Piperazine derivatives useful as ccr5 antagonists

CCR5 piperazine recombinants are useful as antagonists

Piperazine derivatives useful as CCR5 antagonists

Full description

Background of the invention

This application is a partial application of the patent application filed in this office under No. 00210271, dated 05/05/1421 AH, corresponding to 05/08/2000 AD.

The present invention relates to piperazine derivatives useful as selective CCR5 antagonists, to pharmaceutical compositions containing the compounds, and to methods for treating with the compounds. The invention also relates to the use of a combination of the CCRS antagonist of this invention and one or more antiviral agents or other agents useful in the treatment of Human Immunodeficiency Virus. The invention further relates to the use of the CCR antagonist 5 of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft V. host disease, arthritis, and rheumatoid arthritis. Inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.

There is no doubt that the global health crisis caused by HIV, the causative agent of acquired immunodeficiency syndrome (AIDS), and despite the success of recent advances in drug treatments in slowing the progression of AIDS, there is still a need to find a safer, more effective, and less expensive means of control. On the virus.

It has been proven that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins with the virus binding to the membrane of a target cell through interaction with the CD4 cellular receptor and a secondary chemokine co-receptor molecule, and continues with the division and spread of infected cells through the blood and other tissues. There are different chemokine receptors, but for HIV, it is recessive to macrophages

Macrophage-tropic, it is believed to be the main disease-generating strain that multiplies in the body in the early stages of infection, and that the main chemokine receptor required for the virus to enter cells is CCR5. Therefore, obstructing the interaction between the CCR5 HIV viral receptor and HIV can hinder the entry of the virus into the cell. The present invention relates to small molecules that are CCR5 antagonists

It has been proven that 5-CCR receptors are the cause of cell migration in inflammatory diseases such as arthritis, rheumatoid arthritis, allergic dermatitis, psoriasis, asthma and allergic diseases, and it is expected that inhibitors of these receptors will be useful in treating these diseases, and in treating diseases Other infections or inflammatory conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection, and graft-versus-host disease.

Related piperazine derivatives that are muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer's disease are described in US Patent Nos. 5,883,096; 6037352; 5889006.

reveal:

(1998) 9:187-203 Antiviral Chemistry., & Chemotherapy.AM. Vandamme et al reported on current medical treatments for HIV-1 infections in humans including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy (HAART); HAART includes various consortia of

nucleoside reverse transcriptase inhibitors (NRTI), non-reverse transcriptase inhibitors. Non-nucleoside reverse NNRTI & transcriptase inhibitors and HIV protease inhibitors (PI). In patients treated simply, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. However, these multidrug therapies do not eliminate HIV-1 and long-term treatment often results in multidrug resistance. The development of new drug therapies to provide better treatment of HIV-1 remains a priority.

General description of the invention

The present invention relates to the treatment of HIV, which includes administering to a mammal in need of such treatment a significant amount of a CCR5 antagonist of the structural formula I:

<img file="SA2180B1_D0001.tif" />

Or a medicinally acceptable salt thereof, where:

R is R8-thiophenyl, R8-pyridyl, R8-phenyl or R8-naphthyl;

R1 is hydrogen or alkyl C1-C5;

R2 is R11-phenyl,R10,R9;R11-substituted 6-membered heteroaryl,R10,R9;

R11-substituted 6-membered heteroaryl N-oxide, R10, R9; R12, R13-substituted 5-membered heteroarvl; naphthyl; fluorenyl;

<img file="SA2180B1_D0002.tif" />

R3 is C3-C10 cycloalkyl, (C1-C6)alkoxy(C1-C6)alkyl, C1-C6 alkyl, hydrogen, R8-naphthyl, R8-phenyl(C1-C6)alkyl, R8-phenyl, C3-C10 cycloalky. (C1-C6)alkyl R8-heteroaryl, R8-naphthyl(C1-C6)alkyl or R8-heteroaryl(C1-C6)alkyl;

R13, R7, R5, and R4 are selected individually from the group consisting of (C1- and hydrogen C6)-alkyl;

R6 is C1-C6 alkyl,hydrogen or C2-C6 alkenyl; r8 is 1 to 3 substituents selected individually from the group consisting of hydrogen, CH3SO2-, -CN, CH3C(o)-, CF3O-, -CF3, C1-C6 alkoxy, C1-C6 alkyl, halogen, CH3C(=NOCH2CH3). ), CH3C(=NOCH3), R14-benzyl, R14,-phenyl, CF3SO2-

<img file="SA2180B1_D0003.tif" />

-NHSO2(C1,-NHCO(C1-C6 alkyl),-NHCONH(C1-C6alkyl),-NHCOCF3,-NH2 and 5-membered heteroaryl,C6 alkyl)

<img file="SA2180B1_D0004.tif" />

where X is -O-, -NH- or -(N(CH3-);

R10 and R9 are selected individually from the group consisting of halogen, (C1-C6)alkyl Si(CH3)3 and -OCF3, -O-acyl, -OCH3, -CF3, -OH,NR17R18-;

R11 is CH2F,-CN,-NO2,phenyl,hydrogen,R9-,CHF2-,CHO-,-pyrimldinyl,pyridyl N-oxide,pyridyl,CH=NOR17,pyrazinyl,-18r19NHCONH(chloro-(C1-C6)alkyl). ). NHCO2(C1-C6)alkyl,-N(SO2CF3)2 cycloalkyl,SR20-,S0R20-,alkyl,-SO2NH(C1-C6 alkyl),-SO2R20(-,-OSO2(C1-C6 -),-CON(CH2CH2) -O-CH3)2,-CONR17r18,OSO2CF3,OCONH(C1-C6)alkyl,Si(CH3)3,-CO2R17- or (2(B(OC(CH3-);

R12 is NH2, (C1-C6)alkyl- or phenyl-R14;

R14 is 1 to 3 individually selected substituents from the group consisting of hydrogen, halogen, and (Cl-C6)alkoxy, -CN, -CO2R17, -CF3;

R16 and R15 are selected separately from the group consisting of C1-C6 alkyl and hydrogen, or R16 and R15 together are the C2-C5 alkylene group, and with the carbon atom attached to them, they form a spiral ring of 3 to 6 carbon atoms;

r19, r18, and r17 are selected individually from the H-alkyl group C1-C6; And r20 is C1-C6 alkyl or phenyl.

Compounds of formula I are preferred where R is R8-phenyl or R8-naphthyl, in particular where r8 is a single substituent, and in particular where the R8 substituent is at position 4. For R8-phenyl, the preferred R8 substituents are CH3CO-, CH3SO2-, -OCF3, -CF3,

-(Br, CH3C(=NOCH3 and I). For R8-naphthyl, r8 is preferably C1-C6 alkoxy. Compounds of formula I are also preferred, where R3 is hydrogen, C1-C6)alkyl), R8-benzyl, R8. -phenyl or R8-pyridyl; The most preferred selections for R3 are methyl; phenyl, ethyl, benzyl and pyridyl. R1 is preferably hydrogen. For compounds of formula I, R6 is preferably hydrogen or methyl; In particular .methyl R4 is preferably methyl; It is preferable that both r7 and r5 separately be hydrogen.

In compounds of formula I, the preferred r2 is R9, R11-phenyl, R10; R11, R10, pyridyl-R11 or N-oxide thereof, or R9, pyrimidyl, R10-R11. When R2 is pyridyl, 3- or 4-pyridyl is preferred, and when it is pyrimidyl, 5-pyrimidyl is preferred. The R10 and R9 substituents preferably bind to carbon ring members adjacent to the carbon linking the ring to the rest of the molecule and the 11R substituent can bind to any of the remaining unsubstituted carbon ring members, for example, as shown in the following structures:

<img file="SA2180B1_D0005.tif" />

The preferred R10 and R9 substituents are: C1-C6alkyl, especially methyl; halogen, especially chloro or bromo, OH- -NH2, when r2 is phenyl, preferably r11 is hydrogen or OH-; When r2 is pyridyl, R11 is preferably hydrogen; When r2 is pyrimidyl, 11R is preferably hydrogen methyl or phenyl. Examples of particularly favorable r2 combinations are as follows:

<img file="SA2180B1_D0006.tif" />

<img file="SA2180B1_D0007.tif" />

New CCR5 antagonist compounds with structural formula II were also identified:

<img file="SA2180B1_D0008.tif" />

Or a medicinally acceptable salt thereof, where:

(1) Ra is phenyl-R8b-thiophenyl, R8b-pyridyl, R8a or R8-naphthyl;

R1 is hydrogen or alkyl C1-C6;

R2 is R9,-phenyl,R11-R10,R9,R11-substituted 6-membered heteroaryl,R10; r9, R11-substituted 6-membered heteroaryl N-oxide, R10; 12R13-substituted 5-, R membered heteroaryl; naphthyl; ,fluorenyl

<img file="SA2180B1_D0009.tif" />

r3 is alkyl,hydrogen alkyl,C1-C6(cycloalkyl,(C1-C6)alkoxy(C1-C6)C3-C6,cycloalkyl(C1-C6)alkyl C3-C10,phenyl-R8-phenyl(C1-C6)alkyl, R8, R8-naphthyl, 8 heteroaryl-R8 or alkyl(R8-heteroaryl(C1-C6);

r13, r7, r5, and r4 are selected separately from the group consisting of hydrogen C1- and C6)-alkyl;

R6 is alkyl,hydrogen C1-C6 or 6 alkenyl C6-C2;

R8 is 1 to 3 individually selected substituents from the group consisting of hydrogen,

6 alkyl, halogenC-C1, 6 alkoxyC6-C1, CF3O-, -CF3, -(O)CH3SO2-, -CN, CH3C, -,CH3C(=NOCH3), R14-benzyl, R14-phenyl, CF3SO2 (,CH3C( =NOCH2CH3

<img file="SA2180B1_D0010.tif" />

NHSO2(C1-,-NHCO(C1-C6 alkyl)'-NHCONH(C1-C6 alkyl),-NHCOCF3,-NH2-(alkyl 5-membered heteroaryl,C6 and

<img file="SA2180B1_D0011.tif" />

where X is -O-, -NH- or -(N(CH3-);

R8a is 1 to 3 individually selected substituents from the group consisting of hydrogen, 5-membered NHCOCF3, R14-phenyl, CF3SO2-, CN, CF3O-, CF3, ha logen heteroaryl, and

<img file="SA2180B1_D0012.tif" />

Where X is as defined above;

R8b is 1 to 3 individually selected substituents from the group consisting of hydrogen, CH3C(=NOCH3), R14-benzyl, CF3SO2-, -CN, CHC(O)-, CF3O-, halogen (CH3C(,-CF3). =NOCH2CH3

<img file="SA2180B1_D0013.tif" />

5 The -membered heteroaryl, -NHCOCF3

<img file="SA2180B1_D0014.tif" />

Where X is as defined above;

R10 and R9 are selected individually from the group consisting of (C1-C6) alkyl halogen, -

r1817Si(CH3)3, -OCF3,-O-acyl,-OCH3,-CF3,-OH,NR-;

R11 is phenyl,hydrogen,CHO,-CHF2,-CH2F,-CN,-NO2-,-17-,pyrazinyl,pyrimidinyl,pyridyl N-oxide,pyridyl,CH=NOR 19)1CONR18r;NHCONH(chl0r0-(C1-) C6)alkyl),N(R17-,-(NHCONH((C3-C10-cycloalkyl(C10-C6)alkyl), NHSO2N((C1,-NHCOCF3,-NHCOCOalkyl-2(NHC02(C1-C6 cycloalkyl),-N (S02CF3)2,-NHS02(C1-C9)alkyl,C6)alkyl-, .,-SR20 so-, OSO2CF3,-0S02(C1-C6)alkyl,-SO2NH(C1-C6 alkyl),-SO2R20-,

18OCONH(C1-,-CON(CH2CH2-O-CH3)2,-conr17r Si(CH3)3,-CO2R17,C6)alkyl- or 2(2(B(OC(CH3-);

R12 is NH2, (C1-C6)alkyl-or R14-phenyl

14R is 1 to 3 individually selected substituents from the group consisting of hydrogen, (C1-C6)alkoxy, -CN, -CO2R17, -CF3, (C1-C6)alkyl) and halogen;

R16 and R15 are selected individually from the group consisting of hydrogen and a C1-C6 alkyl, or R16 and R15 together are the C2-C5 alkylene group, and with the carbon atom attached to them, they form a spiral ring of 3 to 6 carbon atoms; R17, R18, and R19 are selected individually from the C1-C6 alkyl H group; And r20 is C1-C6 alkyl or phenyl; or (2) Ra is phenyl-pyridyl, R8-R8 or R8-thiophenyl; r2 is fluorenyl;

<img file="SA2180B1_D0015.tif" />

And r17, R16, r15, r14, r13, r12, r11, r10, r9, r8, R7, R6, r5, R4, R3, R1,

R19, ​​R18 and R20

They are as specified in (1).

Preferred compounds of Formula II are those specified in (1).

Those compounds of formula II(1) are most preferred where Ra is phenyl-R8a or -R8 naphthyl, where r8a is CF3O- or R8, and the halogen is C1-6 alkoxy. The a8R or R8 substituent is preferably a single substituent. ; It is particularly preferable to have an alternative R8a or R8 in position 4. We also prefer compounds of formula II(1) where r3 is hydrogen, R8-benzyl, R8-phenyl, (C1-C6)alkyl or R8-pyridyl; The most preferred selections for R3 are pyridyl, benzyl, phenyl, ethyl, and methyl. 1R is preferably hydrogen. For compounds of formula II (1), R6 is preferably hydrogen or methyl, especially methyl. Preferably r4 is methyl; Preferably, R5 and R7 separately are hydrogen.

