Piperidinone derivatives as mdm2 inhibitors for the treatment of cancer.

(54) Title: PIPERIDINONE DERIVATIVES AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER. (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 also relates to pharmaceutical compositions containing an MDM2 inhibitor.

(57) Abstract

The present invention provides MDM2 inhibitor compounds of Formula (I), where 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.

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Institute

Mexican Property

Industrial

PATENT TITLE NO. 343587 _SE_ «CRCTARlA« KQNOMU,

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Headlines):

Home:

Denomination:

Classification:

Inventor (s):

AMGEN INC.

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

PIPERIDINONE DERIVATIVES AS MDM2 INHIBITORS FOR THE TREATMENT OF CANCER.

lnt.CI.8: C07C15 / 18; C07C25 / 06; C07C69 / 00; C07C69 / 22; C07C69 / 42; C07D263 / 52; C07D309 / 00; C07D309 / 04

MICHAEL DAVID BARTBERGER; ANA GONZÁLEZ BUENROSTRO: HILARY PLAKE BECK; XIAOQI CHEN; RICHARD VICTOR CONNORS; JEFFERY DEIGNAN; JASON DUQUETTE; JOHN EKSTEROWICZ; BENJAMIN FISHER; BRIAN MATTHEW FOX; JIASHENG FU; ZICE FU; FELIX GONZÁLEZ LÓPEZ DE TURISO; MICHAEL WILLIAM GRIBBLE JR .; DARIN JAMES GUSTIN: JULIE ANNE HEATH: XIN HUANG; XIANYUN JIAO; MICHAEL JOHNSON; FRANK KAYSER; DAVID JOHN KOPECKY HIS JEN LAI; YIHONG LI; ZHIHONG Ll; JIWEN LIU; JONATHAN DANTE LOW; BRIAN STUART LUCAS; ZHIHUA MA; LAWRENCE MCGEE; JOEL MCINTOSH; DUSTIN MCMINN; JULIO CESAR MEDINA; JEFFRET THOMAS MIHALIC; STEVEN HOWARD OLSON; YOSUP REW; PHILIP MARLEY ROVETO; DAQING SUN; XIAODONG WANG; YINGEAI WANG: XUELEI YAN; MING YU; JIANG ZHU

Number:

MX / a / 2016/001932

REQUEST

International filing date:

June 2011

Divisional Patent Number: 337178

PRIORITY

<td>Country:</td><td>Date:</td><td>Number:</td>

<td>US</td><td>June 4, 2010</td><td> 61/351,827</td>

<td>US</td><td>June 7, 2010</td><td> 61/352,322</td>

<td>US</td><td>March 14, 2011</td><td> 61/452,578</td>

Validity: Twenty years

Expiration Date: June 3, 2031

The reference patent is granted based on articles 1, 2 fraction V, 6 fraction llt, and 59 of the Industrial Property Law. In accordance with article 23 of the Law of the ProptedOKl · Industrial, the presenbHMKMkt-Mna ttm valid for twenty years * non-extendable, counted from the date of submission of the application Mamadonál and MfiHÍ M0ta ¿payment of the fee to keep the 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 / 08/1884, 01/25/18 S6, 12/26/1887, 05/17/1999, 2670172004 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, 3, fraction V, subsection a), 4, and 12, sections I and III of the Regulations of the Mexican Institute of Industrial Property (DOF 14/12/1999, amended on 07/01/2002, 07/15/19) 2004, 07/28/2004 and 09/07/2007); Articles 1, 3, 4, 5, section V, Section 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); 1, 3 and 5 subsection a) of the Agreement that delegates powers to the Deputy Directors General, Coordinator, Divisional Directors, Holders of the Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Industrial Property. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

Issue Date: November 10, 2016

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PIPERIDINONE DERIVATIVES AS 1 '

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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 tension from various attacks including hypoxia and pro-apoptotic oncogene activation.

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

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MUICANO INSTITUTE OF PROPERTY

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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 the

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 downstream alterations 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 tumors^Wt 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

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INSTITUTO MSXICAN OE LA FROFIBDA · ΙΝΒΕΚΤΚΙΑΙ

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from the nuclei to the cytoplasm. All three of these mechanisms would be blocked by neutralizing the MDM2-p53 interaction. In particular, this therapeutic strategy could be applied to tumors that are p53^Wt, and studies with small molecule MDM2 inhibitors have provided promising reductions in tumor growth both in vitro and in vivo.

Furthermore, 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 lymph nodes 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

ΙΜΡΙ

MEXICAN KSTITUTE OF THE MORI INDUSTRIAL AGE

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The present invention relates to piperidinone derivatives of Formula I.

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enantiomers, diastereomers and pharmaceutically acceptable salts thereof, wherein

Q is a link 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 (= O)₂

R^to is each occurring independently selected from H, (C1-C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl, (alkoxy) (C1-C3) alkyl, or cyano;

R^b is H, halo, (C1-C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl, (alkoxy) (C1-C3) alkyl, or cyano;

R^c and R^d are independently H, halo, (C1-C3) alkyl,

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

or R^c and R^d they can optionally combine to form a spiro-cycloalkyl or heterocycle ring system;

R^and is (a) H, or halo; or (b) (Ci-Ce) alkyl, (C3-C8) cycloaikyl, (C3Ce) heterocycle, cyano, halogen, hydroxyl, -OR⁵, NR⁷R⁸, heterocycloalkyl, any of which can be optionally substituted with 1 or more R groups^x as allowed by valence.

or R^and and either of the R 'or R groups can optionally combine to form a spiro-cycloalkyl or heterocycle ring system;

or R^d and either of the R 'or R groups can optionally combine to form a fused cycloaikyl or heterocycle ring system;

or R^d and R^and they can optionally combine to form a fused cycloaikyl 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) alkyl (Ci—

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

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

IMPI 'νϊτιτ, ιτο Mexican • ί LA PftOPIMMD INDUSTRIAL

<img file="MX343587B_D0012.tif" />

or R 'and R linked to the same 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) NHOH, -C (O) NH-NH₂,

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

NR⁷C (O) OR⁵, -C (O) NR⁷R⁸, -NR⁷S (0) ₂R¹⁰, or -NR⁷C (O) NR⁷R⁸, -S (O) / R¹⁰, or CN;

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

R² is (a) -NR⁷R⁸, NR⁷C (O) OR¹⁰, NR⁷C (O) NR⁷R¹⁰, or -C (R^to) R⁵R⁶;

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

or any of R³ and R^to along with the carbon atom of the

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INSTITUI ·· MIXICANO CM LA ntons * AD INDUSTRIAL

<img file="MX343587B_D0013.tif" />

ring to which both are attached, or R⁴ and R^b 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

<img file="MX343587B_D0014.tif" />

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

R⁵, and R⁶ each presented, respectively, are 20 independently selected from (a) H and CN; or (b) - (alkylene) t -OH, - (alkylene) t -OR⁹, - (alkylene) t

-MR⁹, - (alkylene) t -NR¹⁰R^{1: L}, - (alkylene) t ~ C (O) R⁹,

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

<img file="MX343587B_D0015.tif" />

SW)_VR⁹, - (alkylene) t-NHS (O) 2R¹⁰, - (rent

- (alkylene) t-NR¹⁰C (O) R⁹, CÍOJNR ^ R¹¹, NR¹⁰S (O) 2R⁹, S (O) 2NR “t — Y - NR¹⁰C (O) NR- ° Rⁿ; or (a) haloalkyl, haloalkoxy, Ci-6-alkyl, C-alkenyl₂6, C2-6-alkynyl, C3-8-cycloalkyl, (C3-cycloalkyl) (C1-3-alkyl) -C4-8-cycloalkenyl, aryl (Ci-3-alkyl) heteroaryl, heteroaryl (C3-alkyl), heterocycle and heterocycle (Ci-3-alkyl), either of which can optionally be independently substituted with one or more R groups^x as allowed by valence;

R⁷, and R⁸ each occurring respectively are independently selected from H, Ci-6-alkyl, halo (C1-6) -alkyl, cycloalkyl, alkenyl-C₂-6, alkynyl-C₂6, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycle (C1-10alkyl), and (C3-8cycloalkyl) (C1-3alkyl), either of which may optionally be substituted as valency with one or more R^x; or R⁷ and R⁸ can combine to form a heterocycle-C4-Ce ring optionally substituted with one or more R^x;

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

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MEXICAN INSTITUTE OE THE INDUSTRIAL EROPIEIJAD

<img file="MX343587B_D0016.tif" />

C1-3), C4-8-cycloalkenyl, aryl, heteroaryl, and heterocycle any of which may optionally be independently substituted with one or more R groups^x 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 R^x;

or R¹⁰ and R^or they can combine to form a heterocycle ring optionally substituted with one or more R^x;

R^x 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 (O) _VR *, - (alkylene) _t-NR-R⁺⁺,

- (alkylene) _t-C (= 0) R *, - (alkylene) _t~ C (= S) R *,

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

- (alkylene) tC (= S) OR *, - (alkylene) tC (= 0) NR R¹¹,

- (alkylene) tC (= S) NRiR¹¹, - (alkylene) _t-N (R⁺) C (= 0) NR⁺R,

- (alkylene) tN (R⁺) C (= S) NR + R, - (alkylene) _t-N (R⁺) C (= 0) R *,

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MEXICAN INSTITUTE OF PROPERTY

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<img file="MX343587B_D0017.tif" />

- (alkylene) tN (R ~) C (= S) R, - (alkylene) t-OC (= 0) NR⁺R⁺⁺,

- (alkylene) t-OC (= S) NR⁺R, - (alkylene) t-SO2NR⁺R^_+,

- (alkylene) _t-N (R⁺) SO2R *, - (alkylene) _t-N (R⁺) SO2NR⁺R,

- (alkylene) t ~ N (R^-) C (= 0) OR *, - (alkylene) t ~ N (R⁺) C (= S) OR *, or

- (alkylene) tN (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 ~ OR

- (alkylene) t-NR⁺R^__,

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

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

- (alkylene) _t-C (= 0) NR^_R⁺⁺,

- (alkylene) tN (R⁺) C (= 0) NR⁺R “~,

- (alkylene) tN (R¹) C (= 0) R *,

- (alkylene) t-OC (= 0) NR¹R¹¹,

- (alkylene) _t-SO2NR¹R¹,

- (alkylene) _t-N (R¹) S0₂NR¹R,

- (alkylene) tN (R +) C (= S) OR *, or &lt;

> R * is haloalkyl, haloalkoxy,

- (alkylene) t ~ S (O) _VR,

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

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

- (alkylene) tC (= S) OR *,

- (alkylene) tC (= S) NR⁺R⁺⁺,

- (alkylene) _t-N (R⁺) C (= S) NR⁺R ”,

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

- (alkylene) t-OC (= S) NR¹R,

- (alkylene) tN (R¹) SO2R *,

- (alkylene) tN (R) C (= O) OR *, (alkylene) tN (R ') SO2R *;

Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, aryl,

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MIXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX343587B_D0018.tif" />

heteroaryl, and heterocycle

R¹ and R¹¹ they are independently H, alkyl, haloal-qnyl, 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 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 where R² is -C (H) R⁵R⁶ or NR⁷R⁸, phenyl or pyridine, phenyl or pyridyl can optionally be substituted with one or more R^x as allowed by valence.

Preferred compounds within the scope of

Formula I include compounds where R² is R² is selected from

IMPI ¢ 3

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IMPI imctitiiTO MEXICANO MONEDAD 'V, -', -? TWAL

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/

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.0

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<img file="MX343587B_D0033.tif" />

<img file="MX343587B_D0034.tif" />

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

Preferred compounds within the scope of

Formula I include compounds where R¹ is

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL .0

OH, or a heterocycle selected from

<img file="MX343587B_D0035.tif" />

<img file="MX343587B_D0036.tif" />

<img file="MX343587B_D0037.tif" />

<img file="MX343587B_D0038.tif" />

<img file="MX343587B_D0039.tif" />

<img file="MX343587B_D0040.tif" />

<img file="MX343587B_D0041.tif" />

selected from

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<img file="MX343587B_D0043.tif" />

<img file="MX343587B_D0044.tif" />

and

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Preferred compounds

Formula I include compounds from • IMPI

INSTITUTO MEXICANO or LA FROFIEPAU

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industrial

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Within the scope of Formula IA:

of the

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P enantiomers, diastereomers and pharmaceutically acceptable salts thereof where q and p are each independently 0, 1, 2 or

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

Preferred compounds within the scope of

<img file="MX343587B_D0049.tif" />

IB enantiomers, diastereomers, and pharmaceutically acceptable salts thereof wherein q and p are each independently 0, 1, 2o χ, ν or proffered from 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:

<img file="MX343587B_D0050.tif" />

IC

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MIXICANO INSTITUTE Di LA ΡΙΟ »! Σ3ΑΓ> INDUSTRIAL

<img file="MX343587B_D0051.tif" />

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 where R² is selected from

<img file="MX343587B_D0052.tif" />

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

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·. .-Χώ, ··., ·. ν —- '«. · ..μΙ ϊ„ ·. „

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INSTITUTO MSXICA NO VL · ^ -ί- .¿1 DELA PROPERTY ^ -¿

INDUSTRIAL, and any of which can optionally be substituted with one or more R groups^x as allowed by valence.

