solid

white after lyophilization of the collected fractions.

710

ΓΜΡΙ ^

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.54 (t, J = 7.53 Hz, 3

H) 0.92 - 1.08 (m, 2 H) 1.08 - 1.23 (m, 2 H) 1.39 - 1.64 (m, 4

H) 1.77 - 1.92 (m, 1 H) 1.96 - 2.07 (m, 1 H) 2.28 - 2.49 (m, 2

EXAMPLE 173

(S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (N-methylcyclopropanesulfonamido) butan- 2-yl) -2oxopiperidin-3-yl) propanoic

* stereochemistry not established

Step A. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2- yl) -2oxopiperidin-3-yl) methyl acetate.

G

IMPI in5T,/ L? /> 0 = ^. 0 D INDUSTRIAL

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) acid

6- (4-Chlorophenyl) -3-methyl-l - ((S) -1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic (0.055 g, 0.095 mmol; Example 141) in lmL of MeOH and 4mL of benzene a 2.0 M solution of (trimethylsilyl) diazornethane in diethyl ether (0.095 mL, 0.189 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 0.5h and then concentrated. The crude material was purified by reverse phase preparative HPLC (eluent to

90% acetonitrile, water, 0.1% TFA, gradient elution) to provide the title compound as a white powder after lyophilization of the accumulated collected fractions.

Stage B.

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- methyl-1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl ) -2oxopiperidin-3-yl) (S) -methyl propanoate

712 '

* stereochemistry not established

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -l - ('Nmethylcyclopropansulfonamido) butan-2- il) -2-oxopiperidin-3yl) methyl acetate (0.040 g, 0.067 mmol) from Stage A above and HMPA (0.012 mL, 0.067 mmol) in anhydrous THF (1 mL) LDA, 2.0M in THF (0.037) was added mL, 0.074 mmol) at -78 ° C. Allow to stir for 0.5h at -78 ° C. Then iodomethane (0.057 mL, 0.913 mmol) was added. After stirring for 1 h, the reaction was quenched with saturated aqueous NH4CI solution and extracted with EtOAc. The organic compounds were accumulated, washed with saturated aqueous NaCl solution, dried (MgSO4), were filtered, and the filter product was concentrated under reduced pressure to provide a yellow oil. This was used in the next step without further purification.

chlorophenyl) -3-methyl-l - ((S) -1- (NEpapa C. Acid (S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4methylcyclopropansulfonamido) butan -2-il) -9-r> yr> ni nprí di n-3'713

il) propanoic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-l - ((S) -1- (N methylcyclopropansulfonamido) butan-2 (S) -methyl -il) -2-oxopiperidin-3yl) propanoate (0.041 g, 0.067 mmol) from Stage B above in MeOH / THF / HaO (lmL / lmL / 2mL) lithium hydroxide (8.02 mg) was added , 0.335 mmol). The mixture was heated to 60 ° C for 14h. The reaction mixture was acidified with 1N HC1 and extracted with EtOAc (χ2). The organic compounds were accumulated, washed with saturated aqueous NaCl solution, dried (MgSO4), were filtered, and the filter product was concentrated under reduced pressure to provide a colorless film. The crude material was purified by preparative reverse phase HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to provide the title compound as the first elution peak.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.52 (t, 7 = 7.53 Hz, 3

H) 0.97 - 1.06 (m, 2 H) 1.20 - 1.26 (m, 2 H) 1.41 (s, 3 H) 1.43

-1.51 (m, 3H) 1.57 - 1.70 (m, 1H) 1.88 - 2.04 (m, 2H) 2.26

- 2.38 (m, 2 H) 2.78 - 2.97 (m, 5 H) 3.13 (q, 7 = 7.11 Hz, 1 H)

3.32 (ddd, 7 = 13.55, 10.51, · 3.13 Hz, 1 H) 4.86 (d, 7 = 10.56 Hz, l

H) 6.88 - 7.03 (m, 3 H) 7.10 - 7.16 (m, 2 H) 7.24 (m, 3 H).

Acid

714

EXAMPLE 17 4 ____ .....

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S) -2- (cyclopropansulfonamido) pentan-3-yl) -3-methyl-2oxopiperidin -3-yl) acetic (Isomer 1)

* stereochemistry not established

Stage A. N - ((2S, 3S) -3 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin- l-yl) pentan-2yl) cyclopropansulfonamide and N - ((2R, 3S) -3 - ((3S, 5R, 6S) -3-allyl

5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) pentan-2-yl) cyclopropansulfonamide

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((3S) -2-hydroxypentan-3-yl) -3-methylpiperidin2 -one (0.053 g, 0.115 mmol; mixture of stereoisomers; Example

149, Step A) and cyclopropansulfonamide (0.042 g, 0.345 mmol) in

715

IMPI

Mexican INSTITUTE

DELAPROPIWaD INDUSTRIAL toluene (2 mL) cyanomethylene tr-n-butylphosphoran (0.093 mL, 0.345 mmol) was added at room temperature under an argon atmosphere, the solution of which was then stirred at 110 ° C for 2 days. Then the reaction was quenched (saturated NH solution4C1), it was extracted (3 χ EtOAc) and the combined extracts were washed (2 χ water and 1 χ saturated aqueous NaCl solution). The combined organic layer was dried (Na2SW4) and concentrated under reduced pressure. The crude material was purified by reverse phase preparative HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to provide the title compounds as two separate fractions.

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((2S, 3S) -2- (cyclopropanesulfonamido) pentan-3yl) -3- methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from N - ((S) -3 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl2- oxopiperidin-l-yl) pentan-2-yl) cyclopropansulfonamide (Example 174, Step A, fastest eluting isomer) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROPH.RMO-d) δ ppm 0.67 (t, J = 7.43 Hz,

H) 0.92 - 1.04 (m, 2 H) 1.04 - 1.19 (m, 2 H) 1.22 (d,

J = 6.85 Hz, 3 H) 1.50 (s, 3 H) 1.79 - 1.93 (m, 1 H) 1.96 -

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

716

's. > Λ

EXAMPLE 175

Acid

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S) -2- (cyclopropansulfonamido) pentan-3-yl) -3-methyl-2oxopiperidin -3-yl) acetic (isomer 2)

* stereochemistry not established

The title compound was prepared from N - ((3S) -

3- ((3S, 5R, 6S) -3-a.lil-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxopiperidin-l-yl) pentan-2-yl) cyclopropansulfonamide (Example 174, Step A, slower eluting isomer) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.45 - 0.53 (m, 3

H) 0.97 - 1.12 (m, 2 H) 1.18 (m, 1 H) 1.23 - 1.32 (m, 5 H) 1.52 (s, 3 H) 1.70 (m, 1 H) 1.92 (m, 2 Hj 2.40 - 2.54 (m, 2H)

2.74 (d, 7 = 15.06 Hz, 1 H) 3.02 (d, 7 = 15.06 Hz, 1 H) 3.14 (m,

717

Η) 4.85 (d, 7 = 10.56 .Hz, 1 Η) 6.84

7.08 - 7.17 (m, 2 Η) 7.25 (m, 4 Η) (m,

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

H) 6.99 (m, 1H)

EXAMPLE 176

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((3S) -2- (1-methylethylsulfonamido) pentan-3-yl) acid -2oxopiperidin-3-yl) acetic '

* stereochemistry not established

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S) -2hydroxipentan-3-yl) -3-methylpiperidin-2-one (mixture of stereoisomers; Example 149, Step A) and propane-2-sulfonamide by a procedure similar to that described in Example 174.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.47 (t, <J = 7.83 Hz, 3 H) 1.20 (d, <7 = 6.85 Hz, 3 H) 1.41 (dd, J = 14.87, 6.85 Hz , 6 H) 1.51 - 1.60 (s, 3 H) 1.60 - 1.73 (m, 1 H) 1.80 - 2.00 (m, 2 H) 2.50 (t, 7 = 13.89 Hz, 1 H) 2.72 - 2.81 (d, 7 = 14.67 Hz, 1 H) 2.97 (d, 7 = 14.67 Hz, 1 H) 3.07 - 3.23 (m, 2 H) 4.85 (d,

718

J = 10.96 Hz, 1H) 6.87 (m, 1H) 6.97

7.19 (m, 2H) 7.19 - 7.33 (m, 4H).

EXAMPLE 177

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) -1- (N-methylcyclopropansulfonamido) -l-oxobutan- 2yl) -2-oxopiperidin-3-yl) acetic

* stereochemistry was not confirmed

Stage Ά. 2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoic acid

To a stirred solution of methyl 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lyl) butanoate (200 mg , 0.42 mmol; Example 91, Step

A) in THF (5 mL) sodium hydroxide (506 mg, 12.65) was added

IMPI

719 mmol) in water (5 mL) and the reaction was heated under reflux for about 12h.

After this time the reaction was cooled to rt and partitioned between EtOAc (80 mL) and HC1

1.0 M (20 mL). The separated aqueous layer was extracted with EtOAc (30 mL) and the combined organic layers were dried over

MgSO4, filtered and the filter product was evaporated in vacuo to give the title compound as a white solid. Mass Spectrum (ESI) m / z = 460.0 (M + l).

Stage B. (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -N (cyclopropyl sulfonyl) butanamide

* stereochemistry was not confirmed

To a stirred solution of 2 - ((3S, 5R, 6S) -3-allyl-5 (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-Til) butanoic acid (140 mg , 0.304 mmol; Example 177, Step A) In DMF (2 mL) bromotripyrrolidine hexafluorophosphate was added.

1-ylphosphonium (V) (354 mg, 0.76 mmol) and N, N-diisopropylethylamine (OR. 11 mL, 0.61 mmol) and the reaction was

<td></td><td>720IMPI ^ Z/ zu INSTITUTO mex-can ^</td>

<td>waved to ta during</td><td>3 hours. After this time the</td>

Reaction was partitioned between EtOAc (60 mL) and 1.0M aqueous LiCl solution (20 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (SiO2, hexanes: EtOAc, 1: 0 to 1: 1) gave the title compound. Mass Spectrum (ESI) m / z = 563.0 (M + l).

Step C. (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) - N (cyclopropyl sulfonyl) -N-methylbutanamide

* stereochemistry was not confirmed

To a stirred solution of (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -N (cyclopropyl sulfonyl) butanamide (8 mg, 0.014 mmol; Example 177, Step B) In DMF (1.0 mL), potassium carbonate (2.9 mg, 0.021 mmol) and iodomethane (1.1 pL, 0.017 mmol) were added to the reaction. stirred for 1 hour. After this time more iodomethane (1.1 pL, .0177 mmol) and potassium carbonate (2.9 mg, 0.021 mmol) was added and the reaction was stirred at rt

IMPI MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td>during</td><td colspan="2">60 hours. After this</td><td colspan="2">weather</td><td>the</td><td colspan="2">reaction</td><td>I know</td>

<td>divided</td><td>between EtOAc (20 mL)</td><td>and LiCl</td><td> 1.0</td><td>M</td><td> (5</td><td>mL).</td><td colspan="2">The layer</td>

<td>organic</td><td>separated it was washed with</td><td>LiCl 1.</td><td>0 M</td><td> (5</td><td>mL)</td><td>, I know</td><td colspan="2">dried</td>

<td colspan="2">about MgSO4, leaked and</td><td>evaporated</td><td>in</td><td colspan="2">empty</td><td>for</td><td>give</td><td>the</td>

title compound.

Mass Spectrum (ESI). m / z = 577.0 (M + l).

Stage D. Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -3-methyl-l - ((S) -1- (N-methylcyclopropansulfonamido) -

1- oxobutan-2-yl) -2-oxopiperidin-3-yl) acetic

The title compound was prepared from 2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

2- oxopiperidin-l-yl) -N- (cyclopropyl sulfonyl) -Nmethylbutanamide (Example 177, Step C) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.30 (2 H, d, <7 = 8.4 Hz), 7.15 - 7.25 (4 H, m), 6.94 (2 H, d, <7 = 7.6 Hz), 4.79-

4.93 (2 H, m), 3.31 (3 H, s), 3.08 - 3.17 (1 H, m), 2.92 (1

H, d, <7 = 15.1 Hz), 2.70 (1 H, d, <7 = 14.7 Hz), 2.08 - 2.19 (2H,

m), 1.72 (2 H, t, J = 7.5 Hz), 0.92 - 1.39 (8 H, m), 0.840.91 (3 H, m). Mass Spectrum (ESI) m / z = 595.0 (M + l).

722

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Acid

EXAMPLE 178

2-(

methyl-1- ((S) -1- (neopentilamino) -l-oxobutarl-2-il) -2-

* stereochemistry was not confirmed

Stage A. 2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanoic acid

To a stirred solution of 2 - ((3S, 5R, 6S) -3-allyl-5 (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lyl) butanoic acid (110 mg 0.24 mmol; Example 177, Step A or Example 1, Step F) and DIEA (0.050 ml, 0.287 mmol) in dry DMF (1195 pL) at 0 ° C HATU (109 mg, 0.287 mmol) was added. The reaction was stirred at 0or 5 min, followed by addition of 2 eq. of

neopentyl amine (55.9 pL,

0.478 mmol;

723

TCI America). The reaction solution was stirred at 0 ° C for 10 min until complete by LCMS, then filtered. Purification of the solution by reverse phase preparative HPLC (Sunfire ™ Prep C18 OBD 10 pm column (Waters, Milford, MA), gradient elution of 70-100% MeCN in water over a period of 35 min, where both solvents contain 0.1% TFA) provided the title compounds as an epimeric mixture.

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (neopentilamino) -l-oxobutan- 2yl) -2-oxopiperidin-3-yl) acetic

The title compound was obtained from 2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

2-oxopiperidin-l-yl) -N-neopentylbutanamide (88 mg, 0.166 mmol) (Example 178, Step A) by a procedure similar to that described in Example 71, Step F, followed by purification of the residue by phase HPLC reverse (eluent: 55% MeCN / water (0.1% TFA), isocratic elution) using a Sunfire C18 OBD column, 10 uM, (30 x 150 mm), Waters Corp (Milford, MA).

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.79 (t, 7 = 7.46 Hz,

H), 0.93 (s, 9 H), 1.26 (s, 2 Η), 1.43 (s, 3 Η), 1.78

724 (dquin, 7 = 14.38,

7.29, 7.29, 7.29,

7.29 Hz,

IMPI

INDUSTRIAL

Η), 2.08

(t, 7 = 7.70 Hz, 2 Η), 7.13 - 7.24 (m, 3H). Mass Spectrum (ESI) m / z = 547 (M + l).

EXAMPLE 179

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -

1- (4,4-dimethyl-4,5-dihydrooxazol-2-yl) propyl) -3-methyl-2-oxopiperidin-3-yl) acetic

* stereochemistry was not confirmed

Stage A. 2- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -N- (l- hydroxy-2-methylpropan-2-yl) butanamide

725

* Mix of stereoisomers

To a solution of

2 - ((3S, 5R, 6S) -3-allyl-5- (3- chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) N- (l-hydroxy- 2-methylpropan-2-yl) butanamide (Example 177,

Stage A) and 5 eq. 2-amino-2-met ylpropan-l-ol (80 pL,

<td>0.836 mmol;</td><td>Sigma-Aldrich)</td><td>in</td><td>DMF</td><td>(1672 pL)</td><td>to</td><td>o ° c</td><td>I know</td>

<td>added 1.2</td><td>HATU eq (76</td><td>mg,</td><td> 0.201</td><td>mmol). The</td><td colspan="2">solution</td><td>of</td>

<td>reaction is</td><td>stirred during</td><td> 1</td><td>hour,</td><td>time in</td><td>the</td><td>which</td><td>the</td>

reaction was judged to be complete by CLEM. The reaction mixture was diluted with EtOAc (50 mL) and washed with NaHC03 (20mL), HC1 IN, and water. The combined organic layers were dried over Na2SO4, filtered and the filter product concentrated to give the crude material as a clear solution (residual DMF present). The product was used in the next step without further purification.

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (4,4-dimethyl-4,5-dihydrooxazole -2726 il) propyl) -3-methylpiperidin-2-one

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

* stereochemistry 'was not confirmed

To a cold (-78 ° C) solution of 2- ((3S, 5R, 6S) -3-allyl-5 (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l -yl) N- (l-hydroxy-2-methylpropan-2-yl) butanamide (89 mg, 0.167 mmol; Example 179, Step A: Epimeric mixture) in DCM (1674 pL) 3 eq was added. diethylamino sulfur de-trifluoride (26.5 pL, 0.201 mmol) dropwise. The reaction mixture was stirred at -78 ° C for 20 min. The anhydrous K2CO3 (1.5 equiv) was then added in one portion and the mixture allowed to warm to room temperature. The reaction was poured into saturated aqueous NaHCO3 and the biphasic mixture was extracted with EtOAc x 2. The combined organic extracts were dried over MgSO4, were filtered, and the filter product was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 0 to

20% ethyl acetate / hexane) provided the title compound.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.7 6 (t, J = 7.4 6

JL MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

727

(M + l).

Hz, 2H). Mass Spectrum (ESI) m / z = 513

Additional elution provided the other epimerp:

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -

1- (4,4-dimethyl-4,5-dihydrooxazol-2-yl) propyl) -3methylpiperidin-2-one.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.96 (t, 7 = 7.4 6 Hz,

H), 1.19 (s, 3H), 1.27 (s, 3H), 1.30 (s, 3H), 1.65 (br. S., 1H), 1.86-2.06 (m, 4H), 2.60 ( qd, J = 14.06, 7.70 Hz, 2H), 3.20 (ddd, <7 = 13.27, 10.09, 3.30 Hz, 1H), 3.79 - 3.89 (m, 2H), 3.89 - 3.95 (m, 1H) , 4.49 (d, <7 = 10.03 Hz, 1H), 5.15

<td> 7.13</td><td>(m,</td><td>1 H), 7</td><td> .13</td><td> - 7.23</td><td>(m,</td><td>3 H). Mass Spectrum (ESI)</td>

m / z = 513 (M + l).

728

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (4,4-dimethyl-4,5-dihydrooxazole -2yl) propyl) -3-methyl-2-oxopiperidin-3-yl) acetic

The title compound was obtained from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (4,4-dimethyl-4,5-dihydrooxazol-2-yl) propyl) -3 methylpiperidin-2-one (53 mg, 0.103 mmol; Example 179,

Step B) by a procedure similar to that described in Example 71, Step F.

<td></td><td>XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.74</td><td>(t,</td><td>J = 7.46</td>

<J = 8.07 Hz, 1 H) 3.88 (d, J = 8.07 Hz, 1 H) 4.16 (t, J = 6.72

Hz, 1 H) 4.60 (d, J = 9.78 Hz, 1 H) 6.78 (d, J = 7.58 Hz, 1 H)

6.99 - 7.06 (m, 2H) 7.10 (t, J = 7.82 Hz, 2H) 7.14 - 7.18 (m, 1H) 7.22 (d, J = 8.31 Hz, 2H). Mass Spectrum (ESI) m / z = 531 (M + l).

EXAMPLE 180

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l- ((S) -1- (N -. (2, 2,2-trifluoroethyl) acetamido) butan-

2-yl) piperidin-3-yl) acetic

729

Stage A. N - ((S) -2 - ((3S / 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) butyl) -N- (2,2,2trifluoroethyl) acetamide

The title compound was obtained by acetylation of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1 - ((S) -1 - ((2,2,2-trifluoroethyl) amino) butan-2-yl) piperidin-2one (Example 147, Step A) by a procedure similar to that described in Example 28, Step C .

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -1- (N- ( 2,2,2 trifluoroethyl) acetamido) butan-2-yl) piperidin-3-yl) acetic

The title compound was obtained from N— ((S) —2

730

INSTITU i'L 'Mt.

INDUSTRIAL PROPERTY ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

2-oxopiperidin-l-yl) butyl) -N- (2,2,2-trifluoroethyl) acetamide (Example 180, Step A) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.52 (t, J = 8.0

Hz, 3H), 1.50 (s, 3 Η), 1.61 (m, 1 Ή), 1.87 (m, 1 H), 1.90-

EXAMPLE 181

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) —1— ((S) -

1- (1,1-dimethylethylsulfonamido) butan-2-yl) -3-methyl-2- oxopiperidin-3-yl) acetic

chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butyl) -2731 methylpropane-2-sulfonamide

202.6 mg (0.454 mmol) of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutane-2-yl) -3methylpiperidin -2-one (Example 91, Stage B) and 2-methylpropane-

2-sulfonamide (130mg, 0.948mmol, Oakwood) was dissolved in anhydrous toluene (4.5mL). The cyanomethylene tributylphosphorane, 421 mg, was transferred to the reaction vessel by syringe. Almost an additional 30 mg of phosphoran reagent was added 2 minutes after the first addition. The reaction mixture was stirred at 34-41 ° C in a preheated oil bath. The reaction was monitored by CLEM. 133 Additional mg of t-butyl sulfonamide was added after 2 hr 15 min. the reaction mixture was heated to 35 ° C overnight.

The next day, after 26 h, 15 min of total reaction time, an additional 133 mg of t-butyl sulfonamide

MEXICAN INSTITUTE V,

MY PROPERTY

421 Additional mg & TáTes 'TfET'

732 were added.

minutes after cyanomethylenebutyl phosphorane were added.

ΈΤ heating between 40 ° C was continued overnight.

On the third day, the reaction seemed complete by CLEM. After 53 h total reaction time, the mixture was partitioned between ethyl acetate and saturated ammonium chloride. The aqueous phase was again extracted 2X with EtOAc, washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered, and the filtration product concentrated in vacuo to a residue which was chromatographed on a column of 24 g silica, eluting with a gradient from 0 to 30% EtOAc in hexanes. Fractions containing the desired product were combined and concentrated to give the title compound as a colorless white solid which was dried under high vacuum. MS (ESI) m / z = 565 [M + H] ”. '

Step B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1,1-dimethylethylsulfonamido) butan-2-yl acid ) -

3-methyl-2-oxopiperidin-3-yl) acetic

N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butyl) -2methylpropane-2-sulfonamide (lOOmg, 0.177 mmol; Example 181,

<td></td><td>IMPIOUS* MEXICAN INSTITUTE (H OF THE PROPERTY INDUSTRIAL ---</td>

<td>Stage A)</td><td>transferred to a round bottom flask that</td>

<td>contains a</td><td>stir bar, followed by tetrachloride</td>

carbon (1,100 mL), acetonitrile (1.1 mL), and water (1.6 · mL). The flask was then charged with sodium periodate (190 mg, 0.888 mmol) and ruthenium chloride hydrate (IIT) (6 mg, 0.023 mmol), and the resulting reddish-brown suspension was vigorously stirred at room temperature. After

<td>18h time</td><td>reaction, 200</td><td>mg</td><td>additional</td><td>of</td><td>periodate</td><td>of</td>

<td colspan="2">sodium were added along</td><td>with</td><td>other 2 mg</td><td>of</td><td>hydrate</td><td>of</td>

<td>chloride</td><td>ruthenium (III).</td><td>The</td><td>agitation to</td><td>the</td><td colspan="2">temperature</td>

environmental was continued. After 4h, the reaction was quenched by addition of HC1. 1.3M aqueous and diluted with ethyl acetate. The resulting mixture was filtered. Saturated aqueous NaCI solution was added to the aqueous phase to promote phase separation. 'The combined organics were washed with saturated aqueous NaCI solution, dried over sodium sulfate, filtered, and the filter product was concentrated in vacuo. · The resulting residue was chromatographed on a Sunfire ™ HPLC phase prep column. inverse (Waters, Milford, MA), eluting with a gradient of

<td>50 to 95%</td><td>MeCN</td><td>in</td><td>water (0</td><td>.1% TFA</td><td>in both</td><td colspan="3">solvents) during</td>

<td>the course</td><td>of</td><td> 35</td><td>minutes.</td><td colspan="2">Fractions</td><td>than</td><td>they contain</td><td>the</td>

<td>product</td><td colspan="2">wanted</td><td>on top</td><td>purity</td><td>by HPLC</td><td>I know</td><td>combined,</td><td>I know</td>

<td>exhausted</td><td>of</td><td colspan="2">volatile</td><td>at</td><td colspan="2">evaporator</td><td>rotary,</td><td>and</td>

lyophilized to provide

734

IMPI 6 ^

ΜΞΧ-CA 'INSTITUTE ·. · \ .. - ····· .._,

DELAPíA '-T

the title compound as

<td colspan="4">a faded white solid.</td><td rowspan="2">(t, J - 7.58</td><td rowspan="2">Hz,</td><td rowspan="2">3 H)</td>

Η). MS (ESI) m / z = 583 [M + H]1 .

EXAMPLE 182

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -

1- (N, 2-dimethylpropan-2-ylsulfonamido) butan-2-yl) -3-methyl-2- oxopiperidin-3-yl) acetic

Stage A. N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) butyl) -N, 2-dimethylpropane-2-sulfonamide

735

N- ((S) -2- ((3S, 5R, 6S) .- 3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butyl ) -2methylpropane-2-sulfonamide (100 mg, 0.177 mmol; Example 181, Step A) was dissolved in DMF (2.5 mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.45 mmol) was added in a simple portion. After 25 minutes, this mixture was cooled to 0 ° C in an ice water bath, and iodomethane (0.04 mL, 0.643 mmol) was added dropwise by syringe. The mixture was allowed to warm gradually to room temperature, gradually turning into a pale yellow suspension. After 2 h water (2 mL) was added very carefully. The resulting mixture was partitioned between ethyl acetate and saturated aqueous NH4CI solution. The aqueous phase was re-extracted (2X) and the combined organic products were washed with saturated aqueous NaCl solution (2X), dried over sodium sulfate, filtered, and the filtration product was concentrated in vacuo to a greasy oily residue. was processed in

736

Chromatography on a 12 g silica column, eluting with a gradient of 0 to -35% EtOAc in hexanes. Fractions containing the sulfonamide product were accumulated and concentrated to give the title compound. MS (ESI) m / z = 579 [M + H] ".

Step B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (N, 2-dimethylpropan-2-sulfonamido) butan-2 acid -il) -3-methyl-2-oxopiperidin-310 yl) acetic

The compound was prepared from N - ((S) -2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxopiperidin- l-yl) butyl) -N, 2-dimethylpropane-2-sulfonamide (Example 182, Step A) by a procedure similar to that described in Example 181, Step B. The crude material obtained was taken up in methanol, filtered, and purified by Reverse phase HPLC on a prep column Phase HPLC

<td>reverse Sunfire ™</td><td>1 (Waters,</td><td>Milford,</td><td>MA),</td><td>eluting with</td><td>a</td>

<td>50 gradient</td><td>up to 100</td><td>% MeCN in</td><td>Water</td><td>(TFA 0.1%</td><td>in</td>

<td>20 both solvents'</td><td>). The</td><td>volatile</td><td>I know</td><td>separated and</td><td>the</td>

<td colspan="2">suspension reverted to</td><td>dissolve</td><td>with</td><td>Minimum MeCN,</td><td>I know</td>

<td colspan="2">froze, and lyophilized to</td><td colspan="4">give the title compound as</td>

<td>a white solid</td><td colspan="2">colorless.</td><td></td><td></td><td></td>

737

EXAMPLE 183

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) -1- (1-methylethylsulfonamido) butan-2-yl acid ) -2 oxopiperidin-3-yl) acetic

Stage A. N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-o.xopiperidin-l -yl) butyl) propane-2 sulfonamide

738

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 hydroxybutane-2-yl ) -3-methylpiperidin-2-one (Example 91, Step

B) and propane-2-sulfonamide as described in Example

181, Stage A. MS (ESI) m / z = 551 [M + H] ~.

Stage B. 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (1-methylethylsulfonamido) butan-2yl acid ) -2-oxopiperidin-3-yl) acetic

The title compound was obtained from N - ((S) -2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

2-oxopiperidin-l-yl) butyl) propane-2-sulfonamide (Example 183, Step A) by a procedure similar to that described in Example 181, Step B. The residue was purified by reverse phase HPLC on a prep HPLC column reverse phase Sunfire ™ (Waters, Milford, MA), eluting with a gradient of 50-100% MeCN in water (0.1% TFA in both solvents). The chromatography fractions were combined and concentrated in vacuo. The resulting suspension was made homogeneous by addition of minimal MeCN, frozen and lyophilized to give the title compound.

739

XH NMR (500 MHz, CD3OD) δ 0.45 (t, J = 7.58 Hz, 3 H),

1.35 (dd, J = 8.56, 6.85 Hz, 6 H), 1.41 (br. S., 3 H), 1.51 -

1.64 (m, 1H), 1.83 (ddd, J = 14.43, 8.56, 7.34 Hz, 1H),

2.05 (dd, J = 13.69, 2.93 Hz, 1 H), 2.39 (t, J = 13.69 Hz, 1

H), 2.64 (d, J = 13.45 Hz, 1 H), 2.80 (t, J = 9.29 Hz, 1 H),

2.87-3.04 (m, 2H),. 3.23 (dt, J = 13.51, 6.82 Hz, 1 H),

3.33 - 3.40 (m, 1H), 3.85 (dd, <7 = 14.06, 10.15 Hz, 1H),

4.96 (d, <7 = 11.00 Hz, 1H), 6.36 - 7.71 (m, 8H). MS (ESI) m / z = 569 [M + H].

EXAMPLE 184

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (N-ethylpropan-2-ylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic 'OH

Stage A.

740

chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) bullí) -N-é ± lpropano-

2-sulfonamide

The title compound was prepared from N - ((S) -2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

2-oxopiperidin-l-yljbutyl) propane-2-sulfonamide (Example 183, Step A) by a procedure similar to that described in Example 182, Step A, replacing iodomethane with iodoethane. MS (ESI) m / z = 579 [M + H]1 .

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (N-ethylpropan-2-ylsulfonamido) butan-2yl acid ) -3-methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from N - ((S) —2— ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl2 -oxopiperidin-l-yl) butyl) -N-ethylpropane-2-sulfonamide (Example 184, Step A) by a procedure similar to that described in Example .71, Step F. The residue was chromatographed on a prep HPLC column reverse phase

741

MEXICAN INSTITUTE. OF INDUSTRIAL PROPERTY

Sunfire ™ C18 (Waters, Milford, MA), eluting with a gradient of 50 to

100% MeCN in water (TFA at

0.1% in both purities per evaporator

Fractions containing

HPLC were combined and run rotary. The suspension of the product in high volatiles in the redissolved in

Min MeCN, frozen, and lyophilized overnight to give the title compound as a white foam.

XH NMR (500 MHz,

CD3OD) δ

0.52 (t, J = 7.21

Hz, 3H)

1.09 - 1.20 (m, 3H),

1.30 (d,

J = 6.85 Hz,

H),

1.38 (d,

6.85 Hz, 3

H), 1.43 (s, 3H),

1.56 - 1.69 (m, 1

H), 1.82

1.97 (m, 1H), 2.01 (dd, J = 13.69, 2.93 Hz,

H),

13.69 Hz, 1H), 2.64 (d, J = 13.20 Hz, 1H), 2.82 (br. S.,

H), 2.88 - 3.02 (m, (d, J

3.18 Hz, 1H), 3.33

-3.36 (m, 1H), 3.40 - 3.55 (m,

H),

4.29 (d, J = 6.36 Hz,

H), 4.84 (br. D, J = 1.00 Hz,

H),

MS (ESI) m / z = 597 [M + H]+.

EXAMPLE 185

Acid 2 - ((3R, 5R, 6S) —5— (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) - l-hydroxybutan-2-yl) -3-methyl-2- oxopiperidin-3-yl) acetic

IMPI

'742

Stage A. 2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6oxopiperidin-l-yl) -Methyl methyl butanoate

To a 50 ° C solution of 33.8 g (60% in mineral oil,

845 mmol) of sodium hydride in 2-methyltetrahydrofuran (550 mL) a solution of 240 g (750 mmol) of (5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2- was added one (Example 1, Step E) in 2-methyltetrahydrofuran (550 mL) over a period of 45 min. After an additional 1.25 hr at 50'C, 105 mL (912 mmol) of methyl 2-bromobutyrate were added over a period of 20 min. The resulting thick mixture was stirred at 50 ° C for 3.5 h, and then cooled to room temperature and quenched with saturated aqueous NH solution4C1. Water was added to dissolve the precipitate, and the resulting mixture was extracted with ethyl acetate (4X). The combined organic layers were washed with saturated aqueous solution

743

<td>NaCl</td><td colspan="2">(IX), they dried</td><td>about Na2SW4,</td><td>I know</td>

<td>product</td><td>of</td><td>filtration</td><td>concentrated.</td><td>The q</td>

<td>residue</td><td>by</td><td>chromatography</td><td>on gel</td><td>of</td>

<td>Biotage®</td><td>Snap-</td><td colspan="2">™ (Biotage, LLC, Charlotte,</td><td>NC)</td>

pui'lflCcllilÓir, 0 to 35% silica (column

ΓΜΡΙιχΖΐ 1

MEXICAN INSTITUTE \

OF PROPERTY j — tr¿jF filt'íSímwi and -'- er '

EtOAc / DCM, gradient elution) provided the title compound as an oily white solid.

Stage B. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxybutan-2-yl) piperidin-2-one

To an ice-cold solution of 48.5 g (115 mmol) of (S) -methyl 2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6oxopiperidin-l-yl) Butanoate (Example 185, Step A) in ethyl ether (850 mL) 5.96 g (90%, 246 mmol) of lithium borohydride was added. The resulting light yellow solution was stirred at 0 ° C for 3 h, and then MeOH (2.5 mL) and more ethyl ether (100 mL) were added. The evolution of the gas was observed with the addition of MeOH. After 40 min, the reaction was quenched by careful addition of HCI IN until the bubbling disappeared. The mixture was extracted with EtOAc (2X), and the combined organic layers were washed with chloride aseasaatsasast

saturated aqueous sodium (IX). The organic layer was dried over

744

Na2SW4, were filtered, and the filter product was concentrated to give the title compound as a white foam.

The crude product was used directly in the next step without further purification.

Step C. (5R, 6S) -l - ((S) -l- (tert-butyldiphenylsilyloxy) butan-

2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one

To a solution of 44.7 g (114 mmol) of (5R, 6S) -5- (3 chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2yl) piperidin-2-one (Example 185, Step B) and 19.4 g (285 mmol) of imidazole in DMF (350 mL), 39.4 mL (154 mmol) of tert-butyldiphenylsilyl chloride was added. The colorless solution was stirred at room temperature for 17 h. The reaction was partitioned between water and ethyl ether (3X), and then the combined organic layers were washed with saturated aqueous sodium chloride (IX), dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap ™ column (Biotage, LLC, Charlotte, NC), Q up to 60% of

EtOAc / hexanes 745 gradient elution)

IMPI MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

provided the title compound as a white foam.

Step D. (5R, 6S) -1 - ((S) -1- (tert-Butyldiphenylsilyloxy) butan2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2one

To a -78 ° C solution of 98.2 g (156 mmol) of (5R, 6S) -

1 - ((S) -1- (tert-butyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 185, Step C) and 10.0 mL ( 160 mmol) of methyl iodide in dry, degassed THF (400 mL) 200 mL (200 mmol) of a degassed 1M solution of lithium bis (trimethylsilyl) amide in THF was added slowly over 20 min. The orange solution was stirred at -78 ° C for 1.5 h and then warmed to 0 ° C and stirred for an additional 1.5 h. The reaction was quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3X). The combined organic layers were dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap columnIM; Biotage, LLC, Charlotte, NC), 5-55%

746

EtOAc / hexanes, gradient elution) provided the title compound as a light yellow foam.

Step E. (3S, 5R, 6S) -3-allyl-l - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) - 6- (4-chlorophenyl) -3 -methylpiperidin-2-one

OR

TBDPSO

To a -78 ° C solution of 37.3 mL (266 mmol) of diisopropylamine in dry, degassed THF (150 mL) was added 100 mL (250 mmol) of a 2.5M degassed solution of n-butyllithium in hexanes slowly via cannula. The light yellow solution was stirred at -78 ° C for 15 min, then warmed to 0 ° C and stirred for an additional 5 min. To the ice-cold solution of LDA was added a solution of 85.7 g (133 mmol) of (5R, 6S) -1- ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3- chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one (Example 185, Step D) in dry, degassed THF (210 mL) via cannula over a period of 15 min. The dark orange solution was stirred at 0 ° C for 30 min and then 34.5 mL (399 mmol) of allyl bromide was added rapidly by syringe. Then

20 sec, the ice bath was removed and the reaction was

747 Placed in a room temperature water bath and stirred for an additional 15 min. The reaction was quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3X). The combined organic layers were dried over Na2SW4, filtered and the filter product concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap ™ column; Biotage, LLC, Charlotte, NC), 6-14% EtOAc / hexanes, gradient elution) provided the title compound as a white foam.

Stage F. Acid. 2 - ((3R, 5R, 6S) -1 - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2- Oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-l - ((S) -1- (tert-butyldiphenylsilyloxy) butan-

2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2one (Example 185, Step E) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.30 (t, J = 7.53 Hz,

IMPI

i.53 (s, (t, J = 13. 9 Hz, 1 H) (m, 1 H) 2.98

3.08

4.21

748

Η) 1.17 (s, 9 Η) 1.3.4 - 1.48 (m, 1 Η)

1.88 (m, 1 Η) 1.93 - 2.03 (m, 1 Η) 2.29

2.69 (d, J = 15.85 Hz, 1 H) 2.81 - 2.93 (m, 1 H) 3.12 (d, J = 15.65 Hz, 1 Η) 3.1

Hz, 1 H) 4.32 (t, J = 10.27 Hz, 1 H) 4.71 (d, J = 10.76 Hz, 1 H)

6.56 - 6.66 (m, 1H) 6.91 - 6.97 (m, 1H) 7.02 - 7.09 (m, 1H) 7.12 - 7.18 (m, 1H) 7.20 - 7.30 (m, 4H) 7.33 - 7.51 (m , 6 H) 7.64 (td, J = 7.83, 1.57 Hz, 4 H).

Stage G. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methyl-2oxopiperidin -3-yl) acetic.

To an ice-cold solution of 370 g (0.53 mmol) of '2 - ((3R, 5R, 6S) -l - ((S) -l- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3 -chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic (Example 185, Step F) in THF (15 mL) 2.60 mL (2.60 mmol) of a 1M TBAF solution was added in THF. The yellow solution was warmed to rt and stirred for 5 h. At this time 2.60 mL (2.60 mmol) of a 1M solution of TBAF in THF was added and the reaction was stirred for an additional 20 h. The reaction was partitioned between HC1 IN and -EtOAc (4X). The combined organic layers were dried over Na2SO4, filtered and the filter product concentrated. The residue was purified by

HPLC prep. reverse phase (Sunfire ™ Prep Cig OBD 10 pm column (Waters, Milford, MA), gradient elution from 40% MeCN in water to 80% MeCN in water over a period of 30 min, where both solvents contain TFA at 0.1%) provided the title compound as a white solid.

XH NMR (400 MHz, CDC13) δ ppm 7.23-7.28 (2 H, m), 7.15-

7.20 (1 H, m), 7.07-7.14 (1 H, m), 6.98-7.06 (3 H, m), 6.74 (1 H, d, J = 7.1 Hz), 4.55 (1 H, dd J = 9.8 Hz, 2.9 Hz), 3.71-3.79 (1 H, m), 3.58-3.66 (1 H, m), 3.19-3.28 (1 H, m), 3.07-3.16 (1 H, m), 2.96-3.03 ( 1 H, m), 2.75 (1 H, dd, J = 14.9 Hz, 2.9 Hz), 2.16-2.25 (1 H, m), '2.03-2.10, (1 H, m), 1.87-1.98 (1 H ,

m), 1.46 (3 H, s), 1.41-1.54 (m, 1 Η), 0.63 (3 H, dd, J = 7.3 Hz, 3.3 Hz). Mass Spectrum (ESI) m / z = 464.1 (M + lj.

EXAMPLE 186

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-l - ((S) -1- (trifluoromethylsulfonamido) butan-2yl) piperidin-3-yl) acetic

CI

Stage A.

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1750 ((S) -l-hydroxybutan-2-yl) -3-methyl-2-oxopiperidin- 3-yl) methyl acetate

A solution of 2 - ((3R, 5R, 6S) -1 - ((S) -1- (tertbutyldiphenylsilyloxy.) Butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 -methyl-2-oxopiperidin-3-yl) acetic (Example 185) in MeOH (2 mL) and benzene (8 mL) was stirred with (trimethylsilyl) diazomethane, 2.0 M in diethyl ether (2.02 mL, 4.04 mmol) at rt for 0.5h. After that time the mixture was concentrated to give the crude methyl ester, which was treated with TBAF in THF at rt for 30h. The mixture was concentrated and purified by chromatography on silica gel (0 to 100% EtOAc in hexanes) to give the title compound. Mass Spectrum (ESI) m / z = 478 (M + l).

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -l (trifluoromethylsulfonamidoj butan-2 -il) piperidin-3-yl) acetic

A reaction vial under argon was loaded with 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1751 ϊ 1MÍ P í

INSTITUTO MEXICANO \ DE LA PROI-reíTAD V ~

INDUSTRIAL - Hydroxybutan-2-yl) -3-methyl-2 ~ oxopiperidin-3-yl) methyl acetate (0.048 g, 0.1 mmol; Example 186, Step

A), 2 (tributylphosphoranylidene) acetonitrile (0.036 g,

0.15 mmol) and trifluoromethanesulfonamide (0.022 g,

0.15 mmol) in toluene (0.5 mL). The reaction mixture in the reaction vial was sealed and stirred at 110 ° C for

h. Column chromatography on silica gel gave a mixture of 2 - ((3R, 5R, 6S) 5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S ) -1 (trifluoromethylsulfonamido) methyl butan-2-yl) piperidin-3-yl) acetate with an unknown impurity. This mixture was hydrolyzed with LiOH (IN solution in water, 0.3 mL) in ethanol (0.5 mL) for 3 h at rt. HPLC purification (column C18, eluting with 10 to 95% CH3CN in water, with 0.1% TFA) gave the title compound.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.26 (2 H, br. S.),

7.15 - 7.20 (1 H, m), 7.12 (1 H, t, 7 = 7.8 Hz), 7.05 (1 H, d,

H, m), 1.49 (3 H, s), 0.71 (3 H, br. S.). Mass Spectrum (ESI) m / z = 595 (M + l).

EXAMPLES 187 - 195 were prepared, unless

752

IMPI

indicate otherwise, starting with methyl chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) (Example 186,

Step A) by procedures similar to that described in El

Example 186, Step B, replacing trifluoromethanesulfonamide with the appropriate reagent.

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 187</td><td>ci- <ys=or ^ =7 HNy</td><td>4-Chlorobenzenesulfonamide</td>

<td> 188</td><td>-Tv4 = o</td><td>4-Methylbenzenesulfonamide</td>

<td> 189</td><td>Cl \ / θ=0 HNy</td><td>2-Chlorobenzenesulfonamide</td>

<td> 190</td><td>"OR ς ys = o HNy</td><td>2-Methylbenzenesulfonamide</td>

<td> 191</td><td>MeO-V and- S = OX = / HNy</td><td>4-Methoxybenzenesulfonamide</td>

INSTITUTE

OF INDUSTRIAL PROPERTY

753

<td>Benzenesulfonamide</td><td rowspan="4"></td>

<td> 193</td><td>OR \ r?= oHNand</td><td>1-Methylcyclopropane-l- sulfonamide</td>

<td> 194</td><td>9 * or UCNn</td><td>2,3-Dihydro-l, 1-dioxo-l, 2- benzisothiazole</td>

<td> 195</td><td>0 O c '' i Uch</td><td>1,1-2,3-Dihydro-dioxide 3,3-dimethyl-l, 2- benzisothiazole</td>

EXAMPLE 187

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (4-Chlorophenylsulfonamido) butan-2-yl) -3-methyl-2- oxopiperidin-3-yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.77 (2 H, m, <7 = 8.6

<7 = 13.5, 10.7, 2.9 Hz)

2.97 (1 H, d, <7 = 14.4 Hz), 2.79 (1 H, d, <7 = 14.4 Hz), 2.74 (1 H, d, <7 = 13.7 Hz), 2.38 (1 H, t, < 7 = 13.8

Hz), 2.05 (1 H, dd, <7 = 13.9, 2.9 Hz), 1.80 (1 H, dt, <7 = 14.6,

7.5 Hz), 1.52 (3 H, s), 1.43 - 1.50 (1 H, m), 0.51 (3 H, t,

J = 7.1 Hz). Mass Spectrum (ESI) m / z = 637 (M + l).

ΓΜ PI

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3754

EXAMPLE 188 methyl-1 - ((S) -1- (4-methylphenylsulfonamido) butan-2-yl) -2 oxopiperidin-3-yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.72 (2 H, m, J = 8.3

Hz), 7.33 (2 H, m, J = 8.1 Hz), 7.23 (2 H, d, J = 8.1 Hz), 7.11 -

7.19 (2 H, m), 7.05 (2 H, d, J = 6.6 Hz), 6.96 -6.99 (1 H, m),

6.85 - 6.91 (1 H, m) 4.95 (1 H, br. S.), 4.83 (1 H, d,

J = 10.5 Hz), 3.49 (1 H, br. S.), 3.14 (2 H, ddd, J = 13.4, 10.6,

2.8 Hz), 3.02 (1 H, d, <J = 14.9 Hz), 2.70 - 2.81 (2 H, m), 2.45 (3 H, s), 2.36 - 2.44 (1 H, m), 2.01 (1 H , dd, J = 13.9, 2.9

Hz), 1.81 (1 H, dd, <J = 15.3, 7.5 Hz), 1.53 (3 H, s), 1.47 (1

H, ddd, J = 14.2, 7.6, 4.3 Hz), 0.47 (3 H, t, J = 7.5 Hz).

Mass Spectrum (ESI) m / z = 617 (M + l).

EXAMPLE 189

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (2-Chlorophenylsulfonamido) butan-2-yl) -3-methyl-2- oxopiperidin-3-yl) acetic

<td></td><td>XHR</td><td>MN (500</td><td>MHz, CHLOROFORM-</td><td>-d)</td><td>δ</td><td>ppm 7.77</td><td>(2 H,</td><td>m,</td>

(2 H, ddd, 7 = 13.5, 10.7, 2.9 Hz),

2.97 (1 H, d, 7 = 14.4 Hz), ______

755

2.79 (1 H, d, 7 = 14.4 Hz), 2.74 (1 H, d, 7 = 13.7 Hz), 2.38 (1

H, t, 7 = 13.8 Hz), 2.05 (1 H, dd, 7 = 13.9, 2.9 Hz), 1.80 (1

H, dt, 7 = 14.6, 7.5 Hz), 1.52 (3 H, s), 1.43 - 1.50 (1 H,

m), 0.51 (3 H, t, 7 = 7.1 Hz). Mass Spectrum (ESI) m / z =

651 (M + l).

EXAMPLE 190

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((Sj -

1- (2-methylphenylsulfonamido) butan-2-yl) -3-methyl-2- oxopiperidin-3-yl) acetic

<td>XHR]</td><td>MN (500 MHz,</td><td>CHLOROFORM-d)</td><td>δ</td><td>ppm 7.89</td><td> (1</td><td>H</td><td>, d,</td>

<td>0.46 (3H</td><td>, t, 7 = 7.5 Hz)</td><td>. Spectrum</td><td>Ma</td><td>isas (ESI)</td><td>m / z</td><td> =</td><td> 617</td>

(M + l).

756

EXAMPLE 191

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (4-methoxyphenylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.76 (2 H, d, J = 8.8

Hz), 7.24 (2 H, d, <7 = 7.8 Hz), 7.11 - 7.19 (2 H, m), 7.04 (1

H, br. s.), 7.01 (1 H, s), 6.98 (2 H, d, <7 = 4.4 Hz), 6.88 (1

H, d, <7 = 6.8 Hz), 4.92 (1 H, br. S.), 4.83 (1 H, d, <7 = 10.5

<td> 1.50</td><td>(1 H, m),</td><td> 0.47</td><td>(3 H,</td><td>t, <7 = 7.3 Hz).</td><td>Spectrum</td><td>of</td><td>Masses</td>

EXAMPLE 192

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (phenylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3- yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.84 (2 H, d,

J = 7.3 Hz), 7.62 (1 H, t, <7 = 7.3 Hz), 7.55 (2 H, t, <7 = 7.7

Hz), 7.24 (2 H, d, J = Q.1 Hz), 7.12 - 7.19 (2 H, m), 7.05 (2 H, d, <7 = 6.6 Hz), 6.98 (1 H, s), 6.87 (1 H, d, <7 = 6.8 Hz), 5.03 (1 H, br. S.), 4.82 (1 H, d, <7 = 10.5 Hz), 4.01 (2 H,

IMPI

MEXICAN INSTITUTE PE INDUSTRIAL PROPERTY

757

<td>7.7, 4.5 Hz), 0.49</td><td> (3</td><td>H</td><td>t,</td><td>0 = 7.5 Hz)</td><td>. Spectrum</td><td>of masses</td>

(ESI) m / z = 603 (M + l).

EXAMPLE 193

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (1-methylcyclopropansulfonamido) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J = 7.8 Hz), 7.10 - 7.17 (2 H, m), 7.03 (1 H, s), 7.06 (1 H, s) , 6.95 - 6.97 (1 H, m), 6.84 - 6.89 (1 H, m), 4.88 (2 H, br. S.),

4.81 (2 H, d, J = 10.5 Hz), 4.71 (1 H, br. S.), 3.71 (1 H, br. S.), 3.03 - 3.18 (3 H, m), 2.96 - 3.02 (1 H, m), 2.76 (1 H, d, J = 14.7 Hz), 2.40 (1 H, t, ¿7 = 13.8 Hz), 1.98 (1 H, dd, 0 = 13.9, 2.9 Hz), 1.88 (1 H, dt, J = 15.0, 7.5 Hz), 1.52 (3 H,

s), 1.50 (3 H, s), 1.45 - 1.49 (1 H, m), 1.33 - 1.43 (2 H, m), 0.77 - 0.86 (2 H, m), 0.52 (3 H, t, 0 = 7.5 Hz). Mass Spectrum (ESI) m / z = 581 (M + l).

EXAMPLE 194

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) —1 - ((S) -

758

IMPIr ^

INSTITUTE ΜΕ »:? ΛΝΟ γό '· OF THE V INDUSTRIAL PROPERTY *** __:

1- (1,1-Dioxidebenzo [d] isothiazol-2 (3H) -yl) butan-2-yl) -3-methyl2-oxopiperidin-3-yl) acetic

<td></td><td>XH NMR</td><td> (500</td><td>MHz,</td><td>CHLOROFORM-d) δ ppm 7.91</td><td>(1 HOUR,</td><td>d,</td><td> 7=7.6</td>

7 = 14.2, 10.5 Hz), 4.03 (5 H, br. S.),

H, dd, 7 = 14.7,

3.24 (1 (1 H, t, 7 = 13.8 Hz),

3.4 Hz), 3.01 - 3.15

7 = 13.8, 2.8 Hz), 1.53

2.32 r

1.49 dd, (3 H, t, 7 = 7.5 Hz). Mass Spectrum (ESI) m / z =

615 (M + l).

EXAMPLE 195

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (3,3-dimethyl-l, 1-dioxidebenzo [d] isothiazol-2 (3H) -yl) butan-2yl) -3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.88 (1 H, d, 7 = 7.6 Hz), 7.68 - 7.74. (1 H, m), 7.58 - 7.64 (1 H, m), 7.45 (1 H, d, 7 = 7.8 Hz)., 7.25 (1 H, br. S.), 7.02 - 7.12 (3 H, m ), 6.99 (1 H, t, 7 = 7.8 Hz), 6.94 (1 H, s), 6.75 (1 H, d, 7 = 7.6 Hz), 5.02 (1 H, d, 7 = 10.0 Hz), 4.24 (1 H, dd, 7 = 14.8,

10.6 Hz), 3.15 (2 H, d, 7 = 13.0 Hz), 3.03 - 3.13 (3 H, m),

759

<td> 2.92</td><td> (8</td><td>H, br. s.</td><td> ), 2.71</td><td>(1 H, d, 7 = 15.4</td><td colspan="2">Hz), 2</td><td>INDUSTRIAL .36 (1</td><td>H, ''</td><td>t,</td>

s), 0.51 (3 H, t, 7 = 7.5 Hz). Mass Spectrum (ESI) m / z =

643 (M + l).

EXAMPLE 196

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (pyridine-3-sulfonamido) butan-2yl) piperidin-3-yl) acetic, such as the 2,2,2-trifluoroacetic acid salt

Stage A. 2 - ((3R, 5R, 6S) -1 - ((S) -1- (bis (tertbutoxycarbonyl) amino) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) methyl acetate

IMPI

•760

A solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methyl-2oxopiperidin- 3-yl) methyl acetate (282 mg, 0.589 mmol; Example 186, Step A), 2 (tributylphosphoranylidene) acetonitrile (171 mg, 0.707 mmol) and di-tert-butyl iminodicarbonate (256 mg, 1,179 mmol) in toluene (3 mL) under argon was stirred at 110 ° C for 2 h. Purification by flash column on silica gel (0 to 60% EtOAc. In hexanes) gave the title compound. Mass Spectrum (ESI) m / z = 677 (M + l).

Stage B.

2 - ((3R, 5R, 6S) -1 - ((S) -l-aminobutan-2-yl) -5- (3 chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin- 3yl) methyl acetate

A solution of 2 - ((3R, 5R, 6S) -1 - ((S) -1- (bis (tert-

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL butoxycarbonyl) amino) butan-2-yl) -5- (3-chlorophenyl) -6- (4761

IMPI methyl chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetate (167mg, 0.246mmol) prepared in Step A above in dioxane was stirred with HC1 (4M, 0.6mL) at rt for 2h. Chromatography on silica gel (0 to 20% MeOH / DCM) gave the title compound. Mass Spectrum. (ESI) m / z = 477 (M + l).

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-2-oxo-l - ((S) -1- (pyridine-3-sulfonamido) butan-2- yl) piperidin-3-yl) acetic

A solution of 2 - ((3R, 5R, 6S) -1 - ((S) -l-aminobutan-2-yl) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2 -oxopiperidin-3yl) methyl acetate (13 mg, 0.027 mmol; Example 196, Step A) and pyridine-3-sulfonyl chloride (4.84 mg, 0.027 mmol) in pyridine (0.3 mL) was stirred at 110 ° C for 4h . Chromatography on silica gel (0 to 60% EtOAc in hexanes) gave 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo- methyl ((S) -1- (pyridine-3-sulfohamido) butan-2-yl) piperidin-3-yl) acetate. This was hydrolyzed with LiOH (IN solution in water, 0.3 mL) in ethanol (0.5 mL) for 3h at rt. HPLC purification (column C18, eluting with 10 to 95% CH3CN in water, with 0.1% TFA) gave the title compound as a 1: 1 complex with 2,2,2-trifluoroacetic acid.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 9.29 (1 H, br. S.),

8.90 (1 H, d, <7 = 4.4 Hz), 8.32 (1 H, d, <> 8.1 Hz), 7.66 - 7.76 (1

762

OF THE V INDUSTRIAL PROPERTY X »

H, m), 7.15 (1 H, d, J = 8.1 Hz), 7.10 (1 H, t, <> 7.8 Hz), 7.02 (2

H, s), 7.06 (1 H, s), 6.94 (1 H, s), 6.74 (1 H, d,> 7.3 Hz),

<td>s),</td><td> 0.72</td><td>(3 H,</td><td>br. s</td><td>.). Spectrum</td><td>Masses</td><td>(ESI)</td><td>m / z = 604 (M + l).</td>

EXAMPLES 197-199 were also prepared from 2 ((3R, 5R, 6S) -1 - ((S) -l-aminobutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - Methyl 3-methyl-2-oxopiperidin-3-yl) acetate (Example 196,

Step B) by procedures similar to that described in Example

196, Stage

C, replacing pyridine-3sulfonyl chloride with the appropriate reagent.

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 197</td><td>NC - <^ VS = OX = / HNy</td><td>4- Chloride Cyanobenzene-1- sulfonyl</td>

<td> 198</td><td>or?" NC 7</td><td>3- Chloride Cyanobenzene-1- sulfonyl</td>

763

Pyridine-2sulfonyl chloride

EXAMPLE 197

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 (4-cyanophenylsulfonamido) butan-2-yl) -3- methyl-2-oxopiperidin-3yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.95 (2 H, m,> 8.6 Hz), 7.81 - 7.87 (2 H, m), 7.22 (2 H, d,> 8.1 Hz), 7.16 - 7.20 ( 1 H, m), 7.11 - 7.16 (1 H, m) ·, 7.06 (1 H, s), 6.98 (1 H, t, <7 = 1.7 Hz), 6.80 (1 H, d,> 7.6 Hz) , 5.41 (1 H, br. S.), 4.68 (1

H, d,> 10.0 Hz), 3.38 (1 H, br. S.), 3.17 (1 H, ddd,> 13.5,

10.5, 2.7 Hz), 2.98 (1 H, d,> 14.7 Hz), 2.78 (1 H, d,> 14.7

Hz), 2.69 - 2.76 (1 H, m), 2.35 (1 H, t,> 13.8 Hz), 2.00 - 2.08 (2 H, m), 1.55 (1 H, d,> 7.6 Hz), 1.52 (4 H, s), 0.59 (3 H, br. S.). Mass Spectrum (ESI) m / z = 628 (M + l).

EXAMPLE 198

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 (3-cyanophenylsulfonamido) butan-2-yl) -3- methyl-2-oxopiperidin-3yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 8.15 (1 H, t,> 1.5

Hz), 8.07 (l H, d,> 7.8 Hz), 7.89 (1 H, dt,> 7.8, 1.2 Hz), 7.70 (1 H, t,> 7.9 Hz), 7.20 (2 H, d,> 7.8 Hz), 7.17 (1 H, dt,

<7 = 8.3, 1.5 Hz),

7.13 (1 H, t, <> 7.7 Hz),

7.06

764

INSTITUTE Ais: DE LA FRC IND.US (1 H, s)

d, <7 = 14.7 Hz), 2.76 (1 H, br. s.), 2.35 (1 H, t, <> 13.7 Hz), 2.04 (1 H, dd, <> 13.9, 2.9 Hz), 1.56 ( 1 H, d, <> 7.1 Hz), 1.52 (3 H,

s), 0.61 (3 H, br. s.). Mass Spectrum (ESI) m / z = 628 (M + l).

EXAMPLE 199

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1 - ((S) -l- (pyridine-2-sulfonamido) butan-2-yl) piperidin-3-

<td>il) acetic.</td><td>Compound</td><td>obtained as</td><td>the</td><td>get out of</td><td colspan="2">acid</td><td> 2,2,2-</td>

<td colspan="2">trifluoroacetic.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>ΤΗ NMR</td><td>(500 MHz,</td><td>CHLOROFORM-d) δ</td><td>ppm</td><td> 8.73 (1</td><td>H</td><td>d,</td><td> <>4.2</td>

Hz), 3.51 (1 H, br. S.), 3.22 (1 H, br. S.), 3.10 - 3.18 (1 H, m), 3.03 (1 H, d, <> 14.9 Hz), 2.94 ( 1 H, dt, <> 14.0, 4.1 Hz),

2.75 (1 H, d, J = 14.9 Hz), 2.44 (1 H, t, <> 13.7 Hz), 1.99 (4 H, dd, ¿> 14.1, 2.8 Hz), 1.78 - 1.83 (3 H, m) , 1.54 (3H, s), 1.43 -

1.53 (2 H, m), 0.51 (3 H, t, <> 7.3 Hz). Mass Spectrum (ESI) m / z = 604 (M + l).

Acid

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

765

IMPI

EXAMPLE 200

1- (N, 1-dimethylcyclopropansulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

A solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (1-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) methyl acetate (21.7 mg, 0.036 mmol; Example 193), 2 (tributylphosphoranylidene) acetonitrile (8.8 mg, 0.036 mmol) and a drop of MeOH in toluene (0.5 mL) was stirred at 110 ° C during lh. Purification by flash column on silica gel (0 to 60% EtOAc in hexanes) gave 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S ) -1- (N, 1-dimethylcyclopropansulfonamido) methyl-butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetate. This was hydrolyzed with LiOH (IN solution in water, 0.3 mL) in ethanol (0.5 mL) for 3h at rt. HPLC purification (column C18, eluting with 10 to 95% CH3CN in water, with 0.1% TFA) gave the title compound.

CHLOROFORM-d) δ ppm 7.26 (2 H, br. S.),

766 XH NMR (500 MHz,

7.13 (2 H, d, J = 3.7 Hz), 6.94 (2 H, br. S.), 6.88 (1 H, br. S.), 4.80 (1 H, d, <7 = 9.5 Hz), 4.36 (1 H, br. S.), 2.96 - 3.12 (3 H, m), 2.86 - 2.93 (4 H, m), 2.79 (3 H, d, 17 = 14.2 Hz),

2.69 (3 H, d, <7 = 15.4 Hz), 2.41 - 2.64 (15 H, m), 1.96 (1 H, dd, <7 = 14.4, 7.3 Hz), 1.84 (1 H, d, J = 13.7 Hz), 1.55 - 1.64 (2 H, m), 1.53 (3 H, br. S.), 1.38 - 1.48 (6 H, m), 0.81 (2 H, br. S.), 0.51 (3 H, t, <7 = 6.2 Hz). Mass Spectrum (ESI) m / z = 595 (M + l).

EXAMPLE 201

3 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-1 - ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl acid ) -2oxopiperidin-3-yl) propanoic or 3 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- ( Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3-

Stage A.

(5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1,767 hydroxybutan-2-yl) piperidin-2-one

To a mixture of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) piperidin-2-one (20.00 g?

51.0 mmol; Example 185,

Stage

B) and Nmethylcyclopropansulfonamide (10.34 g, 76 mmol) in

100 mL of toluene room temperature cyanomethylenebutyl phosphorane (20.51 mL, 76 mmol) was added.

The resulting mixture was heated to

130 ° C for 12h, then cooled to room temperature and loaded directly onto a column of silica gel for purification, eluting with 0 to 10% MeOH in DCM to provide the title compound. Mass Spectrum (ESI) m / z = 509 (M + l).

Stage B.

N - ((2S) -2 - ((2S, 3R) -3- (3-Chlorophenyl) -2- (4-chlorophenyl) -5-methyl-6-oxopiperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

768

The title compound was obtained as a mixture of diastereomers from N - ((S) -2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6-oxopiperidin-l- yl) butyl) -Nmethylcyclopropansulfonamide (Example 201, Step A) using a procedure similar to that described in Example 185, Step D. Mass Spectrum (ESI) m / z = 523 (M + l).

Stage C. N - ((S) -2 - ((5R, 6S) -3- (But-3-enyl) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2- oxopiperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide (Isomer 1)

* stereochemistry not determined

To a solution of N - ((2S) -2 - ((2S, 3R) -3- (3-chlorophenyl) -2 (4-chlorophenyl) -5-methyl-6-oxopiperidin-l-yljbutyl) -N-

769

IP

INSTITUTO MEXICA of the INDUSTRIAL f

5.0 mmol; Example 201,

10.00 mmol) at -15 ° C.

methylcyclopropansulfonamide (2618 mg,

Stage B) in degassed lithium diisopropylamide THF (5.00 mL,

After stirring at -15 ° C for 30 min, the reaction mixture was cooled to -74 ° C. 4-Bromobut-l-ene (1,066 mL,

10.50 mmol) was added. slowly. The reaction mixture was stirred at -74 ° C for 3 h before warming to rt and then stirred at rt for 66h. They were filtered and purified by HPLC (C18 column eluting with 10 to 95% CH3CN in water, with 0.1% TFA) to give the title compound as the first elution isomer. Its stereoisomer is obtained as the last elution isomer.

<td></td><td>XH NMR</td><td>(500 MHz</td><td colspan="2">, CHLOROFORM-d)</td><td>opm 7.22 (2 H, d,</td><td> 7=7</td><td> .6</td>

10.6, 3.1 Hz), 2.90 (3 H, s), 2.74 - 2.87 (2 H, m), 2.24 -

2.37 (2 H, m), 2.11 - 2.21 (2 H, m), 2.00 (1 H, ddd, 7 = 13.6,

<td>Hz),</td><td> 0.95</td><td> - 1.04 (2</td><td>H, m)</td><td> , 0.53</td><td> (3</td><td>H</td><td>t, 7 = 7.5</td><td>Hz), Spectrum</td>

Stage D.

770

Acid

chlorophenyl) -3-methyl-l - ((S) -1- (N

methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) propanoic or 3 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- ((S) -1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) propanoic

The title compound was obtained from N - ((S) —2— ((5R, 6S) -3- (but-3-enyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxopiperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide (Isomer 1, 604 mg, 1,046 mmol;

Example 201, Step C) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) 5ppm 7.23 (2 H, d, 7 = 7.4 Hz), 7.11 - 7.17 (3 H, m), 6.98 (2 H, m), 6.89 - 6.94 (1 H, m ), 4.75 (1 H, d, 7 = 11.3 Hz), 4.24 (1 H, br. S.), 3.17 (1 H, ddd, 7 = 13.8, 10.8, 3.1 Hz), 2.89 (3 H, s) , 2.63 - 2.82 (3 H, m), 2.55 (1 H, dd, 7 = 8.5, 6.2 Hz), 2.39 - 2.52 (2 H, m), 2.27 - 2.39 (2 H, m) ', 1.82 - 1.94 (2 H, m), 1.73 (1 H, dd, 7 = 13.7, 3.1 Hz), 1.48 - 1.65 (2 H, m), 1.28 - 1.33 (4 H, m), 1.17 - 1.25 (2 H, m ), 0.95 - 1.04 (2H, m), 0.46 0.55 (3H, m). Mass Spectrum (ESI) m / z = 595 (M + l).

771

EXAMPLE 202

X 1U 1 IL

INSTITUTO ME ~ O DELAP ^ G

INDuíjMaL

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl- acid

1- ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2- oxopiperidin-3-yl) acetic

Stage A. (5R, 6S) -1 - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethylpiperidin-2-one

To a -78 ° C solution of (5R, 6S) -1 - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2 -one (764 mg, 1,211 mmol; Example 185, Step C) in THF (6 mL) under argon 1.0M solution of lithium diisopropyl amide in THF (1,211 mL, 1,211 mmol) was added. The mixture was warmed to 0 ° C for 30 minutes. Mix it

772

cooled to -78 ° C and iodoethane (0.117 mL, 1,454 mmol) was added. The resulting solution was stirred at 0 ° C for 1 hour. The mixture was quenched with saturated aqueous NH solution4C1. The mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCI solution, dried over Na2SW4 and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 5 to 25% ethyl acetate / hexanes) to give the title compound as a mixture of diastereomers.

Stage B. (5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3ethyl-1 - ((S) -l-hydroxybutan-2-yl) piperidin-2- one

HO.

Cl (5R, 6S) -1 - ((S) -1- (Tert-butyldiphenylsilyloxy) butan-2-yl) 5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethylpiperidin-2-one (421 mg, 0.639 mmol; Example 202, Step A) formed azeotropes with toluene (3X). THF (1.6 mL) was added. The mixture was bubbled with argon for 5 minutes and then cooled to 0 ° C. 1.0 M solution of lithium diisopropylamide in THF (1,246 mL, 1,246 mmol) was added dropwise. After 25 minutes, allyl bromide. (0.166 mL, 1.917 mmol) was added

773

drop by drop. After 20 minutes, the mixture was quenched with saturated aqueous NH solution4C1. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The residue was dissolved in THF (3 mL) and 1.0M solution of tetrabutylammonium fluoride in THF (2,335 mL, 2,335 mmol) was added. After overnight stirring, the mixture was partitioned between 5% aqueous HC1 and ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 20 to 50% ethyl acetate / hexanes) to give the title compound as the most polar important diastereomer.

Step C. N - ((2S) -2 - ((5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxopiperidin-l-yl) butyl ) -Nmethylcyclopropansulfonamide

IMPI

INSTITUTE λ 't X i C / »Ν O

FROM THE ΡλΟ? Ί £ ΓΛΟ

INDUSTRIAL

(5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-

1 - ((S) -l-hydroxybutan-2-yljpiperidin-2-one (147 mg, 0.319 mmol; Example 202, Step B) and N-methylcyclopropansulfonamide (129 mg, 0.958 mmol) were dissolved in toluene (2 mL) .The mixture was evacuated and refilled with argon (5X) .Cyanomethylenetributylphosphoran (0.251 mL, 0.958mmol) was added .The mixture was evacuated and refilled with argon (5X).

The mixture was heated at 70 ° C for 2 hours. The mixture was loaded onto silica gel and the product was eluted with 5 to 75% ethyl acetate / hexanes to give the title compound.

Stage D. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-ethyl-l - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) acetic

The title compound was obtained from N - ((2S) -2 ((5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2oxopiperidin- l-yl) butyl) -N-methylcyclopropansulfonamide (Example 202, Step C) by a procedure similar to

775 described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.54 (t, <7 = 7.53 Hz,

H). Mass Spectrum '(ESI) m / z = 595.2 (M + l).

EXAMPLE 203

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methoxy-1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) acid -2oxopiperidin-3-yl) acetic

Stage A.

(5R, 6S) -1 - ((S) .— 1— (tert-butyldiphenylsilyloxy) scarf-

2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-hydroxypiperidin-2 one

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

776

(5R, 6S) -1 - ((S) -1- (Tert-butyldiphenylsilyloxy) butan-2-yl) 5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (1,100 g,

<td colspan="2">1,744 mmol; Example 185,</td><td>Stage C)</td><td colspan="3">dissolved in THF (8.72</td>

<td>mL) and</td><td>bubbled with argon</td><td>during</td><td>5 minutes. The</td><td>mixture</td><td>I know</td>

<td>cooled</td><td>down to -78 °</td><td>C and</td><td>solution 1.0</td><td>M</td><td>of</td>

Lithium bis (trimethylsilyl) amide in THF (2,093 mL, 2,093 mmol) was added dropwise. After 30 minutes, peroxybis (trimethylsilane) (0.413 mL, 1.918 mmol) was added dropwise. After 1 hour, the cooling bath was removed. After stirring overnight, the mixture was quenched with saturated aqueous NH solution4C1 and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SW4, and concentrated. The residue was dissolved in EtOH (14 mL) and pyridine ptoluenesulfonate (131 mg, 0.523 mmol) was added. After 1 hour, the mixture was basified with saturated aqueous NaHCC solution> 3. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with aqueous NaCI, dried over Na2SO4

777 saturated solution was concentrated. The residue was instantaneously purified on silica gel (column 40 g, eluent: 5a

50% ethyl acetate / hexanes) to result in the title compound.

Stage B. (5R, 6S) -1 - ((S) -1- (tert-butyldiphenylsilyloxy) butan-

2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methoxypiperidin-2-one

To a solution to

0 ° C of (5R / 6S) -1 - ((Sj-1- (tert butyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-hydroxypiperidin-2-one (476 mg, 0.736 mmol; Example 203, Step A) in THF (7,360 mL) sodium hydride (58.9 mg, 1,472 mmol) was added. After 30 minutes, iodomethane (0.092 mL, 1,472 mmol) was added. 5 minutes, the cooling bath was removed.After 2 hours, the mixture was quenched with saturated aqueous NH solution4C1. The mixture was partitioned between ethyl acetate and water.

MEXICAN INSTITUTE OF INDUSTRIAL PRÓHtDAD

The organic layer was washed with saturated aqueous solution of

<td>NaCl,</td><td>dried over Na2SO4, and concentrated to be the</td>

title compound.

Step C. (3R, 5R, 6S) -3-allyl-l - ((S) -1 - ((tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methoxypiperidin-2-one

A solution of (5R, 6S) -1 - ((S) -1 - ((tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methoxypiperidin-2 -one (495 mg, 0.749 mmol; Example 203, Step B) in THF (7.49 mL) was bubbled with argon for 5 minutes and cooled to 0 ° C. A 1.0 M solution of lithium diisopropylamide in THF (1,461 mL, 1,461 mmol) was added dropwise. The internal temperature did not rise above 2 ° C. After 30 minutes, allyl bromide (0.194 mL, 2,247 mmol) was added. The cooling bath was replaced with a room temperature water bath. After 70 minutes, the mixture was quenched with saturated aqueous solution of

ΪΜΡΙ

779

NH4C1 and extracted with ethyl acetate.

The organic layer was washed with saturated aqueous NaCl solution, dried over

Na2SW4 and concentrated. The residue was purified by flash chromatography on silica gel (column 40 g, eluent: 5 to 30% ethyl acetate / hexanes) to give the title compound as the most polar diastereomer.

Stage D. (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methoxypiperidin- 2 one

To a solution of · (3R, 5R, 6S) -3-allyl-l - ((S) -1 - ((tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- ( 4-chlorophenyl) -3-methoxypiperidin-2-one (260 mg, 0.371 mmol; Example 203, Step C) in THF (1 mL) 1.0 M solution of tetrabutylammonium fluoride in THF (1484 mL, 1484 mmol) was added. After stirring overnight, the mixture was partitioned between water and ethyl acetate. NH aqueous saturated solution4C1 was added to break the emulsion. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SW4, and concentrated. The residue was

INSTITUTE V '.,' S'J I · .....}

DELAt-S-, - V .. -χρ ·

INUUSTP-i- —-- purified by flash chromatography on silica gel (column 12 g, eluent: 35 to 100% ethyl acetate / hexanes)

780 to be the title compound.

methylcyclopropansulfonamide

To a solution of (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methoxypiperidin2 -one (124 mg, 0.268 mmol; Example 203, Step D) in toluene (1.3 mL) N-methylcyclopropansulfonamide (109 mg,

0.804 mmol).

The mixture was evacuated and refilled with argon

Cyanomethylenetributylphosphoran (0.211 mL, 0.804 mmol) was added

The mixture was evacuated and refilled with argon (5X).

The mixture was heated in an oil bath to

70 ° C for 12 hours then cooled to room temperature and stirred for days at room temperature.

The mixture was loaded onto silica gel and the product was eluted with 20-60% ethyl acetate / hexanes. The residue was purified once more by flash chromatography on silica gel (column 12 g, eluent: 10 to 60% ethyl acetate / hexanes) to give the title compound.

Step F. 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methoxy-l - ((S) -l- (N-methylcyclopropanesulfonamido) butan-2-yl acid ) -2-oxopiperidin-3yl) acetic

The title compound was obtained from N - ((S) -2 ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methoxy-2- oxopiperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide (Example 203, Step E) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) ppm 0.59 (t, 7 = 7.53 Hz, 3H) 1.02 -1.05 (m, 2H) 1.16 - 1.27 (m, 2H) 1.59 - 1.77 (m, 1H) 1.85 - 1.99 (m, 2H) 2.22 - 2.40 (m, 1H) 2.75 (d, 7 = 13.30 Hz, 1H) 2.84 - 2.98 (m, 6H) 3.03 - 3.16 (m, 2H) 3.26 ( d, 7 = 15.65 Hz, 1 H) 3.52 (s, 3 H) 4.99 (d, 7 = 10.76 Hz, 1 H) 6.91 -

6.97 (m, 2H) 7.02 (s, 1, H) 7.10 - 7.20 (m, 2H) 7.22 - 7.31 (m, 3H). Mass Spectrum (ESI) m / z = 597.1 (M + l).