R2 should preferably be in Formula II(1) as defined in Formula 1, i.e., R9, R11-, R10, R11-pyridyl, R9 Phenyl-, R10, or N-oxide thereof, or R9, R11-pyrimidyl, R10, where Replace R9, R11, R10 as specified above for preferred compounds of Formula I.

Another aspect of the invention is a drug composition for the treatment of HIV comprising a significant amount of a CCR5 antagonist of Form II in combination with a pharmaceutically acceptable carrier. Another aspect of the invention is a drug composition for the treatment of solid organ transplant rejection, graft-versus-host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, allergic dermatitis, psoriasis, asthma, allergic diseases or multiple sclerosis including a significant amount of a CCR5 antagonist from Formula II in combination with a pharmaceutically acceptable carrier.

Another aspect of this invention is a method for treating HIV that includes administering to a human in need of such treatment a significant amount of a formula II anti-CCR5 compound. Another aspect of the invention is a method for treating solid organ transplant rejection, patch-versus-host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, allergic dermatitis, psoriasis, asthma, allergic diseases or multiple sclerosis, including administering a significant amount to a human in need of such treatment. Of the anti-CCR5 compound of formula I or II.

Another aspect of this invention is the use of the CCR5 antagonist of formulation I or II of this invention in combination with one or more antiviral agents or other agents useful in the treatment of human immunodeficiency virus for the treatment of AIDS. Another aspect of this invention is the use of the CCR5 antagonist of formulation I or II of this invention in combination with one or more other agents useful in the treatment of solid organ transplant rejection, graft-versus-host disease, inflammatory bowel disease, rheumatoid arthritis, or Multiple Sclerosis. CCR5 and antiviral agents or other agents that are components of the combination may be administered as a single dose or may be administered separately; A pharmacological group including separate dosage forms of active substances is also expected.

Detailed description of the invention

As used herein, the following terms are used as defined below unless otherwise noted.

An alkyl represents straight and bent carbon chains and contains 1 to 6 carbon atoms.

An alkenyl represents C2-C6 carbon chains with 1 or 2 unsaturated bonds, provided that no two unsaturated bonds are adjacent to each other.

Substituted phenyl means that the phenyl group can be substituted at any available position on the phenyl ring.

The acyl moiety of carboxylic acid has the formula -(o)aralkyl-,aryl-C(o)-,alkyl-c -(o)alkyl-C(o)-,(C3-C7)cycloalkylC(O)-,C (C3-C7)cycloalkyl-(C1-C6), heteroaryl-c(O)-f, wherein the heteroaryl and alkyl are as specified herein; aryl is R14-phenyl or R14-naphthyl; An aralkyl is aryl-(C1-C6)alkyl, where aryl is as defined above.

Heteroaryl represents cyclic aromatic groups of 5 or 6 atoms or bicyclic groups of 11 or 12 atoms with 1 or 2 heteroatoms selected individually from 0, S or N. The mentioned heteroatom(s) prevent the construction of a ring. A carbocyclic ring with sufficient delocalized pi electrons to provide aromaticity, provided that the rings do not contain adjacent oxygen and/or sulfur atoms. For 6-membered heteroaryl rings, the carbon atoms can be replaced by R10, R9 or R11 groups. Nitrogen atoms can form N-oxide. All regioisomers are expected, for example, 4-pyridyl, 3-pyridyl, and 2-pyridyl. Typical 6-membered heteroaryl groups are pyrimidinyl, pyridyl, pyridazinyl, pyrazinyl N-oxides, etc. For 5-membered heteroaryl rings, the carbon atoms can be replaced by R12 or R13 groups. Typical 5-membered heteroaryl rings are imidazolyl, isothiazolyl, thiazolyl, pyrrolyl, thienyl, furyl, and pyrazolyl.

isoxazolyl. 5-membered rings can be connected to one heteroatom through position 2 or 3; Preferably, 5-membered rings with two heteroatoms are connected through position 4. Typical bicyclic ring systems are benzo-fused ring systems derived from the heteroaryl groups named above, for example phthalazinyl, quinolyl, benzofuranyl, quinazolinyl, indolyl, and benzothienyl.

Preferred substitution points for 6-membered heteroaryl rings at R2 are described above. When R2 is a 5-membered heteroaryl group, the R12 substituents are preferably linked.

r13 and with carbon ring members adjacent to the carbon connecting the ring with the rest of the molecule, preferably R12 being an alkyl; However, if a heteroatom is adjacent to the carbon that connects the ring with the rest of the molecule (i.e., as in 2-pyrrolyl), R12 is preferably bound to

With a carbon ring member adjacent to the carbon that connects the ring with the rest of the molecule.

The halogen represents iodo and the bromo, chloro, and fluoro.

One or more, preferably one but four, antiviral agents useful in anti-HIV-1 therapy may be used in combination with the CCR5 antagonist of the present invention. The antiviral agent or agents may be combined with the CCR5 antagonist in a single dosage form, or the CCR5 antagonist may be administered and the antiviral agent or agents may be administered at the same time or successively as separate dosage forms. Antiviral agents intended for use in combination with compounds of the present invention include nucleotide and nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors

Protease inhibitors and other antiviral drugs listed below that are not included in this

Categories. Specifically, conjugates named HAART (highly active antiretroviral therapy) are hoped to be used in combination with CCR5 antagonists of this invention.

The term “nucleotide reverse transcriptase inhibitors” and “nucleotide reverse transcriptase inhibitors” as used herein means nucleosides, nucleotides, and similar substances that inhibit the activity of HIV-1 reverse transcriptase, the enzyme that catalyzes the conversion of HIV-1 viral genomic RNA. HIV-1 proviral DNA.

Typical suitable NRTIs include zidovudine (AZT) available under the brand name RETROVR from Glaxo-Wellcome, Research Triangle, 27709 NC; ddl) didanosine, available under the trade name VIDEX from Bristol-Myers Squibb, Princeton, 08543 NJ; ddC) zalcitabine, available under the brand name HIVID from Nutley, Roche Pharmaceuticals, NJ 07110; d4T) stavudine, available under the brand name ZERIT from Bristol-Myers Squibb, Princeton,

08543.NJ; lamivudine (3TC) available under the trade name EPIVIR from Glaxo NC 27709, Wellcome Research Triangle; abacavir (1592U89) indicated in W096/30025 and available under the brand name ZIAGEN from Glaxo-Wellcome NC 27709, Research Triangle; bis(POM)-PMEA) adefovirdipivoxil] available under the brand name PREVON from Gilead Sciences, CA 94404; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor described in EP-0358154-0736533 and EP-0736533, which is in development By-Bristol NJ08543, Princeton, Myers Squibb; 10652-BCH, a reverse transcriptase inhibitor (in the form of a racemic mixture of 10618-BCH

(BCH-10619) is under development by Laval, Biochem Pharma Canada, Quebec H7V, 4A7; FTC] emitricitabine-(-)] is licensed from Emory University under Emory Univ U.S. Patent No. 5,814,639 and is under development by Triangle NC27707, Durham, Durham Pharmaceuticals; (labeled) beta-L-FD4 (also called beta-L-D4C (beta-L-2'3',-dideoxy-5-fluoro-cytidine) licensed by Yale University

To New Haven CT 06511, Vion Pharmaceuticals; DAPD, showing purine nucleoside, beta-D-2,6-diamino-purine dioxolane-(-) in 0656778-EP, licensed from the University of Georgia to Triangle Pharmaceuticals and Emory University NC27707, Durham; 9-(23-dideoxy-2-fhroro-bD-threo-(FddA)lodenosine and pentofuranosyl)adenine, a reverse transcriptase inhibitor was discovered.

This acid-stabilized purine inhibitor has been approved by the NIH and is under development by US Bioscience, PA 19428.

The term “non-nucleoside reverse transcriptase inhibitors” (NNRTI) as used herein means non-nucleosides that inhibit the activity of HIV-1 reverse transcriptase.

Typical suitable NNRTIs include nevirapine (BI-RG-587) available as VIRAMUNE from Boehringer lngelheim, manufactured by Roxane Laboratories, HIO 43216, Columbus; BHAP, U-90152 (delaviradine) (available under the name:

Commercial RESCRIPTOR from Bridgewater, Pharmacia &amp; NJ08807 Upjohn; DMP-266 (efavirenz) shown as benzoxazin-2-one as W094/03440, available under the trade name SUSTIVA from DuPont Pharmaceutical, DE, Wilmington, 19880-0723; furopyridine-thio-pyrimide, PNU-142721, under development by Pharmacia and Bridgewater NJ08807, 1549-Shionogi (formerly AG No. 1153-S); Reveals

5-(3,5-dichlorophenyl)-thio-4-isopropyl-l-(4-pyridyl)methyl-lH-imidazo

ylmethyl carbonate

In 96/10019 wo and under clinical development from Agouron Pharmaceuticals, 92037-1020 LaJolla CA; 442-MKC

l-(ethoxy-methyl)-5-(l-methylethyl)-6-(phenylmethyl)-(2,4(lH,3H)-)

pyrimidinedione);

Discovered by Mitsubishi Chemical and under development by Triangle NC27707, Durham Pharmaceuticals; (NSC-675451) (+)-calanolide A, coumarin derivatives are disclosed in NIH US Patent No. 5,489,697, authorized for Med Chem Research, which is jointly developing (+)-calanolide A with Vita-Invest as an enterally administered product.

The term “protease inhibitor” (PI) as used herein means inhibitors of HIV-1 protease, an enzyme required for the proteolytic cleavage of viral polyproteins (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in HIV-1. Contagious HIV. HIV protease inhibitors include compounds with a peptide-like structure, high molecular weight (7600 Daltons) and a intrinsic peptide character, e.g., CRIXIVAN (available from Merck) as well as non-peptide protease inhibitors, e.g., VIRACEPT (available from Agouron).

Typical suitable PIs include saquinavir (Ro 31-8959), which is available in hard gel capsules under the brand name INVIRASE and soft gel capsules under FORTOVASE, Nutley, Roche Pharmaceuticals, NJ 07110-1199; ritonavir

(538-ABT) under the brand name NORVIR from Abbott Laboratories, MK-639 (Indinavir I 60064, Abbott Park) under the brand name CRIXIVAN from Pa. 19486-0004, West Point, Merck &amp; Co; nelfnavir (1343-AG) available under the brand name VIRACEPT from Agouron Pharmaceuticals, La-Jolla CA 92037-1020; Amprenavir (141W94), trade name AGENERASE, is a non-peptide propane inhibitor under development from Vertex Mass. Cambridge Pharmceuticals, 02139-4211 and is available at Research Triangle, Glaxo-Wellcome, NC, under an extended access program; BMS-234475 (lasinavir) available from NJ08543, Princeton, Bristol-Myers Squibb (originally acquired from Novartis, CGP-61755) Switzerland, Basel); 450-cyclic urea, DMP disclosed by Dupont and under development from Triangle Pharmaceuticals; 2322623-azapeptide, BMS, is under development from Princeton, Bristol-Myers Squibb, N.1.08543, as a second-generation HIV-1 PI; 378-ABT under development from III. 60064 Abbott Park, AG-1549, an orally active imidazole carbamate described in Shinonogi (Shionogi #S-1153) and under development from Agouron Pharmaceuticals, LaJolla CA 92037-1020. Other antiviral agents include IL-12, IL-2, ribavirin, hydroxyurea, pentafuside and 11607. Yissum Project No. Droxia (hydroxyurea) is an inhibitor of ribonucleoside triphosphate reductase, the enzyme involved in T-cell activation, disclosed at NCI and under development by Bristol-Myers Squibb; In preliminary medical studies, it has been shown that it has an additive effect on the activity of didanosine and has been studied with stavudine. 2-IL is disclosed in Takeda EP-0176299, Ajinomoto EP-0142268, and Chiron US Patent Nos. 33653 RE, 4530787, 456979, 4604377, 4748234, 4752585, and 44949314, and is available under the trade name aldesleukin IN) from CA 94608 -Chiron, Emeryville, 2997 As a lyophilized powder for intravenous infusion or subcutaneous administration When reconstituted and diluted with water, preferably a dose of about 1 to about 20 million IU/day, subcutaneously; We close the maximum dose of about 15 million international units/day, subcutaneously. The 12-IL

Shown as W096/25171 and available from Nutley, Roche Pharmaceuticals, NJ 1199 Madison, 07110-07110, NJ-07940; Prefer about 0.5 mcg/kg/day I prefer about 10 mcg/kg/day, subcutaneously. DP-178 (pentafuside, 20-T), a 36-amino acid synthetic peptide, is described in US Patent No. 5,464,933 granted by Duke University to Trimeris, which developed pentafuside in collaboration with Duke University; Pentafuside works by:

Inhibiting the association of HIV-1 with target membranes. Pentafuside (3-100 mg/day) given as continuous infusion or subcutaneous injection along with 2 PI'S and efavirenz to HIV-1+ patients refractory to triple combination therapy; It is preferable to use 100 mg/day. Yissum Project No. 11607, a synthetic protein based on the HIV-1 Vif protein, is a recombinant in preclinical development from Yissum Research Development, 91042 Jerusalem, Israel. The formulation and manufacture of Ribavirin, which is -3-l-beta-D-ribofuranosyl-lH-1,2,4-triazole Carboxamide, is described and is available from ICN Pharmaceuticals, Calif; ,Costa Mesa, in

US Patent No. 4211771

The term “anti-HIV-1 therapy HIV” as used herein means any existing anti-HIV drug that is useful for treating HIV-1 infections in humans only or as part of multi-drug combination therapies, especially triple-drug combination therapies. Includes

Known anti-HIV-1 therapies are typical, but not exclusive, multi-drug combination therapies such as (1) at least 3 anti-HIV-1 drugs selected from two NRTIS, one PI, one PI, and one NNRTI; and (2) at least two anti-HIV-1 drugs are selective for, NNRTIs and PIs. Typical appropriate multiple HAART-drug combination treatments include:

(a) Triple combination therapies such as two NRTIs and one PI; or (b) two NRTIs and one NNRTI; and (c) quadruple combination therapies such as two PIs, one NRTIs and a second PI or one NNRTI. In treating naïve patients, anti-HIV-1 therapy with triple combination therapy is preferred; Two NRTIs and one PI are preferred unless there is intolerance to protease inhibitors (PIs). Compliance with the drug is essential. Plasma levels of CD4+ and HIV-1-RNA should be monitored every 3-6 months. When a flat viral load occurs, it can...