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

<img file="MX343587B_D0056.tif" />

or a pharmaceutical salt where:

acceptable thereof, in

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

NR⁷ bear)_V, when n * is an integer from 1 to 6;

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

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R^to each occurring is independently selected from H, (C1-C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl, (alkoxy) (C1-C3) alkyl, or cyano;

R^b is H, halo, (C1-C3) alkyl, (halo) (C1-C3) alkyl, 5 (hydroxy) (C1-C3) alkyl, (alkoxy) (C1-C3) alkyl, or cyano;

R^c and R^d 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 R^c and R^d they can optionally be combined to form a spirocycloalkyl or heterocycle ring system;

R^and is (a) H or halo; or (b) (Ci-Ce) alkyl, (C3-C8) cycloalkyl, (C315 Ce) heterocycle, cyano, halogen, hydroxyl, -OR⁵, NR⁷R⁸, or heterocycloalkyl, any of which can be optionally substituted with 1 or more R groups^x as allowed by valence, or R^and and any of the groups R 'or

R may optionally combine to form a spiro-cycloalkyl or heterocycle ring system, or R^d and any of the R 'or R groups can optionally combine to form a fused heterocyclo or cycloalkyl ring system, or R^d and R^and can optionally combine to form a cycloalkyl or heterocycle ring system

<img file="MX343587B_D0057.tif" />

merged;

R 'and R each occurring, respectively, are independently H, halo, (C1-C3) alkyl, (C1-C3) alkoxy, (halo) (C1-C3) alkyl, (halo) (C1-C3) alkoxy , (alkoxy) alkyl (Ci5 C3), (hydroxy) alkyl (C1-C3), -S-alkyl (C1-C3),

C (0) (C1-C3) alkyl, -NR⁷R⁸, or hydroxyl, or R 'and R linked to the same 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) NHOH, -C (O) NH-NH₂,

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

NR⁷C (O) OR⁵, -C (O) NR⁷R⁸, -NR⁷S (0) 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 groups^x as allowed by valence;

R² is (a) -NR⁷R⁸, NR⁷C (O) OR¹⁰, NR⁷C (0) NR⁷R¹⁰, or -C (R^to) 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;

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R³ and R⁴ they are independently aryl or heteroaryl, either of which may optionally be independently substituted with one or more R groups^x as allowed by valence, or any of R³ and R^to along with the carbon atom of the ring to which both are attached, or R⁴ and R^b 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

<img file="MX343587B_D0058.tif" />

<img file="MX343587B_D0059.tif" />

<img file="MX343587B_D0060.tif" />

P

<img file="MX343587B_D0061.tif" />

R^x z

F

P

<img file="MX343587B_D0062.tif" />

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

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

IP1

I χ i iNSTrrvr · mahcano ⁿAND THE PROPERTY l »».

'NtlISTRIAL Os (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 S (O) VR⁹, - (alkylene) t-NHS (O) 2R¹⁰, - (alkylene) tN (R¹¹) S (O) 2R¹⁰,

- (alkylene) _t-S (O) ₂NR¹⁰Rⁿ, -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, C3-8-cycloalkyl, (cycloalkyl-03-8) (C3-alkyl), cycloalkenyl-C4-8r aryl, aryl (Ci-3-alkyl), heteroaryl, heteroaryl (Ci-3-alkyl), heterocycle or heterocycle (Ci-3-alkyl), any of which can optionally be independently substituted with one or more R groups^x as allowed by valence;

R⁷ and R⁸ each presented, respectively, are independently selected from H, cyano, -O Ci-6 alkyl, Ci-6 alkyl, haloalkyl- (Ci-β), cycloalkyl, alkenyl-C₂-6, alkynyl-C₂-6, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycle (Ci-10alkyl), or (C3-8alkyl) (Ci-3alkyl), either of which may optionally be substituted by valence with one or more R^x, or R⁷ and R⁸ may combine to form a C4-C8 heterocycle ring optionally substituted with one or more R^x;

R⁹ is haloalkyl, haloalkoxy, Ci-6-alkyl, C-alkenyl₂6 / alkynyl-C₂-6, cycloalkyl-C3-8, (cycloalkyl-C3-

<img file="MX343587B_D0063.tif" />

ε) (Ci-3-alkyl), C4-8-cycloalkenyl, aryl, heteroaryl, or heterocycle, any of which can optionally be independently substituted with one or more R groups^x 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 R^x, or R¹⁰ and R¹¹ they can combine to form a heterocycle ring optionally substituted with one or more R^x;

R^x 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 (O) _VR *, - (alkylene) t-NR^_R⁺⁺,

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

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

- (alkylene) tC (= S) OR *, - (alkylene) tC (= 0) NR⁺R^_,

- (alkylene) tC (= S) NR^XR, - (alkylene) t ~ N (R¹) C (= 0) NR ^ -R¹,

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

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

MEXICAN INSTITUTE f »r LA PROPIEDAD * Γ '· &lt;' ΤΜΑ1

- (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) tN (R^-) C (= 0) OR *,

<img file="MX343587B_D0064.tif" />

- (alkylene) t-SO2NR⁺R^_+,

- (alkylene) tN (RJ SO2NR "R⁺⁺,

- (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-OR *, - (alkylene) tS (O) _VR *,

- (alkylene) _t-NR ~ R⁺⁺, - (alkylene) _t-C (= 0) R *,

- (alkylene)_t-C (= S) R *, - (alkylene) tC (= 0) OR *,

- (alkylene) _t-OC (= 0) R *, - (alkylene) t ~ C (= S) OR *,

- (alkylene) _t-C (= 0) NR⁺R ', - (alkylene) t ~ C (= S) NR¹R,

- (alkylene) tN (R¹) C (= 0) NRiR¹, - (alkylene) _t-N (R) C (= S) NR R¹¹,

- (alkylene) _t-N (R) C (= O) R *, - (alkylene) tN (R¹) C (= S) R *,

- (alkylene) t-OC (= 0) NR R¹¹,

- (alkylene) t-S02NR¹R¹,

- (alkylene) _t-N (R ~) S02NR'R⁺⁺,

- (alkylene) t-OC (= S) NR ^ -R,

- (alkylene) tN (R^_) SO2R *,

- (alkylene) tN (R^-) C (= 0) OR *,

- (alkylene) tN (R^-) C (= S) OR *, or - (alkylene) tN (R ~) SO2R *;

R * is H, haloalkyl, haloalkoxy, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, aryl, heteroaryl, or heterocycle;

R and R⁺⁺ are independently H, alkyl, haloalkyl,

<img file="MX343587B_D0065.tif" />

aryl, heteroaryl, heteroarylalkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, arylalkyl, 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:

<img file="MX343587B_D0066.tif" />

or a pharmaceutically acceptable salt thereof, wherein:

IMPIAS

MIXICAN INSTITUTE ¿fw'sffiSSé '-' Jh Oí LA INDUSTRIAL RRORIRDAD

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

NR⁷ bear)_V, when n * is an integer from 1 to 6;

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

R^to each presented is independently selected from H, (C1-C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl, (alkoxy) (C1-C3) alkyl, or cyano;

R^b is H, halo, (C1-C3) alkyl, (halo) (C1-C3) alkyl, (hydroxy) (C1-C3) alkyl, (alkoxy) (C1-C3) alkyl, or cyano;

R^c and R^d 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 R^c and R^d they may optionally combine to form a spiro-cycloalkyl or heterocycle ring system;

R^and is (a) H, or halo; or (b) (Ci-Ce) alkyl, (C3-C8) cycloalkyl, (C3Ce) heterocycle, cyano, halogen, hydroxyl, -OR⁵, NR⁷R⁸, or heterocycloalkyl, any of which can be optionally substituted with 1 or more R groups^x as allowed by valence, or R^and and any of the R groups^F or

R may optionally combine to form a spiro-cycloalkyl or heterocycle ring system, or R^d and any of the R 'or R groups can be optionally combined to

IMPÍ6

ΙΝίΓΓΙΤυΤΟ MEXICAN

FROM INDUSTRIAL V PROPERTY 'form a fused cycloalkyl or heterocycle ring system, or R^d and R^and 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) C1-C3 alkyl, -NR⁷R⁸, or hydroxyl, or

<img file="MX343587B_D0067.tif" />

<td>R 'and R</td><td>linked</td><td>to the</td><td>same</td><td>atom</td><td>carbon</td><td>they can</td>

<td>combine</td><td colspan="2">optionally</td><td>for</td><td>to form</td><td>= 0, 0 R '</td><td>and R</td>

<td>linked</td><td>the same</td><td colspan="2">atom of</td><td>carbon</td><td colspan="2">can be combined</td>

optionally 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 (O) 2NHC (O) R¹⁰, -S (O) 2NR⁷R⁸, -NR⁷C (O) R¹⁰,

NR⁷C (O) OR⁵, -C (O) NR⁷R⁸, -NR⁷S (O) 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 groups^x as allowed by valence;

R² is (a) -NR⁷R⁸, NR⁷C (O) OR¹⁰, NR⁷C (O) NR⁷R¹⁰, o ~ C (R^to) R⁵R⁶; or

IMPI

INJTTTUTO MEXICANO l> E LA PROPIEDAD INDUSTRIAL

<img file="MX343587B_D0068.tif" />

(b) aryl, heteroaryl, cycloalkyl, or heterocycle, any of which can optionally be independently substituted with one or more R groups^x 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 groups^x as allowed by valence, or any of R³ and R^to along with the carbon atom of the ring to which both are attached, or R⁴ and R^b 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

<img file="MX343587B_D0069.tif" />

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

MEXICAN INSTITUTE -S? ./ ?;

M PROPERTY

INDUSTRIAL

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 -NR¹⁰Rⁿ, - (alkylene) _t-C (O) R⁹,

- (alkylene) t -C (O) OR⁹, - (alkylene) t -OC (O) R⁹, - (alkylene) t S (O) _VR⁹, - (alkylene) t-NHS (0) 2R¹⁰, - (alkylene) t ~ N (R¹¹) S (O) 2R¹⁰,

- (alkylene) t ~ S (O) 2NR¹⁰R^{1: l}, - (alkylene) t^_N (R¹¹) S (O) 2NR¹⁰R¹¹,

NR¹⁰C (O) R⁹, -C (O) NR¹⁰Rⁿ, -NR¹⁰S (O) 2R⁹, S (O) 2NR¹⁰, or

NR¹⁰C (O) NR¹⁰R¹¹; or (c) haloalkyl, haloalkoxy, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, (C3-8 cycloalkyl) (alkyl

C1-3), cycloalkenyl-C4-8, aryl,

3) heteroaryl, heteroaryl (Ci-3-alkyl), heterocycle (Ci-3-alkyl), any of which may optionally be independently substituted with one or more R groups^x as allowed by valence;

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

IMPI

INSTITUTO MEXCANO '- · -t ·

OSlAHt PIEDAD 'PZ

INDtlSTWAl can optionally be substituted as valence with one or more R^x, or R⁷ and R⁸ they may combine to form a heterocyclo-Ci-Cs ring optionally substituted with one or more R^x;

R⁹ is haloalkyl, haloalkoxy, Ci-6-alkyl, C-alkenyl₂6, alkynyl-C₂-6, C3-8cycloalkyl, (C38-cycloalkyl) (C1-3alkyl), cycloalkenyl-Cw, aryl, heteroaryl, heterocycle, or heterocycloalkyl, either of which can optionally be independently substituted with one or more R groups^x as allowed by valence;

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

R^x 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 *,

J

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL _

- (alkylene) _t-NR "R⁺⁺,

- (alkylene) tS (O) _VR *,

- (alkylene) tC (= 0) R *,

- (alkylene) tC (= 0) OR *,

- (alkylene) tC (= S) OR *,

- (alkylene) tC (= S) NR⁺R ~ ",

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

- (alkylene) tN (R⁺) C (= S) R *,

- (alkylene) t ~ OC (= S) NR ^ -R

- (alkylene) tN (R) SO2R *,

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

- (alkylene) t-OC (= 0) R *, - (alkylene) tC (= 0) NR⁺R ”,

- (alkylene) tN (R⁺) C (= O) NR⁺R ~⁺,

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

- (alkylene) t-OC (= 0) NR R¹¹,, - (alkylene) t-SO2NR¹R¹,

- (alkylene) tN (R) SO₂NR R¹¹,

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

- (alkylene) tN (R) SÜ2R *, 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) tS (0)_VR *,

- (alkylene) t-NR^_R⁺⁺,

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

- (alkylene) t ~ OC (= 0) R *, - (alkylene) tC (= 0) NR¹R,

- (alkylene) tN (R¹) C (= 0) NR¹R¹,

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

- (alkylene) t-OC (= 0) NRR⁺⁺,

- (alkylene) t-S02NR⁺R^-+,

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

- (alkylene) tC (= 0) OR *,

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

- (alkylene) tC (= S) NR ^,

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

- (alkylene) tN (R⁺) C (= S) R *,

- (alkylene) t-OC (= S) NR⁺R ”,

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

<img file="MX343587B_D0070.tif" />

IMPI

6 MEXICAN INSTITUTE

SAY LA ΡΕΟΡΙΕΓιΑΠ

INDUSTRIAL

- (alkylene) tN (R^-) SO2NRR⁺⁺, - (alkylene) tN (R^-) C (= 0) OR *,

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

R * is haloalkyl, haloalkoxy, Ci-6-alkyl, C26-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, 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 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 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 R^x as allowed by valence.

In another modality, modality 3, of the compounds of »- · **> *« *? «.

<img file="MX343587B_D0071.tif" />

PROPERTY C ^ í¡ ^ &amp; L¿®F INDUSTRIAL aspect A or AA, or the pharmaceutically acceptable salts of

<img file="MX343587B_D0072.tif" />

<img file="MX343587B_D0073.tif" />

<img file="MX343587B_D0074.tif" />

<img file="MX343587B_D0075.tif" />

<img file="MX343587B_D0076.tif" />

<img file="MX343587B_D0077.tif" />

<img file="MX343587B_D0078.tif" />

w.- V

<img file="MX343587B_D0079.tif" />

<img file="MX343587B_D0080.tif" />

tr O, any of which can optionally be substituted with one or more R groups^x as allowed by valence.

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

themselves,

1, 2 or

In aspect

<img file="MX343587B_D0081.tif" />

IA the pharmaceutically acceptable salts of those where q and p are each independently 0,

i.

another modality, modality 5, the compounds of

A or AA have the structure of Formula IB

<img file="MX343587B_D0082.tif" />

or the same, the pharmaceutically acceptable salts of which q and p are each independently 0,

1, 2 or 3.

MEXICAN INSTITUTE OF PROPERTY

In another modality, modality 6, the compuM^s§^!fc'ós

<img file="MX343587B_D0083.tif" />

aspect A or AA have the structure of Formula IC ”

<img file="MX343587B_D0084.tif" />

IC or the pharmaceutically acceptable salts thereof, wherein q and p are each independently C

1, 2 or 3.