EXAMPLE 204

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l ((S) -6-methyl-4-Oxoheptan-3-yl) acid -2-oxopiperidin-3-yl) acetic

782

.or

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

1- ((3S) -4-hydroxy-6-methylh.eptan-3-yl) -3-methylpiperidin-2-one

PH

OR

To a solution of (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-clo.phenyl) -3-methyl-2-oxopiperidin-lil) butanal (1,755 mmol) (Example 91, Step C) in THF (5 mL) at 0 ° C 2M isobutylmagnesium bromide (878 pL, 1,742 mmol) was added under N2. The reaction was allowed to warm to rt After stirring for 2 h at rt, the reaction was quenched with saturated NH solution4C1 and extracted with EtOAc. The combined organic layers were washed (saturated aqueous NaCl solution), dried over MgSO4, filtered and the filter product concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 15 to 35% of

IMPI

783

EtOAc / Hexane, gradient elution) for title compound as a do-dra'a mixture1Lei.eúii'itax.us;

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -6-methyl-4-oxoheptan-3- il) -2oxopiperidin-3-il) acetic

To a rapidly stirred solution of 120 mg (0.239 mmol) of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S) -4-hydroxy- 6-methylheptan-3-yl) -3methylpiperidin-2-one (Example 204, Step A) in a mixture of 1.5 mL of water, 1.0 mL of acetonitrile and 1.0 mL of CC14 Sodium periodate (204 mg, 0.995 mmol) was added, followed by ruthenium (III) chloride hydrate (5.38 mg, 0.024 mmol). After vigorously stirring for 2 h, the reaction was acidified (10% citric acid) and diluted with EtOAc. The reaction mixture was filtered through Celite® (JT Baker, Phillipsberg, NJ, diatomaceous earth) and the filter product was extracted with EtOAc. The combined organic layers were washed with saturated NaCl solution, dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: '10 to 20% iPrOH / hexane, gradient elution) to provide the title compound as

IMPI XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.64 (t, 7 = 8.0 a white solid.

784

Example 205

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (ethylsulfonyl) pentan-3-yl) -3-methyl-2-oxopiperidin-3- yl) acetic

Step A. Diethyl ethylsulfonylomethylphosphonate

785

To a hectic iMPie solution ?:

MEXICAN INSTITUTE \ '

FROM PROPERTY V »- .INDUSTKIAL diethyl ethylthiomethylphosphonate (Aldrich, St. Louis,

MO) (0.912 mL, 4.71 mmol) in dichloromethane (47.1 o ° c metachloroperoxybenzoic acid (2.63 g,

15.2 mmol).

The reaction mixture was stirred

25 ° C for 24 hours. The reaction solvent was removed in vacuo, the crude material was diluted with diethyl ether, then washed with saturated sodium bicarbonate (3X).

The organic layer was dried over Na2SO4, filtered, and the filtration product was concentrated under reduced pressure to provide the title compound as a colorless white solid

Step B. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -1 - ((S, E) -1 (ethylsulfonyl) pent-l-en-3-yl) -3-methylpiperidin-2-one

To a stirred solution of diethyl ethylsulfonylomethylphosphonate (153 mg, 0.625 mmol; Example 202, Step A) in THF (2.60 mL) at -78 ° C, butyllithium (177 pL, 0.443 mmol) was added.

After 30 minutes

786 a solution of (2S) -2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2,2-dimethyl-l, 3-dioxolan-

4-yl) methyl) -3-methyl-2-oxopiperidin-l-yl) butanal (135 mg, 0.260 mmol; Example 150, Step D) in THF (0.50 mL) was added. The reaction was stirred for 15 minutes at -78 ° C and then stirred at 25 ° C for 3 hours. The reaction was partitioned between saturated ammonium chloride and EtOAc (2X), and then the combined organic layers were dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (column 4 g, eluent: 0 to 40% EtOAc / hexanes) provided the title compound as a colorless white solid.

Step C. (3R / 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -1 - ((S) -1- | (ethylsulfonyl) pentan-3-yl) -3-methylpiperidin-2-one

To a solution of (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-

chlorophenyl) -3- ((2,2-dimethyl-l, 3-dioxolan-4-yl) methylT-f-41·

IMPI ((S, E) -1- (ethylsulfonyl) pent-l-en-3-yl) -3-methylpiperidm-2 one (65.0 mg, 0.107 mmol; Example 205, Step B) in 1 <2-dichloroethane (1.07 mL ) at 25 ° C Crabtree catalyst (7.74 mg, 9.61 pinol) was added. ΕΓ reaction system (a hydrogenation pump) was flushed with 3X hydrogen gas, pressurized with hydrogen to 3447.38 kilopascals, and the reaction was stirred at 25 ° C for 24 hours. The reaction mixture was filtered through celite, washed with DCM, and concentrated under reduced pressure to produce the title compound as a colorless white solid.

Stage D. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (ethylsulfonyl) pentan-3-yl) -3- methyl-2oxopiperidin-3-yl) acetic

To a stirred solution of (3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3 - ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -

1 - ((S) -1- (ethylsulfonyl) pentan-3-yl) -3-methylpiperidin-2-one

<td> (70.0</td><td>mg,</td><td> 0.115</td><td>mmol;</td><td colspan="2">Example 202,</td><td>Stage C) in</td><td>THF</td><td> (1.15</td>

<td>mL) a</td><td> 25°</td><td>C se</td><td>added</td><td>a</td><td>solution</td><td>reagent</td><td>of</td><td>Jones</td>

<td>(oxide</td><td>of</td><td>chrome</td><td>(SAW) )</td><td> (138</td><td colspan="2">pL, 0.172 mmol) and the</td><td colspan="2">mix of</td>

The reaction was stirred for 1 hour. The reaction mixture was partitioned between water and EtOAc (2X), and then the combined organic layers were dried over Na2SO4, leaked and

788 the filter product was concentrated under reduced pressure. Purification of the residue by reverse phase high pressure liquid chromatography (column

Eclipse (Agilient Technologies, Santa Clara, CA), I eluted:

30-75% acetonitrile / water) provided the title compound as a colorless white solid.

XH NMR (50 0 MHz,

CDCI3) δppm 0.58 (t, J = 7.34

Hz, 3

Η), 1.43 (t, J = 7.46

Hz, 3 Η), 1.49 (s, 3 Η), 1.51

1.57 (m, 1 Η), 1.86 (dt, J

14.55, 7.40 Hz, 1 Η), 1.98 (dd, J =

12.84, 5.75 Hz, 1 Η), .2.04 (dd, J = 13.94, 2.45 Hz,

H)

2.97

2.76

2.16

[M + H] +.

554.2

Example 206

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (isopropylsulfonyl) pentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

IMPI

MEXICAN INSTITUTE PE INDUSTRIAL PROPERTY

789

Stage A. S- (diisopropoxyphosphoryl) methyl ethanothioate

To a stirred solution of diisopropyl bromomethylphosphonate (5.00 g, 19.3 mmol) in N, N-dimethylformamide (15.4 mL) was added potassium thioacetate (3.75 g, 32.8 mmol) followed by tetrabutylammonium iodide (0.36 g, 0.97 mmol). The reaction mixture was stirred at 85 ° C for 2.5 hours. The reaction mixture was cooled and partitioned between water and EtOAc (3X), and the layers were separated. The combined organic layers were dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (24 g column, eluent: 0 to 90% EtOAc / hexanes) provided the title compound as a colorless white solid.

790

IMPI

MEXICAN INSTITUTE OF THE INDUSTRIAL PRCrlcOAD

Stage B. diisopropyl isopropylthiomethylphosphonate

To a stirred solution of S (diisopropoxyphosphoryl) methyl ethanothioate (1.00 g, 3.93 mmol; Example 206,

Step A) In methanol (39.3 mL) at 0 ° C sodium methoxide (7.87 mL, 3.93 mmol) was added, followed by 2-bromopropane (0.44 mL, 4.72 mmol). The reaction was stirred at 25 ° C for 16 hours. The reaction solvent was removed in vacuo and the crude material was partitioned between water and EtOAc (2X) and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SW4, filtered and the filter product concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (column 40 g, eluent: 0 to 75% DCM / hexanes) provided the title compound as a colorless white solid.

<td colspan="4">Step C. Diisopropyl isopropylsulfonylomethylphosphonate</td>

<td rowspan="2">The</td><td colspan="2">I</td><td rowspan="2">diisopropyl se</td>

<td>isopropylthiomethylphosphonate</td><td>of</td>

<td>turned</td><td>to the title compound</td><td>by</td><td>The procedure</td>

described in Example 205 colorless white.

791

MEXICAN INSTITUTE « , N DEÍ ^ ROTiSDAD pij. 7 \ · · η <R <Du. '> TvJAL.z

Stage A and isolated as a solid

Step D. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -1 - ((S, E) -1 (isopropylsulfonyl) pent-l-en-3-yl) -3-methylpiperidin-2-one

Step E. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -1 - ((S) -1 (isopropylsulfonyl) pentan-3-yl) -3-methylpiperidin-2-one

792

MEXICAN INSTITUTE OF PROPERTY

(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2,2dimethyl-1,3-dioxolan-4-yl) methyl) -1 - ((S , E) -1 (isopropylsulfonyl) pent-l-en-3-yl) -3-methylpiperidin-2-one was converted to the title compound as described in Example

205, Step C and isolated as a colorless white solid.

Step F. Acid- 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (isopropylsulfonyl) pentan-3-yl) -3 -methyl-

2-oxopiperidin-3-yl) acetic (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2,2dimethyl-1,3-dioxolan-4-yl ) methyl) -1 - ((S) -1 (isopropylsulfonyl) pentan-3-yl) -3-methylpiperidin-2-one is

<td colspan="2">converted to compound</td><td>of the title as</td><td>I know</td><td>describes</td><td>at</td>

<td>Example 205, Stage</td><td>D</td><td>and it was isolated as</td><td>a</td><td>solid</td><td>White</td>

<td>colorless.</td><td></td><td></td><td></td><td></td><td></td>

(m, 1H), 2.77 (d, J = 15.85 'Hz, 2H),

793

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

2.95-3.07 (m, 3H),

3.09 - 3.19 (m,

H), 3.19 - 3.31. (m,

Hz, 1H), 6.75

Η)

6.96 (s, 1H), 7.01

7.10 (m, 2H),

7.12 (d, J = 7.63

Hz,

H), 7.14 - 7.19 (m, 1

H), 7.23 - 7.27 (m, 2 Η); EM (ESI)

568.2 [Μ + Η]+.

EXAMPLE 207

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (cyclopropylmethylsulfonyl) pentan-3-yl) -3-methyl-2- oxopiperidin-3-yl) acetic

(2S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 ((2,2-dimethyl-l, 3-dioxolan-4-yl) methyl) -3-methyl-2-oxopiperidin-l-yl) butanal (Example 150, Step D) with diisopropyl (cyclopropylmethylsulfonyl) methylphosphonate (prepared as a colorless white solid in analogy to the procedure of Example 206 steps A and B) were converted to the title compound by sequence as described in Example 205. The title compound is an opaque white solid.

(t.

XH NMR (400 MHz,

J = 7.10 Hz, 3H),

794

CDC13) δ ppm 0.39 - 0.48 (m, 2H), 0.56

0.74 - 0.86 (m, 2H), 1.13-1.25 (m, 1

H), 1.48 (br. S., 3 H), 1.51 - 1.59 (m, 1 H), 1.79 - 1.94 (m,

H), 1.97 - 2.11 (m, 2H), 2.13 - 2.24 (m, 1H), 2.24 - 2.42 (m, 1H), 2.78 (d, J = 14.87 Hz, 1H), 2.92 (d, J = 5.28 Hz, 2

7.27 (m, 2H); MS (ESI) '580.2 [M + H]1.

EXAMPLE 208

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl- acid

2-oxo-l - ((S) -1- (2-oxopyrrolidin-l-yl) butan-2-yl) piperidin-3-yl) acetic

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 3-methyl-l - ((S) -1- (2-oxopyrrolidin-l- il) bütan-2-il) piperidin-2ona

IMPI

MEXICAN INSTITUTE '

OF THE PROPERTY

INDUSTRIAL

To a solution of (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) butanal (84 mg, 0.189 mmol; Example 91, Step C), ethyl 4-aminobutyrate hydrochloride (127 mg, 0.756 mmol) and acetic acid (3 drops.) in DCE / MeOH (3/1, 4.0 mL) was added triacetoxyhydroborate sodium (200 mg, 0.945 mmol) at 25 ° C. After stirring at 25 ° C for 18 hr, the reaction was quenched by adding NaHCO solution3 Saturated aqueous ice-cold and extracted with DCM. The combined organic layers were washed (1 χ saturated aqueous NaCl solution) and concentrated under reduced pressure. The residue was purified by preparative reverse phase HPLC (acetonitrile in water with 0.1% TFA, gradient elution) to give the title compound as a white solid.

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -3-methyl-2-oxo-l - ((S) -1- (2-oxopyrrolidin -lil) butan-2-yl) piperidin-3-yl) acetic

The title compound was obtained from

796

IMPIéB

MEXICAN INSTITUTE ¥ 4 ·,

DE LA FRON '.-'-' Av -T.

INDUSTRIAL --- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

1- ((S) -1- (2-oxopyrrolidin-l-yl) butan-2-yl) piperidin-2-one (Example 208, Step

A) by a procedure similar to that described in Example

71, Stage F.

J =

8.0 XH NMR (400 MHz, .CHLOROFORM-d) δ ppm 0.55 (t,

4.0

Hz, 2H); EM

EXAMPLE 209

Azabicyclo [2.2.1] heptanv5-yl) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid - TFA salt

Stage A. (3S, 5R, 6S) -1 - ((S) -1 - ((IR, 4R) -2-oxa-5azabicyclo [2.2.1] heptan-5-yl) butan-2-yl) - 3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one

rafX = F = 3CS5CtS! S5 »

To a solution of (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) butanal (100 mg, 0.224 mmol; Example 91, Step C) in DCE (2 mL) was added (IR, 4R) -2-oxa-5-azabicyclo [2.2.1] heptane (Butora, G.; Goble, S .; Pastemak , A .; Yang, L .; Zhou, C .; Moyes, C. US Patent Publication No. 2008/0081803 (50 mg, 0.504 mmol) followed by sodium triacetoxyborohydride (95 mg, 0.448 mmol) and acetic acid (1.2 pL, 0.022 mmol). After overnight stirring, the mixture was quenched with saturated aqueous NaHCOs solution. The mixture was extracted with ethyl acetate (2X). The combined organic layers were washed with saturated aqueous NaCI solution, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 1 to 5% methanol / dichloromethane) to give the title compound.

azabicyclo [2.2.1] heptan-5-yl) butan-2-yl) -5- (3-chlorophenyl) -6 Stage B.

Acid 2 - ((3R, 5R, 6S) -1- ((S) -1 - ((IR, 4R) -2-oxa-5-

(4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic - salt of

798

TFA

To a solution of (3S, 5R, 6S) -1 - ((S) -1 - ((IR, 4R) -2-0xa-5azabicyclo [2.2.1] heptan-5-yl) butan-2-yl) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one (87 mg, 0.17 mmol; Example 209, Step A) in THF (0.8 mL), water (0.4 mL ), and t-butanol (0.4 mL) was added 4-methylmorpholine N-oxide (29mg, 0.25mmol) and 5 drops of 4% aqueous. Bear4. After 18 hours, Jones reagent (0.20 mL) was added. After 24 hours, 50 mL water was added to the mixture, and then the mixture was extracted with ethyl acetate (3X). The combined organic layers were washed with water, dried over

<td>Na2SW4</td><td colspan="5">and they concentrated.</td><td colspan="6">The residue was purified by HPLC</td>

<td colspan="2">high school</td><td>of</td><td colspan="2">phase</td><td colspan="2">inverse (eluent:</td><td> 0</td><td colspan="2">up to 100% MeCN</td><td colspan="2">+ TFA</td>

<td>at 0.1</td><td>% in</td><td colspan="2">Water</td><td> +</td><td>TFA</td><td colspan="4">0.1%, for 20 minutes)</td><td colspan="2">for</td>

<td colspan="2">turn out the</td><td colspan="3">compound</td><td>of the</td><td>Title.</td><td></td><td></td><td></td><td></td><td></td>

<td>XH</td><td>NMR</td><td> (400</td><td colspan="2">MHz,</td><td colspan="3">CHLOROFORM-d) δρριη</td><td> 0.95 - 1.17</td><td>(m,</td><td> 3</td><td>H)</td>

<td>3 H).</td><td colspan="2">Spectrum</td><td>of</td><td colspan="2">: Masses</td><td colspan="2">(ESI) m / z = 545.</td><td>2 (M + l).</td><td></td><td></td><td></td>

Acid

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3799

EXAMPLE 210 methyl-1 - ((S) -1 - ((S) -3-methylmorpholine) butan-2-yl) -2 oxopiperidin-3-yl) acetic acid or 2 - ((3R, 5R, 6S) - 5- (3 chlorophenyl) -5- (4-chlorophenyl) -3-methyl-l - ((S) —1 - ((R) -3methylmorpholine) butan-2-yl) -2-oxopiperidin-3-yl) acetic

★ undetermined stereochemistry

Stage A. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methi-2-oxo-l - ((2S) -l-oxobutan-2- il) piperidin-

3-yl) acetic

To a -78 ° C solution of oxalyl chloride (0.166 mL, 0.332 mmol) in dichloromethane (2 mL) was added dimethyl sulfoxide (0.047 mL, 0.663 mmol) dropwise. After ten minutes, 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1hydroxybutan-2-yl) -3-methyl acid -2-oxopiperidin-3-yl) acetic (140 mg,

800

0.301 mmol; Example 185) in dichloromethane (2 mL) was added dropwise. After 15 minutes, triethylamine (0.210 mL, 1,507 mmol) was added dropwise. The mixture was warmed to 0 ° C for 10 minutes and then quenched with 10% citric acid aq. The mixture was diluted with water and extracted with dichloromethane (2X). The combined organic layers were washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated to become the title compound.

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l - ((2S) -1- (3-methylmorpholino) butan-2-yl) -2-oxopiperidin-

3-yl) acetic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -l-oxobutan- 2-yl) piperidin-3yl) acetic (960 mg, 2,076 mmol; Example 210, Step A) in 1,2-dichloroethane (15 mL), 3-me.-methylmorpholine (Enamina Ltd, Kiev, Ukraine) (0.471 mL, 4.15) was added mmol) and sodium triacetoxyborohydride (880 mg, 4.15 mmol) .. After stirring overnight, the mixture was quenched with saturated aqueous NH solution4C1. The mixture was extracted with dichloromethane (2X). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4 anhydrous, and concentrated. The residue was purified by flash gel chromatography

silica (eluent: 1 to 10% methanol / dichloromethane) for

801 the title compound is the major diastereomer.

The stereochemistry of the 3-morpholine stereocenter is unknown.

<td>XH NMR</td><td> (400</td><td colspan="4">MHz, CHLOROFORM-d)</td><td colspan="4">opm 0.50 (t, J = 7.53 Hz, 3</td>

Mass Spectrum (ESI) m / z = 547.2 (M + l).

EXAMPLE 211

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1 (thiomorpholino-1,1-dioxide) butan-2-yl ) -3-methyl-2-oxopiperidin-3 il) acetic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -l-oxobutan- 2802

IMPI to

INSTITUTO MEXICANO V. dscaíxofiedao v INDUSTRIAL · **.

0.219 mmol; Example 210,

Step A) in 1,2-dichloroethane (3 mL) thiomorpholine (0.128 g, 0.947 mmol), sodium (0.093 g, 0.438 mmol), and 2-acetic acid triacetoxyborohydride 1,1-dioxide was added.

After stirring for 2 days, the mixture was quenched with water. The mixture was extracted with ethyl acetate (2X). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4 anhydrous, and concentrated. The colorless film was purified by reverse phase preparative HPLC (column: Gemini-NX Co. 5um; Phenomonex, Torrance, CA; eluent: 0-100% MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes) . Fractions containing the product were transferred to a separatory funnel and saturated aqueous NaHCO solution.3 and dichloromethane were added. The aqueous layer was re-extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4 anhydrous, and concentrated to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.66 (t, 7 = 7.14 Hz,

Η). Mass Spectrum (ESI)

803 m / z =

581.2 (M + l).

EXAMPLE 212

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (3,3 ^ difluoroazetidin-l-yl) butan-2 -il) -3-methyl-2oxopiperidin-3-yl) acetic

To a solution of 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -l-oxobutan- 2yl) piperidin-3-yl) acetic (99 mg, 0.215 mmol; Example 210, Step A) in 1,2-dichloroethane (3 mL) hydrochloride was added to

3,3-Difluoroazetidine (55.7mg, 0.430mmol) followed by Sodium Triacetoxyborohydride (91mg, 0.430mmol). After stirring overnight, the mixture was quenched with water. The mixture was extracted with ethyl acetate (2X). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4 anhydrous and concentrated. The residue was purified by reverse phase preparative HPLC (eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes). The fractions that

IMPI

containing the product were transferred to a separatory funnel and saturated aqueous NaHCO solution3 and dichloromethane were added. The aqueous layer was re-extracted with dichloromethane. The combined organic layers were washed with

804 saturated aqueous NaCI solution, dried over Na2SO4 Anhydrous, filtered, and the filter product concentrated to give the title compound.

XH NMR (400 MHz, ACETONITRILE-cf3) opm 0.48 (t, J = 7.53

Hz, 3H) 1.32 (s, 3H) 1.46 - 1.62 (m, 1H) 1.68 - 1.82 (m, 1

H) 1.90 - 1.98 (m, 2 H) 2.01 - 2.05 (m 1 H) 2.13 - 2.23 (m, 1

H). Mass Spectrum (ESI) m / z = 539.0 (M + l).

EXAMPLE 213

Acid 2- ((3R, 5R, 6S) - * 1- ((2S) -1- (8-oxa-3azabicyclo [3.2.1] octan-3-yl) butan-2-yl) -5- (3 -chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic

805

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) 6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -l-oxobutan- 2yl) piperidin-3-yl) acetic (99 mg, 0.215 mmol; Example 210, Step A) in DCE (3 mL) 48.7 mg (0.43 mmol) of 8oxa-3-azabicyclo [3.2.1] octane (Connolly) was added , T .; Considine, J .;

Ding, Z .; Forsatz, B.; Jennings, M.; MacEwan, M .; McCoy, K .;

Place, D .;

Sharma, A .; Sutherland, K.

Organic Process

Research &

Development. 2010,

14 (2), 459-465. Note: the reference is for HC1 salt).

Sodium triacetoxyborohydride (91 mg, 0.430 mmol) was added followed by acetic acid (1.2 pL, 0.022 mmol). After overnight stirring, the mixture was partitioned between 5% aqueous HC1 and ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by preparative reverse phase HPLC (eluent: 0-100% MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes). Fractions containing the product were transferred to a separatory funnel and saturated aqueous NaHCO solution.3 and dichloromethane were added. The

806

WDUSTRÍÁL aqueous layer was re-extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4 Anhydrous, filtered, and the filter product concentrated to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) opm 0.37 - 0.53 (m, 3 H) 1.48 - 1.58 (m, 4 H) 1.83 - 2.15 (m, 7 H) 2.18 - 2.31 (m, 2 H) 2.50 (s , 2 H) 2.60 (d, 7 = 10.76 Hz, 1 H) 2.70 (d, 7 = 15.65 Hz, 1 H) 2.96 - 3.17 (m, 4 H) 4.29 - 4.42 (m, 2 H) 4.55 (d, 7 = 10.56 Hz, 1 H) 6.65 (dt, 7 = 7.68, 1.44 Hz, 1 H) 6.94 - 7.02 (m, 1 H) 7.06 - 7.13 (m, 1 H) 7.14 - 7.21 (m, 1 H) 7.21 -

7.33 (m, 4H). Mass Spectrum (ESI) m / z = 559.2 (M + l).

EXAMPLE 214

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S)

1- (3,3-dimethylmorpholine) butan-2-yl) -3-methyl-2-oxopiperidin-3 yl) acetic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) acid

6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -l-oxobutan-2-

il) piperidin-3-yl) acetic (70 mg,

0.151 mmol; Example 210,

807

Stage A) in DCE (3 mL) was added

45.9 mg (0.303 mmol) 3,3-dimethylmorpholine hydrochloride (Cottle,

D .; Jeltsch, A.;

Stoudt, T .; Walters,

D. Journal of

Organic

Chemistry. 1946,

11 (3), 286-91 .; Note:

reference is for free base) and sodium triacetoxyborohydride (64.2 mg, 0.303 mmol)

After overnight stirring, the mixture was diluted with saturated aqueous NH solution4C1. The mixture was extracted with DCM (2X). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SW4 anhydrous, filtered and the filter product concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 50% ethyl acetate / hexanes). Fractions containing the product were pooled, concentrated and re-purified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH / DCM) to become the title compound.

<td></td><td>XH NMR</td><td>(400 MHz, CLO1</td><td>ROFORM-d)</td><td>opm 0.47 -</td><td> 0.5</td><td>1 (m 3 H)</td>

Mass Spectrum '(ESI) m / z = 561.3 (M + l).

808

IMPI

MEXICAN INSTITUTE D £ LA FXOPÍEDAD

INDU3TIUAL

EXAMPLE 215

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (3-hydroxy-3- (trifluoromethyl) azetidin-l- il) butan-2-yl) -3methyl-2-oxopiperidin-3-yl) acetic

To a solution of 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -l-oxobutan- 2-yl) piperidin-

3-yl) acetic (70 mg, 0.151 mmol; Example 210, Step A) in DCE (3 mL) was added 53.8 mg (0.303 mmol) of 3 (trifluoromethyl) azetidin-3-ol hydrochloride (Patent Solution Publication from USA No. 2007/0275930) and sodium triacetoxyborohydride (64.2 mg, 0.303 mmol). After stirring for 18 hours, the mixture was partitioned between water and DCM. The aqueous layer was washed with DCM. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SÓ4 anhydrous, filtered and the filter product concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 50% acetate

IMPI

809

MEXICAN INSTITUTE

FROM THE t-ROr.i ^ AD

INDUSTRIAL Ethyl / Hexanes) to become the title compound.

XH NMR (400 MHz, MeOH) δρρπι 0.51 (t,

7 = 7.43 Hz, 3 H)

1.36 (m, 1H) 2,092.26 (m, 2H) 2.38 (dd, 7 = 12.52, 3.91 Hz, 1H) 2.52 - 2.64 (m, 1H)

2.75 (br. S., 1 H) 2.93 (d, 7 = 14.87 Hz, 1 H) 3.11 - 3.27 (m, 2

H) 3.28 - 3.43 (m, 3 H) 3.66 - 3.79 (m, 2 H) 4.62 (d, 7 = 10.56

Hz, 1H) 6.86 - 6.98 (m, 1H) '7.03 (s, 1H) 7.09 - 7.22 (m, 4

H) 7.27 (d, 7 = 7.24 Hz, 2H). Mass Spectrum (ESI) m / z =

587.2 (M + l).

EXAMPLE 216

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) - 1 - (methyl (oxetane-3-yl) amino ) butan-2-yl) -2oxopiperidin-3-yl) acetic

Stage A. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (methylamino) butan-2-yl ) -2oxopiperidin-3-yl) acetic - ammonium salt

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) acid

6- (4-Chlorophenyl) -3-methyl-2-oxo-l - ((S) -l-oxobutan-2 yl) piperidin-3-yl) acetic (201 mg, 0.434 mmol; Example 210 Step A) in DCE (3 mL) methylamine hydrochloride (117 mg, 1,736 mmol) was added followed by sodium triacetoxyborohydride (184 mg, 0.868 mmol) ·. After 4 hours, the mixture was diluted with methanol and DCM, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 20-100% ethyl acetate / hexanes followed by 6: 1: 0.1 DCM: MeOH: NH4OH) to be the title compound.

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (methyl (oxetane-3-yl ) amino) butan-

2-yl) -2-oxopiperidin-3-yl) acetic

To a solution of oxetan-3-one (17.78 mg, 0.247 mmol) in

DCE (3 mL) was added 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1 ammonium salt (methylamino) butan-2-yl) -2-oxopiperidin-3-yl) acetic (61 mg,

'811

0.123 mmol) obtained in sodium triacetoxyborohydride (78

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Stage

A followed by mg, 0.370 mmol) and 3 drops

AcOH. After 45 minutes, 3 my MeOH and oxetan-3-one (12 mg, 0.17 mmol) were added. After stirring overnight, oxetane-3-one (12mg, 0.17mol) and sodium triacetoxyborohydride (60mg, 0.32mmol) were added. After 24 hours, the mixture was diluted with methanol and evaporated on silica gel. The solid was purified by flash chromatography on silica gel (eluent: 0 to 100% [6: 1: 0.1 DCM / MeOH / NH4OH] in DCM). Fractions containing the · product were pooled, concentrated and re-purified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH / DCM) to give the title compound.

* H NMR (400 MHz, CHLOROFORM-d) Sppm 0.51 (t, <7 = 7.53 Hz,

H) 0.78 - 0.93 (m, 1.H) 1.14 - 1.32 (m, 3 H) 1.87 - 1.95 (m

H) 2.04 (d, <7 = 13.30 Hz, 1 H) 2.12 (s, 3 H) 2.19 - 2.38 (m,

H) 2.71 (d, <7 = 15.65 Hz, 1 H) 2.99 - 3.15 (m, 3 H) 3.44 -

3.60 (m, 1H) 4.44 - -4.81 (m, 6H) 6.81 (d, J = 7.24 Hz, 1H)

6.94 - 7.04 (m, 2H) 7.09 - 7.21 (m, 2H) 7.23 - 7.31 (m, 3H). Mass Spectrum (ESI) m / z = 533.2 (M + l).

Acid

EXAMPLE 217

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3¿fe /

812

INSTITUTE K ”> DE LA Γ methyl-2-oxo-l- ((S) -1- (2-oxooxazolidin-3-yl) butan-2-INJ'sesRSSSsass

il) piperidin-3-il) acetic

Stage A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 - ((2-hydroxyethyl) amino) butan-2- yl) -3methylpiperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((R) -1 - ((2-hydroxyethyl ) amino) butan-2-yl) -3methylpiperidin-2-one

(S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butanal (180 mg, 0.405 mmol; Example 91, Step. C) in CICH2CH2CI (1 mL) was stirred with sodium triacetoxyborohydride (172 mg, 0.81 mmol), ethanolamine (0.04 mL, 0.73 mmol) and acetic acid (0.06 mL, 1,013 mmol) at the ambient temperature for 18 h, for which

time the analysis by LC-MS indicates the presence of the product

813

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY desired. The mixture was divided between NaHCO3 saturated and CH2CI2.

The organic layer was concentrated, and the residue was purified by chromatography (silica gel, hexane / EtOAc, then EtOAc / MeOH, up to 15%) to give the title compounds as a 1: 1 mixture of two diastereomers. MS (ESI) m / z = 489 (M + l).

<td>Stage B.</td><td>3 - ((S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-</td>

<td>chlorophenyl)</td><td>1-3-methyl-2-oxopiperidin-l-yl) butyl) oxazolidin-2-one</td>

<td>and</td><td>3 - ((R) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-</td>

chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butyl) oxazolidin-2-one

A mixture of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 - ((2-hydroxyethyl) amino) butan-2- yl) -3methylpiperidin-2-one and · (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((R) -1 - ((2- hydroxyethyl) amino) butan-2-yl) -3methylpiperidin-2-one (60 mg, 0.123 mmol; Example 217, Step A) was mixed with 1,1'-carbonyldiimidazole (99 mg, 0.61 mmol) and 1.8- diazabicyclo [5.4.0] undec-7-ene (37 mg, 0.245 mmol) in

1.4 dioxane (1 mL). The mixture was heated to 100 ° C in a

oil bath for 18 h.

The mixture was allowed to cool to

814 room temperature, diluted with EtOAc and washed with water three times. The product of a pad comprised giving the title compound, additional. MS (ESI) m / z = 515 crude then filtered through silica gel and Na2SW4 so it was used without purification (M + l).

Stage C. Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl.) - 6- (4-chlorophenyl) -3-methyl-l - (((2S) -1- (5-methyl-2- oxooxazolidin-3yl) butan-2-yl) -2-oxopiperidin-3-yl) acetic

The title compound was prepared from the mixture obtained in Example 217, Step B by a similar procedure to that described in Example 71, Step F. A mixture of two diastereomers was isolated, which was then further purified by chiral separation to The title compound (250 x 30 mm Chiralpak® IC column (Chiral Technologies, Inc., West Chester, PA, USA) resulted with 32 g / min MeOH (20mM NH3 )) .

XH NMR (CDC13, 500 MHz) δρρπι 0.57 (t, 3H), 1.50 (s, 3H),

1.70 (m, 1H), 1.90 (m, 1H), 2.00 (m, 1H), 2.25 (t, 1H), 2.78 (br, 1H), 2.98 (br, 1H), 3.13 (m, 3H), 3.62 (m, 2H), 3.85 (br, 1H), 4.40 (m, 3H), 6.67 (m, 1H), 6.93 (s, 1H), 6.99 (br, 2H), 7.14 (m, 2H), 7.24 ( m, 2H). MS (ESI) m / z = 533 (M + l).

815

<td></td><td>EXAMPLE 218</td>

<td>Acid</td><td>2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-</td>

methyl-2-oxo-l - ((S) -1- (2-oxopyridin-l (2H) -yl) butan-2yl) piperidin-3-yl) acetic

Step A. (3S, 5R, 6S) -3-AÜ1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1 - ((S) -l-hydroxybutan-2-yl) -3-methylpiperidin- 2-one

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-hydroxybutan-2-yl) -3-methylpiperidin-2-one (60 mg,

0.134 mmol; Example 91, Step C) was mixed with triphenylphosphine (42 mg, 0.161 mmol), 2-hydroxypyridine (14.1 mg. 0.148 mmol) and diisopropyl azodicarboxylate (0.029 mL,

0.148 mmol) in toluene in an oven dried 3 neck round bottom flask. The mixture was stirred at room temperature for 18 hr under nitrogen. The solvent is

evaporated.

The residue was then purified by chromatography (gel

816 silica, hexane / EtOAc, 1: 0 to 2: 3) to give the title compound as a colorless oil.

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -1- (2-oxopyridin -l (2H) yl) butan-2-yl) piperidin-3-yl) acetic

To a 25 mL round-bottom flask loaded with (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxybutan-2- yl) -3-methylpiperidin-2-one (35 mg, 0.067 mmol; Example 218, Step A) THF, water (until the reaction turned and remained cloudy with gentle stirring) was added, and tBuOH (until the reaction cloudy became translucent). 4-Methylmorpholine 4-oxide monohydrate (13.6 mg, 0.10 mmol) was added followed by osmium tetroxide, 4 wt%, in water (0.016 mL, 0.067 mmol). The reaction was allowed to stir at room temperature for 16 h to complete the formation of the diol. Jones reagent (70 pL) was added to the resulting mixture at room temperature and stirring continued for 18 h. The reaction was quenched with water, diluted with EtOAc, and extracted with additional EtOAc (3x8 mL). The combined organic layers were washed with water, dried over MgSO4, filtered and the filter product concentrated. The light greenish residue was purified by preparative HPLC, to result

817

INSTITUTO iuL'GCAKO

OF THE INDUSTRIAL PS.

the title compound.

<td> 7.77</td><td>(m, 1H). Spectrum</td><td>of masses</td><td>(ESI)</td><td>m / z</td><td> = 541</td><td>(M + l).</td><td></td>

EXAMPLE 219

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (2-oxo-5- (trifluoromethyl) pyridin-1 (2H) yl) butan-2-yl) piperidin-3-yl) acetic

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) —1— (2-oxo-5- (trifluoromethyl) pyridin-1 (2H) yl) butan-2-yl) piperidin-3-yl) acetic was prepared using the procedure described for Example 218 using 2-hydroxy-

5- (trifluoromethyl) pyridine, and tri-n-butylphosphine, azodicarboxylic dipiperidine in Stage A.

XH NMR (CDC13, 500 MHz) δρρπΐθ.54 (t, 3H), 1.42 (s, 3H),

1.60 (m, 1H), 1.78 (m, 1H), 2.01 (m, 2H), 2.77-2.93 (m, 2H),

<td rowspan="2"> 3.13</td><td rowspan="2">(m,</td><td rowspan="2">IH),</td><td rowspan="2"> 3.42</td><td rowspan="2">(my h),</td><td colspan="2"> 818</td><td rowspan="2">MEXICAN INSTITUTE V9 „Λ / OF THE PROPERTY> INDUSTRIAL IH), 4.32 (m, 2H), 6.50</td>

<td>IH),</td><td> 7.11</td><td>(m,</td><td>IH),</td><td>7.23 (m,</td><td>2H),</td><td> 7 .,</td><td>69 (m, 2H). Spectrum</td>

Masses (ESI) m / z = 609 (M + l).

EXAMPLE 220 (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl

1 - ((S) -1- (pyridin-3-yloxy) butan-2-yl) piperidin-2-one

(3S, 5R, 6S) -3-Α1Ϊ1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) - 1 - (pyridin-2-yloxy) butan-2 -yl) piperidin-2-one (10 mg) was prepared as described for Example 218 using 3-hydropyridine instead of 2 hydroxypyridine.

<td>(m,</td><td>IH),</td><td> 7.98</td><td>(my h) ,</td><td> 8.37</td><td>(m,</td><td>IH),</td><td> 8.56</td><td>(s,</td><td>IH).</td><td colspan="2">Spectrum</td>

<td>of</td><td>Masses</td><td>(ESI)</td><td colspan="3">m / z = 541 (M + l).</td><td></td><td></td><td></td><td></td><td></td><td></td>

819

EXAMPLE 221

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((IS) -1- (tetrahydrofuran-2yl) propyl) acid piperidin-3-yl) acetic (Isomer 1)

* stereochemistry not determined

Step A. (3S, 5R, 6S) -3-allyl-l - ((3S) -7 - ((tertbutyldimethylsilyl) oxy) -4-hydroxyheptan-3-yl) -5- (3-chlorophenyl) -6- (4 -chlorophenyl) -3-methylpiperidin-2-one

★ stereochemistry river determined

(3-Bromopropoxy) (tertbutyl) dimethylsilane-derived Grignard reagent was prepared on a 1.8 mmol scale according to Minguez, et al. Biorg. Med. Chem 11, 3335, 2003 as a gray solution in THF (~ 3 mL). About 1.5 mL of Grignard reagent was slowly added to a solution of (S) 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3820 to IV1 Jr 1. Π *

MEXICAN INSTITUTE V,

OF THE PROF'EDAl ·

INDUSTRIAL methyl-2-oxopiperidin-l-yl) butanal (100 mg, 0.22 mmol; Example

After 2 hr, the reaction was diluted in ethyl acetate and washed with saturated ammonium chloride solution followed by saturated aqueous NaCl solution. The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography on silica eluting with ethyl acetate / hexane provided the title compound as a mixture of diastereomers.

XH NMR (400 MHz,

CHLOROFORM-d) representative major diastereomeric signals

3H), 4.25 (d 7 = 10.6 Hz,

IH).

minor diastereomer

5ppm 1.21 (s,

3H), 4.37 (d, 7 = 10.6 Hz,

IH).

Mass Spectrum (ESI) m / z = 618.4 (M + l).

methylpiperidin-2-one

Stage

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4821

A solution of (3S, 5R, 6S) -3-allyl-l - ((3S) -7- (tertbutyldimethylsilyloxy) -4-hydroxyheptan-3-yl) -5- (3-chlorophenyl) -

6- (4-chlorophenyl) -3-methyl-piperidin-2-one (127mg, 0.21mmol;

Example 221, Step A) in THF (1.5 mL) was treated with tetrabutylammonium fluoride (0.62 mL 1M in THF, 0.62 mmol) at room temperature for 1.5 hour. The solvent was removed under vacuum. Purification by chromatography on silica eluting with ethyl acetate / hexane provided the title compound as a mixture of diastereomers.

1H NMR (400 MHz, CHLOROFORM-d) representative signals: major diastereomer opm 1.15 (s, 3H), 4.26 (dj = 10.6 Hz,

IH), minor diastereomer 6ppm 1.20 (s, 3H), 4.31 (d, J = 10.6 Hz,

IH).

Mass Spectrum (ESI) m / z = 504.3 (M + l).

Stage C. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l - ((S) -1 - ((S) -tetrahydrofuran-2-yl) propyl) piperidin-

2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l - ((S) -1 - ((R) -tetrahydrofuran-2-yl) propyl) piperidin-

822

2-one

A solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((3S) -4,7 - dihydroxyheptan-3-yl) -3 methylpiperidin -2-one (55mg, 0.11mmol; Example 221, Step B) and triphenylphosphine (57.2mg, 0.22mmol) in dichloromethane (2mL) was treated with (E) -diethyl diazen-1,2-dicarboxylate (0.033ml 0.22 mmol) at room temperature for 2 hours. Purification by silica chromatography eluting with ethyl acetate / hexane provided one of the title compounds as the major diastereomer as the first eluted compound followed by a minor diastereomer.

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((IS) -1- (tetrahydrofuran-2-yl) propyl) piperidin- 2-one (major diastereomer; first eluted compound) XH NMR (400 MHz, CHLOROFORM-d) opm 0.65 (t, J = 7.43 Hz,

3H) 1.20 (s, 3H) 1.51-1.58 (m, 3H), 1.71 (m, 3H), 1.83-1.97 (m, 4H), 2.54-2.57 (dd, J = 7.53, 3.62 Hz, 2H) , 3.08-3.14

823

MEXICAN INSTITUTE OF THE PROP'i-nm

<td></td><td></td><td></td><td></td><td></td><td>INDUSTRIAL</td><td></td>

<td> 7.15</td><td>(d, <7 = 4Hz,</td><td>2H). Spectrum</td><td>of</td><td>Masses (ESI)</td><td>I m / z =</td><td> 486.3</td>

(M + l).

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1- ((1S) -1- (tetrahydrofuran-2-yl) propyl) piperidin- 2-one (minor diastereomer; second eluted compound) XH NMR (400 MHz, CHLOROFORM-d) 5ppm 0.47 (t, J = 7.53 Hz, 3H),

<7 = 8Hz, 2H). Mass Spectrum (ESI) m / z = 486.3 (M + l)

Stage D. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-2-oxo-l - ((1S) -1- (tetrahydrofuran-2-yl) propyl) piperidin-

3-yl) acetic (Isomer 1)

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-lIMPI

824 ((IS) -1- (tetrahydrofuran-2-yl) propyl) piperidin-2-one (major diastereomer; first eluted compound; Example 121,

Step C) by a procedure similar to that described in Example 71, Step F.

XH NMR (4 00 MHz, CHLOROFORM-d) 6ppm 0.61 (t, J = 1.63 Hz, 3 H)

1.34 (s, 3H) 1.46 - 1.56 (m, 2H) 1.72 (s, br, 3H) 1.82-1.89 (m, 2H) 2.00 - 2.14 (m, 2H) 2.61 (d, <7 = 13.89 Hz, 2H) 2.76 -

2.84 (m, 2H) 3.20 (dd ,. <7 = 13.30, 7.24 Hz, 2H) 3.29 (br.s., 1

H) 3.73 (td, <7 = 7.87, 5.18 Hz, 1 H) 4.34 (d, <7 = 10.37 Hz, 1 H)

6.68 (dd, <7 = 7.43, 1.56 Hz, 1 H) 6.87 (s, 1 H) 7.00 - 7.15 (m, 4

H) 7.14 (dd, <7 = 8.12, 0.5 Hz, 2 H). Mass Spectrum (ESI) m / z =

504.3 (M + l)

EXAMPLE 222

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1 - ((IS) -1- (tetrahydrofuran-2-yl) acid propyl) piperidin-3yl) acetic (Isomer 2)

* stereochemistry not determined

The title compound was prepared from (3S, 5R, 6S) -

(tetrahydrofuran-2-yl) propyl) piperidin-2-one

825

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY «.- ((1S) -1 (minor diastereomer; second compound eluted; Example 121, Step C) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) 5ppm 0.46 (t, 7 = 7.63 Hz, 3

H) 1.15-1.26 (m, 3H) '1.36 (s, br. 3H), 1.46-1.50 (m, 1H), 1.79-

1.85 (m, 4H), 2.05-2.09 (dd, 7 = 12, 4 Hz, 1H), 2.17 (t, <7 = 12 Hz,

1H), 2.51 (s, br, 1H), 2.66 (d, <7 = 12 Hz, 1H), 2.77 (d, <7 = 12 Hz,

H), 3.76 (m, 2H), 4.68 (d, J = 8nHz, 1H), 6.76 (d, <7 = 8 Hz, 1H),

6.92-7.03 (m, 3H), 7.06 (d, 7 = 2.2 Hz, 2H), 7.16 (d, 7 = 8.8 Hz,

2H). Mass Spectrum (ESI) m / z = 504.3 (M + l)

EXAMPLE 223

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-1 - ((IS) -1- (5-oxotetrahydrofuran-2yl) propyl) piperidin-3-yl) acetic

* stereochemistry not determined

The title compound was prepared using the oxidation procedure of Example 221, but using a

826 largest excess ins.t: ~ uto? 'r -) V - r - '^ ¡£ 4 of sodium periodate (7 eq) and reacting' for a longer period of time (18h).

<td></td><td>1H</td><td>NMR (400 MHz,</td><td>CD3OD) δρριη 0.7 (s,</td><td>be, 3H),</td><td> 1.42</td><td>(s,</td>

<td> 7.10</td><td>(s,</td><td>1H) 7.13-7.19</td><td>(m, 2H), 7.31 (s, h</td><td>> r, 4H). Is</td><td>pectr</td><td>0 of</td>

EXAMPLE 224

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((1S) -1- (tetrahydro-2H-pyran- 2yl) propyl) piperidin-3-yl) acetic (Isomer 1)

★ undetermined stereochemistry

Step A. (3S, 5R, 6S) -3-Allyl-l - ((3S) -8 - ((tertbutyldimethylsilyl) oxy) -4-hydroxyoctan-3-yl) -5- (3-chlorophenyl) 6- ( 4-chlorophenyl) -3-methylpiperidin-2-one

827

Title

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

The compound was prepared as a mixture of diastereomers by a procedure similar to that described in

Example 221, Stage

A, substituting (3-bromopropoxy) (tertbutyl) dimethylsilane (4-chlorobutyloxy) (tertbutyl) dimethylsilane during reagent preparation

Grignard.

Mass Spectrum (ESI) m / z = 632.2 (M + l).

Stage B. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1 - ((3S) -4,8-dihydroxyoctan-3-yl) -3- methylpiperidin-2-one

The title compound was obtained from (3S, 5R, 6S) -3-allyl-l - ((3S) -8 - ((tert-butyldimethylsilyl) oxy) -4 hydroxyoctan-3-yl) -5- (3 -chlorophenyl) -6- (4-chlorophenyl) -3 methylpiperidin-2-one (Example 224, Step B) using a procedure similar to that described in Example 221,

828

Step B. The diasteomer ratio was observed by NMR to be around 2: 1.

XH NMR (400 MHz, d4 ~ methanol) representative signals: greater diastereomer δ ppm 0.45 (t, 7 = 7.6 Hz, 3H), 4.76 (d, 7 = 12 Hz, 1H).

minor diastereomer: opm 0.54 (t, 7 = 7.6 Hz, 3H), 4.53 (d, 7 = 12 Hz, 1H).

m / z = 518.2 (M + l).

Step C. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((IS) -1- (tetrahydro-2H-pyran-2 -il) propyl) piperidin-2-one

Cl * stereochemistry not determined

A solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((3S) -4,8-dihydroxyoctan-3-yl) -3methylpiperidin-2 -one (31 mg, 0.060 mmol; diastereomeric mixture; Example 224, Step B) and triphenylphosphine (31.4 mg, 0.12 mmol) in dichloromethane (1.5 mL) was treated with (E) -diethyl diazen-1,2-dicarboxylate ( 0.02 ml, 0.12 mmol) at room temperature for 2 hours. Purification

829

chromatography on silica eluting with ethyl acetate / hexane provided the title compound as a mixture of diastereomers.

NMR (400 MHz, d4-Methanol) representative signals: diastereomer greater opm 0.46 (t, J = 8 Hz, 3H), 4.75 (d, <7 = 12 Hz, IH).

minor diastereomer opm 0.55 (t, <7 = 8 Hz, 3H), 4.53 (d, <7 = 12 Hz, IH).

Mass Spectrum (ESI) m / z = 500.2 (M + l)

Stage D. (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2,3-dihydroxypropyl) -3-methyl-l - ((1S) -1- (tetrahydro-2H-pyran-2yl) propyl) piperidin-2-one

ΌΗ

CI

IC * stereochemistry not determined

A solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((1S) -1- (tetrahydro-2H-pyran-2yl ) propyl) piperidin-2-one (3 mg, 5.99 pmol; Example 224, Step

C) in THF (37.5 pL), H2O (25 pL) and t-butanol (21 pL) was treated with 4-methylmorpholine N-oxide (2.45 mg, 0.021 mmol) and

830

MEXICAN INSTITUTE

FROM INDUSTRIAL PROPERTY 2.5% osmium tetroxide in t-BuOH (2 pL, 0.15 pinol) at room temperature for 18 h. The mixture was diluted with ethyl acetate, washed with water then saturated aqueous NaCl solution, and dried over sodium sulfate. After concentration, the diastereomeric mixture was used in the next step without further purification. Mass Spectrum (ESI) m / z =

534.1 (M + l)

Stage E. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((1S) -1- (tetrahydro-2H- piran-2yl) propyl) piperidin-3-yl) acetaldehyde

* stereochemistry not determined

A solution of (3R, .5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -3- (2,3-dihydroxypropyl) -3-methyl-l - ((1S) -1 (tetrahydro -2H-pyran-2-yl) propyl) piperidin-2-one (3 mg, 5.61 pmol; Example 224, Step D) in water (20.0 pL) and THF (40.0 pL) was treated with sodium periodate (3.60 mg , 0.02 mmol). After a precipitate formed, methanol (40 pL) was added to form an emulsion which was stirred at room temperature for

831

ΪΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY hour. The reaction was diluted with saturated aqueous NaCl solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and the filter product was concentrated to provide a mixture of two diastereomers that was used in the next step. Mass Spectrum (ESI) m / z = 502.1 (M + l)

Stage F. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((IS) -1- (tetrahydro-2H -piran-2yl) propyl) piperidin-3-yl) acetic (Isomer 1)

A solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((IS) -1- (tetrahydro-2H- piran-2yl) propyl) piperidin-3-yl) acetaldehyde (3 mg, 5.97 pmoL; mixture of stereoisomers, Example 224, Step E) in a solution of monobasic 1.25 M potassium phosphate in water (0.050 mL), tbutanol (0.050 mL) and 2-methylbut-2-ene 2.0 M in THF (0.15 mL, 0.30 mmol) were treated with sodium chlorite (2.16 mg, 0.024 mmol) at room temperature for 3 h. The reaction was quenched with 1M sodium thiosulfate solution (0.03 mL). After 10 min, the mixture was acidified with 1M potassium bisulfate solution (0.03 mL) and extracted with ethyl acetate. The organic layers were washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. Reverse phase preparative HPLC purification (eluent: 0 to 100%

MeCN + 0.1% TFA in water + 0.1% TFA, for 20 minutes)

832

INDUSTRIAL gave the title compound as the first elution isomer.

XH NMR (400 MHz, MeOH-D4) opm 0.51 (t, J = 8 Hz, 3H), 1.03

<td>(d,</td><td>J = 8 Hz, 2H</td><td>). Spectrum</td><td>of</td><td>Masses</td><td>(ESI) m / z</td><td colspan="2"> = 518.2</td><td>(M + l).</td><td></td>

The additional elution provided in Example 225 as the second eluted isomer.

EXAMPLE 225

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-

2-oxo-l - ((1S) -1- (tetrahydro-2H-pyran-2-yl) propyl) piperidin-3-yl) acetic (Isomer 2) '

* stereochemistry not determined XH NMR (400 MHz, MeOH-d4) opm 0.39 (t, J = 8 Hz, 3H), 1.001.07 (m, 1H), 1.18-1.20 (m, 1H), 1.32 (s, br, 1Η), 1.37 (s, br,

833

HZ, 2H). Mass Spectrum (ESI) m / z = 518.2 (M + l)

EXAMPLE 226

Acid 2 - ((3R, 5R, 6S) -1 - ((R) -1- (Benzo [d] thiazol-2-yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 -methyl-2-oxopiperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -1 - ((S) -1- (Benzo [d] thiazol-2yl) propyl) -5- (3-chlorophenyl) ) -6- (4-chlorophenyl) -3-methyl-2oxopiperidin-3-yl) acetic (Isomer. 1)

Stage A. 1- (Benzo [d] thiazol-2-yl) propan-l-ol

To a solution of 1,3-benzothiazol-2-carbaldehyde (0.96 g, 5.88 mmol) in THF (15.0 mL) was added bromide. i ethylmagnesium

834 1.0M solution in THF,

i PKÜP

INDUSTRIAL

12.0 · 66 ^ 6 «^ ί ^ ϋΟ ^ · / ιιι» ·· ιΙ ^ ΐΊΐ rxx eq), slowly for 15 minutes (an exotherm was observed). The resulting dark red solution was stirred at room temperature for 55 minutes, then quenched with saturated aqueous ammonium solution chloride (4 mL). The mixture was then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-70% EtOAc in hexane gradient) provided the title compound as a red oil.

Stage B. 2- (1-Bromopropyl) benzo [d] thiazole

To a 0 ° C solution of 891.4 mg (4.61 mmol) of 1 (benzo [d] thiazol-2-yl) propan-l-ol (Example 1, Step A) in THF (12.0 mL) was added triphenylphosphine (1.8 g, 6.86 mmol, 1.5 eq), followed by carbon tetrabromide (2.22 g, 6.69 mmol, 1.5 eq). The resulting mixture was stirred at 0 ° C for 35 minutes, then allowed to warm to room temperature overnight. The reaction mixture was then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-50% EtOAc in hexane gradient) provided the title compound as a dark oil.

Stage C. (3S, 5R, 6S) -3-Allyl-l- ((R) -1- (Benzo [d] thiazol-2yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl ) -3-methylpiperidin-2one and (3S, 5R, 6S) -3-Allyl-l - ((S) -1- (benzo [d] thiazol-2-yl) propyl) -5 (3-chlorophenyl) - 6- (4-chlorophenyl) -3-methylpiperidin-2-one

835

To a suspension of sodium hydride (60% dispersion in oil, 100.0 mg, 2,500 mmol, 3.1 eq) in DMF (1 mL) at 0 ° C was added a solution of 300 mg (0.801 mmol) of (3S, 5R , 6S) -3 allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one (Example 71, Step D) in DMF (1 mL) for 1 minute. After 5 minutes, a solution of 576.7 mg (2.25 mmol, 2.8 eq) of

2- (1-bromopropyl) benzo [d] thiazole (Example 226, Step B) in DMF (1 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature overnight. The reaction was quenched with water, and then concentrated under reduced pressure. Purification by preparative reverse phase HPLC (Agilent Eclipse Plus C18 column (Agilent Technologies, Santa Clara, CA), 0.1% TFA in CH3CN / H2Or, gradient 70% to 90% over 25 minutes) provides a

836

IMPI

INSTITUTO ΛίΣΧΤΑΝΟ 03 LA? RO?! E? AD INDUSTRIAL mixes the title compound as a white solid, ·

Stage D. Acid 2 - ((3R, 5R, 6S) -l - ((R) -l- (Benzo [d] thiazol-2yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl ) -3-methyl-2oxopiperidin-3-yl) acetic or. Acid 2 - ((3R, 5R, 6S) -1 - ((S) -1 (Benzo [d] thiazol-2-yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-2-oxopiperidin-3-yl) acetic (Isomer 1)

To a 97.5 mg (0.177 mmol) solution of (3S, 5R, 6S) -3alyl-1 - ((R) -1- (benzo [d] thiazol-2-yl) propyl) -5- (3-chlorophenyl ) -6 (4-chlorophenyl) -3-methylpipe'ridin-2-one (Example 226, Step C) in acetonitrile (1 mL ·), water (1.5 mL), and carbon tetrachloride (1 mL) were added periodate sodium (154.2 mg, 0.721 mmol,

4.1 eg), followed by ruthenium (III) chloride hydrate (11.0 mg, 0.049 mmol, 0.27 eq). The resulting mixture was stirred at room temperature for 2.75 hours, then passed through a 0.45 pm filter to remove residual solids, and then concentrated under reduced pressure. Purification by preparative reverse phase HPLC (Agilent Eclipse Plus C18 column (Agilent Technologies, Santa Clara, CA), 0.1% TFA in CH3CN / H2O, 40% to 80% gradient over 25 minutes) provided one of the title compounds as the first isomer of elution as a white solid.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 1.05 (t, J-7.46 Hz, 3

H) 1.55 (s, 3 H) 2.10 -2.32 (m, 3 H) 2.41 - 2.54 (m, 1 H) 2.87

-2.98 (m, 2 Η) 3.16-3.25 (m, 1 Η) 4.62 (d, <> 10.27 Hz, 1 H)

837

4.81 (dd, <> 8.56, 6.85 Hz, 1 H) 6.71 (d, <7 = 7.58 Hz, 1 H) 6.80 (d, J = 8.07 Hz, 2 H) 6.88 (d, J = 8.31 Hz, 2 H ) 6.96 (s, 1 H) 7.03 -7.10 (m, 1 H) 7.16 (dd, <7 = 7.95, 0.86 Hz, 1 H) 7.42 - 7.47 (m, 1 H) 7.48 - 7.54 (m, 1 H ) 7.85 (t,> 8.19 Hz, 2H). Mass Spectrum (ESI) m / z = 567 (M + l).

EXAMPLE 227

Acid 2 - ((3R, 5R, 6S) -1 - ((R) -1- (Benzo [d] thiazol-2-yl) propyl) -5 (3-chlorophenyl) -6- (4-chlorophenyl) - 3-methyl-2-oxopiperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -l - ((S) -l- (Benzo [d] thiazol-2yl) propyl) -5- (3- chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic (Isomer 2)

CI

CI.

CI

One of the title compounds (Isomer 2) was prepared from (3S, 5R, 6S) -3-allyl-l - ((S) -1- (benzo [d] thiazol-2yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2-one (Example 226, Step C) as the second isomer eluted as described in Example 226, Step D.

838

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.77 (t, <7 = 7.34 Hz, 3 H) 1.39 (s, 3 H) 2.03 - 2.1.6 (m, 2 H) 2.16 - 2.24 (m, 1 H) 2.58 (dt, <7 = 14.61, 7.49 Hz, 1 H) 2.82 - 2.98 (m, 2 H) 3.20 -

3.29 (m, 1H) 4.75 - 4.84 (m, 2H) 6.75 (d, <7 = 7.58 Hz, '1H)

6.94 (s, 1H) 7.00 (d, J = 8.31 Hz, 2H) 7.05 - 7.11 (m, 3H)

7.13 - 7.17 (m, 1 H) 7.44- - 7.49 (m, 1 H) 7.53 (t, <7 = 7.46 Hz, 1 H) 7.87 (d, <7 = 8.07 Hz, 1 H) 8.01 (d, < 7 = 8.07 Hz, 1H). Mass Spectrum (ESI) m / z = 567 (M + l).

Examples 228 to 240 were also prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2-one (Example 71, Step D) as is described in the

Example

226, substituting

2- (1bromopropyl) benzo [d] thiazole in Example 226, Step C, with an equivalent amount of the appropriate alkylhalide. The required alkyl halides (reagents) are prepared as described in the individual examples

OR

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 228</td><td>N = ( ° 1</td><td>5- (1-Bromopropyl) -3methylisoxazole</td>

839

<td> 229</td><td>fV</td><td>INDu 2- (1-Bromopropyl) -6chloropyridine</td>

<td> 230</td><td> ¿</td><td>2- (1-Bromopropyl) pyridine</td>

<td> 231</td><td></td><td>2- (1-Bromobutyl) pyridine</td>

<td> 232</td><td>or</td><td>2- (l-Bromo-2- cyclopropylethyl) pyridine</td>

<td> 233</td><td> 5</td><td>3- (1-Bromopropyl) pyridine</td>

<td> 234</td><td>and</td><td>2- (1-Bromopropil) pyrazine</td>

<td> 235</td><td>n NyN xjy</td><td>2- (1-Bromopropyl) pyrimidine</td>

<td> 236</td><td>5Γ</td><td>2- (1-Bromopropil) -6- methylpyridine</td>

<td> 237</td><td></td><td>4- (1-Bromopropil) pyridine</td>

. ·. INSTITUTO Mr¿ICA? ¿G>

______ FROM THE 'Ca-r' PROPERTY> <

TRIAL

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

840

<td> 238</td><td><VCF3</td><td>2 (1 Bromoprupil) “6 · (trifluoromethyl) pyridine</td>

<td rowspan="2"> 239</td><td>fvBr</td><td>2- (1-Bromopropil) -6-</td>

<td></td><td>bromopyridine</td>

<td> 240</td><td>/ = \ NyS Oops</td><td>2- (1-Bromopropyl) thiazole</td>

Acid

EXAMPLE 228 methy1-1- ((S) -1- (3-methylisoxazol-5-yl) propyl) -2-oxopiperidin3-yl) acetic acid or 2 - ((3R, 5R, 6S) -5- (3- chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((R) -1- (3-methylisoxazol-5-yl) propyl) -2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) 6ppm 0.74 (t, 7 = 7.43 Hz,

H) 1.33 (s, 3 H) 1.90 -2.11 (m, 2 H) 2.14 - 2.29 (m, 5 H)

2.90 (q, 7 = 7.24 Hz, 2 H) 3.37 - 3.47 (m, 1 H) 4.47 (t, 7 = 7.14

Hz, 1H) 4.60 (d, 7 = 10.37 Hz, 1H) 5.70 (s, 1H) 6.80 (dt,

7 = 7.48, 1.54 Hz, 1H) 6.90 - 7.02 (m, 3H) 7.04-7.19 (m, 4

H). Mass Spectrum (ESI) m / z = 515 (M + l).

Synthesis of 5- (1-bromopropyl) -3-methylisoxazole:

841

IMPI

Stage A. 1- (3-Methylisoxazol-5-yl) propan-l-ol

Ethylmagnesium bromide (3.60 mL, 10.81 mmol) was added slowly to a solution of 3-methylisoxazol-5-carbaldehyde (0.801 g, 7.21 mmol) in 10 mL of THF at -78 ° C. The reaction mixture was stirred at -78 ° C for 2h, then quenched with saturated aqueous NH solution4C1, and extracted with ether

(3x80 mL). The combined organic layers were dried over

Na2SW4 they were filtered and the filter product was evaporated to provide the product, crude. The crude product was purified by chromatography on silica gel, eluting with 10 to 60% EtOAc / hexane to provide the title compound. Mass Spectrum (ESI) m / z = 142.2 (M + l).

Stage B. 5- (1-Bromopropyl) -3-methylisoxazole

CBr was added to a solution of 1- (3-methylisoxazol-5-yl) propan-l-ol (0.589 g, 4.17 mmol) in 15 mL of THF4 (1,730 g,

5.22 mmol) and triphenylphosphine (1,423 g, 5.42 mmol). The reaction mixture was stirred at room temperature for 3h. The solid was completely filtered, and washed with THF. The filtration product was concentrated and the residue was purified by chromatography on silica gel, eluting with 5 until

842

30% EtOAc / hexane to provide the compound of the

Title. Mass Spectrum (ESI) m / z = 204.2 (M + l)

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (6-chloropyridin-2-yl) propyl) -3- methyl-2-oxopiperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l - ((R) - 1 - (6-chloropyridin- 2-yl) propyl) -3-methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) Sppm 0.77 (t, J = 7.43 Hz,

H) 1.30 (s, 3 H) 1.99 -2.13 (m, 2 H) 2.15-2.37 (m, 2 H)

2.70 - 2.90 (m, 2H) 3.20 (ddd, J = 12.96, 9.73, 3.33 Hz, 1H)

4.56 (t, <1 = 7.24 Hz, 1 -H) 4.84 (d, <7 = 9.98 Hz, 1H) 6.82 (dt, <7 = 7.43, 1.56 Hz, 1H) 6.88 (d, <7 = 8.22 Hz, 2H) 6.99 - 7.24 (m, 7H) 7.47 (t, <7 = 7.73 Hz, 1H). Mass Spectrum (ESI) m / z = 545 (M + l).

Synthesis of 2- (1-bromopropyl) -6-chloropyridine:

Stage A. 1- (6-Chloropyridin-2-yl) propan-l-ol

CI \

Ethyl magnesium bromide, 3.0 M solution in diethyl ether (3.53 mL, was added to a solution of 6-chloropicolinaldehyde (1.00 g, 7.06 mmol) in 20 mL of THF at -78 ° C.

10.60 mmol) slowly. The reaction mixture was stirred at -

843

78 ° C for 2h. The reaction mixture was quenched with NH aqueous solution4C1 saturated, and extracted with ether (3 x 100 mL).

The combined organic layers were dried over Na2SW4 and evaporated to provide the crude product. The crude product was purified by chromatography on silica gel, eluting with 10 to 60% EtOAc / hexane to provide the title compound. Mass Spectrum (ESI) m / z = 172 (M + l).

Stage B. 2- (1-bromopropyl) -6-chloropyridine

A mixture of 1- (6-chloropyridin-2-yl) propan-l-ol (0.497 g, 2.90 mmol), CBr4 (1.2g, 3.62mmol) and triphenylphosphine (0.987g, 3.76mmol) in 25mL THF was stirred at room temperature for 2h. The solid was completely filtered and washed with THF. The filtration product was concentrated and the residue was purified by chromatography on silica gel, eluting with 10 to 50% EtOAc / hexane to provide the title compound. Mass Spectrum (ESI) m / z = 236 (M + l).

methyl-2-oxo-l - ((S) -1- (pyridin-2-yl) propyl) piperidin-3844

EXAMPLE 230

ΓΜΡΙ

INSTITUTE ΜΞα, 'ΟΑΝΟ

OF INDUSTRIAL PROPERTY

Yl) acetic acid or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxo-l - ((R) -1- ( pyridin-2 yl) propyl) piperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) opm 0.75 (t, 7 = 7.43 Hz,

3H)

1.21

1.31 (m, 3H), 1.93 - 2.10 (m, 2H), 2.10 - 2.23 (m,

1H), 2.50 (dt, 7 = 14.77, 7.48 Hz, 1H), 2.75 (d, 7 = 13.89

Hz,

1H), 2.97 (d, 7 = 14.28 Hz, 1H),

3.09 - 3.25 (m, 1H), 4.65 (dd,

7 = 8.22, 6.06 Hz, 1H), 4.95 (d,

7 = 9.00 Hz, 1H), 6.80 (d,

6.89 (d, 7 = 8.22 Hz,

2H), 7.02 - 7.21 (m, 6H),

7.34 (d, 7 = 7.83 (d, 7 = 4.30 Hz, (M + l).

Hz, 1H), 7.54 (td,

1 HOUR). Spectrum

Masses (ESI) m / z

511.1

Synthesis of 2- (1-bromopropyl) pyridine:

To a mixture of 2-propylpyridine (2.5 g, 20.63 mmol, purchased from Sigma-Aldrich, St. Louis, MO) and (E) -2.2 '(diazen-1,2-diyl) bis (2-methylpropanonitrile) (1,253 g, 7.63 mmol, purchased from Sigma-Aldrich) in CC14 (60 mL) at rt n-bromosuccinimide (1.93 mL,

22.7 mmol, purchased from

845

INSTITUTO MErévíC ·

OF INDUSTRIAL PROPERTY

Sigma-Aldrich).

The mixture was stirred under fluorescent light at

ta for 12 hr. The precipitate was removed by filtration of the mixture through a pad of Celite® (JT

Baker, Phillipsberq, NJ, diatomaceous earth), which was washed with

CC14 (10 mL). The filter product was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20% EtOAc / hexanes) provided the title compound as a yellow liquid. Mass Spectrum (ESI) m / z = 199.9 and 201.9

(M + l).

EXAMPLE 231

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -315 methyl-2-oxo-l - ((S) -1- (pyridin-2-yl ) butyl) piperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((R) - 1- (pyridin-2yl) butyl) piperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δρριη 1.04 (m, 3H), 1.41 -

846

9.01 (m, IH), 11.51 (br. S.

= 525.1 (M + l).

IH). Mass Spectrum (ESI) m / z

Synthesis of 2- (1-bromobutyl) -6-chloropyridine:

Stage A. 1- (Pyridin-2-yl) butan-l-ol

To a solution of 2-bromopyridine (1.1 g, 6.96 mmol,

(purchased from Sigma-Aldrich) in diethyl ether (8 mL) at -78 ° C under N2 Butyllithium (3.1 mL χ 2.5 M) was added over 10 min.

The reaction solution was stirred at -78 ° C for 1.0 hr. Butyraldehyde (0.602 g, 8.35 mmol, purchased from Sigma-Aldrich) was added dropwise to the mixture over 10 min. After stirring at -78 ° C for 15 min, the mixture was allowed to warm to rt and stirred at rt for 1.5 hr. The reaction mixture was poured into saturated aqueous NH solution4C1 (10 mL), diluted with water (15 mL), and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with water, saturated aqueous NaCl solution, and dried over

MgSO4. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 20-80% EtOAc / Hexanes provided the title compound as a

847 white solid.

Mass Spectrum (ESI)

m / z - 152.1 (M + l).

Stage B. 2- (1-Bromobutyl) pyridine

To a mixture of 1- (pyridin-2-yl) butan-l-ol (0.35 g, 2.3 mmol; Example 231, Step A) and triphenylphosphine (1.1 g, 4.2mmol) in THF (15 mL) at 0 ° C under atmosphere N2 CBr added4 (1.2 g, 3.5 mmol). The mixture was stirred at 0 ° C for 2 min, and then allowed to warm to rt and stirred for 25 min. The precipitate was completely filtered through a pad of Celite® (JT Baker, Phillipsberg, NJ, diatomaceous earth), the solid was washed with cold THF (10 mL). The filter product was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel with 0-5-15% EtOAc / Hexanes provided the title compound as colorless oil. Mass Spectrum (ESI) m / z = 214.0 and 216.0 (M + l).

EXAMPLE 232

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) —1 - ((S) -

2-cyclopropyl-l- (pyridin-2-yl) eti1) -3-methyl-2-oxopiperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-

848

IMPIDO). :

MEXICAN INSTITUTE; '

PROPERTY V t »- - _ J ¿1

INDUSTRIAL. ^ a- - ** chlorophenyl) -1 - ((R) -2-cyclopropyl-l- (pyridin-2-yl) ethyl) -3methyl-2-oxopiperidin-3-yl) aceticXH NMR (400 MHz, .CHLOROFORM-d) δρριη -0.45 - -0.34 (m,

IH), -0.06 (dq, J = 9.19, 4.63 Hz, 1H), 0.16 - 0.39 (m, 2H),

6.78 (d,

J = 7.43 Hz, IH), 6.93 (d, J = 7.83 Hz, 2H),

7.00 - 7.17 (m, 7H),

7.34 (d, J = 7.43 Hz, IH), 7.48 - 7.57 (m,

IH), 8.34

IH). Mass Spectrum (ESI) m / z = 537.2 (M + l).

Synthesis of 2- (l-bromo-.2-cyclopropylethyl) pyridine:

To one

Stage A. 2-Cicloprop

11.89 mmol, purchased from Beta Pharma, Inc., Branford, CT) in

THF (15 mL) at 0 ° C under N2 220 pyridylmagnesium bromide (47.6 mL χ 0.25 M, purchased from Rieke Metáis, was added,

Inc., Lincoln, NE) drop by drop over 15 min. The mixture was stirred at 0 ° C after 30 min, allowed to warm to rt and stirred at rt for 3.5 hr. To the reaction mixture

849

\ »Added saturated aqueous NH solution4C1 (5 mL) followed by water (15 mL). The mixture was extracted with EtOAc (2 * 10 mL). The combined organic layers were dried over Na2SW4. After removal of organic solvents, purification of the residue by flash chromatography on silica gel with 40-70% EtOAc / hexanes gave the title compound as a white solid. Mass Spectrum (ESI) m / z = 164.1 (M + l).

Stage B. 2- (l-Bromo-2-cyclopropylethyl) pyridine

The title compound was prepared from 2-cyclopropyl-1- (pyridin-2-yl) ethanol (Example 232, Step A) using a procedure similar to that described in Example 231, Step B. Mass Spectrum (ESI) m / z = 226.0 and 228.0 (M + l).

EXAMPLE 233

Methyl-2-oxo-l - (((S) -1- (pyridin-3-yl) propyl) piperidin-3yl) acetic acid or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) acid -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((R) -1- (pyridin-3IMPI

CHLOROFORM-d) opm 0.97

850 il) propyl) piperidin-3-yl) acetic XH NMR (400 MHz,

1.10 (d,

7 = 8.6 Hz, 3H), 1.44 (s,

2.23 (m, 2H),

7=13.89

4.37 (d,

6.61 (m,

2.28 (s, IH),

Hz, IH), 3.33

2.62 (d, 7 = 13.89 Hz, IH), (ddd, 7 = 13.40, 10.47, 3.13

7 = 10.37 Hz, 1H), 5.93 (t, 7 = 7.92 Hz, IH)

IH), 6.62 - 6.79 (m,

7.00 (m,

7.15 - 7.23

7 = 8.02 Hz,

2.87

Hz, (d,

IH),, 6.54

3H), 6.83 - 6.90 (m, IH), 6.91

IH), 7.00 - 7.07 (m, IH), '7.26 (dd, (m, IH),

7=8.02,

IH), 8.35 (d, 7 = 5.48 Hz,

7.07 - 7.15 (m, IH),

5.67 Hz, IH), 7.36 (d,

IH), 8.80 (s, 1H).

Spectrum

Masses (ESI) m / z = 511.1 (M + l).

Synthesis of

3- (1-bromopropyl) pyridine

Stage A. 1- (Pyridin-3-yl) propan-l-ol

To a solution of 1- (pyridin-3-yl) propane-l-one (2.46 g,

18.20 mmol, purchased from Lancaster Synthesis Ltd.) in MeOH (15 mL) at rt

under atmosphere N2 Sodium borohydride powder (0.690g, 18.20mmol) was added. After stirring at ta

for 1.5 hr, water (20 ml) was added to the reaction solution. The resulting mixture was stirred for 4 min, extracted with EtOAc (20 mL * 3). The organic layers were combined,

washed with water, saturated aqueous NaCI solution and

851 dried over MgSO4. Removal of the solvents provides the crude title compound as a white solid.

Mass Spectrum (ESI) m / z = 138.0 (M + l).

Stage B. 3- (1-Bromopropyl) pyridine

The title compound was prepared from 1 * · (pyridin-3-yl) propan-l-ol (Example 233, Step A) following the procedure described in Example 231, Step B. Mass Spectrum (ESI) m / z = 199.9 and 201.9 (M + l).

EXAMPLE 234

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (pyrazin-2-yl) propyl) piperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((R) -1 - (pyrazin-2yl) propyl) piperidin-3-yl) acetic

<td></td><td colspan="2">XH NMR (4 00 MHz, CHLOROFORM-d)</td><td>opm</td><td> 0.95</td><td>(t, J = 7.14 Hz,</td>

852

INSTITUTO MFXIC W. '·'

OF THE PEOFIEDAD ÍX'V-jbi INDL'STSIAL

1H), 8.03 - 8.16 (m, 1H), 8.25 (m, 2H), 7.04 (d, 7 = 8.80 Hz, (br. S., 1H), 8.34 (s, 1H).

Mass Spectrum (ESI) m / z =

512.1 (M + l).

Synthesis of 2- (1-bromopropyl) pyrazine:

The title compound was prepared from 2-

propylpyrazine (purchased from Matrix Scientific) following a procedure similar to that described in Example 230.

Mass Spectrum (ESI) m / z = 200.8 and 202.9 (M + l).