Add a fourth drug, for example, P1 one or one. See the table below where they are described Additional typical treatments:

<img file="SA2180B1_D0016.tif" />

Table margins (1) One of the following: zidovudine + lamivudine; didanosine + zidovudine; stavudine lamivudine +; didanosine +stavudine; zalcitabine + zidovudine. (2) (2) nelfinavir, indinavir, ritonavir or saquinavir in soft gel capsules. (3) navirapine or delavirdine.

(4) See

AM. Vandamne et al Antiviral Chemistry &amp; Chemotherapy 9:187 at p 193-197 and Figures 1+2.

(5) Alternative regimens exist for patients who are refractory to a recommended regimen due to problems of coexistence or toxicity, and for those in whom recommended treatment fails or relapses. Nucleoside conjugates may lead to HIV resistance and medical failure in many patients.

(6) Most data we obtain with ritonavir and saquinavir (each 400 mg twice daily).

(7) zidovudine, stavudine or didanosine.

Known agents in the treatment of rheumatoid arthritis, organ transplantation, host-versus-host disease, inflammatory bowel disease and multiple sclerosis that can be given in combination with CCR5 antagonists of the present invention are as follows: solid organ transplant rejection and host-versus-host disease: immunosuppressants such as cyclosporine, (IL-10)interleukin-10 globulin, tacrolimus, anti-lymphocyte agent,

3-steroid antibody and OKT;

Inflammatory bowel disease: IL-10 (see US Patent 5,368,854), azulfidine steroids;

Rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, and steroids,

MS: interferon-beta, steroids and interferon-alpha. Certain compounds of the invention exist in different isomeric forms (e.g.

Enantiomers, diastereoisomers, atropisomers and rotamers). The invention provides for all of these isomers in pure form and in mixtures, including racemic mixtures

Certain compounds are acidic in nature, for example those that have a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of these salts may include potassium, sodium, and calcium salts.

Aluminium, gold and silver. Salts formed with pharmaceutically acceptable amines are also expected

alkyl amines, ammonia, hydroxyalkylamines, N-methylglucamine, etc.

Certain basic compounds also form pharmaceutically acceptable salts, for example, acid addition salts. For example, pyrido-nitrogen atoms form salts with strong acids, while compounds with base substituents such as amino groups also form salts with weaker acids. Examples of acids suitable for forming salt are hydrochloric, sulfuric,

phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic,

Ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids are well known to those skilled in the art. Salts are prepared by contacting the free base form with a sufficient amount of the required acid to produce a salt in the traditional way. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate,

sodium bicarbonate and ammonia. The free base forms differ from their salt forms somewhat in certain physical properties, such as solubility in polar solvents, but... The acid and base salts are in some way equivalent to their free base forms for purposes of the invention.

It is intended that all such a- and base salts are pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention.

The compounds of the invention may be prepared by procedures known in the art, for example by the procedures described in the following reaction programs, by the methods described in the examples below, and by using the methods described in WO98/05292 and W096/26196.

The following solvents and reagents may be referred to herein by the following abbreviations: tetrahydrofuran (THF); EtOH(ethanol); MeOH)methanol); acetic acid (HOAc) or AcOH); EtOAc)ethyl acetate); DMF)NN-dimethylformamide); TFA(trifluoroacid); HOBT) l-hydroxy-benzotriazole; m-chloroperbenzoic acid (MCPBA)); Et3N)triethylamine); diethyl ether (Et2O); dimethylsulfoxide (DMSO); l-(3-dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride

(DEC). RT is room temperature, TLC is thin layer chromatography

Me .thin-layer chromatography is methyl, Et is ethyl, Pr is propyl, Bu is butyl, Ph is phenyl, and Ac is .acetyl.

Program 1

<img file="SA2180B1_D0017.tif" />

Reagents and conditions: (a): r4CH(OSO2CF3)CO2CH3, base (e.g., K2CO3);

(B): C1CH2COC1; (C): NH3; (d): NaBH4-BF3; (e): N-Boc-4-piperidone, 3(NaBH(OAc); (f): CF3CO2H; (g): acylation; (h): N-Boc-4-piperidone, 4(Et2AlCN,Ti(OPr) -i; (i): CH3MgBr.

In program 1, benzylamine (1), where R3 and R are as defined above R1 and is hydrogen, are converted by compound (2) and (3) to diketopiperazine (4), where R4

As determined above, which is reduced to piperazine (5). Depending on the R6 replacement required, this is handled in two ways. Reductive amination gives compound (6), which can be deprotected to compound (7) and finally acylated compounds of formula IA where R5 and R6 are hydrogen; Alternatively, a modified Strecker reaction on compound (5) gives aminonitrile (8), which, after treatment with methyl Grignard to give compound (9), which is deprotected to compound (10) and N-acylation finally gives compounds of the formula IB Where R5 is R6 and H is methyl. Compounds (7) and (10) are acylated under

Standard conditions, for example, with R2COOH and reagent agents such as HOBT and DEC. The use of a chiral compound of formula I, e.g., s)-methyl 4-substituted benzylamine), chiral lactate, and in step (a), e.g., methyl (R)-lactate triflate; It gives chiral compounds of formula IA and IB.

<img file="SA2180B1_D0018.tif" />

Reagents: (J): oxaborazolidine, BH3; (K): CH3SO2CI, base; (to):

CF3CO2H.

In Program 2, compounds are prepared by alkylation of a preformed piperazine derivative. For example, we may obtain preferred compounds having stereochemistry s, s in this way by the chiral reduction of a ketone (11) to an alcohol (12), activation such as mesylate, and displacement by inversion by treatment with a suitable piperazine, which is both monoprotected, and in In this case the final release requires protection removal followed by the steps described in (e)-(g) in Program 1 to obtain the IC, or it may be released before the displacement step, in which case the final steps are (f) and (g) (removal Protection and acylation) as in program 1 To get the compound ID

<img file="SA2180B1_D0019.tif" />

For compounds where R1 and R3 are each hydrogen, either the alkylation method from Program 2 or the reductive amination method as described in Program 3 can be used.

<img file="SA2180B1_D0020.tif" />

For diaryl compounds, where both R and R are aryl, the alkylation method described in Program 4 is preferred.

<img file="SA2180B1_D0021.tif" />

We may also obtain piperazines of formula 14, especially those where R3 is -C2

As shown above in sequence

<img file="SA2180B1_D0022.tif" />

c6 alkyl or benzyl, by a process in which the fraction is introduced

Alkylation-decyanation. The reaction is for compounds where R is CF3O-phenyl, R1 is R3, hydrogen is R4 and ethyl is methyl, but using suitable starting materials, other compounds of formula 14 can likewise be prepared.

<img file="SA2180B1_D0023.tif" />

Reagents: (M): BOC2O, base; (N): R6MgBr; (Q): CCI3CO2H, NaBH3CN; (P):CF3CO2H; (F): BF3, NaBH4.

As shown in Program 6, compounds bearing an additional alkyl group at R5 on the piperazine ring may be prepared from diketopiperazine intermediates (4) of Program 1. Compound (4) is activated by conversion to N(t-butoxycarbonyl (17); addition of a Grignard reagent and subsequent reduction, deprotection and kactame reduction provide compound (21), which can be used to prepare compounds of formula I by the method described for intermediate (5). In program 1.

<img file="SA2180B1_D0024.tif" />

Many piperazines where R is R8-phenyl (or Boc derivatives thereof) shown in formula I can be obtained from a common intermediate, where R8 is I. Many examples are shown in the program above, where R8 is converted to P- and Ph, H,-C(O)NH2,CN,Cl -C1C6H4CH2. Detailed procedures for these conversions are provided in the examples below. The resulting piperazine or Boc-piperazine is then treated as indicated in Program 1.

<img file="SA2180B1_D0025.tif" />

We may obtain some compounds of the invention by the Mannich method, as shown in Example Program 8.

The useful compounds of this invention are represented by the following preparatory examples, which are not intended to limit the scope of the explanation. Alternative motion paths and similar constructions may be apparent within the scope of the invention to those skilled in the art.

<img file="SA2180B1_D0026.tif" />

Step 1: Stir methyl R-lactate (5 g) in CH2CI2 (40 ml) at -C and add trifluoromethanesulfonic anhydride (706 ml), then 2,6-lutidine (708 ml).

milliliters). Remove from cooling, stir for half an hour, wash with 2 m HC1 and add the organic solution of S)-methyl 4-bromobenzylamine (9 g) K2C03 (11.2 g) in water (60 ml). Stirred for 20 hours at room temperature, the organic phase was dried over K2CO3, evaporated and chromatographically resolved on silica gel with CH2C12-Et2O to give the desired product (7.5 g) as a thick oil.

Step 2: Heat and re-condense the steam. The product of step 1 (7.5 g) in 1.2-dichloroethane (40 ml) CICH2COCI (5 ml) for 5 hours, then evaporate and the resulting residue is used directly in the next step.

Step 3: Stir the product of step 2 in DMSO (80 ml), water (10 ml), NaI (8 g), cool on ice, add concentrated NH4OH solution (15 ml) and stir to temperature.

room for 20 hours. Water (200 ml) is added dropwise, the solid is collected, washed well with water and dried at 70 C/5 mM to give diketopiperazine, suitable for the next step.

Step 4: Stir a mixture of the product of step 3 (6.8 g), l,2-dimethoxyethane (60 mL) and 4NaBH (3.4 g) under N2, add BF3.OEt2 (6.8 mL) dropwise, then heat at 100 C for 10 hours. Cool and add CH3OH (20 ml) dropwise, then HC1 concentrate (30 ml). Heat at 100°C for one hour, cool, become basic with an excess of 2 m NaOH and extract with EtOAc. It is dried over K2CO3 and evaporated to obtain piperazine (5.85 g), which is suitable for the next step.

Step 5: Stir for 20 hours at room temperature Mixture of step 4 product (5.48 g), N-Boc-4-piperidinone (4.32 g), HOAc (1.15 mL), CH2C12 (80 mL) NaBH(OAc) 3) sodium triacetoxy-borohydride (8.3 g). Add an excess of aqueous Na2CO3 solution slowly, stir for half an hour, separate and filter the organic phase through a silica gel liner, wash with a 10:1 mixture of Et2O-CH2C12 to filter out all the product. Evaporate and dissolve the residue in Et2O (100 mL). Stir and add a 4 mol solution of HC1 in 1,4-dioxane (10 ml) dropwise. The solid was collected, washed with Et2O, and stirred with CH2C12 and an excess of aqueous NaOH. The organic phase is dried over K2CO3 and evaporated to obtain the desired product (5.45 g).

Step 6: Stir at room temperature for 2 hours the mixture of step 5 product (1.5 g) TFA and (4 ml). Evaporate, dissolve in CH2CI2 and wash with excess 1 N NaOH solution. It is dried over K2CO3 and evaporated to obtain the product (1.15 g).

Compound 1a:

Following the standard procedure, the product of step 6 reacts with 2,6-dimethylbenzoyl chloride in...

NaOH and CH2CI2 are aqueous, and the product turns into hydrochloride. Melting point 185 C-192 C (decomposition). Existing HRMS: 498,213; Calculated MH+: 498.212.

Compound 1b:

Following the standard procedure, the product of step 6 is coupled to 2-amino-6-methylbenzoic acid

Using DEC and HOBT with diisopropylethylamine in DMF, the amide is purified by preparative TLC and converted to hydrochloride. Melting point 188°C - 196°C (decomposition). Existing HRMS: 499.2069; +MH Calculated: 499.2072. Compound 1c:

Following the above method, the product of step 6 is coupled with 2-amino-6-chlorobenzoic acid

After purification, it turns into hydrochloride. Melting point 192-200 C (decomposition). Existing HRMS: 519.153; +MH calculated: 519.1526.