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

<img file="MX343587B_D0085.tif" />

<img file="MX343587B_D0086.tif" />

<img file="MX343587B_D0087.tif" />

<img file="MX343587B_D0088.tif" />

t

<img file="MX343587B_D0089.tif" />

Ν

MEXICAN INSTITUTE

OT UA PROPERTY

INDUSTRIAL

<img file="MX343587B_D0090.tif" />

<img file="MX343587B_D0091.tif" />

<img file="MX343587B_D0092.tif" />

<img file="MX343587B_D0093.tif" />

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

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

R² is selected from

<img file="MX343587B_D0094.tif" />

<img file="MX343587B_D0095.tif" />

<img file="MX343587B_D0096.tif" />

<img file="MX343587B_D0097.tif" />

/

<img file="MX343587B_D0098.tif" />

<img file="MX343587B_D0099.tif" />

<img file="MX343587B_D0100.tif" />

<img file="MX343587B_D0101.tif" />

<img file="MX343587B_D0102.tif" />

<img file="MX343587B_D0103.tif" />

<img file="MX343587B_D0104.tif" />

<img file="MX343587B_D0105.tif" />

IMPÍ

INSTITUTO MSXICANO DF LA PROSISDAD INDUSTRIAL

<img file="MX343587B_D0106.tif" />

<img file="MX343587B_D0107.tif" />

, any of which can optionally be substituted with one or more R groups^x as allowed by valence;

and R¹ is, 0

Oh _t or a heteroaryl or heterocycle selected from

<img file="MX343587B_D0108.tif" />

t

<img file="MX343587B_D0109.tif" />

OR

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX343587B_D0110.tif" />

In another aspect of modality 6 (modality 9) pharmaceutically acceptable salts thereof,

R² is selected from or

<img file="MX343587B_D0111.tif" />

,0

<img file="MX343587B_D0112.tif" />

<img file="MX343587B_D0113.tif" />

.0 fr

<img file="MX343587B_D0114.tif" />

Oh

<img file="MX343587B_D0115.tif" />

<img file="MX343587B_D0116.tif" />

IMPI

ΙΝΓΠΤΙΓΓΟ MVUCANU OF THE FROP1IDAO INfXJSTBlAL

<img file="MX343587B_D0117.tif" />

<img file="MX343587B_D0118.tif" />

<img file="MX343587B_D0119.tif" />

<img file="MX343587B_D0120.tif" />

<img file="MX343587B_D0121.tif" />

any of which can optionally be substituted with one allow for valence; and

R¹ it's more

<img file="MX343587B_D0122.tif" />

MfiXiCANO INSTITUTE OF PROPUDAD group ^^DUS^^{TO THE}

<img file="MX343587B_D0123.tif" />

,0

OH, or a heteroaryl or heterocycle selected from

<img file="MX343587B_D0124.tif" />

<img file="MX343587B_D0125.tif" />

<img file="MX343587B_D0126.tif" />

<img file="MX343587B_D0127.tif" />

<img file="MX343587B_D0128.tif" />

<img file="MX343587B_D0129.tif" />

OR

<img file="MX343587B_D0130.tif" />

IMPI

1ΝΓΓΓΠ / ΤΌ MEXICAN D £ LA INDUSTRIAL PROPHiPAD

<img file="MX343587B_D0131.tif" />

In another aspect of embodiment 6 (embodiment 10), or the pharmaceutically acceptable salts thereof,

R² is selected from

<img file="MX343587B_D0132.tif" />

frf 9

<img file="MX343587B_D0133.tif" />

<img file="MX343587B_D0134.tif" />

<img file="MX343587B_D0135.tif" />

any of which can optionally be substituted with one or more R groups^x as allowed by valence; and

R¹ is

MEXICAN INSTITUTE '.'ti í industrial

<img file="MX343587B_D0136.tif" />

OH, or a heteroaryl or heterocycle selected from

H

N10

<img file="MX343587B_D0137.tif" />

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

<img file="MX343587B_D0138.tif" />

Cl

ID or a pharmaceutically acceptable salt thereof.

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

<img file="MX343587B_D0139.tif" />

IMPI

MEXICAN INSTITUTE OF PROPERTY methyl or ethyl. industrial

In another embodiment, embodiment 13, the ompugslro-s— of the · · - aspect A have the structure of Formula IE

<img file="MX343587B_D0140.tif" />

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

<img file="MX343587B_D0141.tif" />

<img file="MX343587B_D0142.tif" />

<img file="MX343587B_D0143.tif" />

, any of which can optionally be substituted with one or more R groups^x as allowed by valence; and

R¹ is, 0

OH or a heteroaryl or heterocycle selected from

X

MEXICAN INSTITUTE

Say 1.Λ MOMIDAn

INDUSTRY!.

<img file="MX343587B_D0144.tif" />

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

R¹ is

<img file="MX343587B_D0145.tif" />

or a heteroaryl or heterocycle selected from

<img file="MX343587B_D0146.tif" />

<img file="MX343587B_D0147.tif" />

R² is

<img file="MX343587B_D0148.tif" />

R^and it is methyl.

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

R² is

IMPIOUS

Η

-C — CH₂—N — SO₂—R

II

R⁵ R¹¹

H

C — CH₂I

R⁵

SO, —R⁹

M &amp; XICANO INSTITUTE OF INDUSTRIAL PR PIETY

<img file="MX343587B_D0149.tif" />

H

-C — CH₂-SO R⁹

R⁵

H

I c — ch₂-SW₂nr¹⁰r¹¹

R⁵

H

C — CH₂-N (R¹¹)SW₂NR¹⁰R¹¹

R⁵

R⁵ it is cyclopropyl, or Ci-β alkyl;

R⁹ it is haloalkyl, haloalkoxy, Ci-6 alkyl, C26 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, (C3-cycloalkyl) (C3-alkyl), Cw-cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl, or R⁹ it is haloalkyl, haloalkoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, (C3-8cycloalkyl) (C1-3alkyl), aryl, heteroaryl , or heterocycle, any of which can optionally be independently substituted with one or more R groups^x 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

<img file="MX343587B_D0150.tif" />

»F LA FROFIÍDAR

INDUSTRIAL ___ heterocycloalkyl, or cycloalkylalkyl, any of "which may optionally be substituted as valency with one or more R^x, or R¹⁰ and R¹¹ they can combine to form a heterocycle ring optionally substituted with one or more R^x.

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

R¹ is

<img file="MX343587B_D0151.tif" />

<img file="MX343587B_D0152.tif" />

<img file="MX343587B_D0153.tif" />

<img file="MX343587B_D0154.tif" />

and R^and 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-315 yl) 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-320 yl) 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-oxopiperidin -3-yl) acetic;

I Αί Ρ ί

MIXICAN INSTITUTE Γ »ϊ ΙΑ PROPERTY

INDUSTRIAL _ 2- ((3R, 5R, 6S) -1- ((S) ^ -tert-Butoxy-l-cyclopropTTT acid²⁷

2- oxoethyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -15 ((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) -ΙΙΟ ((S) -1- (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) -115 ((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 - ((1-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;

<img file="MX343587B_D0155.tif" />

₆₅ IMPÍ

KSTITlrro MEXICANO

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

2 - ((3R, 5R, 6S) -l - ((S) -1 - ((15 carbamoylcyclopropyl) methoxy) butan-2-yl) -5- (3-chlorophenyl) -6 (4-chlorophenyl) acid - 2-oxopiperidin-3-yl) acetic (isomer 1);

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

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (2-hydroxy-2-methylpropoxy) butan-2-yl acid ) -2-oxopiperidin3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -2oxo-1 - (((3S) -1,1,1-trifluoro-2-hydroxypentan-3 -yl) piperidin-315 yl) 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) -120 ((S) -1-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-il) piperidin MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

3-yl) acetic;

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-310 yl) 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- (315 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) -ΙΣΟ ((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) -2INSTITUTO MEXICANO

OE LA EUOHEDAL industrial

<img file="MX343587B_D0156.tif" />

oxo-1 - ((S) -1- (pyridin-2-yl) pentan-3-yl) piperidin-3yl) 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-oxopiperidin3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 · ((R) -1- (5-methyl-l, 3,4-oxadiazole) 2-yl) propyl) -2-oxopiperidin3-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-chlorophenyl) -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;

<img file="MX343587B_D0157.tif" />

INSTITUTO MEXICANO »E LA PROPIEDAD industrial _ acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3Γ = (cyclohexylmethyl) -2-oxopiperidin-3-yl) acetic;

2 - ((3S, 5R, 6S) -5- (3-chlorophenyl) -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) -110 isobutyl-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-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamide;

Ethyl ethyl 2- (2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -120 (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetamido);

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

<img file="MX343587B_D0158.tif" />

MIXICAN INSTITUTE OF THE FMiFIKIiAP

INIMJSTMIAI

<img file="MX343587B_D0159.tif" />

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-2one;

(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) -120 (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) 71

ΙΜΡϊ

---- MEXICAN INSTITUTE J *>

ÜE THE PROPERTY ΛΣ * Αά J- INDUSTRIAL

6- (4-chlorophenyl) -1- (cyclopropylmethyl) pipendin-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 'acid -piperidin] 5'-yl) acetic;

2- ((2 'R, 3' S, 5 'S) -6-chloro-3' - (3-chlorophenyl) -1 '(cyclopropylmethyl) -2,6'-dioxoespiro [indolin-3,2' acid -piperidin] 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-oxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((R) -l-tert-butoxy-l-oxobutan-2yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- acid methyl-2-oxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 acid, τρ_λ^ .ι · ι „· 4 '·. ·. ,. ·. ·· .IMPIOS

INSTITUTO MSXICANO Dt LA PROPIEDAD 'NÜUSTRJAL.

((S) -1- (cyclopropylmethoxy) butan-2-yl) -3-methyl-2-oxopiperi

3-yl) acetic;

2- ((3S, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-oxo-3- (2- (pyrrolidin-1yl) ethyl) piperidin acid -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- (pentan-3yl) piperidin-2-one;

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

ΙΜΡΪ

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

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

<img file="MX343587B_D0160.tif" />

2-oxo-l- (pentan-3-yl) piperidin-3-yl) -N (trifluoromethylsulfonyl) acetamide;

(3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((35 hydroxy-lH-pyrazol-5-yl) methyl) -3-methy1-1- (pentan -3yl) 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-1- (pentan-3-yl) piperidin-3-yl) methyl ) oxazolidin2,4-dione;

3 - (((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-1- (pentan-3-yl) piperidin-3-yl) methyl ) -1,2,415 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) -320 meth1-2-oxo-1- (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 (3R, 5R, 6S) -3- ((lH-Tetrazol-5-yl) methyl) -5- (3-cTor &amp;^Lfeii37:

6- (4-chlorophenyl) -l-isopropyl-3-methylpiperidin-2-one;

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

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

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) ~ 3-methyl-1 - ((S) -l-morpholinobutan-2-yl) -2-oxopiperidin -315 yl) acetic;

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

IN $ T! Tirrr> MljflCANO

IM PROPERTY

INDUSTRIAL

<img file="MX343587B_D0161.tif" />

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (4- (cyclopropyl sulfonyl) piperazin-1-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- (cyclopropancarbonyl) piperazin-l-yl) butan- 2-yl) -3methyl-2-oxopiperidin-3-yl) 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-methyl2-oxopiperidin-3-yl) acetic;

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

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((IS, 2R, 3S) -2,3-dihydroxycyclopentyl) -3-methyl-2 acid -oxopiperidin3-yl) acetic;

<img file="MX343587B_D0162.tif" />

DS PUW &amp; rXAD MEXICAN INSTITUTE

INDUSTRIAL

<img file="MX343587B_D0163.tif" />

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((IR, 2R, 3S) -2,3-dihydroxycyclopentyl) -3-methyl-2 acid -oxopiperidin3-yl) acetic;

acid

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

acid

2 - ((3R, 3'R, 5R, 6S) -5- (3-chlorophenyl) -6- (410 chlorophenyl) -3-methyl-2-oxo-l '- (2,2,2-trifluoroethyl) -1,3'bipiperidin-3-yl) acetic;

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

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

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

<img file="MX343587B_D0164.tif" />

<img file="MX343587B_D0165.tif" />

7 MEXICAN INSTITUTE

DI INDUSTRIAL PROPERTY acetic methyl-1- (l-methyl-lH-pyrazol-4-yl) -2-oxopiperidin-3yl);

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-methylpyridin-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;

<img file="MX343587B_D0166.tif" />

INSTITUTO MtXICANO • fc THE PROPERTY

INDUSTRIAL

<img file="MX343587B_D0167.tif" />

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (5-chloropyridin2-yl) -3-methyl-l - (((S) -l-morpholinobutan-2-yl) acid - 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- acid 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-oxcbutan-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) -ΙΣΟ ((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-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin- 3-yl) propanoic;

IMPI

MEXICAN INSTITUTE K THE MDUSTEIAL PKOMIDAD

<img file="MX343587B_D0168.tif" />

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-ii) -2 acid -oxopiperidin3-yl) acetic;

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

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl ·) -6- (4-chlorophenyl) -120 acid

MEXICAN INSTITUTE

Dt LA FROmDAÜ C * a «« ¿3S ^ ((S) -6-hydroxy-6-methylheptan-3-yl) -3-methyl-2-oxopí ^ MTi^TOáin^i??=^_J^ il) acetic; ^J 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - (((S) -6,6,6-trifluoro-5 , 5-dihydroxyhexan-35 yl) 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, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -310 methi1-2-oxo-1 - (((3S) -7,7,7-trifluoro- 6-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-methylcyclopropanesulfonamido) 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-220 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) -381 acid

IMPI

INSTITUTO MSXICANO PE LA PROPIEDAD INDUSTRIAL

<img file="MX343587B_D0169.tif" />

methyl-2-oxo-l - ((3S) -6,6,6-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-1- ((S) -l- (N- (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) -1 ((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;

<img file="MX343587B_D0170.tif" />

IMPI

MEXICAN INSTITUTE

DB LA MONEDAD

INDUSTRIAL 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -2-oxopentan-3-yl) acid 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-35 yl) 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) -ΙΙΟ ((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-320 yl) 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) -1 acid_ηΊ IMPI or -j MEXICAN INSTITUTE

FROM THE J¡WJ PROPERTY

INDUSTRIAL ((3S, 4R) -4-hydroxyhexan-3-yl) -3-methyl-2-oxopiperidin-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-methyl1- ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) - 210 oxopiperidin-3-yl) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) - 2oxopiperidin-3-yl) -N- (methylsulfonyl) acetamide;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl15 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-methyl1 - ((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-methyl1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) - 2oxopiperidin-3-yl) -N-hydroxyacetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) - 2-

<img file="MX343587B_D0171.tif" />

oxopiperidin-3-yl) -N-methoxyacetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) - 2oxopiperidin-3-yl) -N - ((R) -2,3-dihydroxypropyl) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1 - ((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-methyl1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) - 210 oxopiperidin-3-yl) -N-cyanoacetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl1 - ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) - 2oxopi_tridin-3-yl) -N- (2- (dimethylamino) ethyl) acetamide;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl15 1 - ((S) -1- (N-methylcypropansuifonamido) 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) butan-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-Chlorophenii) -6- (4-chlorophenyl) -1- acid

<img file="MX343587B_D0172.tif" />

^ΙΜΡ1

OO MEXICAN INSTITUTE

DE LA MORE · * · 'industrial (3S) -2- (cyclopropansulfonamido) pentan-3-yl) -3-methyl-2oxopiperidin-3-yl) acetic (isomer 1);