EXAMPLE 235

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (pyrimidin-2-yl) acid propyl) piperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((R) -1 - (pyrimidin-2yl) propyl) piperidin-3-i1) acetic XH NMR (400 MHz, CHLOROFORM-d) opm 0.78 (t, 7 = 7.43 Hz,

3H), 1.34 (s, 3H), 1.90 - 2.07 (m, 1H), 2.08 - 2.19 (m, 1H),

2.20 - 2.34 (m, 1H), 2.52 (dt, 7 = 14.33, 7.21 Hz, 1H), 2.80 (br. S., 1H), 2.93 (qd, 7 = 7.27, 2.05 Hz, 1H), 3.29 - 3.49 (m,

1H), 4.50 (br. S., 1H), 4.80 (d, 7 = 10.17 Hz, 1H), 6.79 (d,

853

MEXICAN INSTITUTE

INDUSTRIAL PROPERTY> 7.63 Hz, IH), 6.90 - 7.19 (m, 8H), 8.60 (d,> 4.69 Hz, 2H).

Mass Spectrum (ESI). m / z = 512.2 (M + l).

Synthesis of 2- (1-bromopropyl) pyrimidine:

Stage A. 2-Propylpyrimidine

To a 0 ° C solution of triphenylphosphine (2,290 g, 8.73 mmol), nickel (II) acetylacetonate (0.464 mL, 2.62 mmol) and 2-chloropyrimidine (5.00 g, 4.3.7 mmol, purchased from Sigma-Aldrich) in THF ( 45 mL) under N atmosphere2 propylmagnesium chloride (21.83 mL, 43.7 mmol) was added over 5 min. The mixture was allowed to warm to rt and stirred at rt for 3 hr. Saturated aqueous NH solution was added to the reaction mixture4C1 (5 mL) followed by water (12 mL). The mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over Na2SW4, filtered and concentrated. The residue was purified by flash chromatography on silica gel, (eluent: 0 to 50% EtOAc / hexanes) to provide the title compound as a colorless liquid.

Stage Β. 2- (l-Bromopropyl) pyrimidine

854

The title compound was prepared from 2-propylpyrimidine (Example 235, Step A) following a procedure similar to that described in Example 230. Mass Spectrum (ESI) m / z = 201.0 and 203.0 (M + l).

EXAMPLE 236

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (6-methylpyridin-2-yl) propyl) acid -2-oxopiperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((R) -1- (6 -methylpyridin-2-yl) propyl) -2oxopiperidin-3-yl) acetic

<td></td><td>XH NMR (400 MHz,</td><td colspan="2">, CHLOROFORM-d)</td><td>0.99 ppm (br.</td><td>s.,</td><td>3H),</td>

IH), 7.90 (t, <7 = 7.63 Hz, IH), 8.60 (br. S., 1 H). Spectrum

Masses (ESI) m / z - 525.1 (M + l) ..

Synthesis of 2- (1-bromopropyl) -6-methylpyridine:

855

INSTtTUTC OF THE

Stage A. 1- (6-Methylpyridin-2-yl) propan-l-ol

The title compound was prepared from 6-methyl-

2-pyridinecarboxaldehyde (purchased from Tokyo Chemical Industry Co. Ltd.) using a procedure similar to that described above for the synthesis of 2-cyclopropyl-l- (pyridine-

2-yl) ethanol (Example 232, Step A). Mass Spectrum (ESI) m / z = 151.4 (M + l).

Stage B. 2- (1-Bromopropyl) -6-methylpyridine

EXAMPLE 237

The title compound was prepared from 1- (6-methylpyridin-2-yl) propan-l-ol (Example 236, Step A) following a procedure similar to that described in

Example 231, Stage B. Mass Spectrum (ESI) m / z = 214.0 and

216.0 (M + l).

Methyl-2-oxo-l- ((S) -1- (pyridin-4-yl) propyl) piperidin-3 acid

856 il) acetic or Acid 2 - ((3R, 5R / 6S) -5- (3-chlorophenyl) -6- (4

OWNERSHIP & AD VJ---> 'A

INDUSTRIAL ___________ 'chlorophenyl) -3-methyl-2-oxo-l - ((R) -1- (pyridin-4yl) propyl) piperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δρρπι 1.14 (t, <7 = 7.14 Hz,

3H), 1.48 - 1.54 (m, 3H), 1.94 - 2.09 (m, IH), 2.09 - 2.32 (m, 2H), 2.64 (d, <7 = 16: 24 Hz, IH), 2.96 - 3.11 (m , IH), 3.26 (d, 7 = 16.24 Hz, IH), 3.52 - 3.69 (m, IH), 4.39 (d, <7 = 10.37 Hz, IH), 6.02 (br. S., IH), 6.61 ( d, <7 = 7.63 Hz, 3H), 6.77 (br. s., 2H), 6.89 - 7.09 (m, 5H), 7.13 (d, <7 = 7.43 Hz, IH),

8.33 (br. S., IH). Mass Spectrum (ESI) m / z = 511.1 (M + l).

Synthesis of 4- (1-bromopropyl) pyridine:

Stage A. 1- (Pyridin-4-yl) propan-l-ol

The title compound was prepared from 1 (pyridin-4-yl) propane-l-one (purchased from Waterstone Technology) following a procedure similar to that described for the synthesis of 1- (pyridin-3-yl) propane. l-ol (Example 233, Step A). Mass Spectrum (ESI) m / z = 138.0 (M + l).

857

Stage B. 4- (1-Bromopropyl) pyr'idine

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

The title compound was prepared from 1 (pyridin-4-yl) propan-l-ol '(Example 237, Step Aj following a procedure similar to that described in Example 231, Step B. Mass Spectrum (ESI) m / z = 199.9 and 201.9 (M + l).

EXAMPLE 238

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (6- (trifluoromethyl) pyridine -2yl) propyl) piperidin-3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l- ( (Rj-1- (6 (trifluoromethyl) pyridin-2-yl) propyl) piperidin-3-yl) acetic

<td></td><td>1H</td><td>NMR</td><td> (400</td><td>MHz,</td><td>CHLOROFORM-d) δρρκι 0</td><td> .75</td><td>(t, J =</td><td> =7.43</td><td>Hz,</td>

7.54 (d, J = 7.63 Hz, 2H), 7.80 (t, _ J = 7.83 Hz, IH). Spectrum

Masses (ESI) m / z = 579.0 (M + l).

858

IMPI

Synthesis of

2- (1-bromopropyl) -6- (trifluoromethyl) pyridine:

Stage A. 1- (6- (Trifluoromethyl) pyridin-2-yljpropan-l-ol

The title compound was prepared from 2-bromo6- (trifluoromethyl) pyridine (purchased from Oakwood Producís Inc., West Columbia, South Carolina) and propionaldehyde following the procedure as described above for the synthesis of 1- (pyridine- 2-yl) butan-l-ol (Example 231, Step A). Mass Spectrum (ESI) m / z = 206.1 (M + l).

Stage B. 2- (1-Bromopropyl) -6- (trifluoromethyl) pyridine

The title compound was prepared from l- (6 (trifluoromethyl) pyridin-2-yl) propan-l-ol (Example 238, Step

A) following a procedure similar to that described for the synthesis of 2- (1-bromobutyl) pyridine (Example 231, Step

B). Mass Spectrum (ESI) m / z = 268.0 (M + l) and 269.9 (M + l).

EXAMPLE 239

Acid 2- ((3R, 5R, 6S) -1 - ((S) -1- (6-bromopyridin-2-yl) propyl) -5859 '“' ϊ

MEMCANU INSTITUTE

DB LA INDUSTRIAL FRGIr'líDAD (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3il) acetic or 2- ((3R, 5R, 6S) -1 - ((R) -1- (6-bromopyridin-2 yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2 oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) 8ppm 0.66 (t, <7 = 7.43 Hz,

3H), 1.23 (s, 3H), 1.90 - 2.10 (m, 2H), 2.15 - 2.34 (m, 2H),

2.69 - 2.88 (m, 2H), 3.05 - 3.22 (m, IH), 4.29 (t, J = 7.04 Hz,

Mass Spectrum (ESI) m / z = 589.0, 591.0, 593.0 (M + l).

Synthesis of 2-bromo-6- (1-bromopropyl) pyridine:

Stage A. 1- (6-Bromopyridin-2-yl) propan-l-ol

Compound was prepared

title from

2,6-dibromopyridine (purchased from Sigma-Aldrich,

St. Louis,

MO) and propionaldehyde following a procedure similar to that described above for the synthesis of 1- (pyridin-2-yl) butan-1ol (Example 231, step A). Mass Spectrum (ESI) m / z =

219.9 and 217.9 (M + l).

Stage B. 2-Bromo-6- (1-brom'opropyl) pyridine

860

The title compound was prepared from l- (6bromopyridin-2-yl) propan-l-ol (Example 239,

Stage A)

<td>following the procedure as described</td><td>previously</td>

<td>for the synthesis of 2- (1-bromobutyl) pyridine</td><td>(Example 231,</td>

<td>Stage B). Mass Spectrum (ESI) m / z = 277.7,</td><td>279.7 and 281.7</td>

10 (M + l).

EXAMPLE 240

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (thiazol-2-yl) propyl) piperidin-3yl) acetic or Acid. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -3-methyl-2-oxo-l - ((R) -1- (thiazol-2yl) propyl) piperidin -3-yl) acetic

<td>XH</td><td colspan="2">NMR (400 MHz, CHLOROFORM-d) opm</td><td> 0.66</td><td>(t,</td><td><7 = 7.43 Hz,</td>

6H), 7.40 (d, 7 = 3.33 Hz, 1H), 7.83 (d, 7 = 3.13 Hz, 1H), 8.60 (br. S., 1H). Mass Spectrum (ESI) m / z = 517.0 (M + l).

'861

ΓΜΡΙ

Synthesis of 2- (1-bromopropyl) thiazole:

The title compound was prepared from 2-propylthiazole (purchased from

Waterstone Technologies,

Inc.,

Carmel,

IN) following a procedure similar to that described above for the synthesis of

2- (1-bromopropyl) pyridine (Example 230).

Mass Spectrum (ESI) m / z = 205.8 y

207.8 (M + l).

EXAMPLE 241

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S)

1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) propyl) -3-methyl-2oxopiperidin-3-yl) acetic or 2 - ((3R, 5R, 6S) -5- ( 3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -1- (6- (2-hydroxypropan-2yl) pyridin-2-yl) propyl) —3-methyl-2-oxopiperidin-3-yl )acetic

Stage A. 6-ethyl propylpicolinate

862

A solution of ethyl 6-bromopicolinate (8 g, 34.8 mmol, purchased from AK Scientific, Inc., Union City, CA) in THF (200 mL) was bubbled with N2 at 0 ° C for 20 min. To mix under N atmosphere2 Pd (PPh was added3)4 (3.21 g, 2.78 mmol) and a solution of propylzinc bromide (100 mL, 0.5 M in THF, 50.0 mmol) dropwise over 30 min. The mixture was removed from the ice bath and heated to reflux for 18 h. After such time the solution was cooled to rt, poured into saturated aqueous NH solution4C1 (18 mL), diluted with water (30 mL), and extracted with EtOAc (3 χ 30 mL). The combined organic layers were washed with water and saturated aqueous NaCl solution, and dried over Na2SW4. After removal of the organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0 to 50% EtOAc / hexanes provided the title compound. Mass Spectrum (ESI) m / z = '194.0 (M + l).

Stage Β. Ethyl 6- (1-bromopropyl) picolinate

863

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY>> 3 The title compound was prepared from Example 241, Step A following a procedure similar to that described for the synthesis of 2- (1-bromopropyl) pyridine (Example

230). Mass Spectrum (ESI) m / z = 272.0 and 274.0 (M + l).

ethyl chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) propyl) picolinate

The title compounds

were prepared as a mixture of ethyl 6- (1-bromopropyl) picolinate (Example 241, Step B) following a procedure similar to that described in

Example 226, StepC. Mass Spectrum (ESI) m / z = 566.2 (M + l)

Stage D.

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 864

1 - ((R) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) propyl) -3 methylpiperidin-2-one. and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -1- (6- (2-hydroxypropan-2-yl) pyridine -2il) propyl) -3-methylpiperidin-2-one

Ά a 0 ° C solution of

6 - ((R) -1 - ((3S, 5R, 6S) -3-allyl-5 (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lyl) propyl) picolinate Ethyl and 6- ((S) -1 - ((3S, 5R, 6S) -3-allyl5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) propyl ) ethyl picolinate (160 mg, 0.283 mmol, Example 241, Step C) in THF (3 mL) under N2 CH added3MgBr (3.0 M solution in diethyl ether, 0.377 mL, 1,132 mmol). The mixture was removed from the ice bath and stirred at rt for 30 min. CH was added to the reaction mixture3Additional MgBr (3.0 M solution in diethyl ether, 0.24 mL ·, 0.78 mmol). After stirring at rt for 2.0 hr, saturated aqueous NH solution was added to the reaction mixture4C1 (3 mL) and water (4 mL). The mixture was extracted with EtOAc (3 χ 8 mL). The combined organic layers were washed with water, - solution

IMPI

865 saturated aqueous NaCl, and dried over Na2SW4. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 20-80% EtOAc / hexanes provided the title compounds as a mixture of stereoisomers. Mass Spectrum (ESI) m / z = 551.1 (M + l).

Stage E. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (6- (2-hydroxypropan-2-yl) pyridin-2yl) propyl) -3-methyl-2-oxopiperidin-3-yl) acetic or 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((R) -1- (6- (2hydroxypropan-2-yl) pyridin-2-yl) propyl) -3-methyl-2oxopiperidin-3-yl) acetic

The title compound was prepared from a mixture of '(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (.4chlorophenyl) -1 - ((R) -1- ( 6- (2-hydroxypropan-2-yl) pyridin-2yl) propyl) -3-methylpiperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl ) -1 - ((S) -1- (6- (2-hydroxypropan-2yl) pyridin-2-yl) propyl) -3-methylpiperidin-2-one (Example 241, Step D) following a procedure similar to that described above in Example 230, Step C. Purification of the crude mixture as described provided one of the title compounds as a single isomer as a white solid.

866 XH NMR (400 MHz, CHLOROFORM-d)

5ppm 1.08 - 1.17 (m, 3H),

1.32 - 1.50 (m, 9H), 1.87 - 1.97 (m, IH), 1.97 - 2.08 (m,

3H), 7.13 - 7.24 (m, 2H), 7.48 (br. S., IH). Spectrum

Masses (ESI) m / z = 569.1 (M + l).

EXAMPLE 242

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (6-cyclopropylpyridin-2-yl) propyl) -3- methyl-2-oxopiperidin-

3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4- chlorophenyl) -1 - ((R) -1- (6-cyclopropylpyridin-2- il) propyl) -3methyl-2-oxopiperidin-3-yl) acetic

Stage A. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

1- ((S) - 1 - (6-cyclop ^ ropiIpiridin-2-yl) propyl) -3-methylpiperidin-

2- one or (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 867

IMPI

1- ((R) —1— (6-cyclopropylpyridin-2-yl) propyl) -3-methylpiperidin-

2-one

To a mixture solution of ((3S, 5R, 6S) -3-allyl-l (1 - (5-bromopyridin-2-yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one (165 mg, 0.288 mmol; Example 239 in DMF (3 mL) tricyclohexylphosphine (11.32 mg, 0.04 mmol), potassium phosphate (214 mg, 1,009 mmol), cyclopropylboronic acid (49.5 mg) was added , 0.577 mmol) and diacetoxypalladium (4.53 mg, 0.020 mmol) .The mixture was bubbled with N2 for 5 min and then heated to 80 ° C for 5 hr. The resulting solution was cooled to rt, diluted with water (6 mL), and extracted with EtOAc (8 mL χ 2). The organic layers were combined, washed with water, saturated aqueous NaCl solution, and dried over MgSO4 · After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0 to 70% EtOAc / hexanes provided the title compound as a colorless syrup.

Stage

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4868

ΓΜ ΡI i?

INSTITUTO .MEXICANO \\ ·

PROPERTY V'SrcTr 'INDUSTRIAL chlorophenyl) -1 - ((S) -1- (6-cyclopropylpyridin-2-yl) propyl) -3 methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from cyclopropylpyridin-2-yl) propyl) -3-methylpiperidin-2-one (Example 242, Step A) following a procedure similar to that described in. Example 71, Step F).

<td></td><td>XH</td><td>NMR</td><td>(400 MHz,</td><td>, CHLOROFORM-d)</td><td>5ppm 0.95 - 1.08</td><td>(m,</td><td>3H),</td>

IH), 6.74 (d, <7 = 7.63 Hz, 2H), 6.90 - 7.01 (m, 5H), 7.01 7.08 (m, IH), 7.10 (d; <7 = 8.02 Hz, 2H), 7.75 (t, J = 8.02 Hz, IH). Mass Spectrum (ESI) m / z = 551.2 (M + l).

EXAMPLE 243

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-l - ((S) -3,3,3-trifluoro- l- (pyridin-2yl) propyl) piperidin-3-yl) acetic acid, 2,2,2-trifluoroacetic acid salt (1: 1) or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 acid - (4-chlorophenyl) -3-methyl-2-oxo-l- ((R) -3,3, 3tr ± fiuora-l- (pyridin-2-yl) propyl) piper ± d ± nr-3 ^ yl ) acetic, 2,2,2-trifluoroacetic acid salt (1: 1)

869

Stage A. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (pyridi'n-2-ylmethyl) piperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methylpiperidin-2-one (2,246 g, 6 mmol; Example 71 D) in DMF (25 mL) sodium hydride, 60% dispersion in mineral oil (0.504 g, 12.60 mmol) was added and the mixture was stirred at 0 ° C for 5 minutes. To this * was added 2- (bromomethyl) pyridine hydrobromide (1,593 g, 6.30 mmol) at 0 ° C. The resulting mixture was stirred at 0 ° C for 10 min and quenched with NH solution4C1 saturated, extracted with EtOAc, washed with saturated aqueous NaCl solution, dried over MgSO4, I know

filtered and the filter product was concentrated. The residue was purified by flash chromatography on silica gel

870

<td>(eluent:</td><td>0 to 100% EtOAc in hexanes) to give the</td>

title compound. Mass Spectrum (ESI) m / z = 465 (M + l).

Stage B.

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -3,3,3-trifluoro-1- (pyridine- 2yl) propyl) piperidin-2-one or (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((R) -3.3 , 3-trifluoro10 1- (pyridin-2-yl) propyl) piperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l- (pyridin-2-ylmethyl) piperidin-2-one ( 660 mg, 1,418 mmol; Example 243, Step A) in inhibitor-free THF (7 mL) under N2 At -78 ° C lithium diisopropylamide (1,418 mL, 2.84 mmol) was added and the mixture was stirred for 30min. 1,1, l-Trifluoro-2-iodoethane (744 mg, 3.55 mmol; Sigma, St. Louis, MO) was added and the orange reaction was stirred at -78 ° C for 1 h. The reaction was then warmed to rt and stirred overnight. The mixture was quenched with 0.2 mL of MeOH,

filtered, concentrated and the residue was purified by HPLC (column

871

C18, eluting with 10-95% CH3CN in water, with 0.1% TFA) to give the title compound as the minor eluate diastereomer. Mass Spectrum (ESI) m / z = 547 (M + l).

Stage C.

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -3,3,3-trifluoro-1 acid - (pyridine-

2-yl) propyl) piperidin-3-yl) acetic acid 2,2,2 Trifluoroacetic acid (1: 1)

The title compound was obtained from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1- ((S) -3,3, 3-trifluoro-l- (pyridin-2-yl) propyl) piperidin-2-one (61.2 mg, 0.112 mmol; Example 243, Step B) by a procedure similar to that described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) opm 8.96 (1 H, d, J = 4.7

Hz), 8.09 (1 H, t, J = 7.8 Hz), 7.86 (1 H, d, J = 8.2 Hz), 7.56 7.68 (1 H, m), 7.22 (4 H, s), 7.08 - 7.17 ( 3 H, m) ,, 6.94 (1

H, s), 6.90 (1 H, d, J = 6.7 Hz), 5.27 - 5.38 (1 H, m), 4.95 (1

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

872

m), 1.15 (3H, s). Mass Spectrum (ESI) m / z = 565 (M + l).

EXAMPLE 244

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2-oxo-l - ((S) -3,3,3-trifluoro- 1- (pyridin-2yl) propyl) piperidin-3-yl) acetic, such as the acid salt

2,2,2-trifluoroacetic (1: 1)

Stage A. (3S, 5R, 6S) -3-Allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -3,3-difluoro-1- (pyridin-2-yl ) propyl) -3methylpiperidin-2-one

6- (4-chlorophenyl) -3-methyl-l- (pyridin-2-ylmethyl) piperidin-2-

<td>one</td><td colspan="2">(705 mg, 1,515</td><td>mmól;</td><td>Example</td><td> 71,</td><td>Stage D)</td><td>in free THF</td>

<td>of</td><td>inhibitor</td><td> (7</td><td>mL)</td><td>low</td><td>n2</td><td>at -78 ° C</td><td>added</td>

<td colspan="2">diisopropylamide</td><td>of</td><td>lithium</td><td> (1.515</td><td>mL,</td><td>3.03 mmol)</td><td>and the mix</td>

stirred for 30min. 1,1-Difluoro-2-iodoethane (727 mg, 3.79 mmol; Oakwood) was added and the orange reaction mixture was stirred at -78 ° C for 1 h. The reaction was warmed to rt overnight and quenched with 0.2 mL MeOH, filtered and concentrated. The residue was purified by HPLC (column C18, eluting with 10-95% CH3CN in water, with TFA at 0.1%) to give (3S, 5R, 6S) -3-allyl5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -3.3- difluoro-1 (pyridin-2-yl) propyl) -3-methylpiperidin-2-one (HPLC retention time 7.38 min, Agilent Eclipse Plus C18 column, 0.1% TFA in CH3CN / H2O, gradient 70% - 90% over 25 minutes) and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -l - ((S) —3,3- difluoro-1- (pyridin-2-yl) propyl) -3methylpiperidiuf-2-one (HPLC hold time-Lón 7.94 min,

IMPI

Agilent column

Santa Clara, CA)

Eclipse

TFA at

874

Plus

C18 (Agilent Technologies,

0.1% in CH3CN / H2O, gradient 70% 90% over 25 minutes). Mass Spectrum (ESI) m / z = 529 (M + l).

Stage B.

2- ((3R, 5R, .6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -3,3,3-trifluoro- l- (pyridin2-yl) propyl) piperidin-3-yl) acetic / acid

2,2,2 Trifluoroacetic (1: 1)

The title compound was obtained from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

3,3-Difluoro-l- (pyridin-2-yl) propyl) -3-methylpiperidin-2-one (50 mg, 0.095 mmol; Example 244, Step A;) by a procedure similar to that described in Example 71, Stage F.

XH NMR (400 MHz, CHLOROFORM-d) ppm 9.03 (1 H, d, <7 = 4.3

Hz), 8.17 (1 H, t, <7 = 7.8 Hz), 7.79 (1 H, d, <7 = 8.2 Hz), 7.72 (1 H, t, <7 = 6.3 Hz), 7.18 - 7.25 (4 H, m), 7.08 - 7.16 (2 H, m), 6.95 (1 H, s), 6.88 - 6.93 (1 H, m), 5.44 (1 H, br. S.),

IMPI

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

875

5.31 (2 H, d, <7 = 10.4 Hz), 5.21 (6 H, br. S

5.10 (2H, br.

s.), 3.30 - 3.42 (1 H, m), 3.18 (1 H, br. s.), 2.90 (1 H, d, <7 = 15.1 Hz), 2.72 (1 H, d, J = 15.1 Hz ), 2.44 (1 H, d, <7 = 16.4

Hz), 2.27 (1 H, t, <7 = 13.8 Hz), 1.98 - 2.08 (1 H, m), 1.21 (3

H, s). Mass Spectrum (ESI) m / z = 547 (M + l).

EXAMPLE 245

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -2-methyl-l- (pyridin-2-yl) acid propyl) -2-oxopiperidin-

3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((R) -2-methyl-l- ( pyridin-2-yl) propyl) -2oxopiperidin-3-yl) acetic

876

Stage Ά: 2- (l-Bromo-2-methylpropyl) pyridine

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRL-.L

The title compound was prepared from 2isobutylpyridine (5.17 g, 38.2 mmol; Alpha Aesar, Ward Hill, MA) following a procedure similar to that described in Example 230. The reaction mixture was cooled to rt and filtered, The filtered cake was washed copiously with DCM. The filter product was concentrated in vacuo and purified by chromatography on silica gel, eluting with a 0 to 25% gradient of EtOAc in hexanes. Fractions containing the desired product were concentrated to give the title compound.

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -2-methyl-l- (pyridin-2yl ) propyl) piperidin-2-one or (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -2-methyl- l (pyridin-2-yl) propyl) piperidin-2-one.

877

2- (l-Bromo-2-methylpropyl) pyridine (Example 245, Step A) and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- Methylpiperidin-2-one (Example 71, Step D) were combined according to a procedure similar to that described in Example 226, Step C, bringing after separation the title compound as the least abundant diastereomer. MS (ESI) 507 [M + H]1 .

Stage C.

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -2-methyl-l- (pyridin-2-yl) acid propyl) -2-oxopiperidin-

3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((R) -2-methyl-l- ( pyridin-2-yl) propyl) -2oxopiperidin-3-yl) acetic

The title compound was obtained by treating the compound of Example 245, Step B by the procedure as described in Example 71, 'Step F.

XH NMR (500 MHz, DICHLOROMETHANE-d2) 60.87 (d, J = 6.11 Hz,

H), 1.18 (br. S., 3 H), 1.33 - 1.47 (m, 3 Η), 1.96 - 2.10

ΓΜΡΙ

(m, 1 Η),

2.10-2.27 (m, 1 Η),

2.70 - 2.88 (m, 3H), 3.19 878

3.30 (m, 1H), 4.66 (d, J = 9.54 · Ηζ, 1H), 6.73 (d, <7 = 7.58

Hz, 1 H), 6.84 (br. S., 2, H), 6.97 (br. S., 3 H), 7.05 - 7.23 (m, 3 H), 7.55 (t, 7 = 6.60 Hz, 1 H ), 7.82 (t, J = 8.31 Hz, 1

H), 8.79 (d, 7 = 4.89 Hz, 1H). MS (ESI) 525 [M + H]+.

EXAMPLE 246 (3R, 5R, 6S) -3 - ((lH-tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-l- (pentan-3 -il) piperidin-2-one

The title compound was prepared from 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo

1- (pentan-3-yl) piperidin-3-yl) acetic acid (Example 71) as described in Example 86.

XH NMR (400 MHz, CHLOROFORM-d) opm 0.49 (t, <7 = 7.53 Hz,

H). Mass Spectrum (ESI) m / z 486.3 [M + H]+.

879

IMPI

(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- ((R) -2,3 EXAMPLE 247 dihydroxypropyl) -1 - ((2S, 3S) -2-hydroxypentan -3-yl) -3methylpiperidin-2-one and (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((S) -2,3-dihydroxypropyl) -1- ((2S, 3S) -2 hydroxypentan-3-yl) -3-methylpiperidin-2-one

Stage A. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1- ((2S, 3S) -2-hydroxypentan-3-yl) -3- methylpiperidin-2-one

To a stirred solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -2-oxopentan-3yl) piperidine -2-one (185 mg, 0.40 mmol; Example 149, Step B) in THF (4 mL) under a nitrogen atmosphere at -8 ° C (internal temperature) L-Selectride® (Aldrich, St.

Louis, MO) (0.48 mL, 0.48 mmol, 1M solution in THF) drop by

880

drop for 2 minutes (internal temperature reached -5 ° C). After 10 minutes the reaction was quenched with MeOH (0.1 mL) and treated with Oxone® (EKHSOs'KHSO ^ foSO,}, DuPont, Wilmington, DE) (992 mg, 1.61 mmol) in water (30 mL) and then stirred at rt for 2 hours. After this time the reaction was divided between EtOAc (50 mL) and Na2S2O3 (30 mL, saturated aqueous solution). The separated organic layer was washed with brine (20 mL) and then dried over MgSO4, filtered and evaporated in vacuo to give the title compound. Mass Spectrum (ESI) m / z = 460.0 (M + l).

Stage B: (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- ((R) -

2,3-dihydroxypropyl) -1 - ((2S, 3S) -2-hydroxypentan-3-yl) -3methylpiperidin-2-one and (3R, 5R, 6S) -5- (3-chlorophenyl) -6- ( 4chlorophenyl) -3 - ((S) -2,3-dihydroxypropyl) -1- ((2S, 3S) -2hydroxipentan-3-yl) -3-methylpiperidin-2-one

To a stirred solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((-2S, 3S) -2-hydroxypentan-3yl) -3- methylpiperidin-2-one. (75 mg, 0.163 mmol, Example 247, Step A) in t-BuOH (2 mL), 4-methylmorpholine 4-oxide (76 mg, 0.652 mmol) and osmium tetroxide (2.1 mg, 8.14 pmol) were added and the reaction was waved ta from one day to the next. After this time the reaction was divided between EtOAc (100 mL) and Na2S2O3 (40 mL, saturated aqueous solution). The

881

separated organic layer washed with NaHCO3 (40 mL, saturated aqueous solution), dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by reverse phase HPLC (Sunfire ™ Prep Cib OBD 10 pm column (Waters, Milford, MA), elution gradient from 20% MeCN in water to 80% MeCN in water over a period of 30 min. , where both solvents contain 0.1% TFA) to give the title compounds as- a separable diastereomer mixture.

The eluted isomer: XH NMR (400 MHz, CHLOROFORM-d) ppm 6.96-7.28 (8 H, m), 6.73 (1 H, dt, J = 7.6, 1.6 Hz), 4.39 (1 H, d, J = 10.6 Hz), 3.96 - 4.06 (1 H, m), 3.71 (1 H, dd, J = 11.0,

3.5 Hz), 3.56 (1 H, dd, J = ll.l, 7.3 Hz), 3.26 - 3.38 (1 H,

m), 1.78 - 2.15 (6 H, m), 1.44 (3 H, s), 1.19-1.39 (4 H, m), 0.50 - 0.67 (3 H, m). Mass Spectrum (ESI) m / z = 494.0 (M + l).

Eluted 2nd isomer: 1H NMR (400 MHz, CHLOROFORM-d) 5ppm 6.96-7.28 (8 H, m), 6.70 (1 H, dd, J = 6.2, 1.5 Hz), 4.38 (1 H, d, J = 10.4 Hz), 4.31 (1 H, br.s.)> 3.66 - 3.76 (1 H, m), 3.53 - 3.63 (1 H, m), 3.22 - 3.33 (1 H, m), 1.80 - 2.32 (4 H, m),

1.45 (3H, s), 1.16-1.45 (6H, m), 0.40-0.55 (3H, br.s.).

Mass Spectrum (ESI) m / z - 494.0 (M + l).

Acid 2- ((3R, 5R, 6S) .- 5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 882

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

EXAMPLE 248 l-hydroxybutan-2-yl) -3-methyl-2-oxopiperidin-3yl) cyclopropancarboxylic

Stage A. l - ((S) -1- (tert-butyldiphenylsilyloxy) butan-2-yl) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidine-3carboxylate of ( 3S, 5R, 6S) -Methyl

A stirred solution of (5R, 6S) -1 - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin-2-one (1.3 g, 2,016 mmol; Example 185, Step D) in inhibitor-free THF (10 mL) was degassed for 30 minutes with argon. The reaction was transferred via cannula for 5 minutes to a freshly prepared solution of LDA at -78 ° C (the

883

ΙΓίυΟδι ΜΑ »· -LDA was prepared by treating N, N-diisopropylamine (0.72 mL, 5.04 mmol) in inhibitor-free THF (2 mL) at ~ ^ -20 ° C under an argon atmosphere with butyllithium (2.02 mL, 5.04 mmol, 2.5 M in hexanes) for T minute and stir the mixture at -15 ° C for 30 minutes). The resulting reaction mixture was stirred while warming to 0 ° C for 30 minutes. The reaction was cooled to -78 ° C and treated with methyl chloroformate (0.47 mL, 6.05 mmol) dropwise over 2 minutes.

The reaction was stirred at -78 ° C for 2 hours and 30 minutes and then quenched with 30 mL of a saturated aqueous NH solution4C1 and allowed to warm to rt The mixture was partitioned between ethyl acetate (150 mLj and water (50 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (YES2, hexanes: EtOAc, 1: 0 to 4: 1) gave the title compound ·. Mass Spectrum (ESI) m / z = 702.1 (M + l).

Step (3R, 5R, 6S) -1 - ((S) -1- (tertButildiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenylj-6- (4 chlorophenyl) -3- (hydroxymethyl) -3- methylpiperidin-2-one

TBDPSO

884

(3S, 5R, 6S) -methyl chlorophenyl) -3-methyl-2-oxopiperidine-3-carboxylate (450 mg, 0.640 mmol; Example 248, Step A) at 0 ° C in THF (4 mL) under an atmosphere Nitrogen triethylborohydride (1.60 mL, 1.60 mmol, 1M solution in THF) was added dropwise. The reaction was stirred at 0 ° C for 1 hour and then quenched with methanol (0.2 mL) and treated with Oxone® (2KHSO5'KHSO4'K2SO4, DuPont, Wilmihgton, DE) (1.18 g,

1.92 mmol) in water (50 mL). The mixture was stirred for 1 hour and then extracted with ethyl acetate (100 mL). The separated organic layer was washed with Na2S2O3 (50 mL, saturated aqueous solution) and then dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (SiO2, hexanes: EtOAc, 1: 0 to 7: 3) gave the title compound. Mass Spectrum (ESI) m / z = 674.2 (M + l). |

Step C. (3R, 5R, 6S) -1 - ((S) -1- (tertButyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2- oxopiperidin-3-carbaldehyde

ΓΜΡΙ

885

To a stirred solution of (3R, 5R, 6S) -1 - ((S) -1- (tert •. I butyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 3- (hydroxymethyl) -3-methylpiperidin-2-one (210 mg, 0.311 mmol; Example 248, Step B) in CH2CI2 (8 mL) at 0 ° C NaHCO was added3 (131 mg, 1.56 mmol) and persodinano Dess Martín (158 mg, 0.373 mmol) in one serving. The reaction was stirred at rt for 2 hours. The reaction was diluted with CH2CI2 (30 mL) and treated with Na2S2O3 (15 mL, saturated aqueous solution) and

<td>NaHCO3</td><td> (15</td><td colspan="2">mL, aqueous solution</td><td>saturated)</td><td>at</td><td>. to. during</td><td> 2</td>

<td>hours.</td><td>The</td><td>aqueous layer</td><td>separated</td><td>was extracted</td><td>with</td><td>CH2C12 (2 x</td><td> 50</td>

<td>mL) and</td><td>the</td><td>excerpts</td><td>organic</td><td>combined</td><td>I know</td><td colspan="2">dried over</td>

<td>MgSO4,</td><td>I know</td><td>leaked</td><td colspan="3">and evaporated in vacuo</td><td>to give</td><td>the</td>

<td colspan="2">compound</td><td>of the title.</td><td>Spectrum</td><td>of masses</td><td>(ESI)</td><td>m / z = 672</td><td> .2</td>

(M + l).

Stage

3- (, (3R, 5R, 6S) -1- ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl- (£) Methyl 2-oxopiperidin-3-yl) acrylate

To a stirred solution of THF (4 mL) and sodium hydride

886 (16 mg, 0.40 mmol, dispersion at

60% oil) under a nitrogen atmosphere at 0 ° C trimethyl phosphonoacetate (61 pL, 0.43 mmol) was added dropwise over 30 seconds.

The mixture was allowed to warm to rt for 30 minutes. A solution of (3R, 5R, 6S) -1 - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyI-2- oxopiperidine-3-carbaldehyde mg,

0.305 mmol; Example 248, Step C) Resulting mixture stirred by reaction partitioned between EtOAc, separated organic layer dried in THF (3 mL) for 2 added.

hours.

about MgSO4leaked

The

He evaporated it in vacuo. Column chromatography (S1O2, hexanes: EtOAc,

1: 0 to 8: 2) gave the title compound.

Mass Spectrum (ESI) m / z = 728.2 (M + l).

Stage

AND.

methyl butyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) cyclopropanecarboxylate

To a stirred solution of sodium hydride (12 mg,

0.30 mmol, dispersion at

887

IMH

MEXICAN INSTITUTE

DELA INDUSTRIAL PROPERTY

60% in oil) in THF (1.0 mL) under an argon atmosphere, trimethylsulfoxonium iodide (72 mg,

0.33 mmol) portioned for one minute. The reaction was stirred at rt

for 1 hour. A solution of

3- ((3R, 5R, 6S) -1 - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2 ^ yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2- (E) methyl oxopiperidin-3-yl) acrylate (120 mg, 0.165 mmol; Example 248, Step D) in DMSO (1.0 mL) was added dropwise over 1 minute. The reaction was stirred at rt overnight. After this time more sulfur ylide was synthesized by suspending trimethylsulfoxonium iodide (140 mg) in DMSO (0.5 mL) under a nitrogen atmosphere and treating the mixture with NaH (24 mg, 60% dispersion in oil) and stirring for 30 minutes. Sulfur ylide was then added to the reaction and the mixture was stirred at rt for 16 hours After this time more sulfur ylide was synthesized by suspending trimesulf oxonium iodide (140 mg) in DMSO (0.5 mL) under a nitrogen atmosphere and treating the mixture with NaH (24 mg, 60% dispersion in oil ) and stir for 30 minutes. Sulfur ylide was then added to the reaction and the mixture was stirred at rt for 16 hours. The reaction was partitioned between ethyl acetate (70 mL) and NH4CI (30 mL,

- saturated aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. The

888

reverse phase HPLC purification (Sunfire Prep column

Co. 10 pm OBD, gradient elution of 40% MeCN in water to 100% MeCN in water over a period of 40 min, where both solvents contain 0.1% TFA) gave the title compound as the first major and eluted diastereomer. Stereochemistry in cyclopropane is a simple but not assigned diastereomer. Mass Spectrum (ESI) m / z =

742.2 (M + l).

Step F. Acid 2 - ((3R, 5R, 6S) -l - ((S) -l- (tertButildiphenylsilyloxy) buthan-2-yl) -5- (3-chlorophenyl) -6- (4chlorophenyl) -3- methyl-2-oxopiperidin-3yl) cyclopropancarboxylic

Example

248,

Step E (10 mg, 0.01'3 mmol) in THF (1.0 mL) Sodium hydroxide (404 pL, 0.404 mmol, aqueous solution) was added

1M). The reaction was stirred at rt for 24 hours. After this time the reaction was divided between EtOAc (30 mL) and

1.0 M HC1 (5 mL). The separated organic layer was dried over

MgSOz, filtered and evaporated in vacuo to give the compound

889

INDUSTRIAL title as a simple diastereomer. Spectrum

Masses (ESI) m / z

728.2 (M + l).

Stage

chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methyl-2 oxopiperidin-3-yl) cyclopropancarboxylic

To a solution

Step F (10 mg, stirred 0.014 of the acid from Example 248, mmol) in THF (0.2 mL) TBAF (0.1 mL, solution 1.0 was added

M in THF).

After 30 more minutes

TBAF (0.1 mL, '1.0 M solution in THF) was added and the reaction was stirred at rt for hours. After this watery time

MgSO4, the

1M reaction was partitioned between EtOAc (30 filtered and evaporated in vacuo. The residue dried over resultant was purified by reverse phase HPLC (Sunfire Prep column

Ci8 OBD 10 pm, 20% gradient elution

MeCN in water a

80% MeCN in water over a period of min, where both solvents contain 0.1% TFA) to give the title compound.

XH NMR (400

MHz, CD3ÓD) δρρτη

7,29

7.34 (2H,

m), 7.06

2.8T (Γ H, ~ dt,

J = 8.9, 4.5 Hz), 2.4 8 (1 H, t, <7 = 13.5 Hz),

7.21 (5H, m),

6.87 - 6.98 (1 H, m), 4.70 (1 H,

Hz), 4.06 (1 H, dd, 7 = 11.1, 9.3 Hz),

3.45

3.56 (2 H, mj,

IMPI

1.92 - 2.04 (1 H, mj,

1.78

- 1.88 (1 H, m), 1.61 - 1.72 (1 '8 90

H, m), 1.43 - 1.53 (2 H, m), 1.22 - 1.36 (6 H, m), 0.41

0.52 (3H, m). Mass Spectrum (ESI) m / z = 490.0 (M + l).

EXAMPLE 249

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -2- (tert-Butoxy) -l-cyclopropyl-2 oxoethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3yl) acetic

Step A. Ethyl 2-bromo-2-cyclopropylacetate.

To a solution of 2-cyclopropylacetic acid (24.7 g,

247 mmol) in anhydrous DCE (250 mL), thionyl chloride (22 mL, 302 mmol) was added dropwise over 5 minutes at 25 ° C. After refluxing for 2 h, the reaction was cooled to room temperature, N-bromosuccinimide (53.6 g, 301 mmol) and hydrogen bromide (48% aqueous solution)

891

(0.195 mL, 1,727 mmol) resulting mixture were added successively at 25 ° C. Heated it to reflux for 96h.

After the reaction mixture was cooled to room temperature, absolute EtOH (200 mL) was added and the resulting dark brown solution was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure (35 ° C, 4.0 kilopascal) and the residue was suspended in carbon tetrachloride (300 mL) and passed through a glass filter. The filter product was concentrated under reduced pressure (35 ° C, 4.0 kilopascal). Purification of the crude product by chromatography (silica gel, 330 g x 2.5% ethyl acetate / hexane) and concentration of the desired combined fractions under reduced pressure (35 ° C, 4.0 kilopascal) provided the title compound as a pale yellow liquid.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 4.20 - 4.32 (2 H,

m), 3.59 (1 H, d, 7 = 10.4 Hz), 1.53 - 1.66 (1 H, m), 1.29 1.36 (3 H, m), 0.76 - 0.93 (2 H, m), 0.51 - 0.61 (1 H, m),

0.40 - 0.47 (1H, m).

Stage B.

2— ((2S,

(S) -ethyl 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6892 oxopiperidin-l-yl) -2-cyclopropylacetate

To a solution of (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -3-piperidin-2-one (8.01g, 25 mmol; Example 1,

Step E) In DMF (60 mL) 60% sodium hydride in mineral oil (2.0 g, 50 mmol) was added at 0 ° C and the mixture thus obtained was stirred at the same temperature for 30 min. Ethyl 2-bromo-2-cyclopropylacetate (12.18 g, 50 mmol) in DMF (10 mL) was added dropwise to the mixture and the mixture was stirred at room temperature for 2 h, then the reaction was quenched with sat. ammonium chloride and diluted with ethyl acetate. The organic layer was washed with citric acid aq. at 10%,

NaHCO3 solution ac. 5%, water, saturated aqueous solution of

NaCl, then dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with 20% to 50% ethyl acetate in hexane to give the title compound as the first elution diastereomer, a white solid. - - - - - - - ------------ ~ ~ ~

XH NMR (400 MHz, CHLOROFORM-d) δ

ppm

893

<td>2H).</td><td colspan="2">Spectrum</td><td>of masses</td><td>(ESI)</td><td>m / z = 446.2</td><td>(M + l).</td><td></td><td></td>

Step C. 2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -6oxopiperidin-l-yl) -2-cyclopropylacetate (S) -tert-butyl

To a solution of 2 - ((2S, 3R) -3- (3-chlorophenyl) -2- (4chlorophenyl) -6-oxopiperidin-l-yl) -2-cyclopropylacetate (S) - ethyl (500 mg, 1.12 mmol) (Example 249, Step B) in THF / MeOH / H2Or (5/5/5, 15 mL) lithium hydroxide (1.68 mL, 3.36 mmol) was added at rt, and then the reaction was heated to 60 ° C. After stirring at 60 ° C for 1.5 hr, the reaction was quenched with saturated aqueous NH solution4C1 and extracted (2 χ DCM). The combined organic layers were washed (1 χ saturated aqueous NaCl solution), dried over Na2SO4were filtered and the filter product was

894 concentrated and concentrated low

Crude acid (450 mg,

1,076 mmol) synthesized above was dissolved in DCM (10 mL) and sulfuric acid (115 uL, 2,151 mmol) was added, followed by 2-methylprop-l-ene (1,207 g,

21.51 mmol) at -78 ° C. The reaction vessel was sealed and the mixture slowly warmed to room temperature.

After being vigorously stirred for 4 days, the reaction was quenched with NH solution4C1 aqueous sat. and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution and dried over sodium sulfate, filtered, and the filtration product was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 40% EtOAc / hexanes) provided the title compound.

Step D. 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -2-oxopiperidin-l-yl) -2-cyclopropylacetate from (S) tert -butyl

N

895

IMPI MEXICAN INSTITUTE Dt LA? RCFI £ DAD INDUSTRIAL

A solution of lithium bis (trimethylsilyl) amide (1M in THF, 0.165 mL, 0.165 mmol) was added dropwise at -78 ° C to a solution of 2 - ((2S, 3R) -3- (3-chlorophenyl ) -2- (4-chlorophenyl) 6-oxopiperidin-l-yl) -2-cyclopropylacetate (S) -tert-butyl (Example 249, Step C, 71 mg, 0.15 mmol) and allyl bromide (15.54 uL, 0.165 mmol ) in 0.5 mL of THF. The reaction was allowed to warm to room temperature. After stirring for 2 h, the reaction was quenched with sat. Aq. Ammonium chloride solution. and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution and dried over sodium sulfate, then filtered and the filtration product concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with ethyl acetate / hexane provided the title compound.

Stage E. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (N-cyclopropylacetamido) butan-2-ί1) - 3methyl-2-oxopiperidin-3-yl) acetic '

The title compound was obtained from 2 ((38,5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2oxopiperidin-l-yl) -2-cyclopropylacetate (S) -tert-butyl (Example 249, Step D) by the procedure of Example 71, step F. - - - - - ~ ~ ~

896 XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.08 (m, 1 Η), 0.49

EXAMPLE -250

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) - l-cyclopropyl-2-ethoxy-2-oxoethyl) -3- methyl-2-oxopiperidin-3yl) acetic

Stage A. 2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

Ethyl 3-methyl-2-oxopiperidin-l-yl) -2-cyclopropylacetate

897

The coupling of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methylpiperidin-2-one (Example 71, Step D) and

Ethyl 2-bromo-2-cyclopropylacetate (Example 249, Step A) using the procedure as described in Example 9, step A provides the title compound as a mixture of two diastereomers.

Stage B. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) 1 - ((S) -l-cyclopropyl-2-ethoxy-2-oxoethyl) - 3-methyl-2-oxopiperidin-

3— il) acetic

OR

The title compound was obtained from 2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2 oxopiperidin-l-yl) Diastereomeric ethyl -2-cyclopropylacetate (Example 250, Step A) using the oxidation procedure described in Example 71, Step F. The individual stereoisomers were separated by chiral HPLC (150 x 30 mm CHIRALPAK® IC column (CHIRAL TECHNOLOGIES, INC ., West Chester, PA, USA) with 20% IPA (0.1% DEA) / CO2, 50mL / min, in Thar 350 SFC. (Thar Technologies, Inc., Pittsburg,

ΡΑ)) to give the title compound as the fastest eluate.

898

1H NMR (400 MHz, CHLOROFORM-d) δρριη -0.49 - -0.40 (m, 1 H)

0.12 - 0.21 (m, 1H) 0.36 - 0.46 (m, 1H) 0.64 (m, 1H) 1.28 (t, <7 = 7.14 Hz, 3H) 1.37 (s, 3H) 1.40 - 1.56 (m , lH) 2.14 -

2.27 (m, 2H) 2.83 (d, <7 = 14.48 Hz, 1H) 2.95 (d, <7 = 14.48 Hz, 1

H) 3.02 (d, <7 = 9.78 Hz, 1 H) 3.22 - 3.36 (m, 1 H) 4.06 - 4.22 (m, 2 H) 4.75 (d, <7 = 9.39 Hz, 1 H) 6.81 (m, 1 H) 7.00 - 7.21 (m,

H) 7.21 - 7.35 (m, 2H). Mass Spectrum (ESI) m / z = 518.0 (M + l).

EXAMPLE 251

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1cyclopropyl-2-hydroxyethyl) -3-methyl-2-oxopiperidin- 3-yl) acetic

Stage A. (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -Icyclopropyl-2-hydroxyethyl) piperidin-2-one

UCANO INDUSTRIAL PROPERTY

899

A solution of lithium borohydride (2M in THF, 15.46 mL, 30.9 mmol) was added to a 0 ° C solution of 2 - ((2S, 3R) -3 (3-chlorophenyl) -2- (4-chlorophenyl) -6-oxopiperidin-l-yl) -2 (S) -ethyl cyclopropylacetate (Example 249, Step B, 2.3g,

5.15 mmol) in ether (40 mL). After stirring at room temperature for 20 hours, the reaction was quenched with saturated aqueous NH solution4C1 and extracted into EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, and concentrated to give the title compound as a solid, which was used without further purification.

XH NMR (400 MHz, CHLOROFORM-d) δρριη 0.00 (m, 1H), 0.23

<td> 7.27</td><td>(m, 1H).</td><td colspan="2">Mass Spectrum</td><td>(ESI)</td><td>m / z = 404.0 (M + l).</td><td></td>

Stage

900

cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one

The product from Example 251 step A was converted to the title compound by a similar procedure to that described in Example 185 step C.

XH NMR (400 MHz, CHLOROFORM-d) δρριη -0.70 (m, 1H), -0.40

7.18-7.26 (6H), 7.37-7.45 (m, 4H). Mass Spectrum (ESI) m / z = 642.3 (M + l).

Stage C. (5R, 6S) -1 - ((S) -2 - ((tert-Butyldiphenylsilyl) oxy) -1cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2- one

901

(5R, 6S) -1 - ((S) -2 - ((tert-butyldiphenylsilyl) oxy) -1cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin2-one (Example 251 Step B, 7.9g, · 12.29 mmol) was converted to the title compound, mixture of diastereomers by the method of Example 185, - Step D.

<td></td><td colspan="5">XH NMR (400 MHz, CHLOROFORM-d) opm -0.15 (m, 1H), 0.00</td>

7.74-7.78 (m, 4H).

Step D. (5R, 6S) -3-Allyl-l - ((S) -2 - ((tertbutyldiphenylsilyl) oxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3 -methylpiperidin-2-one

902

(5R, 6S) -1 - ((S) -2- (tert-Butyldiphenylsilyloxy) -1cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2-one (5.02 g, 7.64 mmol, Example 251, Step

C) was converted to the title compound by the procedure described by Example 185, Step *. After work, the unpurified product was used as obtained.

Stage E. Acid 2 - ((3R, 5R, 6S) -1 - ((S) -2 - ((tertButildiphenylsilyl) oxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic

(5R, 6S) -3-allyl-l - ((S) -2 - ((tert-Butildiphenylsilyl) oxy) -1-

• R'AL ·

903 cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methylpiperidine-2-one (Example 251, Step D, 106 mg, 0.15 mmol) was treated according to the procedure of Example 185,

Step F to provide 2 - ((3R, 5R, 6S) -1 - ((S) -2 ((tert-butyldiphenylsilyl) oxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) ) -3-methyl-2-oxopiperidin-3yl) acetic. Mass Spectrum (ESI) m / z = 714.3 (M + l) Stage F. Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S ) -l-cyclopropyl-2-hydroxyethyl) -3-methyl-2oxopiperidin-3-yl) acetic

A solution of tetrabutylammonium fluoride, (1.0 M in THF, 0.453 mL, 0.453 mmol) was added to a solution of 2 - ((3R, 5R, 6S) -l - ((S) -2- (tert-butyldiphenylsilyloxy acid) ) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxopiperidin-3-yl) acetic (Example 251, Step E, 108mg, 0.151mmol) in THF (4ml) and the reaction was stirred at room temperature for 20 hours. LC-MS analysis shows incomplete reaction so an extra 0.225ml of tetrabutylammonium fluoride solution was added and the reaction was stirred for another 26 hours. The mixture was diluted in ethyl acetate, then washed with water and saturated aqueous NaCl solution. The organic layer was dried over sodium sulfate and concentrated. Purification by RP-HPLC (Sunfire Prep column

904

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

CIE 10 pm OBD, gradient elution from 10% MeCN in water to 80% MeCN in water over a period of 30 min, where both solvents contain 0.1% TFA) provide the title compound as a solid. ' XH NMR (400 MHz, CHLOROFORM-d) δρριη -0.30 (s, m, 1H), 0.00 (s, m, 1H), 0.37 (m, 2H), 0.79 (m, 1H), 1.22 (s, 3H) , 2.00 (m, 2H), 2.52 (d, 7 = 14.1 Hz, 1H), 2.70 (d, 7 = 13.9 Hz,

1H), 3.00 (m, 2H), 3.2Ό (s, br, 3H), 3.29 (m, 1H), 4.65 (d, 7 = 10th Hz, 1H), 6.61 (m, 1H), 6.84 ( s, br, 2H), 6.97 (m, 3H), 7.04 (m, 2H). Mass Spectrum (ESI) m / z = 476.2 (M + l).

EXAMPLE 252

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2S) -l-cyclopropyl-2-hydroxybutyl) -3-methyl-2oxopiperidin- 3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((IS, 2R) -l-cyclopropyl-2-hydroxybutyl) -3- methyl-2-oxopiperidin-3-yl) acetic

1 - ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methylpiperidin-2-one

905

A solution of tetrabutylammonium fluoride in THF (1M,

2.10 mL, 2.10 mmol) was added to a solution of diastereomers (5R, 6S) -3-allyl-l - ((S) -2- (tert-butyldiphenylsilyloxy) -1 cyclopropylethyl) -5- (3-chlorophenyl) - 6- (4-Chlorophenyl) -3methylpiperidin-2-one (Example 251, Step D, 488mg, 0.700mmol) in THF (10ml). The reaction was stirred at room temperature for 2 hours. The mixture was diluted in ethyl acetate and washed with water and saturated aqueous NaCI solution. The organic layer was dried over sodium sulfate. Chromatography on silica gel eluting with ethyl acetate / hexane gave the title compound as a single diastereomer. Mass Spectrum (ESI) m / z = 458.0 (M + l)

Stage B. (S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2 cyclopropylacetaldehyde

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

906

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methylpiperidin-2-one (Example 252, Step A, 80 mg, 0.17 mmol) was converted to the title compound as a white foam by the procedure described in Example 91, Step C. Mass Spectrum (ESI) m / z = 45.6.1 (M + l)

Step C. (3S, 5R, 6S) -3-Ali1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1 - ((IS, 2S) -l-cyclopropyl-2-hydroxybutyl) -3- methylpiperidin-2one or (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2R) -l-cyclopropyl-2-hydroxybutyl) '- 3-methylpiperidin-2-one

By the procedure of Example 149,

Step A, substituting methyl magnesium bromide for ethyl magnesium bromide, (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4c1or of eηi1) -3 -met i1-2-oxop ipe ridin-1-i1) -2-

IMPI

907 MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL cyclopropylacetaldehyde (Example 252, Step B, 90mg, 0.20mmol) was converted to the title compound which was obtained as the second eluate diastereomer after chromatography.

<td></td><td colspan="4">XH NMR (400 MHz, CHLOROFORM-d) δρριη -0.43 (m, IH),</td><td> -0.16</td>

<td> 7.01</td><td> -7.07</td><td>(m,</td><td>2H), 7.16-7.18 (m, 2H). Spectrum</td><td>of</td><td>Masses</td>

Stage

D. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((1S, 2S) -l-cyclopropyl-2-hydroxybutyl) -3-methyl acid

2-oxopiperidin-3-yl) acetic or 2 - ((3R, 5R, 6Sj-5- (3Clorophenyl) -6- (4-chlorophenyl) -1 - ((1S, 2R) -l-cyclopropyl-2-hydroxybutyl) acid) -3-methyl-2-oxopiperidin-3-yl) acetic

He got the. title compound by treating the compound of Example 252, Step C by the method described in Example

908

IMPICi

INSTITUTO 'OS LA PROPIEDAD INDUSTRIAL

71, Stage F.

<td></td><td colspan="3">XH NMR (400 MHz, '</td><td colspan="5">Methanol-d4) dppm -0.16</td><td>(s, br,</td><td>1 HOUR),</td>

<td> 7.28</td><td>(m, 2H).</td><td colspan="2">Spectrum</td><td colspan="2">of masses</td><td>(ESI)</td><td>m / z</td><td> = 504</td><td>.1 (M + l).</td><td></td>

EXAMPLE 253

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- cyclopropyl-2- (N-methylcyclopropansulfonamido) ethyl) -3-ethyl-

2- oxopiperidin-3-yl) acetic

Step A. (5R, 6S) -1 - ((S) -2 - ((tert-Butyldiphenylsilyl) oxy) -1cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3ethylpiperidin-2- one

909

ÍNST! T'JTO

D £ LA

Using the procedure described for Example 185,

Step D, substituting methyl iodide for methyl iodide, (5R, 6S) -1 - ((S) -2- (tert-butyldiphenylsilyloxy) -1 cyclopropylethyl) -5- (3-chlorophenyl) -6- (4 chlorophenyl ) piperidin-2-one (Example 251, Stage B, 2.6 g,

4.05 mmol) was converted to the title compound as a foam.

<td></td><td colspan="4">XH NMR (400 MHz, Methanol-d4) 8ppm -0.39</td><td>(m,</td><td>IH), -0.22</td>

6H), 7.58-7.62 (m, 4H). Mass Spectrum (ESI) m / z =

670.2 (M + l)

Stage B. (5R, 6S) -3-Allyl-l - ((S) -2 - ((tertbutyldiphenylsilyl) oxy) -1-Cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3 -ethylpiperidin-2-one

910

Using the procedure described for Example 185, Step E, (5R, 6S) -1 - ((S) -2- (tert-butyldiphenylsilyloxy) -1cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl ) -3methylpiperidin-2-one (Example 253, Step A, 1.6 g, 2.38 mmol) was converted to the title compound which was used without further purification.

Step C. (3S, 5R, 6S) -3-Á1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1- ((S) -l-cyclopropyl-2-hydroxyethyl) -3-ethylpiperidin- 2-one

The title compound was prepared using a similar procedure as Example 202, Step A. It was isolated as the second diastereomer chromatography on eluted silica gel after elution with ethyl acetate / hexanes.

XH NMR (400 MHz, Methanol-d4) δρριη -0.48 (m, 1H), -0.01

911

(s, br, 3H), 7.29 (s, br, 2H). Mass Spectrum (ESI) m / z =

472.1 (M + l). ·

Stage D. N - ((S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) -Nmethylcyclopropansulfonamide

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-hydroxyethyl) -3-ethylpiperidin-2-one (Example 253, Step C, 125mg, 0.265 mmol) was converted to the title compound by the procedure described in Example 202, Step C.

1H NMR (400 MHz, Methanol-d4) δρριη -0.46 (s, br, 1H), 0.24 (s, br, 1H), 0.48 (s, br, 2H), 0.96 (t, 7 = 7.5 Hz, 3H) ,

912

0.99 (m, 6H), 1.71-1.79 (m, 2H), 1.88 (m, IH), 2.35 (t, J = 16 Hz, IH), 2.51 (s, br, IH), 2.69 (m, 2H) , 3.43 (m, 2H), 4.89 (m, IH), 5.17-5.28 (m, 2H), 5.94-6.05 (m, IH), 7.0 (m, IH),

7.05 (m, IH), 7.17-7.19 (m, 4H), 7.30 (m, 2H). Spectrum

Masses (ESI) m / z = 589.2 (M + l).

Stage E. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (Nmethylcyclopropansulfonamido) ethyl) -3- ethyl-2-oxopiperidin-3yl) acetic

The title compound was obtained from N - ((S) —2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) ^ 6- (4-chlorophenyl) -3-ethyl2 -oxopiperidin-l-yl) -2-cyclopropylethyl) -Nmethylcyclopropansulfonamide (Example 253, Step D) by the procedure described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) 8ppm -0.71 (s, br, IH), -

<td>2H),</td><td>7.06 (m, 3H),</td><td> 7.16</td><td>(S,</td><td>br,</td><td>2H).</td><td>Espe</td><td>ctro</td><td>of Masses (ESI)</td>

EXAMPLE 254 ¿12 = 3

913

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 2- (cyclopropanesulfonamido) -l-cyclopropylethyl) -3-ethyl-2oxopiperidin -3-yl) acetic

Stage A. N - ((S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) cyclopropansulfonamide

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-hydroxyethyl) -3-ethylpiperidin-2-one (Example 253, Step C,) was coupled with cyclopropansulfonamide by the procedure described in Example 202, step C to result in the title compound as a white foam.

<td></td><td>XH NMR (400 MHz, CHLOROFORM-d)</td><td>opm</td><td> -0.28</td><td>(s,</td><td>br,</td><td>lHb</td>

(m, 2H), 5.63-5.73 (m, IH), 6.49 (dt, <7 = 7.5, 1.5 Hz, IH),

6.72 (t, <7 = 1.9 Hz, 2H), 6.85-6.91 (m, 3H), 6.94 (s, br, 2H).

Mass Spectrum (ESI) m / z = 575.2 (M + l).

Stage B. N - ((2S) -2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3- (2,3-dihydroxypropyl) -3-ethyl-2 -oxopiperidin-l yl) -2-cyclopropylethyl) cyclopropansulfonamide

A solution of N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) cyclopropansulfonamide (Example 254, Step A, 80mg, 0.139mmol) in THF (375 pL), water (250 pL) and t-butanol (208 pL) was treated with 4-methylmorpholine N-oxide (57.0 mg ,

915 j

in t-

INSTIT ΊD ', 0.486 mmol) followed by' ^ .5% butanol (45.6 pL, 3.47 pinol) osmium tetroxide. After stirring at room temperature for 16 hr, the mixture was diluted with ethyl acetate and washed with water and saturated aqueous NaCl solution. The organic layer was dried over sodium sulfate and concentrated to provide the title compound as a mixture of diastereomers (85 mg) that was used directly in the next step. Mass Spectrum (ESI) m / z = 609.1 (M + l)

Stage C. N - ((S) -2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxo-3- (2-oxoethyl) piperidin-l-yl) -2-cyclopropylethyl) cyclopropansulfonamide

Sodium periodate (89 mg, 0.418 mmol) was added to a clear solution of N - ((2S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - (2,3-dihydroxypropyl) -3-ethyl2-oxopiperidin-l-yl) -2-cyclopropylethyl) cyclopropansulfonamide (Example 254, Step B, 85mg, 0.14mmol) in water (0.5mL) and

916

THF (1 mL). After several minutes a solid formed. Methanol (1 ml) was added and the resulting emulsion was stirred for 30 min. The reaction was diluted with saturated aqueous NaCl solution and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate and concentrated under reduced pressure to provide the title compound (94 mg) which was used without purification in the next step. Mass Spectrum (ESI) m / z = 577.0 (M + l)

Stage D. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -2- (cyclopropansulfonamido) -1cyclopropylethyl) -3-ethyl- 2-oxopiperidin-3-yl) acetic

A solution of sodium chlorite (58.9 mg, 0.651 mmol) in 0.25 χ 1.25 M monobasic potassium phosphate in water (1 mL) at 0 ° C was added to a clear solution of N - ((S) —2— (( 3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxo-3 (2-oxoethyl) piperidin-l-yl) -2-cyclopropylethyl) cyclopropanesulfonamide (Example 254 , Step C, 94mg, 0.163mmol) in 1.25M monobasic potassium phosphate in water (lmL) + t-butanol (1mL) + 2M 2-methylbut-2-ene in THF (4.07mL, 8.14mmol). -After stirring at room temperature for 4 hours, the reaction was quenched with C.6 rl

917

of 1M sodium thiosulfate solution. After stirring for 10 min at room temperature, the mixture was acidified with 1.2 mL of 1M potassium bisulfate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water then saturated aqueous NaCl solution, and dried over sodium sulfate. Reverse phase HPLC purification (Sunfire Prep Ci column8 10 pm OBD, gradient elution from 20% MeCN in water to 80% MeCN in water over a period of 30 min, where both solvents contain 10 0.1% TFA) provides the title compound.

<td></td><td>XH NMR (4 00 MHz, CHLOROFORM-d) δρρτη</td><td> 0.00</td><td>(s,</td><td>br,</td><td>1 HOUR) ,</td>

(m, 1H), 2.34 (t, <7 = 13.8 Hz, 1H), 2.47 (m, 1H), 2.84 (s, br, 15 3H), 3.05 (dd, <7 = 13.0, 5.18 Hz, 1H), 3.24 (ddd, <7 = 13.5, 10.3,

2.74 Hz, 1H), 3.53 (s, br, 1H), 4.84 (d, <7 = 10.4 Hz, 1H), 6.78 (dt, <7 = 7.63, 1.37 Hz, 1 H) 7.02 (t, <7 = 1.86 Hz, 2H) 7.10 -

7.20 (m, 5H). Mass Spectrum (ESI) m / z = 593.0 (M + l).

EXAMPLE 255

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (ethylsulfonamido) ethyl) -3-ethyl- acid 2-oxopiperidin-

3-yl) acetic

918

IMPI

Stage A. N - ((S) -2- ((3S, 5R, 6S) -3-AÜ1-5- (3-chlorophenyl j-6- (4chlorophenyl) -3-ethyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) ethanesulfonamide

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2-hydroxyethyl) -3ethylpiperidin-2-one ( Example 253, Step C) with ethylsulfonamide according to the procedure of Example 202, Step D provides the title compound.

<td></td><td>XH NMR</td><td> (400</td><td>MHz, CHLORINE FOR:</td><td>MO-d) opm</td><td>-0.29 (s,</td><td>br,</td><td>IH),</td>

IH), 1.69 (m, IH), 2.01 (t, 7 = 13.7 Hz, IH), 2.38-2.40 (m,

919

IH) (d,

IH)

2.44-2.48 (m, IH), 2.77 (m, 4H), 2.99-3.12 (m, 2H), 4.58

7 = 10.6 Hz, IH), 4.96 (s, IH), 4.98 (dd, 7 = 7.0, 2.0 Hz,

5.43 (s, br, IH), 5.67-5.76 (m, IH), 6.54 (dt, 7 = 7.4,

1.6 Hz, IH), 6.75 (s, br, 2H), 63.87-6.93 (m, 3H), 6.94 (s, br, 2H).

Mass Spectrum (ESI) m / z = 563.2 (M + l).

Stage B. N- ((2S) -2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3- (2,3-dihydroxypropyl) -3-ethyl-2 -oxopiperidin-lil) -2-cyclopropylethyl) ethanesulfonamide

The title compound was prepared as a mixture of diastereomers using a procedure similar to that described in Example 254, Step B.

Stage C. N - ((S) -2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxo-3- (2-oxoethyl) piperidin-l-yl) -2cyclopropylethyl) ethanesulfonamide

920

The title compound was prepared using a similar procedure as described for Example 254, Step C. Mass Spectrum (ESI) m / z = 565.2 (M + 1).

Stage D, Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (ethylsulfonamido) ethyl) -3ethyl- 2-oxopiperidin-3-yl) acetic

The title compound was obtained using a similar procedure as described for Example 254, step D.

XH NMR (400 MHz, CHLOROFORM-d) opm -0.51 (s, br, 1H),

<td> 7.19</td><td>(m,</td><td>5H).</td><td>Mass Spectrum</td><td>(ESI</td>

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 921

EXAMPLE 256 l-cyclopropyl-2- (N-methylcyclopropansulfonamido) ethyl) -3-methyl2-oxopiperidin-3-yl) acetic

Stage A. N - ((S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) N-methylcyclopropanesulfonamide

similar procedure as described for Example 202, Step D.

XH NMR (400 MHz, CHLOROFORM-d} 5ppm -0.71 (s, br, 1H), 0.31 (s, br, 1H), 0.31 (s, br, 1H), 0.40 (s, br, 1H), 1.01

MEXICAN INSTITUTE

OF INDUSTRIAL PROPERTY

922

<td> 7.23</td><td>(m, 2H).</td><td>I waited</td><td>ctro</td><td colspan="2">of masses</td><td>(ESI)</td><td>m / z</td><td> = 575</td><td>.2 (M + l).</td><td></td>

Stage B. N - ((2S) -2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3- (2,3-dihydroxypropyl) -3-methyl-2 -oxopiperidin-lil) -2-cyclopropylethyl) -N-methylcyclopropansulfonamide

The title compound was prepared as a mixture of diastereomers using a procedure similar to that described in Example 254, Step B. Mass Spectrum (ESI) m / z =

609.1 (M + l).

Stage C. N - ((S) -2 - ((3R, 5R, 6S) -5- (3-Chlorophenylj-6- (4-chlorophenyl) -3-methyl-2-oxo-3- (2-oxoethyl) piperidin -l-yl) -2-cyclopropylethyl) -N-methylcyclopropansulfonamide

923

The title compound was prepared using a similar procedure as described for Example 254, Step C. Mass Spectrum (ESI) m / z = 577.2 (M + l).

Step D. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) 1 - ((S) -l-cyclopropyl-2- (N-methylcyclopropanesulfonamido) ethyl acid) -3-methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared using a similar procedure as described for Example 254, Step D.

XH NMR (400 MHz, Methanol-d4) δρριη -0.71 (s, br, 1H), -0.28

<td> 7.11</td><td>(m,</td><td>3H),</td><td> 7.31</td><td>(s,</td><td>br,</td><td>2H).</td><td colspan="2">Spectrum</td><td>Mass,</td><td>s (ESI) m</td><td>/ z =</td>

593.2 (M + l).

.924

EXAMPLE 257

Acid

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2R) -l-cyclopropyl-2-hydroxypropyl) -3-methyl-2- oxopiperidin-

3-yl) acetic.

Step A. (3S, 5R, 6S) -3-Allyl-l - ((S) -2- (tert-butyldiphenylsilyloxy)

1-cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2-one

The diastereomer mixture prepared from (5R, 6S) -1 - ((S) -2-

<td colspan="2">6- (4-chlorophenyl) -3-methylpiperidin-2-</td><td>ona (4.34</td><td>g.</td><td colspan="2">6.61 mmol)</td>

<td>by the method of</td><td>Example 251</td><td>, Stage D</td><td>I know</td><td>purified</td><td>by</td>

<td>gel chromatography</td><td>of silica ',</td><td>eluting</td><td>with</td><td>acetate</td><td>of</td>

fractions containing the desired ethyl / hexanes epimer.

They were combined and concentrated to give (3S, 5R, 6S) -3-allyl-l ((S) -2- (tert-butyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (3-

chlorophenyl) -6- (4-chlorophenyl) -B-mpt-i lpipñridi n-2-one blunt> iina white foam weighing 3.01 g (65% yield). MS (ESI) m / z = 696 [M + H]+.

925

Stage B. (3S, 5R / 6S) -3-Α1Ϊ1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methylpiperidin- 2-one. (see also Example 252 step A)

Treating (3S, 5R, 6S) -3-allyl-l - ((S) -2- (tertbutyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6- (4chlorophenyl) -3-methylpiperidin- 2-one (Example 257, Step A, 3.00 g, 4.31 mmol) according to the procedure of Example 252, Step A gave (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- ( 4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methylpiperidin-2-one as a white foam (1,905 g, 97%).

<td>XH</td><td>NMR</td><td>(500 MHz,</td><td>CHLOROFORM-d) δ 0.00</td><td> - 0.</td><td> .15</td><td>(m, 1</td><td>H)</td><td> , 0.18</td>

926

(m, 2 Η), 5.74-5.97 (m, 1 Η), 6.74 (d, J = 7.58 Hz, 1 Η), 6.86

- 7.10 (m, 3H), 7.10 - 7.26 (m, 4H). MS (ESI) m / z = 458 [M + H]+

Step C. (S) -2 - ((3S, 5R, 6S) -3-Allyl-S- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2cyclopropylacetaldehyde . (see also Example 252 step B)

OR.

Cl (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methylpiperidin-2- ona (Example 257, Step B, 1.01 g, 2.2 mmol) was converted to the title compound as a white foam (866 mg, 86%) by the procedure described in Example 91, Step C. MS (ESI) m / z - 456 [M + H]+.

Stage D. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((1S, 2R) -l-cyclopropyl-2-hydroxypropyl) -3- methylpiperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((1S, 2S) l-cyclopropyl-2-hydroxypropyl) '-3-methylpiperidin-2-one

927

By the procedure of Example 149, Step A, (S) -2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxopiperidin- l-yl) -2-cyclopropylacetaldehyde (Example 257, Step C, 866 mg, 1,897 mmol) was treated with methyl magnesium bromide to give diastereomeric alcohols (3S, 5R, 6S) -3-allyl-5- (3- chlorophenyl) -6- (4-chlorophenyl) -1- ((1S, 2R) -l-cyclopropyl-2-hydroxypropyl) -3methylpiperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) 6- (4-chlorophenyl) -1 - ((1S, 2S) -l-cyclopropyl-2-hydroxypropyl) 3-methylpiperidin-2-one as a white foam . MS (ESI) m / z = 472 [M + H]1 .

Stage E. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2-oxopropyl) -3-methyl-2oxopiperidin -3-ilkacetic.

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 928

I P.í

Am 'Τ'Ί - · -..-.- 0

INST i> '>TO í '; 7-'b'b, A Γ-F LA Ι ιί'ΟΓΊ c industrial

1 - ((S) -l-cyclopropyl-2-hydroxypropiI) -3-methylpiperidin-2one (Example 257, Step D, 809 mg, 1.71 mmol) was treated according to the procedure described in Example 71, Step

F, to result, after SFC purification, acid 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l - ((S) -Ιοί clopropi1-2-oxopropi1 ) -3-methyl-2-oxopiperidin-3yl) acetic as a white solid.

XH NMR (500 MHz, Methanol-D4) δ-0.70 - -0.47 (m, 1 Η),

- 7.01 (m, 1 Η), 7.08 (s, 1 Η), 7.11 - 7.54 (m, 6 H). MS (ESI) m / z = 488 [M + H]+.

Step F. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((1S, 2R) -l-cyclopropyl-2-hydroxypropyl) -3 methyl- 2-oxopiperidin-3-yl) acetic

Reduction

(4-Chlorophenyl) -1 - ((S) -l-cyclopropyl-2-oxopropyl) -3-methyl-2929 oxopiperidin-3-yl) acetic in methanol at 0 ° C with sodium borohydride provides a mixture. of diastereomeric alcohols in ~ 2: 1 ratio.

The residue was purified by chromatography on silica gel, eluting with a gradient of isopropanol in hexanes. Fractions containing the major isomer were concentrated and then lyophilized from acetonitrile / water to provide the title compound as a fluffy soft solid.

XH NMR (500 MHz, Methanol-d4) 5ppm -0.29 (br s, l H),

(br s, l H), 4.82 (d, J = 11.00 Hz, 1 H), 6.61 - 7.64 (m, 8

H). MS (ESI) m / z = 490 [M + H]1 .

EXAMPLE 258

2 - ((3R, 5R, 6S) -5- (3-Chlorof.enyl) -6- (4-chlorophenyl) -1 ((1S, 2S) -l-cyclopropyl-2-hydroxypropyl) -3-methyl acid -2oxopiperidin-3-yl) acetic

930 '

The L-Selectride® (Aldrich

Louis,

5.0 ml, 5.00 mmol) was added dropwise and spi

INSTITUTE

OF THE

INDUST'Ñ'Aí-

MO), (1M in THF, over the course of 5 minutes to a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2oxopropyl) -3-methyl-2-oxopiperidin-3-yl) acetic (Example emplo

257, Step E, 1,035 g, 2.12 mmol) in THF (35 ml) at -78 ° C. After 90 min, the mixture was allowed to warm to 0 ° C and was carefully quenched by the addition of saturated ammonium chloride. The aqueous phase was extracted three times with ethyl acetate. The combined organic layer was washed with 1M HC1, water, saturated aqueous NaGl solution and dried over sodium sulfate. After the invacuo concentration, the residue was purified by silica chromatography eluting with a gradient of isopropanol in hexanes. The fractions containing the major isomer were concentrated and then lyophilized from acetonitrile / water to provide the title compound as a white powder. Stereochemistry assigned by analogy to Example 152.