<img file="SA2180B1_D0027.tif" />

Step 1: Stir the product of Example 1, Step 4 (1 g), Nt-butoxycarbonyl-4-piperidinone (0.77 g), Ti(OiPr)4) titanium(IV) isopropoxide,) (1 g) for 20 hours at room temperature. In CH2CI2 (15 mL), the vapor is recondensed for 3 hours and cooled to room temperature. Add Et2AlCN (diethylaluminumcyanide) (4.2 mL of 1 mol toluene solution) and stir for 5 days at room temperature under dry N2. The reaction develops in aqueous NaOH-CH2CH2, the organic phase is dried and evaporated and analyzed chromatographically on silica gel with CH3OH-CH2CI2 (100:1) to obtain the product.

Required (0.72 g).

Step 2: The product of step 1 (0.7 g) reacts in dry THF (15 mL) under N2 with CH3MgBr (4 mL of 3 mol Et30 solution) at room temperature for 20 hours. The reaction develops in EtOAc-water and the organic phase is filtered through silica gel, washed with EtOAc, and evaporated to obtain the desired product (0.65 g).

Step 3: The Step 2 product is removed from protection with TFA according to the procedure described in Example 1, Step 6.

Compound 2a:

The product of Step 3 reacts with dimethylbenzoyl chloride as described in Example 1 and turns into the HCl salt. Melting point 180-187 C (decomposition). Found HRMS: 512.2272; +MH Calculated: 512.2276.

Compound 2b:

The product of Step 3 reacts with 2-amino-6-chlorobenzoic acid as described in Example 1. The crude product is raised by preparative TLC analysis and converted to the HCl salt. Melting point 200-195 C (decomposition). HRMS found: 535.1662; +MH calculated: 535.1652.

Compound 2c:

The product of Step 3 reacts with 2-hydroxy-6-methylbenzoic acid as described in Example 1. The crude product is raised by preparative TLC analysis and converted to the HCl salt. Melting point 206-210 C (decomposition). Existing HRMS: 514.2067; +MH Calculated: −14.2069

Compound 2D:

The product of Step 3 is reacted with 2-amino-6-methylbenzoic acid using a procedure similar to that described in Example 1. The crude product is purified by preparative TLC analysis and converted to the HCl salt. Melting point 202-209 C (decomposition). Found HRMS: 513.2227; +MH Calculated: 513.2229.

Example 3

<img file="SA2180B1_D0028.tif" />

Step 1: Recondense the steam and stir the mixture of S-alanine methyl ester hydrochloride (14 g), anhydrous Na2CO3 (60 g), dry CH3CN (125 mL), chlorodiphenylmethane (22.3 g) and Nal (5 g) for 6 hours. . Cool, add ice-H2O and extract with Et2O (350 ml, then 50 ml). The extracted Et2O was combined and washed with parts of 1 mAqueous HCl: 200 ml, 100 ml, then 4 x 10 ml. Combine the acid-water extractants, stir, and add an increase of Na2CO3 in small portions until the mixture becomes basic. It is extracted with Et2O, dried with MgSO4 and evaporated to obtain the compound N-diphenylmethyl (23.2 g).

Step 2: The vapor of all the above compounds is recondensed with CICH2COC1 (10 ml) in dichloroethane (60 ml) for 4 hours. Evaporate, and covalently evaporate with toluene (20 mL). The residue is dissolved in CH2CI2 (20 ml), stirred for half an hour with activated carbon (10 g), filtered and evaporated. The residue was stirred with ice in DMSO (200 ml) and gradually added concentrated aqueous ammonia (100 ml), then Nal (10 g). Stir at room temperature for 20 hours. Add iced water (500 ml), collect the solid, wash well with water, then with several small portions of a 1:10 mixture of Et2O-hexane, and dry at 50 C with high vacuum to obtain solid diketopiperazine (15.5 g). A small sample of hexanes-CH2Cl2 is recrystallized: melting point 186-188 C; α]D20] = +272.6.

Step 3: Stir the product of step 2 (4 g) in dimethoxyethane (40 mL) NaBH4 (1.6 g) under N2 and add BF3.OEt2 (3.2 mL) slowly. The steam is re-condensed for 20 hours, cooled and added CH3OH (10 ml) dropwise, then concentrated HCl (15 ml). The steam is re-condensed for two hours and the reaction develops in an excess of 2 M aqueous NaOH and extracted with CH2C12. Dry over K2CO3 and evaporate. It is analyzed chromatographically on silica, by filtration with mixtures of CH3OH-CH2CI2 and finally by 5:1:0.1 v/v/v

NH4OH:CH3OH:CH2CI2 The portions of the product combine and evaporate to obtain the desired product (1.95 g) as a smaller, duller colored gum.

Step 4: Stir a mixture of the product of step 3 (0.5 g), N-allyloxycarbonyl-4-piperidone.

(0.4 g), CH2C12 (5 mL) NaBH(OAc)3 (0.7 g) at room temperature for

20 hour. The reaction develops in CH2C12 and an excess of aqueous NaOH, dried over MgSO4, evaporated and separated the product by preparatory TLC analysis, filtering with 10% Et2O in CH2C12, to obtain the required compound (0.8 g) in the form of oil, contaminated with a small amount of initiating ketone, but suitable for the step. next.

Step 5: Stir a mixture of the product of step 4 (0.8 g), CH3CN (20 ml), water (5 ml), piperidine (1.5 ml). Add tri(4-sulfophenyl)phosphine (0.072 g) and palladium (II) acetate (0.02 g) and stir at room temperature under N2 for 2 hours. The reaction proceeds with aqueous NaOH, extracted with a mixture of 5:1 v/v CH2CI2:toluene, dried over K2CO3 and evaporated to obtain an oil of a smaller, suitable colour.

for acylation.

Compound 3a:

Stir and re-condense the vapor of a mixture of the product of step 5 (0.1 g), N-(2,6-dimethoxy benzoyl)-4-piperidinone (0.1 g), CH2C12 (2 mL), NaBH(0Ac)3 (0.15 g) for 2.5 hours. , cools, and the reaction develops with NaOH and aqueous CH2C12. It is dried on MgSO4, evaporated and the main product is separated by preparative TLC analysis, filtering with 3:1 v/v of CH2CI2:Et2O. The hydrochloride precipitates to obtain the desired compound as HCI salt (0.13 g). Melting point: 173-177 C (decomposition). Found HRMS: 482.3175; +MH Calculated: 482.3171.

Compound 3b:

The product of step 5 is coupled to 2-amino-6-chlorobenzoic acid using DEC-HOBT as described in Example 1, the product is isolated by PTLC analysis and the hydrochloride is precipitated to give compound 3b. Melting point: 188-195 C (decomposition). Existing HRMS: 503.2567; +MH Calculated: 503.2578.

Compound 3c:

The product of step 5 is coupled to 2,4-dimethylnicotinic acid using DEC-HOBT as described above, the product is isolated by PTLC analysis and the hydrochloride is precipitated to give compound 3c. Melting point: 185-188 C (decomposition). HRMS found: 483.3114; +MH Calculated: 483.3124.

Using procedures similar to those described above, prepare the following compounds:

<img file="SA2180B1_D0029.tif" />

<img file="SA2180B1_D0030.tif" />

<img file="SA2180B1_D0031.tif" />

3d: Melting point 170 - 175 C.

3f: Melting point 180 - 185 Celsius.

<img file="SA2180B1_D0032.tif" />

Step 1: Cool in an ice bath a solution of 4-trifluoromethyl acetophenone (1.88 g; 10 mmol) in dry THF (10 ml) and treat with freshly prepared solid S)-2-methyl)oxaborolidine (0.54 g; 2 mmol). Grammy). After 10 minutes, add dropwise over 5 minutes a solution of borane-methyl sulfide complex 2 mol (3 ml; 6 mmol) in THF. TLC after 30 minutes shows that the starting material has converted to a more polar product. Carefully quench the reaction with about 5 mL CH3OH

Until the effervescence stops; Volatile materials are removed by vacuuming. The residue is dissolved in CH2C12 and washed with 1 M HCJ, water, 10% NaHCO3 solution, and saline solution. Concentration by suction produces 2 g of yellow gum. Silica gel chromatography (FSGC) using 10-20% EtOAc in hexanes gives the desired chiral alcohol (1.6 g, 84%) as a colorless oil. RfTLC = 0.6 in 25% hexanes:EtOAc.

Step 2: To a solution of the product of step 1 (1.55 g; 8.16 mmol) in 10 ml CH2C12 cooled in an ice bath add Et3N (2.3 ml; 16.32 mmol) and CH3SO2CI (0.87 ml; 10.6 mmol). ) to form a colored solution

Cloudy white. The reaction is quenched with water and the organic product is extracted in CH2C12, washed with water, 1 m HCl, 10% NaHCO3 solution and brine. Concentration by vacuum gives chiral mesylate (2.1 g; 96%) as a pale yellow oil. Rf TLC = 0.6 in 25%

hexanes:EtOAc

Step 3: Heat and recondense the vapor a solution of the step 2 product (2.1 M; 7.8 mM), 2(s)-methyl piperazine protected by N-BOC (1.56 g; 7.8 mM).

gram molecule; Prepared from the reaction of commercial 2(s)-methyl piperazine with N-(tert-butoxy).

carbonyloxy)phthalimide) and 2,2,6,6-tetramethyl piperidine (1.34 mL; 8 mL

mol) in 14 mL dry CH3CN until TLC analysis indicates complete disappearance of mesylate (16 hours). Cool the reaction mixture to room temperature, dilute with CH2CI2 (50 ml) and wash with water (3 x 100 ml) and brine. The extracted organic matter is dried on solid MgSO4 and then concentrated to obtain 2.8 g of colored gum.

yellow. FSGC (20% EtOAc in hexanes) is used to isolate the desired SS-diastereomer. (1.5 g; 52%) benzylic epimer (RS)-diastereomer) (0.5 g; 17%) for 69% conjugation. RfTLC=0.75 (SS) and 0.56 (RS) in 25% hexanes:EtOAc.

Step 4: Add TFA (6 ml) to a solution of the step 3 product in 12 ml CH2CI2 and stir the resulting yellow-orange solution at room temperature for 8 hours. The reaction is quenched by adding 1 standard NaOH solution to adjust the pH to 10.

The development of the extraction reaction in CH2Cl2 gives 1.1 g of a yellow colored syrup. FSGC using 10% CH3OH in CH2C12 removes the less polar impurity and gradient filtration by 41 Et3N in 10% amine is needed to filter out the desired free CH2CI2:CH3OH from the s,s) diastereomer. Productivity = 0.9 g (75%). Rf TLC = 0.5 in CH2CI2:CH3OH%10

Step 5: Stir a colorless solution of the product of step 4 (0.9 g; 3.3 mmol), 4-piperidinone (0.86 g; 4.3 mmol), NaB(OAc)3H (1.05 g; 4.95 mmol) and ice AcOH (80 μl) in 8 ml CH2C12 at ambient temperature for 1 day. TLC analysis indicates the absence of the starting material. Dilute the reaction mixture with CH2C12 (50 mL), wash with 1 N NaOH, water (twice) and saline. The extracted material, CH2C12, was dried on anhydrous MgSO4 and concentrated to obtain 1.7 g of a smaller color oil. FSGC (425 acetone in hexanes) is used to separate the pure product (1.3 g; 86%) as a white foam. Rf TLC=0.6 at 25% hexanes/acetone.

Step 6: Add TFA (5 mL) to a solution of the product of Step 5 (1.3 g; 2.87 mmol) in CH2C12 (10 mL) and stir the resulting yellow-orange solution at room temperature for 7 hours. The reaction is quenched with 1 N NaOH solution and the pH is adjusted to 10. The organic product is extracted in 50 ml ch2cI2, washed with water, then brine, and dried with 4MgSO4. Concentration gives the free amine (0.98 g; 98%) as a yellow syrup. RfTLC = 0.1 at 25% hexanes/acetone.

Step 7: Dissolve the product of step 6 (0.78 g; 2.21 mmol), dec (0.65 g; 3.4 mmol), HOBT (0.46 g; 3.4 mmol) and 2-amino-6. -chloro benzoic acid (0.51 g; 2.9 mmol) in 8 ml CH2C12 added to diisopropylethyl amine (0.7 ml) and stir the mixture at ambient temperature for 16 hours. TLC prolongation shows the absence of an initiator and the formation of two intermediate polarity intercalators (rotomers with hindered amide as the major product). The crude product (1.3 g) is isolated by the development of the extraction reaction and purified through FSGC using 25% acetone.

in CH2CI2 as a filter to give the title compound (0.88 g; 80%) as a yellow colored foam.

pale. RfTLC = 0.45 and 0.5 in 25% CH2Cl2:acetone.

Add a solution of hydrogen chloride in Et2O (1 mol; 3 ml) and a solution of the free base of the title compound (0.76 g; 1.54 mol) in CH2C12 (5 ml) to immediately obtain a white precipitate. After stirring at room temperature for 2 hours, the volatiles were removed on a rotary evaporator and the white residue was suspended in dry toluene (3 x 10 ml) and boiled in a constant temperature solution. The resulting white solid was suspended in dry Et2O containing 10% EtOAc, stirred for 30 minutes, filtered and washed with Et2O (100 ml). The HC1 salt of the title compound is dried under high vacuum to produce an off-white solid (0.88 g; 95%). Melting point: 205-210 C.