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (3S) -2- (cyclopropansulfonamido) pentan-3-yl) -3-methyl-25 acid oxopiperidin-3-yl) acetic (isomer 2);

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

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

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

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methi-2-oxo-l - ((S) -1- (N- (2,2 , 2-trifluoroethyl) acetamido) butan20 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-methyl-2-oxopiperidin-3-yl) acetic;

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

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

<img file="MX343587B_D0173.tif" />

((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 -25 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) -ΙΙΟ ((S) -l-hydroxybutan-2-yl) -3-methyl-2-oxopiperidin -3yl) acetic;

2- ((3R, 5R, 6S) -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- 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 -220 oxopiperidin-3-yl) acetic;

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

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 acid₈₇ ΊΜΡΙλ3>

INSTITUTO MtXICANO · ι_Μ-~&lt;

Ο £ LA PHOFIOAO V * Μ-, industrial ΧΓΒΓ¹* ((S) -1- (2-methylphenylsulfonamido) butan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (4-methoxyphenylsulfonamido) butan-2-yl) -3- methyl-25 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) -ΙΙΟ ((S) -1- (1-methylcyclopropansulfonamido) butan-2-yl) -3- 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-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (pyridin-3-sulfonamido) butan-220 yl) 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 LA MOHíDAn

INDUSTRIAL

<img file="MX343587B_D0174.tif" />

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

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

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

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -189 acid

IMPI Mexican institute OF INDUSTRIAL PROPERTY

<img file="MX343587B_D0175.tif" />

((S) -1- (ethylsulfonyl) pentan-3-yl) -3-methyl-2-oxopiperidin-3yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (isopropylsulfonyl) pentan-3-yl) -3-methy1- 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) -3methyl-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-methylmorpholine) butan- 2-yl) -2oxopiperidin-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) -120 acid

<img file="MX343587B_D0176.tif" />

((S) -1- (3,3-difluoroazetidin-l-yl) butan-2-

<img file="MX343587B_D0177.tif" />

oxopiperidin-3-yl) acetic;

acid

2 - ((3R, 5R, 6S) -1 - ((2S) -1- (8-oxa-3 azabicyclo [3.2.1] octan-3-yl) butan-2-yl) -5- (3- chlorophenyl) -65 (4-chlorophenyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

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

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;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3 methyl-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) -3 methyl-2-oxo-l - ((S) -1- (2-oxopyridin-l (2H) -yl) butan-220 yl) piperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3 methi1-2-oxo-1 - ((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) -391

IM F

<img file="MX343587B_D0178.tif" />

^{, Νβτ}ΓΓυτο MSXICAN M the industrial property S? · ® '¹ methi1-1 - ((S) -1- (pyridin-3-iyoxy) butan-2-yl) piperidin-2-one;

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

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

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

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

2 - ((3R, 5R, 6S) Acid -1 - ((S) -1- (benzo [d] thiazoi-2yl) propyl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 -meti1-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-1 - ((S) -1- (3-methylisoxazol-5-yl) propyl acid) -2-oxopiperidin20

MEXICAN INSTITUTE

FROM THE fXON-TA! >

INDUJTXIAL "

3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -T methyl-1 - ((R) -1- (3-methylisoxazol-5-yl) propyl acid ) -2-oxopiperidin3-yl) acetic;

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

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -1- (6-chloropyridin-2-yl) propyl) -3- acid metii-2-oxopiperidin-310 yl) 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) -3 methyl-2-oxo-l - ((R) -1- (pyridin-2-yl ) 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) -3 methyl-2-oxo-1 - ((R) -1- (pyridin-2- il) butyl) piperidin-3yl) acetic;

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

INSTITUTO MÍXICANO BS LA PROPIEDAD INDUSTRIA !.

<img file="MX343587B_D0179.tif" />

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

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

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((S) -1- (pyrazin-2-yl) acid propyl) piperidin-3yl) acenxcu, 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-394

<img file="MX343587B_D0180.tif" />

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- f 4-rl omfeni i) -3methyl-1 - ((R) -1- (6-methylpyridin-2-yl) acid propyl) -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) -3methi1-2-oxo-1 - ((R) -1- (pyridin-4-i1) 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-yl) acid propyl) piperidin-395

IMPI

MEXICAN INSTITUTE Γ> Ε LA PÍOPIE Al?

il) acetic; industrial acid 2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlor-o £ &lt;

methyl-2-oxo-l - ((R) -1- (thiazol-2-yl) propyl) piperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -1- (6- (2-hydroxypropan-2-yl) pyridine- 2-yl) propyl) -3-methi-12-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -1- (6- (2-hydroxypropan-2-yl) pyridine- 2-i1) propyl) -3-methyl 2-oxopiperidin-3-yl) acetic;

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

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -115 ((R) -1- (6-cyclopropylpyridin-2-yl) propyl) -3- methy1-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - (((S) -3,3,3-trifluoro-1 - (pyridin-2yl) propyl) piperidin-3-i1) acetic;

2 - ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -3methyl-2-oxo-l - ((R) -3,3,3-trifluoro-1 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-oxopiperidin-

<img file="MX343587B_D0181.tif" />

MEXICAN INSTITUTE • S LA PROHEIM »industrial

3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-chlorophenyl) -6- (4-chlorophenyl'r acid^{: r}396 methyl-1 - ((R) -2-methyl-l- (pyridin-2-yl) propyl) -2-oxopiperidin3-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-oxopiperidin3-yl) acetic;

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

IMPI

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX343587B_D0182.tif" />

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

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -15 ((IS, 2R) -l-cyclopropyl-2-hydroxybutyl) -3-methyl-2oxopiperidin -3-yl) acetic;

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

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((S) -2- (cyclopropansuiphonamido) -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 215 oxopiperidin-3-yl) acetic;

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

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

IMPI ΐΜΤΓτυτο méxicaw), Déla RROFItOAl) industrial

<img file="MX343587B_D0183.tif" />

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -fi — Md nrnfpnil) -1 ((S) -l-cyclopropyl-2- (l-methylethylsulfonamido) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -15 ((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 -oxopiperidin3-yl) acetic; or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1 ((R) -cyclopropyl (pyridin-2-yl) methyl) -3-methyl- acid 2-oxopiperidin15 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- (320 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

INSTITUTO MtXICANO Di LA PROPIEDAD INDUSTRIAL

<img file="MX343587B_D0184.tif" />

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

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— (1— hydroxybutane-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;

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

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-220 acid

IMPI

100

MIXICAN INSTITUTE Dt LA FRORIDAP

INDUSTRIAL

<img file="MX343587B_D0185.tif" />

yl) -5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxopiperidin-3yl) 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-trifluoroethylamino) butan-2-yl) piperidin-3-yl) acetic acid ;

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-dioxidothiomorpholino) 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;

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1101

IMPI

INSTITUTO MtXICANO M LA FFOFIIDAf INDUSTRIAL

<img file="MX343587B_D0186.tif" />

(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) piperidin-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;

<img file="MX343587B_D0187.tif" />

ΙΜΡΙ

MEXICAN INSTITUTE

TOO Bl THE PROPERTY

-LU ¿INDUSTRIAL 2- (5- (3-Chlorophenyl) (Ari n-i (cyclopropylmethyl) -2-oxopiperidin-3-yl) acetic acid;

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

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

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

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -110 (cyclopentylmethyl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -2-oxo-l (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;

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

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

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

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

IMP I

MEXICAN INSTITUTE »E LA PROFUDAL 'INDUSTRIAL

<img file="MX343587B_D0188.tif" />

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

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

Ethyl 2- (3- (3-chlorophenyl) -2- (4-chlorophenyl) -5- (2 - ((3morpholinopropyl) amino) -2-oxoethyl) -6-oxopiperidin-lyl) butanoate;

3 - ((lH-Tetrazol-5-yl) methyl) -5- (3-chlorophenyl) -6- (4chlorophenyl) -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-methyl-l, 3,4-oxadiazol-2-yl) methyl) piperidin-2-one;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -115 (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- (420 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'-dioxoespiro [indolin-3,2'-piperidin] 104 acid

IMPI

INSTITUTO M tí (CANO I HEARD THE INDUSTRIAL IXOPIDITY

<img file="MX343587B_D0189.tif" />

5'-yl) acetic;

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

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

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1 (cyclopropylmethyl) -2-OXO-3- (2- (pyrrolidin-1yl) 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-isopropylIM acid

105

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

<img file="MX343587B_D0190.tif" />

2- (5- (3-chlorophenyl) -6- (4-chlorof acid institute £ HLA

<img file="MX343587B_D0191.tif" />

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

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -Ιό cyclopentyl-3-methyl-2-oxopiperidin-3-yl) acetic;

5- (3-chlorophenyl) -6- (4-chlorophenyl) -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-l10 (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-1 (pentan-3-yl) piperidin-3-yl) -N (trifluoromethylsulfonyl) acetamide;

5- (3-chlorophenyl) -6- (4-chlorophenyl) -3 - ((3-hydroxy-lH15 pyrazol-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-3methyl-2-oxopiperidin-3-yl) methyl) -1,2,4-oxadiazol-5 (4H) - ona;

3- ((5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2-oxo-l INSTITUTO Mr. XICANXJ

SAY THE OWN> AI?

INDUSTRIAL

106

<img file="MX343587B_D0192.tif" />

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

3- ((5- (3-chlorophenyl) -6- (4-chlorophenyl) -l-isopropyl-3methyl-2-oxopiperidin-3-yl) methyl) -1,2,4-thiadiazol-5 (4H) - ona;

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

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-ethyl-2-oxo1- (pentan-3-yl) piperidin-3-yl) acetic acid;

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

acid

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

<img file="MX343587B_D0193.tif" />

MEXICAN INSTITUTE M PROPERTY

INDUSTRIAL

<img file="MX343587B_D0194.tif" />

(cyclopropyl sulfonyl) piperazin-l-yl) butan-2-yl) -3-methyl-2-oxopiperidin-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) -1- (1- (5, 5-dimethyl-2-oxooxazolidin-3-yl) butan-2-yl) -3-methyl-2oxopiperidin acid -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;

108

2- (5- (3-chlorophenyl) -6- (4-chloroeniÍ) -1 - “(YΙΜΡΪ

MEXICAN INSTITUTE Say THE PROPERTY

<img file="MX343587B_D0195.tif" />

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

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

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-2oxo-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- (pyriinidin-2-yl) piperidin-3-rl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (3-methylpyridin-2-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) -1 (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) -1,2-thiazinan-6-yl) acetic acid;

109

<img file="MX343587B_D0196.tif" />

2- (5- (3-Chlorophenyl) -6- (5-clQ £ QEIridin-2-yl) -3-methyl-1- (l-morpholinobutan-2-yl) -2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (5-chloropyridin-2-yl) -3methyl-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) -1- (1- (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

<img file="MX343587B_D0197.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX343587B_D0198.tif" />

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

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-hydroxy6-methylheptan-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-5,5-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-3 acid -il) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (7-hydroxy7-methyloctan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1lll acid

MSXICAN INSTITUTE ΒΪ THE PROPERTY

INDUSTRIAL

<img file="MX343587B_D0199.tif" />

(N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N-cyclopropylmethylsulfonamido) butan-2-yl) -3-methy1-2oxopiperidin-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-oxopip.eridin-3-yl acid) acetic;

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;

<img file="MX343587B_D0200.tif" />

112 acid

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

<img file="MX343587B_D0201.tif" />

methoxipentan-3-yl) -3-methyl-2-oxopiperidin-. ;

acid

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

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

acid

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

acid

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

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- (N15 methylcyclopropansulfonamido) 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)^INST'iS7?_D^M.'^{! 5r, c}*^N&lt;’

OF THE PROPERTY

INDUSTRIAL

113

<img file="MX343587B_D0202.tif" />

<img file="MX343587B_D0203.tif" />

N- (2-hydroxyethyl) acetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (Nmethylcyclopropansulfonamido) 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-i1) -2-oxopiperidin-3-yl)

N- (2,3-drn _-'—: cipropyl) acetamide;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-l- (1- (N15 methylcyclopropansulfonamido) 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- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1 (cyclopropansulfonamido) butan-2-yl) -3-metii-2-oxopiperidin-3 · ixim-ηιτ * »ucvi / ί '

114

MEXICAN INSTITUTE OE INDUSTRIAL PROPERTY

<img file="MX343587B_D0204.tif" />

il) acetic;

2 - (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methy1-1- (1 (N-methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) propanoic acid;

acid

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

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) acetamido) butan-2yl) piperidin acid -3-yl) acetic;

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

115 il) acetic;

msxican institute of industrial PROPERTY

<img file="MX343587B_D0205.tif" />

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N> ~ 2 - dimethylpropan-2-ylsulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin- 3-yl) acetic;

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

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

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

acid

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (2-chlorophenylsulfonamido) butan-2-i1) -3-methyl-2-oxopiperidin-3yl) acetic;

<img file="MX343587B_D0206.tif" />

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

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (4-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) -1- (1— (1— 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 methy1-2oxopiperidin-3-yl) acetic;

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

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-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;

Acidic IMPI

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (3117

<img file="MX343587B_D0207.tif" />

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

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

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-ii) -2-oxopiperidin-3yl) propanoic acid;

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

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methoxy-l (1- (N-methylcyclopropansulfonamido) butan-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- (1118

<img file="MX343587B_D0208.tif" />

IMPI

MEXICAN INSTITUTE Of LA PRONEDAP (isopropylsulfonyl) pentan-3-yl) -3-methyl-2-oxopipeif'i^T"3! -N il) acetic; —— 2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1 (cyclopropylmethylsulfonyl) pentan-3-yl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

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

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (3,3difluoroazetidin-l-yl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl acid )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-dimethylmorpholine) butan-2-yl) -3-methyl-2-oxopiperidin-3119 yl) acetic acid;

<img file="MX343587B_D0209.tif" />

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (í- (3 hydroxy-3- (trifluoromethyl) azetidin-l-yl) butan-2-yl) -3-methyl2- oxopiperidin-3-ii) 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-ii) propyl) piperidin-3yl) acetic acid;

acid

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2120

<img file="MX343587B_D0210.tif" />

οχο-1- (1- (tetrahydro-2H-pyran-2-yl) propyl) piperidin-3yl) acetic;

acid

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

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

acid

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

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

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-1- (1- (pyridin-2-i1) 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- (1-