XH NMR (500 MHz, DMSO-d6) δ -0.69 (br s, 1 Η), -0.35 (br s, 1 H), 0.17 (br s, 1 Η), 0.36 (br s, 1 Η), 1.07 (br s, 1

Η), 1.27 (s, 4 Η), 1.98

931

2.23 (m, 2 Η)

2.53 - 2.58 (m, 1 ——— * - timbi μι * γ1, ii j

H), 2.93 (d, J = 13.94 Hz, 1 H), 3.36 - 3.49 (m, 1 H), 3.74

- 4.44 (m, 1H), 4.46 - 5.11 (m, 2H), 6.60 - 7.59 (m, 8

H). MS (ESI) m / z = 490 [M + H].

EXAMPLE 259

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) —1 - ((S) -l-cyclopropyl-2- (1-methylethylsulfonamido) ethyl) -3 acid -methyl-2 oxopiperidin-3-yl) acetic

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2cyclopropylethyl) propane-2-sulfonamide

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1932 ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methylpiperidin-2-one (Example 252, Step A, 59.3 mg, 0.129 mmol;) and isopropyl sulfonamide (48.7 mg, 0.395 mmol) were coupled by the procedure as described in Example 202, Step C to form the isolated title compound after chromatography in silica gel as a colorless white solid. MS (ESI) m / z = 563 [M + H] ".

Step B: Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (1-methylethylsulfonamido) ethyl) -3- methyl-2-oxopiperidin-3yl) acetic.

The title compound was obtained from N - ((S) -2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl2- oxopiperidin-l-yl) -2-cyclopropylethyl) propane-2-sulfonamide (Example 259, Step A) by a procedure similar to that described in Example 7Ϊ, Step F. The product was purified by reverse phase HPLC, eluting with MeCN 60 to 95% in water (TFA 0.1% in both solvents). The high purity fractions were combined, stripped of volatiles, and the resulting solution was frozen and lyophilized to provide the title compound as a colorless white solid. ~ ~ΧΗ NMR (500 MHz, CD3OD) δρριη -0.98 - -0.71 (m, 1 Η) -0.38 χ ·

933

(ESI) m / z = 581 [M + H]+.

EXAMPLE 260

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) l-cyclopropyl-2- (N-methylcyclopropanesulfonamido) ethyl) -3- acid methyl

2-oxopiperidin-3-yl) acetic.

Stage A: (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1 - ((R) -l-cyclopropyl-2- (methylamino) ethyl) -3 -methylpiperidin-2one

934

(S) -2 - ((3S, 5R, 6S) -3-Allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2-cyclopropylacetaldehyde (Example 252 , Step B, 554 mg, 1.21 mmol) was taken in 10 mL of anhydrous toluene and stripped to dryness in vacuo twice to effect azeotropic removal of moisture residues. After removal of the residual solvents under high vacuum, the aldehyde was dissolved in dichloroethane (12 mL). Methylamine (2.0 M in THF,

6.1 mL, 12.20 mmol) and acetic acid (2 mL, 35.0 mmol) were added to the solution, which was stirred at room temperature for about '30 minutes. Sodium triacetoxyborohydride (1.12 g, 5.28 mmol) was added as a solid in a single portion, and the mixture was stirred at room temperature overnight. HPLC analysis shows that epimerization has occurred to give both diastereomers. The reaction was quenched with saturated sodium bicarbonate solution. The amine diastereomers were extracted into dichloromethane. The organic phase was washed with water, and dried-over sodium sulfate. After concentration

935

IMPI

INSTITUTO MEXICANO DELA PROPERTY INDUSTRIAL the resulting residue gave a slightly cloudy solution in redissolution in ethyl acetate, and they were subsequently dried again over magnesium sulfate. Concentration gave a mixture of diastereomers as a white-yellowish foam (577 mg). The two epimeric products were separated by SFC 'chromatography (250 x 30 mm CHIRALPAK® IC column (CHIRAL TECHNOLOGIÉS, INC., West Chester, PA, USA) with 42 g / min IPA and [20 mM NH3] and 78 g / min CO2. In concentration, the first eluate, 3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (methylamino) was obtained ) ethyl) -3methylpiperidin-2-one epimer. Concentration of fractions containing the second eluted component gave the title compound. MS (ESI) m / z = 471 [M + H]1.

Stage B: N - ((R) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2cyclopropylethyl) -N-methylcyclopropansulfonamide

(3S, 5R-, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-

((R) -l-cyclopropyl-2- (methylamino) ethyl) -3-methylpiperidin-2-one

936 (Example 260, Step A, 168 mg, 0.356 mmol) was transferred as a 3 mL solution of anhydrous toluene to an oven dried 10 mlL round bottom flask and the solution was stripped to dryness on a rotary evaporator. This was repeated twice to effect azeotropic removal of moisture residues. Cyclopropansulfonyl chloride and pyridine were added to the flask. The reaction was monitored during termination by LC-MS. Finally 5x (O.ISml of sulfonyl chloride and 0.15 mL of pyridine) were added over the course of 4 days. Dichloromethane was added when the solids start to appear. The reaction mixture was diluted with ethyl acetate and citric acid solution (10%).

Aqueous was washed twice with ethyl acetate.

The phase

The combined organic layer was washed with saturated aqueous solution of

NaCl and dried over sodium sulfate. After concentration in vacuo, the yellow residual oil was purified by chromatography on silica, eluting with a gradient of ethyl acetate in hexanes. Fractions containing the title compound were combined and concentrated to give the title compound as a white foam. MS (ESI) m / z = 575 [M + H]+

Stage C.

Acid 2- ((3R, 5R, 63) -5- (3-chlorophenyl 1) --6- (4937 chlorophenyl) -1 - ((R) -l-cyclopropyl-2- (N-

methylcyclopropansulfonamido) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic.

The title compound was obtained from N - (. (R) -2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl

2-oxopiperidin-l-yl) -2-cyclopropylethyl) -Nmethylcyclopropansülfonamide (Example 260, Step B, 153 mg, 0.265 mmol) by a procedure similar to that described in Example 71, Step F. The compound was purified by reverse phase HPLC on a Sunfire ™ C18 column (Waters, Milford, MA), eluting with a gradient of 50-100% MeCN in water (0.1% TFA in both solvents), then further purified by chromatography SFC (250 x 30 mm Lux2® column (Phenomenex, Torrance, CA 90501, USA) with 32 g / min methanol [2O. MM. NH3] + 48 g / min CO2 at Thar 80 SFC (Thar Technologies, .Pittsburg, PA). Outlet pressure · = 100 bar; Temp. = 23C; Wavelength = 220 nm. Injections of 0.8 mL of 95 mg / 15 mL [6.3 mg / mL of sample solution in methanol, that is 5.1 mg / injection] are used. Run time = 6 min, cycle time =

3.5 min). The pooled fractions were concentrated to give the title compound as a white solid.

XH NMR (500 MHz, CHLOROFORM-d) δ 0.14 (d, 7 = 3.91 Hz, 2

H), 0.51 (t, 7 = 5.26 Hz, 2 H), 0.93 - 1.11 (m, 2 H), 1.14 1.23 (m, 1 H), 1.25-1.28 (m, 1 H), 1.46 (br s, 3 H), 1.52 1.76 (m, 2 Η), 1.87 - 2.00 (m, 1 Η), 2.20 - 2.39 (m, 2 H)

938

- 7.26 (m, 6H). EM (ESI). m / z = 593 [M + H] ".

EXAMPLE 261

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2-hydroxy-4-methylpentan-3-yl) -3 acid -methyl-2oxopiperidin-3-yl) acetic.

Stage

TO:

Methyl 4- (3-chlorophenyl) -5- (4-chlorophenyl) -2-methyl-5-oxopentanoate

Methyl methacrylate (82 mL, 773 mmol) was added to a solution of

2- (3-chlorophenyl) -1- (4-chlorophenyl) ethanone (195.2 g, 736 mmol;

Example 1, Step A) in anhydrous THF (1.5

939

L) under a nitrogen atmosphere.

A suspension of potassium tbutoxide (8.26 g, 73.6 mmol) in anhydrous THF (340 mL) (sonicated to break up solids) was then prepared and cannulated in the solution containing the

2- (3 solution was cooled to ~ 16 ° C and the orange solution was left at room temperature for 2.5d. (After

TLC shows the absence of the material concentrated under vacuum. The oil was diluted with ethyl acetate (900 mL), stir the residual reddish brown mixture, and washed with water (4 x

190 mL) and then saturated aqueous NaCl solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as a racemic mixture of diastereomers.

XH-NMR (500 MHz, CDC13) δ 7.88 (m, 4H), 7.39 (m, 2H),

7.27-7.12 (series of m, 4H)., 4.62 (dd, J = 9.0, 5.6 Hz,

Step B: Racemic mixture of 4- (3-chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoate of (4R, 5R) -methyl, 4 (3-chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoate

940

Anhydrous methanol (600 mL) was placed in a 3L three neck round bottom flask equipped with a stir bar and temperature probe under an atmosphere of N2 and cooled to around -20 ° C. Sodium borohydride (26.2 g, 693 mmol) was added in 5g portions. By means of an addition funnel, a solution of methyl 4- (3-chlorophenyl) -5- (4-chlorophenyl) -2-methyl-5-oxopentanoate (253 g, 693 mmol; Example 261, Step A) in methanol ( 600 mL) was added dropwise to the reaction, maintaining a temperature between -27 ° C to -30 ° C. The reddish solution was stirred at -30 ° C for 30 minutes and then allowed to warm to -15 ° C. The reaction was monitored during completion by TLC. The reaction was quenched by slowly adding water (68.6 mL, 3.8mol) through the addition funnel. The mixture was allowed to warm to room temperature. Solvents were removed under vacuum. The residual yellowish oil was diluted in ethyl acetate (1.2 L) and washed with water (400 mL). The organic layer was washed with saturated aqueous NaCl solution (2 x 300 mL), forming an emulsion. After

941 Wait for most of the emulsion to separate, the organic layer was dried over magnesium sulfate. The solution was filtered through filter paper and concentrated under vacuum to provide racemic mixing diastereomers an

<td>TLC</td><td>(20% EtOAc</td><td colspan="2">/ Hexane)</td><td>RF = 0.34.</td><td></td>

Stage C.

Hydroxy-2-methylpentanoic acid and (4S, 5S) -4- (3-Chlorophenyl) -5 (4-chlorophenyl) -5-hydroxy'i-2-methylpentanoic acid.

A solution of the racemic mixture of 4- (3-chlorophenyl)

5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoate (4R, 5R) -methyl and

(4S, 5S) -methyl 4- (3-chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoate (245.7 g, 669 mmol; Example 261, Step B) in THF (1.17 L) it was prepared by warming up to 40 ° C. The flask

942

cooled to ~ 14 ° C, internal temperature. A solution of lithium hydroxide hydrate (42.1 g, 1.0 mol) in water (585 mL) was cautiously added to the THF solution. The mixture was allowed to stir at room temperature and monitored by LC / MS for the absence of starting material (-2.5 h). When finished, the solution is. cooled again to a temperature of -14 ° C. 2N HCI (526 mL) was added slowly. The layers were divided and the aqueous layer (pH ~ 2) was washed with ethyl acetate (1 x 500 mL then 1 x 250 mL). The combined organic layers were dried over magnesium sulfate and concentrated to yield 264 g of a racemic mixture of (4R, 5R) -4- (3-chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoic acid and (4S, 5S) -4- (3-chlorophenyl) -5- (4chlorophenyl) -5-hydroxy-2-methylpentanoic acid was obtained. The crude material containing some residual solvent was used as is in the subsequent transformation. The product (estimated after correction of the solvent 227 g) is a mixture of diastereomers approximately 1: 1 in position

XH-NMR (500 MHz, CDC13) δ 7.31 (m, 2H), 7.25 (m, 3H),

943

1.05 (d, J = 6.9 Hz, 1.5H) ppm.

Alternatively, (4R, 5R) -4- (3-Chloroteriil ') - b- (4 chlorophenyl) -5-hydroxy-2-methylpentanoic acid, as a mixture of methyl diastereomers, can be prepared from 4— Racemic methyl (3- chlorophenyl) -5- (4-chlorophenyl) -2-methyl-5-oxopentanoate.

In a three necked flask, a solution of racemic methyl 4 - (3 - chlorophenyl) -5- (4-chlorophenyl) -2-methyl-5-oxopentanoate (500 g, 1.37 mol, 1 eq) in 2-propanol anhydrous (2.5 L) was loaded with KOfcBu (46.1 g, 0.41 mol, 0.3 eq) and stirred for 30 min until a light yellow solution formed. The solution was then treated with a solution of dichloro {(S) - (-) - 2,2'-bis [di (3,5-xylyl) phosphino] -1,1 'binaphthyl} [(2S) - (+ ) -1,1-bis (4-methoxyphenyl) -3-methyl-l, 2-butandiamine] ruthenium (II) (5 g, 4.1 mmol, 0.003 eq, Strem Chemicals Inc., Newburyport, MA) in anhydrous toluene (250 mL) and stirred at rt for 2 hours (Note: most of the methyl ester was converted to isopropyl). The solution was transferred to two Parr shakers, sealed and purged with hydrogen 3 times. The reaction was stirred at rt under 414 kilopascals of hydrogen pressure. After 18 hrs, the reaction was quenched with NH4C1 sat., Concentrated, and extracted with EtOAc (2 LX 2). The. Combined organic products were washed with brine and concentrated as a brown oil and

944 they were used as such in the next stage. ·

The crude intermediate (542 g, 1.37 mol) was dissolved in THF (3 L) and MeOH (1 L) and charged with 2Μ LiOH (1 L). The solution was turned at rt overnight, concentrated for most THF and MeOH, and quenched with 1 L of 2M HC1.

After phase separation, the aqueous layer was extracted with EtOAc (1 LX 2). The combined organic products were washed with brine, dried over Na2SW4 anhydrous, filtered and concentrated in vacuo. This product, (4R, 5R) -4- (3-Chlorophenyl) -5- (4-chlorophenyl) -5-hydroxy-2-methylpentanoic acid, as a mixture of methyl diastereomers, was taken crude in the next step.

Stage D. (5R, 6R) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyltetrahydro-2H-pyran-2-one and (5S, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl tetrahydro-2H-pyran-2-one

The hydroxy acid diastereomer mixture (227g, 643mmol; Example 261, Step C) was lactonized under Dean-Stark conditions in toluene (1.07L) with pyridine 4-methylbenzenesulfonate (PPTS-, 4.84g, 19.728mmol) under an atmosphere of

945

I IPI

MEXICAN INSTITUTE OF PROPERTY. „INDUSTPI / Xi * nitrogen. After 2 h of vigorous reflux the solution was

cooled to room temperature and transferred to a separatory funnel. The residue from the flask was rinsed with ethyl acetate. The combined organic phase was washed in succession with water (lx250mL), sat. Sodium bicarbonate solution. (1 x 250 mL), and saturated aqueous NaCl solution (1 x

250 mL). After drying with magnesium sulfate, concentration under reduced pressure provides a mixture of diastereomeric lactons as a light brown solid.

<td></td><td>H-NMR</td><td> (500</td><td>MHz, CDC13)</td><td>δ 7.24-6.95 (series</td><td>of</td><td>m, 6H),</td>

0.5H), 3.67 (dt, J = 7.6, 4.2 Hz, 0.5H), 3.55 (td, J = 7.8,

<td colspan="2">4.6 Hz, 0.5H), 2.97</td><td>(m,</td><td colspan="3">0.5 H), 2.81 (double of quintets, J</td>

Hz, 0.5H), 1.85 (ddd, J = 14.2, 12.7, 7.6 hz, 0.5H), 1.41 (d,

J = 7.1 Hz, 1.5H), 1.39 (d, J = 6.9 Hz, 1.5H) ppm.

Stage E: (3S, 5R, 6R) -3-AÜ1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one and (3R, 5S, 6S) -3Alil -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2Hpiran-2-one

A solution of racemic lactone from the previous step (Example 261, Step D, -190.28 g, 568 mmol) in THF (946 mL) was prepared in a 1 neck round bottom flask equipped with a Claisen adapter, 500mL graduated funnel , and internal temperature probe under a nitrogen atmosphere.

The solution was cooled to a temperature of -35 ° C. Allyl bromide (120 mL, 1.42 mol) was added via the addition funnel, keeping the temperature below -30 ° C during the addition. A solution of LHMDS (1M in THF, 738 mL, 738 mmol) was added dropwise to the reaction, keeping the temperature below -30 ° C. The reaction was allowed to warm slowly to -5 ° C over a period of 1h. The solution was re-cooled to around -20 ° C and added via cannula in a solution of ammonium chloride in water at around 5C. After separation of the layers, the aqueous layers were extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution and dried over sodium sulfate.

Concentration under vacuum provides 219 g of a light yellow solid. The solids turned thick mixture to the

room temperature for 2 h with hexane (2 L). The

947 Solids were then collected by filtration, rinsed with hexane (2 X 100 mL) and. dried to provide the title compounds as a racemic mixture.

XH-NMR (500 MHz, CDC13) δ 7.24 (m, 1H), 7.20-7.15 (m,

3H), 6.91 (t, J = 1.7 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.59 (m, 2H), 5.84 (ddt, J = 17.6, 10.3, 7.6 Hz, 1H), 5.71 (d, J =

5.4 Hz, 1H), 5.21-5.13 (m, 2H), 3.81 (dt, J = 12.0, 4.2 Hz,

Stage F: Separation of (3S, 5R, 6R) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one and (3R, 5S, 6S ) 3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro2H-pyran-2-one

(racemic)

Chiral CFS

-Chromatography

A racemic mixture of (3S, 5R, 6R) -3-allyl-5- (3 chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one and (3R, 5S, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-

using

948

INSTITUTO MEXICANO de la fíio?; INDUSTRIAL age methyltetrahydro-2H-pyran-2-one can be separated by Chiral Supercritical Fluid Chromatography (SFC) as follows: Using a 250 'x 30mm Lux2® column (Phenomenex, Torrance, CA 90501, USA) ) with 20 g / min of methanol (20 mM NH3) + 60 g / min C02 in a SFC Thar 80. Outlet pressure = 100 bar; Temp. = 23C; Wavelength = 220 nm. Using 0.3 mL injections of 5.0 g / 80 mL (62.5 mg / mL of sample solution in methanol / dichloromethane (75: 5), this is 18.75 mg / injection. Run time = 8 min, Cycle time = 3 min .

The first peak collected was assigned as (3R, 5S, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyltetrahydro-2Hpiran-2-one. The second peak collected was determined to be (3S, 5R, 6R) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyltetrahydro-2H-pyran-2-one by subsequent chemical shunt with (S) -2-amino-l-butanol and conversion for the same compound as prepared in Example 91, Step B, by the procedures described by Example 261, Steps G and H. The NMR of the separated enantiomers was consistent with the spectra of the racemate described above.

Alternatively, (3S, 5R, 6R) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyltetrahydro-2H-pyran-2-one can be prepared from 4- (3- racemic methyl chlorophenyl) -5- (4-chlorophenyl) -2methyl-5-oxopentanoate.

In a three-necked flask, a solution of 4- (3-chlorophenyl) -5- (4-chlorophenyl) -2-methyl-5-oxopentanoate of

racemic methyl (500 g, 1.37 mol, 1 eq) in anhydrous 2-propanol (2.5 L) was loaded with KOtBu (46.1 g, 0.41. Mol, 0.3 eq) and stirred for 30 min until a light yellow solution formed. The solution was then treated with a solution of Dichloro {(S) - (-) - 2,2'-bis [di (3,5-xylyl) phosphino] -1,1 'binaphthyl} [(2S) - (+ ) -l, 1-bis (4-methoxyphenyl) -3-methyl-l, 2-butanediamine] ruthenium (II) (5 g, 4.1 mmol, 0.003 eq, / Strem Chemicals Inc., Newburyport, MA) in anhydrous toluene ( 250 mL) and stirred at rt for 2 hours (Notice most of the methyl ester was converted to isopropyl). The solution was transferred to two Parr shakers, sealed and purged with hydrogen 3 times. The reaction was stirred at rt under 414 kilopascals of hydrogen pressure. After 18 hrs, the reaction was quenched with NH4C1 sat., Concentrated, and extracted with EtOAc (2 L x 2). The combined organic products were washed with brine and concentrated as a brown oil and used as such in the next step.

The crude intermediate (542 g, 1.37 mol) was dissolved in THF (3 L) and MeOH (1 L) and loaded with 2Μ LiOH (1 L). The solution was turned at rt overnight, concentrated to remove most of the THF and MeOH, and quenched with 1 L of 2M HC1. After phase separation, the aqueous layer was extracted with EtOAc (1 L x 2). Combined organic products were washed with brine, dried over Na2SW4 anhydrous, filtered and concentrated in vacuo.

950

Step G: (S) -2 - ((2R, 3R) -2- (3-Chlorophenyl) -3- (4-chlorophenyl) -3hydroxypropyl) -N - ((S) -l-hydroxy-3-methylbutan- 2-yl) -2methylpent-4-enamide

A mix of

5.33 mmol) and (S) -2-amino-3-methylbutan-l-ol (550 mg, (3S, 5R, 6R) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) - 3-methyltetrahydro-2H-pyran-2-one (Example 261,

Stage H, 2or compound, 500 mg, 1,332 mmol) was heated to

100 ° C for 24h. After cooling to temperature

<td>environment, waste</td><td>it was dissolved in ethyl acetate and</td>

<td>washed 3X with HC1 IN</td><td>(5 mL) followed by saturated solution</td>

<td>aqueous NaCl (5 mL j</td><td>The organic phase was dried over MgSO4,</td>

filtered, and the filter product was concentrated to give the title compound.

XH-NMR (500 MHz, DMSO-d6) δ 7.21 (m, 2H), 7.10 (m, 2H),

7.06 (br s, IH), 6.99 (m, 2H), 6.86 (br d, J = 8.8 Hz, IH),

6.84 (br d, J = 7.1 Hz, IH), 5.53 (dddd, J = 16.9, 10.3, 8.1,

951

6.6 Hz, 1H), 5.46 (d, J = 4.4 Hz, 1H), 4.90 (m, 2H), 4.78 (t, J = 4.2 Hz, 1H), 4.56 (t, J = 5.1 Hz, 1H), 3.56 (m, 1H),

3.37 (m, 2H), 2.87 (dt, J = 7.8, 4.2 Hz, 1H), 2.29 (dd, J =

13.7, 6.4 Hz, 1H), 2.14 (dd, J = 14.4, 7.8 Hz, 1H), 1.97 (dd, J = 14.4, 3.9 Hz, 1H), 1.88 (dd, J = 13.9, 8.1 Hz, 1H), 1.76 (octet, J = 6.4 Hz, 1H), 0.97 (s, 3H), 0.81 (d, J = 6.8 Hz,

3H), 0.75 (d, J = 6.6 Hz, 3H) ppm.

Stage H. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-hydroxy-3-methylbutan-2-yl) - 3-methylpiperidin-2-one

(S) -2 - ((2R, 3R) -2- (3-Chlorophenyl) -3- (4-chlorophenyl) -3hydroxypropyl) -N - ((S) -l-hydroxy-3-methylbutan-2-yl ) -2-methylpent-4-enamide (Example 261, step G) was transferred as an anhydrous benzene solution to a pre-weighed, oven dried 50 mL round bottom flask and stripped to dryness. The azeotropic distillation of benzene / water was carried out twice more, and the residue was dried under high vacuum for 2 h, after which it weighed 550 mg. An oven dried stir bar was added to the flask. The container was sealed and purged with nitrogen and then anhydrous dichloromethane (23 mL)

952 was added, followed by triethylamine (1.3 mL, resulting stirred solution was cooled to

The

INSTITUTE ΜΞΖ, ΟΑΚΟ OF INDUSTRIAL PROPERTY

9.33 mmol).

0 ° C

Methanesulfonyl chloride (0.270 mL, 3.49 mmol) was added dropwise by micro syringe. After 1 hr, the reaction was quenched by addition of HCI (1.2M, 12 mL) and diluted in ethyl acetate.

The organic layer was washed with 1.2M HCI (30 mL), saturated sodium bicarbonate (2 X 25 mL), and saturated aqueous NaCl solution. After drying over magnesium sulfate and concentration in vacuo an intermediate was obtained as an opaque white foam (0.64 g,). 1.8 Bis (dimethylamino) naphthalene, 314 mg, 1,465 mmol) and water (0.104 mL, 5.75 mmol) were added to the intermediate, followed by dioxane (23 mL). The mixture was heated under nitrogen at 110 ° C overnight. After cooling, the mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution. The aqueous phase was re-extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with ethyl acetate in hexanes. Chromatography fractions containing predominantly the desired product were combined. The product was further purified by chromatography on a column of silica g, eluting with a gradient of 0 to 50% ethyl acetate

953

in hexanes to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ 0.73 (d, J = 6.4 6 Hz, 3

<td>7.53 Hz,</td><td>1 HOUR)</td><td> , 6.72</td><td>(apparent d,</td><td>J = 7.63 Hz, 1</td><td>Η), 6.95 (t,</td>

Stage I. (S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -3 -methylbutanal

Dess-Martin periodicin (938 mg, 2,212 mmol) was added as a solid to a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - (( S) -l-hydroxy-3-methylbutan-2yl) -3-methylpiperidin-2-one (Example 261, Step H, 365.4 mg, 0.794 mmol) in dichloromethane (8 mL) and water (0.04 mL, 2,220

954

mmol). The resulting suspension was vigorously stirred at room temperature for 1.5 h. The reaction was quenched with sodium thiosulfate solution (1M aq, 6 mL). The additional sodium thiosulfate solution (1M aq, 6 mL) was added and stirred until the calcareous suspension became a slightly cloudy biphasic mixture. The aqueous phase was separated and re-extracted with dichloromethane. The organic layer was washed with sodium thiosulfate solution, saturated aqueous sodium bicarbonate, and saturated aqueous NaCl solution. After drying over sodium sulfate and concentration, the residue was purified on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexanes. Fractions containing the desired product were pooled to give the title compound as a white foam. MS (ESI) m / z = 458 [M + H].

Stage

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -2-hydroxy-4-methylpentan-3-yl) -3methylpiperidin-2- one

Methylmagnesium bromide (1.4 mL, 1,960 mmol,

1.4 M in 1: 3 THF: toluene) by syringe to a nitrogen solution of (S) -2- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4955

Chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -3-methylbutanal (Example 261, Step I, 286 mg, 0.624 mmol) in THF (6.5 mL) at 0 ° C. The iron bath was removed. After 2 hr, the solution was re-cooled to 0 ° C and quenched by careful addition of saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0 to 40% ethyl acetate in hexanes. Fractions containing the desired product were combined and re-purified to give the title compound '(a mixture of diastereomeric alcohols) as a white foam. MS (ESI) m / z = 474 [M + H]1 .

Stage K. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -2-methyl-4-oxopentan-3- il) -2oxopiperidin-3-il) acetic.

956

(3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -2-hydroxy-4-methylpentan-3-yl) -3-methylpiperidin -2-one (Example 261, Step J, 244 mg, 0.51 mmol) was converted by a similar procedure to that described in Example 257, Step E to the title compound obtained after chromatography on silica gel eluting with ethyl acetate in hexanes as a white solid. MS (ESI) 490 [M + H]-.

Stage L. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((2S, 3S) -2-hydroxy-4-methylpentan-3-yl) -3-methyl2-oxopiperidin-3-yl) acetic

The title compound was obtained from 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) 2-methyl- 4-oxopentan-3-yl) -2-oxopiperidin-3-yl) acetic (Example 2 61, Step K, 7 9.9 mg, 0.16 mmol) by a procedure similar to that described in Example 258. After work, the material purified by chromatography on a 24 g silica column. eluting with a gradient of 10 to 20% isopropanol in hexanes. The pure fractions were combined, concentrated, redissolved in MeCN /

957

1: 1 water, passed through a cloth microfilter, frozen, and lyophilized to give the title compound as a white solid. The stereochemistry assigned by analogy to Example 152.

XH NMR (400 MHz, Methanol-d4) δ 0.62 (d, J = 7.04 Hz, 3

H), 0.67 (d, J = 6.65 Hz, · 3 H), 1.26 (d, J = 6.46 Hz, 3 H),

1.42 (s, 3H), 2.13 - 2.29 (m, 3H), 2.49 (t, J = 7.14 Hz, 1

H), 2.62 (d, J = 13.69 Hz, 1 H), 3.01 (d, J = 13.69 Hz, 1 H),

3.57 (td, J = 10.81, 6.16 Hz, 1 H), 4.23 (t, J = 6.65 Hz, 1

H), 4.70 (d, J = 10.95 Hz, 1H), 6.65 - 7.51 (m, 8H). MS (ESI) m / z = 492 [M + H]1 .

EXAMPLE 262

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) cyclopropyl (pyridin-2-yl) methyl) -3-methyl-2 acid -oxopiperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -cyclopropyl (pyridin-2-yl) methyl) -3-methyl-2oxopiperidin-3-yl) acetic

CI

Stage A. (1S, 2R) -4.-Carboxy-2- (3-chlorophenyl) -1- chloride (4958

INSTITU TO Mi DE LA PK! IND chlorophenyl) butan-1-amini.o

A suspension of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one. (Example 1, Step E, 29 g, 91 mmol) in 5M hydrochloric acid (91 mL, 453 mmol) was brought to reflux. After 2 h, TLC indicates complete consumption of starting material to the open ring product (elution with ethyl acetate, 75% in hexanes; RF starting material = 0.5, RF product = 0.0). The reaction contents were co-distilled with toluene (4 x 100 mL) then brought to dryness. The solids were suspended in diethyl ether (100 mL), filtered, and washed with ether (100 mL). The white crystalline solid was brought to dryness under high vacuum to provide the title compound.

2H).

959

Stage B.

Acid (4 R, 5S) -4- (3-Chlorophenyl) -5- (4 • i

INDUSTRIAL chlorophenyl) -5- (cyclopropyl (pyridin-2-yl) methylamino) pentanoic

Cyclopropyl (pyridin-2-yl) methanone (0.393 g,

2.67 mmol) [Meijer, Louis Η. P. et al., Tetrahedron,

40,

5185 with pure tetra-isopropoxy-titanium (0.782 mL,

2.67 mmol) and stirred at room temperature for 20 min

(IS, 2R) -4-carboxy-2- (3-chlorophenyl) -1- (4-chlorophenyl) butan-l-amino (0.500 g, 1.334 mmol) was added; Example 262,

Step A) as a solid and stirred overnight. Methanol (13 mL) was added followed by careful addition of sodium borohydride (0.151 g, 4.00 mmol). The resulting solution was stirred at room temperature for 10 min. The reaction was quenched with HCI (1N aq.), Extracted with dichloromethane and washed with saturated aqueous NaCl solution. The combined organic layer was dried over sodium sulfate and concentrated to provide a crude product used in the next step without further purification.

Stage C.

(5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1960 ((S) -cyclopropyl (pyridin-2-yl) methyl) piperidin-2-one or (5R, 6S) - 5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) cyclopropyl (pyridin-2-iT) methyl) piperidin-2-one

The crude product from Example 162, Step B was dissolved in dichloroethane (13 mL) in the presence of 4Á molecular sieves (15 pieces) and heated under reflux overnight. The reaction was filtered through Celite® (JT Baker,

Phillipsberg, NJ, -diatomaceous earth), rinsed dichloromethane and concentrated under reduced pressure.

with

The residue was purified by reverse phase HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to give the title compound as the first

elution diastereomer.

Step D. (5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) —1 - ((S) - cyclopropyl (pyridin-2-yl) methyl) -3-methylpiperidin-2-one or (5R, 6S) -5- (3-Chlorophenyl ·) -6- (4-chlorophenyl) -1 - ((R) cyclopropyl (pyridin-2-yl) methyl) -3-methylpiperidin-2-one

961

A solution of LHMDS (1M in THF, 0.585 mL, 0.585 mmol) was added to a solution of the compound of Example 262, Step C (0.220 g, 0.487 mmol) and iodomethane (0.040 mL, 0.634 mmol) in THF (5.0 mL) at -78 ° C. The reaction was allowed to warm to room temperature, then quenched (NH solution4C1 aqueous sat.), Extracted (2 * EtOAc), and washed (saturated aqueous NaCl solution). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude material was absorbed into a plug of silica gel and purified by chromatography (YES2, 40 g, eluting with 20% to 60% ethyl acetate in hexane) to provide the title compound as a mixture of diastereomers.

Step E. (5R, 6S) -3-AÜ1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -cyclopropyl (pyridin-2-yl) methyl) -3-methylpiperidin- 2-one or (5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) cyclopropyl (pyridin-2-yl) methyl) -3-methylpiperidin -2-one; ί

0.838 mL, mmol)

Or .838 mix I add

0.27 9

Stage D (0.130 g,

Example 262,

LHMDS (1.0M in THF, from to a solution

diastereomeric mmol) and allyl bromide (0.095 mL,

1,117 mmol) in THF (2.80mL). The reaction mixture was stirred at room temperature for 5min, then heated to ° C for 3h. The solution was diluted with solution

NH4C1 was extracted (2 * ethyl acetate), and washed (saturated aqueous NaCl solution).

The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude material was absorbed into a plug of silica gel and purified by chromatography (S1O2, 40 g, eluted with a gradient from 0 to 35% EtOAc in hexane) to provide the title compound as a mixture of diastereomers as a white foam.

Step F. Acid · 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4_chlorofenyl) -1- ((Sj-cyclopropyl (pinidin-2-yl) methyl) -3- metü-2oxopiperidin-3-yl) acetic

963 or acid

L'iEXICANO INSTITUTE OF INDUSTRIAL PROPERTY

Chlorophenyl) -6- (4-chlorophenyl) -1 - ((R) -cyclopropyl (pyridin-2 yl) methyl) -3-methyl-2-oxopiperidin-3-yl) acetic

The compound of Example 262, Step E (90 mg, 0.178 mmol) was treated by a procedure similar to that described in Example 71, Step F. Separation of diastereomers by preparative reverse phase HPLC (eluent: 10 to 90 acetonitrile %, water, 0.1% TFA, gradient elution) gave the title compound as the first elution diastereomer.

XH NMR (4 00 MHz, CHLOROFORM-d) δ ppm 0.0 9 (br s, 1 H)

7 = 15.06 Hz, 1 H) 3.29 - 3.41 (m, 1 Ή) 4.83 (d, 7 = 9.98 Hz,

H) 5.08 (d, 7 = 10.37 Hz, 1 H) 6.80 (d, 7 = 7.63 Hz, 1 H)

6.96 (m, 5H) 7.04 - 7.17 (m, 2H) 7.63 (d, 7 = 8.22Hz, 1H) 7.72 (t, 7 = 6.65Hz, 1H) 8.07 (t, 7 = 7.24Hz, 1 H) 9.06 (d, 7 = 4.89 Hz, 1H). MS (ESI) m / z = 523.2 (M + l).

964

EXAMPLE 263

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (thiophene-2-sulfonamido) ethyl acid) - 3-methyl-2oxopiperidin-3-yl) acetic

I

Step A. Acid 2 - ((3R, 5R, 6S) -l - ((S) -2 - ((tertButildiphenylsilyl) oxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic

To a rapidly stirred solution of (3S, 5R, 6S) -3-allyl1- ((S) -2- (tert-butyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 3-methylpiperidin-2-one (1450 mg, 2.08 mmol; Example 251, Step D) in a mixture of water (11 mL), acetonitrile (7.2 mL), and CC14 (7.2 mL) sodium periodate (1780 mg, 8.32 mmol) was added, followed by hydrate

965

ruthenium (III) chloride (47 mg, 0.21 mmol). After stirring vigorously for 16 h, additional water (5.4 mL), acetonitrile (3.6 mL), and CCI4 (3.6 mL) were added to the resulting clear dark solution as additional sodium periodate (890 mg, 4.16 mmol) was added and ruthenium (III) chloride hydrate (24 mg, 0.10 mmol). After vigorously stirring for an additional 4 hr, the reaction was acidified (10% citric acid) and diluted (EtOAc). The reaction mixture was filtered through a pad of Celite® (JT Baker, Phillipsberg, NJ, diatomaceous earth) and the filtrate was removed (2xEtOAc). The combined organic layers were washed (brine), dried (Na2SW4), and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (80 g SiO2, 30%, 40%, and 50%

EtOAc / Hex) provides the title compound as a pale yellow foam.

Stage B. 2 - ((3R, 5R, 6S) -l - ((S) -2 - ((tertbutyldiphenylsilyl) oxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) - 3-methyl-2-oxopiperidin-3-yl.) Methyl acetate

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

.9 6’6

Ά a solution of 2 - ((3R, 5R, 6S) -1 - ((S) -2- (tertbutyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic (1400 mg,

1.96 mmol; Example 263, Step A) 2.0 M (trimethylsilyl) diazomethane in hexanes (1.96 mL, 3.92 mmol) was added dropwise at a mixture of MeOH (3.1 mL) and benzene (12.5 mL). After stirring at 0 ° C for 1 hr, the reaction was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (40 g S1O2, 10%, and 20%

EtOAc / Hex) provides the title compound as a pale yellow foam.

Stage C. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methyl-2 -oxopiperidin-3yl) methyl acetate

967

To a solution of 2 - ((3R, 5R, 6S) -1 - ((S) -2- (tertbutyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3- methyl-2-oxopiperidin-3-yl) methyl acetate (578 mg, 0.793 mmol; Example 263, Step B) in THF (3.2 mL) 1M TBAF in THF (2.38 mL, 2.38 mmol) was added at 0 ° C and the reaction mixture was allowed to warm to rt. After stirring at rt for 6 h, the reaction was quenched (NH4C1 sat.), Extracted (2> <EtOAc) and washed (brine). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (40 g SiO2, 10% and 50% EtOAc / Hex) provides the title compound as a colorless foam.

Stage D. 2 - ((3R, 5R / 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -l-cyclopropyl-2- (thiophene-2-sulfonamido) ethyl ) -3-methyl-2oxopiperidin-3-yl) methyl acetate

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methyl-2oxopiperidin -3-yl) methyl acetate (100 mg, 0.184 mmol; Example 263, Step C). and cyanomethylenetributylphosphoran (177 pL, 0.734 mmol) in toluene (0.92 mL) thiophene-2-sulfonamide (90 mg, 0.55 mmol) was added and the resulting solution was stirred at 35 ° C overnight. The reaction was quenched (NH4C1 sat.), Extracted (2 * EtOAc), and washed (brine). The combined organic layers were dried '(Na2SC> 4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (24 g S1O2, 35% EtOAc / Hex) provides the title compound as a pale yellow foam.

Stage E. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (thiophene-2-sulfonamido) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic

To a solution of 2 - ((3R, 5R / 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (thiophene-2969

IMPIC> ^

MEXICAN INSTITUTE ----- 'α'Λ

OF THE SCALE V t ¡p

INDUSTRIAL methyl sulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetate (30 mg, 0.048 mmol; Example 263, Step D) in a mixture of water (0.16 mL), MeOH (0.16 mL), and THF (0.16 mL) LiOH aq was added. 2M (48 pL, 0.095 mmol) at rt and the resulting solution was stirred at rt for 5 h. The reaction was quenched (NH4C1 sat.), Extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g S1O2, gradient elution from 50% to 100% EtOAc in Hex and 30% iPrOH / DCM) provides the title compound as a white powder.

<td></td><td></td><td>XH</td><td>NMR</td><td> (400</td><td colspan="2">MHz,</td><td>CHLOROFORM-d) δ</td><td>ppm 7.50 - 7.66 (2H,</td>

0.41 - 0.57 (2 H, m), -0.02 - 0.10 (1 H, m), -0.35 - -0.20 (1

H, m); MS (ESI) 621.0 [M + H]1.

EXAMPLE 264

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N-methylthiophene-2-sulfonamido) ethyl acid ) -3-methyl-2oxopiperidin-3-yl) acetic —--------- IMPI

l.'tlTITUTÓ MEXICANO

OF INDUSTRIAL PROPERTY

970

Ά a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (thiophene-2-sulfonamido) ethyl) - Methyl 3-methyl-2-oxopiperidin-3-yl) acetate (31 mg, 0.049 mmol; Example. 263) In DMF (0.25 mL) sodium hydride (60% dispersion in mineral oil; 6 mg, 0.15) was added mmol) at rt, and the solution was stirred for 10 min. Then the iodomethane (28 mg, 0.20 mmol) was added and the resulting solution was stirred at rt for 5 h. The reaction was quenched (NH4C1 sat.), Extracted (2xEtOAc), and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure provides a mixture of the title compound and methyl ester.

To a solution of this crude mixture in water (0.16 mL),

MeOH (0.16 mL), and THF (0.16 mL) lithium hydroxide (2.4 mg, 0.098 mmol) ata was added and the resulting solution was stirred at

TA overnight. The reaction was quenched (NH4C1 sat.), Extracted (2 * EtOAc) and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under pressure

purification of the residue by chromatography

971

IMPI reduced. Silica gel (4 g SiO2, 50% and 90%

EtOAc / Hex) provides the title as a powder composed of the blank.

EXAMPLE 265

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 2- (5-chlorothiophene-2-sulfonamido) -1-cyclopropylethyl) acid -3-meth1-2oxopiperidin-3-yl) acetic

((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1The title compound was prepared from 2-

972

IMPI methyl cyclopropyl-2-hydroxyethyl) -3-methyl-2-oxopiperidin-3yl) acetate (Example 263, Step C) by procedures similar to those described in Example 263, Step D and E, substituting thiophene-2-sulfonamide in Step D with the appropriate amount of 5-chlorothiophene-2-sulfonamide.

EXAMPLE 266

2- ((3R, 5R, 6S) -1- ((S) -2- (5-Cloijo-N-methylthiophene-2-sulfonamido) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) ) -3-methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from

973

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlor'phenyl) -1- ((S) -2- (5-chlorothiophene-2) methyl ester precursor sulfonamido) -1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3yl) acetic (Example 265) by a procedure similar to

<td>described in</td><td>Example 264.</td><td></td><td></td><td></td>

0.65 (1H, m); MS (ESI) m / z = 669.0 [M + H]1, 667.0 [MH] '.

EXAMPLE 267

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N- (difluoromethyl) -2-methylpropan -2 ylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic

CI

974

Stage A

INSTITUTE ME? D £ LA PROP chlorophenyl) -3-methyl-2-o.xopiperidin-l-yl) -2-Cl

2-methylpropan-2-sulfonamide

The title compound was obtained from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 cyclopropyl-2-hydroxyethyl ) -3-methylpiperidin-2-one (300 mg, 0.654 mmol; Example 252, Step A) and 2-methylpropan-2sulfonamide (189 mg, 1.37 mmol) by a procedure similar to that described in Example 127, Step F reacting by a total of 21h. Purification of the residue by chromatography on silica gel (40 g SiC> 2, 30% and 50% EtOAc / Hex) provides the title compound as a pale yellow foam.

Stage B. N- ((S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) N- (difluoromethyl) -2-methylpropan-2-sulfonamide

975

To a solution of N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2-cyclopropylethyl) -2-methylpropan-2-sulfonamide (88 mg, 0.152 mmol; Example 267, Step A) In DMF (1.0 mL) 60% sodium hydride in mineral oil (24 mg, 0.61 mmol) was added and the resulting solution was stirred at rt for 10 min. Chlorodifluoromethane was then bubbled into the reaction for 10 min while the reaction went off. stirred vigorously and the resulting reaction was stirred for 2 h. The reaction was quenched (NH4CI sat.), Extracted (2xEtOAc) and washed (brine). The layers

<td>organic combined se</td><td colspan="2">dried (Na2SO4) and</td><td>concentrated</td><td>low</td>

<td>reduced pressure.</td><td>The</td><td>purification</td><td>of the residue</td><td>by</td>

<td>gel chromatography</td><td>of</td><td>silica (12 g</td><td>Si02, 20% and</td><td> 30%</td>

<td>EtOAc / Hex) provides</td><td>the</td><td>composed of</td><td>title like</td><td>a</td>

colorless film.

Stage C. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4.97 6

chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (N- (difluoromethyl) -2methylpropan-2-ylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic

The title compound was prepared from N - ((S) 2- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-2 -oxopiperidin-l-yl) -2-cyclopropylethyl) -N (difluoromethyl) -2-methylpropan-2-sulfonamide (57 mg, 0.091 mmol; Example 267, Step B) by a procedure similar to that described in Example 71, - Stage F. Purification of the residue by reverse phase preparative HPLC (Gemini ™ Prep Cie 5 pm column, Phenomenex, Torrance, CA; 50% to 75% MeCN gradient elution in water, where both solvents contain 0.1% TFA) provides the compound of the

<td>Title</td><td>how</td><td>a</td><td>white foam.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

m), 2.79 (1 H, d, J = 15.1 Hz), 2.35 - 2.69 (2 H, m), 1.74 -

1.94 (2 H, m), 1.53 (3 H, s), 1.47 (9 H, s.), 0.36 - 0.49 (1 H, m), 0.23 - 0.35 (1 H, m), -0.34 - -0.15 (1H, m), -0.87 -0.71 (1H, m); MS (ESI) m / z = 645.0 [M + H] ~, 643.0 [MH] ~.

Examples 268 and 269 were also prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1cyclopropyl- 2-hydroxyethyl) -3-methylpiperidin-2-one (Example

252, Step A) by procedures similar to those described in Example 267, substituting 2-methylpropan-2-sulfonamide in Step A with the appropriate amount of reagent listed in the table.

977

MEXICAN INSTITUTE

Say LA.PROPÍEÜAD

INDUSTRIAL

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 268</td><td></ vw</td><td>ethanesulfonamide</td>

<td> 269</td><td><1 ww</td><td>cyclopropansulfonamide</td>

EXAMPLE 268

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N- (difluoromethyl) ethylsulfonamido) ethyl acid) -3-methyl-2-oxopiperidin-3-yl) acetic

<td>XH NMR</td><td> (500</td><td>MHz,</td><td colspan="2">CHLOROFORM-cf)</td><td>δ</td><td>ppm -0.78</td><td>(br. s.,</td><td> 1</td><td>H)</td>

2.40-2.52 (m., 2H) 2.78 (d, J = 15.41 Hz, 1 H) 3.08 - 3.27 (m,

Η) 3.42 - 4.02 (br. S.,

Η) 4.57 - 4.74

978

<7 = 7.34 Hz, 1 Η) 6.95 (s, 1 Η) 7.08 - 7.18 (m, 2 Η) 7.27 (m.,

Η); Mass Spectrum (ESI) m / z = 617 (M + l).

EXAMPLE 269

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N (difluoromethyl) cyclopropanesulfonamido) ethyl) acid - 3-methyl-2oxopiperidin-3-yl) acetic

<td>XH NMR</td><td>(500 MHz,</td><td>CHLOROFORM-d)</td><td>δ</td><td>ppm -0.79 (br.</td><td>s.,</td><td> 1</td><td>H)</td>

<td>6.93 (s, 1</td><td>H) 7.07 -</td><td>7.18 (m, 2H)</td><td> 7</td><td>.27 (m., 4H);</td><td colspan="3">Spectrum</td>

EXAMPLE 270

1- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 2- (cyclopropanesulfonamido) -1-cyclopropylethyl) -3-methyl-2oxopiperidin -3-yl) cyclopropancarboxylic

979

Stage A. 2 - ((3R, 5R, 6S) -1 - ((S) -2 - ((tertbutyldiphenylsilyl) oxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) - (S) -Methyl 3-methyl-2-oxopiperidin-3-yl) -3-hydroxypropanoate

To a solution of diisopropylamine (249 pL, 1.75 mmol) in THF (1.2 mL) was added n-BuLi 1.6 M in hexanes (984 pL ·,

1.57 mmol) slowly at -15 ° C. After 30 minutes, a solution of 2 - ((3R, 5R, 6S) -1 - ((S) -2- (tert-butyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4 -chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) methyl acetate (255 mg, 0.35 mmol; Example 263, Step B) in THF (1.2 mL) was added dropwise to the LDA solution and the solution resulting

980 stirred at -15'C for 30 min (the solution turns yellow

sparkly) . Then formaldehyde in N current2 it was brought to the reaction surface for 5 min (formaldehyde was generated by cracking para-formaldehyde (105 mg, 3.50 mmol) with a heat gun) at -15 ° C. After stirring at -15 ° C for 30 min, the reaction was allowed to warm to rt and stirred for 4 h. The reaction was quenched (NH4C1 sat. ice-cold), extracted (2 * EtOAc) and washed (brine *!). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, 20% and 50% EtOAc / Hex) provides the title compound as a colorless film.

Stage

2 - ((3R, 5R, 6S) -1 - ((S) -2 - ((tertbutyldiphenylsilyl) oxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl -2-oxopiperidin-3-yl) methyl acrylate

To a solution of 2 - ((3R, 5R, 6S) -1 - ((S) -2- (tertbutyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (

(4) Chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) -3981 (S) -methyl hydroxypropanoate (132 mg, 0.173 mmol; Example

270, Step A) and triethylamine (97 pL, 0.69 mmol) in DCM (2.2 mL), a solution of methanesulfonyl chloride (27 pL, 0.35 mmol) in DCM (2.2 mL) was added at 0 ° C. Then the reaction was allowed to warm to rt and stirred for 3 h. The reaction was quenched (water), extracted (2xEtOAc) and washed (brine). The combined organic layers were dried (Na2SC> 4) and concentrated under reduced pressure to provide a crude mesylated compound,

2 - ((3R, 5R, 6S) -1 - ((S) -2- (tertbutyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2- (S) -methyl oxopiperidin-3-yl) -3 (methylsulfonyloxy) propanoate.

DBU (78 pL, 0.52 mmol) was added to a solution of the crude mesylated compound above in DCM (2.2 mL) and the resulting solution was stirred at rt for 1 h. The reaction was quenched (NH4C1 sat. ice cold), extracted (2xEtOAc) and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 10% and 20% EtOAc / Hex) provides the title compound as a colorless film.

982

methyl butyldiphenylsilyl) oxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-2-oxopiperidin-3yl) cyclopropanecarboxylate

To a suspension of trimethylsulfoxonium iodide (39 mg, 0.18 mmol) in DMSO (0.71 mL) was added a suspension of 60% sodium hydride in mineral oil (7.1 mg, 0.18 mmol). After stirring 15 min, a solution of 2 - ((3R, 5R, 6S) -1 ((S) -2- (tert-butyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (315 methyl chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acrylate (66 mg, 0.089 mmol; Example 270, Step B) in DMSO (0.71 mL) was added and the mixture was stirred a ta for 3 h. The reaction was quenched (NH4C1 sat. ice cold), extracted (2> <EtOAc), and washed (brinex3). The combined organic layers,

they dried up (Na2SW4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10% and 20% EtOAc / Hex) provides the title compound as a colorless film.

Stage D. 1 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1983

Methyl ((S) -l-cyclopropyl-2-hydroxyethyl) -3-methyl-2-oxopiperidin-3yl) cyclopropancarboxylate

To a solution of 1 - ((3R, 5R, 6S) -1 - ((S) -2- (tertbutyldiphenylsilyloxy) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3- Methyl methyl-2-oxopiperidin-3yl) cyclopropancarboxylate (53mg, 0.070mmol; Example 270, Step C) in THF (0.70mL) 1M TBAF in THF (0.21mL, 0.21mmol) was added and the reaction was stirred at TA overnight. The reaction was quenched (NH4C1 sat.), Extracted (2 * EtOAc), and washed (brine). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10%, 45%, and 55% EtOAc / Hex) provides the title compound as a white foam

Stage E. 1 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -2- (cyclopropansulfonamido) -1-cyclopropylethyl) -3-methyl -2-methyl-oxopiperidin-3-yl) cyclopropancarboxylate

984

The title compound was prepared from 1 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1cyclopropyl-2-hydroxyethyl) -3 methyl methyl-2-oxopiperidin-3yl) cyclopropanecarboxylate (35mg, 0.068mmol; Example 270, Step D) and cyclopropansulfonamide (25mg, 0.20mmol) by a procedure similar to that described in Example 202, Step C. Purification of the residue by chromatography on silica gel (4 g 'SiO2, 45% and 60% EtOAc / Hex) gives the title compound as a pale yellow.

Step F. 1 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -2- (cyclopropanesulfonamido) -1cyclopropylethyl) -3-methyl-2 acid -oxypiperidin-3yl) cyclopropancarboxylic

The title compound was prepared from 1 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -2 (cyclopropanesulfonamido) -1-cyclopropylethyl ) -3-methyl-2-oxopiperidin-3-yl) methyl cyclopropancarboxylate (27 mg,

985

MEXJCAN INSTITUTE?

OF INDUSTRIAL PROPERTY

0.043 mmol;

similar to

Example 270, described in

Step E) by procedure Example 2 63, Step E. Purification of the residue by reverse phase preparative HPLC (Gemini ™ column

Prep Cis 5 pm, Phenomenex,

Torrance, CA; gradient elution from 45% to 70% MeCN in water, where both solvents contain 0.1% TFA) provides the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.03 - 7.26 (6 H,

EXAMPLE 271 (Intermediary)

A: N- (2-fluorophenyl) ethanesulfonamide

To a solution. Ethanesulfonyl chloride (0.368 ml,

3.89 mmol) in DCM (1 ml) and pyridine (1 ml), 2-fluoroaniline (0.360 ml, 3.89 mmol) was added at rt and the reaction was stirred at 50 ° C for 5 hours. The reaction was then stirred at rt overnight. The reaction was diluted with EtOAc and washed with H2O- and saturated NaCl solution. The organic layer was dried over Na2SO4 and concentrated. The purification of the residue by

J iy. <RtirjgM.Kw »ggi

986

Flash chromatography on silica gel (eluent: 0% to 35% EtOAc / hexane) provides the "title compound" as a white solid.

XH NMR (400 MHz, CHLOROFORM-d). δ ppm 1.42 (t, J = 8 Hz,

<td></td><td>The</td><td>following</td><td>they prepared in </td><td>a</td><td>Similarly</td><td> -</td>

<td></td><td>B:</td><td>N- (phenyl)</td><td>ethanesulfonamide:</td><td>XH</td><td>NMR- (400</td><td>MHz,</td>

<td colspan="4">CHLOROFORM-d) δ ppm 1.38 (t, <7 = 8 Hz,</td><td colspan="2">3H), 3.14-3.20 (</td><td>cq, <7 = 8</td>

C: N- (3-fluorophenyl) ethanesulfonamide: 1H NMR (40D MHz, CHLOROFORM-d) δ ppm. 1.42 (t, <7 = 8 Hz, 3H), 3.17-3.23 (cq, <7 = 8

Hz, 2H), 6.78 (s, br, IH), 6.89 (m, IH), 6.99 (m, IH). , 7.04 (m, IH), 7.77 (m, IH).

D: N- (pyridin-3-yl) methanesulfonamide: XH NMR (400 MHz, methanol-d4) δ ppm 3.05 (s, 3H), 7.43-7.46 (dd, <7 = 4, 8 Hz,

IH), 7.78-7.81 (dd, <7 = 2, 4 Hz, IH), 8.33 (d, <7 = 4 Hz, IH),

8.45 (s, IH). Mass Spectrum (ESI) m / z = 173.2 (M + l).

E: N- (phenyl) cyclopropansulfonamide: XH NMR (400 MHz,

CHLOROFORM-d) δ ppm 0.96-1.00 (m, 2H), 1.18-1.22 (rn, 2H),

2.48-2.55 (m, 1H), 7.20-7.22 (m, IH), 7.28-7.30 (m, 2H),

7.37-7.39 (m, 2H).

F: propan-1-sulfonamide [CAS no. 24243-71-8]

987

A stream of anhydrous ammonia was bubbled into a solution of propan-l-sulfonyl chloride (7.3g, 51.2mmol) in anhydrous THF (100ml) in an ice bath. Bubbling was continued for 1 hour during which much white solid precipitated. The reaction was then stirred at rt for 2 days. The reaction mixture was diluted with EtOAc, washed with H20 and sat. NaCl, dried with Na2SW4, and then concentrated. Purification of the crude using flash chromatography on silica gel (eluting with 0% to 35% EtOAc / hexane) gives the title compound as a white solid (3.Og, 47.6%).

XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.10 (t, J = 8 Hz,

3H), 1.91 (m, 2H), 3.11 (m, 2H), 4.94 (s, 2H).

G: Cyclobutansulfonamide [CAS no. 445305-91-9]

An anhydrous ammonia stream was bubbled for 30 min through a stirred solution of cyclobutansulfonyl chloride (5 g, 32.3 mmol; Hande Sciences) in dry THF (100 mL) at 0 ° C, which. causes the formation of a white precipitate. The suspension was warmed to room temperature and · stirred overnight. The mixture was filtered and the filter cake was washed copiously with ethyl acetate. The filtrate was concentrated under reduced pressure, redissolved in ca. 150 mL EtOAc, and washed 3X with brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue

988 Item

White partially crystalline L "" 'g- f S which was triturated with hexa dried under high vacuum to give cy 1 obutansuífoñainiHa ^ as a 1 fluffy white solid, 1.8 g (41% yield).

NMR (400 MHz, CHLOROFORM-d) δ 1.96 - 2.10 (m, 2 H), 2.30 -

2.43 (m, 2H), 2.43 -'2.59 (m, 2H), 3.72 - 4.01 (m, 1H),

4.70 (br. S., 2H).

EXAMPLE 272

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) l-cyclopropyl-2- (N- (2-fluorophenyl) ethylsulfonamido) acid) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic

Stage Ά. N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2 -cyclopropylethyl) N- (2-fluorophenyl) ethanesulfonamide '

989

To a mixture of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2-hydroXyethyl) -3methylpiperidin-2- one (Example 252, Step A, 70 mg, 0.153 mmol) and N- (2-fluorophenyl) ethanesulfonamide (93 mg, 0.458 mmol) in toluene (lml), cyanomethylene tr-n-butylphosphoran (0.111 ml, 0.458 mmol) was added to ta and the mixture was wetted with N2 for about 20 minutes. The reaction was sealed and heated to 70 ° C overnight. The reaction mixture was purified by flash chromatography on silica gel (eluent: 0% to 35% EtOAc / hexanes) to provide the title compound as a solid.

XH NMR (400 MHz, methanol-d4) ppm -1.25 (s, br, 1 H), 0.64 (s, br, 1 H), 0.00 (s, br, 1 H), 0.16 (s, br, 1 H ), 0.73

990

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY Mass Spectrum (ESI) m / z = 643.2 (M + l)

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (N- (2fluorophenyl) ethylsulfonamido) acid) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic

To a solution of N - ((S) -2 - ((3S> 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2-cyclopropylethyl) -Ν- (2-fluorophenyl) ethanesulfonamide (Example 272, Step A, 72mg, 0.112mmol) in THF (0.600ml), water (0.396ml) and BuOH (0.3ml) was added 4-oxide 4methylmorpholine (45.9 mg, 0.392 mmol) followed by osmium (VIII) oxide (0.037 ml, 2.80 pmol). The reaction was stirred at RT overnight. Sodium periodate (71.8 mg, 0.336 mmol) was added and the reaction stirred at rt for 2 hours. KH was added to this reaction2PO4 1.25M (0.80 ml), 1 M solution of 2-methylbut-2-ene in THF (2.24 ml, 4.47 mmol) and sodium chlorite (50.6 mg, 0.56 mmol) and the reaction was stirred at rt for 2 hours. During the end of the reaction 0.8 ml of NaS was added2OR3 ac. 1 M and the reaction was stirred at rt for 10 minutes followed by adding 0.8 ml of KHSO4 ac. 1 M.

The reaction was then diluted with EtOAc and washed with H2O and NaCI sat. The organic layer was dried with Na2SW4 and concentrated. The product was purified by reverse phase preparative HPLC

991 (eluents: 40-85% acetonitrile in water with 0.2L% TFA gradient on Gemini ™ Prep Cig 5 um column, Phenomenex,

Torrance, CA) to give the title compound as a white solid.

<td colspan="3">XH NMR (400 MHz, iaethanol-d4) ppm </td><td> -1.28</td><td>! (s, br, IH),</td><td> 0.63</td>

Mass Spectrum (ESI) m / z = 661.2 (M + l)

Examples 273-289 were prepared in a similar manner to Example 272. Using the corresponding sulfonamide and the alcohol of Example 252, Step A, allyl sulfonamides were formed in Step A and converted to the corresponding carboxylic acids in Step B .

<td>Example</td><td>Reagent used</td><td>Source or CAS #</td>

<td> 272</td><td>N- (2-fluorophenyl) ethanesulfonamide</td><td>Example 2 7 LA</td>

<td> 273</td><td>N- (2- fluorophenyl) methanesulfonamide</td><td> [98611-90-6]</td>

<td> 274</td><td>N- (phenyl) cyclopropansulfonamide</td><td>Example 27 1E</td>

275

Example 271B

ΙΜ ΡI

MEXICAN INSTITUTE · $

OF THE EROPITY

<td> 276</td><td>ethanesulfonamide</td><td>------------- ÍNDUSTJUjU --- [1520-70-3]</td><td></td>

<td> 277</td><td>N- (3-fluorophenyl) ethanesulfonamide</td><td>Exercise z / lC</td><td rowspan="13"></td>

<td> 278</td><td>N- (2-cyanophenyl) methanesulfonamide</td><td> [50790-29-9]</td>

<td> 279</td><td>propan-1-sulfonamide</td><td>Example 271F</td>

<td> 280</td><td>N- (phenyl) methanesulfonamide</td><td> [1197-22-4]</td>

<td> 281</td><td>N- (3-cyanophenyl) methanesulfonamide</td><td> [50790-30-2]</td>

<td> 282</td><td>N- (pyridin-3-yl) methanesulfonamide</td><td>Example 27ID</td>

<td> 283</td><td>N- (thiophene-2- ylmethyl) methanesulfonamide</td><td>BBB-SCI 3B3- 026467, Libertyville, IL</td>

<td> 284</td><td>N- (3-MeOPhenylmethyl) methanesulf onamide-</td><td></td>

<td> 285</td><td>alpha-toluenesulfonamide</td><td> [4563-33-1]</td>

<td> 286</td><td>pyridin-2-ylmethanesulfonamide</td><td>Princeton PBMR006092, Monmouth Junction NJ</td>

<td> 287</td><td>pyridin-3-ylmethanesulfonamide</td><td>Princeton PBMR006093, Monmouth Junction NJ</td>

<td> 288</td><td>N- (pyridin-2-yl) methanesulfonamide</td><td> [74351-44-3]</td>

<td> 289</td><td>methanesulfonamide</td><td> [3144-09-0]</td>

Example 273

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N- (2-fluorophenyl) methylsulfonamido) acid) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

'9 9 3

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2-cyclopropylethyl) N- (2-fluorophenyl) methanesulfonamide

1H NMR (400 MHz, methanol-d4) δ ppm -1.20 (s,

3H), 1.48

2H)

2.19 (d, (s, br, IH),

IH), (m,

7=8

4.50

0.00 (s, br,

Hz, (d,

1.64 (d,

2H), 2.72

5.65 (m,

2H), 6.96-7.08 (m, 6H),

IH), 0.13

7 = 12 Hz, (s, 3H),

7 = 8 Hz, IH), 4.59

IH), 6.70 (s, br,

7.19 (m, IH), 7.27 (s,

IH),

2.99 br, IH), 0.88

1.94-1.99 (s, (m, IH), 3.54 (s, br, 1H), 4.962H), 6.80 (s, br, (m, IH) m / z = 629.2 (M + l).

Stage

B acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (N- (2994

fluorophenyl) methylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3 yl) acetic XH NMR (400 MHz, methanol-d4) δ ppm -1.27 (s, br, 1H),

<td>Espe</td><td>ctro</td><td>of masses</td><td>(ESI) m / z =</td><td colspan="2"> = 647.0</td><td>(M + l).</td><td></td><td></td><td></td><td></td>

Example 274

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N-phenylcyclopropanesulfonamido) ethyl) -3- methyl2-oxopiperidin-3-yl) acetic

IMPI

Stage A:

N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4995 chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) - 2-cyclopropylethyl) N-phenylcyclopropansulfonamide

XH NMR (400 MHz, methanol-d4) δ ppm -1.24 (s, br, 1H), -

<td>Espe <</td><td>other</td><td>from N</td><td>slabs</td><td>(ESI)</td><td>m / z</td><td> = 637</td><td>.2 (M + l).</td><td></td>

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (Nphenylcyclopropanesulfonamido) ethyl) -3- acid methyl-2-oxopiperidin-3yl) acetic

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY XH NMR (400 MHz, methanol-d4) δ ppm -1.28 (s, br, 1H),

996

Mass Spectrum (ESI) m / z = 655.2 (M + l).

Example 275

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N-phenylethylsulfonamido) ethyl) -3- acid methyl-2oxopiperidin-3-yl) acetic

Stage A: N - ((S) -2- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) N-phenylethanesulfonamide

Mass Spectrum (ESI) m / z = 625.2 (M + l).

Stage B: acid. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (Nphenylethylsulfonamido) ethyl) -3-methyl-2- oxopiperidin-3yl) aceticXH NMR (400 MHz, methanol-d4 ') δ ppm -1.26 (s, br, IH), ~ 0.55 (s, br, IH), 0.19 (s, br, IH), 1.06 (s, 3H), 1.13 (t,

J = 8Hz, 3H), 1.51 (s, br, IH), 1.88 (dd, J = 4, 8 Hz, IH), 2.00 (s, br, IH), 2.03 (t, 'J = 12 Hz, IH ), 2.48 (d, J = 12 Hz, IH),

998

<td colspan="2">Spectrum</td><td>of masses</td><td>(ESI)</td><td>m / z =. 643.2 (M + l)</td><td></td>

MEXICAN INSTITUTE VxT • OF PROPERTY VV 77 / (m, 1 ^^^ 7 ^ ¾ ^

Example 276

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (ethylsulfonamido) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l- .il) -2cyclopropylethyl) ethanesulfonamide

XH NMR (400 MHz, methanol-d ^) δ ppm -1.06 (s, br, IH), 0.98 (m, IH), - (3.02 (m, IH), 0.14 (m, IH), 1.08 (s, 3H), 1.14

999 (t, <7 = 4 Hz, 3H), 1.39

2.05 (m, 1H), 2.10 (t, 1H), 2.8 9 (m, 3H), 3.12

Hz, 1H), 4.96-5.06 (m, (s, 1H), 6.93 (m, 3H),

Mass Spectrum (ESI) (m, 1H), 1.59 (dd, <7 = 16 Hz, 1H), 2.42 (m, 1H), 3.74 (m,

2H), 5.71 (m, 1H),

7.06 (m, 2H).

m / z = 549.0 (M + l).

(m, 1H), 2.50 (m,

1H), 4.68 (d, <7 = 12

6.79 (m, 2H), 6.87

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (ethylsulfonamido) ethyl) -3methyl- 2-oxopiperidin-3-yl) acetic 1H NMR (400 MHz, methanol-d ^ δ ppm -1.06 (s, br, 1H), -

6.87 (m, 3H), 7.05 (s, br, 2H).

Mass Spectrum (ESI) m / z = 567.0 (M + l)

Example 277

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N- (3-fluorophenyl) ethylsulfonamido) acid) ethyl) -3-;

methyl-2-oxopiperidin-3-yl) acetic

IMPI

MEXICAN INSTITUTE '' -

OF INDUSTRIAL PROPERTY

0 0

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2-cyclopropylethyl) N- (3-fluorophenyl) ethanesulfonamide

XH NMR (400 MHz, methanol-d4) δ ppm -1.20 (s, br, 1H), -

<td>Espe</td><td>ctro</td><td colspan="2">of masses</td><td>(ESI) '</td><td>m / z </td><td> = 643</td><td>.2 (M + l).</td><td></td><td></td><td></td><td></td>

Stage

B:

acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) - 6— (4 -

1001 fluorophenyl) ethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic

<td></td><td colspan="3">XH NMR (400 MHz, methanol-d4}</td><td>δ ppm —1</td><td> ..06</td><td>(s,</td><td>br, 1H), -</td>

<td colspan="2">Mass Spectrum</td><td>(ESI)</td><td>m / z = 661</td><td>.2 (M + l)</td><td></td><td></td><td></td>

Example 278

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 2- (N- (2-cyanophenyl) methylsulfonamido) -1-cyclopropylethyl ) -3methyl-2-oxopiperidin-3-yl) acetic

Chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2-cyclopropylethyl) Step A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3- chlorophenyl) -6- (41002

N- (2-cyanophenyl) methanesulfonamide

XH NMR (400 MHz, methanol-di) δ ppm -1.22 (s, br, 1H), -

Mass Spectrum (ESI) m / z = 636.2 (M + l).

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -2- (N- (2-cyanophenyl) methylsulfonamido) - 1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl) acetic 1H NMR (400 MHz, methanol-d4) δ ppm -1.12 (s, br, 1H), -

6.98 (d, J = 8

1003

MEXICAN INSTITUTE OF THE PROSINDUS

Hz, 2H), br, 2H), 7.57 (m, IH) 17x9 (m,

Mass Spectrum (ESI) m / z = 654.0 (M + l).

Example 279

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (propylsulfonamido) ethyl) -3-methy1- acid 2oxopiperidin-3-iljacetic '

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) propan-1-sulfonamide

CI

1004

Raw product used directly in Stage B.

Mass Spectrum. (ESI) m / z = 563.2 (M + l).

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (propylsulfonamido) ethyl) 3-methyl acid -2-oxopiperidin-3-yl) acetic 1H NMR (400 MHz, methanol -d.4) 'δ ppm -0.85 (s, br, IH), 0.25 (s, br, IH), 0.22 (s, br, IH), 0.35 (m, IH), 1.08 (t,

7 = 4 Hz, 3H), 1.43 (s, 3H), 1.55 (s, br, IH), 1.84 (m, 2H),

2.10 (dd, <7 = 4, 8 Hz, IH), 2.30 (s, br, IH), 2.36 (t, <7 = 12 Hz, IH), 2.67 (d,> 6 Hz, IH), 2.98 ( d,> 16 Hz, IH), 3.05 (m,

3H), 3.41 (m, IH), 3.8.8 (m, IH), 4.92 (d, <7 = 8 Hz, IH), 7.02 (m, 2H), 7.08 (s, 1H), 7.14 (m, 3H), 7.26 (s, br, 2H).

Mass Spectrum (ESI) m / z = 581.2 (M + l).

Example 280

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N-phenylmethylsulfonamido) ethyl) -3- methyl-2oxopiperidin-3-yl) acetic

Stage A:

N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (41005

chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2-cyclopropylethyl) N-phenylmethanesulfonamide

Mass Spectrum (ESI) m / z = 611.2 (M + l).

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (Nphenylmethylsulfonamido) ethyl) -3- acid methyl-2-oxopiperidin-3yl) acetic XH NMR (400 MHz, methane1-d and δ ppm -1.26 (s, br, IH),

<td>Spectrum</td><td colspan="2">of masses</td><td>(ESI)</td><td>m / z</td><td> = 629</td><td colspan="2">.0 (M + l).</td><td></td><td></td><td></td>

Acid

Example 281

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1006

2- (N- (3-cyanophenyl) methylsulfonamido) -1-cyclopropylethyl) -3methyl-2-oxopiperidin-3-yl) acetic

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2-cyclopropylethyl) N- (3-cyanophenyl) methanesulfonamide

<td></td><td colspan="3">XH NMR (400 MHz,</td><td>CHLOROFORM-</td><td>di) δ ppm -1.17</td><td>(s,</td><td>br,</td><td>,1 HOUR) ,</td>

1007 (m, 4H), 7.33-7.40 (m, 2H), 7.50 (s, 1H),

MEXICAN INSTITUTE OF PROPERTY

7.54 (dN,DUW.

Mass Spectrum (ESI) m / z = 636.2 (M + l).

Stage B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -2- (N- (3-cyanophenyl) methylsulfonamido) -1-cyclopropylethyl acid ) -3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, methanol-ά4) δ ppm -1.21 (s, br, IH), -

br, IH), 0.18 (s, br, IH), 0.95 .89 (d, 7 = 8 Hz, 2H), 1.99 (s, br,

2.72 (s, 3H), 2.75 (d, 7 = 12 Hz, br, IH), 4.37 (s, br, 1Ή), 6.80

7.45-7.49 (m, IH), 7.52 (d, 7 = 8 (s, br, IH).

654.1 (M + l).

Example 282

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N- (pyridin-3-yl) acid methylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic

Stage

TO:

Ν - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (41008 i m. R i.

MEXICAN INSTITUTE 02 chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) -2-cyclopropylethyl) N- (pyridin-3-yl) methanesulfonamide

XH NMR (400 MHz, methanol-d4) δ ppm -1.18 (s, br, IH),

(m, IH), 7.84 (s, br, IH), 8.31 (m, 11H), 8.60 (s, br, IH).

Mass Spectrum (ESI) m / z = 612 ·. 2 (M + l).

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (N- (pyridin-3yl) acid methylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, methanol-d4) δ ppm -1.19 (s, br, IH), -

3.38 (s, br, IH),

1009

INSTITUTE V S'h

Ds LA P? .0?! IS £ h-.U w

INDUSTRIAL

4.43 (s, br, 2H), 6.83 (m, 3H), 6.98 (m,

5H), 7.52 (s, br,

IH).

Mass Spectrum (ESI) m / z = 630.1 (M + l).

Example 283 l-cyclopropyl-2- (N- (thiophene-2-ylmethyl) methylsulfonamido) ethyl) 3-methyl-2-oxopiperidin-3-yl) acetic

Stage A: N- ((S) -2- ((3S, 5R, -6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l -yl) -2-cyclopropylethyl) N- (thiophene-2-ylmethyl) methanesulfonamide XH NMR (400

1010 ·

representative) 5.30-5.35 (m, IH), 5.40 (s, IH), 6.06 (m, _ ^ CTaiim> · ΐιΜ · η— »»·· ι ·· ιιι ·· ι · ιιιι ...... ....... T

IH). Mass Spectrum (ESI) m / z = 631.2 (M + l).

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (N- (thiophene-2-methyl)) acid methylsulfonamido) ethyl) -3-methyl-2-0xopiperidin-3yl) acetic 1H NMR (400 MHz, methanol-d4) δ ppm -1.12 (s, br, IH), -

Example 284

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N- (3-methoxybenzyl) methylsulfonamido) acid) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic

1011

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-iT ) -2-cyclopropylethyl) N- (3-methoxybenzyl) methanesulfonamide

XH NMR (400 MHz, methanol-d4) δ ppm -1.07 (s, br, 1H), -

Mass Spectrum (ESI) m / z = 655.2 (M + l).