The product of step 6 is converted to other amides (4a-4e) as described in step 7 using appropriate carboxylic acids. The physical data for the compounds (4a-4e) have the following structures:

<img file="SA2180B1_D0033.tif" />

Where R8 and R2 are as specified in the table:

<img file="SA2180B1_D0034.tif" />

<img file="SA2180B1_D0035.tif" />

<img file="SA2180B1_D0036.tif" />

Dissolve a solution of racemic benzyl chloride 24 (1.26 g, 5.62 mmol) which is freshly prepared from the corresponding carbinol, 2(S)-methyl piperazine (1.12 g, 5.62 mmol (TMP) 2,2,6). 6-tetramethyl piperidine (109 ml, 11.2 mmol) in dry DMF (2 ml) and heated to 100 - 110 C (internal temperature) for 10 hours. TLC analysis shows the absence of compound 24 and the formation of two well-separated products. The mixture is diluted with water and the organic materials are extracted in Et2O U. The extracted organic material is washed with saturated NHG and brine and concentrated by vacuum to obtain 2 g of raw product. Flash chromatography on silica gel and filtration first with 25% hexane-Et2O and then 25% hexane-EtOAc give approximately 0.5 g of compound 25a and about 0.5 g of compound 25b, respectively (combined yields of about 45%). Rf TLC = 0.6 (for compound 25a) and 0.4 (for compound 25b) in 25% hexanes-EtOAc. The pure compound 25a as described is pretreated to obtain the final products 5a which have the formula:

<img file="SA2180B1_D0037.tif" />

Where R2 is as specified in the table:

<img file="SA2180B1_D0038.tif" />

<img file="SA2180B1_D0039.tif" />

<img file="SA2180B1_D0040.tif" />

<img file="SA2180B1_D0041.tif" />

Stir for 24 hours at room temperature mixture of aldehyde 26 (3.9 g, 20.5 mmol), 2(S)-methyl-N-BOC-piperazine (4.1 g, 20.5 mmol) Ti(OiPr). (4) (6.1 mL; 20.5 mmol) in 40 mL CH2C12. Et2AlCN is introduced and stirred for another day. Process the reaction mixture as described

Already to obtain 4.71 g (58%) of cyano amine 27 after Rf TLC (FSGC = 0.45/0.5 for diastereomers shown with 25% hexanes-Et2O as solvent).

Step 2: Add sodium hexamethyldisilazide (1 mol; 3.1 mol) to a solution of compound 27 (1 mol; 2.5 mol) in dry THF cooled in a dry ice/acetone bath. The smaller solution cures the resulting bright color with CH3CH2I (7.5 mM; 0.6 mL). Remove the dry ice bath and stir the reaction at ambient temperature for 15 minutes followed by gentle heating in a warm water bath (40°C) for 30 minutes. TLC analysis indicates the presence of two well-separated spots. Development of the standard extraction reaction and purification by FSGC yielded two alkylated compounds (combined yield: 0.7 g; 70%) RfTLC = 0.6 and 0.4 (25% hexanes/EtOAc).

Step 3: The product of step 2 is stirred with NaBH(OAc (twice) and OEt2:MgBr2 (once and equal) in CH3CN for one day. The reaction mixture is quenched with water, the organic materials are extracted in EtOAc and treated to obtain 0.8 g of crude product. FSGC (25% hexanes-EtOAc) gives about 0.4 g of each diastereomer (combined yield Rf TLC = 0.55 (28a) and 0.45 (28b) in 25% hexanes-EtOAc.

Step 4: Compound 28a (SS-diastereomer) is processed by the usual Step 5 sequence to complete the synthesis of compounds Example 6, 6a and 6b that have an ipso-methyl group as well as compounds 6c and 6d that are missing an ipso-methyl group:

<img file="SA2180B1_D0042.tif" />

<img file="SA2180B1_D0043.tif" />

<img file="SA2180B1_D0044.tif" />

Example 7

The synthesis of compounds with an alkyl or arylsulfonyl group R8 at the para position begins with

The corresponding para-substituted acetophenone is processed as in Example 4, steps 1-6 to obtain a sulfone containing compounds from Example 7 that have the formula:

<img file="SA2180B1_D0045.tif" />

Where R2 and R8 are as specified in the table:

<img file="SA2180B1_D0046.tif" />

<img file="SA2180B1_D0047.tif" />

<img file="SA2180B1_D0048.tif" />

Step 1: Stir at ambient temperature for 24 hours a solution of the product of Example 4, Step 4 (1.25 g; 4.6 mmol), N-BOC-4-piperidinone (0.91 g; 4.6 mmol ) Ti(OiPr)4) (1.4 mM; 4.6 dmol) in 10 mM CH2CI2. The reaction mixture was then treated with Et2AICN (5.5 mL; 1 mol in toluene solution) and stirred for 20 hours. The reaction mixture was diluted with EtOAc and stirred with a saturated NaHCO3 solution (10 minutes) and the layers were separated as much as possible. The turbid organic layer (from a non-separable aqueous layer) is treated with excess celite and filtered, and the filter paste is washed with EtOAc. The layers of filtrate were separated, the organic layer was washed with water and brine, dried on anhydrous MgS04, and concentrated to obtain 2.16 g (98%) of a smaller amber color of gum.

Step 2: Strecker amine from step 1 (2.16 g) is dissolved in dry THF, cooled on ice and treated with CH3MgBr (7.5 mL of 3 mol solution in Et2O). After one hour, remove the ice bath and stir the heterogeneous yellow reaction mixture at room temperature for 18 hours. The reaction is quenched with a saturated nh4ci solution, diluted with water

It is extracted with CH2CI2. The concentration yields 2.2 g of yellow colored gum which is purified by FSGC. Filtering the main product away from the more polar impurities using a 1:1 mixture of EtOAC:CH2CI2 isolates the ipso-methyl compound as a smaller colored gum (85.1 g;

88%). RfTLC = 0.5 in 1:1 hexanes:Et2O.

Step 3: Add TFA (6 mL) to a solution of step 2 product (1.5 g; 3.2 mL

mol) in 10 ml CH2CI2 and stirred for two hours at 25 C. The reaction is quenched with 1 N NaOH solution to a pH of 9-10 and treated by extraction in

CH2C12 To obtain 1.2 g of a crude product. FSGC with 1:1 EtOAc:CH2Cl2 increases all less polar impurities and stepwise elution by 10% CH3OH in CH2CI2 and eventually by 10% (~7 mN) CH3OH in CH2C12 results in the isolation of the free piperidine as a yellow-colored gum (1.07 g; 90% ) Rf TLC = 0.2 in 10% 0CH2CI2:CH3OH

Step 4: Stir for 24 hours at 25°C solution of product of step 3 (1.03 g; 2.8

2,4-dimethyl nicotinic acid (0.42 g; 2.8 mmol), DEC (0.8 g; 4.2 mmol), hobt (0.57 g; 4.2 mmol) diisopropyl ethyl amine (1 mL; 5.6 mmol) in CH2CI2 (15 mL). Dilute the reaction mixture with CH2CI2 (25 ml), wash with water, 10% NaHCO3 solution and brine, then concentrate to obtain 1.6 g of crude oil.

FSGC of this material using gradient filtration with 10% CH2CI2/acetone then 2-5% CH2CI2 in CHbOH gives the title compound (1.1 g; 80%) as a white foam. Rf TLC = 0.45 in 5%.CH2CI2-CH3OH

The free base of the title compound (1 g; 2 mmol) isolated above is dissolved in

Mix 1:1 of Et2O:EtOAc (8 ml) and add a fresh solution of hydrogen chloride.

In Et2O (6.1 ml of 1 mol solution), a white precipitate immediately forms. After stirring for one hour at 25°C, the volatiles were removed by vacuum. The product is suspended in Et2O and filtered, the filtrate is washed with Et2O. The HCI salt of the resulting title compound was dried by vacuum (1.1 g, melting point 213-215 C). HRMS

(+MH) 503.2997.

The following amides 8a-8e are prepared in a manner similar to step 3 using suitable acids, and compounds 8f-8h are similarly prepared, where the R8- substituent is the P- group.

methyl sulfonyl.

<img file="SA2180B1_D0049.tif" />

Where R8 and R2 are as specified in the table:

<img file="SA2180B1_D0050.tif" />

<img file="SA2180B1_D0051.tif" />

Using described procedures following the table, prepare 8Q-8H compounds from the building:

<img file="SA2180B1_D0052.tif" />

Where R11 is as specified in the table:

<img file="SA2180B1_D0053.tif" />

<img file="SA2180B1_D0054.tif" />

8s: The tri-hydrochloride salt of Example 8 Step 3 (75 mg, 0.16 mmol), EDC (61 mg, 0.32 mmol), HOBT (49 mg, 0.32 mmol) , iPr2NEt (0.16 mM, 0.96 mM), and 2,6-dimethyl-

4-hydroxy-benzoic acid (53 mg, 0.32 mmol) was raised in CH2CI2 and stirred at 25°C for 20 hours. Concentrate the solution. Purification by preparative TLC analysis (SiO2, EtOAc) gives the title compound as a yellow colored oil. Melting point (2× HCl salt) 210-220 C. MH+ (HRMS) calculated for: C29H39O2N3F3: 518.2994;

Found: 518.2997.

8R: Raise compound 8Q (100 mg, 0.19 mmol), ethyl isocyanate (0.05 mL, 0.58 mmol), Et3N (0.13 mL, 0.95 mmol) in CH2CI2 and stir for 16 hours at 25 percentage. Dilute the solution in CH2CI2 and wash with 1 N NaOH. The organic layer (4Na2SO) was dried, filtered, and concentrated. Purification by preparative TLC analysis (1/2 SiO2, hexanes/EtOAc) yields the title compound as a yellow colored oil: 8H compound (250 mg, 0.48 mmol), methane sulfonyl anhydride (250 mg, 1.44 mmol). and NaH (38 mg, 60% by weight in oil) in THF and stirred for 20 hours at 25°C. The solution was diluted with EtOAc, washed with NaHCO, and saturated. The organic layer (4Na2SO) is dried, filtered and concentrated.

Testing by preparative TLC analysis (1/1 SiO2, hexanes/EtOAc) gives the title compound as a yellow colored oil (280 mg, 98%).

8T: Remove the tri-hydrochloride salt from the product of Example 8, Step 3 (50 mg, 0.1 mmol), EDC (38 mg, 0.2 mmol), HOBT (27 mg, 0.2 mmol), iPr2NEt (0.07 ml). , 0.4 mmol), and -2,6-dimethyl-4-(4-pyridyl-N-oxide)-benoic acid (73 mg, 0.3 mmol)

(See preparation below) in CH2C12 and stirred for 19 hours at 25°C. Concentrate the solution. Purification by preparative TLC analysis (1/2 SiO2, hexanes/acetone) gives compound 8T as a yellow oil (23 mg, 39%). 2,6-dimethyl-4-(4-pyridyl-N-oxide) Benzoic acid preparation

<img file="SA2180B1_D0055.tif" />

Step A: Allow to stir 4-benzyloxy-2,6-dimethyl benzoic acid (8.7 g, 34 ml

gram molecule; ,50 ,1985 Thea, s. et al Journal of the American Chemical Society)

(1867), Mel (3.2 mL, 51 mmol) Cs2CO3 and (17 g, 51 mmol) in DMF at 25 C for 17 h. The solution is filtered and divided between Et2O and water. The aqueous layer is extracted with 0Et2O. The combined Et2O layers are washed with water and salt solution. The organic layer (MgSO4) was dried, filtered and concentrated. Purification by flash chromatography (10/1 Et2O/hexanes; SiO2) yielded 8.6 g (94%) of the methyl ester as a colorless oil.

Step B: The protected phenol was raised with benzyl (8.5 g, 32 mmol) Pd/C (750 mg, 10 weight % Pd) in CH3OH. The solution is filled under a pressure of 3515 g/cm2 (50 psi) of H2 and shaken in a Parr apparatus at 25°C for 17 hours. Filter the solution (Celite). The concentration yields 5.6 g (98%) of phenol as a white solid.

Step C: Dissolve phenol (3.5 g, 19.4 mmol) iPr2NEt (3.76 g, 29.1 mmol) in CH2C12 at 0 C. Add triflic anhydride (4.2 mL, 25.2 mmol) to the solution at 0°C. The solution is warmed to 25°C and stirred at this temperature for four hours

And a half. Dilute the solution with CH2CI2 and wash with saturated NaHCO3. The aqueous layer is extracted with CH2CI2. The combined organic layers were dried over Na2SO4. Filtration and concentration yield crude aryl triflate. Purification by flash chromatography (10/1, EtO/hexanes, SiO2) yielded 5.7 g (93%) of triflate as a yellow oil.

Step D: Raise triflate (1 g, 3.2 mmol), 4-pyridyl boronic acid (1.2 g, 9.6 mmol), 4(Pd(PPh3) (370 mg, 0.32 mmol). ) Na2C03 (1 g, 9.6 mmol) in HO/DME (1/4, 25 ml). Heat to 90 C (oil bath) under N2 for 18 hours. Divide the solution between EtOAc and water With EtOAc, the combined layers of EtOAc (Na2SO4) are dried, filtration and concentration give a dark brown oil. Purification by flash chromatography (1/3 SiO2, EtOAc/hexanes) yields 770 mg (100%) of the pyridyl derivative as colored oil.

orange .