<img file="MX343587B_D0211.tif" />

IM.Pl

-ΙΟΊ MEXICAN INSTITUTE

1Z1 Say LA ΡΗΟΝΕΠΑΟ

INDUSTRIAL (6-methylpyridin-2-yl) propyl) -2-oxopiperidin-3-yl) aceticj_ 2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -3-methyl-2oxo-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-3yl) acetic acid ;

2- (1- (1- (6-bromopyridin-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-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-methyl-2oxopiperidin- acid 3-yl) acetic;

2- (5- (3-chlorophenyl) -6- (4-chlorophenyl) -1- (1- (6-cyclopropylpyridin-2-i1) 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;

122

IMPí • MSTTTirr · Mexican · € LA RtOklEOA · INDUSTRIAL

<img file="MX343587B_D0212.tif" />

5- (3-chlorophenyl) -6- (4-chlorophenyl) -3- (2,3dihydroxypropyl) -1- (2-hydroxypentan-3-yl) -3-methypipiperidin-2one;

2 - (5- (3-Chlorophenyl) -6- (4-chlorophenyl) —1— (1-hydroxybutane-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;

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1— (1-cyclopropi1-2-ethoxy-2-oxoethyl) -3-methi-2-oxopiperidin-3yl) acetic acid;

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

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

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

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

acid

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1123

ΙΜΡΙ

MEXICAN INSTITUTE Say Industrial PROPERTY

<img file="MX343587B_D0213.tif" />

cyclopropyl-2- (ethylsulfonamido) ethyl) -3-ethyl-2-oxopiperidin-3yl) acetic;

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- (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-methylcyclopropansulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

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

IMPi

MEXICAN INSTITUTE> S LA P Ȓ) PlSD_ADINDUSTRIAL

<img file="MX343587B_D0214.tif" />

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

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;

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-yl) 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-220 acid

IMPI

125

INSTITUTO MMCANO Df LA PXOMDA »

INDUSTRIAL

<img file="MX343587B_D0215.tif" />

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

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- (2hydroxipentan-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-methi-2-oxopiperidin-3yl) 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;

acid

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1- (N, 1126

ΙΑ ί

INSTITUTE «· λι € ανΟ

FROM Ι.Λ KWUMEDAi 'INDUSTRIAL

<img file="MX343587B_D0216.tif" />

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

2- (5- (3-Chlorophenyl) -6- (4-chlorophenyl) -1- (1cyclopropyl-2- (N-methylcyclopropansulfonamido) ethyl) -3-methyl-25-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-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-methylthiophene-2-sulfonamido) ethyl acid ) -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) acid -320 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) -1IMPI

127

INSTITUTO MI »(CANO M LA PRO Alt DAD

INDUSTRIAL

<img file="MX343587B_D0217.tif" />

((S) -l-cyclopropyl-2- (N- (difluoromethyl) -2-methylpropan-2ylsulfonamido) 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) ethylsuifonamido) 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-cyclopropylethi) -3-methyl-2-oxopiperidin -3-yl) cyclopropancarboxylic acid;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N- (2-fluorophenyl) ethylsuifonamido) 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, 6Ξ) -5- (3-ChlorophenylL) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-phenylethisulfonamido) ethyl) -3- acid methyl-220

128

ΙΜΡΙ

MBGCANO M INSTITUTE INDUSTRIAL PROPERTY

<img file="MX343587B_D0218.tif" />

oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (ethylsulfonamido) ethyl) -3-methyl- acid 2oxopiperidin-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 methyl2-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-2129

IMPI Mexican nsTmrro DE LA ÍROPIHÍA · INeilSTRIAL

<img file="MX343587B_D0219.tif" />

ylmethyl) methylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3yl) 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-iimethylsuifonamido) ethyl) acid - 3metii-2-oxopiperidin-3-yl) acetic;

acid _k 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (pyridin-3-ylmethylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3 -il) 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-ii) 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-ethymethylsulfonamido) ethyl) -3- acid methyl-220 oxopiperidin-3-yl) acetic;

MEXICAN INSTITUTE

130

OE THE PROPERTY ->

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-CT6f^Td'feri ^ ((S) -l-cyclopropyl-2- (N-isopropylmethylsulfonamido) ethyl) -^¿-3— * · '-— methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -15 ((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-1 - ((S) -3-methyl-l- (N-methylcyclopropansulfonamido) butan15 2 -il) -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-Chlorophenyl) -6- (4-Chlorophenyl) -120 ((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;

IMPI ^

131 MEXICAN INSTITUTE

-LOX GIVE PROPERTY - * 1 »

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

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -35 methyl-2-oxo-l - ((S) -1- (phenylsulfonyl) butan-2 acid -il) piperidin-3yl) acetic;

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

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-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-oxopiperidin15 3-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) -120 ((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;

IMPI SB¹

132 INSTITUTO M¡iXICAN ·

Say THOMEDAD

INKUSTRIAL 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-1 - ((S) -1- (oxetane-3-ylsulfonyl) butan- 2-yl) -2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3 methyl-1 - ((S) -1 - (((3-methylhexetan-3-yl) ) methyl) sulfonyl) butan-2yl) -2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-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) -1 - ((S) -1 - ((R) -sec butylsulfonyl) butan-2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) ) 15 3-methyl-2-oxopiperidin-3-yl) acetic;

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;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- (cyclopentyl sulfonyl) -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;

IMPI

133

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX343587B_D0220.tif" />

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

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -15 ((S) -l-cyclopropyl-2- (o-tolylsulfonyl) ethyl) -3- acid 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-methyl15 2-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;

acid

2 - ((3R, 5R, 6S) -1 - ((S) -2 - ((2-Chloro-420 fluorophenyl) 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) -3methyl acid -2-oxopiperidin-3-yl) acetic;

134

IMPI

MEXICAN INSTITUTE DS LA TROnSDA »INDUSTRIAL

<img file="MX343587B_D0221.tif" />

2- ((3R, 5R, 6S) -5- (3-Chlorof enyl) -6 - »- i4 ^ = TJ.orcphenyl) -1 ((S) -l-cyclopropyl-2 - ((2,2 , 2-trifluoroethyl) sulfonyl) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -15 ((S) -l-cyclopropyl-2 - ((trifluoromethyl) sulfonyl) ethyl) -3 acid -methyl2-oxopiperidin-3-yl) acetic;

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

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -2- ((2-Chlorophenyl) sulfonyl) -1-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-215 oxopiperidin-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) -120 ((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;

135

IMPI ^ J

MEXICAN INSTITUTE

Dt PROPERTY acid 2- ((3R, 5R, 6S) -1- ((S) -2- (Butyl ^ suT ^ oniTjnTTcyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorbi'enil) - 3-etíÍ-2oxopiperidin-3-il) 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- (cyclopentylsulfonyl) -1-cyclopropylethyl) -3-ethyl-2oxopiperidin -3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((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;

2- ((3R, 5R, 6S) -l - ((S) —1— (tert-Buti1sulfonyl) -320 methylbutan-2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -3-methyl-l- (methylsulfonyl) butan-2- acid i1) -2oxopiperidin-3-yl) acetic;

MEXICAN INSTITUTE

IX THE PRORITY

INDUSTRIAL

136 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) -15 ((S) -1- (cyclopropyl sulfonyl) butan-2-yl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Cryophenyl) -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-Chiorophenyl) -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- 215 oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Cryophenyl) -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) -320 ethyl-1 - ((S) -1- (isopropylsulfonyl) butan-2-yl) - 2-oxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) -1- (tert-butylsulfonyl) butan2-yl) -5- (3-Chlorophenyl) -6- (4-Ciorophenyl) -3-ethyl acid -2-oxopiperidin-3-yl) acetic;

<img file="MX343587B_D0222.tif" />

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (cyclobutyl sulfonyl) butan-2-yl) -3-ethyl- 2-oxopiperidin3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -15 ((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- acid 2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) -2- (tert-Butyl sulfonyl) -1-cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl- 215 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) -120 ((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- acid 2oxopiperidin-3-yl) acetic;

138

IMPI

<img file="MX343587B_D0223.tif" />

INDUSTRIAL 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (tert-pentylsulfonyl) eun) -3 -methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -15 ((S) -l-cyclopropyl-2 - ((2,4-difiuorophenyl) sulfonyl) acid ethyl) -3methyl-2-oxopiperidin-3-i1) 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- 215 oxopiperidin-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) -120 ((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 -methyl-2-oxopiperidin-3-yl) acetic;

139

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL FMOFIIDAD

<img file="MX343587B_D0224.tif" />

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

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

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- ((S) -isopropylsulfinyl) butan-2-yl) - 3-methy1-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- ((R) -isopropylsulfinyl) butan-2-yl) acid - 3-methy1-2oxopiperidin-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) -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 -220 oxopiperidin-3-yl) acetic;

140

<img file="MX343587B_D0225.tif" />

Dü IA FROFIE MEXICAN INSTITUTE »AI>

INDUSTRIAL

<img file="MX343587B_D0226.tif" />

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) -1 ((2R, 3S) -2- (ethylsulfonyl) pentan-3-yl) -3- methyl-2-oxopiperidin3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3methyl-1 - ((S) -1- (N- (oxetane-3-yl) sulfamoyl ) butan-2-yl) -2oxopiperidin-3-ii) 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) -2oxoplperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -1 - ((S) -2- (N- (tert-Butyl) sulfamoyl) 1- cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) ) -3-methyl2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (N-methylsulfamoyl) ethyl) -3- acid methyl-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;

ΙΜΡΙ

141

MEXICAN INSTITUTE DF THE PROPERTY

INDUSTRIAL

<img file="MX343587B_D0227.tif" />

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- (morpholinosulfonyl) ethyl) -3-methyl- acid 2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (piperidin-1-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-l-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, Ndimethylsulfamoyl) (methyl) amino acid ) 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 -l ... IMPI ^^ í ^

Z Mexican institute

EX THE OWN V—

IN »U (TXIAI.

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

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropyl-2- (3,4,4-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) -dioxoimidazolidin-lyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -l-cyclopropii-2- (3-isopropyl-2,2-dioxide) acid -4-oxo-3,410 dihydro-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] imidazol1-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- (420 Chlorophenyl) -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;

acid

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4ΙΝβΤΙΤΙ ΙΤΟ MEXICAN

DF. THE PROFtBPAÜ

INDUSTRIAL

143

<img file="MX343587B_D0228.tif" />

Chlorophenyl) -3-methyl-l - ((S) -1- (N-methylethylsulfonamido) butan-2yl) -2-oxopiperidin-3-yl) acetic;

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;

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;

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

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

2 - ((3R, 5R, 6S) -1 - ((S) -1- (tert-Butyl sulfonyl) butan acid

2-yl) -5- (3-chloro-5-fluorophenyl) -6- (4-Chlorofenix) -3-methyl-2oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chloro-5-fluorophenyl) -6- (4 'acid

Chlorophenyl) -1 - ((S) -1- (isopropylsulfonyl) butan-2-yl) -3-methyl2-oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin

3- yl) -1 - ((S) —1— (cyclopropyl sulfonyl) butan-2-yl) -3-methyl-220 oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -l - ((S) -1- (tert-Butylsulfonyl) butan acid

2-yl) -6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) -3-methyl-2oxopiperidin-3-yl) acetic;

2- ((3R, 5R, 6S) -6- (4-Chlorophenyl) -5- (5-chloropyridin

144

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PPOP1ÍDAD

<img file="MX343587B_D0229.tif" />

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

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) 20 acid

145

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX343587B_D0230.tif" />

3-methyl-l - ((R) -1 - ((S) -morpholin-2-yl) propyl) -2-oxopiperidin-3yl) acetic;

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

- ((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- ( 2morpholinoethyl) -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 -520

<img file="MX343587B_D0231.tif" />

ΙΜΡΙ

Λ C HSTITUTO MEXICANO ^{χ υ} OF THE PROPERTY

INDUSTRIAL azaspiro [2.5] octan-l-carboxylic;

(3S, 6S, 7R) -7- (3-Chlorophenyl) -6- (4-Chlorophenyl) -5 ((S) -1- (N-methylcyclopropansulfonamido) butan-2-yl) -4-oxo-5azaspiro [2.5] octan-l-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-310 yl) 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) -115 ((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 ((IS, 2S) -l-cyclopropyl-l-hydroxybutane-2-yl) -3 acid -methyl-2-oxopiperidin-3-yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((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;

MEXICAN INSTITUTE »B THE PROPERTY

INDUSTRIAL

147 2- ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1isopropyl-6-methyl-2-oxopiperidin-3-yl) acetic acid;

(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;

(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 - ((S) -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-Chlorophenyl) -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) -1IMPI

148

MEXICAN INSTITUTE Dt LA EROHSDAD INDUSTRIAL

<img file="MX343587B_D0232.tif" />

(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) -1cyclopropyl-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- (4Clorophenyl) -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- (1cyclopropyl-2- (N-methylthiophene-2-sulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid ;

2 - (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2- (5-chlorothiophene-2-sulfonamido) -1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

MEXICAN INSTITUTE

DB PROPERTY

INDUSTRIAL acid

149

2- (1- (2- (5-Chloro-N-methylthiophene-2-sulfonamido) -1cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2oxopiperidin-3-yl )acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (N- (difluoromethyl) -2-methylpropan-2ylsulfonamido) ethyl) -3-methyl-2-oxopiperidin -3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N- (difluoromethyl) ethylsuifonamido) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (N- (difluoromethyl) cyclopropanesulfonamido) ethyl) 3-methyl-2-oxopiperidin-3-yl) acetic acid ;

1- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (cyclopropansulfonamido) -1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl) cyclopropancarboxylic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (N- (2-fluorophenyl) ethylsuifonamido) ethyl) -3methyl-2-oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (N- (2-fluorophenyl) methylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2- (N-phenylcyclopropansulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

IMPI 2- (5- (3-Chlorophenyl) -6- (4-ChlorophenylTj * -l150 acid

MEMCANO INSTITUTE DS THE PROPERTY

<img file="MX343587B_D0233.tif" />

cyclopropyl-2- (N-phenylethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

acid

- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (ethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin3-yl) acetic;

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N- (3-fluorophenyl) ethylsulfonamido) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic ;

2 - (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2- (N- (2cyanophenyl) methylsulfonamido) -1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid ;

2 - (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) —1— (1-cyclopropyl-2- (propylsulfonamido) ethyl) -3-methyl-2oxopiperidin-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) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) - 1— (1-cyclopropyl-2- (N- (pyridin-3-yl) methylsulfonamido) ethyl) -3methi-2-oxopiperidin- acid 3-yl) acetic;