Stage B:

acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4.chlorophen.il) -1- ((S) .- l-cyclopropyl-2- (N- (31012

IMPIv> ts

MEXICAN INSTITUTE Vx 'DE LA PROPIEDAD O *' <τ> /> Ζ methoxybenzyl) methylsulfonamido) ethyl) -3-methyl-2-oxopiperudin = 3 ^ yl) acetic XH NMR (400 MHz, methanol-d4) δ ppm -1.23 (s, br, IH), -

<td>Spectrum</td><td colspan="2">of Masses (ESI)</td><td>m / z</td><td> = 67</td><td colspan="2">3.0 (M + l).</td><td></td><td></td><td></td>

Example 285

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (phenylmethylsulfonamido) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) 1-phenylmethanesulfonamide

1013

XH NMR (400 MHz, CHLOROFORM- ^) δ ppm -0.36 (s, br, 1H),

<td>Spectrum</td><td colspan="2">of masses</td><td>(ESI) m / z = 61</td><td> 1.2</td><td>(M + l).</td><td></td><td></td><td></td>

Stage B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (ίσΙο ^ ίβηίΙ ^ Ι-ΗεΗΐ-οΐσΙορ ^ ρϋ ^ (phenylmethylsulfonamido) ethyl) -3-methyl-2- oxopiperidin-3yl) acetic JH NMR (400 MHz, CHLOROFORM- ^) δ ppm -0.92 (s, br, IH),

-0.35 (s, br, IH), 0.15 (s, br, 1H), 0.29 (m, 1H), 1.42 (s,

3H), 1.48 (s, IH), 2.05 (dd, <7 = 4, 12 Hz, IH), 2.20 (s, IH),

2.33 (t, <7 = 16 Hz, IH), 2.65 _ (d,> 12 Hz, IH), 2.84 (dd,> 4,

Hz, IH), 2.96 (d,> 12 Hz, IH), 3.38 (m, IH), 3.72 (m,

IH), 4.37 (s, 2H), 4.97 (m, IH), 7.01 (d,> 4 Hz, 2H), 7.06

1014 (s, 1H), 7.13 (m, 3H), 7.24 (s, br, 2H)

Mass Spectrum (ESI) m / z = 629.2 (M + l).

Example 286

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- cyclopropyl-2- (pyridin-2-ylmethylsulfonamido) ethyl) -3-methyl-

2- oxopiperidin-3-yl) acetic

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2-cyclopropylethyl)

1- (pyridin-2-yl) methanesulfonamide

XH NMR (400 MHz, methanol-d4) δ ppm -1.08 (s, br, 1H), 0.49 (s, br, 1H), 0.02 (s, br, 1H), 0.12 (s, br, 1H), 1.09 (s, 3H), 1.36 (s , br, 1H), 1.63 (dd, J = 4, 12 Hz, 1H), 1.93

MEXICAN INSTITUTE 7 ^ · ”'f,

DE IA P:; O'í1 * pAD ^^ xS *** ^ INDUSTRIAL - ' 1 -

1H), 7.42 (d, 7 = 8Hz, · 1H), 7.70 (m, 1H), 8.40 (m, 1H).

Mass Spectrum (ESI) m / z = 612.2 (M + l).

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (pyridin-2ylmethylsulfonamido) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, methanol-d4) δ ppm -1.07 (s, br, 1H), -

<td>Espe</td><td>ctro</td><td>of Masses (ESI)</td><td>m / z = 630.1 (M + l).</td><td></td><td></td><td></td><td></td>

Example 287

Acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- cyclopropyl-2- (pyridin-3-ylmethylsulfonamido) ethyl) -3-methyl-

2- oxopiperidin-3-yl) acetic

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

1016

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) 1- (pyridin-3-yl) methanesulfonamide

XH NMR (400 MHz, methanol-d ^) δ ppm -1.06 (s, br, 1H), -

<td>Spectrum</td><td colspan="2">of Masses (ESI)</td><td>m / z = 612</td><td>.2 (M + l).</td><td></td><td></td><td></td><td></td>

Stage B:

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- acid (41017

chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (pyridin-3 ylmethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, methanol-d4) δ ppm -0.59 (s, br, 1H),

1H), 9.02 (m, 1H), 9.10 (s, 1H). '

Mass Spectrum (ESI) m / z = 630.1 (M + l).

Example 288

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N- (pyridin-2-yl) methylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic

Stage A: N - ((S) -2 - ((3S / 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) N- (pyridin-2-yl) methanesulfonamide

Say LA FHOPi

<td>Espe</td><td>ctro</td><td colspan="2">of masses</td><td>(ESI) m / z</td><td colspan="2">= 612.2 (M + l).</td><td></td><td></td><td></td><td></td>

Stage B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (N- (pyridin-2yl) acid methylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, methanol-da) δ ppm -0.75 (s, br, IH),

1019

1Η), 7.35 (m, 2H), 7.51 (s, br, 3H), (d, J = 4 Hz, IH), 8.15 (s, br, 'IH).

7.87 (s, br, IH), 8.03

Mass Spectrum (ESI) m / z = 630.1 (M + l).

Example 289

2- ((3R, 5R, 6S) -5- (3-chlorophenylj -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (methylsulfonamido) ethyl) -3-methyl-2oxopiperidin -3-yl) acetic

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2cyclopropylethyl) methanesulfonamide

1H NMR (4 00 MHz, methanol-d4) δ ppm -0.87 (s, br, IH),

0.24 (m, IH), 0.22 (m, IH), 0.38 (m, IH), 0.90 (m, IH), 1.28

1020

MtXIC INSTITUTE /

DE LA PROÍTE -. 'AD

<td>Espe</td><td>ctro (</td><td colspan="2">of masses</td><td>(ESI) m / z =</td><td>= 535.2 (M + l).</td><td></td><td></td><td></td><td></td>

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (methylsulfonamido) ethyl) -3methyl- 2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, methane ld.4) δ ppm -1.07 (s, br, 1H), -

6.93 (m, 3Ή), 7.04 (s, br, 2H).

Mass Spectrum (ESI) m / z = 553.2 (M + l).

Example 290

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N-ethylmethylsulfonamido) ethyl) -3- acid methyl-2oxopiperidin-3-yl) acetic

BS¡s »

1021

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) N-ethylmethanesulfonamide

To a solution of N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2cyclopropylethyl) methanesulfonamide (Example 289, Step A, 86mg, 0.161mmol) in DMF (1.5ml) Sodium hydride (16.06mg, 0.401mmol) was added at rt and the reaction was stirred at rt for 30 minutes. Iodoethane (0.058 mL, 0.723mmol) was added to this reaction and the reaction was stirred at rt for 2 hours. The reaction was diluted with EtOAc, washed with water and sat. NaCl, dried with Na2SO4 and then concentrated. Crude was used in the following reaction. Mass Spectrum (ESI) m / z = 563.2 (M + l).

Stage B:

1022

INSTITL chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (N-ethylmethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3 yl) acetic

The title compound was prepared using similar procedures as described by Example 272, Step B.

XH NMR (400 MHz, methanol-d ^ δ ppm. -0.67 (s, br, 1H), -

3H), 7.27 (s, br, 2H).

Mass Spectrum (ESI) m / z = 581.2 (M + lj.

Example 291

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) l-cyclopropyl-2- (N-isopropylmethylsulfonamido) ethyl) -3- methyl-2oxopiperidin-3-yl) acetic

1023

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-2-oxopiperidin-l- yl) -2-cyclopropylethyl) N-isopropylmethanesulfonamide

This compound was prepared using similar procedures as described by Example 290, Step A.

Mass Spectrum (ESI) m / z = 577.2 (M + l).

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (Nisopropylmethylsulfonamido) ethyl) -3- acid methyl-2-oxopiperidin-3yl) acetic

This compound was prepared using similar procedures as described by Example 272 Step B.

XH NMR (400 MHz, methanol -d4) δ

ppm

1024

-0.43 (s, br, 1H),

Mass Spectrum (ESI) 'm / z = 595.2 (M + l).

Examples 292-294 were prepared using similar procedures as described by Example 272 starting with (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ( (S) -1cyclopropyl-2-hydroxyethyl) -3-ethylpiperidin-2-one (Example

253, Stage C).

<td>Example</td><td>Reagent used</td><td>Source or CAS #</td>

<td> 292</td><td>propan-2-sulfonamide</td><td> [ 81363-76-0]</td>

<td> 293</td><td>cyclobutansulfonamide</td><td>Example 271G</td>

<td> 294</td><td>cyclopentansulfoñamide</td><td> [73945-39-8]</td>

Example 292

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -l-cyclopropyl-2- (1-methylethylsulfonamido) ethyl) -3 acid -ethyl-2oxopiperidin-3-yl) acetic

1025

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-ethyl-2-oxopiperidin-l- yl) -2 cyclopropylethyl) propan-2-sulfonamide

-0.32 (s,

br,

1 HOUR) , XH NMR (400 MHz, methanol-d ^) δ

(s, br, 2H).

Mass Spectrum (ESI) m / z = 577.2 (M + l).

Stage

B:

acid

IMrS (L „institute; and Y'y-- · J.-Χ i

OF THE rl'.C'fX · '

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (41026 methylethylsulfonamido) ethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic

<td></td><td colspan="2">XH NMR (4</td><td colspan="3">00 MHz, CHLOROFORM-</td><td>di) δ</td><td>ppm</td><td colspan="2">-0.47 (s,</td><td>br,</td><td>IH),</td>

Mass (ESI) m / z = 595.2 (M + l).

Example 293

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S)

2- (cyclobutansulfonamido) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin-3-yl) acetic

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxopiperidin-l-yl )-2-

cyclopropylethyl) cyclobutansulfonamide

1027

Mass Spectrum (ESI) m / z = 589.2 (M + l).

Step B: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -2- (cyclobu'tansulfonamido) -1-cyclopropylethyl) -3-ethyl acid -2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, methanol-cL) δ ppm -0.48 (s, br, 1H), -

Masses (ESI) m / z = 607.0 (M + l).

Example -294

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 2- (cyclopentansulfonamido) -1-cyclopropylethyl) -3-ethyl-20

1028 oxopiperidin-3-yl) acetic

Ι. ' .ΊΊΤΙΓΓΟ MEXICAN I x OF PROPERTY / iD l INDUSTRIAL

Stage A: N- ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxopiperidin-l-yl ) -2-cyclopropylethyl) cyclopentansulfonamide

<td></td><td>XH NMR (400 M:</td><td>Hz, methanol -d4) δ</td><td>ppm </td><td> -0.32</td><td>(s,</td><td>br,</td><td>1 HOUR) ,</td>

<td>(s,</td><td colspan="2">br, 2H). Mass Spectrum (ESI) i</td><td>m / z -</td><td> 603.</td><td colspan="2">3 (M + l).</td><td></td>

chlorophenyl) -1 - ((S) -2- (cyclopentansulfonamido) -11029

IMPI

MEXICAN INSTITUTE

Stage

B:

cyclopropylethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic acid XH NMR (400 MHz, CHLOROFORM-d!) Δ ppm -0.47 (s, br, 1H),

2H). Mass Spectrum. (ESI) m / z = 621.1 (M + l).

EXAMPLE 295

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) -3-methyl-l- (N-methylcyclopropanesulfonamido) butan2 -il) -2-oxopiperidin-3-yl) acetic '

Stage A: N - ((S) -2- ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -3-methylbutyl) -N1030

methylcyclopropansulfonamide

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 hydroxy-3-methylbutan -2-yl) -3-methylpiperidin-2-one (Example 261, Step H, 109mg, 0.237mmol) and Nmethylcyclopropansulfonamide (W02005 / 108358, 120mg, 0.888mmol) using the general procedure described in Step A of Example 272 and purified by chromatography on silica eluting with ethyl acetate in hexanes. The product was obtained as a beige foam (113.5 mg, 83%). LCMS (ESI): m / z = 577.2 (M + H).

Step B: 2 '- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -3-methyl-l- (Nmethylcyclopropanesulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic

A mixture of N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -3methylbutyl) -N-methylcyclopropansulfonamide (Example ¿ya, Etapa

A, 112.5 mg, 0.195 mmol) ,. sodium periodate (170 mg, 0.795 mmol), and ruthenium (III) chloride hydrate (6 mg, 0.023 mmol) in acetonitrile (1.0 mL), carbon tetrachloride (1.0 mL), and water (1.5 mL) were stirred. vigorously at room temperature overnight.

The reaction mixture was acidified with aqueous citric acid (10% by weight), diluted in ethyl acetate, and filtered through a pad of Celite® (JT Baker, Phillipsberg, NJ, diatomaceous earth). The filtrate was partitioned between 2M aqueous HCI and ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to a residue which was purified by preparative HPLC (Sunfire ™ Prep Cie OBD 10 pm column, 30 X 150 mm, Waters, Milford, MA ) eluting with a gradient from 50 to 100% acetonitrile in water (0.1% trifluoroacetic acid in both solvents). The chromatography fractions containing the product were stripped of volatiles, redissolved in minimal volumes of acetonitrile and water, frozen, and lyophilized to give the product as a white solid.

XH NMR (500 MHz, methanol-d4) δ ppm 0.63 (d, J = 6.60 Hz,

H), 0.69 (s, 3H), 0.95 - 1.22 (m, 4H), 1.40 (s, 3H),

2.07 (dd, J = 13.7, 3.2 Hz, 1H), 2.23 (dquin, J = 9.5, 6.7

1032

= 595.2 (Μ + Η).

EXAMPLE 296

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 1- (cyclopropansulfonamido) -3-methylbutan-2-yl) -3 -methyl-2oxopiperidin-3-yl) acetic.

Stage A. N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -3methylbutyl) cyclopropansulfonamide

1033 I know

CELERY

MEXICAN INSTITUTE

FROM PROPERTY 't'

INDUSTRIAL prepared using

mmol) according to the

The title compound cyclopropansulfonamide (101 mg, 0.834 procedure described in Step Ά of Example 272 and is purified by chromatography on silica eluting with a gradient of ethyl acetate in hexanes. The product was obtained as a solid. CLEM (ESI) : m / z = 563.2 (M + Hj.

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (cyclopropanesulfonamido) -3-methylbutan-2yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic.

The title compound was prepared by the general procedure described in Step B of Example 295. The product was obtained as an opaque white powder.

XH NMR (500 MHz, methanol-d ^ δ ppm 0.59 (d, J = 6.9 Hz, 3 Η), 0.63 (d, J = 6.4 Hz, 3 Η), 0.95 - 1.10 (m, 3 Η), 1.10 -

I. 18 (m, 1 H), 1.42 (s, 3 Η), 2.09 (dd, J = 13.7, 3.2 Hz, 1 Η), 2.14 - 2.24 (m, 1 Η), '2.38 (t, J = 13.7 Hz, 1 Η), 2.52 -

2.61 (m, 1 Η), 2.62-2.80 (m, 2 Η), 3.01 (d, J = 13.5 Hz, 1 H), 3.21 (dd, J = 14.1, 2.1 Hz, 1 Η), 3.51 (ddd, J = 13.6,

II. 2, 3.1 Hz, 1 H), 3.33 (br s, 1 Η), 5.07 (d, J = 11.25 Hz, 1 Η), 7.04 (d, J = 7.34 Hz, 1 Η), 7.07 - 7.63 (m, 7 H). LCMS (ESI): m / z = 581.2 (M + H).

1034

MEXICAN INSTITUTE

I heard THE INDUSTRIAL PROPERTY

EXAMPLE 297 Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (ethylsulfonamido) -3-methylbutan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic

Stage A. N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) -3methylbutyl) ethanesulfonamide

The title compound was prepared from ethanesulfonamide (76 mg, 0.696 mmol; Allichem) by the general procedure described in Step A of Example 295, and purified by chromatography on silica gel eluting with a gradient of ethyl acetate in hexanes. The product was obtained in 89% yield. LCMS (ESI) m / z = 551.2 (M + H).

<td colspan="2"></td><td colspan="2"> 1035</td><td>ΙΡΓΑί INSTll D ΙΛ - ·Γ· INDUSTRY!</td><td>SAW;</td>

<td>Stage</td><td>B.</td><td>acid</td><td>2- ((3R, 5R, 6S) -5-</td><td>(3-chlorophenyl</td><td> ) -6-(4-</td>

chlorophenyl) -1- ((S) -1- (ethylsulfonamido) -3-methylbutan-2-a_ ZL) -3methyl-2-oxopiperidin-3-yl) acetic.

The title compound was prepared using the procedure described in Step B of Example 295 oZto-had as a white solid (56% yield).

XH NMR (500 MHz, methanol-d4) δ ppm 0.59 (d, J = 6. Hz, 3

H),. 0.62 (d, J = 6.6 Hz, 3 Η), 1.36 (t, J = 7.5 Hzr 3 Η),

1.42 (s, 3H), 2.09 (d, J = 10.5 Hz, 1H), 2.14 - 2.2Z ^ (m, 1

7.17 - 7.87 (m, 4H). LCMS (ESI): m / z = 569.2 (M + H).

Example 298

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 1- ((S) 1- (cyclobutansulfonamido) butan-2-yl) -3-methyl- acid 2-oxopipe aridin-

3-yl) acetic

IMPI

1036

Stage A. N- ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lyl) butyl ) cyclobutansulfonamide.

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxybutan-2-yl) -3-methylpiperidin-2-one (Example 91, Step B, 250 mg, 0.560 mmol) and cyclobutansulfonamide (Example 271G, 256 mg, 1894 mmol) using the general procedure described in Step A of Example 272, albeit with a oil bath heated to 40 ° C. The crude product was purified by chromatography on silica gel eluting with a gradient of EtOAc in hexanes. The product was obtained as a white powder (220 mg, 70%). LCMS (ESI): m / z = 563.2 (M + H).

IMPI

Stage B.

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (41037 chlorophenyl) -1 - ((S) —1— (cyclobutansulfonamido) butan-2-yl) -3methyl-2- oxopiperidin-3-yl) acetic.

The title compound was prepared from N— ((S) —2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl2 -oxopiperidin-l-yl) butyl) cyclobutansulfonamide (Example 298, Step A, 50mg, 0.089mmol) by the general procedure described in Step B of Example 295. The crude product was purified by preparative HPLC chromatography (Sunfire ™ Prep Ci8 OBD 10 pm column, 30 X 150 mm, Waters, Milford, MA) eluting with a 50 to '95% gradient of acetonitrile in water (0.1% trifluoroacetic acid in both solvents) to provide a white powder.

1H NMR (500 MHz, methanol-dA δ ppm 0.44 (t, J = 7.6 Hz, 3

= 7.6 Hz, 2H). LCMS (ESI): m / z = 581.2 (M + H).

1038

Example 299 Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S)

1- (N-ethylcyclobutansulfonamido) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic

Stage A. N- ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenylj-6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl) butyl) -Netylcyclobutansulfonamide

By the method of Example 290, Step A, the N— ((S) —2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 -methyl2-oxopiperidin-l-yl) butyl) cyclobutansulfonamide (Example 298, Step A) was treated with ethyl iodide to provide the title compound as a white foam. LCMS (ESI) m / z = 591.2 (M + H). ~ ~ ~ ~ ~ ~ ~ YY

IMPI

Stage Β.

acid

1039

chlorophenyl) -1 - ((S) -1- (N-ethylcyclobutansulfonamido) butan-2 yl) -3-methyl-2-oxopip'eridin-3-yl) acetic.

The title compound was prepared from N - ((S) -2 ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl

2-Oxopiperidin-l-yl) butyl) -N-ethylcyclobutansulfonamide (Example 299, Step A) by the general procedure described in Step B of Example 295 and obtained as a fluffy white solid.

XH NMR (500 MHz, methanol-d4) δ ppm 0.50 (t, J = 7.21 Hz, 3 Η), 1.05 - 1.13 (m, 3 Η), 1.43 (s, 3 Η), 1.54 - 1.67 (m, 1 Η), 1.88 (dquin, J = 15.2, 7.5 Hz, 1 Η), 1.93 - 2.12 (m, 3 Η), 2.22 - 2.36 (m, 2 Η), 2.37 - 2.59 (m, 3 Η), 2.64 (d, J =

13.20 Hz, 1H), 2.70 - 2.99 (m, 3 Η), 3.17 (dq, J = 14.6,

7.2 Hz, 1 H), 3.33 - 3.43 (m, 1 Η), 3.96 (quin, J = 8.4 Hz, 1 Η), 4.06 - 4.33 (m, 1 Η), 4.83 (m, 1 Η), 7.02 ( d, J = 7.1 Hz,

H), 7.05 (s, 1 H), 7.08 - 7.21 (m, 3 Η), 7.27 (br. S., 3

H). LCMS (ESI): m / z = 609.2 (M + H).

EXAMPLE 300

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (phenylsulfonyl) butan-2- acid il) piperidin-3yl) acetic

Stage A. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-methyl-l - ((S) -1- (phenylthio) butan-2-yl) piperidin-2-one

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methylpiperidin

2-one (180 mg, 0.403 mmol; Example 91, Step B) in 2 mL of toluene, cyanomethylene tributylphosphoran (324 uL, 1.21 mmol) and bencentiol (121 pL 1.21 · mmol) were added at rt. The mixture was heated to 110 ° C for 2 h. The reaction cooled, quenched (NH solution4C1 sat. aq.), extracted (2> <EtOAc), and washed with brine. The combined organic layers were dried over Na2SW4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10, 20, 40% EtOAc / hexane)

1041 provides the title compound.

--- OF PROPERTY V * - “> INDUSTRIAL.

Step B. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -1- (phenylsulfonyl) butane -2il) piperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1- ((S) -1- (phenylthio ) butan-2-yl) piperidin-2-one (Example 300,

Step A) by a procedure similar to that described in Example 71, Step F. The crude product was purified by reverse phase preparative HPLC (Gemini ™ Prep C column18 5 pm; Phenomenex, Torrance, CA; MeCN in water with 0.1% TFA, gradient elution) to give a white solid.

<td>(m,</td><td>1 HOUR)</td><td> 9</td><td>7.93 (d, J =</td><td>8Hz, 2H);</td><td>Spectrum</td><td>of masses</td><td> (</td><td>ESI)</td>

588.1 [Μ + H].

1042

EXAMPLE 301

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) -1- (methylsulfonyl) butan-2-yl) -2 -oxopiperidin-3yl) acetic

Stage A. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 3-methyl-l - ((S) -1 - (((trimethylsilyl) methyl) uncle) butan-2yl) piperidin-2-one

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1hydroxybutan-2-yl) -3-methylpiperidin-2-one (Example 91, Step B) by a procedure similar to that described in Example 300, Step A, replacing bencentiol with the appropriate amount of (trimethylsilyl) metanthiol.

<td> 10 4 3</td><td>IMPI MEXICAN INSTITUTE --- Q OF THE FROJÍEDaD * - .J INDUSTRIAL</td>

Step B. (3S, 5R, 6S) -3-Allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 3-methyl-l - ((S) -1- (methylthio) butan-2- il) piperidin-2-one

(3S, 5R, 6S) -3-ali1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 3-methyl-l - ((S) -1 - (((trimethylsilyl) methyl) thio) butan-2yl) piperidin-2-one (60mg, 0.118mmol, Example 301, Step A) was dissolved in a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.5mL, 3.5mmol) at room temperature. The resulting solution was stirred at room temperature for 16h. After such time volatiles were removed under reduced pressure, and the residue was purified by chromatography on silica gel (4 g SiO2, 10, 20, 40% EtOAc / hexane) to provide the title compound.

Step C. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- ((S) -1- (methylsulfonyl) butan-2-yl acid ) -2oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1 - ((S) -1- (methylthio ) butan-2-yl) piperidin-2-one (Example 301,

IMPI

Step B) by a procedure similar to that described in

1044

<td>Example</td><td>71, Eta</td><td>pa F.</td><td></td><td></td><td></td>

<td>4 H), 7.</td><td>27 (m,</td><td colspan="2">2 H); Mass Spectrum (ESI) 526.0 [M +</td><td>Η] '</td><td>F-</td>

Examples 302 to 311 were also prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2- il) -3-methylpiperidin-2one (Example 91, Step B) by procedures similar to those described in Example 300, replacing bencentiol with the appropriate amount of thiol. The required thiols are either commercially available, prepared as described in the following table, or prepared by the following general procedure from the corresponding alcohols.

General Thiol Procedure

Methanesulfonyl chloride (1 eq.) Was added dropwise to a solution of 0.5 M · of the corresponding alcohol and triethylamine (1 eq.) In dichloromethane. The resulting mix

I

The reaction was then divided with

1045

I

MEXICAN INSTITUTE O-f '·' • DE LA PRu.'l IJ -'- U

IND'JSTT · .'-.! · ------- stirred at rt for 2 h '. water, washed with brine, dried over sodium sulfate, filtered and concentrated. This material was dissolved in DMF to give a 0.5M solution of the mesylate. To this sodium sulfhydrate (1.2 eq.) Was added. The resulting mixture was stirred overnight at 45 ° C. The mixture was then partitioned with ether / water, washed with brine, dried over sodium sulfate, filtered, the filtrate was concentrated under reduced pressure. The obtained crude thiol was used in the next step without further purification.

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 302</td><td></td><td>1-propantiol</td>

<td> 303</td><td></td><td>2-methyl-l-propantiol</td>

<td> 304</td><td></td><td>cyclopropylmethanthiol; prepared from bromomethylcyclopropane by the procedure described in US patent no. 3975429.</td>

<td> 305</td><td></td><td>cyclobutylmethanthiol;</td>

<td></td><td></td><td>prepared from</td>

MEXICAN INSTITUTE

OF PROPERTY: INniLITRiAL

1046

<td rowspan="2"></td><td rowspan="2"></td><td>bromomethylcyclobutane for a</td>

<td>pro cedimi in L er "1S iltll 1 hia that described for the preparation of cyclopropylmethanthiol in US patent no. 3975429.</td>

<td> 306</td><td></td><td>cyclopentanotiol; prepared from bromocyclopentane by a similar procedure to that described for the preparation of cyclopropylmethantiol in US Patent no. 3975429.</td>

<td> 307</td><td></td><td>oxetan-3-ylmetantiol</td>

<td> 308</td><td>ICF</td><td>prepared by the above general procedure</td>

<td> 309</td><td></td><td>prepared by the above general procedure</td>

<td> 310</td><td>HBy</td><td>prepared by the above general procedure</td>

<td> 311</td><td>\ Áy o</td><td>butan-2-thiol</td>

<td> 312</td><td></td><td>butan-2-thiol</td>

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -31047

EXAMPLE 302 methyl-2-oxo-l - ((S) -1- (propylsulfonyl) butan-2-yl) piperidin-3yl) acetic XH NMR _ (400 MHz, CHLOROFORM-d) δ ppm 7.23 - 7.27 (2 H,

m), 7.01 - 7.21 (4 H, m) ·, 6.93 - 7.00 (1 H, m), 6.84 (1 H, dt, 7 = 7.1, 1.6 Hz), 4.93. (1 H, d, 7 = 10.8 Hz), 4.05 - 4.20 (1

H, m), 3.33 (1 H, t, '7 = 10.1 Hz), 3.12 (1 H, ddd, 7 = 13.7,

Mass Spectrum (ESI) 554.2 [M + H].

EXAMPLE 303

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (isobutyl sulfonyl) butan-2-yl) -3-methyl- acid 2-oxopiperidin-3yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.27 - 7.24 (2 H,

m), 7.02 - 7.20 (4 H, m), 6.93 - 7.00 (1 H, m), 6.84 (1 H, dt, 7 = 7.2, 1.5 Hz), 4.93 (1 H, d, 7 = 10.6 Hz), 4.15 (1 H, t,

7 = 12.2 Hz), 3.33 (1 H, t, 7 = 9.5 Hz), 3.13 (1 H, ddd, 7 = 13.6,

10.9, 2.6 Hz), 2.84 - 3.03 (3 H, m), 2.66 - 2.83 (2 H, m),

2.33 - 2.47 (2 Ή, m), 2.12 (1 H, ddd, 7 = 14.3, 979, 7.3 Hz),

ΙΜΡΙβ '<*> 1

1048

MUICnNO V? INSTITUTE OF INE'USTRIAL PHILOSOPHY. * ~ -

<td> (3</td><td>H</td><td>t, 7 = 7.5</td><td>Hz); Spectrum</td><td>Masses</td><td>(ESI)</td><td> 568</td><td>.2 [M + H]+.</td><td></td>

EXAMPLE 304

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 1- ((cyclopropynylmethyl) sulfonyl) but.an-2-yl) acid -3-methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm

7.23 - 7.27 (2

H

m), 7.00

7.22 (4

H, m), 6.94

6.98 (1

H

m), 6.85 (1

H

dt, 7 = 7.1,

1.5 Hz),

4.95 (1 H, d, 7 = 10.8

Hz), 4.17 (1

H, t,

7 = 12.1 Hz)

10.9, 2.7

Hz), 2.39

3.35 (1

H, t, 7 = 9.7

Hz), 2.83

3.07 (4

Hz), 3.13 (1

H, ddd,

7=13.6,

H, m), 2.77 (1 H, d,

7 = 14.9 (1 H, t, 7 = 13.8 Hz), 2.07

2.22 (1 H, m),

1.91 (1

H, dd, 7 = 13.9, 2.7 Hz), 1.48 (3 H, s), 1.40

1.47 (1 H, m),

1.12 - 1.25 (1 H, m), 0.75 - 0.85 (2 H, m),

0.37 - 0.48 (5H,

m); Mass Spectrum (ESI) 566.2. [M + H]+.

EXAMPLE 305

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- ((cyclobutylmethyl) sulfonyl) butan-2-yl) -3 acid -methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 - 7.27 (2 H, ~ m), 6.99 - 7.20 (4 II, m), 6.93 - 6.98 (1 H, m), 6.84 (1 H,

1049

7 = 12.2 Hz), 3.31 (1 H, t, '7 = 10.1 Hz), 3.05 - 3.18 (3 H, m),

2.84 - 3.02 (2 H, m), 2.67 - 2.82 (2 H, m), 2.36 (1 H, t,

7 = 13.8 Hz), 2.20 - 2.31 (2 H, m), 2.01 - 2.18 (2 H, m)., 1.82

-1.97 (4 H, m), 1.47 (3 H, s), 1.38 - 1.46 (1 H, m), 0.40 (3

H, t, 7 = 7.5 Hz); Mass Spectrum (ESI) 580.2 [M + H].

EXAMPLE 306

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -

1- (cyclopentylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic

<td></td><td>XH</td><td colspan="3">NMR (400 MHz, CHLOROPH</td><td>| RMO-d) δ ppm 0.</td><td>40 (t, J</td><td> = 8.0</td>

<td>4 H)</td><td>, T-</td><td>25 (m, 2H)</td><td colspan="2">; Spectrum</td><td>of Masses (ESI) 5</td><td>80.1 [M +</td><td>H] + .</td>

EXAMPLE 307

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (oxetane-3-ylsulfonyl) butan-2- acid il) -2oxopiperidin-3-yl) acetic - --- NMR (400 MHz, CD3OD) δ ppm 0.39— (t, J = 1.63 Hz, 3 H)

MrJCCZ INSTITUTE NO

OF THE FP.Ci'iEDA O

INDUSTRIAL

1050

<td>H) 7.28 (br</td><td colspan="3">s, 3H); Mass Spectrum (ESI)</td><td>m / z =</td><td colspan="2">568 (M + l).</td>

EXAMPLE 308

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-

methyl-1 - ((S) -1 - (((3-methyloxetan-3-yl) methyl) sulfonyl) butan-2yl) -2-oxopiperidin-3-yl) acetic

Mass Spectrum (ESI) m / z = 608 (M + l).

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-

1051

EXAMPLE 309

methyl-2-oxo-l- ((S) -1- ((, tetrahydro-2H-pyran-4yl) sulfonyl) butan-2-yl) piperidin-3-yl) acetic

<td>3 H)</td><td> 7.</td><td>30 (br s, 3H); AND</td><td colspan="2">mass spectro</td><td>(ESI) m,</td><td>/ z = 596</td>

(M + l).

EXAMPLE 310

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 1 - ((2-hydroxy-2-methylpropyl) sulfonyl) butan- 2-yl) -3-methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CD3OD) δ ppm 0.38 (t, J = 7.43 Hz, 3 H)

1.17 - 1.27 (m, 2H) 1.38 (s, 3H) 1.44 (s, 6H) 1.46 - 1.56 (m, 1H) 2.01 - 2.12 (m, 2H) 2.26 (t, 77 = 13.69 Hz, 1 H) 2.50

- 2.66 (m, 1H) 2.94 (d, J = 13.50 Hz, 1H) 3.33 - 3.46 (m, 3

H) 4.19 (dd, J = 13.99, 11.05 Hz, 1 H) 4.97 (d, J = 10.76 Hz, 1

H) 6.85 - 6.99 (m, 1 H) 7.03 (s, 1 Hj 7.08 - 7.18 (m, 3 H) - - - - 7.2-6 ~ (br- s, 3 H); Mass Spectrum (ESI) m / zT = 584 (M + l).

1052

OF INDUSTRIAL PROPERTY

EXAMPLE 311 *

Acid 2- ((3R, 5R, 6S) -1 - ((S) -1 - ((R) -sec-butylsulfonyl) butan-2yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-

3-yl) acetic or 2 - ((3R, 5R, 6S) -1 - ((S) -1 - ((S) -secbutyl sulphonyl) butan-2-yl) -5- (3-chlorophenyl) -6 - (4-chlorophenyl) -

3-methyl-2-oxopiperidin-3-yl) acetic

The crude product was purified by reverse phase preparative HPLC (Gemini ™ Prep Cig 5mm column; Phenomenex, Torrance, CA) (50% gradient elution to 85% MeCN in water, where both solvents contain 0.1% TFA, method in 27 min) to provide the title compound as the fastest eluting isomer (tR = 9.43 min).

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (d, J = 7.43

Hz, 2H), 7.04 - 7.15 (m, 3H), 6.96 (s, 1H), 6.85 (td, J = 1.83, 6.70 Hz, 1H), 4.96 (d, J = 10.56Hz, 1H), 4.15 (ddd , J = 3.13, 10.81, 13.45 Hz, 1H), 3.29 (t, J = 10.17 Hz, 1H),

3.14 (ddd, J = 2.93, 10.86, 13.60 Hz, 1H), 2.77 - 2.93 (m, 2H), 2.62 - 2.74 (m, 2H), 2.38 (t, J = 13.79 Hz, 1H), 2.02 -

2.20 (m, 2H), 1.85 (dd, J = 2.84, 13.79 Hz, 1H), 1.54 - 1.66 (m, 1H), 1.37 - 1.53 (m, 7H), 1.08 (dt, J = 3.33, 7.43 Hz, 3H), 0.41 (t, J = 7.53 Hz, 3H). Mass Spectrum (ESI) m / z =

668.2 [M] ~.

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -1 - ((R) -sec-butylsulfonyl) butan-2-

1053

EXAMPLE 312

yl) -5- (3-chlorophenylj-6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-

3-yl) acetic or 2 - ((3R, 5R, 6S) -1 - ((S) -1 - ((S) -sec butylsulfonyl) butan-2-yl) -5- (3-chlorophenyl) - 6- (4-chlorophenyl) -

3-methyl-2-oxopiperidin-3-yl) acetic

The crude product was purified by preparative reverse phase HPLC

Torrance, CA) water, where to provide (column (elution

Gemini ™ Prep C18 5mm;

50% gradient to both solvents contain TFA to the title compound as the

Phenomenex,

85% MeCN in slower eluting isomer (tR = 10.2 min).

<td></td><td></td><td>XH</td><td>NMR (4</td><td>00 MHz,</td><td>CHLOROFORM-d) δ ppm</td><td> 9.97</td><td>(t,</td><td>J =</td><td> 2.74</td>

(t, J = 7.53 Hz, 3H); Spectrum

3.33, 7.43 Hz, 3H), 0.41

Examples 313 to 323 were prepared from (3St5R, 6S) -3 ^ al ±= -5-Y3-chlorophenylj -6— (4-chlorophenyl) -1—4 (SJ — 1cyclopropyl-2-hydroxyethyl) -3 -methylpipéridin-2-oria (Example

1054

252, Step A) by procedures similar to those described in Example 300, replacing bencentiol with the appropriate amount of thiol.

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 313</td><td></td><td>cyclopentanotiol; prepared from bromocyclopentane by a procedure similar to that described for the preparation of cyclopropylmethantiol in US Patent No. 3975429.</td>

<td> 314</td><td></td><td>example 308</td>

<td> 315</td><td>Oy</td><td>bencentiol</td>

<td> 316</td><td>Oy</td><td>o-toluentiol</td>

<td> 317</td><td>or;</td><td>2-chlorobencentiol</td>

INSTITUTE i

FROM THE INDUSTRY!

1055

<td>4-chlorobencentiol</td>

<td> 319</td><td></td><td>4-fluorobencentiol</td>

<td> 320</td><td>Oy</td><td>4-mercaptopyridine</td>

<td> 321</td><td></td><td>2-chloro-4-fluorobencentiol (Oakwood Producís, West Columbia, SC)</td>

<td> 322</td><td></td><td>cyclopropylmethanthiol; prepared from bromomethylcyclopropane by a procedure similar to that described in US Patent no. 3975429.</td>

<td> 323</td><td></td><td>2,2,2-trifluoroetantiol</td>

EXAMPLE 313

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 2- (cyclopentylsulfonyl) '- l-cyclopropylethyl) -3-methyl- 2oxopiperidin-3-yl) acetic

<td>XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.08</td><td>(br</td><td> •</td><td>yes</td><td>1 HOUR)</td>

5 6

INDUSTRIAL INSTI '----

V, ·

Η); Mass Spectrum (ESI) m / z = 592 (M + l).

EXAMPLE 314

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2 - (((3-methyloxetan-3-yl ) methyl) sulfonyl) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic

Mass Spectrum (ESI) m / z = 608 (M + l).

EXAMPLE 315

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 20 l-cyclopropyl-2- (phenylsulfonyl) ethyl) -3-methyl acid -2-oxopiperidin-

3-yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm -1.12 - -1.02 (m, 1

H) -0.33 (m, 1 H) 0.19 - 0.27 (m, 1 H) 0.29 - 0.35 (m, 1 H)

1.60 (s, 3 H) 1.77 - 1.89 ¿m -, - 1 H) -1.92 (dd, <7 = 13.69, 2.93

1057

IMPIfBz

INSTITUTE V '' DE LA F ', C, ·'

INDl-'TkLÍL K .___

Hz, 1 H) 2.57 (t, J = 13.94 Hz, 1 H) 2.81 (d, J = 15.16 Hz, 2 H)

(t, J = 12.

Η) 7.87

Η) 7.20-7.

3.00 (dd, <7 = 7.03, 1.

<td> 7.98</td><td>(m,</td><td> 2</td><td colspan="2">H); Mass Spectrum (ESI)</td><td>m / z</td><td> = 600</td>

(M + l).

EXAMPLE 316

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (o-tolylsulfonyl) ethyl) -3- methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (1 H, dd,

<7 = 7.9, 1.1 Hz), 7.51 - 7.64 (1 H, m), 7.34 - 7.48 (3 H, m),

7.22 - 7.34 (2 H, m), 7.06 - 7.18 (3 H, m), 6.98 - 7.04 (1

H, m), 6.86 - 6.96 (1 H, m), 5.02 (1 H, d, <7 = 10.8 Hz), 4.60 (1 H, t, <7 = 12.4 Hz), 3.20 (1 H, .ddd, <7 = 13.7, 10.8, 2.7 Hz),

3.09 (1 H, d,> 14.9 Hz), 2.99 (1 H, dd, <7 = 14.0, 2.2 Hz),

2.77 - 2.87 (2 H, m), 2.71 (3 H, s), 2.53 (1 H, t, <7 = 13.8

Hz), 1.94 (1 H, dd, <7 = 13.8, 2.8 Hz), 1.78 - 1.86 (1 H, m),

I. 56 (3 H, s), 0.17 - 0.40 (2 H, m), -0.40 - -0.30 (1 H, m),

-1.12 - -1.00 (1H, m); Mass Spectrum (ESI) 614.2 [M + H]1.

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1058

EXAMPLE 317 ty

2 - ((2-Chlorophenyl) sulfonyl) -1-cyclopropylethyl) -3-methyl-2oxopiperidin-3-yl) acetic

<td> 5</td><td></td><td>XH NMR (500 MHz, CHLOROFORM-d)</td><td colspan="2">δ ppm -1.08</td><td>(br s, 1</td><td>H) -</td>

Mass Spectrum (ESI)

1.47 Hz, 1H);

H) 8.15 (dd, 7 = 7.83, m / z = 636 (M + l).

EXAMPLE 318

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -

2 - ((4-Chlorophenyl) sulfonyl) -1-cyclopropylethyl) -3-methyl-2oxopiperidin-3-yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm -0.38 - -0.22 (m, 1 H) 0.26 (br s, l H) 0.33 (dd, 7 = 8.93, 4.52 Hz, 2 H) 1.59 (s, 3

H) 1.83 (br s, l H) 1.96 (dd, 7 = 13.82, 2.81 Hz, 1 H) 2.55 (t,

7 = 13.94 Hz, 1H) 2.84 (d ,. 7 = 15.16 Hz, 2H) 2.98 (dd, 7 = 13.94,

2.45 Hz, 1 H) 3.11 (d, 7 = 14.92 Hz, 1 H) 3.22 (ddd, 7 = 13.69,

10.76, 2.93 Hz, 1 H) ~ 4.99 - (d, - 7 = 10.51 Hz, - 1 H) _ 6.88 - 6.96 (m, 1 Η) 6.98

7.03 (m.

5 9

Η) 7.09 -

Η) 7.56 - 7.66 (m, 2 Η) -7.83 - 7.94 (m, 2 Η); Spectrum

Masses (ESI) m / z = 636 (M + l).

EXAMPLE 319

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2 - ((4-fluorophenyl) sulfonyl) ethyl acid) -3-methyl-2oxopiperidin-3-yl) acetic

<td></td><td>XH NMR</td><td> (500</td><td>MHz.,</td><td>CHLOROFORM-d)</td><td>δ ppm</td><td> -1.05</td><td>(br s, l H) -</td>

H) 3.06 - 3.28 (m, 2H) 4.48 (t, 7 = 12.10 Hz, 1H) 4.99 (d,

<td>8.01 (m, 2H);</td><td colspan="2">Spectrum</td><td>Masses (ESI) m / z =</td><td> 618</td><td>(M + l).</td><td></td>

EXAMPLE 320

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 20 l-cyclopropyl-2- (pyridin-4-ylsulfonyl) ethyl) acid -3-methyl-2oxopiperidin-3-yl) acetic 1H NMR (500 MHz, CHLOROFORM-d) δ ppm -1.01 (br s, l H) 3 H) 1.83 (br s, 1 Η) 1.96 (dd, - 7 = 13.94, 2.93 Hz, 1 H) 2.52

0.30 (br s, l H) 0.28 (br s, l H) 0.30 - 0.46 (m, 1 H) 1.58 (s, (t,> 13.94 Hz, 1 H) 2.83 (m, 2 H) 3.00 (dd, > 13.94, 2.45

1060

MEXICAN INSTITUTE '

OF PROPERTY V

INDUSTRIAL

Hz, 1 Η) 3.11 (d,> 15.16 Hz, 1 H) 3.21 (ddd,> 13.69, 10.64,

2.81 Hz, 1 H) 4.55 (br s, l H) 4.94 (d,> 10.51 Hz, 1 H) 6.88 (d,> 7.09 Hz, 1 H) 6.99 (s, 1 H) 7.08 - 7.20 (m, 2 H) 7.20 5 7.39 (m, 4H) 7.77 - 7.83 (m, 2H) 8.92 - 8.99 (m, 2H);

Mass Spectrum (ESI) m / z = 601 (M + l).

EXAMPLE 321

Acid

2 - ((3R, 5R, 6S) -1 - ((S) -2 - ((2-Chloro-410 fluorophenyl) sulfonyl) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) ) -3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.05 (br S, .1H), 0.29 (br s, lH), 0.25 (br s, lH), 0.29 - 0.44 (m, IH), 1.56 (s ,

3H), 1.84 (br s, IH), 1.89 - 2.03 (m, IH), 2.50 (t,> 13.89

<td> 20</td><td> >8.80, 5.87</td><td>Hz, IH); Spectrum</td><td>Masses</td><td>(ESI) m / z = 652</td><td>.0 and</td>

653.9 (M + l).

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1061

EXAMPLE 322 l-cyclopropyl-2 - ((cyclopropylmethyl) sulfonyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORMS) δ ppm -1.06 (m, 1 H), -

<td>1 HOUR)</td><td> , 7.</td><td> 13</td><td>(m,</td><td>3 H)</td><td> , 7.</td><td>27 (m,</td><td>3 H)</td><td>; Spectrum</td><td>of</td><td>Ma</td><td>sas</td><td> (</td><td>ESI)</td>

EXAMPLE 323

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- cyclopropyl-2 - ((2,2,2-tr.ifluoroethyl) sulfonyl) ethyl) -3-methyl-

2- oxopiperidin-3-i1) acetic XH NMR (500 MHz, CHLOROFORMS) δ ppm 7.08 - 7.17 (2 H,

<td>~ H, br-.</td><td>s. -); -</td><td>Espect ro -de- Ma.</td><td>sas (ESIL m / z_ - 606 (M + l).</td><td></td><td></td>

1062

EXAMPLE 324

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) l-cyclopropyl-2 - ((trifluoromethyl) sulfonyl) ethyl) -3 acid -methyl-2oxopiperidin-3-yl) acetic

INSTITUTE

OF THE PRO ?. INDUSTRY!

Step A. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1 - ((S) -l-cyclopropyl-2 - ((trifluoromethyl) thio) ethyl ) -3methylpiperidin-2-one

A mixture of ((trifluoromethyl) thio) copper (41.3 mg, 0.251 mmol, TCI America, Portland, OR), 2 (tributylphosphoranilide, no) acetonitrile (194 mg, 0.803 mmol), and (3S, 5R, 6S) -3 -allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1cyclopropyl-2-hydroxyethyl) -3-methylpiperidin-2-one (115 mg, 0.251 mmol, Example 252, Step A) was stirred at 110 ° C for 3h. A few drops of 4N HC1 in dioxane were added and the mixture was stirred for 30 min.- ^ toluene 40.15-mlj was added. and_ agitation_

1063 continued at 110 ° C for 20h.

The

IMPI

MEXICAN INSTITUTE OF THE ΡκΟΡΙΕμΑΙ »INDUSTRIAL HPLC purification (column

Gemini ™ Prep Cié 5pm; Phenomenex, Torrance, CA; gradient elution of 10% to 95% MeCN in water with 0.1% TFA) gives the title compound.

Mass Spectrum (ESI) m / z = 542 (M + l).

Step B. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2 ((trifluoromethyl) sulfonyl) ethyl) acid - 3-methyl-2-oxopiperidin-310 yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1cyclopropyl-2 - (( trifluoromethyl) thio) ethyl) -3-methylpiperidin-2one (Example 324, step A) by a procedure similar to that described in Example 71, Step F. The Crude product was purified by reverse phase preparative HPLC (column

Gemini ™ Prep Cié 5pm; Phenomenex, Torrance, CA; gradient elution of 10% to 95% MeCN in water, where both solvents contain 0.1% TFA). ~ r—1H NMR (500 MHz, CDCI3) δ ppm 7.10 - 7.17 (3 H, m), 6.93 (1 H, s), 6.82 - 6.86 (1 H, m), 4.70 (1 H, d, 7 = 10.5 Hz) ,

3.17 - 3.2 6 (2 H, m), 3.02 (1 H, d, 7 = 14.7 Hz), 2.85 (1 H, d,

7 = 14.9 Hz), 2.77 (1 H, br. S.), 2.35 (1 H, t, 7 = 13.9 Hz),

1.99 (2 H, dd, 7 = 13.9, -2.9 Hz), 1.51 (3 H, s), 1.26 (1 H, s),

0.41 - 0.50 (1 H, m), 0.31 (1 H, br. S.), -0.23 (1 H, br.

1064

INSTITUTE i

OF THE IND'J t.

s.), -1.01 (1 H, br. s.); Mass Spectrum (ESI) m / z = 592 (M + l).

Examples 325 to 335 were prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1cyclopropyl-2-hydroxyethyl ) -3-ethylpiperidin-2-one (Example

253, Step C) by procedures similar to those described in Example 300, replacing bencentiol with the appropriate amount of thiol.

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 325</td><td></td><td>bencentiol</td>

<td> 326</td><td>Οζ '</td><td>2-chlorobencentiol</td>

<td> 327</td><td>Οζ</td><td>2-fluorobencentiol</td>

<td> 328</td><td></td><td>3-fluorobencentiol</td>

1065

<td> 329</td><td></td><td>4-fluorobenzenethiol</td>

<td> 330</td><td> ·/</td><td>propantiol</td>

<td> 331</td><td></td><td>butantiol</td>

<td> 332</td><td></td><td>3-methylbutantiol</td>

<td> 333</td><td>Oy</td><td>cyclopentanotiol; prepared from bromocyclopentane by a similar procedure to that described for the preparation of cyclopropylmethantiol in US Patent no. 3975429.</td>

<td> 334</td><td>Oy</td><td>cyclohexanothiol; prepared from bromocyclopentane by a similar procedure to that described for the preparation of cyclopropylmethantiol in US Patent no. 3975429.</td>

<td> 335___________</td><td>J4e-</td><td>trimethylsilylmethantiol - (as per Example 301)</td>

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 1066

EXAMPLE 325

l-cyclopropyl-2- (phenylsulfonyl) ethyl) -3-ethyl-2-oxopiperidin-3yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm -1.01 (br. M., 1 H)

<td colspan="4">Mass Spectrum (ESI) m / z =</td><td> - 614</td><td>(M + l).</td><td></td>

EXAMPLE 326

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 2- ((2-chlorophenyl) sulfonyl) -1-cyclopropylethyl) - 3-ethyl-2oxopiperidin-3-yl) acetic

<td></td><td></td><td colspan="3">XH NMR (500 MHz, CHLOROFORM-df</td><td>δ ppm -T.01</td><td>- (br -.—</td><td></td><td>H) _____</td>

Η) 6.97 - 7.04 (m, 1 Η) 7.09 - 7.22 (m, 3 Η) 7.33 - 7.48

1067

(m, 3 Η) 7.48 - 7.56 (m, 1 Η) 7.56 - 7.67 (m, 2 Η) 8.14 (dd,

7 = 7.95, 1.59 Hz, 1 Η); Mass Spectrum (ESI) m / z = 648 (M + l).

EXAMPLE 327

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- ((2-fluorophenyl) sulfonyl) ethyl) -3-ethyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.00 (br s, lH), 0.26 (br s, 1H), 0.19-0.45 (m, 2H), 1.02 (t, 7 = 7.43 Hz, 3H),

1.87 (dd, 7 = 13.69, 2.93 Hz, 2H), 1.97 - 2.20 (m, 2H), 2.49 (t, 7 = 13.79 Hz, 1H), 2.83 (d, 7 = 15.26 Hz, 2H), 3.08 (d ,

7 = 15.26 Hz, 1H), 3.19 (ddd, 7 = 13.55, 10.71, 2.74 Hz, 1H),

3.30 (d, 7 = 13.89 Hz, 1H), 4.57 (br S, 1H), 4.95 (d, 7 = 10.76

Hz, 1H), 6.89 (d, 7 = 6.85 Hz, 1H), 7.02 (s, 1H), 7.08 - 7.23 (m, 3H), 7.23 - 7.35 (m, 3H), 7.35 - 7.52 (m, 2H) , 7.67 -

7.91 - 8.05 (m, 1H); Mass Spectrum (ESI) m / z = 632.0 (M + l).

EXAMPLE 328

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) —1 - ((S) -l-cyclopropyl-2 - ((3-fluorophenyl) sulfonyl) ethyl acid ) -3-ethyl-2oxopiperidin-3-yl) acetic ------------- 20

1068

<td></td><td>INDUSTRIAL.XH NMR (400 MHz, CHLOROFORM-d) δ ppm -0.97 (br s, 1H</td><td> --- J -2 · ' ),</td>

<td>2H),</td><td colspan="2">7.57 - 7.66 (m, 3H), 7.70 (d, 7 = 7.83 Hz, 1H); Spectrum</td>

Mass (ESI) m / z = 632.0 (M + l).

EXAMPLE 329

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2 - ((4-fluorophenyl) sulfonyl) ethyl acid) -3-ethyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -0.97 (br s, lH), 0.31 (br s, lH), 0.32 (d, 7 = 4.89 Hz, 2H), 1.05 (t, 7 = 7.53 Hz,

3H), 1.26 (s, 1H), 1.88 (dd, 7 = 13.69, 2.93 Hz, 2H), 1.97 -

2.21 (m, 2H), 2.52 (t, 7 = 13.79 Hz, 1H), 2.83 (d, 7 = 15.26 Hz,

1H), 2.92 - 3.13 (m, 2H), 3.13 - 3.30 (m, —tffh, —4 ^ 38— (br ---__ s, 2H), 5.01 (d, 7 = 10.56 Hz,. 1H), 6.91 (d, 7 = 6.65 Hz, 2H),

7.01 (s, 2H), 7.07 - 7.22 (m, 3H), 7.28-7.37 (m, 3H), 7.83 8.03 (m, 2H); Mass Spectrum (ESI) m / e = 632.0 (M + l).

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1069

tNDUSTRSAL

EXAMPLE 330 l-cyclopropyl-2- (propylsulfonyl) ethyl) -3-ethyl-2-oxopiperidin-

3-yl) acetic XH NMR (400 MHz, methanol-d4) δ ppm -0.71 (s, br, 1H),

0.00 (br s, (br s, 1H), 0.60 (br s, 1H)

1H), 0.51

1.19 (t,

m / z = 580.2 (M + l).

Mass Spectrum (ESI)

EXAMPLE 331

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -2- (Butylsulfonyl) -1cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2oxopiperidin- 3-yl) acetic XH NMR (400 MHz, methanol-d4} δ ppm -0.73 (s, br, 1H),

Mass Spectrum (ESI) m / z = 594.2 (M + l).

1070

X

EXAMPLE 332

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 5 l-cyclopropyl-2- (isopentyl sulfonyl) ethyl) -3-ethyl acid -2oxopiperidin-3-yl) acetic XH NMR (400 MHz, methanol-da) δ ppm -0.73 (br s, 1H),

(s, 1H), 7.36 (m, 3H), 7.50 (br s, 2H); Mass Spectrum (ESI) m / z = 608.2 (M + l) ·.

EXAMPLE 333

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) ------- 2-4GLYCLLPpentylsulfonyl) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin-3-yl) acetic '------— XH NMR (400 MHz, iaethanol-d4) δ ppm -0.94 (br s, 1H), 0.23 (br s, 1H), 0.30 (br s, 1H), 0.39 (br s, 1H), 0.99 (t, < 7 = 4 Hz, 3H) ', 1.73-1.83 (m, 6H), 1.87 (m, 1H), 2.05 (m, 5H),

2.42 (t, <7 = 12 Hz, 1H), 2.68 (d, <7 = 12 Hz, 1H), 2.78 (br s,

1H), 2.94 (d, <7 = 12 Hz, · 1H), 3.48 (br s, 1H), 3.50 (m, 1H),

1071

3.61 (m, 1H), 4.27 (br s, 1H), 4.98 (d, J = 12 Hz, 1H), 7.02 (d, J = 8 Hz, 2H), 7.08 (s, 1H), 7.17 (m, 3H), 7.31 (br s, 2H);

Mass Spectrum (ESI) m / z = 606.2 (M + l).

EXAMPLE 334

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 2- (cyclohexylsulfonyl) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin -3-yl) acetic

<td></td><td></td><td colspan="2">XH NMR (400 MH</td><td>.7., Methanol</td><td>-d4)</td><td colspan="2">δ ppm -0</td><td>.97 (s, br, 1H</td><td> ) , ~</td>

<td></td><td>1 HOUR) ,</td><td> 7.16-7.21</td><td>(m,</td><td>3H), 7.31</td><td>(s,</td><td>br,</td><td>2H);</td><td>Spectrum of M</td><td>handles</td>

(ESI) m / z = 620.2 (M + l)

EXAMPLE 335 ------- 7 -----—

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (methylsulfonyl) ethyl) -3-ethyl- acid 2-oxopiperidin-3yl) acetic XH NMR (400 MHz, methanol-d4) δ ppm -0.71 (s, br, 1H),

0.00 m (s, br, 1H¡, 0.47 (s, br, 1H), 0 · 55 (s, br, 1H), 1.14

1072

<td>(s,</td><td>br, 2H);</td><td colspan="3">Mass Spectrum (ESI) m / z =</td><td>552.2 (M + l).</td><td></td>

Examples 336 to 339 were prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxy-3- methylbutan-2-yl) -3-methylpiperidin-2-one (Example

261, Step H) by procedures similar to those described in Example 300, replacing bencentiol with the designated reagent.

<td></td><td>Example</td><td>R</td><td>Reagent used</td>

<td rowspan="3"></td><td> 336</td><td>F3c ^ y</td><td>trifluoroetantiol</td>

<td> 337</td><td>one in</td><td>2-methylpropan-2-thiol</td>

<td> 338</td><td>I</td><td>trimethylsilylmethantiol (as per the Example 301)</td>

1073

EXAMPLE 336

INSTITUTE ME

OF INDUSTRIAL PROPERTY

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -e ^ T ^ -CIoroTeniTp ^ methyl-1 - ((S) -3-methyl-l - ((2,2,2- trifluoroethyl) sulfonyl) butan2-yl) -2-oxopiperidin-3-yl) acetic XH NMR (500 MHz, methanol-d4) δ ppm 0.52 (s, 3 Η), 0.67

8.26 (m, 3H); Mass Spectrum (ESI) m / z = 608 (M + H)

EXAMPLE 337

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -1- (tert-Butylsulfonyl) -3methylbutan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) - 3-methyl-2oxopiperidin-3-yl) acetic XH NMR (500 MHz, methanol-d4) δ ppm 0.51 (d, J - 6.9 Hz, 3 H), 0.65 (d, J = 6.6 Hz, 3 Η), 1.37 (s, 3 Η), 1.45 (s, 9 Η), 2.01-2.10 (m, 1 Η), 2.11-2.25 (m, 1 Η), 2.30 (t, J = 13.7 Hz, 1 Η), 2.61 (d, J = 13.5 Hz, 1 Η ), 2.99 (d, J = 13.7 Hz, 1

H), 3.10 (dd, J = 13.7, 1.71 Hz, 1 Η), 3.25 - 3.29 (m, 1 Η),

3.57 (ddd, J = 13.6, 11.1, 2.9 Hz, 1 Η), 3.96 (dd, J = 13.8, _

1074

10.4 Hz, 1 Η), 5.15 (d, J = 11.3

H), 7.04 - 7.17 (m, 3 H), 7.18 Hz, 1 H), 6.98 - 7.03 (m, 1

8.01 (m, 3H); Spectrum

Masses (ESI) m / z = 582.2 (M + H).

EXAMPLE 338

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((S) -3-methyl-l- (methylsulfonyl) butan-2 acid -il) -2oxopiperidin-3-yl) acetic * H NMR (500 MHz, methanol-d4) δ ppm 0.50 (d, J = 6.9 Hz ,. 3

4.07 (dd, J = 13.9, 10.5 Hz, 1 H), 5.09 (d, J = 11 Hz, 1 H),

6.98 (dt, J = 7.2, 1.4 Hz, 1H), 7.03 - 7.08 (m, 1H), 7.08 -

7.16 (m, 2H), 7.29 (br s, 4H); Mass Spectrum (ESI) m / z = 540.2 (M + H).

EXAMPLE 339

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (ethylsulfonyl) butan-2-yl) -3-methyl- acid 2-oxopiperidin-3yl) acetic /

M-XKUNO INSTITUTE OF INDUSTRIAL PROPERTY

1075

Stage A. (3S, 5S, 6R, 8S) -8-AÍÍ1-6 (3-chlorophenyl) -5- (4-chlorophenyl) -3-ethyl-8-methyl-2,3,5,6, trifluoromethanesulfonate, 7,8hexahydrooxazolo [3,2-a] pyridin-4-io

By the method of Example 361 Step A using (S) —2— aminobutanol instead of L-valinol, the title compound was obtained as the first eluting diastereomer.

XH NMR (500 MHz, DMSO-d6) δ ppm. 7.95 (1H, br. S), 7.34 -

7.60 (2 H, m), 7.18 - 7.34 (4 H, m), 7.13 (1 H, dt, <7 = 7.5,

1.3 Hz), 5.88 (1 H, m), 5.37 (1 H, dd, <7 = 16.8, 1.6 Hz), 5.28 (1 H, dd, <7 = 10.0, 2.0 Hz), 5.16 (1 H, d , <7 = 10.8 Hz), 5.06 (1 H, t, <7 = 9.8 Hz), 4.78 (1 H, dd, <7 = 9.5, 7.1 Hz), 4.45 (1 H, m, <7 = 2.7 Hz ), 3.88 - 3.98 (1 H, m), 2.66 - 2.85 (2 H, m), 2.33 (1 H, t, <7 = 13.4 Hz), 1.99 (1 H, dd, <7 = 13.7, 3.4 Hz ), 1.32 (3 H, s), 0.94 (1 H, m), 0.59 (3 H, t, <7 = 7.2 Hz), 0.41-0.53 (1

z = 428.2 (M+) .

1076

H, m); Mass Spectrum (ESI) m /

Stage B. (3S, 5R, 6S) -3-Α1Ϊ.1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1 - ((S) -1- (ethylthio) butan-2-yl) -3-methylpiperidin-2-one

To a trifluoromethanesulfonate solution of (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3eti 1-8-meth 1-2,3,5, 6, 7, .8-hexahydrooxazolo [3,2-a] pyridin-4-io (86 mg, 0.15 mmol; Example 339, Step A) In DMF (0.74 ml) sodium ethantiolate (38 mg, 0.45 mmol) was added ). After stirring at 25 ° C for 1.5 h, the reaction was quenched (NH4C1 sat. ac.), extracted (2xEtOAc), and washed (2xsalt). The combined organic layers were dried over Na2SW4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 10% and 20% EtOAc / hex) provides the title compound as a colorless liquid.

Step C. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -1- (ethylsulfonyl) butan-2-yl) -3 acid -methyl-2oxopiperidin-3-yl) acetic

1077

To a rapidly stirred solution of (3S, 5R, 6S) -3-alyl-

5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (ethylthio) butan-2 yl) -3-methylpiperidin-2-one (60 mg, 0.12 mmol; Example 339 , Stage B) in a mixture of water (0.66 mL), acetonitrile (0.44 mL), and CC14 (0.44 mL) sodium periodate (157 mg, 0.734 mmol) was added, followed by ruthenium (III) chloride hydrate (2.8 mg, 0.012 mmol). After vigorously stirring for 5 hr, the reaction was acidified (10% citric acid) and diluted (EtOAc). The reaction mixture was filtered through a pad of Celite® (JT Baker, Phillipsberg, NJ, diatomaceous earth) and the filtrate was removed (2> <EtOAc). The combined organic layers were washed with brine, dried over Na2SO4 filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by reverse phase preparative HPLC (Gemini ™ Prep Cie 5 pm column, Phenomenex, Torrance, CA; 40% to 60% MeCN gradient elution in water, where both solvents contain 0.1% TFA) provides the composed of the title as a white foam.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 - 7.2 6 (2 H, m), 7.01 - 7.20 (4 H, m), 6.93 - 6.98 (1 H, m), 6.85 (1 H, d, 7 = 7.0 Hz), 4.94 (1 H, d, 7 = 10.6 Hz), 4.15 (1 H, t, 7 = 12.1 Hz), 3.2 4 - 3.37 (1 H, m), 2'92 - 3.18 (4 H, m), 2.71 - 2.82 (2 H, m), 2.38 (1 H, t, 7 = 13.8 Hz), 2.06 - 2.21 (1 H, m),

1.92 (1 H, dd, 7 = 13.7, 2.7 Hz), 1.4 8 (3 H, s), 1.42 - 1.4 6 (1

H, m) 1.44 (3 Η, t,

J = 7.5 Hz), 0.41

1078

I Mi. PI

MEXICAN INSTITUTE V. --- OF INDUSTRIAL PROPERTY (3 H, t, 7 = 7.5 Hz);

Mass Spectrum (ESI)- m / z = 540.1 [M + H.

EXAMPLE 340

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (cyclopropyl sulfonyl) butan-2-yl) -3-methyl- acid 2-oxopiperidin-3yl) acetic

Step A. (3S, 5R, 6S) -3AÜ1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1- ((S) -1- (cyclopropyl sulfonyl) butan-2-yl) -3-methylpiperidin -2ona

To a trifluoromethanesulfonate solution of (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3ethyl-8-methyl-2,3,5,6, 7,8-hexahydrooxazolo [3,2-a] pyridin-4-io (75 mg, 0.130 mmol; Example 339, Step A) in acetonitrile

IMPI

1079.

(1.3 mL) cyclopropansulfinic salt (50 mg, 0.39 mmol) sodium was added at 25 'C. After stirring at 90 ° C for 1 day, the reaction was quenched with NH solution4C1 sat. aq., extracted (2xEtOAc) and the combined organic layers were washed with brine (2 *), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The purification of the residue by gel chromatography of

Silica (12 g SiO2, 35% and 45% EtOAc / hex) provides the title compound as a colorless liquid.

Stage B.

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -1 - ((S) -1- (cyclopropyl sulfonyl) butan-2-yl) -3methyl-2- acid oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 (cyclopropyl sulfonyl) butan- 2-yl) -3-methylpiperidin-2-one (Example 340, Step A) by a procedure similar to that described in Example 339 Step C.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 - 7.26 (2 H,

Hz), 2.31

- 2.49 (2 H, m), 2.06 - 2.24 (1 H, m), 1.90 (1 H,

1080

INSTITUTO ΜΕΧι · -Λ.Νθ DE LA PITOHUíAD INDUSTRIAL

dd,> 13.7, 2.7 Hz), 1.40 - 1.56 (1 H, m), 1.47 (3 H, s),

1.23 - 1.36 (2H, .m), 1.01 - 1.16 (2H, m), 0.42 (3H, t,> 7.5Hz); Mass Spectrum (ESI) 552.2 [M + H]+ .

Examples 340 and 341 were prepared from (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-ethyl-8-methyl-2, trifluoromethanesulfonate. 3,5,6,7,8 hexahydrooxazolo [3,2-a] pyridin-4-io (Example 339, Step A) by a procedure similar to that described in either Example

339 or Example 340, · using an equivalent amount of the appropriate reagent in Step B.

<td>Example</td><td>R</td><td>Method</td><td>Reagent used</td>

<td> 341</td><td>AND '</td><td>Example 339</td><td>propan-2-thiolate, prepared in situ at from cesium carbonate (206 mg, 0.63 mmol) and 2-propantiol (59 pl, 0.63 mmol)</td>

<td> 342</td><td></td><td>Example 339</td><td>2-methylpropantiolate, prepared in situ at from 2-methylpropan-</td>

INSTITUTO teiCAÑO D £ LA PROPIEDAD INDUSTRIAL

1081

<td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td>2-thiol (113 μΐ, 1.00</td>

<td>mmol) and carbonate sodium (106 mg, 1.00 mmol)</td>

<td> 343</td><td> 0to</td><td>Example 340</td><td>acid cyclobutansulfinic salt of sodium,</td>

EXAMPLE 341

Acid 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 1- (isopropylsulfonyl) butan-2-yl) -3-methyl- 2-oxopiperidin-3yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 - 7.26 (2 H, br s), 7.02 - 7.21 (4 H, m), 6.92 - 6.94 (1 H, s), 6.85 (1 H, d, 7 = 7.0 Hz), 4.97 (1 H, d, 7 = 10.8 Hz), 4.10 (1 H, t, 7 = 11.7 Hz), 3.27 - 3.42 (1 H, m), 2.98 - 3.16 (3 H, m ), 2.70-2.78 (2 H, m), 2.40 (1 H, t, 7 = 13.9 Hz), 2.08 - 2.26 (1 H, m),

1.86 - 1.93 (1 H, s), 1.49 (3 H, s), 1.43 (3 H, d, 7 = 6.8 Hz),

1.43 (3H, d, 7 = 6.8Hz), 1.40 - 1.50 (1H, m) 0.41 (3H, t, 7 = 7.5Hz); Mass Spectrum (ESI) m / z = 554.2 [M + H]+.

EXAMPLE 342

Acid 2- ((3R, 5R, 6S) -1- ((S.) - 1 - (tert-butylsulfonyl) bu.tan-2-yl)

5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.21 - 7.26 (2 H,

8 2 r

c <Λ. Λ_ JL \

INSTITUTO .MEX'CANí * DE LA FROP'iraD VINDUSTRIAL

<td>1.44 (9 H, s), 0.41 (3 H, t, <7 = 7.6</td><td>Hz);</td><td colspan="2">Mass Spectrum</td>

EXAMPLE 343

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (cyclobutyl sulphonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.21 - 7.27 (2 H,

H, t, <7 = 7.6 Hz); Mass Spectrum (ESI) 566.2 [M + H]+ .

1083

Synthesis of cyclobutansulfinic acid, sodium salt

The reagent was prepared by procedures similar to those described in W02007 / 14011 and WO2010 / 39982. To a suspension of magnesium (306 mg, 12.6 mmol) in ether (7.4 mL) was added a solution of bromocyclobutane (1.00 g, 7.41 mmol) in ether (7.4 mL) in several small portions at 25 ° C. After the initial exotherm has ceased, the mixture was further heated at reflux for 1 h. The suspension was then added in small portions to an ice cold solution of sulfuryl dichloride (3.00 g, 22.2 mmol) in DCM (12 mL).

The suspension was warmed to room temperature and the volatiles were removed under reduced pressure. The residue was dried under vacuum, then extracted with hexane (80 mL). The hexane suspension was filtered and the filter cake was washed with hexanes. The combined filtrates were dried (Na2SO4) and concentrated under reduced pressure to give crude cyclobutansulfonyl chloride. The crude cyclobutansulfonyl chloride (1.15 g, 7.44 mmol) was added to a suspension of sodium sulfite (2.16 g, 17.1 mmol) in water (9.7 ml) and sodium carbonate (1.42 g, 13.4 mmol). The resulting solution was heated to reflux for 1 hr. The reaction was cooled and lyophilized to remove the water. Ethanol (50 mL) is

1084

IMPIOS Mexican Institute fyyy OF PROPERTY

INDUSTRIAL ÍÍÍ1 — X- * 'was added to the residue, and the resulting mixture was heated under reflux for 2h.

The mixture was filtered. Filtering is <

concentrated under reduced pressure to give the crude title compound which was used as is in the next step

EXAMPLE 344

1 - ((S) -1- (ethylsulfonyl) butan-2-yl) -2-oxopiperidin-3yl) acetic

Stage

TO.

methanesulfonate

chlorophenyl) -5- (4-chlorophenyl) -3,8-diethyl-2,3,5,6,7,8hexahydrooxazolo [3,2-a] pyridin-4-io

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-ethyl-l - ((S) -l-hydroxybutane-2-yl) piperidin-2one (300mg, 0.652 mmol) (Example 202, Stage B) in DCM (6 mL)

1085 triethylamine (270 μϊ, 1,955 mmol) and methanesulfonic anhydride (170 mg,

0.977 mmol) successively at 0 ° C. The reaction was allowed to warm to rt.

After stirring at rt for 2 h, the reaction was quenched with 10% aq citric acid, extracted with DCM, and the combined extracts were washed with water, dried over

Na2SW4, filtered and the filtrate was concentrated to give the title compound.

Stage B. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -

3-ethyl-l - ((S) -1- (ethylthio) butan-2-yl) piperidin-2-one

The title compound was prepared from (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3,8-diethyl-2,3,5 methanesulfonate , 6,7,8-hexahydrooxazolo [3,2a] pyridin-4-io (Example 344, step A) by a procedure similar to that described in Example 339, step B.

Step C. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-l - ((S) -1- (ethylsulfonyl) butan-2-yl acid ) -2oxopiperidin-3-yl) acetic

1086

The title compound is

MEXICAN INSTITUTE

PB LA fROTicCAO ÍNDUSTkíAL

prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-l ((S) -1- (ethylthio) butan-2 -il) piperidin-2-one (Example 344, step B) by a procedure similar to that described in Example 339, step C.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 (t, J = 8.0

<td>(m, 3</td><td colspan="2">H); Mass Spectrum (ESI) m / z = 554.0 [M + H]1 .</td><td></td>

Examples 345 through. 347 were prepared from (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3,8-diethyl-2,3,5,6 methanesulfonate, 7,8-hexahydrooxazolo [3,2a] pyridin-4-io (Example 344, Step A) by a procedure

Stage B.

similar to that described in either Example 339 or Example 340, using an equivalent amount of the appropriate reagent in

1087

<td>Example</td><td>R</td><td>Method</td><td>Reagent used</td>

<td> 345</td><td>AND</td><td>Example 339</td><td>propan-2-thiolate, prepared in situ at from cesium carbonate (206 mg, 0.63 mmol) and 2-propantiol (59 μΐ, 0.63 mmol)</td>

<td> 346</td><td>V</td><td>Example 339</td><td>2-methylpropantiolate, prepared in situ at from 2-methylpropan2-thiol (113 μΐ, 1.00 mmol) and carbonate sodium (106 mg, 1.00 mmol)</td>

<td> 347</td><td> 0to</td><td>Example 340</td><td>cyclobutansulfinic acid sodium salt, prepared as described in Example 343</td>

<td> 348</td><td></td><td>Example 340</td><td>acid sodium salt cyclopropansulfinic, prepared by the method as described in Example 343</td>

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-ethyl1088 acid

EXAMPLE 345

1- ((S) -1- (isopropylsulfonyl) butan-2-yl) -2-oxopiperidin-3yl) acetic

<td></td><td>XH Rl</td><td colspan="3">MN (400 MHz, CHLOROFORM-d) δ</td><td>ppm 0.4 0 (t, J</td><td> = 8</td><td> .0</td>

<td>(m,</td><td>4 H),</td><td> 7.27</td><td>(m,</td><td colspan="2">2 H); Mass Spectrum (ESI) m / z =</td><td> 5 68</td><td> .0</td>

EXAMPLE 346

Acid 2- ((3R, 5R, 6S) -1 - ((S) -1- (tert-butylsulfonyl) butan-2-yl) 5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- ethyl-2-oxopiperidin-3yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.39 (t, 7 = 8.0

Hz, 3 H), 0.97 (t, J = 8.0 Hz, 3 Ή), 1.43 (s, 9 H), 1.50 (m,

H), 1.85 (dd, J = 12, 4 Hz, 1 H), 1.97 (m, 2 H), 2.15 (m, 1

H), 2.38 (t, 7 = 12 Hz, 1 H), 2.80 (d, J = 16 Hz, 1 H), 2.96 (d, J = 16.0 Ηζ, Ι H), 3.14 (m, 2 H), 3.35 (m, 1H), 4.01 (m,

H), 5.02 (d, J = 8 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H),

6.98 (s, 1 Η), 7.13 (m, 4 Η), 7.38 (m, 2 Η); Spectrum

Masses (ESI) m / z = 582.1 [Μ + H] 1. —1089

EXAMPLE 347

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1- (cyclobutyl sulfonyl) butan-2-yl) -3-ethyl-2-oxopiperidin-3yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.39 (t, J = 8.0

<td>(m,</td><td> 3</td><td>H)</td><td> , 7.28</td><td>(m, 3H)</td><td>; Spectrum</td><td>from M</td><td>handles</td><td>(ESI) 580</td><td>.0 [M +</td>

EXAMPLE 348

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (cyclopropyl sulfonyl) butan-2-yl) -3-ethyl- 2-oxopiperidin-3yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.42 (t, J = 8.0 Hz, 3 H), 0.97 (t, J = 8.0 Hz, 3 H), 1.10 (m, 2 H), 1.26 (m, 2 H), 1.52 (m, 1 H), 1.83 (dd, J = 16, 4 Hz, 1 H), 1.96 (m, 2 H), 2.14 (m, 1 H), 2.34 (d, J = 16.0 Hz, 1H), 2.42 (m, 1H), .Zi

1090

<td>(m, 4</td><td>H),</td><td> 7.27</td><td>(m,</td><td>2 H);</td><td>Mass Spectrum</td><td>(ESI)</td><td>m / z = 566.0</td>

[Μ + Η] 1 .