Step E: Dissolve the pyridyl derivative (390 mg, 1.6 mmol) mCPBA (550 mg, 3.2 mmol) in CH2C12. Stir the solution at 25 C for 18 hours. Dilute the length with CH2C12 and wash with 1 N NaOH. The organic layer (Na2SO4) is dried. Filtration and concentration yield 400 mg (97%) of N-oxide as an orange colored oil. MH+ (HRMS) calculated for C15H16O3N: 258.1130; Found: 258.1131.

Step F: Raise the methyl ester (400 mg, 1.6 mmol) in 5 mL of 3 M NaOH and 2 M EtOH. The solution is heated and the vapor is re-condensed for 20 hours. Concentrate the solution. The residue is treated with concentrated acid HCl. The resulting solid is filtered and washed with water and brine. After high vacuum drying, the free acid (377 mg, 100%) was obtained as a yellowish-tan colored solid. Melting point &gt; 225°C (decomposition). MH+ (HRMS) calculated for C14H14O3N: 244.0974; Found: 244.0981.

8Z: The tri-hydrochloride salt of the product of Example 8, step 3 (1.34 g, 2.8 mmol), 2,6-dimethyl-4-formyl benzoic acid (500 mg, 2.8 mmol).

(see preparation below), EDC (1.1 g, 5.6 mmol), HOBT (760 mg, 5.6 mmol), iPtNEt (2 ml, 11 mmol)

For standard coupling conditions. Determination by flash chromatography (1/2 SiO2, EtOAc/hexanes) yields 898 mg (61%) of compound 8D as a yellow foam.

Preparation of 2,6-dimethyl-4-formyl benzoic acid

<img file="SA2180B1_D0056.tif" />

Step A: Raise tert-butyl ester, 4-hydroxy-2,6-dimethyl-benzoic acid (6.4 g, 29 mmol) iPr2NEt (5.6 g, 43 mmol) in CH2C12 and cool to 0 C. Slowly add Tf2O (5.8 mL, 34 mmol) to the solution at 0 C. Stir the solution for 3 hours at 0°C. The solution is divided between NaHCO3 and saturated CH2CI2, and the aqueous layer is extracted with CH2C12. The combined organic layers (Na2SO4) are dried. Filtration and concentration give a brown oil. Determination by flash chromatography (1/20 SiO2, Et2O/hexanes) yields 7.99 g (82%) of triflate as a yellow solid.

Step B: Lift triflate (5 g, 15 mmol), LiCI (1.25 g, 30 mmol), Pd(PPh3 (340 mg, 0.3 mmol)) and vinyl tributyl tin (4.5 mmol, 16 (mmol) in THF under N2. The solution is heated at 70 C for 16 hours. The solution is divided between KF and saturated EtOAc. The organic layer is separated, and the aqueous layers are extracted with MgSO4. The combined organic layers are dried Yellow colored oil. Purification by flash chromatography (1/20 SiO2, Et2O/hexanes) yields 1.96 g (57%) of olefin as a yellow oil.

Step C: Raise olefin (0.6 g, 2.6 mmol) in MeOH/CH2Cl2 (1/1). The solution is cooled to -78 C. Ozone bubbles are pumped through the solution until the color is stabilized

Dark Blue. The reaction is quenched with dimethyl sulfide. The reaction to give the aldehyde concentrates

Oil picture.

Step D: Raise tert-butyl ester (650 mg, 8.2 mmol) TFA (3 mL) in CH2C12 and stir for 19 hours at 25 C. The concentration of the solution gives the acid as a beige solid.

8z: Raise the compound 8z (100 mg, 0.19 mmol), HCl-H2NOMe (28 mg, 0.34 mmol), NaOAc (32 mg, 0.46 mmol) in MeOH. The solution was stirred for 17 hours at 25°C. Concentrate the solution. The residue NaOH and CH2C12 are divided into 1 m. The aqueous layer is extracted with CH2C12. The combined organic layers (Na2SO4) are dried. Filtration and concentration yield the raw product. Purification by preparative TLC (1/1 EtOAc/hexanes; SiO2) yielded 85 mg (84%) of 8z.

8 g: The tri-hydrochloride salt of the product of Example 8, Step 3 (75 mg, 0.16 mmol) and 4-difluoromethyl-2,6-dimethyl-benzoic acid (32 mg, 0.16 mmol) is subjected to conditions Standard pairing (iPr2NEt/OBT/EDC). Purification by preparative TLC analysis (1/2 Sio2, EtOAc/hexanes) yielded 64 mg (73%) of the 8g compound.

Prepare 4-difluoromethyl-2,6-dimethyl benzoic acid

<img file="SA2180B1_D0057.tif" />

Step A: Lift aldehyde (400 mg, 1.7 mmol), bis(2-methoxyethyl]amino]-sulfur trifluoride (640 mg, 2.9 mmol), EtOH (0.02 ml, 0.34 mmol) in 1.2 -dichloroethane and stirred for 6 hours at 65°C and for 19 hours at 25°C. The solution is quenched with NaHCO and saturated. The combined organic layers are dried (NaSO2). Purification by TLC is preparative. 1 Et2O/hexanes, SiO2) gives 210 mg (50%) of the difluoro derivative.

Step B: Raise tert-butyl ester (210 mg, 0.82 mmol) HCl and (2.1 ml of 4 mol dioxane, 8.2 mmol) in MeOH. The solution was stirred for 20 hours at 45°C. The solution is concentrated to obtain the acid as a solid

In white colour.

8 D: The tri-hydrochloride salt of the product of Example 8, step 3 (811 mg, 1.7 mmol), 4-[(ethylamino)carbonylamino]-2,6-dimethyl benzoic acid (400 mg, 1.7 mmol) ( See preparation below) for standard coupling conditions (iPr2NEt/HOBT/EDC) Purification by flash chromatography (1/1 SiO2) yields 803 mg (81%) of 8Th as foam.

Preparation of 4-(ethylamino)carbonylamino]-2,6-dimethyl benzoic acid

<img file="SA2180B1_D0058.tif" />

Step A:

Raise 3,5-dimethyl aniline (8.5 ml, 149 mmol) in CH2C12. Cool the solution in a water bath. Slowly add trifluoroacetic anhydride (29.5 ml, 2.9 mmol) to the solution. After addition, the solution was stirred for 15 minutes at 25°C. Bromine (7.3 mL, 142 mmol) is added slowly to the solution while the water bath remains at room temperature. The solution was stirred for three and a half hours at 25°C. The solution is quenched with 10% Na2S2O3. The aqueous layer extracts CH2C12. The combined organic layers (MgSO4) were dried, treated with activated carbon and filtered. Concentration gives an orange solid. Purification by recrystallization (Et2O/hexanes) yielded two amounts (total of 34 g, 77%) of the brominated derivative as a white solid.

Step B:

The aryl bromide (17 g, 57 mmol) is raised in THF and cooled to-

78 C below N2. Add slowly to the solution at -78°C LiBr/methyllithium (54 mL of 1.5 mol in Et2O, 80 mmol). Stirring for 5 minutes, slowly add sec-BuLi (62 mL of a 1.3-mmol solution in cyclohexane, 80 mM) to the reaction mixture at 78 C. After 5 minutes, di-t-butyl dicarbonate (22.5 g, 1.3 mM) in THF is added to the solution at -78 C. The solution is warmed to 25°C. After 30 minutes, divide the mixture between CH2CI2 and water. The aqueous layer is extracted with CH2C12. The combined organic layers (MgSO4) are dried. Filtration and concentration give a yellow solid. Purification by flash chromatography (1/1 to 1/4 SiO2, CH2Cl2/hexanes) gives 13.1 g (72%) of tert-butyl ester as a yellowish-white solid. Raise trifluoro-acetamide (10 g, 31 mmol) NaOH (2.5 g, 62 mmol) in H2o/MeOH (1/3) and heat for 3 hours at 60°C. Divide the solution between CH2C12 and water. The aqueous layer is extracted with CH2C12. The combined organic layers are washed with water and dried (Na2SO4). Filtration and concentration yielded 6.4 g (93%) of aniline as an orange solid. Aniline (1 g, 4.5 mmol), ethyl isocyanate (0.4 ml, 5 mmol), CuCl (90 mg, 0.9 mmol) in DMF at 0°C. The solution was warmed to 25°C and stirred for 2 hours at this temperature. The solution is divided between NH4OH and EtOAc 10%. The aqueous layer is extracted with EtOAc. Wash the layers

Combined with brine and dried (MgSO4). Filtration and concentration yield a yellow solid. Purification by flash chromatography (1/3 to 1/1 SiO2, EtOAc/hexanes) yielded 9.4 mg (69%) of urea as a yellow solid. Step D:

tert-butyl ester (900 mg, 3.1 mmol) and 4 mol HCl were raised in dioxane (3 ml) in iPrOH and heated at 45°C for three and a half hours and at 25°C for 16.5 hours. The solution is concentrated under low pressure. We divide the residue between NaOH and 1 mEt2O. The aqueous, basic layer is extracted with 0Et2O. The aqueous layer is cooled to 0 C and acidified with concentrated HCl (pH = 1-2). The aqueous layer was extracted with EtOAc. The combined EtOAc (Na2SO4) layers are dried. Filtration and concentration yielded 400 mg (55%) of the acid as a white solid.

8aa:

The tri-hydrochloride salt of the product of Example 8, Step 3 (2 g, 4.3 mmol) and the benzoic acid 4-amino-2,6-dimethyl (710 mg, 4.3 mmol) undergo

(See preparation below) for standard coupling conditions (iPr2NEtTIOBT/EDC). Purification by flash chromatography (1/2 SiO2, acetone/hexanes) yielded 1.16 g (52%) of 8a as a yellow foam.

Preparation of 4-amino-2,6-dimethyl Benzoic Acid

<img file="SA2180B1_D0059.tif" />

The tert-butyl ester (950 mg, 4.3 mmol) HCl and (11 ml, 4 mol dioxane) are raised in MeOH and heated for 20 hours at 45°C. The solution is concentrated to obtain the acid (710 mg) in a quantitative result.

8bb:

By raising the compound 8aa (100 mg, 0.19 mmol) ethane sulfonyl chloride (0.2 ml, 0.21 mmol) in pyridine and stirring at 25 C for 19 hours. Concentrate the solution. The residue is divided between 1 NaOH and 1 part CH2C12. The aqueous layer is extracted with CH2C12. The combined organic layers (Na2SO4) are dried. Filtration and concentration give a brown oil. Preparative TLC analysis (1/2 SiO2, acetone/hexanes) yields 100 mg (86%) of 8BB as a colorless oil.

8C:

Combine the trihydrochloride salt of the product of Example 8, Step 3 (127 mg, 0.27 mM) 4-fluoro-2,6-dimethyl benzoic acid (58 mg, 0.35 mM)

Grami) (see Preparation below) according to the general procedure (iPr2NEt/HOBT/EDC). The purification

Preparatory TLC analysis (1/2 SiO2, EtOAc/hexanes) yields 8g as a colorless oil (87 mg of bis-HCl salt, 54%). Preparation of 4-fluoro-2,6-dimethyl benzoic acid

<img file="SA2180B1_D0060.tif" />

Heat 4-amino-2,6-dimethyl benzoic acid (200 mg, 1.1 mmol) N0BF4 (196 mg, 1.7 mmol) in 1,2-dichlorobenzene at 100°C for 30 minutes. The solution was cooled and diluted with MeOH and water. A few globules (2-3) of KOH are added, and the solution is heated with steam re-condensing for 16 hours. Concentrate the solution. The residue is divided between NaOH and Et2O 1 m. The aqueous layer was extracted with Et2O. The aqueous layer is cooled to 0°C and acidified with concentrated HCl (pH = 1-2). The aqueous layer is extracted with CH2C12. The organic layers (Na2SO4) are dried. Filtration and concentration yielded 58 mg (31%) of the acid as a yellowish-brown solid.

8DD:

The trihydrochloride salt of the product of Example 8, Step 3 (150 mg, 0.31 mmol) is combined with 4-chloro-2,6-dimethyl benzoic acid (76 mg, 0.41 mmol) (see Preparation below) according to the general procedure ( iPr2NEt/BT/EDC). Purification by preparative TLC analysis (1/4 SiO2, acetone/hexanes) yields 8D as a colorless oil.

Preparation of 4-chloro-2,6-dimethvl Benzoic Acid

<img file="SA2180B1_D0061.tif" />

4-amino-2,6-dimethyl benzoic acid (172 mg, 0.96 mmol) raises CuC12 (155 mg, 1.15 mmol) into CH2CN at 0°C. Added

To the solution at 0 C tert-butyl nitrite (0.17 ml, 1.4 mmol). The solution is warmed to 25°C and then at 65°C for 45 minutes. Divide the solution between Et2O and water. The aqueous layer was extracted with Et2O. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration give the methyl ester. The methyl ester is hydrolyzed as described above to produce the KOH (fluoro) derivative. After the extraction reaction progresses, we obtain 4-chloro-2,6-dimethyl benzoic acid (158 mg, 489) as a colored solid

yellow.