151

MEXICAN INSTITUTE BE LA PM (NOUSTIIAL PROPERTY

<img file="MX343587B_D0234.tif" />

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorof^leniYV-l ^ (T^{: r} cyclopropyl-2- (N- (thiophene-2-ylmethyl) 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;

2 - (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (pyridin-3-ylmethylsulfonamido) ethyl) -3-methyl-215 oxopiperidin-3-yl) acetic acid;

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- (ΙΣΟ cyclopropyl-2- (methylsulfonamido) ethyl) -3-methyl-2-oxopiperidin3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N-ethylmethylsuifonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

152

<img file="MX343587B_D0235.tif" />

IMPI

INSTITUTO AT.XICANO

OF THE FROF1ÍDAP

INDUSTRIAL 2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N-isopropylmethylsulfonamido) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (1-methylethylsulfonamido) ethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (cyclobutansulfonamido) -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-Chlorophenii) -6- (4-Chlorophenyl) -3-methyl-l- (3methyl-1- (N-methylcyclopropansulfonamido) butan-2-yl) -2oxopiperidin-3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (cyclopropansulfonamido) -3-methylbutan-2-ii) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (ethylsulfonamido) -3-methylbutan-2-yl) -3-methyl-2-oxopiperidin3-yl) acetic acid;

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

153

<img file="MX343587B_D0236.tif" />

IMPI

MEXICAN INSTITUTE r> F LA 2- 2- (5- (3-Chlorophenyl) -β- (4-01θΓθίθηΐΤ'Γ “Ύethylcyclobutansulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin3-yl) acetic acid;

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- (ΙΣΟ (cyclopentyl sulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

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

2- (5- (3-Ciorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (1154 acid)

IMPI

MEXICAN INSTITUTE »E LA PÍORIPAD (((3-methyloxetan-3-yl) methyl) sulfonyl) butan-2-yl) -z!¹¹-™¹''¹'oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2oxo-1- (1 - ((tetrahydro-2H-pyran-4-yl) sulfonyl) butan-2yl) piperidin acid -3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- ((2hydroxy-2-methylpropyl) sulfonyl) butan-2-yl) -3-methyl-2oxopiperidin-3- acid il) acetic;

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

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (cyclopentyl sulfonyl) -1-cyclopropylethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2 - (((3-methyloxetan-3-yl) methyl) sulfonyl) ethyl) -3methyl-2-oxopiperidin -3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (phenylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (o-tolylsulfonyl) ethyl) -3-methyl-2-oxopiperidin3-yl) acetic acid;

<img file="MX343587B_D0237.tif" />

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 - ((2155 IMPI

ΙΝΓΠΤυΤΟ MEXICAN DE LA PROMOAD

Chlorophenyl) sulfonyl) -1-cyclopropylethyl) -3-methyl-2-^{DUST, UAL} oxopiperidin-3-yl) acetic; ........ .....— 2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2- (

Chlorophenyl) sulfonyl) -1-cyclopropylethyl) -3-methyl-25 oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1cyclopropyl-2 - ((4-fluorophenyl) sulfonyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -ΙΙΟ cyclopropyl-2- (pyridin-4-ylsulfonyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

2- (1- (2 - ((2-Chloro-4-fluorophenyl) sulfonyl) cyclopropylethyl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyloxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1-cyclopropyl-2 - ((cyclopropylmethyl) sulfonyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -Ιοί ciopropi1-2 - ((2,2,2-trifluoroethyl) sulfonyl) ethyl) -3-methyl20 oxopiperidin-3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1cyclopropyl-2 - ((trifluoromethyl) sulfonyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

<img file="MX343587B_D0238.tif" />

(4 (1 (1-1-2 (1 (12 (acid

- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1IMPI

156

MEXICAN INSTITUTE D € THE PROPERTY tMDUSTMAL

<img file="MX343587B_D0239.tif" />

cyclopropyl-2- (phenylsulfonyl) ethyl) -3-ethyl-2-oxopiperidin-3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 - ((2Clorophenyl) sulfonyl) -1-cyclopropylethyl) -3-ethyl-2-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- (1-cyclopropyl-2 - ((3-fluorophenyl) sulfonyl) ethyl) -3-ethyl-2-oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclop -'-. ii 1-2- ((4-1luorophenyl) sulfonyl) ethyl) -3-ethyl-2oxopiperidin- 3-yl) acetic;

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-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (isopentyl sulfonyl) ethyl) -3-ethyl-2-oxopiperidin3-yl) acetic acid;

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2157

IMPI

MSXICAN INSTITUTE • IIA PWJRBMO (cyclopentylsulfonyl) -1-cyclopropylethyl) -3-ethyl-2-

<img file="MX343587B_D0240.tif" />

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- (methylsulfonyl) 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) -1- (1 (ethylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

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

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1158 nSTITUTO MEXICANO JA

Say THE PROPERTY 'C ^ iMllLy (isopropylsulfonyl) butan-2-yl) -3-methyl-2-oxopi ^ ©) i? Rtíin ^? - yl) acetic; 2- (1- (1- (tert-Butylsulfonyl) 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 (cyclobutyl sulphonyl) 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— (1— cyclopropyl-2- (ethylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3yl) acetic acid;

Acidic IMPI

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1159

MEXICAN INSTITUTE m LA PROMEOAO

INDUSTRIAL

<img file="MX343587B_D0241.tif" />

cyclopropyl-2- (isopropylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-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- (1cyclopropyl-2- (cyclopropylsuifonyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (icyclopropyl-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-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1-cyclopropyl-2 - ((2,4-difluorophenyl) sulfonyl) ethyl) -3-methyl-2oxopiperidin-3-yl acid) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (ethylsulfonyl) ethyl) -3-ethyl-2-oxopiperidin-3yl) acetic acid;

ΙΜΡΙ

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1160 acid

MEXICAN INSTITUTE CS LA MONEDAR

INDUSTRIAL

<img file="MX343587B_D0242.tif" />

cyclopropyl-2- (isopropylsulfonyl) ethyl) -3-ethyl-2-oxopiperidin3-yl) acetic;

2- (1 - ((2- (tert-Butylsulfonyl) -1-cyclopropylethyl) 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-ethyl-2-oxopiperidin-3yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (cyclopropyl sulfonyl) ethyl) -3-ethyl-2oxopiperidin-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- (3,3dimethyl-1- (methylsulfonyl) butan-2-yl) -3-methyl-2-oxopiperidin3-yl) acetic acid ;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (ethylsulfonyl) -3,3-dimethylbutan-2-yl) -3-methyl-2-oxopiperidin3-yl) acetic acid ;

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1 (isopropylsulfonyl) -3,3-dimethylbutan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic;

Acidic IMPI

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1161

MEXICAN INSTITUTE P6 THE PROPERTY

INDUSTRIAL

<img file="MX343587B_D0243.tif" />

cyclopropyl-2- (pentan-3-ylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-3-yl) acetic;

acid

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

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

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (2 (ethylsulfonyl) pentan-3-yl) -3-methyl-2-oxopiperidin-3yl) acetic;

2- (5- (3-Ciorophenyl) -6- (4-Chlorophenyl) -3-methyl-l- (1 (N- (oxetan-3-yl) sulfamoyl) butan-2-yl) -2-oxopiperidin -3yl) 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-iimethyl) 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 ;

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1162

ΙΜΡΙ

INÍTITI / ΓΟ MEXICANO UÉ THE INDUSTRIAL PROPERTY

<img file="MX343587B_D0244.tif" />

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

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (N-iscpropylsulfamoyl) ethyl) -3-methyl-2oxopiperidin-3-yl) acetic acid;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (morpholinosulfonyl) ethyl) -3-methyl-2-oxopiperidin-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-2-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;

acid

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1IMPI

<img file="MX343587B_D0245.tif" />

163

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL ____ cyclopropyl-2 - ((N, N-dimethylsulfamoyl) (methyl) amino) ethyl) -3methyl-2-oxopiperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1cyclopropyl-2- (3-methyl-2,5-dioxoimidazolidin-l-yl) ethyl) -3methyl-2-oxopiperidin acid -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-Ciorophenyl) -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- (1-cyclopropyl-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-Ciorophenyl) -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- (ethylsuifonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3164 acid

IMPI il) acetic;

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX343587B_D0246.tif" />

2- (5- (3-Chloro-5-fluorophenyl) -6- (4-0.1 nrnfpní 1) -9methyl-1- (1- (N-methylethylsulfonamido) butan-2-yl) -2oxopiperidin-3-yl acid )acetic;

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-Chloro-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-3165

<img file="MX343587B_D0247.tif" />

IMPI

MEXICAN

Γ ( _t Λ 03 -9IC0AD il) acetic;

2- (6- (4-Chlorophenyl) -5- (5-chloropyridin-3-yl) -1- '(I (cyclopropansulfonamido) butan-2-yl) -3-methyl-2-oxopiperidin-3yl) acetic acid ;

2- (6- (4-Chlorophenii) -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-methylcyclopropanesulfonamido) butan-2-yl) -2-oxo-3- (2 (pyrrolidin-l-yl) acid ethyl) piperidin-3-yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3- (2 (dimethylamino) ethyl) -1- (1- (NΙΜΡΙ

166

MEXICAN INSTITUTE Dt LA FROMtDAD

INDUSTRIAL

<img file="MX343587B_D0248.tif" />

methylcyclopropansulfonamido) butan-2-yl) -2-oxopiperidin-3yl) acetic;

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -3- (2-morpholinoethyl) 2-oxopiperidin-3-yl) acetamide ;

7- (3-Chlorophenyl) -6- (4-Chlorophenyl) -5- (1- (Nmethylcyclopropansulfonamido) butan-2-yl) -4-oxo-5azaspiro [2.5] octan-l-carboxylic acid;

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

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

2- (5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1-isopropyl6-methyl-2-oxopiperidin-3-yl) acetic acid;

5- (3-Chlorophenyl) -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

IMPI

MEXICAN INSTITUTE DB THE INDUSTRIAL PROPERTY

<img file="MX343587B_D0249.tif" />

5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1- (1- (1,1-Dioxideisothiazolidin-2-yl) butan-2-yl) -3 - ((6-hydroxypyridin-2yl) 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-dimethylhexahydrofuro [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 acid -220 oxopiperidin-3-yl) acetic;

168

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL MOBILITY

<img file="MX343587B_D0250.tif" />

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) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1- (isopropylsulfonyl) -3,3-dimethylbutan-2-yl) acid -3-methyl-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- (ethylsulfonyl) butan-2-yl) -3-methyl- acid 2-oxopiperidin-3yl) acetic;

2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1methyl-2-oxopiperidin-3-yl) acetic acid; or 2 - ((3R, 5R, 6S) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 ((S) -1 - ((cyclopropylmethyl) sulfonyl) butan-2-yl) - acid 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- (-1cyclopropyl-2- (methylsulfonyl) ethyl) -3-methyl-2-oxopiperidin-320 yl) acetic acid;

<img file="MX343587B_D0251.tif" />

₁₆₉ IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL 2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 (isopropylsulfonii) -3-methylbutan-2-yl) -3-methyl-2oxopiperidin-3-yl acid) acetic;

2 - (- 1 - (- 1- (tert-butylsulfonyl) butan-2-yl) -5- (35 Chlorophenyl) -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-ii acid )acetic;

2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 (ethylsulfonyl) -3-methylbutan-2-yl) -3-methyl-2-oxopiperidin-315 yl acid) acetic;

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 - (- 120 cyclopropyl-2- (N-phenylcyclopropansulfonamido) ethyl) -3-methi-2oxopiperidin-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

<img file="MX343587B_D0252.tif" />

IMPI

MEXICAN INSTITUTE

PROPERTY 2- (-5- (3-Chlorophenyl) -6- (4-Chlorof¿r? OT)^Ll^: cyclopropyl-2- (methylsulfonyl) ethyl) -3-methyl-2-oxopiperidm-3yl) acetic;

2 - (- 5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -1 - (- 1 (isopropylsulfonyl) -3-methylbutan-2-yl) -3-methyl-2oxopiperidin-3-yl) acetic acid ; or 2- (-1 - (- 1- (tert-butylsulfonyl) butan-2-yl) -5- (3-Chlorophenyl) -6- (4-Chlorophenyl) -3-methyl-2-oxopiperidin-3i1) 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 $ 3 ^ 1 _. . -. . . ._η MEXICAN INSTITUTE to form a hydroxyl radical. ^{d £ UA}, m * st »Íal

Where the term alkyl is used, either alone or within.

In other terms such as haloalkyl or alkylamino, it 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

IMPI

172

INSTITUTO MBXICAN P * '.A PRONBDAO ^' ^ TRIAL

<img file="MX343587B_D0253.tif" />

radicals that have two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, 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 than tren; c 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

J », · *« a · » ₁₇₃ IMPI / -3 MEXICAN INSTITUTE

OE (INDUSTRIAL PROPERTY substituted with halo as defined above. Monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals are included, 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

<img file="MX343587B_D0254.tif" />

<img file="MX343587B_D0255.tif" />

174

IMPI

INSTITUI »MEXICANO ÜS LA FROPIRDAO INDUSTRIAL most 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

MEXICAN INSTITUTE '

Dt OWNED ·

MDUSTRIAL

175

<img file="MX343587B_D0256.tif" />

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. The phenyl substituted with -O-CH2-O- 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 -SS- portions are not included. The heterocyclyl group can have 1 to 4 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

MEXICAN INSTITUTE OF THE ΕΕ · ΕΙ SDA D,, _z INDUSTRIAL, __ oxygen and 1 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, dihydropyranium, dihydrofuryl, and dihydrothiazolyl.

Examples of unsaturated heterocyclic radicals, also called heteroaryl radicals, include unsaturated 5- to 6-membered heteromonocyclyl group containing 1 to 4 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, 2H1,2,3-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 nitrogen atoms, eg oxazolyl, isoxazolyl, oxadiazolyl [eg 1,2,4-oxadiazolyl, 1,3,4 oxadiazolyl, 1 , 2,5-oxadiazolyl]; heteromonocyclic group of

177

ΙΜΡΙ

INSTITUTO MRXICAN · DS THE PROPERTY nDUSTRlAL

<img file="MX343587B_D0257.tif" />

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 5 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 enough 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 condensed 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

ΙΜΡΙ

178

MIXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX343587B_D0258.tif" />

quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl 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, pyrazidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo [1,4] dioxanyl, indolinyl, indolinyl, indolinyl dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,

2,3,4,4a, 9,9a-hexahydro-lH-3-aza-fluorenyl, 5,6,7-trihydrol, 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.