EXAMPLE 349

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (ethylsulfonyl) ethyl) -3-methyl- acid 2-oxopiperidin-3yl) acetic

Stage Ά. (3S, 5S, 6R, 8Sj-8-A1Í1-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-cyclopropyl-8-methyl- methanesulfonate

2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io

The title compound was prepared from

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1-

1091 cyclopropyl-2-hydroxyethyl) -3-methylpiperidin-2-one (Example

252, Step A) by a procedure similar to that described in

Example 344, step A.

Stage B. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1 - ((S) -l-cyclopropyl-2- (ethylthio) ethyl) -3 -methylpiperidin-2-one

The title compound was prepared from (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-cyclopropyl-8-methyl-2,3 methanesulfonate , 5,6,7,8 hexahydrooxazolo [3,2-a] pyridin-4-io (Example 349, Step A) and sodium ethathiolate as described in Example 339.

Step C. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (ethylsulfonyl) ethyl) -3methyl- acid 2-oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) —1cyclopropyl-2- (ethylthio ) ethyl) -'3-methylpiperidin-2-one (Example 349, step B) by a procedure similar to that described in

CHLOROFORM-d) δ ppm 7.20 - 7.26 (3 H,

1092

Example 339, step C XH NMR (400 MHz,

m), 7.07 - 7.17

H, (1 H, m), 4.90 (1

H, d, <7 = 10.6 Hz), 4.25 - 4.46 (1 H,

m),

H, (1 H, d,

H, m), 2.92

3.11 - 3.24 (1

2.99 - 3.09 (3

<td>H, m)</td><td> , -1.15 - -0</td><td> .95</td><td> (</td><td>1H, m); Spectrum</td><td>Masses</td><td>(ESI) 552.2</td>

<td></td><td>The examples</td><td colspan="2"> 350</td><td colspan="2">up to 356 prepared to</td><td>from</td>

(3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-cyclopropyl-8-methyl-2,3,5,6,7,8 hexahydrooxazolo methanesulfonate [3,2-a] pyridin-4-io (Example 349, Step A) by a procedure similar to that described in either Example

339 or Example 340, using an equivalent amount of the appropriate reagent in Step

CI

BSK »

<td>Example</td><td>R</td><td>Method</td><td>Reagent, used</td>

<td> 350</td><td>and</td><td>Example 339</td><td>propan-2-thiolate, prepared in situ at from 2-propantiol and sodium carbonate</td>

<td> 351</td><td></td><td>Example 339</td><td>2-methylpropantiolate, prepared in situ at from 2-methylpropan2-thiol and sodium carbonate</td>

<td> 352</td><td> 0to</td><td>Example 340</td><td>cyclobutansulfinic acid sodium salt, prepared as described in Example 343</td>

<td> 353</td><td></td><td>Example 340</td><td>cyclopropansulfinic acid sodium salt, prepared by the method as described in Example 343</td>

<td> 354</td><td>I</td><td>Example 340</td><td>Sodium methanesulphinate</td>

<td> 355</td><td></td><td>Example 339</td><td>2-methylbutan-2-thiolate, prepared in situ at from 2-methylbutan-2thiol and NaH</td>

<td> 356</td><td>s'f '' LL LL</td><td>Example 339</td><td>2,4-di- fluorobencentiolate prepared in situ at from 2,4-di- fluorobencentiol and NaH</td>

INSTITUTO MtÁ'A ..

FROM THE INDUSTRIAL RKOPÍTOAD

1094 EXAMPLE 350

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (isopropylsulfonyl) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 - 7.26 (3 H, m), 7.04 - 7.20 (3 H, m), 6.93 - 6.97 (1 H, m), 6.84 - 6.88 (1 H, m ), 4.93 (1 H, d, <7 = 10.8 Hz), 4.34 (1 H, br. S.), 3.05

- 3.18 (3 H, m), 2.86 (1 H, d, <7 = 13.3 Hz), 2.77 (2 H, d, <7 = 15.3 Hz), 2.46 (1 H, t, · <7 = 13.8 Hz ), 1.86 (2 H, dd, <7 = 13.5,

2.5 Hz), 1.51 (3 H, s), 1.44 (6 H, d, <7 = 6.8 Hz), 0.31 - 0.44 (1 H, m), 0.18 - 2.80 (1 H, m), -0.35-- 0.23 (1 H, m), -Ί.15

- -1.02 (1H, br. S.); Mass Spectrum (ESI) 566.2 [M + H]+.

EXAMPLE 351

2 - ((3R, 5R, 6S) -1 - ((S) -2- (tert-Butyl sulfonyl) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl- 2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 - 7.26 (3 H, m), 7.03 - 7.17 (3 H, m), 6.93 - 6.97 (1 H, m), 6.82 - 6.92 (1 H, m ), 4.95 (1 H, d, <7 = 10.6 Hz), 4.30 (1 H, t, <7 = 12.0 Hz),

3.14 (1 H, ddd, <7 = 13.6, 10.8, 2.6 Hz), 3.07 (1 H, d, <7 = 15.1 Hz), 2.92 (1 H, d, <7 = 11.9 Hz), 2.79 (1 H , d, <7 = 15.1 Hz), 2.72 (1 H, t, J = 9.6 Hz), 2.45 (1 H, t, <7 = 13.8 Hz), 1.88 (2 H, dd, <7 = 13.6, 2.4 Hz), 1.50 (3 H, s), 1.44 (9 H, s), 0.30 - 0.44 (1

1095

H, m), 0.17 - 0.30 (1 Η, m), -0.37 --0.26 (1 Η, m), -1.15 -1.05 (1 Η, m); Mass Spectrum (ESI) 580.2 [M + H]+.

EXAMPLE 352

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 2- (cyclobutyl sulfonyl) -1-cyclopropylethyl) -3-methyl-2oxopiperidin -3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 - 7.27 (3 H,

m), 7.07 - 7.15 (3 H, m), 6.94 - 6.98 (1 H, m), 6.84 - 6.93 (1 H, m), 4.93 (1 H, d, 7 = 10.6 Hz), 4.23 (1 H , t, 7 = 11.3 Hz),

3.77 (1 H, quin, 7 = 8.3 Hz), 3.12 - 3.22 (1 H, m), 3.08 (1 H, d, 7 = 15.1 Hz), 2.70 - 2.83 (3 H, m), 2.53 - 2.69 ( 2 H, m),

2.47 (1 H, t, 7 = 13.8 Hz), 2.27 - 2.40 (2 H, m), 2.04 - 2.19 (2 H, m), 1.73 - 1.97 (2 H, m), 1.51 (3 H, s) , 0.30 - 0.41 (1

H, m), 0.20 - 0.30 (1 H, m), -0.35 - -0.25 (1 H, m), -1.12 -0.95 (1 H, m); Mass Spectrum (ESI) 578.1 [M + H] ”.

EXAMPLE 353

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) l-cyclopropyl-2- (cyclopropyl sulfonyl) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18 - 7.26 (3 H,

m), 7.06 - 7.15 (3 H, m), 6.92 - 6.97 (1 H, m), 6.82 - 6.88 (1 H, m), 4.87 (1 H, d, 7 = 10.6 Hz), 4.44 (1 H , br. s.), 3.11

1096

MEXICAN IMRUTE

FROM LA? TO? EAfl

LEDuETRlAL

- 3.23 (1 H, m), 3.01 - 3.10 (2 H, m), 2.78 (1 H, d, 7 = 15.1 Hz), 2.73 (1 H, br. S.), 2.35 - 2.47 (2 H, m), 1.88 (1 H, dd, 7 = 13.8, 2.6 Hz), 1.76 - 1.85 (1 H, m), 1.49 (3 H, s), 1.24 -

1.35 (2 H, m), 1.03 - 1.16 (2 H, m), 0.32 - 0.44 (1 H, m), 0.20 - 0.30 (1 H, m), -0.33 - -0.21 (1 H, m), -1.02 - -0.98 (1H, br. S.); Mass Spectrum (ESI) 564.1 [M + H]+.

EXAMPLE 354

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (methylsulfonyl) ethyl) -3-methyl acid -2-oxopiperidin-

3 — i 1) acetic

<td></td><td>XH NMR (400</td><td>MHz,</td><td colspan="3">CHLOROFORM-d). δ ppm -1.03 (br s, l H) -</td>

<td> - 7.</td><td>20 (m, 2H)</td><td> 7.27</td><td>(m, 4H);</td><td>Mass Spectrum</td><td>(ESI) m / z =</td>

EXAMPLE 355

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (tert-pentylsulfonyl) ethyl) -3- methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.11 (br s, lH), í'nstüu> C u. ' -ac \ No

OF THE ι? ^ Λ> INC'JSíRíAE · **λ-----

S, 1H), 1.04 (t, (s, 3H), 1.7 3

1097

0.31 (br S, 1H), 0.23 (br s, IH), 0.36 (br> 7.53 Hz, 3H), 1.28 - 1.44 (m ,. 6H), 1.50

1.95 (m, 4H), 2.48 (t,> 13.89 Hz, IH), 2.76 (d,> 15.26 Hz, 2H), 2.91 (d,> 13.11 Hz, IH), 3.04 - 3.23 (m, 2H), 4.28 (t,> 11.15 Hz, IH), 4.90 - 5.07 (m, IH), 6.84 - 6.93 (m, IH),

6.94-7.03 (m, IH), 7.05-7.37 (br s, 6H); Mass Spectrum (ESI) m / z = 594.0 (M + l).

EXAMPLE 356

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- ((2,4-difluorophenyl.) Sulfonyl ) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.06 (br s, lH), -

EXAMPLE 357

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (ethylsulfonyl) ethyl) -3-ethyl- acid 2-oxopiperidin-3yl) acetic

1098

Step A. (3S, 5S, 6R, 8S) -8-A1Í1-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-cyclopropyl-8-ethyl- methanesulfonate

2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1cyclopropyl-2-hydroxyethyl) -3-ethylpiperidin-2-one (Example 253, Step C) by a procedure similar to that described in Example 344, step A.

Stage B. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1 - ((S) -l-cyclopropyl-2- (ethylthio) ethyl) -3 -ethylpiperidin-2-one

1099

The title compound was prepared from (3S, 5S, 6R, 8S) -8-A1Í1-6- (3-chlorophenyl) -5- (4 chlorophenyl) -3-cyclopropyl-8-ethyl-2, 3,5,6,7,8 hexahydrooxazolo [3,2-a] pyridin-4-io (Example 357, Step A) and sodium ethanthiolate by the method described in Example 339. ·

Step C. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (ethylsulfonyl) ethyl) -3ethyl- acid 2-oxopíperídin-3-il) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1cyclopropyl-2- (ethylthio ) ethyl) -3-ethylpiperidin-2-one (Example 357, step B) by a procedure similar to that described in Example 339, step C.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm -0.99 (br s, l H) 0.25 (br s, l H) 0.30 (br s, l H) 0.40 (br s, l H) 0.98 (t, J = 7.46 Hz, 3 H) 1.44 (t,> 7.58 Hz, 3 H) 1.83 (m, 2H) 1.92 2.09 (m, 2 H) 2.41 (t, J = 13.69 Hz, 1 H) 2.71 - 2.88 (m, 2 H)

2.94 (d, J = 13.45 Hz, 1 H) 3.00 - 3.20 (m, 4 H) 4.30 (br. S ,,

IMPI

1100

H) 4.92 (d, 7 = 10.76 Hz, 1 H) 6.81 - 6.87 (m, 1 H) 6.97 (m,

H) 7.08 - 7.26. (m, 3H); 7.30-7.50 (m, 4H); Spectrum

Masses (ESI) m / z = 566 (M + l).

Examples 358 to 360 were prepared from (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4 chlorophenyl) -3-cyclopropyl-8-ethyl-2 methanesulfonate. , 3,5,6,7,8hexahydrooxazolo [3,2-a] pyridin-4-io (Example 357, Step A) by a procedure similar to that described in either Example

339 or Example 340, using an equivalent amount of the appropriate reagent in Step B.

<td>Example</td><td>R</td><td>Method</td><td>Reagent used</td>

<td> 358</td><td>V</td><td>Example 339</td><td>propan-2-thiolate, prepared in if you a from 2-propantiol and NaH</td>

<td> 359</td><td> ¥</td><td>Example 339</td><td>2-methylpropantiolate, prepared in situ at from 2-methylpropan2-thiol and NaH</td>

<td> 360</td><td></td><td>Example 340</td><td>Cyclopropansulphinate</td>

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -

1101

EXAMPLE 358 l-cyclopropyl-2- (isopropylsulfonyl) ethyl) -3-ethyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.01 (br s, lH), 0.27 (br s, lH), 0.29 (br s, lH), 0.39 (br s, lH), 0.98 (t, < 7 = 7.53 Hz, 3H), 1.33 - 1.52 (m, 6H), 1.71 - 1.94 (m, 2H),

2.01 (q, <7 = 7.43 Hz, 2H), 2.42 (t, <7 = 13.79 Hz, 1H), 2.70 -

2.95 (m, 3H), 2.99 - 3.24 (m, 3H), 4.28 (br S, 1H), 4.95 (d, <7 = 10.56 Hz, 1H), 6.83 - 6.94 (m, 2H), 6.94 - 7.05 ( m, 2H),

7.05 - 7.21 (m, 4H); MS (ESI) m / z = 580.0 and 581.9 (M + l).

EXAMPLE 359

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -2- (tert-Butylsulfonyl) -1cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl- 2oxopiperidin-3-yl) acetic XH NMR (500 MHz, CHLOROFORM-d) δ ppm -1.05 (br s, l H) -

Mass Spectrum (ESI) · m / z = 594 (M + l).

INSTITUTE M

FROM THE PRO? ' INDUS

1102

EXAMPLE 360

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (cyclopropyl sulfonyl) ethyl) -3-ethyl- 2oxopiperidin-3-yl) acetic ' XH NMR (500 MHz, CHLOROFORM-d) δ ppm -0.99 (br s, l H) 0.25 (br s, l H) 0.29 (br s, l H) 0.36 - 0.45 (m, 1 H) 0.97 (t,

<td>H) 7</td><td> .35 - 7.45</td><td>(m,</td><td>- 3 H);</td><td colspan="2">Mass Spectrum</td><td colspan="2">(ESI) m / z =</td><td> = 5</td><td> .7 8</td>

(M + l).

EXAMPLE 361

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (ethylsulfonyl) -3-methylbutan-2-yl) -3 acid -methyl-2-oxopiperidin-3 yl) acetic

IMPI

1103

Stage A. (3S, 5S, 6R, 8S) -8-A1I1-6 (3-chlorophenyl) -5- (4-chlorophenyl) -3-isopropyl-8-methyl- trifluoromethanesulfonate

2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io

L-valinol (Sigma Aldrich, St. Louis, MO) (3.64 g), (3S / R, 5R / S, 6R / S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) were heated ) -3-methyltetrahydro-2H-pyran-2-one racemic (3.17g; Example 261, step E) and lithium t-butoxide (0.025g) as a melt for 17hr using an oil bath set to 135 ° C. After cooling, the glassy solid was dissolved in dichloromethane. The organic layer was washed with saturated ammonium chloride solution followed by sodium hydroxide IN solution and then brine. The organic layer was dried over magnesium sulfate and concentrated to give 3.88g of a mixture of diastereomers. A 2.61 g portion (67% of the total) of the mixture ca. 1: 1 obtained above was dissolved in toluene and evaporated to dry three times to remove residual moisture. Dichloromethane (55ml) and 2,6dimethylpyridine (3.3ml, 28.5mmol) were added and the resulting stirred solution was cooled to -50 ° C in a dry ice / acetonitrile bath.

Anhydride was added

trifluoromethanesulfonic (2.4 ml, 14.27 mmol) during the

1104 10 minute course in such a way that the internal temperature never exceeds - 45 ° C. After 40 min, the reaction was quenched by the addition of 2M HCI. The mixture was warmed to room temperature, diluted in dichloromethane, washed with HCI 2

N, water, and finally brine. The organics were dried over magnesium sulfate, filtered, and concentrated to a yellow foam weighing ca. 2.6 g. A portion of this material (1.92 g, 74%) was purified by medium pressure liquid chromatography using a 120 g column, eluting with a gradient from 20 to 100% acetone in hexanes. Fractions containing the fastest eluting diastereomer (less polar) were concentrated to give the title compound as a white foam.

XH NMR (400 MHz, CDC13) δ ppm 0.62 (d, J = 2.4 Hz, 3 H), 0.64 - 0.74 (m, 4 H), 1.51 (s, 3 H), 2.04 (dd, J = 14.1, 3.5 Hz, 1 H), 2.54 - 2.79 (m, 3H), 3.58 (ddd, J = 13.7, 10.8,

3.5 Hz, 1 H), 4.59 (dd, J = 10.2, 4.7 Hz, 1 H), 4.67 (dd, J =

9.2, 4.9 Hz, 1 H), 5.23 - 5.45 (m, 3 H), 5.71 (d, J = 11 Hz, 1 H), 5.83 (ddt, <7 = 17, 9.9, 7.4 Hz, 1 H), 7.06 (t, J = 1.8 Hz, 1 H), 7.11 - 7.16 (m, 1 H), 7.19 (t, <7 = 7.7 Hz, 1 H),

7.23 - 7.32 (m, 3H), 7.39 (br s, 2H); Mass Spectrum (ESI) m / z = 442.2 (M ").

Stage B.

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (41105 Acid)

chlorophenyl) -1 - ((S) -1- (ethylsulfonyl) -3-methylbutan-2-yl) -3 methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-isopropyl-8-methyl-2,3 trifluoromethanesulfonate , 5,6,7,8hexahydrooxazolo [3,2-a] pyridin-4-io (Example 361, step A) by procedures similar to those described in Example 339, using an equivalent amount of ethantiol in Step B.

XH NMR (500 MHz, methanol-d4) δ ppm 0.51 (d, J = 7.1 Hz, 3 H), 0.66 (d, J - 6. 6 Hz, 3 Η), 1.37 (s, 3 H), 1.41 (t, J =

7.5 Hz, 3 H), 2.05 (dd, J = 13.7, 2.9 Hz, 1 H), 2.18 (dq, J =

14.2, 6.9 Hz, 1 H), 2.31 (t, .J = 13.7 Hz, 1 H), 2.62 (d, J =

13.7 Hz, 1 H), 3.00 (d, J = 13.7 Hz, 1 H), 3.14 - 3.24 (m, 3

H), 3.25 - 3.30 (m, 1 H), 3.57 (ddd, J = 13.8, 10.9, 2.9Hz,

H), 4.02 (dd, J = 13.9, 10.5 Hz, 1 Η), 5.12 (d, J = 11Hz,

H), 7.00 (dt, J = 7.3, 1.5 Hz, 1H), 7.04 - 8.17 (m, 7H);

Mass Spectrum (ESI) m / z = 554.2 (M + l).

EXAMPLE 362

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (isopropylsulfonyl) -3-methylbutan-2-yl) -3 acid -methyl-2oxopiperidin-3-yl) acetic

1106

IMPIf

Μ ΕΧΪΟΛ-ΝΟ \ INSTITUTE OF INDUSTRIAL PROPERTY

The title compound was prepared from (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-isopropyl-8-methyl-2,3 trifluoromethanesulfonate , 5,6,7,8 hexahydrooxazolo [3,2-a] pyridin-4-io (Example 361, step A) by procedures similar to those described in

Example 339, using an equivalent amount of propan-2-thiol in Step B.

<td></td><td>XH NMR (500 MHz, methane.</td><td colspan="2">ld4) δ ppm 0.50</td><td>(d,</td><td> <7=6</td><td>> .9 H</td><td>[z,</td>

3.65 f

. 7 (m,

H),

4.01 (dd, J = 13.7, 10.5 Hz, 1 H)

5.13 (d, J

Hz,

H),

6.93 - 7.03 (m, 1H), 7.03 - 8.23 (m, 7H);

Mass Spectrum (ESI) m / z = 568.0 (M + l).

IMPI

1107

EXAMPLE 363

Acid 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4 - gold t in i 1) - T- ((t5) -

3,3-dimethyl-l- (methylsulfonyl) butan-2-yl) -3-methyl-2 oxopiperidin-3-yl) acetic

Step A. (S) -2 - ((2R, 3R) -2- (3-Chlorophenyl) -3- (4-chlorophenyl) -3hydroxypropyl) -N - ((S) -l-hydroxy-3,3- dimethylbutan-2-yl) -2methylpent-4-enamide

(S) -tert-leucinol (0.937 g, 7.99 mmol) and (3S, 5R, 6R) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyltetrahydro-2H- were combined. pyran-2-one (lg, 2.66 mmol; Example 261, Step F) in a reaction flask and heated to 100 ° C. After 2d, the reaction mixture was cooled to RT and dissolved in ethyl acetate. The organic phase was washed with 3 x 10 mL HC1 IN and 1 x 10 mL brine, dried over MgSO4, filter

1108 and concentrated to

IMPIf

MEXICAN INSTITUTE fL

FROM OINDUSTRIAL PROPERTY provide the title compound.

XH-NMR (500

MHz,

CDCI3) δ 7.21-7.10 (series of m, 5H),

Hz,

7.07 (t, J = 1.7

Mass Spectrum (ESI) m / z = 492.2 (M + l).

Stage B. (3S, 5S, 6R, 8S) -8-A1H-3- (tert-butyl) -6 (3-chlorophenyl) -5- (4-chlorophenyl) -8-methyl-2,3 triflate, 5,6,7,8hexahydrooxazolo [3,2-a] pyridin-4-io

To a solution of (S) -2 - ((2R, 3R) -2- (3-chlorophenyl) -3- (4-chlorophenyl) -3-hydroxypropyl) -N - ((S) -l-hydroxy-3,3dimethylbutan -2-yl) -2-methylpent-4-enamide (Example 363, step A, 950 mg, 1,929 mmol) in DCM (19 mL) at -50 ° C 2,6lutidine (896 µΐ, 7.72 mmol) was added followed by solution

IMPI i π r, n Mexican institute i 1 U and DE la fF.OPIEDAD

INDUSTRIAL trifluoromethanesulfonic anhydride (1M DCM, 4.34 mL, 4.34 mmol). The progress of the reaction was monitored by CL / ΕΜ. An additional charge of 450 uL. (2 eq) 2,6-lutidine followed by

1.12 eq of triflic anhydride (2.16 mmol, 2.16 mL of 5 1M solution in dichloromethane). The reaction was allowed to warm to

0 ° C and then emptied into CuSO solution4 sat. ac. To the mixture was added 100 mL of ethyl acetate. The layers were separated and the organic phase was washed with CuSO4 sat. ac. The combined organic layers were concentrated and purified by silica gel column chromatography (eluent: 20 to

50% acetone in hexanes) to provide the title compound.

1H-NMR (500 MHz, DMS0-d6) δ ppm 7.80 -7.42 (series of m,

3H), 7.38-7.28 (series of m, 4H), 7.14 (d, J = 7.6 Hz, IH), 15 5.85 (ddt, J = 17.2, 10.0, 7.3 Hz, IH), 5.61 (d, J = 7.1 Hz,

<td> 20 1.08</td><td>(s,</td><td>3H),</td><td>0.62 (s, 9H); Spectrum</td><td>Masses</td><td>(ESI) m / z =</td>

474.2 (M-) .

IMPI

MEXICAN INSTITUTE

-OF THE PROPERTY

2 - ((3R, 5R, 6S) -5- (3-ChloropheniÍT-

1110

Stage C.

chlorophenyl acid) -1 - ((S) -3,3-dimethyl-l- (methylsulfonyl) butan-2-yl) -

3-methi1-2-oxopiperidin-3-i1) acetic

The title compound was prepared from (3S, 5S, 6R, 8S) -8-allyl-3- (tert-butyl) -6- (3-chlorophenyl) -5- (4-chlorophenyl) -8-methyl triflate -2,3,5,6,7,8-hexahydrooxazolo [3,2a] pyridin-4-io (Example -363, Step B) by procedures similar to those described in Example 340, using an equivalent amount of methanesulphinate sodium in Stage 10 B.

EXAMPLE 364

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (ethylsulfonyl) -3,3-dimethylbutan-2-yl) acid -3-methyl-215 oxopiperidin-3-yl) acetic

I<img file="MX337178B_D2203.tif" />P1

INSTITUTO MEX'OANO t, DE LA PROPIEDAD Κ.Γ. ~~ ·· ^ Ι

INDUSTRIAL '«sa.JSL- ^ Example 340, using a sodium in lili similar to those described in the equivalent amount of ethanesulphinate XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.13 - 7.60 (m, 4

H), 7.04 - 7.12 (m, 2 H), 6.94 - 7.00 (m, 2 H), 5.90 (ddt,

H), 0.71 (s, 9H); Mass Spectrum (ESI) m / z = 550.2 (M + l).

EXAMPLE 365

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -l - ((S)

1- (isopropylsulfonyl) -3,3-dimethylbutan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic

Stage A. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1112 '

1- ((S) -l-hydroxy-3,3-dimethylbutan-2-yl) -3-methylpiperidin-2 one

To a trifluoromethanesulfonate solution of (3S, 5S, 6R, 8S) -8-allyl-3- (tert-butyl) -6- (3-chlorophenyl) -5- (4-chlorophenyl) -8-methyl-2,3, 5,6,7,8-hexahydrooxazolo [3,2a] pyridin-4-io (290 mg, 0.478 mmol; Example 363, Step B) in

1,2-dichloroethane (4.78 mL) 5 mL of NaHCC solution> 3 sat was added. ac. The reaction mixture was heated to 50 ° C by 3d. The reaction mixture was emptied into a separating funnel and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sat. NaHCO3 solution. aq., dried over MgSO4, filtered and the filtrate was concentrated. Purification by column chromatography using 25-35% ethyl acetate in hexanes on a 4g silica gel column provides the title compound.

XH-NMR (500 MHz, DMSO-d6) δ ppm 7.50-7.05 (series of m, 7H), 6.97 (d, J = 7.3 Hz, 1H), 5.87 (dddd, J = 16.9, 10.0, 8.3, 6.6 Hz , 1H), 5.26 (br d, J = 16.6 Hz, 1H), 5.14 (dd, J =

1113

INSTITUTE ΜΣ? '. Ι'Σ7. \ Ό r, <

Dt LA PRa?; TpA? J

<td>2.65 (dd, J = 13.7, 8.</td><td>3 Hz, IH), 2</td><td> .50</td><td>(m, obscured by</td>

<td>solvent), 2.07 (t, J =</td><td>13.5 Hz, IH),</td><td> 1.75</td><td>(dd, J = 13.2, 3.0</td>

<td>Hz, IH), 1.12 (s, 3H), 0</td><td>.63 (s, 9H);</td><td colspan="2">Mass Spectrum (ESI)</td>

Step B. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (isopropylsulfonyl) -3,3-dimethylbutan-2yl) acid -3-methyl-2-oxopiperidin-3-.il) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxy-3,3- dimethylbutan-2-yl) -3-methylpiperidin-2-one (Example 365, step A) by a procedure similar to that described in Example 300, replacing bencentiol with the appropriate amount of propan-2-thiol.

XH-NMR (500 MHz, DMS0-d6) δ ppm 12.36 (s, IH), 7.81 (br s, IH), 7.48 (br s, IH), 7.25 (br s, IH), 7.22 (t, J = 7.8

Hz, IH), 7.15 (ddd, J = 7.8. 2.0, 0.7 Hz, IH), 7.04 (t, J =

1.7 Hz, IH), 7.00 (br d, J = s 7.8 Hz, IH), 5.05 (d, J = 11.2

Hz, IH), 3.90 (dd, J = 13.7, 11.0, 2.6 Hz, IH), 3.70 (ddd, J = 13.7, 11.0, 2.6 Hz, IH), 3.45 (m, 2H), 3.12 (dd, J = 13.4, 2.0, IH), 2.97 (d, J = 13.9 Hz, IH), 2.52 (m, solvent obscured), 2.14 (t, J = 13.2 Hz, ÍH), 2.03 (dd, J = 13.4 Hz,

IH), 1.32 (d, J = 6.8 Hz, 3H), 1.31 (d, J (s, 3H), 0.62 (s, 9H); Mass Spectrum

6.6 Hz, 3H), 1.23

1114

582.2 (M + l).

EXAMPLE 366

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -l-cyclopropyl-2- (pentan-3-ylsulfonyl) ethyl) acid -3-methyl-2oxopiperidin-3-yl) acetic

Step A. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1- ((S) -l-cyclopropyl-2-mercaptoethyl) -3-methylpiperidin- 2-one

To a methanesulfonate solution of (3S, 5S, 6R, 8S) -8alyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-cyclopropyl-8-methyl-

2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io (370 mg; Example 349, Step A) in DMF (1.6 mL) sodium acid sulfide (105 mg) was added , 1.88 mmol). After, shake at RT

1115

overnight, the reaction was quenched (NH solution4C1 sat.

aq.), extracted (2 * EtOAc) and the combined organics washed with brine (3 *). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, gradient elution from 10% to 40% EtOAc in hex) provides the title compound.

Stage B. (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1 - ((S) -l-cyclopropyl-2- (pentan-3-ylthio) ethyl) -3methylpiperidin-2-one

CI

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2-mercaptoethyl) -3methylpiperidin-2 -one (49 mg, 0.10 mmol; Example 366, Step A) and 3-bromopentane (51 μΐ, 0.41 mmol) in DMF (0.52 mL) 60% sodium hydride in mineral oil (17 mg,

0.41 mmol) at 25 ° C. The reaction was stirred at 25 ° C for 1 hr.

1116

OF THE INDUSTRIAL PROHcuAU -. then heated to 60 ° C. After stirring at 60 ° C overnight, the reaction was quenched (10% aq citric acid), extracted (2xEtOAc), and washed (3x brine). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 9% and 18% EtOAc / hex) provides the title compound.

Step C. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2- (pentan-3ylsulfonyl) ethyl) acid - 3-methyl-2-oxopiperidin-3-yl) acetic

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((S) -1cyclopropyl-2- (pentan -3-ylthio) ethyl) -3-methylpiperidin-2-one (Example 366, Step B) by procedures similar to those described in Example 71, Step F.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 - 7.34 (3 H,

m), 7.06 - 7.16 (3 H, m), 6.93 - 6.98 (1 H, s), 6.83 - 6.90

s), 1.06 - 1.19 (6 H, m), 0.32 - 0.42 (1 H, m), 0.18 - 0.28 (1 H, m), -0.35 - -0.25 (1 H, m), -1.12 - -1.02 (1H, m);

Mass Spectrum (ESI) m / z = 594.2 [M + H].

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1117

EXAMPLE 367

1- ((S) -isopropylsulfinyl) butan-2-yl) -3-methyl-2-oxopiperidin

3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4 chlorophenyl) —1 - ((S) -1 - ((R) -isopropylsulfinyl) butan -2-yl) -3 methyl-2-oxopiperidin-3-yl) acetic; more polar isomer.

Stage A. 2 - ((3R, 5R, 6Ξ) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) —1 - (isopropylthio) butan-2-yl) -3- methyl-2-oxopiperidin-3 yl) methyl acetate

The above compound was obtained from 2 ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxybutan-2-yl) -3- methyl-2-oxopiperidin-3-yl) methyl acetate (Example 186, Step A, 187 mg, 0.391 mmol) and propan-2thiol (119 mg, 1.56 mmol) by a procedure similar to

1118

INSTITUTE ~~ r.

ΟΞ LA F? .G?; 3.DAD- t '.-.- N1'

IT-ípUSTFJAL xa 'Ito * described in Example 300, Step A, using the appropriate amount of propantiol and reacting for a total of 3h. Purification of the residue by chromatography on silica gel (12 g, SiO2.5% to 20% EtOAc / Hex) provides the title compound as a pale yellow oil.

XH NMR (400 MHz, .CHLOROFORM-d) δ ppm 7.22 (d, J = 8.4

Hz, 2H), 7.05 - 7.18 (m, 2H), 7.02 (t, J = 1.7 Hz, 2H), 6.79 (td, <7 = 1.4, 7.4 Hz, IH), 4.66 (d, <7 = 10.6 Hz , IH), 3.70 (s, 3H), 3.41 (dd, J = 11, 12.7 Hz, IH), 3.16 (ddd, J = 3.1,

<td>3H);</td><td>Spectrum of Ma</td><td colspan="2">sas (ESI) m / z = 558.</td><td>1 [M</td><td>-Η] ',</td><td> 560.</td><td>1 [M + H] ”.</td>

Stage B. 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1 - ((Sj-isopropylsulfinyl) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) methyl acetate and 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-clo.phenyl) -1- ((S) -1 - ((R) isopropylsulfinyl) methyl butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetate

1119

3-Chlorobenzoperoxoic acid (45.4 mg, 0.203 mmol) was added to a solution of .2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) - Methyl 1- (isopropylthio) butan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetate (136 mg, 0.253 mmol; Example 367, Step A) in DCM (3 mL) at 0 ° C. After lh at 0 ° C the reaction was monitored by CLEM (MS (ESI) 552.2 [M + H]1,

554.0 [MH]) which shows conversion at 60%. At this time 0.2 eg was added. additional 3-chlorobenzoperoxoic acid. The reaction was monitored again after 2 hours showing 85% conversion and was quenched at this time with sat. NaHCO3 solution. ac. The solution was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (12 g, SiO2, 10-60% EtOAc / hexane, 50 min) to give the title compounds as a 2: 1 mixture of diastereomers, as a pale yellow oil.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 - 7.29 (m,

4H), 7.20 - 7.26 (m, 2H), 7.19 - 7.20 (m, 1H), 7.04 - 7.20

1120 (m, 6H), 6.95 - 7.02 (m, 2H), 6.82

4.90 (m, 1H), 3.62 - 3.74 (m, 5H), 3.37 - 3.48 (m, 1H), 3.07 - 3.32 (m, 3H), 2.59 - 2.95 (m, 6H), 1.93 - 2.33 (m, 5H ),

1.47 - 1.74 (m, 3H), 1.22 - 1.42 (m, 17H), 0.79 - 0.95 (m, 2H), 0.37 - 0.56 (m, 4H.); Mass Spectrum (ESI) m / z =

552.2 [MH] ”, 554.0 [M + H] ~.

Step C. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 - ((S) -isopropylsulfinyl) butan-2-yl acid ) -3methyl-2-oxopiperidin-3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -l - ((S) -l- ( (R) isopropylsulfinyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic; more polar isomer

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 - ((S) -isopropylsulfinyl) butan-2-yl ) -3methyl-2-oxopiperidin-3-yl) methyl acetate and 2 - ((3R, 5R, 6S) 5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 - (((R) isopropylsulfinyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) methyl acetate (100 mg, 0.181 mmol, as a 2: 1 mixture of isomers; Example 267, Step B) in MeOH / THF / H2O (1 mL / 2 mL / Ι mL) lithium hydroxide (43.3 mg, 1,810 mmol) was added. The reaction mixture was allowed to stir for 18h. After this period, the reaction mixture was acidified with HC1 IN and extracted with EtOAc (3 x 10 mL); The organics were grouped,

1121 washed with concentrated in «

preparatory of

INSTITUTE * '.re> V'7;. <1 OF THE i V '—7? ·' '

IN .. nu brine, dried (MgSO4), filtered “and empty. The crude material was purified by reverse phase HPLC ^ (Gemini ™ Prep Ci column8 5mm;

Phenomenex, Torrance, CA; 25% gradient elution to

55% MeCN in water, where both solvents contain 0.1% TFA, min method) to provide one of the title compounds as the most polar isomer (tR = 21.45 min) XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (d, J = 8.0 Hz,

2H), 7.00 - 7.17 (m, 4H), 6.80 - 6.98 (m, 2H), 4.80 (d, J =

10.8 Hz, 1H), 3.53 - 3.73 (m, 1H), 3.11 - 3.30 (m, 2H), 2.68

- 3.00 (m, 4H), 1.97 - 2.29 (m, 3H), 1.40 - 1.54 (m, 4H),

1.36 (d, J = 6.9 Hz, 3H), 1.28 (d, J = 6.9 Hz, 3H), 0.41 (t, J = 7.5 Hz, 3H); Mass Spectrum (ESI) 538.2 [MH]-, 540.2 [M + H]+.

The additional elution from Example 367 provides the least polar isomer:

EXAMPLE 368

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) 1 - ((S) -isopropylsulfinyl) butan-2-yl) - 3-methyl-2-oxopiperidin-

3 — yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1 - ((R) -isopropylsulfinyl) butan- 2-yl) -3methyl-2-oxopiperidin-3-yl) acetic;

1122

Least polar isomer (tR = 21.45 min).

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 - 7.27 (m,

2H), 7.10 (td, J = 7.9, 15.7 Hz, 4H), 6.96 (s, IH), 6.81 (d,

<td> 14.3</td><td>Hz,</td><td>3H)</td><td>; Espe</td><td colspan="2">ctro of</td><td>Masses (ESI)</td><td>m / z</td><td> =538.2</td><td>[Μ-H] ',</td>

540.2 [M + H].

EXAMPLE 369

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((2S, 3S) -2- (methylsulfonyl) pentan-3-yl) acid -2-oxopiperidin-3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((2R, 3S) -2 ( methylsulfonyl) pentan-3-yl) -2-oxopiperidin-3-yl) acetic

1123

Step A. (3S, 5S, 6R, 8S) -8-A1I1-6 (3-chlorophenyl) -5- (4-chlorophenyl) -3-ethyl-2,8-dimethyl- 4-methylbenzenesulfonate

2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io

To a solution of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((3S) -2-hydroxypentan-3-yl) -3methylpiperidin-2 -one (2.25 g, 4.89 mmol; Example 151, Step

C) in toluene (65 mL), ptoluenesulfonic acid monohydrate (930 mg, 4.89 mmol) was added. After heating to reflux using a Dean-Stark trap for 2.5 hr, the reaction was concentrated under reduced pressure to provide the title compound as a pale yellow powder.

1124

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Stage B. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chloro

3-methyl-l - ((2S, 3S) -2- (methylsulfonyl) pentan-3-yl) piperidin-2 one and (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6 - (4-chlorophenyl) -3methyl-1 - ((2R, 3S) -2- (methylsulfonyl) pentan-3-yl) piperidin-2-one

The reaction was set up in a high pressure reaction vessel. To a 4-methylbenzenesulfonate solution of (3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3 ethyl-2,8-dimethyl-2,3 , 5,6,7,8-hexahydrooxazolo [3,2-a] pyridine-

4-io (0.200g, 0.325mmol; Example 370, step A) in acetonitrile (2ml) added sodium methanesulphinate (0.166g, 1.627mmol) at 25 ° C. Then the reaction was heated to 110 ° C for 24h. The reaction was quenched with NH solution4C1 sat. aq., extracted (2xEtOAc) and washed (2 * brine). The combined organic layers were dried (Na2SW4) and concentrated under reduced pressure. Purification by chromatography on silica gel (40 g SiO2, gradient elution, 20% to 40% EtOAc in hexanes) provides the title compounds as a mixture of two stereoisomers.

IMPI

Stage C.

acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-

1125 chlorophenyl) -3-methyl-l - ((2S, 3S) -2- (methylsulfonyl) pentan-3-yl)

2-oxopiperidin-3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3Clorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((2R, 3S) -2 (methylsulfonyl) pentan-3-yl) -2-oxopiperidin-3-yl) acetic

The title compound was obtained from a mixture of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((2S, 3S) -2- (methylsulfonyl) pentan-3-yl) piperidin-2-one and (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((2R, 3S) -2- (methylsulfonyl) pentan-3-yl) piperidin-2-one (Example 370, Step B) by a procedure similar to that described in Example 71, Step F. The crude product was purified by reverse phase preparatory HPLC (♦ · TM column

Gemini Prep Cig 5pm; Phenomenex, Torrance, CA; eluent: 40 to 60% acetonitrile, water, 0.1% TFA, gradient elution) to provide the title compound as the first isomer of elution as a single stereoisomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.46 (t, J = 7.5 Hz,

<td>6.97 (m,</td><td>1 HOUR)</td><td> 7.07</td><td> - 7.</td><td>18. (m,</td><td>2 H),</td><td>7.27 (m,</td><td>4 H); Spectrum</td>

<td>of masses</td><td>(ESI)</td><td>m / z</td><td> = 540</td><td>(M + l)</td><td></td><td></td><td></td>

ws »axr.¿ ·

1126

EXAMPLE 370

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -2- (ethylsulfonyl) pentan-3-yl) -3- methyl-2-oxopiperidin-

3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4 chlorophenyl) -1 - ((2R, 3S) -2- (ethylsulfonyl) pentan-3 -yl) -3-methyl2-oxopiperidin-3-yl) acetic; first isomer of elution

(3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-ethyl-2,8-dimethyl-2,3,5,6,7, methylbenzenesulfonate 8hexahydrooxazolo [3,2-a] pyridin-4-io. (Example 369, Step A) by a similar procedure to that described in Example 369, replacing sodium methanesulphinate in Step B with sodium ethanesulphinate. The crude product was purified by reverse phase preparative HPLC (Gemini ™ Prep Ci column8 5mm; Phenomenex, Torrance, CA; eluent: 40 to 60% acetonitrile, water, 0.1% TFA, gradient elution) to provide the title compound as the first isomer of elution as a single stereoisomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.45 (t, J = 7.53 Hz,

Η) 1.41 (t, 7 = 7.53 Hz,

Η)

1.48 1.62

112 7

1.92 (m, 2H) 2.29 - 2.43 (m, 2H) 2.70 (0, ^ 7 = 15.45 "

2.92 - 3.19 (m, 5H) 3.49 - 3.56 (m, 1H) 5.02 (d, 7 = 10.56

Hz, 1H) 6.84 (dt, 7 = 6.99, 1.88 Hz, 1H) 6.95 (t, 7 = 1.96 Hz,

H) 7.08 - 7.19 (m, 3H) 7.25 (br s, 3H); Mass Spectrum (ESI) m / z = 554 (M + l).

The additional elution provides:

EXAMPLE 371

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2R, 3S) -2- (ethylsulfonyl) pentan-3-yl) -3- methyl-2-oxopiperidin3-yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4 chlorophenyl) -1 - ((2S, 3S) -2- (ethylsulfonyl) ) pentan-3-yl) -3-methyl2-oxopiperidin-3-yl) acetic; second elution isomer

The title compound was obtained in Example 370 as the second elution isomer.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.20 (t, 7 = 7.63 Hz,

H) 1.12 - 1.30 (m, 3 H) 1.30 - 1.45 (m, 6 H) 1.45 - 1.60 (m, 1 H) 1.71 - 1.80 (m, 1 H) 1.85 - 1.98 (m, 1 H) 2.40 (t ,

IMPI

7 = 13.79 Hz, 1 H) 2.63 (d, 7 = 15.26 Hz, 1 H) 2.86 -3.09 (m, 5

1128

H) 4.05 - 4.19 (m, 1H) 4.93 (d, 7 = 10.76 Hz, 1H) 6.78 (dt,

7 = 6.90, 1.93 Hz, 1H) 6.89 (t, 7 = 1.96Hz, 1H) 6.95 - 7.11 (m, 4H) 7.11 - 7.25 (m, 2H); Mass Spectrum (ESI) m / z =

554 (M + l).

EXAMPLE 372

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (N- (oxetane-3-yl) sulfamoyl ) butan-2-yl) -2oxopiperidin-3-yl) acetic.

Step A. 2 - ((3R, 5R, 6S) -l - ((S) -l- (benzylthio) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl -2-oxopiperidin-3yl) methyl acetate

<td></td><td>1129J MEXICAN INSTITUTE V Ά FROM THE ΓλΟ? '- OD \ ~ INDUSTRIAL</td>

<td>To one</td><td>solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-</td>

chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetate from Example 186, Step A) in benzyl mercaptan (0.106 cyanomethylene tributylphosphoran) The solution was heated to concentrated in vacuo.Color chromatography on silica gel in hexanes).

methyl (214.4 mg, 0.448 mmol; toluene (2.0 mL) added mL, 0.90 mmol), followed by 0.8 96 mmol; TCI).

3.75 hours, after the residue by 0% to 50% EtOAc titer as oil (0.235 mL, Ί00 ° C by purification (12 g SiO2, provides the compound of

Step B. (S) -2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3- (2-methoxy-2-oxoethyl) -3-methyl-2 -oxopiperidin-ll) butan-l-sulfonic

To a solution

2 - ((3R, 5R, 6S) -1 - ((S) -1 (benzylthio) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxopiperidin -3-yl) methyl acetate (1.31 g, 2.24 mmol; Example 372, Step A) in acetic acid (9.5 ml) and water

1130

IMPI

CELA MEXICAN INSTITUTE-INDUSTRIAL PROPERTY (1.0 ml) hydrogen peroxide (31.3% solution in water, 0.23 ml, 2.35 mmol) was added. The resulting solution was stirred at room temperature for. 3 hours, then chlorine gas was bubbled into the reaction for one minute. After stirring at room temperature for one hour, the reaction was concentrated in vacuo, then some mL of anhydrous benzene was added and the solvent was removed under reduced pressure on a rotary evaporator. This procedure was repeated several times to provide the title compound as a yellow solid. This crude material was used directly in the next stage without purification.

Stage C. 2 - ((3R, 5R, 6S) -. 5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (N- (oxetane-3- yl) sulfamoyl) butan-2-yl) -2oxopiperidin-3-yl) methyl acetate

To a solution of (S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2-methoxy-2-oxoethyl) -3-methyl2- oxopiperidin-l-yl) butan-l-sulfonic (189.8 mg, 0.35 mmol;

1131

Example 372, Step B) Oxalyl chloride (0.061 mL, 0.70 mmol) was added in dichloromethane (5.0 mL), followed by DMF (2 drops). The reaction was stirred at room temperature for 3.5 hours, then concentrated in vacuo. The sulfonyl chloride intermediate was dissolved in dichloromethane (5.0 mL), then treated with 3-oxetanamine (50.0 mg, 0.684 mmol; Pharmablock R & D Co. Ltd., Nanjing, China) and N, N-diisopropylethylamine (0.122 mL, Q.699 mmol). After stirring at room temperature for 16 hours, the reaction was quenched with methanol (2.0 mL), then concentrated in vacuo. Purification of the residue by chromatography on silica gel (4 g S1O2, 0% -50% EtOAc in hexanes) provides the title compound as a colorless oil.

Stage D.

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl-l - ((S) -1- (N- (oxetan-3-yl) sulfamoyl ) butan

2-yl) -2-oxopiperidin-3-yl) acetic

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (N- (oxetane-3- yl) sulfamoyl) butan2-yl) -2-oxopiperidin-3-yl) methyl acetate (41.1 mg, 0.069 mmol; Example 372, Step C) in THF (2: 0 ml) and MeOH (1.0 ml) hydroxide was added lithium 1 N (3.0 mi,

3.0 mmol). The suspension was stirred at room temperature for 15 hours, then made acidic to pH 4 using 1N HC1, and then

1132

MEXICAN INSTITUTE

DB THE PROPERTY VHCsrc & a INDUSTRIAL Tíí—

<td>concentrated in</td><td>empty. , The purification of the residue by</td>

<td>chromatography</td><td>in silica gel (4 g SiO2, 5 to 25%</td>

<td>gradient of</td><td>a 1: 6.5 MeOH / acetone mixture in hexanes)</td>

provides the title compound. The material was further purified by reverse phase preparative HPLC (Eclipse Plus Cis column, 30 x 250 mm, 5 pm; Agilent, Santa Clara, CA) (eluent: 0.1% TFA in acetonitrile / water, gradient 30% to 60% over 25 min) to provide the title compound, as a white solid.

- 6.97 (m, 1H) 7.02 (s, 1H) 7.10 - 7.19 (m, 3H) 7.28 (br s, 3H); Mass Spectrum (ESI) m / z = 583.2 [M + H]+.

Examples 373 and 374 were prepared from (S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2methoxy-2-oxoethyl) ) -3-methyl-2-oxopiperidin-l-yl) butan-1-sulfonic (Example 372, Step B) by procedures similar to those described in Example 372, replacing

3-oxetanamine in Step B with the appropriate reagent.

1133

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 373</td><td></td><td>(3-methyloxetan-3-yl) methanamine (Pharmablock R & D Co. Ltd., Nanjing, China)</td>

<td> 374</td><td>to go7</td><td>oxetane-3-ylmethanamine (Pharmablock R & D Co. Ltd., Nanjing, China)</td>

. EXAMPLE 373

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (N - ((3-methyloxetan-3- il) methyl) sulfamoyl) butan2-yl) -2-oxopiperidin-3-yl) acetic XH NMR (500 MHz, methanol-d ^ δ ppm 0.42 (t, <7 = 7.58 Hz, 3 H) 1.25 (s, 2 H) 1.34 (s, 3 H) 1.39 (s, 3 H) 1.53 (ddd, <7 = 14.24, 7.76, 3.18 Hz, 1 H) 1.97-2.08 (m, 2 H) 2.16 (s, 1 H) 2.18 (s, 1 H) 2.29 (t, J = 13.69 Hz, 1 H) 2.57 - 2.64 (m, 1H) 2.95 (d, <7 = 13.45 Hz, 1H) 3.00 - 3.06 (m, 1H) 3.19 (br s, 1H) 3.35 - 3.42 (m, 1H) 4.04 (t, <7 = 12.35 Hz, 1 H) 4.37 (d, <7 = 6.11 Hz, 1 H) 4.54 (d, <7 = 6.11 Hz, 1 H) 4.91 (d, <7 = 10.76 Hz, 1 H) 6.96 ( d, <7 = 7.34 Hz, 1 H) 7.03 (s, 1 H) 7.11 - 7.2 0 (m, 3 H) 7.28 (br s, 3 H); Mass Spectrum (ESI) 611.2 [M + H] ".

Acid

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -31134

EXAMPLE 374 methyl-1 - ((S) -1- (N- (oxetan-3-ylmethyl) sulfamoyl) butan-2-yl) -2 oxopiperidin-3-yl) acetic XH NMR (500 MHz, methanol-ch) δ ppm 0.41 (t, J = 7.58 Hz, 3

H) 1.38 (s, 3 H) 1.46 - 1.59 (m, 1 Η) 2.01 - 2.08 (m, 2 H)

2.28 (t, J = 13.69 Hz, 1 H) 2.60 (d, J = 13.69 Hz, 1 H) 2.94 (d,

J = 13.69 Hz, 1 H) 3.03 (d, 7 = 12.47 Hz, 1 H) 3.10 - 3.25 (m, 3

H) 3.34 - 3.42 (m, 2H) 3.95 - 4.07 (m, 1H) 4.42 - 4.51 (m,

H) 4.76 - 4.82 (m, 2H) 4.88 - 4.91 (m, 1H) 6.95 (dt,

J = 7.03, 1.62 Hz, 1 H) 7.00 - 7.04 (m, 1 H) 7.09 - 7.18 (m, 3

H) 7.28 (br s, 3H); Mass Spectrum (ESI) 597.1 [M + H]+.

. EXAMPLE 375 Acid 2- ((3R, 5R, 6S) -1 - ((S) -2- (N- (tert-Butyl) sulfamoyl) -1cyclopropylethyl) -5- (3-chlorophenyl) -6- (4- chlorophenyl) -3-methyl-2oxopiperidin-3-yl) acetic

1135

Step A. (3S, 5R, 6S) -3-Allyl-l - ((S) -2- (benzylthio) -1cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methylpiperidin-2 -ona

A mixture of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2-hydroxyethyl) -3methylpiperidin-2-one (1.35 g, 2.94 mmol; Example 252, Step A), benzyl mercaptan (0.691 ml, 5.89 mmol) and 2-

<td colspan="2">(tributylphosphoranilidene)</td><td colspan="4">in acetonitrile (1,579 mi,</td><td> 5.89</td>

<td>mmol) was heated to</td><td colspan="2">100 ° C by</td><td>2h. Mix</td><td>of</td><td colspan="2">reaction is</td>

<td>cooled down to TA, and</td><td>I know</td><td>extracted</td><td>with 80 mL</td><td>of</td><td>EtOAc.</td><td>The</td>

<td>organic combined</td><td>I know</td><td>washed</td><td>with solution</td><td>of</td><td>NH4C1</td><td>sat.</td>

ac. and brine, dried over Na2SO4, filtered and the filtrate was concentrated. The crude product was purified by chromatography on silica gel eluting with 0 to 50% EtOAc / hexane to give the title compound.

Mass Spectrum (ESI) m / z = 564.1 (M + l).

Stage

1136

OF THE PROr

S) -2 Butyl) sulfamoyl) -1-cyclopropylethyl) -5- (3 chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic

To a solution of (3S, 5R, 6S) -3-allyl-l - ((S) -2 (benzylthio) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methylpiperidin -2-one (0.075 g, 0.133 mmol; Example 375, Step A) in 5 mL of a MeCN / HOAc / H mixture2Or (40: 1.5: 1) at 0 ° C 1,3-dichloro-5,5-dimethylimidazolidin-2,4-dione (0.052 g, 0.266 mmol) was added in portions (Alpha Aesar, Ward Hill, MA). The reaction mixture was stirred at 0 ° C 5 ° C for 2h. This solution was added over a mixture of tertbutylamine (97 mg, 140 pL, 5.0eq.) And DIEA (5.0eq.) In 2 mL of DCM at 0 ° C. The resulting mixture was stirred at room temperature for 3h. Solvents were removed under reduced pressure and the residue was purified by chromatography on silica gel eluting with 30 to 80% EtOAc / hexane to provide the corresponding sulfonamide. This sulfonamide was converted to the title compound by a procedure similar to that described in Example 71, Step F. The crude product was purified by reverse phase HPLC (40 to 90% acetonitrile in water, gradient with 0.1% TFA) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.09 (br s, 1 Η),

-0.26 (br s, 1 Η), 0.19 - 0.50 (m, 2 Η), 1.42 (s, 9 Η),

I<img file="MX337178B_D2250.tif" />CHEEP**

INDUSTRIAL --2.97 - 3.26

1137

1.54 (s, 3 Η), 1.88 (d, 7 = 13.30 Hz,

Hz, 1 H), 2.76 (d, 7 = 15.26 Hz, 1 H),

4.14 - 4.52 (m, 2H), 4.82 (d, 7 = 10.76 Hz, 1H), 6.86 (d, 7 = 5.87 Hz, 1H), 6.97 (s, lH), 7.06 - 7.22 (m, 3 H), 7.29 (br s, 3H). Mass Spectrum (ESI) m / z = 595.2 (M + l).

Examples 376 to 382 were prepared from (3S, 5R, 6S) -3-allyl-l - ((S) -2- (benzylthio) -1-cyclopropylethyl) -5 (3-chlorophenyl) -6- ( 4-chlorophenyl) -3-methylpiperidin-2-one (Example 375, Step A) by procedures similar to those described in Example 375, replacing tertbutylamine in Step B with the appropriate reagent.

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 376</td><td>^ NH</td><td>methylamine</td>

<td> 377</td><td></td><td>dimethylamine</td>

<td> 378</td><td>^ NH</td><td>isopropylamine</td>

<td> 37 9</td><td>0 N</td><td>morpholine</td>

<td> 380</td><td> 0</td><td>INO'JS'iíüAL. M: Yes-.- piperidine</td>

<td> 381</td><td>Q</td><td>pyrrolidine</td>

<td> 382</td><td>i</td><td>Azetidine</td>

EXAMPLE 376

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N-methylsulfamoyl) ethyl) -3- methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.13 - -0.88 (m, 1

H), 7.19 - 7.27 (m, 3H). Mass Spectrum (ESI) m / z =

553.0. (M + l).

Acid

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S.) 1139

EXAMPLE 377

l-cyclopropyl-2- (N, N-dimethylsulfamoyl) ethyl) -3-methyl-2 oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.07 (br s, 1 H),

-0.28 (br s, 1H), 0.18 - 0.44 (m, 2H), 1.53 (s, 3H), 1.87 (dd, <7 = 13.79, 2.84 Hz, 2H), 2.50 (t, J = 13.79 Hz, 1H), 2.60 (br s, 1H), 2.73 - 2.84 (m, 2H), 2.90 (s, 6H), 3.07 -

3.19 (m, 2H), 4.19 (t, J = 12.42Hz, 1H), 4.83 (d, <7 = 10.56

Hz, 1H), 6.83 - 6.89 (m, 1H), 6.95 (s, 1H), 7.07 - 7.16 (m, 3H), 7.27 (br s, 3H). Mass Spectrum (ESI) m / z = 567.0 (M + l).

. EXAMPLE 378

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (N-isopropylsulfamoyl) ethyl) -3- acid methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.08 (br s, 1 H),

H), 4.10 - 4.46 (m, 1H), 4.81 (d, <7 = 10.56 Hz, 1H), 6.84 (d, <7 = 6.46 Hz, 1H), 6.95 (s, 1H), 7.06 - 7.16 (m, 3H),

7.27 (br s

H). Mass Spectrum (ESI) m / z

1140

= 581.2 (M + l).

EXAMPLE 379

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (morpholin sulfonyl) ethyl) -3-methyl- 2-

<td colspan="4">oxopiperidin-3-yl) acetic</td><td rowspan="2">1.06 (br</td><td rowspan="2">s, 1</td><td rowspan="2">H),</td>

<td></td><td>XH NMR</td><td> (400</td><td>MHz, CHLOROFORM-d) δ ppm -</td>

6.86 (m, 3 (d, 7 = 7.04

7.06 - 7.16

Hz, 1H), 6.95 (s, 1H),

H),

7.21

7.33 (m, 3H). Spectrum

Masses (ESI) m / z =

609.2 (M + l).

EXAMPLE 380

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) l-cyclopropyl-2- (piperidin-1-ylsulfonyl) ethyl) - 3-methyl-2oxopiperidin-3-yl) acetic

<td>XH NMR</td><td> (400</td><td>MHz,</td><td>CHLOROFORM-d)</td><td>δ</td><td colspan="2">ppm -1.</td><td>09 (br s, 1H)</td>

1141

2.81 (m, 2 Η), 3.07 - 3.20 '(m, 2 Η),

Η), 4.13 (d, <7 = 13.11 Hz, 1 Η), -4.85

3.24 (t, <7 = 5.28 Hz, 4 (d, <7 = 10.76 Hz, 1 Η),

6.8 6 (d, <7 = 7.04 Hz, 1H),. 6.94 (s, 1 Η), 7.07 - 7.18 (m, 3

Η),

7.23 - 7.38 (m, '3H). Mass Spectrum (ESI) m / z =

607.2 (M + l).

EXAMPLE 381

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (pyrrolidin-1-ylsulfonyl) ethyl) acid - 3-methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -1.08 (br s, 1 Η),

-0.28 (br s, 1 Η), 0.17 - 0.42 (m, 2 Η), 1.52 (s, 3 Η),

1.81 (br s, 1H), 1.88 (dd, <7 = 13.79, 2.84 Hz, 1 Η), 1.94-

2.01 (m, 4 Η), 2.50 (t, <7 = 13.79 Hz, 1 Η), 2.62 (br s, 1 Η),

2.78 (d, <7 = 15.06 Hz, 1 Η), 2.86 (d, <7 = 12.13 Hz, 1 Η), 3.05

- 3.20 (m, 2 H), 3.28 - 3.45 (m, 4 Η), 4.24 (br s, 1 Η),

4.84 (d, <7 = 10.56 Hz, 1. Η), 6.89 (d, <7 = 6.65 Hz, 1 Η), 6.98 (s, 1 H), 7.07 - 7.19 (m, 3 Η), 7.21 - 7.37 (m, 3H).

Mass Spectrum (ESI) m / z = 593.0 (M + l).

EXAMPLE 382

2 - ((3R, 5R, 6S) -1 - ((S) Ύ- (Azetidin-1-ylsulfonyl) -1-cyclopropylethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl acid -2oxopiperidin-3-yl) acetic

XH NMR (400 MHz

CHLOROFORM-d) δ ppm -1.07 (br s, 1 Η),

1142

7.07 - 7.17 (m, 3 Η), 7.24 - 7.28 (m, 3 H). Spectrum

Masses (ESI) m / z = 579.0 (M + l).

EXAMPLE 383

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2 - ((N, N-dimethylsulfamoyl) amino) acid) ethyl) -3-methyl-2 oxopiperidin-3-yl) acetic

Step A. (3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -ΙΕ (1S) -l-cyclopropyl-2 - [(dimethylsulfamoyl) amino] ethyl] -3-methyl -

3- (prop-2-en-l-yl) piperidin-2-one

IMPI

1143

I Η

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1cyclopropyl-2-hydroxyethyl) -3-methylpiperidin-2-one (Example 252, Step A) and N, N-dimethylsulfamide (TCI America, Portland, OR) following a similar procedure to that described in Example 202, Step C.

Mass Spectrum (ESI) m / z = 561.5 (M + l).

Step B. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-2 - ((N, Ndimethylsulfamoyl) amino) acid) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic

The title compound was prepared from (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - [(1S) -1cyclopropyl-2 - [(dimethylsulfamoyl) amino] ethyl] -3-methyl-3- (prop2-en-l-yl) piperidin-2-one (Example 383, Step A) following a similar procedure to that described in Example 226, Step D.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm -0.34 (br s, 1H),

1144

7.03 - 7.21 (m, 4H), 7.24 - 7.28 for Masses (ESI) m / z = 582.0 (M + l).

EXAMPLE 384

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2 - ((N, N-dimethylsulfamoyl) (methyl ) amino) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic

Step A. (3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 [(IS) -l-cyclopropyl-2 - [(dimethylsulfamoyl) (methyl) amino] ethyl] -

3-methyl-3- (prop-2-en-l-yl) piperidin-2-one

1145

The title compound was prepared from (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - [(1S) -1cyclopropyl-2 - [(dimethylsulfamoyl) amino] ethyl] -3-methyl-3- (prop2-en-l-yl) piperidin-2-one (Example 383, Step A) following a procedure similar to that described in Example 264.

Step B. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - (((S) -l-cyclopropyl-2 - ((N, Ndimethylsulfamoyl) (methyl ) amino) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic

The title compound was prepared from (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - [(1S) -1cyclopropyl-2 - [(dimethylsulfamoyl) (methyl ) amino] ethyl] -3-methyl-

3- (prop-2-en-l-yl) pipefidin-2-one (example 384, Step A) following a procedure similar to. described in the ExampleXH NMR (400 MHz, CHLOROFORM-d) δ ppm z

226,

Stage D.

114 6 ivt h 'i DI institute; L ?.

industrial

<td>3H),</td><td>7.25 (br s, IH)</td><td>; Spectr</td><td>or of</td><td>Masses (E</td><td>YES) m / z</td><td> = 596.</td>

(M + l).

Examples 385 to 389 were prepared from cyclopropyl-2-hydroxyethyl) -3-methylpiperidin-2-one (Example

252, step A) following procedures similar to those described in Example 202, Step C and D, replacing Nmethylcyclopropansulfonamide in Step B with the appropriate reagent.

<td>Example</td><td>R</td><td>Reagent used</td>

<td> 385</td><td>/-F0VNand 0</td><td>1-methylhydantoin (Sigma-Aldrich, St. Louis, MO)</td>

Pl INSTITUTE OF THE PL III

1147

<td> 386</td><td>VNand 0</td><td>1,5,5-trimethylimidazolidin- 2,4-dione (Sigma-Aldrich, St. Louis, MO))</td>

<td> 387</td><td>HVNand 0</td><td>5,5-dimethylimidazolidin-2,4dione (Sigma-Aldrich, St, Louis, MO)</td>

<td> 388</td><td></td><td>bentazon (Chem Service, West Chester, PA)</td>

<td> 389</td><td>andNand 0</td><td>IH-benzo [d] imidazol-2 (3H) one (Sigma-Aldrich, St. Louis, MO)</td>

EXAMPLE -385

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- ((S) l-cyclopropyl-2- (3-methyl-2,5) -dioxoimidazolidin-l-yl) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.24 (br s, IH),

0.58 (br s, 2H), 1.12 - 1.36 (m, IH), 1.36 - 1.55 (m, 3H),

1.99 - 2.11 (m, IH), 2.11 - 2.26 (m, IH), 2.71 (d, J = 15.1 Hz, IH), 3.01 - 3.08 (m, 4H), 3.08 - 3.23 (m, 2H), 3.53 ( br s,

IH), 3.78 - 4.01 (m, 3H), 4.63 (br s, IH), 5.58 (br s, IH),

6.68 (d, J = 7.6 Hz, IH), 6.92 - 7.02 (m, IH), 7.06 - 7.22 (m, 3H), (7.24-7.32 (m, 3H); Mass Spectrum (ESI) m / z = 572.0 (M + l).

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1148

EXAMPLE 386 l-cyclopropyl-2- (3,4,4-trimethyl-2,5-dioxoimidazolidin-lyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.23 (br s, IH), 0.56 (br s, 2H), 1.32 - 1.55 (m, 10H), 2.02 (dd, <7 = 13.9, 2.7 Hz, IH ), 2.15 - 2.32 (m, IH), 2.72 (d, <7 = 15.1 Hz, IH), 2.84 -

2.96 (m, 4H), 3.04 - 3.25 (m, 3H), 3.55 (br s, 1H), 3.87 -

4.10 (br s, IH), 4.87 (br s, IH), 6.66 (d, <7 = 7.0 Hz, IH),

6.99 (s, IH), 7.08 (t, <7 = 7.8 Hz, 2H), 7.17 (d, <7 = 8.6 Hz, 2H),

7.28 7.32 (m, 2H); Mass Spectrum (ESI) m / z = 600.0 (M + l).

EXAMPLE 387

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (4,4-dimethyl-2,5-acid) -dioxoimidazolidin-lil) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.18 (br s, IH), 0.56 (br s, 2H), 1.37 - 1.52 (m, 11H), 2.05 (dd, <7 = 13.89, 2.93 Hz,

(br s, IH); Mass Spectrum (ESI.) M / z = 586.0 (M + l).

EXAMPLE 388

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (3-isopropyl-2,2-dioxide) acid -4-oxo-3,4-dihydrolH-benzo [c] [1,2,6] thiadiazin-l-yl) ethyl) -3-methyl-25 oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm -0.11 (br s, IH),

0.45 (br s, 2H), 1.22 - 1.34 (m, IH), 1.43 - 1.66 (m, 9H),

1.95 - 2.14 (m, IH), 2.21 (t, 7 = 13.60 Hz, IH), 2.83 (d, 7 = 14.

Hz, IH), 3.07 (d, 7 = 14.5 Hz, IH), 3.14 - 3.28 (m, lH), 3.51

Mass Spectrum (ESI) m / z = 698.0 (M + l).

EXAMPLE 389

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) l-cyclopropyl-2- (2-oxo-2,3-dihydro -lH-benzo [d] imidazol-1yl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic

<td> 20</td><td>XH NMR</td><td> (400</td><td>MHz,</td><td>CHLOROFORM-d)</td><td>δ ppm</td><td> -0.29 - -0.06</td><td>(m,</td>

IH), 4.34 (s, IH), 6.45 (br s, IH), 6.63 (br s, IH), 6.75

1150

Di (br s, 1H), 7.01 (d, 7 = 6.5 Hz, 2H), 7.11 (d, 7 = 7 ^ Jl ^^ ÍU ^ .- ~

7.15 - 7.27 (m, 4H), 9.55 (br s, 1H); Mass Spectrum (ESI) m / z = 592.0 (M + l).

EXAMPLE 390

2 - ((3R, 5R, 6S) -5- (3-Chloro-4-fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic acid.

Stage A. (5R, 6S) -5- (3-'Chloro-4-fluorophenyl) -6- (4chlorophenyl) piperidin-2-one

The title compound was prepared using 2- (3-chloro-4-fluorophenyl) acetic acid according to the procedures described in Example 1, Steps AE. The individual enantiomers were separated by chiral HPLC (flow ratio: 400 mL / min in a Varian SD-2 prep HPLC system (Wakefield, RI) and a Grace MODCOL spring loading column (Hesperia, CA) with an inside diameter 10 cm and packed a

1151

up to a length of approximately 35 cm with 2.0 kg of

Chiralcel® OD CSP (Chiral Technologies, Inc., West Chester,

PA, USA) using 25% isopropyl alcohol / methanol as the eluant) to give the title compound as an opaque white solid. [to]D = + 152 ° (T = 23 ° C, c = 1.0, CHC13) .

Step B. (4R, 5S) -5-Amino-4- (3-chloro-4-fluoro-phenyl) -5- (4-chlorophenyl) pentanoic acid hydrochloride

A suspension of (5R, 6S) -5- (3-chloro-4-fluorophenyl) -6 (4-chlorophenyl) piperidin-2-one (5.00 g, 14.78 mmol; Example 390, step A) in 5M HCI ( 15 mL) was heated to reflux for seven hours. The reaction mixture was cooled to RT and diluted with toluene. The solvent was removed in vacuo and any remaining water was removed by azeotropic distillation with toluene four times to provide a white solid (5.81 g).

chlorophenyl) -l-isopropylpiperidin-2-one

1152.

Stage C.

Sodium triacetoxyborohydride (1796g, 8.48mmol) was added to a solution of (4R, 5S) -5amino-4- (3-chloro-4-fluorophenyl) -5- (4-chlorophenyl) pentanoic acid hydrochloride (2.56g , 6.52 mmol; Example 390, Step B) and acetone (0.491 mL, 6.68 mmol) in anhydrous DMF (6.52 mL) at rt. The reaction mixture was stirred at rt for 16 hours. Dichloroethane (25 mL) was added followed by 3A molecular sieves. The reaction mixture was heated to 70 ° C for 22 hours, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel using a 220 g column and eluting with 30 to 100% EtOAc / hexanes provides the desired product as a white solid.

Stage D. (3S, 5R, 6S) -3-A1Í1-5- (3-chloro-4-fluorophenyl) -6- (4chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one

1153

A solution of (5R, 6S) -5- (3-chloro-4-fluorophenyl) -6- (4 chlorophenyl) -l-isopropylpiperidin-2-one (0.50 g, 1.32 mmol; Example 390, Step C) in THF Anhydrous (3 mL) was degassed by bubbling argon through the solution for 15 'minutes. LHMDS (1M in THF that was degassed by bubbling argon through the solution for 15 minutes) (1.64 mL, 1.64 mmol) was added to the lactam solution at -15 ° C dropwise while maintaining the temperature below -8 ° C. After 15 minutes at -15 ° C yOdomethane (0.085 mL, 1,354 mmol) was added. Thirty-five minutes later freshly prepared LDA (3.29 mmol) in THF (1 mL) was added to the reaction mixture. After 30 minutes the reaction mixture was cooled to -78 ° C and allyl bromide (0.398 mL,

4.60 mmol) slowly while maintaining the temperature at or below -68 ° C. The reaction mixture was allowed to warm as the cold bath was heated. After 16 hours the temperature of the reaction mixture was 18 ° C. The reaction was quenched with MeOH (0.5 mL), washed with 10 mL of 50% brine / water, brine, dried '(Na2SO4), decanted and concentrated in

1154 , nstd ^ Í®ÍES5 empty to provide a yellow oil. Purification by flash chromatography on silica gel (eluent: 515% EtOAc / hexanes, gradient elution) provides the title compound.

Stage E. Acid 2 - ((3R, 5R, 6S) -5- (3-Chloro-4-fluorophenyl) -

6- (4-chlorophenyl) -l-isopropyl-3-methyl-2-oxopiperidin-3- yl) acetic

A solution of potassium permanganate (0.341 g, 2.155 mmol) in water (2 mL) was added to a solution of (3S, 5R, 6S) -

3-allyl-5- (3-chloro-4-fluorophenyl) -6- (4-chlorophenyl) -1isopropyl-3-methylpiperidin-2-one (0.312 g, 0.718 mmol; Example 390, step D) and chloride hydrate of tetrabutylammonium (0.021 g, 0.072 mmol) in DCM (2 mL) at 0 ° C. After 5 minutes the reaction mixture was removed from the ice bath and stirred at rt. After 2 hr at rt the reaction mixture was diluted with aq sodium bisulfite. This solution was filtered and then extracted with DCM three times. The combined organics were pooled, washed with 50 mL of 10% sodium bisulfite, brine, dried (MgSO4), filtered and concentrated in vacuo to provide a yellow oil. Purification by flash chromatography on silica gel using a 24g column and eluting with 0 to 50% IPA / hexanes provides the fractions containing the desired product and an impurity.

1155

Overnight the desired product is crystallized as colorless prisms and collected by vacuum filtration to provide the title compound.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 1.25 (d, J = 6.8

Hz, 3 H), 1.26 (d, J = 6.8 Hz, 3 H), 1.40 (s, 3 H), 2.00 (dd, J = 3.4 and 13.9 Hz, 1 H), 2.09 (dd, J = 11.9 and 13.7 Hz, 1H),

2.67 (d, J = 15.4 Hz, 1 H), 3.02 (dt, J = 3.2 and 9.3 Hz, 1 H), 3.03 (d, J = 15.4 Hz, 1 Hj, 3.41 (m, 1 H), 4.41 ( d, J = 9.0

Hz, 1H), 6.70-6.73 (m, 1H), 6.95-6.99 (m, 3H), 7.06 (dd, J = 2.5 and 6.9 Hz, 1H), 7.28 (d, J = 9.5 Hz, 2 H); Mass Spectrum (ESI) m / z = 452.2 [M + H]+.

EXAMPLE 391

Acid

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4chlorophenyl) -l-isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic

Stage A. (5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4chlorophenyl) piperidin-2-one

115 6

The title compound was prepared using 2- (3-chloro-5-fluorophenyl) acetic acid according to the procedures described in Example 1, Steps AE. The individual enantiomers were separated by chiral HPLC (150 χ 50 mm Chiralpak® AD-H column (Chiral Technologies, Inc., West Chester, PA, USA) with 50 g / min methanol + (20 mM NH3) + 130 g / min CO2 at Thar 350 SFC (Thar Technologies, Inc., Pittsburg, PA)). [to]D = + 114 ° (T = 23 ° C, c = 4.0, CHC13) .

Stage B. (4R, 5S) -5-Amino-4- (3-chloro-5fluorophenyl) -5- (4-chlorophenyl) pentanoic acid hydrochloride

The title compound was prepared from (5R, 6S) -

5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 391, Step A) using the procedure described in Example 390, Step B.

1157

Stage C.

MEXTGV INSTITUTE or

OF THE INDUSTRIAL PROPERTY

(5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4chlorophenyl) -l-isopropylpiperidin-2-one

The title compound was prepared from (4R, 5S) -5-amino-4- (3-chloro-5fluorophenyl) -5- (4-chlorophenyl) pentanoic acid hydrochloride (Example 391, step

B) using the procedure described in Example 390, Step C.

Stage D. (3S, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one and (3R, 5R, 6S) -

5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3methylpiperidin-2-one

A solution of (5R, 6S) -5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -1-isopropylpiperidin-2-one (0.400 g, 1.052 mmol; Example 391, Step C) is. dissolved in benzene and the solvent removed under vacuum three times. The resulting oil is

1IVA if a

INDUSTRIAL mL) and degassed by

115 8 solution

Be for 15 minutes

LHMDS

1.0 M in dissolved in anhydrous 2-methylTHF (2 bubble argon through it while cooling to -15 ° C.

THF) (1,315 ml, 1,315 mmol). and the solution turned yellow. After 10 minutes, iodomethane (0.069 ml, 1104 mmol) was added dropwise while maintaining the temperature below -10 ° C. Forty minutes later the reaction mixture was quenched with NH4C1 sat. ac. and heated up to ta. The layers were separated and the aqueous layer was extracted with EtOAc twice. Organics pooled, brine washed, dried (Na2SO4), decanted and concentrated in vacuo to provide an orange oil. Purification by flash chromatography on silica gel using a 24 g column and eluting with 10 to 30% EtOAc / hexanes provides a 96: 4 mixture of (3S, 5R, 6S) -5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one and (3R, 5R, 6S) 5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl- 3methylpiperidin-2-one as a colorless syrup.