8 laugh:

Combine the trihydrochloride salt of the product of Example 8, Step 3 (180 mg, 0.38 mmol) and 4-chloro-2,6-dimethyl benzoic acid (95 mg, 0.41 mmol) (see Preparation below) according to the procedure General (iPr2NEt/HOBT/EDC) purification

Preparatory TLC analysis (1/4 SiO2, acetone/hexanes) gives compound 8H as a colorless oil (140 mg of bis-HCl salt, 56%). Preparation of 4-bromo-2,6-dimethvl Benzoic Acid

<img file="SA2180B1_D0062.tif" />

Step A: Heated triflate(500 mg, 1.48 mmol), mmol, 1.48 mmol), LiCl (377 mg, 8.9 mmol), Pd(PPh3)4(171 mg, 0.15 mmol). mol) in THF (70 C) under N2 for 21 h. The solution is divided between Et2O and a pH stabilizer (NH4OAc) whose pH = 7. The aqueous layer was extracted with Et2O. The combined Et2O layers were washed with brine and dried (Na2SO4). Filtration and concentration yield crude aryl stannane as a yellow-coloured semi-solid. Step B:

aryl stannane (0.74 mmol) rises in CH2C12 at 0 C. Bromine (7.0 mL of Br2 1 mol in CH2C12) is added to the solution. Stir the solution for 30 minutes at 0°C. Dilute the solution with CH2C12 and wash with Na2S2O3

10%. The aqueous layer is extracted with CH2CI2. The combined organic layers (Na2SO4) are dried. Filter the solution. TFA (2 mL) was added to the solution, and the solution was stirred for 17 hours at 25 C. Concentrate the solution. The residue is divided between NaOH and 1 mEt20. The aqueous layer was extracted with Et20. The aqueous layer is cooled to 0°C and acidified with concentrated HCl (pH = 1-2). The aqueous layer is extracted with CH2CI2. The combined organic layers (Na2SO4) are dried. Filtration and concentration yield 100 mg (59%) of the acid as a white solid.

Using the procedures described following the table, prepare compounds 8F-8HH having the structure:

<img file="SA2180B1_D0063.tif" />

Where R11 is as specified in the table:

<img file="SA2180B1_D0064.tif" />

8W:

Combine the trihydrochloride salt of the product of Example 8, Step 3 (100 mg, 0.21 mmol) with 4-mehoxy-benzoic acid and 2,6-dichloro (140 mg, 0.63 mmol) according to the general procedure (iPr2NEt/HOBT/EDC) Testing with TLC analysis is preparatory

(1/3 SiO2, EtOAc/hexanes) gives compound 8W as a colorless oil (27 mg, 23%).

8zz:

Combine the trihydrochloride salt of the product of Example 8, Step 3 (330 mg, 0.7 mmol) and 2,6-dichloro-4-hydroxy-benzoic acid (290 mg, 1.4 mmol) (see Preparation below) according to the general procedure (iPr2NEt /HOBT/EDC). It is piety

Preparatory TLC analysis (1/1 SiO2, EtOAc/hexanes) gives compound 8zz as a colorless oil (75 mg, 19%).

Preparation of 2,6-dichloro-4-hydroxy-benzoic acid

<img file="SA2180B1_D0065.tif" />

Raises 4-methoxy-benzoic acid-2,6-dichloro (500 mg, 2.3 mmol)

In CH2CI2 and cools to -78°C. The compound BBr3 (6.9 milliliters of a 1 mol solution of CH2CI2) is added to the solution at -78 C. The solution is warmed to 25°C and stirred at this temperature for 16 hours. The solution is quenched with 3 M NaOH. The aqueous layer is extracted with CH2CO2. The layer is cooled Aqueous (0 C) and acidified with concentrated HCl (pH = 1-2). The aqueous layer is extracted with CH2C12. Filtration and concentration yield crude phenol, which is used without further purification.

8H: Combine the trihydrochloride salt of the product of Example 8, Step 3 (96 mg, 0.2 mmol), 2,6-dichloro-4-(4-pyridyl-N-oxide)-benzoic acid (55 mg 0.2 mol mol) (see Preparation below) according to the general procedure (iPr2NEt/HOBT/EDC). Purification by preparative TLC analysis (1/5 acetone/hexanes, SiO2) yields a compound of 8 h as a colorless oil (54 mg, 43%).

Preparation of 2,6-dichloro-4-(4-pyridyl-N-oxide)Benzoic acid

<img file="SA2180B1_D0066.tif" />

Apply 2,4,6-trichloro benzoic acid, tert-butyl ester (500 mg, 1.8 mmol), 4-pyridyl boronic acid (270 mg, 2.16 mmol), Pd(PCy3)2Cl2 (130 mg, 0 18 mmol CsF (540 mg, 3.6 mmol) in NMP and heated at 100 C under N2 (16 hours). Divide the solution

Between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine and dried (Na2SO4). Filtration and concentration yield the raw product. Preparative TLC analysis (1/1 SiO2, EtOAc/hexanes) yielded 68 mg (12%) of pyridyl ester. The tert-butyl ester converts to acid as before for the dimethyl derivative (b.TFA/a.mCPBA).

Using suitable starting materials and the procedures described for Examples 8Q to 8HH, prepare compounds having the following structure:

<img file="SA2180B1_D0067.tif" />

Where R11 is as specified in the table:

<img file="SA2180B1_D0068.tif" />

<img file="SA2180B1_D0069.tif" />

<img file="SA2180B1_D0070.tif" />

All melting points are based on bis hydrochloride salts (2 × HCI), except for compound 8AA, which is made on the free base.

Using the triflate intermediate derivatives described in compound 8s by procedures similar to those described above and following the table for compounds 8s-8f, prepare compounds of the following structure:

<img file="SA2180B1_D0071.tif" />

Where R11 is as specified in the table:

<img file="SA2180B1_D0072.tif" />

8exp:

<img file="SA2180B1_D0073.tif" />

Step 1: Heat at 80 C for 17 hours the triflate substrate (see compound 8D) (1.4 g), (0.2 g) Zn(CN)2, (0.3 g) Pd(PPh3)4 DMF, and (1.5 ml).

Cool reaction 10 to room temperature, dilute with saturated aqueous NaHCO3 and EtOAc. The EtOAc layer is removed, washed with water, dried with brine and evaporated to give crude oil which is purified by preparatory plate chromatography (silica plates 2000 micromolecular; 8:1 EtOAc:hexanes as filtrate), to give; After isolating the appropriate package, the intermediate material was cyano (0.2 g) with a yield of 77%.

Step 2: Dissolve the product of step 1 (0.2 g) in MeOH (1.5 mL) and add HCl (4 mol solution in 1,4-dioxane; 2 mL). The resulting solution was stirred for 3 hours at 50°C and evaporated. This crude intermediate (0.038 g) and the product of Example 8, Step 3 (65 mg; trihydrochloride form) were treated in the same manner as in Example 8, Step 4, using DMF (2 mL), HOBT. (45 mg), DEC (60 mg) and diisopropylethyl amine (0.1 ml) to give, after isolation and purification, the free base form of compound 8S, which is converted to its HCl salt (45 mg) in 95% yield.

<img file="SA2180B1_D0074.tif" />

Step 1: Dissolve 2,6-dimethyl-4-formyl benzoic acid (1.96 g) (see compound 8D) in t-butanol (94 ml) and 2-methyl-2-butene (24 ml). Add dropwise to the first solution a solution of NaCIO2 (6.89 g), NaH2PO4, monohydrate (8.17 g) and water (45 ml). After the addition is complete; Adjust the pH to 3 and two layers are produced. The organic layer is removed and heated to give intermediate acid (1.8 g) as a white crystalline solid, which is used without purification.

Step 2: To a solution of the product of step 1 (0.62 g), CH2CI2 (5 ml) and DMF (1 drop), add oxalyl chloride (0.31 ml) and stir the resulting solution for 10 minutes, at which time add another portion of oxalyl chloride ( 0.3 ml). Stir the reaction for 10 minutes, add toluene and evaporate the mixture until dry. Add CH2C12(10

ml) and EtNH2 (1 ml) and stir the reaction for two days, then divide it between CH2CI2 and brine. The CH2C12 layer is evaporated and HCl is added (4 ml of a 4 mol solution in 1,4-dioxane). The resulting solution was stirred for 3 hours and evaporated to give a solid, which was washed with Et2O and collected to give the amide (0.13 g) with a yield of 24%. Step 3: The product of Example 8, Step 3 (60 mg; trihydrochloride form) and the product of Step 2 (35 mg) are treated in the same manner as in Example 8, Step 4, to give, after reaction progression and purification, compound 8a in the free base form, which is converted To HCl salt (50 mg) with a yield of 62%.

<img file="SA2180B1_D0075.tif" />

Step 1: To a solution of the intermediate amine (2 g) (see Compound 8S) add NaH (0.4 g in 0.6% oil dispersion). The resulting suspension was stirred for 15 minutes and Me2SO4 was added. After heating for an hour and a half with vapor recondensation, the reaction was cooled to room temperature, poured into a saturated aqueous NH4CI solution and extracted with Et2O. After evaporation, the crude reaction mixture was analyzed chromatographically on a silica gel, filtering with EtOAc:hexanes 4:1, to give, After evaporating the appropriate parts, the intermediate material is methylamine (0.8 g) with a yield of 38%.

Step 2: Heat for 17 hours while re-condensing the vapor. Step 1 product (0.12 g), THF (5 ml), EtNCO (54 mg). Add EtNCO (54 mg), 1,4-dioxane (2 ml) and heat the resulting solution in a sealed tube at 65°C for 17 hours. The solution is cooled, evaporated and purified by chromatographic analysis. A preparatory dish (silica gel; 25% CH2Cl2:EtOAc) is added to give the product. What is required is (0.1 g) as a crystalline solid with a yield of 64%.

Step 3: The product of Step 2 (0.1 g) is treated in the same manner as Example 8, Step 3 to give the required intermediate material (0.08 g) which is used directly in the next step.

Step 4: The product of Example 8, Step 3 (75 mg; trihydrochloride form) and the product of Step 3 (0.04 g) are treated in the same manner as Example 8, Step 4, to give a post-evolution reaction.

Purification, compound 8F is in the free base form, which is transformed into a salt (65 mg) with a yield of 62%.

Using procedures described above and using commercially available acids, compounds 8ag-8br are prepared having the structure:

<img file="SA2180B1_D0076.tif" />

Where R10 and R11 are as specified in the table:

<img file="SA2180B1_D0077.tif" />

<img file="SA2180B1_D0078.tif" />

Using procedures similar to those described above; Bring the following vehicles:

<img file="SA2180B1_D0079.tif" />

Where R2, R6, R3, R8 are the determination in the table:

<img file="SA2180B1_D0080.tif" />

<img file="SA2180B1_D0081.tif" />

Step 1: Heat for 5 hours with and re-condense the vapor a solution of 4-N-BOC-2(S methyl piperazine (1.5 g; 7.5 mmol), 4-methoxy-benzyl chloride (1.1 ml; 8. 1 mmol) diisopropyl ethyl amine (1.5 ml) in

CH3CN dry. The reaction mixture is cooled to room temperature and the volatile substances are removed by vacuum. The residue is dissolved in CH2C12 (30 ml) and washed with water and saline solution. The focus

It gives the crude product, which is purified by FSGC (10% hexanes-EtOAc) to yield 2.1 g (88%) of the product as a pale yellow liquid. Add TFA (6 mL) to a solution of the above compound (2.1 g; 6.56 mmol) in 12 mL CH2C12 and stir the mixture at 25 C for 1.5 hours. The reaction is quenched with 1 mN NaOH and adjusted to a pH of 10. The progression of the extractive reaction in CH2C12 gives the desired product (1.4 g; 97%) as colorless gum.

Step 2: Stir for 24 hours at 25°C Mixture of step 1 product (1.4 g; 6.36 mmol), N-BOC-4-piperidinone (1.27 g; 6.4 mmol) Ti(0iPr) (4) (9.1 milliliters; 6.4 mol tons). A 1 mol solution of Et2AlCN in toluene (7.6 mL) is added to the reaction mixture and the mixture is stirred at ambient temperature for another day. Develops interaction. Strecker amine thus obtained is isolated (2.7 g; 100%) as described in Example 8, Step 2. Rf TLC = 0.3 in 25% 0CH2CI2-EtOAc

Strecker amine (2.7 g; 6.3 mmol) is dissolved in 15 ml dry THF at 0 C and CH3MgBr (3 mol, Et2o; 10.5 mmol) is added. After 1 hour, the ice bath was removed and the reaction was warmed to room temperature for 15 hours. TLC analysis of the heterogeneous reaction mixture shows no change from the starting material; The mixture is heated at 60°C for 5 hours and no change is observed in the TLC analysis course. The mixture quenches

The reaction with NH4CI is saturated and the organic products are extracted into CH2CI2. FSGC of the raw product (2.7 g) using 15% hexanes-acetone as filter material provides ipso-methyl compound

Required as colorless glue (2.3 g; 87%).

Step 3: Mix the product of step 2 (1.7 g; 4.08 mmol), ammonium formate (1.4 g; 22 mmol) and 10% palladium over carbon (0.4 g) in 20 mL CH3OH and heat for 5 minutes. Hours with steam re-condensing. The reaction mixture is filtered through celite and the volatile materials are removed. The residue is dissolved in CH2CI2 and washed with a 10% NaOH solution, water and saline solution. Vacuum concentration yields 1.1g (92%) of pale yellow gum.