179

The term heterocycle follows ring systems:

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<img file="MX343587B_D0260.tif" />

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or

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180

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halo

MEXICAN INSTITUTE

DS THE PROMOTION xmismiAL

181 or

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% / w »and the like.

The term sulfonyl, if used alone or linked to other terms such as alkylsulfonyl, respectively means divalent radicals -SO2-.

The terms sulfamyl, aminosulfoniium, 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 alkylaminosuiphonyl radicals are lower alkylaminosuiphonyl radicals having one to six carbon atoms. Even more preferred are lower alkylaminosuiphonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosuiphonyl radicals include N-methylaminosulfonyl, and N-ethylaminosulfonyl.

The terms carboxy or carboxyl, if used alone or with other terms, such as carboxyalkyl, mean CO₂H.

182

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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-dialylaminocarbonyl 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-Narylaminooarbonyl 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

183

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

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. . one . one . Ί,. · Η,. -I ΙΝΙΛΙΜΜΛΙ T —— pindylmethyl 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 phenylalkylenyl linked to alkyl moieties having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, and phenylethyl. The aryl in the aralkyl 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 trifluoromethylthio.

The term "alkylamino" encompasses N-alkylamino and N, N-

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184

MEXICAN INSTITUTE Df THE PROPERTY

INDUSTRIAL __ dialkylamino where amino groups are independently substituted with one 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

Ιί ·· ίί »Γ * Τ 1 * 40« I

185

IMPI

MEXICAN BMTITUTO • Ε THE PROPERTY

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replaced at the aryl ring portion. industrial -—

The terms N-alkyl-N-arylamino and N-áráTqú i1-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 lower aminoalkyl 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

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186

INSTITUTE V substituted, such as N-methylaminomethyl,^DF^ iMflipSliM &lt;iii aminoethyl, 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 Ν, Ν-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.

IMPIOS

MEXICAN INSTITUTE DB PROPERTY

The term carboxyalkyl encompasses radidcLfes¹ aTquTlo

187 linear or branched 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.

ΙΜΡΙ @

188

ΙΝΧΤΓΠΙΤ · MEXICAN of prombdad

The term aralkoxy encompasses araTqüilo radicals

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they 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, bonded to an oxygen atom.

The term "heteroarylalkyoxy" encompasses heteroarylalkyl radicals containing oxy linked through an oxygen atom to other radicals. The radicals heteroar.

Ifld preferred:

or lower heteroaryl-alkoxy radicals having optionally substituted heteroaryl radicals linked to 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

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MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX343587B_D0277.tif" />

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 PROPERTY

INDUSTRIAL

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can be used in one radical group to indicate the point of attachment to another group. In 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. £ 1 patient term includes female and male subjects.

The term pharmaceutically acceptable means that the referenced substance, such as a compound of the

Formula I, or a salt of a compound of Formula I, or a formulation containing a compound of Formula I, or a particular excipient, are 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

IMPI

MÍXICANO DELA PROPISDAD INSTITUTE. INDUSTRIAL

<img file="MX343587B_D0279.tif" />

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

IMPI

MEXICAN INSTITUTE

192

MEXICAN INSTITUTE • E LA PROMSDA »INDUSTRIAL

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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. Furthermore, it should be recognized that the compositions can be of 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 the

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

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INSTITUTO MEXICANO Dt LA PROFISOAD a therapeutically effective amount of a comj59'é^Té't^Lor Formula I, IA, IB, IC, ID or IE, or an acceptable pharmaceuticane 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, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkett lymphoma); hematopoietic tumors of myeloid lineage (including chronic and acute 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

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

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neuroblastoma, glioma, and schwanomas); and other tumors (including melanoma, seminoma, teratocarcinoma, 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 , cancer gives lung cancer of small size, 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 (p53^Wt). In another particular modality, the cancer is identified as p53^Wt 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.

IMPI

195

MEXICAN INSTITUTE • i LA PROPUDAD INDUSTRIAL ·

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with respect to p53 and / or CDKN2A. In one aspect, a patient who has a cancer that is p53^Wt will be selected for treatment "" in patients who have cancer that mutates with respect to p53. In another aspect, a patient who has cancer that is both p53^Wt 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 p53^Wt 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,

ΙΜΡΙ

196

INSTITUTO MÍRICA NO DE LA MONEDAD

INDUSTRIAL

<img file="MX343587B_D0285.tif" />

characterized by polycystic ovary syndrome (syndrome

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.

Compounds of Formula I, IA, IB, IC, ID or IE, or 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.

IMPI

197

MEXICAN INSTITUTE OF PROPERTY

INDUSTRIAL

<img file="MX343587B_D0286.tif" />

for cancer therapy. In yet another embodiment, antineoplastic agents are selected from antibiotic-like agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-like agents, kinase inhibitors, miscellaneous agents, and combinations thereof. It is noted that the additional pharmaceutically active compounds / agents can be traditional small organic chemical molecules or can 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 the treatment of cancers and that can be used in combination with one or more compounds of the present invention include: methotrexate; tamoxifen;

fluorouracil; 5-fluorouracil; hydroxyurea; mercaptopurine;

cisplatin; carboplatin; daunorubicin; doxorubicin; etoposide; vinblastine; vincristine; pacitaxel; thioguanine;

idarubicin; dactinomycin; imatinib; gemcitabine;

altretamine; asparaginase; bleomycin; Capecitabine;

carmustine; NaCl solution ac. cladysat .; cyclophosphamine;

cytarabine; decarazine; docetaxel; idarubicin; ifosfamide;

irinotecan; fludarabine; mitosmycin; mitoxane; mitoxantrone;

topotecan; vinorelbine; adriamycin; mitram; imiquimod;

alemtuzmab; exemestane; bevacizumab; cetuximab; azacitidine;

198 'Safií

MIXICAN INSTITUTE OF FROFIBILITY clofarabine; decitabine; desatinib; dexrazoxan &lt;^^DU,'Sfó^lepirubicin keta; oxaliplatin; erlotinib; raloxiféTH fülvestrant; letrozole; gefitinib; gemtuzumab; trastuzumab; gefitinib;

ixabepilone; lapatinib; 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 Growth Factor 1 Receptor Inhibitors (IGFR-1), cFMS Inhibitors, HER 2 Inhibitors, c-met Inhibitors, Aurora Kinase Inhibitors, inhibitors

CDK 4 and / or 6, and B-raf inhibitor.

Additional pharmaceutically active agents that can also be used in the treatment of cancers and that can

199

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TMPI

Α ΤΓΓ · '· -. X'CAN

Ρ. ..-¹ - 'i - * 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 harmful to 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>386; 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 colspan="2">(Motesanib),</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 for

200

ΙΜΡΙ6

INSTITUTO MSXICANO DS LA rXOPltDAI »INDUSTRIAL

<img file="MX343587B_D0288.tif" />

cancer cell growth, including enhanced apoptosis and cell killing. Examples of proteins in the PI3K pathway include PI3K, mTOR, and PKB (also known as Akt). The PI3K protein exists in several isoforms including α, 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 inhibitor I heard. In another aspect the compound is a selective PI3K δ inhibitor.

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.

W02010 / 151737; PCT published application no. W02010 / 151735;

θ MEXICAN INSTITUTE ^{, N}OF THE IMMWt AGE

INDUSTRIAL ---- PCT published application no. W02010151740; published request

PCT no. WO2008 / 118455; PCT published application no. WO2008 / 118454; PCT published application no. WO2008 / 118468;

US published application no. US20100331293; US published application no. US20100331306; published request for

USA does not. US20090023761; US published application no.

US20090030002; published request for published

USA

USA request

US20090137581;

US2009 / 0054405; US published application no. US

not.

not

US

US

2009/0163489; US published request

2010/0273764; US published request

2011/0092504; or PCT published application no. W02010 / 108074.

Preferred PI3K inhibitors for use in combination with compounds of the present invention include:

<img file="MX343587B_D0289.tif" />

202

<img file="MX343587B_D0290.tif" />

or a pharmaceutically acceptable salt thereof.

Also preferred is a compound of Formula lia below, or a pharmaceutically acceptable salt thereof,

<img file="MX343587B_D0291.tif" />

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

203

MEXICAN INSTITUTE OF LA MONEDAD

INDUSTRIAL “· --— 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 path

PI3K. 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 no. WO

2010/083246 Al.

The compounds of the present invention can be used in

204

Dt LA rRV * r «c '** ·

INDUSTUAL combination with CDK4 and / or 6 inhibitors. 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 (Snow them); bicalutamide; broxuridine; celmoleucine;

cetrorelix; cladribine; clotrimazole; DA 3030 (Dong-A);

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

IMPI

<img file="MX343587B_D0292.tif" />

MEXICAN INSTITUTE Μ ΙΛ HWflEIXAO fadrozol; finasteride; f ludarabffiáT * phosphate phosphate;

misaligned;

molgramostim;

photemustine; gallium nitrate; genrt'U2llRÍab zogamycin;

gimeracil / oteracil / tegafur combination; glycopine;

goserelin; heptaplatin; human chorionic gonadotropin; human fetal alpha fetoprotein; Ibandronic acid;

alpha interferon; inferred natural alpha; interferon alfa2; inferred alpha-2a; inferred alpha-2b; alphaNl interferon; inferred alpha-n3; they inferred alphacon-1; natural alpha interferon; inferred beta; inferred beta-la;

inferred beta-lb; inferred natural gamma; they inferred gamma-la; inferred gamma-lb; interleukin 1 beta;

yobenguano; irsogladin; lanreotide; LC 9018 (Yakult);

leflunomide; lenograstim; lentinan sulfate; letrozole;

leukocyte alpha interferon; leuprorelin; levamisole + fluorouracil; liarozole; lobaplatin; lonidamine;

lovastatin; masoprocol; melarsoprol; metoclopramide;

mypristone; miltefosine; mirimostim; Mitoguazone double-stranded RNA; mitolactol; mitoxantrone;

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

<img file="MX343587B_D0293.tif" />

OF THE PROPERTY

206 . . . INBÍJSTM1AL polyclonal rabbit antithomyocyte; polyethylene giicol interferon alfa-2a; porfimer sodium; raltitrexed;

rasburicase; rhenium etidronate Re 186; retinamide RII;

romurtida; samarium (153 Sm) lexidronam; sargramostim;

sizofiran; sobuzoxane; sonermin; strontium chloride 89;

suramine; tasonermin; tazarotene; tegafur; temoporfin; 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 estimalomer; abarelix; AE 941 (Asterna); ambamustine;

antisense oligonucleotide; bcl-2 (Genta); APC 8015 (Dendreon); dexaminoglutethimide; diaziquone; 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; monoclonal antibody

CA 125 (MAb) (Biomira); Cancer MAb (Japan Pharmaceutical

Development); HER-2 and Fe MAb (Medarex); 105AD7 MAb

<img file="MX343587B_D0294.tif" />

207 idiotypical (CRC Technology); Idiotypic CEA MAb (Trilex); LYM-l-iodide 131 MAb (Techniclone); polymorphic epithelial mucin-yttrium 90 MAb (Antisome); marimastat; menogaril;

mitumomab; motexafin gadolinium; MX 6 (Galderma); nolatrexed; protein P 30; pegvisomant; porphyromycin; prinomastat; RL 0903 (Shire); rubitecan; satraplatin;

sodium phenylacetate; sparphosic acid; SRL 172 (SR

Pharma); SU 5416 (Pfizer); TA 077 (Tanabe);

tetrathiomolybdate; taliblastin; 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

<img file="MX343587B_D0295.tif" />

208 IMPI

MEXICAN INSTITUTE

DELA PROP1SPAD _ administered separately, the invention relates to £ F &amp;^L in addition 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 pack (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

IMPI ^{, NSTI}™ TO MEXICANO Dt INDUSTRIAL PROPERTY

<img file="MX343587B_D0296.tif" />

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

210

<img file="MX343587B_D0297.tif" />

IMPÍ

MEXICAN INSTITUTE

M LA PROMEDAl) memory aids will be easily apparent^N.^0l* üná daily can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also the daily dose of the compound of the present invention can 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

IMPI

IN «TIT1 ITfl Μ.ΥΙΓΛΕΚ ·. M

INSTITUTO MEXICANO W LA PROPERTY INDUSTRIAL be administered to a patient either orally, rectally, for example, intravenously, parenterally, (intramuscularly, or subcutaneously) intracisternally, intravaginally, intraperitoneally, intravesicularly, locally (for example, powders, ointments, or drops), or like 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 sprays. 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

<img file="MX343587B_D0298.tif" />

ΙΜΡΙ

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL such as preservatives, humectants, emulsifiers, 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 can 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, for example, 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

IMPIOS

2 ^ 3 MEXICAN INSTITUTE

GIVE THE ÉRC.ÉI®AD

IWHISTWAL 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; and (i) lubricants, such as, for example, 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

JJVJi. JL 4t. MEXICAN INSTITUTE,. ,, PROPERTY active compounds may also be in fO'rroa

<img file="MX343587B_D0299.tif" />

Encapsulated, 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, such as, for example, ethyl alcohol, isopropyl alcohol, 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 iso-stearyl alcohols, ί-

215

<img file="MX343587B_D0300.tif" />

INCTITUTC

OF. INDUSTRIAL PROPERTY polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, or mixtures of these substances, and 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 excipients or carriers 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 the preservatives, buffers, or propellants that may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of the invention.

The compounds of the present invention can be administered to a patient at dosage levels in the

216

<img file="MX343587B_D0301.tif" />

ΙΜΡΪ

INSTITUTO MSXICANO r «THE PROPERTY

INDUSTRIAL range from about 0.1 to about 3,000 mg per day. For a normal adult who has a body weight of about 70 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 hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate salts,

I

217

INSTITUTE

<img file="MX343587B_D0302.tif" />

MSXICANO E INDUSTRIAL PROPERTY 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 example, SM Berge, et al., Pharmaceutical Salts, J Pharm

Sci, 66: 1-19 (1977).