Stage E. (3S, 5R, 6S) -3-A1Í1-5- (3-chloro-5-fluorophenyl) -6 (4-chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one and (3R, 5R , 6S) -3-allyl-5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) l-isopropyl-3-methylpiperidin-2-one

1159

A solution of (3S, 5R, 6S) -5- (3-chloro-5-fluorophenyl) -6 (4-chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one and (3R, 5R, 6S) - 5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -1isopropyl-3-methylpiperidin-2-one (0.320 g, 0.812 mmol; Example 391, Step D) in anhydrous 2-methylTHF (1.5 mL ) was degassed by bubbling argon through the solution for 15 minutes and then cooled to -15 ° C. Freshly prepared LDA (1.22 mmol) was added in 2-¿methyl-THF (1.5 mL) slowly while maintaining the temperature at or below -14 ° C. After 30 minutes at -15 ° C the reaction mixture was cooled to -74 ° C and allyl bromide (0.176 ml, 2.029 mmol) was added slowly while maintaining the temperature below -70 ° C. After 2 hours additional allyl bromide (0.176 ml, 2.029 mmol) was added and the reaction mixture was allowed to warm to rt. The reaction was quenched with NH4C1 sat. ac. and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organics were pooled, washed with brine, dried (Na2SO4), decanted and concentrated under vacuum to provide a pale yellow oil. Purification by flash chromatography on silica gel using a 24 g column

1160 eluting with 0 up

50% acetone / hexanes provides a colorless oil as a 3.3: 1 mixture of (3S, 5R, 6S) -3-allyl-5 (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl -3-methylpiperidin-2-one fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3-methylpiperidin-2 Stage F. 2- ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) ) 6- (4-chlorophenyl) -l-isopropyl-3-methyl-2-oxopiperidin-3yl) acetic

Ruthenium (III) chloride hydrate (2.19 mg,

9.72 pmol) to a solution of (3S, 5R, 6S) -3-allyl-5- (3-chloro-5fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3-methylpiperidin-2one and (3R, 5R, 6S) -3-allyl-5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one (0.192 g,

0.442 mmol; Example 391, Stage E) 'and NaI04 (97 mg) in EtOAc (1 mL), ACN (1 mL), and water (2mL) at rt. After 3 minutes,

<td>added NaIO4 (97</td><td>mg). The remaining two portions of NaIO4</td>

<td>(97 mg each)</td><td>were added after three and six minutes</td>

<td>respectively.</td><td>After 30 minutes the reaction mixture</td>

filtered and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organics were pooled, washed with NaHSO3 10% ac., Brine, dried (Na2SW4), they decanted and

1161 .Λ

INDUSTRIAL concentrated in vacuo to provide a brown oil. Purification by flash chromatography on silica gel using a 24 g column and eluting with 5 until

30% (15% MeOH / acetone) / hexanes provides a 3.3: 1 mixture of acid

2 - ((3R, 5R, 6S) -5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic acid and chlorophenyl acid) -l-isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic (170 mg, 85%). The individual isomers were separated by

Chiral HPLC (2 χ column (250 mm χ 30 mm) Chiralpak® AD-H (Chira! Technologies, Inc., West

Chester, PA,

USA) with 20 g / min methanol + (20 mM NH3) + 80 g / min CO2 in

Thar 350 SFC (Thar Technologies, Inc., Pittsburg,

PA)) to provide the title compound.

<td></td><td>XH</td><td>NMR (4 00 MHz, CLORj</td><td>FORM-d)</td><td>δ ppm</td><td> 1.</td><td> 26</td><td>(d, 7 =</td><td> 6.9</td>

2.2 (d,

Hz,

J = 8.4

Η), 6.99 and 8.4 Hz, 1 m / z

452.2 [Μ + H] '.

EXAMPLE 392

Acid

1162·

2- ((3S, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4chlorophenyl) -l-isopropyl-3-methyl-2-oxopiperidin-3-yl) acetic

Additional elution from the HPLC column in Example 391, Step F provides the title compound (14.8 mg). XH NMR (400 MHz, CHLOROFORM-d) 5 'ppm 1.22 (d, J = 6.9 Hz, 3 H), 1.27 (d, J = 7.0 Hz, 3 Η), 1.58 (s, 3 Η), 1.72 (dd , J = 3.1 and 13.3 Hz, 1 Η.), 2.32 (t, J = 13.5 Hz, 1 Η), 2.65-2.75 (m, 2 H), 3.13 (dt, J = 2.9 and 10.6 Hz, 1 Η) , 3.26 (m, 1 Η),

4.33 (d, J = 10.4 Hz, 1 Η), 6.53 (d, 7 = 9.0 Hz, 1 Η), 6.74 (s, 1 H), 6.91-6.97 (m, 3 Η), 7.27 (d, 7 = 8.6 Hz, 2H); Mass Spectrum (ESI) m / z = 452.2 [Μ + H]1.

EXAMPLE 393

Acid

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4 chlorophenyl) -1 - ((S) -1- (ethylsulfonamido) butan-2-yl) -3 -methyl-2oxopiperidin-3-yl) acetic '

Stage

TO.

1153

IMPIg

INSTITUTO LÁíXlCAMp D¿ LA PKOrlcDAL). INDUSTRIAL

(3S, 5R, 6S) -3-Allyl-l - ((S) -1 - <(tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chloro-5-fluorophenyl) -

6- (4-chlorophenyl) -3-methylpiperidin-2-one

The title compound was prepared as described in Example 185, Step E by replacing 2- (3-chlorophenyl acetic acid with 2- (3-chloro-5-fluorophenyl) acetic acid in Example 1, Step A.

Stage B. (3S, 5R, 6S) -3-A1Í1-5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutane-2-yl) -3 -methylpiperidin-2 one

1164

To a solution of (3S, 5R, 6S) -3-allyl-l - ((S) -1 - ((tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chloro-5-fluorophenyl)

6- (4-Chlorophenyl) -3-methylpiperidin-2-one (2.15 g, 3.06 mmol; Example 393, Step A) in THF (30.6 ml) at rt TBAF (1.0 M in THF) was added (6.12 ml, 6.12 mmol). The light yellow mixture was stirred at RT overnight. The mixture was diluted with water and EtOAc. The organic layer was washed with brine, dried over Na2SW4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (column 40 g; eluent: 0 to 50% EtOAc in hexanes) to give the title compound.

Stage C. N - ((S) -2 - ((3S, 5R, 6S) -3-Allyl-5- (3-chloro-5fluorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin -lyl) butyl) ethanesulfonamide

IMP

INSTITUTE ΜΕΧ '?;

OF THE PROPERTY

INDUSTRIAL

1165

La (3S, 5R, 6S) -3-allyl-5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methylpiperidin -2-

<td>ona (100 mg,</td><td colspan="2"> 0.215</td><td>mmol; Example</td><td> 393,</td><td>Stage</td><td>B)</td><td>and</td>

<td>ethanesulfonamide</td><td> (70</td><td> .5</td><td>mg, 0.64 6 mmol)</td><td colspan="2">they docked</td><td>by</td><td>the</td>

<td colspan="2">procedure like</td><td>I know</td><td>describes in the</td><td>Example</td><td> 202,</td><td>Stage</td><td>C</td>

to form the title compound, isolated after chromatography on silica gel (column 4 g; eluent 0 to 50% EtOAC / hexanes) as an opaque white solid.

Stage D. 2- ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (ethylsulfonamido) butan-2-yl acid ) -3-methyl-2oxopiperidin-3-yl) acetic

To a solution of N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -3-methyl-2- oxopiperidin1-yl) butyl) ethanesulfonamide (Example 393, Stage C, 120 mg, 0.216 mmol) in EtOAc: MeCN: water (1,450 mL) (2/2/3) at rate added sodium periodate (185 mg, 0.864 mmol) slowly. Then ruthenium chloride hydrate (1,071 mg, 4.75 pmol) was added. The mixture was vigorously stirred at rt for 2 h. Then

IM

the mixture was filtered and the solid was

1166 filtrate was extracted with EtOAc 2x

The combined organic layers were dried over Na2SW4, filtered and the filtrate was concentrated under reduced pressure.

The residue was purified by

Reverse phase preparative HPLC (column: Gemini ™ Prep Cis um; Phenomenex, + 0.1% TFA in water

Torrance, CA; eluent: 0 to 100% MeCN + 0.1% TFA, envelope. 20 minutes) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.53 (t, J = 7.6 Hz,

H) 1.40 (t, J = 7.3 Hz, 3 H) 1.46 - 1.56 (m, 4 H) 1.80 - 1.94

<td>H)</td><td> 7.07</td><td>(br s,</td><td>2 H)</td><td> 7.24</td><td> - 7</td><td>'. 30 (m, 2</td><td>H); Mass Spectrum</td>

(ESI) m / z = 573 (M + l).

EXAMPLE 394

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (N-methylethylsulfonamido) butan- 2il) -2-oxopiperidin-3-iljacetic

MEXICAN INSTITUTE

OF THE PROPERTY

1167

INDUSTRIAL

To a solution of 2 - ((3R, 5R, 6S) -5- (3-chloro-5 fluorophenyl) -6- (4-chlorophenyl) -l - (. (S) -l (ethylsulfonamido) butan-2 acid -yl) -3-methyl-2-oxopiperidin-3yl) acetic (Example 393, Step D, 26.6 mg, 0.046 mmol) in DMF (464 μΐ) at rt a 60% sodium hydride dispersion in mineral oil was added (5.57 mg, 0.139 mmol). The thick gray mixture was stirred at rt for 30 min then iodomethane (5.80 µΐ, 0.093 mmol) was added. The mixture was stirred at rt for 1 h. The mixture was quenched with 1M HC1 and diluted with EtOAc. The aqueous layer was extracted with 2x EtOAc. The organic layer was dried over Na2SW4, filtered and the filtrate was concentrated. The residue was purified by reverse phase preparative HPLC (column: Gemini ™ Prep C18 10 um; Phenomenex, Torrance, CA; eluent: 0 to 100% MeCN + 0.1% · TFA in water + 0.1% TFA, over 20 minutes) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (t, 7 = 7.5 Hz, 3 H) 1.38 (t, 7 = 7.4 Hz, 3 H) 1.52 (s, 3 H) 1.57-1.63 (m, 1 H)

1.85 - 2.00 (m, 2 H) 2.46 (t, 7 = 13.9 Hz, 1 H) 2.66 -2.89 (m, 6 H) 2.94 - 3.16 (m, 4 H) 4.31 (dd, 7 = 13.7, 10.8 Hz, 1 HOUR)

Η);

1168

4.81 (d,

7 = 10.8 Hz,

H) 6.59 (br

2.1 Hz,

H) 6.80 (t, 7 = 1.8 Hz,

Η)

Hz, 1H)

7.01 (br s, s, 2 (ESI) m / z = 587 (M + l).

EXAMPLE 395

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (methylsulfonyl) butari-2- il) -2oxopiperidin-3-il) acetic

Stage A. (3S, 5S, 6R, 8S) -8-Allyl-6- (3-chloro5-fluorophenyl) -5- (4-chlorophenyl) -3-ethyl-8-methyl-2,3,5 methanesulfonate , 6,7,8hexahydrooxazolo [3,2-a] pyridin-4-io

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) 1- ((S) -l-hydroxybutan -2-yl) -3-methylpiperidin1169

393, Step B) by a procedure similar to that described in

Example 344, Stage A.

Stage B. (3S, 5R, 6S) -3-AÜ1-5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (methylsulfonyl) butan -2il) piperidin-2-one

To a methanesulfonate solution of (3S, 5S, 6R, 8S) -8alyl-6- (3-chloro-5-fluorophenyl) -5- (4-chlorophenyl) -3-ethyl-8methyl-2,3,5, 6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io (Example 395, step A, '100 mg, 0.184 mmol) in MeCN (1.8 mL) methanesulfinic acid, sodium salt (56.5 mg) was added , 0.553 mmol). The mixture was heated to 114 ° C. After heating for 24 hours, the mixture was cooled to room temperature and stirred for 2 days. The mixture was partitioned between EtOAc and aq NH4CI. The organic layer was washed with brine, dried over Na2SW4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (eluent: 20 to 60% EtOAc / hexanes, gradient elution) to provide the title compound.

1170

Step C. 2- ((3R, 5R, -6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-chlorophenyl) -3-methyl-l - ((S) -1- (methylsulfonyl) butan-2-yl) -2oxopiperidin-3-yl) acetic

To a solution of (3S, 5R, 6S) -3-allyl-5-Ο-οΙοΓΟ-δί luorophenyl) -6- (4-chlorQphenyl) -3-methyl-l- ((S) -1 (methylsulfonyl) butan -2-yl) piperidin-2-one (Example 395, Step B, 58 mg, 0.110 mmol) in acetonitrile (1.0 mL), EtOAc (1.0 mL), and water (1.5 mL) added ruthenium chloride hydrate ( III) (0.55 mg, 2.42 pmol) and sodium periodate (144 mg, 0.672 mmol). After 2 hours, the mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH / DCM) to provide the title compound.

<td></td><td>XH RM</td><td>N (401</td><td>3 MHz, CL</td><td>.OROFORM</td><td>Od)</td><td colspan="2">δ ppm 0.43 (t, <7 = 7.5</td><td>Hz,</td>

H) 6.75 (s, 1 H) 6.89 (dt, J = 8.3, 1.9 Hz, 1 H) 7.12 (br s, 2

1171

IMPIOS

MEXICAN INSTITUTE \ ~ 7¾ jx

OF MOKITY <

H) 7.21 - 7.35 (m, 2H). Mass Spectrum (ESI) m / z = 544.0 (M + 1). "

Examples 396 to 398 were prepared from (3S, 5S, 6R, 8S) -8-allyl-6- (3-chloro-5fluorophenyl) -5- (4-chlorophenyl) -3-ethyl-8- methyl-2, 3,5,6,7,8hexahydrooxazolo [3,2-a] pyridin-4-io (Example 395, Step A) by a procedure similar to those described in either Example 339 or Example 395, using an equivalent amount of the appropriate reagent in Step B. Example 399 was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chloro-5 fluorophenyl) -6- (4-chlorophenyl) -1- ((S) -l-hydroxybutane- 2-yl) -3 methylpiperidin-2-one (Example 393, step B) by a procedure similar to that described in Example 300, using an equivalent amount of the appropriate thiol in Step A.

<td>Example</td><td>R</td><td>Method</td><td>Reagent used</td>

<td> 396</td><td>Ethyl</td><td>Example 395</td><td>Ethanesulfinic acid, sodium salt</td>

<td> 397</td><td></td><td>Example 395</td><td>Acid cyclopropansulfunic, salt of sodium</td>

MfcA INSTITUTE OF THE INDO PP.O2:

1172

<td> 398</td><td></td><td>Example 339</td><td>2-methylpropantiolate, prepared in situ at from 2-methylpropan2-thiol and sodium hydride</td>

<td> 399</td><td></td><td>Example 300</td><td>2-propantiol</td>

EXAMPLE 396

2- ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (ethylsulfonyl) butan-2-yl) -3 -methyl-2oxopiperidin-3-yl) acetic XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.42 (t, 7 = 7.5 Hz,

H) 1.45 (t, 7 = 7.5 Hz, 3 H) 1.49 (s, 3 H) 1.65 (br s, 1 H)

<td>Hz, 1H)</td><td> 7.12 (</td><td>br s, 2H)</td><td> 7.21</td><td>- 7.34 (m, 2</td><td>H).</td><td>Spectrum</td><td>of</td>

Masses (ESI) m / z = 558.0 (M + 1).

EXAMPLE 397

Acid

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4-methyl-2-oxopiperidin-3-yl) acetic chlorophenyl) -1 - ((S) -1- (cyclopropyl sulfonyl) butan-2-yl) -31173 XH NMR (4 00 MHz, CHLOROFORM-d)

H) 1.05 - 1.15 (m, 2 H) 1.25 - 1.33 (m, 2 H) 1.38 - 1.54 (m, 4 H) 1.90 (dd, 7 = 13.8, 2.8 Hz, 1 H) 2.07 - 2.21 (m, 1 H)

2.34 (t, 7 = 13.8 Hz, 1 H) 2.42 (tt, 7 = 8.0, 4.8 Hz, 1 H) 2.76 (d, 7 = 15.1 Hz, 1 H) 2.88 - 3.01 (m, 2 H) 3.13 (ddd , 7 = 13.4,

10.8, 2.5 Hz, 1 H) 3.31 (t, 7 = 10.4 Hz, 1 H) 4.20 (dd, 7 = 13.5,

11.2 Hz, 1 H) 4.90 (d, 7 = 10.8 Hz, 1 H) 6.61 (dt, 7 = 9.0, 2.0 Hz, 1 H) 6.74 (s, 1 H) 6.88 (dt, 7 = 8.4, 2.1 Hz, 1H) 7.11 (br s, 2H) 7.21 - 7.34 (m, 2H). Mass Spectrum (ESI) m / z = 570.0 (M + 1).

EXAMPLE 398

2 - ((3R, 5R, 65) -1 - ((S) —1— (tert-Butyl sulfonyl) butan-2-yl) 5- (3-chloro-5-fluorophenyl) -6- (4-chlorophenyl) ) -3-methyl-2oxopiperidin-3-yl) acetic

The crude product was purified by SFC column 20 mL / min;

x 250mm Chiralpak® IC (Chiral Technologies, Inc., West Chester, PA, USA) using methanol (20mM NH3)/CO2 as the eluent in Thor SFC (Thor Technologies, Inc. Pittsburg, PA) to provide the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 (t, 7 = 7.5 Hz,

H) 1.38 - 1.68 (m, 13 H) 1.88 (dd, 7 = 13.7, 2.5 Hz, 1 H)

2.06 - 2.26 (m, 1H) 2.38 (t, 7 = 13.8 Hz, 1H) 2.73 (d, 7 = 15.

Hz, 1 H) 2.80 (d, 7 = 13.5 Hz, 1 H) 3.01 (d, 7 = 15.3 Hz, 1 H)

3.11 (t, <7 = 11.8 Hz, 1H) 3.33 (t, J = 10.4

1174 <7 = 13.0, 11.3 Hz, 1

Η) 4.97 (d, <7 = 10.8

Hz,

Hz, 1H) 6.75 (s,

H) 6.89 (d, <7 = 8.4

Hz,

Η) 7.14 (br s, 2

H) 7.25 - 7.36 (m,

H). Spectrum

Masses (ESI) m / z = 586.0 (M + 1.).

EXAMPLE 399

Chlorophenyl acid) -1 - ((S) -1- (isopropylsulfonyl) butan-2-yl) -3-methyl

2-oxopiperidin-3-yl) acetic

The crude product was purified by preparative thin layer chromatography on silica gel (eluent: 10% MeOH / DCM) followed by preparative reverse phase HPLC purification (column: Gemini ™ Prep Cie 10 um; Phenomenex, Torrance, CA; eluent: 0 to 100% MeCN + 0.1% TFA in water + 0.1% TFA, over 20 minutes) to give the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 (t, <7 = 7.5 Hz, 3 H) 1.34 - 1.55 (m, 10 H) 1.88 (dd, J = 13.8, 2.6 Hz, 1 H)

2.07 - 2.24 (m, 1 H) 2.38 (t, <7 = 13.8 Hz, 1 H) 2.68 - 2.81 (m, 2 Η) 3.01 (d, <7 = 15.5 Hz, 1 H.) 3.06 - 3.18 (m , 2 H) 3.35 (t, <7 = 10.2 Hz, 1 H) 4.08 (dd, <7 = 13.1, 11.5 Hz, 1 H) 4.95 (d, <7 = 10.8 Hz, 1 H) 6.63 (d, < 7 = 9.0 Hz, 1 H) 6.75 (s, 1 H) 6.89 (dt, <7 = 8.2, 2.0 Hz, 1 H) 7.14 (br s, 2 H) 7.24 - 7.37 (m, 2 H). Mass Spectrum (ESI) m / z = 572.0 (M + 1).

EXAMPLE 400

2- ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) acid 1175

1- ((S) -1- (cyclopropyl sulfonyl) but.an-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic

Stage A. 1- (4-Chlorophenyl) -2- (5-chloropyridin-3-yl) ethanone

1- (4-Chlorophenyl) ethanone (17.22 ml, 133 mmol) was added to an ice-cold solution of 3-bromo-5-chloropyridine (24.3 g, 126 mmol) and sodium 2-methylpropan-2-olate (30.3 g , 316 mmol) in THF (158 ml) under an argon atmosphere. Then (9,9-dimethyl-9H-xanthene-4,5diyl) bis (diphenylphosphine) (0.731 g, 1,263 mmol) and diacetoxypalladium (0.283 g, 1,263 mmol) were added and the solution was heated to 70 ° C for 1.5 hour . The solution was cooled to RT and diluted with ice, 2N HC1 (95 mL) followed by EtOAc (300ml). The layers were divided and the aqueous layer was washed with EtOAc (2xl00ml). The organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue

1176

obtained was enriched on a silica gel column. Fractions containing the product were combined and concentrated. 130 ml of Et was added to the obtained residue2O and the suspension was heated to reflux in a water bath. The suspension was then cooled in an ice bath. Solids were collected by filtration to provide the title compound.

XH NMR (500 MHz, DMSO-d5) δ ppm 8.53 (1 H, d, 7 = 2.4 Hz),

8.43 (1 H, d, 7 = 1.7 Hz), 8.05 - 8.11 (2 H, m), 7.85 (1 H, t,

7 = 2.1 Hz), 7.63 - 7.68 (2 H, m), 4.55 (2 H, s).

Stage B. 1-methyl 5- (4-chlorophenyl) -4- (5-chloropyridin-3-yl) -2-methyl-5-oxopentanoate

The title compound was obtained from l- (4-chlorophenyl) -2- (5-chloropyridin-3-yl) ethanone (Example 400, Step A, 25.3 g, 95 mmol) by a procedure similar to that described in the Example. 261, Step A. The racemic product is a 1: 1 mixture of diastereomers.

XH NMR (500 MHz, DMSO-d6) δ ppm 8.57 (1 H, d, 7 = 2.0 Hz),

8.54 (1 H, d, 7 = 1.7.Hz), 8.50 (2 H, dd, 7 = 4.4, 2.4 Hz), 8.05

1177

INSTITUTE fu Ζ ΝΟ OF INDUSTRIAL PROPERTY

- 8.09 (4 Η, τη),

7.90 (2 Η, t, <7 = 2.1 Ηζ),

7.57 - 7.64 (4 Η,

<td>H, d, <7 = 7.1 Hz), 1.08</td><td>(3 H, d,</td><td><7 = 7.1 Hz);</td><td colspan="3">Mass Spectrum</td>

(ESI) m / z = 366.1 [Μ + Η]+.

Stage C.

Racemic mixture of 5- (4-chlorophenyl) -4- (5 chloropyridin-3-yl) -5-hydroxy-2-methylpentanoate of (4R, 5R) methyl and 5- (4-chlorophenyl) -4- (5 (4S, 5S) -methyl-chloropyridin-3-yl) -5-hydroxy2-methylpentanoate

1-Methyl 5- (4-chlorophenyl) -4- (5-chloropyridin-3-yl) -2-methyl-5-oxopentanoate (Example 400, Step B, 31 g, mmol) was converted to the title compounds by a procedure similar to that described in Example 261, Step

The product is a 1: 1 mixture of diastereomers at position 2.

XH NMR (500

MHz,

CHLOROFORM-d) δ ppm 8.43 (2 H, s), 8.13

.7, 7.03 <7 = 6.8, 2.0 Hz), 7.24

7.10 (4 H, m), 4.88 (1 H, d, J = 5.6 Hz), <7 = 5.6 Hz), 3.64 (3 H, s), 3.56 (3 H, s), 2.91

IMP

INSTITUTO MEX! C.

OF THE

2.2 9 (1H, mTB7

1178

<7 = 6.8 Hz); Mass Spectrum

Stage D. (4R, 5R) -5- (4-Chlorophenyl) -4- (5-chloropyridin-3yl) -5-hydroxy-2-methylpentanoic acid and (4S, 5S) -5- (4-chlorophenyl) -4 - (5-chloropyridin-3-yl) -5-hydroxy-2-methylpentanoic

The racemic mixture of methyl (5R, 5R) 15-methyl (5- (4-chlorophenyl) -4- (5-chloropyridin-3-yl) -5-hydroxy-2-methylpentanoate) (4S, 5S) -methyl-chloropyridm-3-yl) -5-hydroxy2-methylpentanoate (Example 400, Step C,

16.5 g, 43.4 mmol) was converted to the title compounds by the procedure described in Example 261, Step C. Mass Spectrum (ESI) m / z-354 ·. 1 [M + H].

Step E. (5R, 6R) -6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) -3methyltetrahydro-2H-pyran-2-one and (5S, 6S) -6- (4- chlorophenyl) -5 (5-chloropyridin-3-yl) -3-methyltetrahydro-2H-pyran-2-one

The diastereomeric mixture of (4R, 5R) -5- (4-chlorophenyl) -4- (5-chloropyridin-3-yl) -5-hydroxy-2-methylpentanoic acid and (4S, 5S) -5- (4-chlorophenyl) - acid 4- (5-chloropyridin-3-yl) -5-hydroxy-2-methylpentanoic (Example 400,

Step D, 15.39 g, 43.4 mmol) was converted to the title compounds by the procedure described in Example 261,

Step D. The product is a 3: 2 mixture of diastereomers at position 2.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 8.42 (0.6 H, d,

7 = 2.4 Hz), 8.37 (1 H, d, 7 = 2.2 Hz), 8.22 (0.6 H, d, 7 = 2.0

Hz), 7.91 (1 H, d, 7 = 2.0 Hz), 7.35 (0.6 H, t, 7 = 2.1 Hz), 7.23

- 7.27 (1.3 H, m), 7.-16 - 7.23 (3 H, m), 7.08 (1.3H, d,

7 = 8.6 Hz), 6.90 (2 H, d, 7 = 8.6 Hz), 5.80 (0.6 H, d, 7 = 3.9

Hz), 5.74 (1 H, d, 7 = 4.4 Hz), 3.67 - 3.73 (0.6 H, m), 3.60 (1

H, ddd, 7 = 9.3, 6.4, - 4.6 Hz), 2.96 - 3.10 (1 H, m), 2.74 2.84 (0.6 H, m), 2.69 (1 H, ddd, 7 = 14.4, 9.0, 8.1 Hz) , 2.30 -

2.39 (0.6 H, m), 2.18 (0.6 H, ddd, 7 = 13.8, 9.2, 4.4 Hz), 1.76

- 1.86 (1 H, m), 1.44 (1.8 H, d, 7 = 7.1 Hz), 1.42 (3 H, d,

7 = 6.6 Hz).

Stage F.

(3S, 5R, 6R) -3-Α1Ϊ1-6- (4-chlorophenyl) -5- (5-

1180 chloropyridin-3-yl) -3-methyltetrahydro-2H-pyran-2-one (3R, 5S, 6S) -3-allyl-6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) - 3methyltetrahydro-2H-pyran-2-one

The mixture of (5R / 6R) -6- (4-chlorophenyl) diastereomers

5- (5-chloropyridin-3-yl) -3-methyltetrahydro-2H-pyran-2-one and (5S, 6S) -6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) - 3-methyltetrahydro-2H-pyran-2-one (Example 400, Step E, 12.2 g,

36.28 mmol) was converted to the title compounds by the procedure described in Example 261, Step E.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 8.44 (1 H, d, <7 = 2.2 Hz), 8.11 (1 H, d, J = 2.0 Hz), 7.18 - 7.24 (2 H, m), 7.07 (1 H, t, <7 = 2.1 Hz), 6.62 - 6.67 (2 H, m), 5.82 (1 H, ddt, <7 = 17.1, 9.9, 7.4 Hz), 5.71 (1 H, d, <7 = 5.1 Hz), 5.13 -

5.23 (2 H, m), 3.85 (1 H, dt, <7 = 11.7, 4.7 Hz), 2.48 - 2.66 (2 H, m), 1.93 - 2.07 (2 H, m), 1.42 (3 H, s ).

Stage G. (S) -2 - ((2R, 3R) -3- (4-Chlorophenyl) -2- (5-chloropyridin-

3-yl) -3-hydroxypropyl) -N - ((S) -l-hydroxybutan-2-yl) -2methylpent-4-enamide and (R) -2- ((2S, 3S) -3- (4- chlorophenyl) -2- (51181

IMPIf , NST!Yes? \

INDUSTRY!.

chloropyridin-3-yl) -3-hydroxypropyl) -N - ((S) -l-hydroxybutan-2yl) -2-methylpent-4-enamide

The racemic mixture of (3S, 5R, 6R) -3-allyl-6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) -3-methyltetrahydro-2Hpiran-2-one and (3R, 5S, 6S ) -3-allyl-6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) -3-methyltetrahydro-2H-pyran-2-one (Example 400, Step F, 12.4 g, 33.0 mmol;) converted to the title compounds by the procedure described in Example 261, Step G.

Mass Spectrum (ESI) m / z = 465.2 [M + H] 1.

Stage H. (3S, 5R, 6S) -3-A1Í1-6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) -1 - ((S) -l-hydroxybutane-2-yl) -3methylpiperidin -2-one

The mixture of (S) -2 - ((2R, 3R) -3- (4-chlorophenyl) -2- (5-chloropyridin-3-yl) -3-hydroxypropyl) -N - ((S) 1182 diastereomers

l-hydroxybutan-2-yl) -2-methylpent-4-enamide and (R) -2 - ((2S, 3S) -

3- (4-chlorophenyl) -2- (5-chloropyridin-3-yl) -3-hydroxypropyl) -N ((S) -l-hydroxybutan-2-yl) -2-methylpent-4-enamide (Example 400 , Step G, 6.34 g,) was combined in DCM (68 ml) and triethylamine (13.3 ml, 95 mmol). After cooling in an ice bath, trimethylamine hydrochloride (1953 g, 20.43 mmol) was added. 4-Methylbenzenesulfonic anhydride (17.78 g, 54.5 mmol) was added slowly as a solid, keeping the temperature below 10 ° C. The brown solution was allowed to warm slowly to room temperature, and then stirred overnight. The next day more trimethyl amine hydrochloride (0.271mg, 2.91mmol) was added and the solution was stirred for another day. The reaction was quenched with ice water. The layers were divided and the aqueous layer was washed with DCM. The combined organics were dried over MgSO4, filtered, and concentrated to provide a brown oil. The oil was dissolved in MeCN (100 ml) and then heated to 60 ° C for 4 hours. The solution was concentrated and the residue was dissolved in 100 ml of DCM. ñ this was added 100 ml of NaHCO3 sat. and the biphasic solution was stirred at rt. for 5 days. The solution was divided and the aqueous layer was washed with DCM. The organics were dried over MgSO4, filtered and concentrated. The product was purified by chromatography, on silica gel to give

1183

((S) -l-hydroxybutan-2-yl) -3-methylpiperidin-2-onasome the second elution diastereomer.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (1 H, d, <7 = 2.0 Hz), 7.91 (1 H, d, <7 = 1.5 Hz), 7.35 (1 H, t, <7 = 1.8 Hz), 7.26 (1 H, br s), 7.00 (2 H, br d, <7 = 6.8 Hz), 5.78 - 5.94 (1 H, m), 5.15 - 5.24 (2 H, m), 4.45 ( 1 H, d, <7 = 10.3 Hz), 3.59 -

3.73 (2 H, m), 3.13 - 3.27 (3 H, m), 2.62 (2 H, d, <7 = 7.6 Hz), 2.02 - 2.11 (1 H, m), 1.85 - 2.00 (2 H, m ), 1.40 - 1.52 (1 H, m), 1.30 (3 H, s), 0.66 (3 H, t, <7 = 7.5 Hz). Mass Spectrum (ESI) m / z = 447.2 [M + H].

Stage I. (3S, 5S, 6R, 8S) -8-allyl-5- (4-chlorophenyl) -6- (5-chloropyridin-3-yl) -3-ethyl-8-methyl-

2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io

CI

The title compound was prepared from (3S, 5R, 6S) -3-allyl-6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) -1 ((S) -l-hydroxybutan -2-yl) -3-methylpiperidin-2-one (Example

400, Step H) by a procedure similar to that described in

Example 344, Stage A.

Mass Spectrum (ESI) m / z = 429.2 [M].

1184

INSTITUTE

D £ THE INDUSTRIAL PROPERTY

Step J. (3S, 5R, 6S) -3-A1Í1-6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) -1 - ((S) -1- (cyclopropyl sulfonyl) butan-2-yl ) -

(3S, 5S, 6R, 8S) -8-allyl-5- (4-chlorophenyl) -6- (5-chloropyridin-3-yl) -3-ethyl-8-methyl- methanesulfonate

2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io (Example 400, Step I, 0.188g, 0.358 mmol) was converted to the title compound by a procedure similar to described in Example 340 using cyclopropan sulfinic acid, sodium salt (Oakwood Producís, West Columbia, SC).

MS (ESI) m / z = 535.1 [M + H]1.

Step K. 2 - ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) -1 - ((S) -1- (cyclopropyl sulfonyl) butan-2-yl acid ) -

3-methyl-2-oxopiperidin-3-yl) acetic

To a solution of (3S, 5R, 6S) -3-allyl-6- (4-chlorophenyl) -5 (5-chloropyridin-3-yl) -1- ((S) -1- (cyclopropyl sulfonyl) butan-2yl ) -3-methylpiperidin-2-one. (Example 400, Stage J, 0.06 g,

1185·

0.112 mmol) in DCM (2,241 ml) acetic acid (0.160 ml, 2.80 mmol) and tetrabutylammonium chloride hydrate (3.32 mg, 0.011 mmol) were added. The solution was cooled in an ice bath. A solution of potassium permanganate (0.053 g, 0.336 mmol) in lml of water was prepared and added dropwise to the above solution (rinsed with lml of water). The solution . Purple was stirred in the ice bath for 30 minutes and then allowed to warm to room temperature and left overnight. The next day, a sodium bisulfite solution (10% in water) was added. The pH of the ac layer. It was adjusted up to 30% H2SO4 in water. The layers were divided and then the aqueous was washed with DCM followed by 10% iPrOH / DCM. The combined organics were concentrated under vacuum. The product was purified by. silica gel chromatography to provide the title compound as a white solid.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38 (.1 H, d, 7 = 2.2

Hz), 8.00 (1 H, d, 7 = 1.7 Hz), 7.67 (1 H, t, 7 = 2.0 Hz), 7.26 (2 H, br s, solvent overlap), 7.17 (2 H, br s) , 4.99 (1 H, d, 7 = 11.0 Hz), 4.28 (1 H, dd, 7 = 13.4, 11.2 Hz), 3.51 (1

118 6

J = 5.6 Hz), 1.07 - 1.11 (2 H, m), 0.43 (3

H, t, J = 7.6 Hz)

Mass Spectrum (ESI) m / z = 553.0 [M + H]+.

EXAMPLE 401

Acid 2 - ((3R, 5R, 6S) -1 - ((S) -1- (tert-Butylsulfonyl) butan-2-yl) 6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl ) -3-methyl-2oxopiperidin-3-yl) acetic

Stage A. 2- (3S, 5R, 6S) -3-Allyl-l - ((S) -1- (tert-butylthio) butan-2yl) -6- (4-chlorophenyl) -5- (5-chloropyridin -3-yl) -3methylpiperidin-2-one

La (3S, 5R, 6S) -3-A1Í1-6- (4-chlorophenyl) -5- (5-chloropyridin-

3-yl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methylpiperidin-2-one (Example 400, Step H, 0.2g, 0.447 mmol) was converted to the title compounds as a clear film (0.145g, 62%) by the procedure described in Example 339, Step B using an equivalent of 2-methylpropantiol.

1187

XH NMR (500 MHz, CHLOROFO'RMO-d) δ ppm 8 .'40 (1 H, d, <7 = 2.2

Hz), 7.98 (1 H, d, <7 = 1.7 Hz), 7 ..41 (1 H,. T, <7 = 2.1 Hz), 7.24 (2 H, br d, <7 = 8.3 Hz), 6.99 (2 H, br d, <7 = 6.6 Hz), 5.87 (1 H,

m), 5.13 - 5.23 (2 H, m), 4.65 (1 H, d, <7 = 10.8 Hz), 3.51 (1

H, t, <7 = 11.4 Hz), 3.19 (1 H, ddd, <7 = 13.7, 10.8, 2.9 Hz), 2.63

- 2.74 (1 H, m), 2.53 - 2.62 (3 H, m), 2.16 (1 H, t, <7 = 13.6

Hz), 2.08 (1 H, m, <7 = 14.2, 8.8, 7.3 Hz), 1.88 (1 H, dd, <7 = 13.4, 3.2 Hz), 1.51 - 1.60 (1 H, m), 1.36 (9 H, br s), 1.31 (3 H, br s), 0.49 (3 H, t, <7 = 7.6 Hz). Mass Spectrum (ESI) m / z = 519.2 [M + H]+.

Stage B. Acid 2 - ((3R, 5R, 6S) -1 - ((S) -1- (tertButyl sulfonyl) butan-2-yl) -6- (4-chlorophenyl) -5- (5-chloropyridin-

3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

A solution of (3S, 5R, 6S) -3-allyl-l - ((S) -1- (tertbutylthio) butan-2-yl) -6- (4-chlorophenyl) -5- (5-chloropyridin-3yl ) -3-methylpiperidin-2-one (Example 401, Step A, 0.147 g, 0.283 mmol;) with acetic acid (0.972 mL, 16.98 mmol) and tetrabutylammonium chloride hydrate (8.37 mg, 0.028 mmol) in 4ml DCM cooled in an ice bath. A solution of potassium permanganate (0.268 g, 1698 mmol) in 3 mL of water was added. The purple solution was stirred while cooling with an ice bath and was. allows to heat up to temperature

1188

Added

After

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY NaS solution2O3 ac.

Filtering the solution to filtrate was partitioned and then the ambient layer for 2 hours, along with additional DCM, through AC filter paper. washed with DCM. The combined organics were dried over Na2SW4 and concentrated. The product was purified by chromatography on silica gel followed by preparative HPLC (Agilent column, EXTEND Cie PrepHT, 5μΜ, 30 x 250mm) eluting with a gradient of 20% MeCN / H20 / 0.1% TFA up to 80% MeCN / H20 / 0.1% TFA for 25 minutes. Fractions containing the product were combined, frozen in an acetone / dry ice bath, and the solvents were removed in a lyophilizer to provide the title compound as an opaque white solid.

XH NMR (500 MHz, DMSO-d6) δ ppm 12.38 (1 H, br s), 8.42 (1 H, d, 7 = 2.2 Hz), 8.02 (1 H, d,> 1.7 Hz), 7.57 (1 H, t,

7 = 2.0 Hz), 7.11 - 7.47 (4 H, m), 4.83 (1 H, d, 7 = 11.0 Hz), 3.84 (1 H, dd, 7 = 13.0, 10.5 Hz), 3.47 - 3.57 (1 H , m), 3.13 (1 H, br s), 3.05 (1 H, d, 7 = 12.5 Hz), 2.91 (1 H, d, 7 = 13.9 Hz), 2.13 - 2.23 (1 Ή, m) ., 2.03 - 2.13 (2 H, m), 1.81 - 1.97 (1 H, m), 1.43 - 1.53 (1 H, m), 1.33 (9.H, s), 1.26 (3 H, s), 0.33 (3 H, t, 7 = 7.6 Hz). Mass Spectrum (ESI) m / z = 569.2 [M + H]

Acid 2 - ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) 1189 institute

P ·1 -'mousTObM.

EXAMPLE 402

1- ((S) -1- (cyclopropansulfonamido) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic

Stage A. N- ((S) -2- ((3S / 5R, 6S) -3-AÜ1-6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) -3-methyl-2-oxopiperidin -lil) butyl) cyclopropansulfonamide

La (3S, 5R, 6S) -3-allyl-6- (4-chlorophenyl) -5- (5-chloropyridin-

3-yl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methylpiperidin-2-one (Example 400, Step H, 0.076g, 0.170 mmol) was converted to the title compound by a procedure similar to that described in Example 272, Step A, using cyclopropansulfonamide.

MS (ESI) m / z = 550.2 [M + H]+.

1190

Stage

acid

II ....... l*,** "chloropyridin-3-yl) -1 - ((S) -1- (cyclopropansulfonamido) butan-2 yl) -3-methyl-2-oxopiperidin-3-yl) acetic

N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-6- (4-chlorophe.nil) -5- (5 chloropyridin-3-yl) -3-methyl-2- oxopiperidin-lyl) butyl) cyclopropansulfonamide (Example 402, Step A, 0.073g, 0.133 mmol) was converted to the title compound by a procedure similar to that described in Example 400, Step K.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 8.4 6 (1 H, d, <7 = 1.7 Hz), 8.17 (1 H, br s), 7.75 (1 H, s), 7.25 (2 H, br s, solvent overlap), 7.02 - 7.18 (2H, m), 5.08 (1H, br

s), 4.92 (1 H, d, J = 11.0 Hz), 3.78 (1 H, br s), 3.46 - 3.56 (1 H, m), 3.14 (1 H, dt, <7 = 14.2, 4.5 Hz) , 3.02 (1 H, br s),

2.77 - 2.95 (2 H, m), 2.43 - 2.50 (1 H, m), 2.36 (1 H, t, <7 = 13.8 Hz), 2.00 (1 H, dd, <7 = 13.7, 2.7 Hz), 1.79 - 1.89 (1H,

m), 1.50 - 1.59 (1 H, m), 1.48 (3 H, s), 1.15 - 1.20 (2H,

m), 0.98 - 1.05 (2 H, m), 0.51 (3 H, t, <7 = 7.6 Hz). Mass Spectrum (ESI) m / z = 56.8.2 [M + H]+.

EXAMPLE 403

2- ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) 3-methyl-l - ((S) -1- (N-methylcyclopropansulfonamido) butane -2-yl) 2-oxopiperidin-3-yl) acetic

MEXICAN INSTITUTE

PE PROPERTY;

INDUSTRIAL

1191

Stage A: N - ((S) -2 - ((3S, 5R, 6S) -3-A1Ü-6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) -3-methyl-2-oxopiperidin -l-yl) butyl) -Nmethylcyclopropansulfonamide

La (3S, 5R, 6S) -3-A1Í1-6- (4-chlorophenyl) -5- (5-chloropyridin-

3-yl) -1 - ((S) -l-hydroxybutan-2-yl) -3-methylpiperidin-2-one (Example 400, Step H, O.lg, 0.224 mmol) was converted to the title compound by a procedure similar to that described in Example 272, Step A using Nmethylcyclopropansulfonamide.

MS (ESI) m / z = 564.2 [M + H]1 .

Step B. 2 - ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) -3-methyl-l - ((S) -1- (NSC3

1192 IJ ”ΐ '

INS-U \ uJ Methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperiidLfílli-3il) acetic

N - ((S) -2- ((3S, 5R, 6S) -3-allyl-6- (4-chlorophenyl) -5- (5-chloropyridin-3-yl) -3-methyl-2-oxopiperidin-l -yl) butyl) -Nmethylcyclopropanesulfonamide (Example 403, Step A, 0.090g, 0.159 mmol) was converted to the title compound by a similar procedure to that described in Example 400, Step K.

1H NMR (500 MHz, Acetone-dand) δ ppm 8.38 (1 H, d, J = 1.7

Hz), 8.11 (1 H, s), 7.68 (1 H, t, J = 2.0 Hz), 7.21 - 7.43 (4 H, m), 4.92 (1 H, d, J = 10.8 Hz), 4.02 - 4.21 (1 H, m), 3.57 (1 H, ddd, (7 = 13.8, 10.9, 2.9 Hz), 2.99 (1 H, d, J = 14.2 Hz),

2.91 - 2.96 (5 H, m), 2.76 (1 H, d, (7 = 14.2 Hz), 2.53 - 2.62

<td>Spectrum</td><td>of Masses (ESI</td><td>) m / z = 582</td><td> .0</td><td>[M + H] 1 .</td><td></td><td></td><td></td>

EXAMPLE 404

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin-2-yl) 1 - ((S) -1- (ethylsulfonyl) butan-2-yl) - 3-methyl-2-oxopiperidin-3yl) acetic

1193

Stage A.

(3S, 5R, 6S) -3-Allyl-S- (3-chlorophenyl) -6- (5chloropyridin-2-yl) -1 - ((S) -1- (ethylthio) butan-2-yl) -3 methylpiperidin-2-one

La (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (5-chloropyridin2-yl) -1 - ((S) -l-hydroxybutane-2-yl) -3-methylpiperidin -2-one (Example 121, Step L, 100 mg, 0.224 mmol) was azeotroped three times in benzene on a rotary evaporator. The residue was dissolved in toluene and transferred to a reaction vessel. The container was soaked with argon. Ethantiol (33.1 pl, 0.447 mmol) was added followed by cyanomethylene tributylphosphoran '(216 pl, 0.894 mmol). The container was sealed and the solution was heated to 100 ° C for 4 h. The reaction mixture was diluted with DCM (10 ml) and Símaleimide (Silicycle, 2.1 g; 0.66 mmol / g; 40-63 microns) was i

1194

II filtered it. Concentrated on an evaporator for about 1 hr, rinsed with DCM. The rotary. The residue was dissolved in DCM and loaded directly onto a gold-capped 12 g Redisep® dry column (Teledyne Isco, Lincoln, NE). The column was eluted with a gradient from 0 to 5% MeOH: DCM. Fractions containing the desired product were combined and concentrated to provide the title compound as a colorless film.

Step B. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (5-chloropyridin-2-yl) -1 - ((S) -1- (ethylsulfonyl) butan-2-yl acid ) -3methyl-2-oxopiperidin-3-yl) acetic.

The (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (5-chloropyridin2-yl) -1 - ((S) -1- (ethylthio) butan-2-yl) - 3-methylpiperidin-2-one (Example 404, step A) was converted to the title compound by a similar procedure to that described in Example 395, Step C.

XH NMR (400MHz, CDC13) δ ppm 8.65 (d, J = 2.3 Hz, 1 Η),

7.48 (dd, J = 2.4, 8.1 Hz, 1 Η), 7.16 - 7.07 (m, 2 Η), 6.98 (s, 1 H), 6.92 - 6.86 (m, 2 Η), 5.00 (d, J = 10.2 Hz, 1 Η),

4.25 - 4.16 (m, 1 Η), 3.57 - 3.46 (m, 1 Η), 3.26 (br s, 1 Η),

3.15 (d, J = 15.3 Hz, 1 Η), 3.10 · - 3.01 (m, 2 H), 2.91 (d, J = 15.5 Hz, 1 H), 2.80 (d, J = 11.7 Hz, 1 Η), 2.36 (t, J, =

13.9 Hz, 1 H), 2.04 - 1.90 (m, 2 H),: Xí

1195

1.50 - 1.4 0 (m, 7H),

0.38 (t, J = 7.0 Hz, 3H); Mass Spectrum (ESI) m / z =

541.2 [M + H] '.

EXAMPLE 405

Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1 - ((S) -morpholin-2-yl) propyl) -2-oxopiperidin-3yl) acetic, TFA salt or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((S ) -1 - ((R) -morpholin-2-yl) propyl) -2oxopiperidin-3-yl) acetic, TFA salt

Step A. 2 - ((S) -1-hydroxypropyl) morpholin-4-carboxylate (S) -tert-butyl and 2 - ((S) -l-hydroxypropyl) morpholin-4-carboxylate (R) -tert-butyl and 2 - ((R) -hydroxypropyl) morpholin-4-carboxylate (S) -tert-butyl and 2 ((R) -1-hydroxypropyl) morpholin-4-carboxylate (R) -tertbutyl butyl

(rae) -tert-butyl (0.996 g, 4.63 mmol) (Tyger Scientific Inc., Ewing, NJ, USA) in THF (25 mL) at rt a solution of 3.0M ethylmagnesium bromide in diethyl ether (1851 mL) was added , 5.55 mmol) dropwise. After 4 hr, the mixture was quenched with NH solution4C1 sat. ac. The mixture was extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to provide a mixture of the title compounds.

Stage B.. 2 - ((3) -1 - (((4bromophenyl) sulfonyl) oxy) propyl) morpholin-4-carboxylate (S) tert-butyl and 2 - ((3) -1 - (((4bromophenyl) sulfonyl) oxy (propyl) morpholin-4-carboxylate (R) -tert-butyl and 2 - ((R) —1 - ((((4- bromophenyl) sulfonyl) oxy) propyl) morphplin-4-carboxylate (S) tert- butyl and (R) tert-butyl morpholin-4-carboxylate 2 - ((R) -l - (((4bromophenyl) sulfonyl) oxypropyl)

1197

To a solution of the diastereomer mixture of Example 405, step A (509 mg, 2,075 mmol;) in DCM (6.9 mL) was added DMAP (558 mg, 4.56 mmol) and 4bromobenzenesulfonyl chloride (795 mg, 3.11 mmol). After stirring for 18 hr, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SW4, filtered and the filtrate was concentrated. . The residue was purified by flash chromatography on silica gel (column 40 g, eluent: 5 to 30% EtOAc / hexanes) to provide a mixture of the title compounds.

Stage C. 2 - ((S) -1 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-l-yl ) propyl) morpholin-4-carboxylate (S) -tert-butyl and 2- ((S) -1 - ((3S, 5R, 6S) -3-allyl5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lyl) propyl) (R) -tert-butyl morpholin-4-carboxylate and 2 - ((R) - 1 - ((3S, 5R, 6S) -3-allyl-5 - (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-2-oxopiperjidin-l-yl) propyl) morpholin-4-carboxylate of (S) -tert-butyl and 2 - ((R) - 1 - ((3S, 5R, 6S) -3-allyl-5- (3IMPI

1198 chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-lil) propyl) morpholin-4-carboxylate (R) -tert-butyl

124 mg, 0.267 mmol) were dissolved in toluene and concentrated in vacuo twice. Dioxane (1 mL) was added followed by sodium tert-butoxide (25.7 mg, 0.267 mmol). The mixture was heated at 85 ° C for 2 days. The mixture was partitioned between EtOAc and NH solution4C1 diluted ac. The organic layer was washed with brine, dried over Na2SW4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (column 4 g, eluent: 5 to 35% EtOAc / hexanes) to provide a mixture of the title compounds.

Stage D. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l - (((S) -1 - ((S) -morpholin-2 -yl) propyl) -2oxopiperidin-3-yl) acetic, TFA salt or 2 - ((3R, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- ((S) -1 - ((R) -

morpholin-2-yl) propyl) -2-oxopiperidin-3-yl) acetic, TFA salt

1199

The mixture of diastereomers obtained in Example 404,

Step C (100mg, 0.166mmol) was dissolved in THF (1mL). Water (about 0.5 mL) was added until the solution became cloudy. T-BuOH was added until the solution became clear. NMO (29.2 mg, 0.249 mmol) was added followed by 4% aq osmium tetroxide solution. (5.28 μΐ, 0.831 pmol). After stirring for 18 h, another 3 drops of OsO solution were added4 at 4% ac. After stirring for 4 h, 0.20 mL of Jones reagent was added. After 2 days, the mixture was partitioned between NaHCO3 ac. and DCM. The aqueous layer was extracted with DCM 'and EtOAc. The combined organic layers were washed with brine, dried over Na2SW4, filtered and the filtrate was concentrated. The mixture was stirred in DCM (3 mL) and TFA (1 mL, 12.98 mmol) for 25 minutes and concentrated. The residue was purified by preparative reverse phase HPLC (column: Gemini-NX Ci8 5um; Phenomonex, Torrance, CA; eluent: 30 to 50% MeCN + 0.1% TFA in water + 0.1% TFA over 20 minutes) to provide three of the four possible diastereomers of the title compound. The first elution of these diastereomers is Example 405:

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.33 (t, J = 7.5 Hz,

H) 1.30 - 1.42 (m, 1H) 1.47 (s, 3H) 1.68 -1.82 (m, 1H)

1.82 - 1.91 (m, 1H) 2.19 - 2.26 (m, 2H) 2.56-2.64 (m, 3

1200 institute.

FROM THE i'RU .- 'li'-A'J,

INCUc TíüAl ----

<td>(br s, 1</td><td>H) 11.</td><td> . 54</td><td>(br s</td><td>, 1 HOUR)</td><td>Mass Spectrum (ESI)</td><td>m / z =</td>

EXAMPLE 406

Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((R) -1 - ((S) -morfolin-2-yl) propyl) -2-oxopiperidin-3yl) acetic, TFA salt or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-met.yl-l- ( (R) -1- ((R) -morfolin-2-yl) propyl) -2-

Additional elution from the HPLC column in Example

405, Step D provides one of the title compounds as the second elution isomer.

XH NMR (400 MHz

CHLOROFORM-d) δ ppm 0.93 - 1.11 (m, 3

1201,

IMPI

MEXICAN INSTITUTE

D £ LA PnOUlMD

INDUSTRIAL

Mass Spectrum (ESI) m / z = '519.1 (M + 1).

EXAMPLE 407

Acid

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 methyl-1 - ((R) -1 - ((R) -morfolin-2-yl) propyl) -2-oxopiperidin-3yl) acetic, TFA salt or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -3-methyl-l - ((R ) -1 - ((S) -morfolin-2-yl) propyl) -2-

405 provides the other (relative to Example 406) of the title compounds as the third elution isomer.

»• ττν.ΑΏΛ - .. ·, ·! -'-. • .v .-. Rr.ss sl

1202

Hz, XH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 (t,> 7.5

<td>(br s, 1</td><td>H).</td><td>Is</td><td colspan="2">; pectro de Masas</td><td>(ESI) m / z = 519.1 (M</td><td>+ i).</td>

EXAMPLE 408

2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (N-methylcyclopropansulfonamido) butan-2-yl) -3- acid (2morpholinyl) -2-oxopiperidin-3-yl) acetic

Step A. (3R, 5R, 6S) -3-Allyl-l - ((S) -l - ((tertbutyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2 - ((4-methoxybenzyl) oxy) ethyl) piperidin-2-one and

1203 (3S, 5R, 6S) -3-Alil-l - ((S) -1- ((tert-

butyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2 - ((4-methoxybenzyl oxy) ethyl) piperidin-2-one

The title compound was obtained from (3R, 5R, 6S) -l - ((S) —1 - ((tert-butyldiphenylsilyl) oxy) butan-2-yl) 5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example emplo

127, Step A) and 1 - ((2-iodoethoxy) methyl) -4-methoxybenzene [J.

Am. Chem. Soc., 124, 8206-8219, (2002)] by a procedure similar to that described in Example 69, Step A.

Purification of the residue by flash gel chromatography up to 20% EtOAc / hexane, gradient elution over 30 min) provides the desired products as a mixture of C3 epimers.

834.4 (M + l) and 856.4 (M + Na).

Stage B. (3R, 5R, 6S) -3-Allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -l - ((S) -l-hydroxybutan-2-yl) -3- (2- ((4methoxybenzyl) oxy) ethyl) piperidin-2-one

1204

To a solution of a mixture of (3R, 5R, 6S) -3-allyl-l ((S) -1 - ((tert-butyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2 - ((4methoxybenzyl) oxy) ethyl) piperidin-2-one and (3S, 5R, 6Sj-3-allyl-l ((S) -1 - ((tert-butyldiphenylsilyl) oxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2 - ((4methoxybenzyl) oxy) ethyl) piperidin-2-one (19.23g, 23.03 mmol;

Example 408, Step A) In .THF (92 ml) at rt a solution of TBAF (1.0M in THF, 34.5 ml, 34.5 mmol) was slowly added. The reaction was monitored by LCMS, and when judged complete it was concentrated under reduced pressure (no heat), then diluted in 400mL EtOAc. HC1 (IN, 150 ml) was added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed several times with water, dried over MgSCU, filtered, and the filtrate concentrated. Purification by chromatography on silica gel (eluent: 10-20% EtOAc / hexane, gradient elution over 30 min) provides the compound of. title along with its C3 epimer as a colorless, transparent foam. Stereoisomers

1205

MEXICAN INSTITUTE

OF THE PROPERTY _

INDUSTRIAL _ separated by chiral HPLC (flow ratio:

individual

120 ml / min, lg by injection, on a Chiralcel® OD-H cm ID x cm column, 20 pm; Daicel Chemical Industries LTD, using 6% isopropyl alcohol / hexane as the eluant) to give the title compound as the first elution isomer (tR

11-23 min) as a clear, viscous oil.

<td></td><td colspan="3">XH NMR (500 MHz, CHLOROFORM-d) δ ppm</td><td> 0.61</td><td>(t,</td><td> 0=1.3</td><td>Hz,</td>

H) 7.10

H) 6.85 (m, 2

7.06 (t, <7 = 7.8 Hz,

7.21 (m, <7 = 8.6

Hz, 2H). Mass Spectrum (ESI) m / z = 596.2 (M + H) 'and 618.2 (M + Na).

Stage C. N- ((S) -2- ((3R, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2- (4-methoxybenzyloxy) ethyl ) -2-oxopiperidin-lil) butyl) -N-methylcyclopropansulfonamide

1206

INSTITUTO MEXIlA.u »-. FROM THE FROflcDAl) IN'DUSlRIAí.

The title compound was prepared from (3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxybutan-2-yl) -3- (2- (4-methoxybenzyloxy) ethyl) piperidin-2one (Example 408, Step B) and N-methylcyclopropansulfonamide by a procedure similar to that described in Example 201, Step A.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.55 (br s, 3 H)

<td>(s,</td><td colspan="4">1 HOUR) . Mass Spectrum (ESI) m / z =</td><td> 713.2</td><td>(M + l) and</td><td> 735.2</td>

(M + Na).

Stage D.

N - ((S) -2 - ((3R, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (41207

chlorophenyl) -3- (2-hydroxyethyl) -2-oxopiperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide

To a solution of 3.09g (4.33 mmol) N - ((S) —2 ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- ( 2- (4methoxybenzyloxy) ethyl) -2-oxopiperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide (Example 408, step C) in a mixture of DCM (82 mL) and water (4.56 mL) [18: 1] 2 was added , 6di-tert-butylpyridine (2.93 mL, 12.99 mmol) followed by DDQ (3.93 g, 17.32 mmol). The reaction mixture was vigorously stirred at room temperature for 15 min. The reaction mixture was diluted with 150 mL of NaHCC solution> 3 sat / brine and extracted into 600 mL of ethyl acetate, then 200 mL of EtOAc x 2 (the precipitate was removed by filtration). The combined organic layers were dried over MgSO4, filtered and the filtrate was evaporated. Purification by chromatography on silica gel (eluent: 50-100 %%

EtOAc / hexane, gradient elution) provides the product

1208

IMPI institu'O v.:;'CA'O

OF THE INDUSTRIAL PRC? '£ fAD

desired as a foam.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 0.54 (br s, 3 H)

<td>s, 1H) 7.26</td><td colspan="2">(br</td><td>s, 2H).</td><td colspan="2">Mass Spectrum (ESI) m /</td><td colspan="2">z = 593.2</td>

(M + l) and 615.2 (M + Na).

Stage E. N- ((S) -2- ((3R, 5R, 6S) -3-AÜ1-5- (3-chlorophenyl) -6- (4 chlorophenyl) -2-OXO-3- (2 ([ triisopropylsilyl) oxy) ethyl) piperidin-l-yl) butyl) -N methylcyclopropansulfonamide

To a solution of 2.52 g (4.25 mmol) of N - ((S) -2 ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (21209 hydroxyethyl) -2-oxopiperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide (Example 408,

Step D), DMAP (0.026 g, 0.212 mmol), and imidazole (0.723 g, 10.61 mmol) in DCM (16.98 mL) at 0 ° C was added slowly by syringe TIPS-C1 (1.17 mL, 5.52 mmol). The reaction was stirred at room temperature, with the addition of reagents until the reaction was judged complete by LCMS and TLC. The reaction mixture was quenched by the addition of 6 mL of MeOH, then extracted with DCM (70ml x 2). The combined organics were washed with water (30 mL), NH solution4C1 satd. ac. (20mL), dried over

Na2SO4, filtered and the filtrate was concentrated. Purification by chromatography on silica gel (eluent: 0 to 40% EtOAc / DCM, gradient elution) provides the title compound as a clear, colorless oil.

Mass Spectrum (ESI) m / z = 749.4 (M + l).

Stage F. N - ((S) -2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2-oxo-3- (2-oxoethyl) -3- ( 2 (triisopropylsilyloxy) ethyl) piperidin-1-yl) butyl) -N methylcyclopropansulfonamide

The

1210

N - ((S) -2 - ((3R, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -2-oxo-3- (2- (triisopropylsilyloxy) ethyl ) piperidin1-yl) butyl) -N-methylcyclopropansulfonamide (Example 408, Step E) was treated by a procedure similar to that described in Example 91, Step E. Purification by chromatography on silica gel (12g SiO2, eluent: 0 to 30% EtOAc / hexane, gradient elution) provides the title compound as a clear oil.

Mass Spectrum (ESI) m / z = 751.2 (M + l)

Stage G. N - ((S) -2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3- (2-morpholinyl) -2-oxo-3- ( 2 (triisopropylsilyloxy) ethyl) piperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide

1211

IMPI

VFXMANO INSTITUTE

SHE ·· 'AV

N - ((S) -2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-3- (2-oxoethyl) -3- (2 ( (triisopropylsilyl) oxy) ethyl) piperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide (Example 408, Step F) and morpholine were combined according to a procedure similar to that described in Example 91, Step F. Purification by gel chromatography Silica (eluent: 50-100% EtOAc / DCM, gradient elution over 15 min) provides the title compound as a clear, colorless glass.

Mass Spectrum (ESI) m / z = 822.4 (M + l)

Stage Η. N - ((S) -2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2-hydroxyethyl) -3- (2-morpholinethyl) -2oxopiperidin- l-yl) butyl) -N-methylcyclopropansulfonamide

The

N- ((S) -2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2-morpholinyl) -2-OXO-3- (2 (triisopropylsilylox .i) ethyl) piperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide (Example 408, Step G) was treated 10 according to a procedure similar to that described in

Example 69, step D to provide the title compound.

<td></td><td>XH NMR (500 MHz,</td><td>Chlorine</td><td colspan="2">OFORMO-d) δ ppm 0.53 (t, <7 = 7.6</td><td>Hz,</td>

Mass Spectrum (ESI) m / z = 666.2 (M + l)

1213

Stage I. 2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (N-methylcyclopropanesulfonamido) butan-2yl) -3- acid (2-morpholinyl) -2-oxopiperidin-3-yl) acetic

N - ((S) -2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2-hydroxyethyl) -3- (2-morfolinetilj-2oxopiperidin- l-yl) butyl) -N-methylcyclopropansulfonamide (Example 408, Step H) was treated according to a procedure similar to that described in Example 69, step E. The reaction (using 4 eq. of Jones Reagent) is completed in less than 2 minutes at 0 ° C, after which it was quenched with MeOH (10 eq) and diluted in EtOAc. The solution was decanted from the insoluble material, washed with NaHCO solution3 ac., dried over MgSO4, filtered and concentrated under reduced pressure. Purification by HPLC prep. phase reversed (Sunfire Prep Cis OBD 10 pm column (Waters, Milford, MA), gradient elution from 40% MeCN in water to 75% MeCN in water over one period

<td>30 min, where both solvents</td><td>they contain</td><td>TFA</td><td>to the</td><td> 0.1%)</td>

<td>provides the title compound</td><td>like salt</td><td>TFA.</td><td></td><td></td>

<td>XH NMR (500 MHz, CHLOROFORM-d)</td><td>δ ppm 0.49</td><td>(t,</td><td> <7=7</td><td>.5 Hz,</td>

H) 0.96 - 1.16 (m, 3 H) 1.17 - 1.28 (m, 1 H) 1.56 - 1.67 (m, 1 H) 1.85 (dt, <7 = 15.2, 7.7 Hz, 1 H) 2.00 (dd, <7 = 13.6, 3.1

Hz, 1H) 2.06 - 2.16 (m, 1H) 2.22 - 2.41 (m, 3H) 2.57 1214

2.66

Η) (m, 1 Η)

MEXICAN INSTITUTE

2.71 (br s, 1H) 2.85 (s, 3H) 2.87 - 2.96 (m,

2.99 (br s, 1 Η) 3.03 (br s,

Η)

3.34 (br s, 1H) 3.52 - 3.66 (m, 2H) 3.70 (d, 7 = 12Hz, 1H)

3.79 - 3.96 (m, 2H) 4.03 (d, 7 = 11Hz, 2H) 4.38 (br s, 1H)

4.68 (d, 7 = 10.5 Hz, 1H) 6.84 - 6.94 (m, 2H) 6.98 (s, 2H)

7.10 - 7.17 (m, 2H) 7.22 - 7.27 (m, 1H) 8.42 (br s, 3H)

11.01 (br s, 1H). Mass Spectrum (ESI) m / z = 680.2 (M + l)

Examples 409-411 were prepared from N - ((S) 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-3- ( 2oxoethyl) -3- (2- (triisopropylsilyloxy) ethyl) piperidin-1yl) butyl) -N-methylcyclopropansulfonamide (Example 408, Step F) by similar procedures. to those described in Example 4 08, replacing morpholine in Step G with the appropriate amine.

<td>Example</td><td>R =</td>

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

1215

EXAMPLE 409

2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3- (2 (1,1-dioxidothiomorpholin) ethyl) -1 - ((S) -1 acid - (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic, TFA salt XH NMR (500 MHz, CD3OD) δ ppm 0.51 (t, 7 = 7.5 Hz, 3 H)

1.00 - 1.07 (m, 1H) 1.07 - 1.19 (m, 2H) 1.21 - 1.30 (m, 2H) 1.54 - 1.68 (mj 1H) 1.79 - 1.91 (m, 1H) 1.95 (dd, 7 = 13.7, 2.7 Hz, 1 H) 2.26 (t, 7 = 13.5 Hz, 2 H) 2.29 - 2.39 (m, 2 H) 2.61 (d, 7 = 13 Hz, 1 H) 2.73 (br s, 1 H) 2.79 (d, 7 = 13.7

Hz, 1H) 2.84 (s, 3H) 2.88 - 2.96 (m, 1H) 3.2 | 0 (ddd,

7 = 13.4, 10.7, 3.1 Hz, 1 H) 3.52 (br s, 3 H) 3.57 (d, 7 = 8.3 Hz, 3 H) 3.86 (br s, 4 H) 4.43 (t, 7 = 12.1 Hz, 1 H) 4.70 (d, 7 = 10.8 Hz, 1 H) 6.87 (d, 7 = 7.1 Hz, 1 H) 6.99 (s, 3 Hj 7.12 -

7.21 (m, 2H) 7.27 (br s, 1H). Mass Spectrum (ESI) m / z =

728.2 (M + l).

1216

EXAMPLE 410

Acid 2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) 1- (N-methylcyclopropansulfonamido) butan-2-yl) -2- oxo-3- (2-

<td colspan="8">(pyrrolidin-l-yl) ethyl) piperidin-3-yl) acetic, HCI salt</td>

<td>(d,</td><td colspan="3">7 = 7.8 Hz, 2H). Spectrum</td><td colspan="2">Masses (ESI)</td><td>m / z = 728</td><td> .2</td>

(M + l).

EXAMPLE 411

2- ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3- (2 (dimethylamino) ethyl) -1 - ((S) -1- (N-methylcyclopropansulfonamido) ) butan-2-yl) -2-oxopiperidin-3yl) acetic, HCI salt

IMPI (ddd, 7 = 14.5, 7.6, 5 Hz, 1 H) 2.29 - 2.44 (m, 2 H) 2.55

1217

(m, 1H) 7.09 (s, 1H) 7.12 - 7.26 (m, 3H) 7.32 (d, 7 = 7.6

Hz, 2H). Mass Spectrum (ESI) m / z = 638.2 (M + l).

EXAMPLE 412

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (Nmethylcyclopropansulfonamido) butan-2-yl) -3- (2 -morpholinyl) -2oxopiperidin-3-yl) acetamide, HC1 salt

HATU (119 mg, 0.313 mmol) was added to a solution of mg (0.522 mmol) of the 2 - ((3S, 5R, 6S) -5 (3-chlorophenyl) -6- (4-chlorophenyl) TFA salt. ) -1 - ((S) -1- (Nmethylcyclopropansulfonamido) butan-2-yl) -3- (2-morpholinethyl) -2oxopiperidin-3-yl) acetic (Example 408, step I) and TEA (72.8 pL, 0.522 mmol) in DMF (2.09 mL). The mixture was stirred for 3

1218

INDLST ^ íaL min at room temperature, then a NH solution3 (7M in

MeOH, 0.45 mL, 3.13 mmol) was added. The starting material was consumed within minutes. The mixture was concentrated under reduced pressure and purified by prep HPLC. reverse phase (Sunfire Prep Cié OBD 10 pm column (Waters, Milford, ΜΑ), gradient elution from 40% MeCN in water to 75% MeCN in water over a period of 30 min, where both solvents

<td>they contain</td><td>TFA 0.1%). Added</td><td>some</td><td>drops</td><td>HC1</td>

<td>before</td><td>lyophilization, so</td><td>that he</td><td>compound</td><td>of the</td>

<td>title is</td><td>generated as the HC1 salt.</td><td></td><td></td><td></td>

<td colspan="2">1H NMR (500 MHz, CHLOROFORM-d) δ</td><td>ppm 0.55</td><td>(t, 7 = 7.6</td><td>Hz,</td>

<td colspan="2">Hz, 2H). Spectrum</td><td>of</td><td>Masses</td><td>(ESI) m / z =</td><td>679.2 (M + l)</td><td> •</td><td></td>

IMPI

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (N1219

EXAMPLE 413 methylcyclopropansulfonamido) butan-2-yl) -3- (2-morpholinyl) -2oxopiperidin-3-yl) acetamide, HC1 salt

Chlorophenyl) -3- (2- (1,1-dioxidothiomorpholino) ethyl) -1 - ((S) -1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic acid (Example 409) it was treated according to a procedure similar to that described in the Example

412 to provide the title compound.

XH NMR

Hz, 3H)

H) 2.75

H) 2.59 (dt, <7 = 12.6, 6.4 Hz, (d, <7 = 14.7 Hz, 1

H) 3.37

3.49 (m, 1H) 3.50 3.65 - 3.75 (m,

H) 3.95 (br s, 4 H) 4.38 (t, (s, 3 H) 2.98

122 0

IMPI

IhKTfTUTO

7 = 12 Hz, 1 H) 4.79 (d, 7 = 10.8 Hz, 1 H) 7.01 (dd, 7 = 6.5, 2.1 a—— I III

Hz, 1H) 7.07 (s, 1H) 7.10 - 7.26 (m, 3H) 7.32 (d, 7 = 7.1

Hz, 2H). Mass Spectrum (ESI) m / z = 727.2 (M + l).

EXAMPLE 414

Acid (IR, 3S, 6S, 7R) -7- (3-Chlorophenyl) -6- (4-chlorophenyl) -5- ((S) -

1- (N-methylcyclopropansulfonamido) butan-2-yl) -4-oxo-5 azaspiro [2.5] octan-l-carboxylic acid and (3S, 6S, 7Rj-7- (3-Chlorophenyl) -6- (4-chlorophenyl) -5 - ((S) -1- (Nmethylcyclopropansulfonamido) butan-2-yl) -4-oxo-5azaspiro [2.5] octan-l-carboxylic

Step A. (3R, 5R, 6S) -3-Allyl-l - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- ((2- (trimethylsilyl) ethoxy) methyl) piperidin-2-one

1221

Lithium bis (trimethylsilyl) amide, (solution 1M in toluene, 4.7 6 mL, 4.7 6 mmol) was added to a solution of (5R, 6S) -1- ((S) -1- (tert-butyldiphenylsilyloxy) butan -2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) piperidin-2-one (Example 185, Step C, 2.0 g, 3.17 mmol) and 3-bromopropene (0.27 4 mL, 3.17 mmol) in THF at -78 ° C. The reaction was warmed to 0 ° C and stirred for 2 hours. After re-cooling to -78 ° C, a solution of LDA (7.93 mmol in THF) was added followed by 2- (chloromethoxy) ethyltrimethylsilane (0.842 mL, 4.76 mmol). The reaction was heated to 50 ° C and stirred for 1.5 hour. The reaction mixture was diluted with EtOAc and washed with HC1 (IN). The organic extract was washed with NaCl satd. and dried on Na2SW4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel, eluting with a gradient from 0% to 20% EtOAc in hexane, to provide the (3S, 5R, 6S) -3-allyl-l- ((S) -1 ( tert-butyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((2- (trimethylsilyl) ethoxy) methyl) piperidin-2-one as the first elution diastereomer and the compound of

1222

title as the second diastereomer as an oil.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm -0.07 - 0.05 (m, 9

H) 0.37 (t, 7 = 7.6 Hz, 3 H) 0.91 - 1.05 (m, 3 H) 1.28 - 1.46 (m, 2 H) 1.79 (dd, 7 = 13.6, 2.8 Hz, 1 H) 1.86 (ddd, 7 = 14.1, 9.3, 7.2 Hz, 1H) 2.35 (dd; 7 = 13.8, 7.9 Hz, 1H) 2.49 - 2.65

5.19 (m, 2H) 5.76 - 5.95 (m, 1H) 6.66 (d, 7 = 7.6 Hz, 1H)

6.92 (t, 7 = 1.8 Hz, 2H) 6.97 - 7.10 (m, 3H) 7.15 (d, 7 = 7.4

Hz, 2H).

Stage B. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl)

1- ((S) -l-hydroxybutan-2-yl) -3 - ((2 (trimethylsilyl) ethoxy) methyl) piperidin-2-one

A 1M solution of TBAF in THF (2.15 mL, 2.15 mmol) was added to a solution of (3S, 5R, 6S) -3-allyl-l - ((S) -1- (tertbutyldiphenylsilyloxy) butan-2-yl) -5- (3-chlorophenyl) -6- (41223

chlorophenyl) -3 - ((2- (trimethylsilyl) ethoxy) methyl) piperidin-2-one

<td>(Example</td><td>414, Step A; 860 mg, 1,074</td><td>mmol)</td><td>in THF. The</td>

<td>reaction</td><td>heated to reflux by 3</td><td>hours</td><td>After</td>

<td>cool,</td><td>diluted with EtOAc and washed with</td><td>HC1</td><td>(IN in water).</td>

<td colspan="2">The organic extract was washed with NaCl</td><td>satd</td><td>and dried on</td>

Na2SO4. The solution was filtered and concentrated to give the crude material as a glass which was purified by chromatography on silica eluting with 20% EtOAc in hexane, to provide the title compound as a solid.

Stage C. N - ((S) -2 - ((3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-3 - ((2- ( trimethylsilyl) ethoxy) methyl) piperidin-1) butyl) cyclopropansulfonamide

The title compound was prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1hydroxybutan-2-yl) -3 - ((. 2 (trimethylsilyl) ethoxy) methyl) piperidin-2-one (Example 414,

Step B) and N-methylcyclopropansulfonamide by a

1224

procedure similar to that described in Example 201, Step A.

The product was purified by chromatography through a pre-packed RediSep® silica gel column (Teledyne Isco, Lincoln, NE) (12 g), eluting with a gradient from 0% to 80% EtOAc in hexane, to provide the compound of the title like an oil.