Examples of pharmaceutically acceptable esters of the compounds of the present invention include Ci-Cs alkyl esters. 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 C1-C3 alkyl amines, and secondary Ci-Ce dialkyl amines. In the case of amines

IMPIíSB

218

<img file="MX343587B_D0303.tif" />

INSTITUTO MRXICANO Γχ - «» «3ί PE LA Pk'PIEUAP secondary, the amine may also be in the^Nr,F^sA heterocycloalkyl group of 5 or 6 members which contains ai "minus one nitrogen atom. Amides derived from ammonia, C1-C3 primary alkyl amines and C1-C2 diakyl 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 prodrug use 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 (CiCe, alkanoyloxymethyl (C2-CI2), 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-l219

IMPI

Mexican Institute of Industrial Property

<img file="MX343587B_D0304.tif" />

(alkanoyloxy) ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, l-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-cryotonolactonyl , gamma-butyrolacton-4-yl, di-N, (C1-C2) Nalkylamino (C2-C3) alkyl (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 (Ci-Cs), 1 (alkanoyloxy (C1-C6)) ethyl 1-methyl-l- (alkanoyloxy (CiC6)) ethyl, alkoxycarbonyloxymethyl (Ci-Cé), Nalkoxycarbonylaminomethyl (C1-C6), succinoyl, alkanoyl (C1-C6), of-aminoalkanoyl (C1-C4), arylacyl and α -aminoacyl, or oiaminoacyl-a-aminoacyl, where each α-aminoacyl group is independently selected from naturally occurring amino acids L, -P (O) (OH) 2, -P (O) (Oalkyl (Οι-Οε)) 2 or

220

ΙΜΡΙ

MEXICAN INSTITUTE • E LA ΧΧΟΧΙΕΠΑΟ INDUSTRIAL

<img file="MX343587B_D0305.tif" />

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 corresponding pure enantiomers. Also, some compounds may be atropisomers (eg, substituted biaryls).

ΙΜΡΙ

ΙΚΤΓΠΓΓΌ MIXICANO

OF THE PROPERTY

INDUSTRIAL

The compounds of the present invention may exist

221

<img file="MX343587B_D0306.tif" />

in non-solvated forms as well as solvates 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 otherwise stated.

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,

<img file="MX343587B_D0307.tif" />

Similar. It is also contemplated that the present invention checks may 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 ¹³C, ¹⁴C, ¹⁵N, ¹⁶OR, ¹⁷0, ¹⁸OR, ³¹P, ³²P, ³⁵Yes, ¹⁸F, and ³⁶C1. In one aspect, the present invention is concerned with compounds where one or more hydrogen atoms are replaced with deuterium atoms (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.

223

IMPI

MEXICAN INSTITUTE OF MHUSTBIAL PROPERTY

<img file="MX343587B_D0308.tif" />

Tritiated isotopes, i.e. ³H, and carbon 14, that is, ¹⁴C, are particularly preferred for their ease of preparation 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

224

MIXICAN INSTITUTE Dt THE PROPERTY

INDUSTRIAL

<img file="MX343587B_D0309.tif" />

F, Cl), sulfonates (eg, mesylate, tosylate), sulfides (eg, SCH3), N-hydroxysuccinimide, Nhydroxybenzotriazole, 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.

'-H-NMR spectra were typically acquired on a Bruker Avance III 500 spectrometer system (Bruker,

Bilerica, MA) operating at a frequency ^X500.13 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

<img file="MX343587B_D0310.tif" />

225

IMPI

MEXICAN INSTITUTE

BE THE IIOUÍTRIAL PROPERTY

<img file="MX343587B_D0311.tif" />

a frequency ¹400.23 MHz H, equipped with a probe

Bruker 5 mm PABBO with a z axis gradient. Samples were typically dissolved in 500 pL of either DMSO-d6 or CD3OD for NMR analysis. Chemical changes ^ -H are also referenced to the residual solvent signals from DMSO-d6 to 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; nt, multiplet; br s, broad singlet) and coupling constants in Hertz.

Electron ionization mass spectra (El) were typically recorded on a mass spectrometer

Agilent Technologies 6140 Quadrupole CL / EM. 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 are typically either available from commercial sources such as SigmaAldrich, St. Louis, MO, or by way of literature.

The following abbreviations may be used herein:

226

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MEXICAN INSTITUTE £> € INDUSTRIAL PROPERTY

<img file="MX343587B_D0313.tif" />

+ go or pos. ion

Δ

Ac

AC2O

Ac

AcOH

Bn

Boc

BSA

Bu

Bz

Caled or Calc'd

Conc.

CSA d

DBU

DCE

DCM

DEA

About

Positive ion

Hot

Acetyl

Acetic anhydride

Aqueous

Acetic acid

Benzyl tert-butyloxycarbonyl

Bovine serum albumin

Butyl

Benzoyl

Calculated

Concentrated

Camphor-10-sulfonic acid day (s)

1,8-diazabicyclo [5.4.0] undec-7-ene dichloroethane

Dichloromethane

Diethylamine

Persodynane Dess1,1,1-triacetoxy-l, 1-dihydro-l, 2Martin; benziodoxol-3- (1H) -one reagent

Dess-Martin

IMPI

227

M4XICAN INSTITUTE OF LA mOPI »t> Al? INDUSTRIAL

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DIEA OR DIPEA

DMAP

DME

DMF

DMSO dr

DTT

DVB

EDO eq

ESI or ES

Et

Et₂OR

Et₃N

EtOAc

EtOH g

h

HEY YOU

HBTU

DIEA or DIPEA

DMAP

DME

DMF

DMSO dr

DTT

DVB

EDO eq

ESI or ES

Et

Et₂OR

Et₃N

EtOAc

EtOH g

h

HEY YOU

HBTU

Diisopropylethylamine

4-dimethylaminopyridine

1,2-dimethoxyethane

N, N-dimethylformamide

Dimethyl sulfoxide

Diastereomeric ratio dithiothreitol

Divinylbenzene

N-Ethyl-N'- (3dimethylaminopropyl) carbodiimide

Equivalent

Electrocracy ionization

Ethyl

Diethyl ether

Triethylamine

Ethyl acetate

Ethyl alcohol gram (s) hour (s) O— (7— azabenzotriazol-l-yl) -Ν, Ν, Ν ', N' tetramethyluronium hexafluorophosphate

O-benzotriazol-N, N, Ν ', Ν'-tetramethyl228

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MEXICAN INSTITUTE OF THE FROM INDUSTRIAL AGE

Hex

HMPA

HOAt

HOBt

HPLC

IPA or iPrOH

Jones reagent

KHMDS

KOAc

CLEM, CL-EM or CL / EM

LDA

LHMDS or LiHMDS

L-Selectride®

M m / z mCPBA

I

MeCN

Mel uronium-hexafluorophosphate hexanes hexamethi1phosphoramide l-hydroxy-7-azabenzotriazole hydroxybenzotriazole

High pressure liquid chromatography

Isopropyl alcohol

Solution of chromium (IV) oxide and sulfuric acid in water

Potassium hexamethyldisilazide

Potassium acetate

Liquid chromatography mass spectrometry

Lithium diisopropylamide

Lithium hexamethyldisilazide tri-sec-lithium butylborohydride (Sigma-Aldrich, St. Louis)

Molar (mol L '¹) mass divided by load

M-Chloroperoxybenzoic acid

Methyl

Acetonitrile

Iodomethane

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<img file="MX343587B_D0315.tif" />

MeOH

Mg min mL

M

EM

MsCl

MTBE or MtBE m / z

NaHMDS

NaOtBu

NBS nBuLi

NMO

NMP

NMR

N-Selectride®

PBS

PMB

Pr ppm

229

Methyl alcohol milligram (s) minute (s) milliliter (s)

Mole (s)

Mass spectrometry

Methanesulfonyl chloride

Methyl tert-butyl ether

Mass to load ratio

Sodium hexamethyldisilazide tert-butoxide

N-bromosuccinimide n-butyl lithium

N-methylmorpholin-N-oxide l-methyl-2-pyrrolidinone

Sodium tri-sec-butylborohydride nuclear magnetic resonance (Sigma-Aldrich, St. Louis)

Phosphate saline buffer

Paramethoxybenzyl

Propilo parts per million

MIXICAN INSTITUTE! ¡

OF THE MOEISDAL

INDUSTRIAL

230 rae

RP-HPLC or RPHPLC

TA or ta sat. or sat'd or satd

CFS

TBAF

TBDMS

TBDMS-C1

TBDPS

TEMPO tert ot

TFA

THF

TIPS

TLC

TMS

TPAP tR tBuOH v / v racemic

Reverse phase high pressure liquid chromatography

Room temperature

Saturated

Supercritical Fluid Chromatography

Tetrabutylammonium fluoride

Tert-butyldimethylsilyl

Tert-Butyldimethylsilyl chloride tert-butyldiphenylsilyl (2,2,6,6-tetramethylpiperidin-lil) tertiary oxidanyl

Trifluoroacetic acid

Triisopropylsilyl tetrahydrofuran

Trimethylsilyl or trimethylsilane thin layer chromatography

Tetrapropylammonium perruthenate

Holding time

Tert-butyl alcohol

Volume by volume

231

SüiüMPXiOS

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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 10 provided.

Reaction scheme 1

1.

OR.

^r4ZV o

• OH NaHMDS;

OR

R³\&lt; 2

OR

R³S

R⁴

O t-BuOK

2. NaBH₄

Oh

<img file="MX343587B_D0317.tif" />

R⁴

<img file="MX343587B_D0318.tif" />

As shown in Reaction Scheme 1, the compounds of the present invention wherein R^to and R^b Both are

H, can be prepared by reacting an appropriately substituted aryl acetic acid 1 and an aryl acid

232

<img file="MX343587B_D0319.tif" />

carboxylic 2 in an organic solvent 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 can again be obtained from 4 by converting the alcohol to a toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate, followed by reaction with sodium azide in an 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 base treatment, such as LiOH, K2CO3 or

NaHCCh in an aqueous mixture with an appropriate organic solvent, such as THF, will make piperidin-2-one 6 cyclic.

The individual enantiomers of racemic 6 can be separated by chiral HPLC using, for example, a Chiralcel® column.

OD-H 20mm ID x 250mm (Daicel Chemical Industries LTD,

Fort Lee, NJ) using 40% isopropyl alcohol / hexane as the eluent.

233

Reaction scheme 2

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<img file="MX343587B_D0320.tif" />

<img file="MX343587B_D0321.tif" />

<img file="MX343587B_D0322.tif" />

As shown in Reaction Scheme 2, piperidin-2-one 6 can be further modified, for example by arylating or alkylating nitrogen by methods well known to those of ordinary skill in the art. For example,] _q 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, alkyl trifluoromethanesulfonate , or alkyl toluenesulfonate to give intermediate 8. If desired, the sequence can be repeated to give the compounds of the 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

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<img file="MX343587B_D0323.tif" />

2,4-dimethoxybenzyl with TFA such a transformation is performed.

Similar transformations are well documented (see, for example, PGM Wuts and TW Greene, Greene's protective groups in organic synthesis, 4^to ed., John Wiley &amp; Sons, New 5 York, (2007)). Re-subjecting Compound 16 to alkylation conditions similar to those described above gives 17.

Reaction scheme 3

<img file="MX343587B_D0324.tif" />

<img file="MX343587B_D0325.tif" />

<img file="MX343587B_D0326.tif" />

<img file="MX343587B_D0327.tif" />

<img file="MX343587B_D0328.tif" />

As further shown in Reaction Scheme 3, if one of the alkyl groups contains a double bond, this

235

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MEXICAN INSTITUTE • F INDUSTRIAL PROPERTY

<img file="MX343587B_D0329.tif" />

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 KMnCú or RuCl3 (see, for example, RU Lemieux, E. von Rudloff, Can. J.

Chem., 38, 1703, (1955)) this transformation will take place. 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 art.

For example, carboxylic acid 11 can be activated by condensation with a variety of coupling reagents, including hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (HOSu), for example, using similar or a wide variety of reagents such as those developed for bonding peptides.

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 of Formula 11 to an amide 12 by this sequence. Using ammonia as the nucleophile, the

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INDUSTRIAL

236 Compound 13. Dehydration of amide 13 to a nitrile can be accomplished by a variety of methods. 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, RC Larock;

Comprehensive Organic Transformations, 2^gives ed., John Wiley &amp;

Sons, New York, pp. 1983, (1999)). Nitrile can, again, be converted to other groups such as a tetrazole by reacting nitrile with an azide, such as sodium azide, lithium azide or hydrazoic acid in a solvent such as DMF or water.

Reaction scheme 4

<img file="MX343587B_D0330.tif" />

As shown in Reaction Scheme 4, acid 11 can also be used to produce heterocyclic derivatives,

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such as, for example, oxadiazol-5 (4H) -onas 19, and

237 JSTITUTO MEXICANO [1,3,4] -oxadiazoles 18, [1,2,4] [1,2,4] -oxadiazoles 20 by methods

<td>well known</td><td>for those</td><td>of ability</td><td>ordinary</td><td>in</td><td>the</td>

<td>technique. By</td><td>example at</td><td>convert the</td><td>acid 11</td><td>in</td><td>a</td>

<td>diacylhydrazide,</td><td>followed by</td><td>treatment</td><td>with a</td><td>base</td><td>to</td>

Elevated temperature will be provided 18. In another example 11 it is converted to a nitrile as described in Reaction Scheme 3, which is treated with hydroxylamine. Reaction with 1,1'-carbonyldiimidazole in the presence of a base, such as

DBU, generated 19. Still in 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.

238

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LA RROF1KI * AI> INDUSTRIAL MEXICAN INSTITUTE

<img file="MX343587B_D0332.tif" />

Reaction scheme 5

Bear ^hjl J ~^{Re NM0} * ^H? ^F'^Re

<img file="MX343587B_D0333.tif" />

MeCLJDMe

<img file="MX343587B_D0334.tif" />

r²-lg

NaH / DMF r3

<img file="MX343587B_D0335.tif" />

'0 ^ H⁺

O Λ0Η

NaIO₄ θ P

R⁴

CrO-i r^3AV

R⁴ θ / P ^r! v ^^0H

As shown in Reaction Scheme 5, the compound of Formula 16 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 effect such a transformation . 21 can be converted to 22 by reaction with acetone or 2,2-dimethoxypropane in the presence of an acid, such as methanesulfonic acid, p-toluenesulfonic acid or 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

MIaICAí'r INSTITUTE. ' SAY THE BROWN

INDUSTRIAL treat 22 with an alkylhalide, 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. Treating 23 with an acid such as HCl or H2SO4 in the presence of water will give diol 24, which can be cleaved to aldehyde 25 by a variety of oxidizing agents, such as periodic acid or lead tetraacetate (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

<img file="MX343587B_D0336.tif" />

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

241

<img file="MX343587B_D0337.tif" />

Conditions well known to 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 acylated or sulfonylated by 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

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242

MSυ MSKJCANO • f THE INHirrtlAL EWOFBDAD

<img file="MX343587B_D0338.tif" />

including Grubbs catalysts of I^to generation and Grubbs of

2^gives 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

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