Mass Spectrum '(ESI) m / z = 665.2 (M + l).

Stage D. N - ((S) -2 - ((3S, 5R, 6S) -3-A1H-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-3 - ((2- ( trimethylsilyl) ethoxy) methyl) piperidin1-yl) butyl) -N-methylcyclopropansulfonamide

A solution of N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-ΟΧΟ-3 - ((2 (trimethylsilyl ) ethoxymethyl) piperidin-1yl) butyl) cyclopropansulfonamide (Example 414, Step C, 1.5 g,

2,253 mmol) in THF was treated with sodium hydride (60% dispersion in mineral oil, 6.76 mmol) and iodomethane (0.280

1225

WST1TUTC mhmcano DE LA ΡκυΡ-Λ '; ·1? < · <

mi, 4.51 mmol) at room temperature for 3 hours. Mix

The reaction one went out with

HCI (IN) and diluted with DCM organic extract washed with satd NaCl and dried over Na2SW4.

The solution was filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography through a pre-packed RediSep® silica gel column (Teledyne Isco, Lincoln, NE) (4g), eluting with a gradient from 0% to 80% EtOAc in hexane, to provide the compound of the title like an oil.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm -0.06 - 0.03 (m, 9 H) 0.54 (t, 0 = 6.9 Hz, 3 H) 0.80 - 1.03 (m, 5 H) 1.13 (d, 0 = 8.8 Hz, 1 H) 1.14 - 1.23 (m, 2 H) 1.56 - 1.65 (m, 2 H) 1.75 - 1.93 (m, 2 H) 2.28 (t, <J = 4.5 Hz, 1 H) 2.51 (t, 0 = 13.8 Hz, 1

1226

Step E. Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3 yl) methyl

A solution of N- ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3 chlorophenyl) -6- (4-chlorophenyl) -2-oxo-3- ((2 ( trimethylsilyl) ethoxy) methyl) piperidin-l-yl) butyl) -Nmethylcyclopropansulfonamide (Example 414, Step D, 1.85 g, 2.72 mmol) in DCM was treated with boron trifluoride (diethyl etherate, purified, redistilled, 0.672 ml, 5.44 mmol ) for 2 hours. The mixture of. Reaction was diluted with DCM and washed with satd NaCl. The organic extract was dried over Na2SW4, filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography on a pre-packed RediSep® Silica Gel Column (Teledyne Isco, Lincoln, NE) (12 g), eluting with a gradient from 0% to 80% EtOAc in hexane, to provide the N- ( (S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (hydroxymethyl) --2-oxopiperidin-l-yl) butyl) -N-methylcyclopropansulfonamide intermediate (1.55 g, 2.67 mmol,

Yield%) as an oil which was used directly in the next reaction.

Methanesulfonyl chloride (0.200 ml, 2.59 mmol) was added to a solution of N - ((S) -2 - ((3S, 5R, 6S) -3-allyl-5- (3 chlorophenyl) -6- (4- chlorophenyl) -3- (hydroxymethyl) -2-oxopiperidin1-yl) butyl) -N-methylcyclopropansulfonamide (1.0g, 1.725mmol) and triethylamine (0.480ml, .3.45mmol) in DCM. The reaction was stirred for 2 hours. The reaction mixture was diluted with DCM and washed with HCI (IN) and NaCI satd and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography through a pre-packed RediSep® silica gel column (Teledyne Isco, Lincoln, NEj (12 g), eluting with a gradient from 0% to 80% EtOAc in hexane, to provide the compound of the titer as an oil Mass Spectrum (ESI) m / z = 657.2 (M + l).

Step F. ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -1- (N-methylcyclopropansulfonamido) butan2-yl) -2- methanesulfonate OXO-3- (2-oxoethyl) piperidin-3-yl) methyl

1228

Ozone is bubbled 'through

a solution of chlorophenyl) -l - ((S) -1- (N-methylcyclopropansulfonamido) butan-2yl) -2-oxopiperidin-3-yl) methyl (Example 414, Step

1,703 mmol) in 10% MeOH-DCM at -78 ° C until blue.

followed by the

17.03 mmol).

The reaction adding

The ambient reaction. The raw material a column of (Teledyne Isco, 0% gradient the compound of the

H) XH NMR

0.95 (dt,

2.32 (m, 2

E, 1.12 g, develop was purged with nitrogen gas, warmed to temperature, purified by prepackaged RediSep® silica gel chromatography

Lincoln, NE) (12 g), eluting with up to 80% EtOAc in hexane, to provide title as an oil.

(400

J = 5

H)

<td>MHz,</td><td colspan="2">CHLOROFORM-d)</td><td>δ ppm 0.35 - 0</td><td> .59</td><td>(m, 3</td>

2.94 - 3.11 (m,

- 4.82 (m, 3 Η) 5.02

1229'

7.15 - 7.23 (m, 2 Η), 9.89 (s, 1H).

Step G: 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) - Methyl 3 (((methylsulfonyl) oxy) methyl) -2-oxopiperidin-3-yl) acetate

A methanesulfonate solution of ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (Nmethylcyclopropansulfonamido) butan-2-yl) -2-ΟΧΟ -3- (2oxoethyl) piperidin-3-yl) methyl (Example 414, Step F, 1.0 g, 1,516 mmol) in MeOH was treated with Oxone (0.932 g, 1,516 mmol) over the weekend. The reaction mixture was diluted with DCM and water. The organic extract was washed with NaCl satd and dried over Na2SW4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The product was purified by chromatography through a pre-packed RediSep® silica gel column (Teledyne Isco, Lincoln,

ΝΕ) (12 g), eluting with a gradient of in hexane, to provide the compound

1230

0% to 80% EtOAc of the title as an oil.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.46 - 0.63 (m, 5

H) 1.01 (dd, J = 7.7, 2.3 Hz, 4 H) 1.15 - 1.26 (m, 4 H) 1.79 -

Stage H. 7- (3-Chlorophenyl) -6- (4-Chlorophenyl) -5 - ((S) —1— (Nmethylcyclopropansulfonamido) butan-2-yl) -4-oxo-5azaspiro [2.5] octan-l- (1S, 3S, 6S, 7R) -methyl carboxylate and 7 (3-chlorophenyl) -6- (4-chlorophenyl) -5 - ((S) -1- (N-methylcyclopropanesulfonamido) butan-2-yl) -4 -oxo-5azaspiro [2.5] octan-l-carboxylate (IR, 3S, 6S, 7R) -methyl

CI

A

1231 bis (trimethylsilyl) amide solution

lithium, (1.0M in toluene, 290 μΐ, 0.290 mmol) was added to a solution of

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (N methylcyclopropansulfonamido) butan-2-yl) -3 (( Methyl (methylsulfonyl) oxy) methyl) -2-oxopiperidin-3-yl) acetate (Example 414, Step G, 200 mg, 0.290 mmol) in THF at 0 ° C for 10 min. The reaction mixture was quenched with HC1 IN and extracted with DCM. The organic extract was washed with Na solution2CO3 sat. ac. and dried on Na2SW4. The solution was filtered and concentrated in vacuo to give the crude material as a white glass. The product was purified by chromatography on a pre-packed Redi-Sep silica gel column (4g), eluting with a gradient from 0% to 80% EtOAc in hexane, to provide the title compounds as a mixture of diastereomers.

XH NMR (400 MHz, CHLORINE FORM-cf) δ ppm 0.40 (t, <7 = 7.5 Hz,

H) 0.69 - 0.86 (m, 3 H) 0.86 - 0.95 (m, 2 H) 1.01 - 1.14 (m, 3 H) 1.14 - 1.23 (m, 2 H) 1.25 (dd, <7 = 6.5, 4.3 Hz, 2 H)

<td> 7.06</td><td>(d,</td><td> <7=5.</td><td>1 Hz,</td><td>2H) 7.17 (s, 2H).</td><td colspan="2">Spectrum</td><td>of</td><td>Masses</td>

(ESI) m / z = 593.2 (M + H+) .

Stage I:

acid

1232

butan-2yl) -4-oxo-5-azaspiro [2.5] octan-l-carboxylic acid and (1S,

3S, 6S, 7R) -7- (3-Chlorophenyl) -6- (4-chlorophenyl) -5 - ((S) -1- (N methylcyclopropansulfonamido) butan-2-yl) -4-oxo-5 azaspiro [ 2.5] octan-l-carboxylic

The diastereomeric ester mixture from Example 414, Step H was treated with NaOH (3N in MeOH) overnight at room temperature. The reaction mixture was acidified with HC1 IN (IN) and extracted into DCM. The organic extract is

<td>washed with</td><td>NaCl satd and dried</td><td colspan="2">on Na2SO4. The product</td><td>I know</td>

<td>purified</td><td>by chromatography</td><td>on silica,</td><td>eluting with</td><td>a</td>

<td>gradient</td><td>40% EtOAc in</td><td>hexane for</td><td>provide</td><td>the</td>

title compounds as a mixture of diastereomers as a white glass.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.39 (t, <7 = 7.5 Hz,

H) 0.81 (s, 1H) 0.89 - 1.02 (m, 2H) 1.16 - 1.21 (m, 2H)

1.21 - 1.30 (m, 1 H) 1.37 (dd, <7 = 9.2, 5.7 Hz, 1 H) 1.47 (ddd, <7 = 14.5, 7.6, 4.1 Hz, 1 H) 1.84 (ddd, J = 14.5, 8.7 , 7.3 Hz, 1 H) 1.95 - 2.05 (m, 1 H) 2.18 (dd, <7 = 7.0, 5.7 Hz, 1 Hj 2.22 -

6.82 - 6.95 (m, 3H) 6.98 - 7.11 '(m, 2H) 7.18 (d, <7 = 8.4 Hz

123 3

Η); Mass Spectrum (ESI) m / z = 579.1

EXAMPLE 415

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2S, 3S) -1,2-dihydroxipentan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic or 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((2R, 3S) -1,2-dihydroxipentan- 3-yl) -3-methyl-2oxopiperidin-3-yl) acetic

Stage A. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -l-oxobutan-2-yl ) piperidin-3-yl) methyl acetate

To a stirred solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2-yl) -3methyl-2- oxopiperidin-3-yl) methyl acetate (Example 186, Step A, 360 mg, 0.752 mmol) in DCM (3.76 mL) was added

Persodyne Dess-Martin (383 mg,

0.903 mmol)

1234 and the reaction was stirred at rt for 20 minutes. After this time the reaction was treated with Na2S2OR3 (30 mL, saturated aqueous solution) and DCM (40 mL) and stirred at rt for 10 minutes. The organic layer was separated and washed with Na2S2OR3 (20 mL, saturated aqueous solution) and NaHCO3 (20 mL, saturated aqueous solution), dried over MgSO4, filtered and concentrated to give the title compound. MS (ESI) m / z = 476.0 (M + l).

Stage B. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -pent-l-en-3 -il) piperidin-3-yl) methyl acetate

Tebbe reagent (Bis (cyclopentadienyl) -μchloro (dimethylaluminum) -μ-m'ethylentitanium, 0.5M solution in toluene, 1.7 mL, 0.85 mmol) was added dropwise over 5 minutes to a stirred solution of 2 - ((3R Methyl 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -l-oxobutan-2-yl) piperidin-3yl) acetate ( Example 415, Step A, 360 mg, 0.756 mmol) in toluene (4.7 mL) at 0 ° C. The reaction was stirred at 0 ° C for 20 minutes and at rt for 30 minutes. The reaction

re-cooled to 0 ° C and an additional portion added

1235

of Tebbe reagent (0.5 M solution in toluene, 1 mL, 0.5 mmol). The reaction was allowed to warm to rt for 20 minutes. The reaction was re-cooled to 0 ° C and treated with sat. NaHCCb solution. ac. (40 mL) and EtOAc (100 mL). The separated aqueous layer was extracted with EtOAc (2 x 60 mL) and the combined organic extracts were washed with brine (80 ml), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Column chromatography on silica gel (24 g, SiO2, eluent: hexanes: EtOAc, 1: 0 to 3: 1, gradient elution) gives the title compound. MS (ESI) m / z = 474.0 (M + l).

Stage C. 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((3S) -1,2-dihydroxipentan-3-yl) -3-methyl -2-oxopiperidin-3yl) methyl acetate

To a stirred solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l - ((S) -pent-l- in-

3-yl) piperidin-3-yl) methyl acetate (Example 415, Step B,

mg, 0.18 mmol) in THF (1 mL) t-butanol

1236 (1 mL) and water (1.5 mL) 4-methylmorpholine 4-oxide (63.0 mg, 0.54 mmol) and OsO were added4 (1.1 mg, 4.5 pmol). The reaction was stirred at RT overnight. The reaction was diluted with EtOAc (40 mL) and Na2S2OR3 (20 mL, saturated aqueous solution). The separated aqueous layer was extracted with EtOAc (20 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and evaporated in vacuo to give the title compound as a 5: 1 mixture of diastereomers.

Mass Spectrum (ESI) m / e = 508.0 (M + l).

Stage D. 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((2S, 3S) -1,2-dihydroxipentan-3-yl) -3 acid -methyl-2oxopiperidin-3-yl) acetic acid or 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((2R, 3S) -1.2- dihydroxipentan-

3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

A solution of LiOH in water (1M, 502 μΐ, 0.502 mmol) was added to a stirred solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ( Methyl (3S) -1,2-dihydroxipentan-3yl) -3-methyl-2-oxopiperidin-3-yl) acetate (Example 415, Step C; 85 mg, 0.167 mmol) in EtOH (1.67 mL). The reaction was stirred at rt for 4 hours. After this time the reaction was quenched with NH solution4C1 sat. ac. (20 mL) and treated with EtOAc (40 mL). The separated aqueous layer was extracted ssszsebe

with EtOAc (2 x 20 mL) and the combined organic extracts are

1237 dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC (Gemini ™ Prep Cie column 10pm;

Phenomenex, Torrance, CA, using 25 to 75% acetonitrile in water with 0.1% TFA as eluant) to give one of the title compounds as the minor diastereomer, as the first elution component.

1H NMR (400 MHz, methanol-d4) δ ppm 7.26 (4 H, br s), 7.11

1.72 (1 H, ddd, J = 14.6, 7.6, 5.2 Hz), 1.38 (3H, s), 0.51 (3

H, t, J = 7.5 Hz); Mass Spectrum (ESI) m / z = 494.0 (M + l).

EXAMPLE 416

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((2R, 3S) -1,2-dihydroxipentan-3-yl) -3-methyl acid -2-oxopiperidin-3yl) acetic or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((2S, 3S) -1,2-dihydroxipentan- 3-yl) -3-methyl-2oxopiperidin-3-yl) acetic

ILtLU.'XJ *

In the purification described in Example 415, Step D, the other of the title compounds was isolated as the major diastereomer, as the second elution component.

XH NMR (500 MHz, methanol-d4) δ ppm 7.18 - 7.25 (3 H, br s), 7.05 - 7.17 (4 H, m), 6.88 - 6.98 (1 H, m), 4.83 (1 H, d,

7 = 10.8 Hz), 3.96 (1 H, br s), 3.59 (1 H, dd, 7 = 11.2, 5.4 Hz),

3.51 (1 H, dd, 7 = 11.2, 5.1 Hz), 3.39 - 3.46 (1 H, m), 2.81 -

2.99 (2 H, m), 2.61 (1 H, d, 7 = 13.7 Hz), 2.12 - 2.27 (2 H,

m), 1.84 - 1.96 (1 H, m), 1.60 (1 H, ddd, 7 = 14.2, 7.8, 4.6

Hz), 1.41 (3 H, m), 0.43 (3 H, t, 7 = 7.3 Hz); Spectrum

Masses (ESI) m / z = 494.0 (M + l).

EXAMPLE 417

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((1S, 2S) -l-cyclopropyl-l-hydroxybutane-2-yl) -3- methyl-2 oxopiperidin-3-yl) acetic acid or 2 - ((3R, 5R, 6S) -5- (3Clorophenyl) -6- (4-chlorophenyl) -1 - ((IR, 2S) -1-cyclopropyl- Hydroxybutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

Step A. (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) 1- ((2S) -l-cyclopropyl-l-hydroxybutane-2-yl) - 3-methylpiperidin

2-one

Cyclopropylmagnesium bromide (0.5M solution in THF, 2.0 mL, 1,013 mmol) was added dropwise via syringe over a period of 1 min to a stirred solution of (S) -2 - ((3S, 5R, 6S ) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxopiperidin-l-yl) butanal (Example 91, Step C, 150 mg, 0.338 mmol) in THF (1.7 mL) at rt. The reaction mixture was stirred at rt for 20 minutes and then quenched with NH4C1 (30 mL, saturated aqueous solution) and diluted with EtOAc (50 mL). The organic layer was dried on MgSO4, filtered and evaporated in vacuo. Purification by column chromatography (24g SiO2, Hexanes: EtOAc, 1: 0 to 4: 1) gives the title compound as

1240 a mixture of diastereomers.

MS (ESI) m / z = 486.2 (M + l).

MEXICAN INSTITUTE OF THE

INOUIT. '.

Step B. acid · 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-cyclopropyl-l-oxobutan-2-yl) - 3-methyl-2oxopiperidin-3-yl) acetic

To a stirred solution of (3S, 5R, 6S) -3-allyl-5-ΟοΙοΓοίβηίΙ) -6- (4-chlorophenyl) -1- ((2S) -1-cyclopropyl-lhydroxybutan-2-yl) -3- methylpiperidin-2-one (Example 417, Step A; 60 mg, 0.123 mmol) in EtOAc (lmL), acetonitrile (1 mL) and water (1.5 mL), ruthenium chloride hydrate (2.8 mg, 0.012 mmol) was added and Sodium meta-periodate (6.83 μΐ, 0.123 mmol) (portioned over 5 minutes). The reaction was stirred at rt for 20 minutes and then partitioned between EtOAc (60 mL) and water (20 mL). The separated aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. Purification by column chromatography (12g, SIO2, hexanes / IPA, 1: 0 to 9: 1) gives the title compound.

1241

MS (ESI) m / z = 502.1 (M + l).

IMPIp>.

MEXICAN INSTITUTE X ..1'' .- / zá

PROPERTY t '= · 7

INDUSTRIAL -

Step C. Acid 2 - ((3R, 5R, 6S) -5- (3-Chlorophenylj-6- (4-chlorophenyl) -1 - ((IS, 2S) -l-cyclopropyl-l-hydroxybutan-2-yl) - 3methyl-2-oxopiperidin-3-yl) acetic or 2 - ((3R, 5R / 6S) -5- (3Clorophenyl) -6- (4-chlorophenyl) -1 - ((IR, 2S) -1-cyclopropyl -hydroxybutan-2-yl) -3-methyl-2-oxopiperidin-3-yl) acetic

To a stirred solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -Ί - ((S) -1-cyclopropyl-l-oxobutan2-yl) -3 acid -methyl-2-oxopiperidin-3-yl.) acetic (Example 417, Step B, 33 mg, 0.066 mmol) in THF (657 μΐ) at -78 ° C a solution of L-selectride (144) was added dropwise μΐ, 0.144 mmol). The reaction mixture was stirred at -78 ° C for 20 minutes and then allowed to warm to rt for 30 minutes. After this time the reaction was quenched With a solution of oxone (121 mg, 0.197 mmol) in water (3 mL). The reaction was diluted with EtOAc (30 mL) and the separated aqueous layer was extracted with EtOAc (2 x 10 mL), dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (4g, S1O2, hexanes: IPA, 1: 0 to

4: 1) gives the title compound as a single stereoisomer.

XH NMR (400 MHz, CDCI3) δ ppm 6.95-7.27 (7 H, m), 6.72 (1 H, dt, J = 7.6, 1.6 Hz), 4.58-4.70 (1 H, m), 3.07-3.34 (1 Ή,

m), 2.80-2.93 (2 H, m), 2.09-2.25 (4 H, m), 1.47 (3H, s),

IMPI institute pe la rí'OTTjí; '; -'

INDUSTRIAL

1242

0.28-1.47 (M + l).

(10H, m);

Mass Spectrum (ESI) m / z = 504.0

EXAMPLE 418

2 - ((3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 isopropyl-6-methyl-2-oxopiperidin-3-yl) acetic acid

Stage A. (S) -2- (3-Chlorophenyl) -1- (4-chlorophenyl) peht-4-on-canvas and (R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) pent -4-in-l-ona

To a solution of ΚΌΗ (57.1 g, 1.02 mol) in water (113 mL) was added N-benzyl-N, N-diethylethanamine chloride (1,289 g, 5.66 mmol). A solution of 2- (3-chlorophenyl) -1 (4-chlorophenyl) ethanone (Example 1, Step A) (30 g, 113 mmol) in toluene (113 mL) was added followed by 3-bromoprop-l-ene ( 10.77 mL, 124 mmol). The resulting biphase was vigorously stirred at room temperature for 21 hours, then separated. The organic layer was washed with aqueous citric acid solution followed by brine then dried over MgSO4 anhydrous and concentrated to

1243 provide the pale yellow compounds.

Title

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 2.49 - 2.67 (m, 1

Stage B. (R) -N- ((R) -2- (3-Chlorophenyl) -1- (4-chlorophenyl) pent-4 en-l-yliden) -2-methylpropan-2-sulfinamide

2- (3-Chlorophenyl) -1- (4-chlorophenyl) pent-4-en-l-one (Example 418, Step A, 48 g, 157 mmol), titanium (IV) ethoxide, technical grade (65.9 mL, 315 mmol) and (R) - (+) - 2-methyl-2-propanesulfinamide (Combi-Blocks, San Diego, California, 33.1

g, 267 mmol) were dissolved in 400 mL of THF. The mixture was heated with stirring under reflux for 18 hours. The reaction was cooled and emptied into brine. The resulting white solid was removed by filtration, rinsed with ethyl acetate. Ethyl acetate was added to the biphasic filtrate and the layers were separated. The organic layer was washed with brine,

1244 then dried with anhydrous magnesium sulfate and concentrated. The

IMPIíYY

MEXICAN INSTITUTE

FROM INDUSTRIAL PROPERTY crude product was purified by three chromatographies (prepackaged RediSep® 330g silica gel column (Teledyne Isco, Lincoln, NE), eluting with hexane: ethyl acetate, 95: 5 to 85: 5) to provide the title compound of second elution on TLC on silica gel in hexane / ethyl acetate, the diastereomer (R) -N - ((S) -2- (3 chlorophenyl) -1- (4-chlorophenyl) pent- 4-en-l-ylidene) -2methylpropan-2-sulfinamide third elution on TLC gel

<td>silica</td><td>in hexane / acetate</td><td>of</td><td>ethyl,</td><td>and</td><td>something</td><td>of</td><td>ketone</td>

<td>departure</td><td>eluting first</td><td>in</td><td>TLC</td><td>in</td><td>gel</td><td>of</td><td>silica in</td>

<td colspan="2">hexane / ethyl acetate.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>XH</td><td colspan="3">NMR (400 MHz, CHLOROFORM-d) δ</td><td>ppm</td><td> 1.28</td><td>(s,</td><td>9 H) 2.58-</td>

Step C. (R) -N- ((2S, 3R) -3- (3-Chlorophenyl) -2- (4-chlorophenyl) hex-5-en-2-yl) -2-methylpropan-2-sulfinamide

1245

A solution of (R) -N - ((R) -2- (3-chlorophenyl) -1- (4-chlorophenyl) pent-4-enyliden) -2-methylpropan-2-sulfinamide (Example 418, Step B,

9.97 g, 24.41 mmol) in THF (98 ml) se

Methyllithium (1.6M in ether,

16.78 ml, 26.9 mmol) over a period of six min. The reaction was removed from the cold bath and diluted with 500 mL of ether and quenched with 150 mL of saturated aqueous ammonium chloride solution. The organic layer was separated and washed with brine, then dried with anhydrous magnesium sulfate and concentrated to provide a colorless oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a prepackaged RediSep® silica gel column (3 x 80 g) (Teledyne Isco, Lincoln, NE), eluting with 30% acetate. ethyl in hexane. Fractions containing the desired product, eluting as the bottom spot on TLC on silica gel in hexane / ethyl acetate, were combined and concentrated under reduced pressure to provide the title compound as a glass.

XH NMR (400 MHz, DMSO-dg) δ ppm 1.06 (s, 9 H) 1.80 (s, 3 H) 2.23 (td, 7 = 13.3, 7.5 Hz, 1 H) 2.62 - 2.76 (m, 1 H) 3.30 (d, 7 = 3.3 Hz, 1 H) 4.81 (d, 7 = 10.4 Hz, 1 H) 4.85 - 4.97 (m, 1 H) 5.10 (s, 1 H) 5.31 - 5.52 (m, 1 H) 6.79 ( d, 7 = 7.2 Hz, 1 H)

6.97 (s, 1H) 7.05 - 7.23 (m, 4-H) 7.28 (d, 7 = 8.8 Hz, 2H).

1246

Stage D.

2-amine

A solution of (R) -N- ((2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) hex-5-en-2-yl) -2-methylpropan-2-sulfinamide (Example 418 , Step C, 5.96 g, 14.04 mmol) in THF (56.2 mL) was treated with hydrochloric acid in water (36-38 wt%, 6.40 mL, 211 mmol) for three hours. The reaction was diluted with 300 mL of ether and the acidic aqueous layer was made alkaline with NaHCO solution.3 sat. ac. The organic layer was washed with NaHCO solution3 sat. ac., dried over MgSO4 and concentrated to provide the title compound as a colorless glass.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 3 H) 1.46 (br s, 2 H) 2.09 - 2.25 (m, 1 H) 2.41 (ddd,> 13.6, 12.7, 6.9 Hz, 1 H ) 2.99 (dd,> 11.9, 3.3 Hz, 1H) 4.71 - 4.88 (m, 2H)

5.39 (ddt,> 17.0, 10.2, 6.8 Hz, 1 H) 6.99 - 7.13 (m, 1 H)

7.17 - 7.31 (m, 3H) 7.31 - 7.38 (m, 2H) 7.38 - 7.48 (m, 2

H).

isopropylhex-5-en-2-amine

Stage E.

(2 $, 3R) -3- (3-Chlorophenyl) -2- (4-chlorophenyl) -N1247

A mix

I

IMPI

INSTITUTE, -υ-χτο-, Ν. · '.

SAY THE FKMIFJAD

INDUSTRIAL

(2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) hex-5-en-2-amine (Example 418, Step D) (270 mg,

0.843 mmol), acetic acid (0.243 mL, 4.22 mmol), acetone (3.10 mL, 42.2 mmol) and sodium cyanoborohydride (0.442 mL,

8.43 mmol) in methanol (4 mL) was heated to 65 ° C overnight. After 16 hours, an additional 10 equivalents of sodium cyanoborohydride was added and heating continued for another 5 hours then equilibrated to room temperature and concentrated under reduced pressure. The concentrate was partitioned between aqueous sodium hydroxide solution and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to provide a yellow oil. The crude product was adsorbed on silica and purified by chromatography (24 g

Prepackaged RediSep® silica gel column (Teledyne Isco, Lincoín, NE)) eluting with 30 to 100% gradient ethyl acetate in hexane. The product-containing fractions were combined and concentrated to provide the title compound as colorless glass.

IMPI

XH NMR (400 MHz

CHLOROFORM-d) δ ppm 0.95 (d, 7 = 6.1 Hz,

1248

Step F. (4R, 5S) -4- (3-Chlorophenyl) -5- (4-chlorophenyl) -5 (isopropylamino) hexan-l-ol

I

To a solution of (2S, 3R) -3- (3-chlorophenyl) -2- (4-chlorophenyl) -Nr-isopropylhex-5-en-2-amine (Example 418, Step E, 160 mg, 0.442 mmol) in THF (4 mL) cooled by an ice-water bath, borane-tetrahydrofuran complex was added, (1.0M in THF, 2.21 mL, 2.21 mmol). After 90 minutes, 5 additional equivalents of. borane-THF were added and the cooling bath was removed. After 30 minutes the reaction was cooled in an ice-water bath and quenched by the addition of 0.5 mL water followed by 4N aqueous sodium hydroxide (1.1 mL, 4.42 mmol) and aqueous hydrogen peroxide solution, (30% ( w / w), 0.45 mL, 4.42 mmol). Mix

IMPI

1249 Biphasic was rapidly stirred at 0-5 ° C for 15 minutes then partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, then dried with anhydrous magnesium sulfate and concentrated to provide a colorless oil. The product was isolated by chromatography on silica (24g Prepackaged RediSep® Silica Gel Column (Teledyne Isco, Lincoln, NE)) eluting with 50 until

100% gradient ethyl acetate in hexane to provide the title compound as a colorless oil.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 0.91 (d, 7 = 6.3 Hz,

H) 1.06 (d, 7 = 6.3 Hz, 3 H) 1.13 - 1.37 (m, 2 H) 1.48 (s, 3

H) 1.56 - 1.86 (m, 3H) 1.89 - 2.04 (m, 1H) 2.50 - 2.75 (m,

H) 3.52 (t, 7 = 6.4 Hz, 2 H) 6.76 (d, 7 = 7.6 Hz, 1 H) 6.89 -

6.98 (m, 1H) 7.01 - 7.08 (m, 1H) 7.08 - 7.17 (m, 3H) 7.17

- 7.26 (m, 2H).

Step G. (4R, 5S) -4- (3-Chlorophenyl) -5- (4-chlorophenyl) -5 (isopropylamino) hexanoic acid

I

a solution of (4R, 5S) -4- (3-chlorophenyl) -5- (4IMPI

5 0 chlorophenyl) -5- (isopropylamino) hexane-l-ol (Example 418, Step F, 185 mg, 0.486 mmol) in wet acetonitrile (0.75% water v / v) (3 mL) at room temperature added for three minutes a solution of periodic acid (0.44M in acetonitrile (0.75% water, v / v), 2.76 mL, 1,216 mmol) with chromium trioxide (2.43 mg, 0.024 mmol). The reaction was stirred for 15 minutes. A solution of 0.6 g of disodium acid phosphate in 10 mL of water was added to the reaction. The aqueous mixture was extracted with toluene. The organic layer was washed with water / brine then with a solution of 0.2 g of sodium acid sulphite in 5 mL of water. The organic layer was then dried with anhydrous magnesium sulfate and concentrated to provide a peach colored foamy solid. The product was isolated by chromatography on silica (24g Prepackaged RediSep® Silica Gel Column (Teledyne Isco, Lincoln, NE)) eluting with 50-100% gradient ethyl acetate in hexane to provide the title compound as a foam colorless.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J = 6.7 Hz, 4 H) 1.32 (d, <7 = 6.7 Hz, 4 H) 1.43 (s, 3 H) 1.76 - 1.88 (m, 1 H) 2.22 - 2.38 (m, 1 H) 2.55 - 2.67 (m, 2 H) 2.79 (quin, <7 = 6.65 Hz, 1 H) 3.11 (dd, <7 = 13.1, 2.4 Hz, 1 Ή) 6.21 (d, <7 = 7.8 Hz, 1 H) 6.49 (s, 1 H) 6.91 (dd, <7 = 7.9, 7.9 Hz, 1 H) 6.96 -

7.17 (m, 3H) 7.23 (d, <7 = 8.2 Hz, 2H).

IMPI

Stage Η.

(5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1-

1251 isopropyl-6-methylpiperidin-2-one

Oxalyl chloride (—0.38 M in benzene, 0.617 mL, 0.234 mmol) was added to a room temperature solution of (4R, 5S) -4- (3-chlorophenyl) -5- (4-chlorophenyl) -5 ( isopropylamino) hexanoic (Example 418, Step G, 84 mg, 0.213 mmol) in benzene (3 mL) followed by a drop of DMF. The reaction solution was stirred at room temperature for 25 minutes then heated to 80 ° C. After 3.5 hours the reaction was removed from the heat and saturated aqueous sodium bicarbonate solution was added. The organic phase was diluted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, then dried with anhydrous magnesium sulfate and concentrated to provide a red-orange oil. The product was isolated by chromatography on silica (12g RediSep 'Rf cartridge) eluting with 20-40% gradient ethyl acetate in hexane to provide the title compound as a pale yellow film. [to]D = + 89.33 ° (T = 24.0 ° C; c = 1, CHC13)

XH NMR (400 MHz

CHLOROFORM-d) δ ppm

1252

1.25 (d, 7 = 6.7 Hz,

<td>Hz, 1H) 7.05</td><td colspan="2">-7.27 (m,</td><td>3 H)</td><td> 7.27 -</td><td> 7.</td><td> 42</td><td colspan="2">(m, 2H); Spectrum</td>

<td>of Masses (ESI)</td><td>m / z =</td><td> = 376.]</td><td>. [M +</td><td> H].</td><td></td><td></td><td></td><td></td>

Chlorophenyl) -l-isopropyl-6-methylpiperidin-2-one and (3S, 5R, 6S) methylpiperidin-2-one stage

Sec-butyllithium (0.8N in cyclohexane, 0.274 mL, was added,

0.219 mmol) over a period of one minute to a degassed solution (Argon bubbled through the minute solution at rt) of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-isopropyl -6-methylpiperidin-2-one (Example 418,

Step H, 75 mg, 0.199 mmol) in THF (6 mL) cooled by an acetone-dry ice bath. The cooling bath was removed and the reaction equilibrated to room temperature.

KS »'

IMPI

ZOJ INSTITUTO MEXJCaNO

D2 U? NO ”IEDAD INDUSTRIAL for 15 minutes. The reaction was stirred at room temperature for 30 minutes. Allyl bromide (1M in THF, 0.219 mL, 0.219 mmol) was added over one minute at room temperature. After two hours the reaction was quenched by the addition of saturated aqueous ammonium chloride solution. The organic layer was diluted with ethyl acetate and separated. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were then dried with anhydrous magnesium sulfate and concentrated to provide a faintly orange glass. The diastereomeric products were isolated by chromatography on silica gel (12g Pre-packed RediSep® Silica Gel Column (Teledyne Isco, Lincoln, NE)) eluting with 20 to 80% gradient ethyl acetate in hexane to provide 25 mg of ( 3R, 5R, 6S) -3alyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-isopropyl-6methylpiperidin-2-one as the first elution product on TLC on silica gel plate (RF = 0.52 in 3: 1 eluent hexane: ethyl acetate) and 25 mg of (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-isopropyl-6-methylpiperidin -2one as the second elution product on TLC on silica gel plate (Rf = 0.28 at 3: 1 eluent hexane: ethyl acetate).

Diastereomer 1:

(3R, SR, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-

1254 chlorophenyl) -l-isopropyl-6-methylpiperidin-2-one XH NMR (400 MHz, CHLORINE FORM-d) δ ppm 1.17 (d, ¿7 = 6.7 Hz,

H) 6.20 (d, J = 7.8 Hz, 1 H) 6.50 (s, 1 H) 6.90 (dd, ¿7 = 7.8, 7.8

Hz, 1H) 7.00 - 7.08 (m, 1H) 7.08 - 7.37 (m, 4H); MS (ESI)

416.2 [M + H]+

Diastereomer 2: (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4 chlorophenyl) -l-isopropyl-6-methylpiperidin-2-one XH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, <J = 6.7 Hz,

H) 1.35 (d, J = 6.7 Hz, 3 H) 1.43 (s, 3 H) 1.75 - 1.80 (m, 1

H) 2.25 - 2.48 (m, 2H) 2.56 - 2.68 (m, 1H) 2.69 - 2.89 (m,

H) 3.23 (dd, J = 13.6, 2.6 Hz, 1 H) 4.91 - 5.06 (m, 2 H) 5.76 (dddd, J = 17.6, 9.5, 8.3, 5.9 Hz, 1 H) 6.25 (d, ¿7 = 7.8 Hz, 1 H)

6.51 (dd, ¿7 = 1.8, 1.8 Hz, 1 H) 6.87 - 6.97 (m, 1 H) 6.97 -

7.12 (m, 3H) 7.19 - 7.32 (m / 2H); MS (ESI) 416.2 [Μ + H] “

Step J. 2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-isopropyl-6-methyl-2-oxopiperidin-3-yl) acetic acid

The title compound was prepared from. "Η isopropyl-6-methylpiperidin-2-one (Example 418, Step I,

1255 similar to that described in Example 1, Stage H.

ppm 1.16 (d, J = 6.7 Hz, XH NMR (400 MHz, CHLOROFORM-d) δ

(ESI)

432.0 [M - H] ~,

EXAMPLE '419

Isopropyl-6-methyl-2-oxopiperidin-3-yl) acetic acid

Title

Compound

Prepared from (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1isopropyl-6-methylpiperidin-2-one (Example 418, Step

I

Diastereomer 2) by a procedure similar to that described in Example 1, Step H.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 1.18 (d, 7 = 6.7 Hz,

1256

H) 1.34 (d, 7 = 6.7 Hz, 3 H) 1.47 (s, 3 H) 1.75 (d, 7 = 13.9

Hz, 1 H) 2.46 - 2.65 (m, 2 H) 2.92 (quin, 7 = 6.7 Hz, 1 H) 2.99

- 3.22 (m, 3H) 6.26 (d, 7 = 7.8 Hz, 1H) 6.51 (s, 1H) 6.94 (dd, 7 = 7.9, 7.9 Hz, 1H) 6.98 - 7.12 (m, 3H) 7.28 (d, 7 = 8.6

Hz, 2H); Mass Spectrum (ESI) m / z = 432.0 [Μ - H].

EXAMPLE 420 (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1,1dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6-methoxypyridin-2yl) methyl) piperidin-2-one.

Step A: (5R, 6S) -5- (3-chlorophenyl) -6- ^ (4-chlorophenyl) -1- ((S) -1 (1, l-dioxideisothiazolidin-2-yl) butan-2-yl ) piperidin-2-one.

This compound was made according to the procedure

1257

IMPI & s

MEXICAN INSTITUTE «-« St-rSÍÍ,

DELA INDUSTRIAL PROPERTY of Example 174, Step A, using propansulfatam (J. Org.

Chem., 1963, 28 3537, · 4.63 g, 38.2 mmol) and (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -l-hydroxybutan-2yl) piperidin -2-one (Example 185, Stage

B, 6.0 g, 15.29 mmol).

The title compound was crystallized from ethyl acetate and hexanes.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24 (d, J = 8 (d, (m, 2Ή), 6.99 - 7.09 (m, 3H), 6.86

Hz, 2H), 7.10 - 7.20

<td>1H), 1.97 - 2</td><td> .04</td><td>(m,</td><td>1H), 1.91 (quind,</td><td>J =</td><td> 7.5, 14.8</td><td>Hz, 1H),</td>

<td> 1.44 - 1.61</td><td>(m,</td><td>1 HOUR) ,</td><td>0.53 (t, J = 7.5</td><td>Hz,</td><td colspan="2">3H). Spectrum</td>

Masses (ESI) m / z = 495.1 (M + l).

Stage B. 2- (Iodomethyl) -6-methoxypyridine

I

To a 0 ° C solution of iodine (1,094 g,

4.31 mmol) imidazole (0.294 g, 4.31 mmol) in dichloromethane (10.27 ml) triphenylphosphine (1,131 g,

4.31 mmol) solution.

The reaction was allowed to stir for 1 h at 0 ° C,

After min stirring (6-methoxypyridin-2yl) methanol (Adesis, New Castle, DE, 0.5g, 3.59mmol) was added to the

IMPI

Quench with water (50 mL) and extract with Et2O. The organic

1258 Combines were dried over MgSO4, and concentrated in vacuo. Silica gel chromatography (gradient elution 1 to 5% Et2Or in pentane) provides 2- (iodomethyl) -6 methoxypyridine. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.49 (dd, J = 7.3, 8.3 Hz, 1H), 6.96 (d, J = 7.1Hz, 1H), 6.61 (d,

J-8.1 Hz, 1H), 4.44 (s, 2H), 3.94 (s, 3H). Spectrum

Masses (ESI) m / z = 249.9 (M + l).

Stage C. (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (1, l-dioxideisothiazolidin-2-yl) butan-2- yl) -3 - ((6methoxypyridin-2-yl) methyl) piperidin-2-one.

To a solution of (5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1, l-dioxideisothiazolidin-2-yl) butan-2yl) piperidin- 2-one (Example 420, Step A, 0.7 g, 1,413 mmol) in THF (5.65 ml) at -78 ° C, secbutyllithium, (1.4 M in cyclohexane, 1.06 ml, 1483 mmol) was added dropwise. The reaction was heated to -10 ° C. After about 5 minutes, the reaction was returned to a -78 ° C bath. A solution of 2- (iodomethyl) -6-methoxypyridine (Example 420, Step B, 0.387 g, 1554 mmol) in THF (1 mL) was added dropwise to the cooled reaction mixture. The reaction was allowed to warm to room temperature and stirred for 1 h. the reaction contents were emptied into saturated sodium bicarbonate and the

1259

The

Jvi r 1

INSTl 'r'J7C ·

D £ La FRO .- .Ea-xL · • INDUSTRIAL aqueous layer was extracted with dichloromethane (3 x 50 mL).

Combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (gradient elution step up to

50% diethyl ether in dichloromethane) provides the title compound as the most polar diastereomer.

XH NMR (500 MHz, CHLOROFORM-d) δ ppm 7.50 (t, J = 7.8

Hz, IH), 7.25 (d, J = 8.6 Hz, 2H), 7.09 - 7.18 (m, 3H), 7.03 (d, J = 8.3 Hz, 2H), 6.92 - 6.99 (m, IH), 6.82 (d , J = 7.3

Hz, IH), 6.58 (d, J = 8.1Hz, IH), 4.87 (d, J = 7.6 Hz, IH),

3.80 (s, 3H), 3.36 - 3.46 (m, 2H), 2.99 - 3.32 (m, 7H), 2.26

- 2.50 (m, 2H), 2.03 - 2.15 (m, IH), 1.90 - 2.03 (m, 2H),

1.43 - 1.73 (m, 2H), 0.56 (t, J = 7.6 Hz, 3H). Mass Spectrum (ESI) m / z = 616.1 (M + l).

EXAMPLE 421 (3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1,1 dioxideisothiazolidin-2-yl) butan-2-yl ) -3 - ((6-methoxypyridin-2yl) methyl) piperidin-2-one

From the purification described in Example 42Ó,

1260

1- (1, l-Dioxideisothiazolidin-2-yl) butan-2-yl) -3- ((6methoxypyridin-2-yl) methyl) piperidin-2-one was isolated as the least polar diastereomer.

<td>XH</td><td>NMR (!</td><td>500 MHz,</td><td>CHLOROPH.</td><td>RMO-d}</td><td colspan="2">δ ppm 7.46 (t</td><td> , 7 =</td><td> 7.8</td>

2H), 2.10 (m, 2H), 1.57 (q, J = 12.9

Hz, 1H), 1.85 - 2.01

1.63 (m,

J = 2.2, 7.1

Hz, 1H), 0.53 (t, J = 7.6 Hz, 3H).

Mass Spectrum (ESI)

EXAMPLE .422 (3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1,1-dioxideisothiazolidin-2-yl) butan-2-yl ) -3 - ((6-hydroxypyridin-2 yl) methyl) piperidin-2-one

OR

1261

Τ / Τ ΤΗ) Τ

INSTÍTU7

Ό ~ 1Λ < Λ~

INLJJST RL1L

To the product of Example 420, Step C (0.05 g, mmol) in chloroform (1.62-2 ml) was added iodotrimethylsilane (0.046 ml, 0.324 mmol). The reaction was heated to 50 ° C. After 4 hours, the reaction was quenched with saturated bicarbonate (10 mL) and extracted with dichloromethane (2 x 15 mL) and 5% MeOH in CH2CI2 (1. x 15 mL). The combined organics were dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography (0.5 to 7.5% MeOH in dichloromethane) provides the title compound.

XH NMR (500 MHz, CHLOROFORM-d) δ 7.36 (dd, <7 = 6.7, 9.2

<td>(m,</td><td>IH), 0.61</td><td>(t,</td><td>J = 7.5 Hz,</td><td>3H)</td><td colspan="2">. Mass Spectrum (ESI)</td>

m / z = 602.2 (M + l).

EXAMPLE 423 (3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1,1— dioxideisothiazolidin-2-yl) butan-2- yl) -3 - ((6-hydroxypyridin-2yl) methyl) piperidin-2-one

INSTiTUTC MEXJ / JANO DE LA PROl-IHDAD INDUSTRIAL

1262

Following the procedure of Example 422 using the product of Example 421, (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1, 1 Dioxide Isothiazolidin-2-yl) Butan-2-yl) -3 - ((6-hydroxypyridin-2yl) methyl) piperidin-2-one.

<td></td><td>XH]</td><td>NMR</td><td>(500 MHz, CHLOROFORM-d)</td><td>δ ppm 7.22</td><td>(dd,</td><td>J =</td><td> 6.6</td>

6.7, 9.60 Hz, 1H), 3.18 (td, 7 = 6.7, 9.6 Hz, 1H), 3.11 (t, J = 7.5 Hz, 2H), 2.87 - 3.04 (m, 3H), 2.76 - 2.86 (m, 1H ), 2.71 (dd, J = 2.7, 14.4 Hz, 1H), 2.32 (quin, J = 7.0 Hz, 2H), 2.17 (q, J = 13 Hz, 1H), 1.84 - 1.99 (m, 2H), 1.37 - 1.58 (m, 2H), 0.43 (t, 7 = 7.6 Hz, 3H).

EXAMPLE 424 (3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1,1 dioxideisothiazolidin-2-yl) butan-2-yl ) -3 - ((6-methoxypyridin-2yl) methyl) -3-methylpiperidin-2-one

1263

Added sec-butyl lithium (1.4 M in cyclohexane, 0.59 ml,

0.824 mmol) to a solution of (3S, 5R, 6S) -5- (3-chlorophenyl) -6 (4-chlorophenyl) -1 - ((S) -1- (1, l-dioxideisothiazolidin-2-yl) butah

2-yl) -3- ((6-methoxypyridin-2-yl) methyl) piperidin-2-one (Example

420, Step C, 0.484 g, 0.785 mmol) in THF (3.92 ml) at -78 ° C. After 15 minutes iodomethane (0.098 ml, 1.57 mmol) was added and the reaction was allowed to warm to room temperature. The reaction contents were emptied into saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (3 x 30 mL).

The combined organics were dried with sodium sulfate and concentrated in vacuo.

Chromatography on silica gel (10% gradient elution step 30 to 90% EtOAc in hexanes) provides the elution diastereomer.

title as the first compound of the

<td></td><td>XH NMR (500 MHz,</td><td colspan="3">CHLOROFORM-d) δ 7.4 8 (t,</td><td>J -</td><td> = 7.6</td><td>Hz,</td>

ΐΛ

1264

13.6 Hz, IH), 0.50 (t, J = 7.6 Hz, 3H).

(ESI) m / z = 630.2 (M + l).

MEX INSTITUTE. DE LA! 'I: OrI INDU3TR

EXAMPLE 425 (3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1,1-dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6-methoxypyridin-2-

The title compound is the second diastereomer eluting from the purification described in Example

424 .

<td>XH</td><td colspan="3">NMR (500 MHz, CHLOROFORM-d) δ ppm 7.53 (t,</td><td>J =</td><td> 7.7</td>

<td>IH), 2.</td><td>02 - 2.12 (m, IH),</td><td>1.95 (quind,</td><td>T = 7.6, 14.8</td><td>Hz,</td><td>IH),</td>

Mass Spectrum (ESI) m / z = 630.2 (M + l).

(3S, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1,11265

EXAMPLE 426

Dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6-hydroxypyridin-2yl) methyl) -3-methylpiperidin-2-one

Following the procedure of Example 422 using the product of Example 424, (3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -l - ((S) -l- (l, l-dioxideisothiazolidin) was obtained -2-yl) butan-2-yl) -3- ((6-hydroxypyridin-2yl) methyl) -3-methylpiperidin-2-one.

<td></td><td>XH</td><td>NMR (500 MHz,</td><td>CHLOROFORM-d) δ p</td><td>> pm 7.33</td><td>(dd,</td><td> 7 =</td><td> 6.7</td>

2H), 1.49 (s, 3H), 0.52 (t, J = 7.5 Hz, 3H). Spectrum

Masses (ESI) m / z = 616.1 (M + l).

(3R, 5R, 6S) -5- (3-Cl.orophenyl) -6- (4-chlorophenyl) -1- ((S) -1- (1,11266

EXAMPLE 427

Dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6-hydroxypyridin-2-

Example 422 using the product of Example 425, (3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1- (1,1 dioxideisothiazolidin-2) was obtained -il) butan-2-yl) -3 - ((6-hydroxypyridin-2yl) methyl) -3-methylpiperidin-2-one.

<td></td><td>XH NMR</td><td> (500</td><td>MHz, CHLOROFORM-d) δ</td><td>ppm 7.36 -</td><td> 7.44</td><td>(m,</td>

1.88 - 1.96 (m, J = 2.9 Hz, IH), 1.44 - 1.59 (m, IH), 1.39 (s, 3H), 0.48 (t, J = · 7.6 Hz, 3H). Mass Spectrum (ESI) m / z = 616.1 (M + l).

1267

EXAMPLE 428 (3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 - ((S) -1-

3-methylpiperidin-2-one.

Oxalyl chloride (0.063 ml, 0.715 mmol) was added to a solution of 2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4methyl-2-oxopiperidin-3-yl) acetic acid (Example 349, 0.316 g,

0.572 mmol) in dichloromethane (1.9 mi). The reaction was stirred for 3h at room temperature. Solvents were removed in vacuo.

To the solids were added (0.42 mi,

1.26 mmol) and the reaction was stirred at 90 ° C.

After h, the reaction was cooled, charged with THF (1 mL) and

HC1 (1.4M, 0.982 ml, 1.375 mmol), and brought to reflux per min. After cooling, the reaction was emptied into water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo

Gradient Chromatography 1 ¥ 1 A .JL \,

MEXICAN INSTITUTE <CS lAfRCf iSOAO up to 5% 2M ammonia in 'MeOH in dichloromethane)' ”'provides

1268

the title compound.

XH NMR

6.96 - 7.10 (500 MHz, CHLOROFORM-d) δ 7.11 (d, 7 = 10.8 Hz, IH), -4.13 (ddd, 7 = 2.9, 10.6, 13.6 Hz,

7.30 (m,

3H), (m, 3H), 6.89 (s,

(br s,

13.

IH), 2.28 (t, J

<td>0.41 (m,</td><td>2H),</td><td> -0.33</td><td>(br s,</td><td>IH), -1.01</td><td>(br s,</td><td>IH). Spectrum</td>

<td>of masses</td><td>(ESI)</td><td>m / z =</td><td> 566.2</td><td>(M + l).</td><td></td><td></td>

EXAMPLE 429

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 (diethylamino) -3-methyl-2-oxopiperidin-3-yl) acetic acid

Step A. 2 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxopiperidin-3-yl) methyl acetate

6 9

Sodium periodate added

slowly to a solution containing ruthenium (III) chloride hydrate (0.277 g, 1,229 mmol) and (3S, 5R, 6S) -3-allyl-5- (3 chlorophenyl) -6- (4-chlorophenyl) - 3-methylpiperidin-2-one (4.6 g,

12.29 mmol; Example 71, step D) in acetonitrile (35.1 mL), ethyl acetate (35.1 mL) and water (52.7 mL) while maintaining the temperature below 20 ° C. The resulting mixture was then stirred for 2 h at room temperature. The reaction was then filtered and concentrated, and the resulting residue was further processed by dissolving in ethyl acetate. The organics were washed with water and brine, dried over

MgSO4, filtered and concentrated. The residue was then dissolved in a small amount of a mixture of ether and methanol (1: 1) and a 2M solution of (trimethylsilyl) diazomethane in diethyl ether (12.29 ml, 24.58 mmol) was added. This solution was then allowed to stir at room temperature overnight. The solution was concentrated and the resulting residue was purified on silica gel (eluent: hexane / ethyl acetate 0 to 100%, gradient elution) to give the title compound. Mass Spectrum (ESI) m / z = 40'6 (M + l).

methyl chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetate

Stage B.

2 - ((3R, 5R, 6S) -l-amino-5- (3-chlorophenyl) -6- (41 XA

INDUSTRIAL

mmol) was added to a solution of

hydride

A suspension of ore (0.953 g, 23.82

<td>oxopiperidin-3-yl) acetate</td><td>methyl</td><td>(Example</td><td>429, stage A,</td>

<td>4.84 g, 11.9 mmol) in DMF</td><td>(25 mL).</td><td>L Mix</td><td>resulting it</td>

<td>stirred for 15 min at</td><td>23 ° C.</td><td colspan="2">Added 0- (2.4-</td>

<td>dinitrophenyl) hydroxylamine</td><td>(4.74 g,</td><td>23.82 mmol)</td><td>at temperature</td>

<td>environment. The solution</td><td>stirred</td><td>for 1 h</td><td>at temperature</td>

stirred environment then solvent quench with MeOH (1 mL)

It is in excess under reduced pressure and the residue is purified by chromatography on silica (eluent: 0 to 5% MeOH in DCM;

Mass Spectrum (ESI) m / z = 421 (M + l), 443 (M + 23).

Step C. 2 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (diethylamino) -3-methyl-2-oxopiperidin-3-yl) methyl acetate

1271

Ethyl iodide (67.1 uL, 0.831 mmol) was added to a solution of 2 - ((3R, 5R, 6S) -l-amino-5- (3-chlorophenyl) -6- (4 chlorophenyl) -3-methyl- 2-oxopiperidin-3-yl) methyl acetate (Example 429, step B, 35 mg, 0.083 mmol) and DIEA (145 pL, 0.831 mmol) in DMF. The resulting mixture was stirred at 80 ° C for 12h. The mixture was concentrated and purified by reverse phase HPLC (Sunfire ™ Prep Ci column8 OBD 10 pm; Waters, Milford, MA; 40-90% water / acetonitrile gradient with 0.1% TFA). The desired fractions were pooled and concentrated to give the title compound.

Mass Spectrum (ESI) m / z = 477 (M + l).

Stage D. 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (diethylamino) -3-methyl-2-oxopiperidin-3yl) acetic acid

A solution of methyl 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (diethylamino) -3-methyl-2-oxopiperidin-3-yl) Example 429, step C) in water / methanol (1: 1) was treated with lithium 'hydroxide (IN, 5 eg) at room temperature for 15h. The mixture was concentrated and purified by reverse phase HPLC (Sunfire ™ Prep Cig OBD 10 pm column; Waters, Milford, MA; 40-90% water / acetonitrile gradient with 0.1% TFA). The desired fractions were then pooled and concentrated to give the title compound.

XH NMR (500 MHz, Methanol-d4) δ ppm 0-222 (t. .7 = 7 H z — _. .3 —HA 1272

KBXíCANO INSTITUTE

DE LA PÍ'.O.-iE-IAO. INDUSTRIAL

<td>(m, 2</td><td>H)</td><td> 7.229</td><td>(m, 4</td><td>H); Spectrum of Ma</td><td>sas</td><td>(ESI) m / z =</td><td> 4 63</td>

(M + l), 485 (M + 23).

EXAMPLE 430

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 (dimethylamino) -3-methyl-2-oxopiperidin-3-yljacetic acid

Methyl 2 - ((3R, 5R, 6S) -l-amino-5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetate (Example 429) was treated. step C) by a procedure similar to that described in Example 429, using methyl iodide instead of ethyl iodide in Step C.

XH NMR (500 MHz, Methanol-φ) δ ppm 1,356 (s, 3H) 2,088 (dd, <7 = 14, 3.5 Hz, IH) 2,166 (t, J = 13.5 Hz, IH) 2,599 (br s, 6H ) 2,601 (d, <7 = 13.5, IH) (m, 7 H) 2,933 (d, <7 = 13.5 Hz, 1

H)

3,429 (ddd, J = 13, 10.5, 3.5 Hz, 1

H) 4,672 (d, J = 10.5 .1 '

1273

Hz,

H)

H) 7,206 (d, J = 8.5

Hz,

H);

Mass Spectrum (ESI) m / z =

435 (M + l).

EXAMPLE 431 (2S, 3S, 5S, 6R, 7aR, lOaS) -6- (3-Chlorophenyl) -5- (4-chlorophenyl) -3ethyl-2,7a-dimethylhexahydrofide [2,3-b] oxazolo [3, 2-a] pyridin9 (5H) -one

Stage A: (3S, 5R, 6S) -3-A1Í1-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- ((2S, 3.S) -2-hydroxypentan-3-yl) -3methylpiperidin -2-one

L-Selectride ™ (1M in THF, 5.24 ml, 5.24 mmol) was added to a solution at -10 ° C'de (3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) 6- (4 -chlorophenyl) -3-methyl-l - ((S) -2-oxopentan-3-yl) piperidin-2one (Example 149, step A, 2 g, 4.36 mmol) in THF (29.1 ml)

I taking care to keep the temperature below -7 ° C

1274

INSTITUTO MS DE LA '. \ X INDUS

The reaction was stirred for 40 min then quenched in an aqueous solution of

Oxone ™ (10.73 g, 17.45 mmol) in 60 mL of water.

The temperature was noted to rise to 40 ° C during the addition.

The reaction was cooled to RT using water / ice bath and stirred at rt for 1h, then diluted with ethyl acetate.

The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine and dried over MgSO4, filtered and concentrated.

The crude material was dried under high vacuum overnight.

Purification by column chromatography using 10-20% acetone in hexanes provides the title compound.

XH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 - 7.27 (m, 2

Η), 7.16 (ddd, <7 = 8, 2, 1.2 Hz, 1 Η), 7.10 (t, <7 = 7.7 Hz, 1 Η),

6.95 - 7.07 (m, 2 Η), 6.93 (t, <7 = 1.8 Hz, 1 Η), 6.70 (dt, <7 = 7.5, 1.2 Hz, 1 H), 5.80 - 5.92 (m, 1 Η), 5.13 - 5.25 (m, 2

460.2.

1275

Step B: (2S, 3S, 5S, 6R, 8S) -8-Alyl6- (3-chlorophenyl) -5- (4-chlorophenyl) -3-ethyl-2,8-dimethyl- 4-methylbenzenesulfonate

2,3,5,6,7,8-hexahydrooxazolo [3,2-a] pyridin-4-io

A

(3S, 5R, 6S) -3-allyl-5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 - ((2S, 3S) -2hydroxipentan-3-yl) -3-methylpiperidin-2- solution one (Example 431, Step A, 600 mg, 1,303 mmol) in toluene (43 mL) with pyridinium p-toluenesulfonate (PPTS, 327 mg,

1.30 mmol) was treated by lh under DeanStark conditions. When monitored by NMR it indicates about 95 to 97% completion, the reaction was treated with additional 3% (10. mg) of PPTS and returned to reflux for 30 min. The reaction mixture was concentrated under high vacuum and used as it is for subsequent reactions.

XH NMR (500 MHz, DMSO-d6) δ ppm 8.15-7.10 (series of m, 12H), 5.89 (ddt, 7 = 17.4, 10.3, 7.3, Hz, 1 H),

5.38 (d, 7 = 11.0 Hz, 1H), 5.36 (dd, 7 = 16.9, 1.7 Hz, 1

5.17 (quin, J = 6.3

1276

INSTr cr - i INDUSTRIAL AGE

H), 3.97 (ddd,

Η), 5.27 (dd, J = 10.1, 2.1 Hz, 1 H),

Hz, 1H), 4.12 (td, J = 6.5, 2.6 Hz,

J = 13.7, 11.0, 3.4 Hz, 1H), 2.81 (ABX, JAB = 13.7 Hz,

<td>H),</td><td>0.5 8 (t, J = 7. 2 Hz,</td><td>3 H),</td><td> 0.45</td><td>(dquin, J =</td><td> = 14</td><td> • 7,</td>

Step C: (2S, 3S, 5S, 6R, 7aR, 1OaS) -6- (3-Chlorophenyl) -5 (4-chlorophenyl) -3-ethyl-2,7a-dimethylhexahydrofide [2, Ιό] oxazolo [3, 2-a] pyridin-9 (5H) -one

A 4-methylbenzenesulfonate solution of (2S, 3S, 5S, 6R, 8S) -8-allyl-6- (3-chlorophenyl) -5- (4c1oropheni1) -3-eti1-2,8-dimethi1-2.3 , 5,6,7,8 hexahydrooxazolo [3,2-a] pyridin-4-io (Example 431, Step B, 775 mg, 1,261 mmol) in dichloromethane (12 mL) at 0 ° C with acetic acid (2.89 mL , 50.4 mmol) and tetra-n-butylammonium chloride (35.0 mg, 0.126 mmol) was treated by adding KMnO4 (797 mg, 5.04 mmol) as a solution in water (12 mL), followed by rinsing with water (12 mL).

After 20 min at 0 ° C, the reaction was quenched by

1277 adding 15 mL of Na2S2O3 diluted with

150 mL of ethyl acetate and the layers were separated.

The organic phase was washed with water and brine, dried over MgSO4, filtered through Celite® (JT Baker, Phillipsbérg, NJ, diatomaceous earth), and concentrated.

The sample was placed under high vacuum overnight to provide product with incorporated acetic acid (about 4 eq)

An aliquot was purified using · 60-80% ethyl acetate in hexanes to provide the title compound.

H) 1H NMR (400

7.07

7.16

MHz, DMSO-d6) (m, 2H),

7.05 ppm 7.18

7.26 (dt, <7 = 7 .0, 1.7 (m,

Hz,

3.92 (who,

H) f

Hz,

H),

7 = 6 .1 Hz,

3.84 (d,> 10.8

(M + H) m / z = 460.2.

The compounds of the present

1278 1 ^ vención ^ .xhib ^ i ^ U.

inhibition of the interaction between HDM2 and p53 in the following tests.

Homogeneous time resolved fluorescence assay (HTRF1 assay)

Standard test conditions for the in vitro HTRF assay consist of a total reaction volume of 50 ul in 384 wells Costar polypropylene plates in IX buffer solution PBS pH 7.4, 1 mM DTT, 0.1% BSA, 2.5 nM GST-hMDM2 (aa 1-188), biotinylated 5 nM -p53 (aa 1-83), 1.8 nM SA-XLent (Cisbio; Bedford, MA), 0.6 nM anti-GST crypto monoclonal antibody (Cisbio; Bedford, MA) and 200 mM KF. Amino acid residues 1-188 of human MDM2 were expressed as an amino terminal glutathione-S-transferase (GST) fusion protein (GST-hMDM2) in Escherichia coli. Residues 1-83 of human p53 were expressed as an amino terminal AviTag ™ -TrxA-6xHis fusion protein (biotinylated p53) in E. coli. Each protein was purified from cell paste by affinity chromatography.

Specifically, 10 uL of GST-hMDM2 was incubated with 10 ul of diluted compound (various concentrations, serially diluted) in 10% DMSO for 20 minutes at room temperature. 20 uL of biotinylated p53 was added to the GST-hMDM2 + compound mixture, and then incubated at room temperature for 60

min. 10 uL of detection buffer solution consisting of SA-XLent, anti-GST cryptate antibody and KF was added to GST-hMDM2, biotinylated p53 and compound reaction and left at temperature. environment to reach balance for> 4 hrs. The final DMSO concentration in the reaction was 2%. Time resolution fluorescence readings were measured on a microplate multi-label reader. The percentage of inhibition was calculated in relation to nutlin-3.

As the potencies of HDM2 inhibitors increased, an improved HTRF-assay (HTRF2 assay) was developed. All assay conditions remained the same as described above, with the exception of the following changes in reagent concentrations: 0.2 nM GST-hMDM2 (1-188), 0.5 .nM biotinylated p53 (1-83), 0.18 nM SAXLent, and 100 mM KF.

The results are provided in the table below.

Table 1

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

1280

IMPI

MEXICAN INSTITUTE

D £ INDUSTRIAL PROPERTY

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

I Μ Ρ I ^ 5 * 5

INSTITUTO MEXICANO DS LA 'PROPIEDAD V * -

INDIsTRiAl,

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

IMPI

1282

<td>Example</td><td>. HTRF1 IC50 (μΜ)</td><td></td>

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

1284

AND'

Table 2

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

1285

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

1286

<td rowspan="2">Example</td><td rowspan="2">HTRF1 IC50 (μΜ)</td><td>HTRF2 ICso (μΜ)</td>

1287

INSTITUTE .ν.ί · Χ '· 0ΑΙ \ Ο

OF INDUSTRIAL PROPERTY '/ <4 ..' - “t- \

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTR ^ 2 ... I £ sa_UjML ^</td>

1288

<td>Example</td><td>.HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

Table 3

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

1289

<td>Example</td><td>HTRF1 ICso (PM)</td><td>HTRF2 IC50 (μΜ)</td>

IMPI

1290

<td rowspan="2">Example</td><td rowspan="2">HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

1291

1292

<td>Example</td><td>HTRF1 ICso (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

A j

<td></td><td> 1293</td><td>IMPI .m'X'caxo institute Say Ú4 Γ.ν / γ ^ Γ-ΛΓ ·</td>

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>htrW'TCso (Wr</td>

ΟΞ LA PAO

INDUSTRY"·

1294

<td>Example</td><td>• HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

1295

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

IMPI instítut 'macano

DV. INDUSTRIAL PROPERTY

1296

<td>Example</td><td>HTRF1 IC50 (μΜ)</td><td>HTRF2 IC50 (μΜ)</td>

The compounds in the present invention exhibit cyclin-dependent kinase inhibitor activation

P21

WAF1 / CIP1

P21 TaqMan® test

Inhibition of the interaction between hMDM2 and p53 results in activation of the p53 pathway through stabilization and accumulation of p53. P53 activates transcription of many genes, one of which is p2iWñFi / ciPi. whatQn In order to assess the potency of hMDM2 inhibitors, quantitative reverse transcription polymerase chain reaction (qRT-PCR or TaqMan®) was used to measure the levels of p21 transcribed in compound-treated cells relative to dimethyl sulfoxide (DMSO) cells. .

: n .:

1297 ': anus

INDUSTRIAL control treated with

On Day 1, SJSA-1 cells were plated at a density of 3xl04 cells / well in 96-well cell culture plates in 100 ul growth medium (RPMI

1640 mM HEPES; 1 mM sodium pyruvate; IX Penicillin Streptomycin-Glutamine (PSQ); and 10% fetal bovine serum (all reagents from Invitrogen; Carlsbad, CA)). Cells were grown overnight at 37 ° C and 5% CO2.

On Day 2, hMDM2 inhibitors were serially diluted in DMSO (Sigma-Aldrich; Sf. Louis, MO). 5 ul of each compound dilution was added to 245 ul of filtered assay medium (RPMI 1640, 10mM HEPES, 1mM sodium pyruvate, and IX PSQ), containing 10% FBS. Alternatively, the assay was also run in the presence of 10% human serum or 10% mouse serum, or in the absence of any serum. Growth medium was removed from SJSA-1 cells in plates and replaced with 100 ul / well of test medium. Then 100 ul of diluted inhibitor containing medium was added to each well, to a final volume of 200 ul. Titration of the compound dose provided final concentrations ranging from 0.04 9 uM - 50 uM, plus a DMSO control. Cells were incubated in the presence of inhibitor at 37 ° C and 5% CO2 for 7 hours. At the end of the incubation period, the medium was removed from the cells, and the plates were stored at -80 ° C.

9 8

OF THE v /

On Day 3, the RNA. Total DMSO-treated SJSA-1 cells were purified using Qiagen BioRobot Universal work following the inhibitor and station protocol manufacturer's RNeasy 96 BioRobot 8000 kit (Qiagen; Valencia,

CA), with the following exceptions:

with the addition of buffer solution to the DNase treatment, the

Elute, and the elution volume changed the protocol started from RLT lysis, addition of final Top fluid at 120 ul was omitted. After the BioRobot Universal completed the RNA extraction procedure, the collection plate containing total RNA from each well was briefly centrifuged to collect the eluate at the bottom of the tubes.

To measure the levels of p21 transcript present, qRT-PCR was used. Levels of both the p21 and the cleanse gene, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were assayed from total RNA from each well treated with inhibitor or

DMSO in technical duplicates. Each qRT-PCR assay well contains the following components of the

One-Stage RT-PCR Master Mix

TaqMan® (Invitrogen) ul Master Mix

PCR Universal 2X TaqMan from

Reverse Transcriptase

40X Multiscribe ™ / Inhibitor Blend

TaqMan® (Invitrogen) or 1 ul of Gene Expression Assay

RNase, 1 ul of either Expression Assay

Gen ρ21 20X

GAPDH 20X TaqMan® (Invitrogen), plus 5 ul

1299

IM.PI

INSTITUTE DEυ OF THE INDUSTRIAL DEPTH OF total RNA and ul of DEPC-H2O (EMD Chemicals; Gibbstown, qRT-PCR were tested on the instrument

Applied Biosystems

Prism 7900HT, using relative quantization (delta delta

Ct) method with the following cycling conditions: 30 minutes at 48 ° C, followed by 10 minutes at 95 ° C, then 40 cycles of 15 seconds at 95 ° C and 1 minute at 60 ° C. Data were analyzed with Applied Biosystems SDS2.2 software, using GAPDH as the endogenous control and samples treated with DMSO as the calibrator. SDS2.2 software calculated with

Relative quantification (RQ) or times greater than p21 levels relative to DMSO control for each sample treated. The induction of p21 times maximum (100%) was defined by the maximum of a fitted curve of a reference compound. The induction of p21 times in each tested inhibitor dose was converted to a value representing the maximum percentage.

Dose response curves were generated using XLFit software (ID Business Solutions, Alameda, CA) to calculate IC50 transit values for each inhibitor tested.

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149 members in 43 offices

This recordMember, by publication datePriority claim33 more offices are in the list below

Priority claims7

Priority claims
Document	Office	Kind	Date
61351827	United States of America	–	2010-06-04
35182710	United States of America	P	2010-06-04
61352322	United States of America	–	2010-06-07
35232210	United States of America	P	2010-06-07
61452578	United States of America	–	2011-03-14
201161452578	United States of America	P	2011-03-14
2011039184	United States of America	W	2011-06-03

Members149

Family members, oldest first
Document	Office	Kind
CA2799972A1	Canada	A1	2011-12-08
CA3060703A1	Canada	A1	2011-12-08
CA3157177A1	Canada	A1	2011-12-08
CA3207676A1	Canada	A1	2011-12-08
WO2011153509A1	World Intellectual Property Organization (WIPO)	A1	2011-12-08
US2011319378A1	United States of America	A1	2011-12-29
UY33430A	Uruguay	A	2011-12-30
TW201211020A	Taiwan Province of China	A	2012-03-16
AU2011261263A1	Australia	A1	2012-12-13
AR082763A1	Argentina	A1	2013-01-09
SG186147A1	Singapore	A1	2013-01-30
IL223201A0	Israel	A0	2013-02-03
IL223201D0	Israel	D0	2013-02-03
PH12012502410A1	Philippines	A1	2013-02-18
CR20120659A	Costa Rica	A	2013-03-11
PE20130229A1	Peru	A1	2013-03-22
EP2576510A1	European Patent Office (EPO)	A1	2013-04-10
MX2012014044A	Mexico	A	2013-05-22
MA34342B1	Morocco	B1	2013-06-01
CN103180296A	China	A	2013-06-26
EA201291356A1	Eurasian Patent Organization (EAPO)	A1	2013-06-28
CO6710897A2	Colombia	A2	2013-07-15
JP2013530958A	Japan	A	2013-08-01
CL2012003415A1	Chile	A1	2013-08-09
US8569341B2	United States of America	B2	2013-10-29
AU2011261263B2	Australia	B2	2013-11-21
HK1182711A	Hong Kong, China	A	2013-12-06
HK1182711A1	Hong Kong, China	A1	2013-12-06
US2014011796A1	United States of America	A1	2014-01-09
JP5420797B2	Japan	B2	2014-02-19
HK1186462A	Hong Kong, China	A	2014-03-14
HK1186462A1	Hong Kong, China	A1	2014-03-14
KR20140032929A	Republic of Korea	A	2014-03-17
TN2012000559A1	Tunisia	A1	2014-04-01
JP2014062093A	Japan	A	2014-04-10
TWI433844B	Taiwan Province of China	B	2014-04-11
AU2011261263C1	Australia	C1	2014-05-29
KR20140091009A	Republic of Korea	A	2014-07-18
IL233411A0	Israel	A0	2014-08-31
IL233411D0	Israel	D0	2014-08-31
TW201434816A	Taiwan Province of China	A	2014-09-16
US2014315895A1	United States of America	A1	2014-10-23
KR101456801B1	Republic of Korea	B1	2014-10-31
NZ604074A	New Zealand	A	2014-11-28
EP2576510B1	European Patent Office (EPO)	B1	2015-04-29
CN103180296B	China	B	2015-05-27
IL223201A	Israel	A	2015-05-31
ZA201400948B	South Africa	B	2015-06-24
DK2576510T3	Denmark	T3	2015-06-29
SI2576510T1	Slovenia	T1	2015-06-30
PT2576510E	Portugal	E	2015-07-01
ES2540992T3	Spain	T3	2015-07-15
HRP20150704T1	Croatia	T1	2015-08-14
SMT201500168B	San Marino	B	2015-09-07
EP2927213A1	European Patent Office (EPO)	A1	2015-10-07
ME02150B	Montenegro	B	2015-10-20
PL2576510T3	Poland	T3	2015-10-30
RS54030B1	Serbia	B1	2015-10-30
CN105153014A	China	A	2015-12-16
UA110481C2	Ukraine	C2	2016-01-12
AR096697A2	Argentina	A2	2016-01-27
TWI519519B	Taiwan Province of China	B	2016-02-01
MX337178BThis record	Mexico	B	2016-02-15
NZ627385A	New Zealand	A	2016-02-26
TW201609649A	Taiwan Province of China	A	2016-03-16
US9296736B2	United States of America	B2	2016-03-29
JP5908446B2	Japan	B2	2016-04-26
EA023004B1	Eurasian Patent Organization (EAPO)	B1	2016-04-29
US2016137667A1	United States of America	A1	2016-05-19
IL246296A0	Israel	A0	2016-07-31
IL246296D0	Israel	D0	2016-07-31
JP2016147891A	Japan	A	2016-08-18
SG10201604817QA	Singapore	A	2016-08-30
JO2998B1	Jordan	B1	2016-09-05
HK1215707A	Hong Kong, China	A	2016-09-09
HK1215707A1	Hong Kong, China	A1	2016-09-09
BR112012030923A2	Brazil	A2	2016-11-08
MX343587B	Mexico	B	2016-11-10
JP6077695B2	Japan	B2	2017-02-08
US9593129B2	United States of America	B2	2017-03-14
CY1116513T1	Cyprus	T1	2017-03-15
TWI582076B	Taiwan Province of China	B	2017-05-11
CL2016001733A1	Chile	A1	2017-05-12
US2017144971A1	United States of America	A1	2017-05-25
PH12016501048A1	Philippines	A1	2017-05-29
IL233411A	Israel	A	2017-08-31
KR20180059574A	Republic of Korea	A	2018-06-04
KR101863407B1	Republic of Korea	B1	2018-06-29
EP2927213B1	European Patent Office (EPO)	B1	2018-11-14
PT2927213T	Portugal	T	2019-02-21
SMT201900099T1	San Marino	T1	2019-02-28
US2019062276A1	United States of America	A1	2019-02-28
DK2927213T3	Denmark	T3	2019-03-11
TR201902034T4	Türkiye	T4	2019-03-21
RS58366B1	Serbia	B1	2019-03-29
HRP20190273T1	Croatia	T1	2019-04-05
LT2927213T	Lithuania	T	2019-04-25
SI2927213T1	Slovenia	T1	2019-04-30
EP3483143A1	European Patent Office (EPO)	A1	2019-05-15
HUE041488T2	Hungary	T2	2019-05-28

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