Step 4: Gently warm (60-70°C) for 16 hours a solution of the product of step 3 (0.12 g; 0.4 mmol), p-trifluoromethyl benzyl bromide (0.1 g; 0.4 mmol) diisopropylethyl amine (0.1 mL) in dry CHCN. The mixture is cooled and the organic product is isolated by developing the extraction reaction in CH2CI2. FSGC (10-30% CH2CI2-Et2O Rf = 0.4) produces the main product as a colorless film (0.12g; 68%).

Treatment of the above product (in CH2CI2) with TFA (1 mL) for 1 hour and then switching to a basic and standard reaction phase provided the desired compound (0.09 g; 96%) as a colorless film.

Step 5: Combine the product of step 4 (0.045 g; 0.13 mmol) and 6-chloroanthranilic acid (0.022 g; 0.13 mmol) as described in Example 1 and after the reaction has developed and CH3OH 5% FSGC in CH2CI2) isolate the title compound. As a colorless film (0.058 g; 90%).

The HCl salt of the title compound is prepared in the usual way by reacting the free base with HCl 1 mol-Et2O and treating the precipitate to obtain a beige solid.

(0.066 g).

Using a similar procedure, the product of Step 3 is converted to other compounds, first by alkylation of the piperazine nitrogen with a suitable halide, then removing protection and coupling the piperidinyl moiety with the appropriate acid to form amides with the general structure:

<img file="SA2180B1_D0082.tif" />

Where R and R2 are as specified in the table:

<img file="SA2180B1_D0083.tif" />

<img file="SA2180B1_D0084.tif" />

Using a similar procedure described below, also prepare compounds where R is 4-ethoxynaphthyl: Step 1.3: See Example 9.

Step 4a: Treat 4-hydroxynaphthaldehyde (0.86 g) K2CO3 (1.38 g, 2 equiv) in CH3CN (35 mL) with CH3CH2I (0.8 mL, 2 equiv) and stir the resulting mixture for 20 hours at room temperature. The reaction mixture was concentrated by vacuum, the residue was treated with EtOAc, and the mixture was filtered. The filtrate is divided with dry EtOAc concentrated water

(MgSO4) by vacuuming to give an orange-brown residue (0.89 g). This residue was placed in thin layer dishes (10, 1000 µm) and filtered with CH2CI2 to give the title compound (0.82 g).

Step 4: Under argon, stir the products of Step 3 (0.27 g; 0.95 mmol) and Step 4a (0.571 g; 2.9 mmol) in CH2C12 (25 mM) for 30 minutes at room temperature. Add Na(OAc)3BH (0.506 g; 3.4 mM). After 19 hours, the reaction mixture was quenched with dilute NaOH. Wash off the aqueous layer with

CH2CI2 (3 times). The combined CH2CI2 solution was washed with water (3 times) and then with salt solution. Concentrate the dry CH2C12 (MgSO4) solution to about 50 mL. Add 15 Amberlyst (4.5 meq/g: 2.4g, 11.025 mmeq). After 19 hours, add additional Amberlyst (3.2 g). After 7 hours, wash the resin with CH2CI2 (5 times), THF (5 times), H2O:THF (5 times), H2O (5 times), CH3OH (5 times), CH2C12 (5 times). Filter the resin with 2 mol NH3 in CH3OH (300 ml) (3 times), followed by vacuum concentration to produce a smaller amber colored oil (0.215 g). The raw material is placed on thin-layer preparatory plates (4, 1000 microns) and filtered with NH3:CH2CI2 2 mol in CH3OH (9:1) to give a smaller amber color oil (0.125 g, 36%).

Step 5: Using boxer carboxylic acid in Procedure Example 9, Step 5, prepare the following compounds:

<img file="SA2180B1_D0085.tif" />

LCMS found M+H = 531; *HPLC retention time is 5.52 minutes.

<img file="SA2180B1_D0086.tif" />

LCMS existence M+H = 516; *HPLC retention time is 5.66 minutes. HPLC*: VYDAC 218TP5405 column; Gradient level 5-95% B over 10 minutes on and off for 2 minutes; Solution A is 0.1% TFA/H2O; Solution B is 0.1% TFA/CH3CN at 245 nm.

Using a similar procedure in which the initiator piperazine does not have a methyl substituent, the following compound is prepared:

<img file="SA2180B1_D0087.tif" />

<img file="SA2180B1_D0088.tif" />

Step 1: Heat for 14 hours with quenching vapor re-condensing a solution of (4-N-BOC 2(s methyl piperazine (0.4 g; 2 mmol), p-iodobenzaldehyde (0.46 g; 2 mmol) NaBH). (OAc)3W (0.65 g; 3 mmol) in 6 ml CH2C12. Cool the contents, dilute with CH2C12 (30 ml) and wash with 1 m NaOH, water and D-oil solution (0.8 g FSGC). (25% hexane-EtOAc) gives the desired product (0.66 M; 79%) as a colorless film Rf

TLC = 0.6 in 25% hexane-EtOAc.

The BOC protecting group is removed from the product (0.66 g; 1.58 mmol) by treatment with TFA (1 mL) in CH2CI2 (2 mL). After the standard reaction progresses, mono-alkylated piperazine (0.5 g; 100%) is obtained as a colorless gum.

Step 2: Add NaBH(OAc (0.63 g; 3 mmol) and 2 drops of AcOH to a solution of the product of Step 1 (0.5 g; 1.58 mmol) N-BOC-and piperidinone (0.6 g; 3 mmol). ) in 5 ml CH2CI2 and stir the solution

Output at ambient temperature for 16 hours. After the development of the usual FSGC reaction, we obtain the desired product (0.6 g; 76%) as a colorless oil. Rf TLC = 0.4 in 25% CH2CI2-acetone

Free piperidine (0.38 M; 79%) was prepared from the protected compound N-BOC (0.6 g;

1.2 mM) by treatment with TFA (2 mL) in CH2CI2 (5 mL

Compound 10a: 6-chloroanthranilic acid (0.065 g; 0.38 mmol) is coupled to the product of step 2 (0.127 g; 0.32 mmol) in the presence of DEC (0.092 g; 0.48 mmol), HOBT (0.065 g; 0.48 mmol

Gram) diisopropylethyl amine (0.1 ml), and then isolate the product, as previously described. This procedure produces compound 10a (0.13 g; 73%) as a colorless film. Rf TLC = .45/ 0.5 for a pair of rotomers in 2% CH2CI2-CH3OH.

The HCl salt of the title compound is prepared in the usual way. Melting point 198-202 C;

MH+ (HRMS) = 0553.1231

Compound 10b: Coupling the product of step 2 with 6-methyl anthranilic acid gives compound 10b (HCl salt) with a yield of 73%. Melting point 197-200 C; MH+ (HRMS) = 533.1774.

Compound 10g: 2,6-dimethyl benzoic acid is coupled to the product of step 2 to obtain amide 10g (HCI salt) in 50% yield. Melting point 2.2-2.5 C; HRMS (+MH)=532.1826.

<img file="SA2180B1_D0089.tif" />

Step 1: Drop s)-methylbenzylamine (27 mL, 0.2 mol) in CH2CI2 (50 mL) into ice-cold trifluoroacetic anhydride (40 mL) in CH2CI2 (200 mL) during 15 minutes. Stir the mixture for 1 hour at room temperature, then cool in an ice water bath. Add iodine (27 g, 0.106 mol) and then bis(trifluoroacetoxy)iodo]-benzene (25 g, 0.058 mol). After stirring in the dark overnight at room temperature, add more

bis(trifluoroacetoxy)iodo)-benzene] (24 g, 0.056 mol) and stir the mixture.

For another day at room temperature. Dilute the mixture with CH2CI2 (500 ml) and Na2SO3, chilled with ice (10% aqueous, 500 ml) and stir for half an hour. The organic layer was separated, washed with NaHCO3, filtered through a short silica gel column, and washed with CH2CI2.

(500 milliliters). After evaporating CH2CI2, add Et2O (125 ml) and stir the mixture for 10 minutes.

minutes. Gradually add hexanes (600 mL) to the Et2O solution and stir the mixture for half an hour. The precipitate was collected and washed with hexanes. The white solid is dried at room temperature and we obtain iodo (36.5 g, 53% yield, Rf = 0.7, hexanes/EtOAc, 3:1).

Step 2: Dissolve the product of step 1 (11.2 g, 0.033 mol) in CH3OH (200 ml) and add NaOH (15 g, 0.375 mol) in water (100 ml) dropwise. Stir the mixture for two and a half hours at room temperature. After CH3OH was fine, the aqueous layer was extracted with Et2O (3×100 mL) and the combined organic fraction was washed with brine, dried over Na2SO4, filtered and concentrated to give free amine. Methy-R-lactate (4.08 g, 0.039 mol) is dissolved in CH2CI2 (40

ml) and the mixture is stirred and cooled in CO2-acetone to -78°C under a N2 atmosphere. Add trifluoromethane sulfonic anhydride (10.2 g, 0.036 mmol) then 2,6-lutidine (6.27 g, 0.059 mol) and stir the mixture. For 5 minutes at -78°C. Warm the mixture to room temperature and stir for 30 minutes. Add more CH2CI2 to the mixture and wash the solution with HCl2. Add the freshly prepared amine from above to the triflate solution followed by K2CO3 (18 g, 0.132 mol) in water (20 ml). Stir the mixture at room temperature overnight. The development of the extractive reaction with CH2CI2 followed by silica gel column chromatography gave the secondary amine (8.27 g, 75% yield, Rf = 0.65, EtOAc/hexanes, 1:3) as a yellow colored syrup.

Step 3: Step 2 amine (7.3 1 g, 0.052 mol) is dissolved in dichloroethane (100 mL) CICHCOCI (117.2 g, 82 mL, 1.04 mol). Stir the mixture and allow the steam to re-condense for 3 hours. The solvent CICH2COCI is removed by vacuuming, the remaining yellow syrup is dissolved in DMSO (40 ml) at 0°C, and Nal (5.2 g, 0.035 mol) and NE4OH (56 ml, 1.04 mol) are added. Stir the mixture for 30 minutes at 0°C, warm to room temperature and stir overnight. Add water (100 milliliters) to the mixture and filter

The sedimented material is washed with water. The resulting white solid was dried in air to give diketopiperazine (14.3 g, yield 477, Rf = 0.56 EtOAc/hexanes, 1:3).

Step 4: Step 3 diketopiperazine (14.3 g, 0.04 mol) is dissolved in dimethoxyethane (200 ml) and NaBH4 (15.1 g, 0.4 mol) and BF3.OEt2 (34 g, 29.5 ml) are added to the solution. 0.24 mol). The mixture is stirred for 3 hours with the condition of re-condensing the steam, then cooled to about 0°C in an ice bath. Slowly add CH3OH (500 ml) and then concentrated HCI (300 ml) to the mixture. The solution was stirred for 1 minute at room temperature and then for 45 minutes with a 20 recondensation condition. The mixture is concentrated and NaOH is added until the pH becomes &gt; 10. Progress of the extraction reaction with EtOAc gives the desired piperazine as a yellow colored syrup (12.9 g, 98% yield).

Step 5: The product of step 4 (1.9 g, 5.79 mmol), 4-N-BOC piperidone (5.73 g, 28.8 mmol), NaBH(OAc)3 (6. 1 g; 28.8

Add 2 mol AcOH and 2 mol (5.76 mol, 11.52 mol) in CH2CI2 (150 ml) and stir the mixture overnight. After removing the solvent, NaOH (3 M) was added and the extraction reaction was crystallized with EtOAc followed by silica gel chromatography to give pure piperazino-piperidine (2.21 g, 75% yield, Rf = 0.18, EtOAc/hexanes, 1:1) as a syrup.

Step 6: Dissolve the product of step 5 (1.9 g, 3.7 mmol) in CH2CI2 (10 mL) and add TFA (10 mL). Stir the mixture for two hours at room temperature. After removing the TFA solvent, under reduced pressure, a NaOH solution (3 m) is added to the remaining syrup and the extraction reaction with EtOAc proceeds giving free piperazino-piperidine (3.1 g, 85% yield) as a yellow colored syrup. To a solution of free -piperazino piperidine (200 mg, 0.484 mmol) in CH2CI2 (2 ml) add 2,6-dimethylbenzoic acid (150 mg, 0.99 mmol), DEC.

(191 mg, 0.99 mmol) HOBT (135 mg, 0.99 mmol

Grammy). The mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. A NaOH solution (3 m) was added to the remaining syrup and the extraction reaction with EtOAc proceeded followed by column chromatography giving the title compound (210 mg, 80% yield, Rf = 0.37, CH3oH/CH2C12, 20:1). HRMS as HCl salt (calculated for MH+ (C27H37N3OI)) 546.1981, found: −46.1965 points

Melting 190 C (decomposition).

Using a similar procedure, prepare compounds of the formula:

<img file="SA2180B1_D0090.tif" />

Where R10 and R9 are as specified in the table:

<img file="SA2180B1_D0091.tif" />

<img file="SA2180B1_D0092.tif" />

Step 1: To a solution of the product of Example 11, Step 4 (1.4 g, 4.2 mmol) 1-tert-butoxycarbonyl-4-piperidone (0.93 g, 4.67 mmol) in CH2CI2 is added 4(Ti(OiPr) (1.19 g, 4.2 mmol) and stir the mixture at room temperature overnight. Add 1 mol Et2AlCN (5.04 ml, 5.04 mmol), stir the mixture overnight at room temperature and evaporate the solvent. Saturated NaHCO3 is added to the residue and the extraction reaction with EtOAc produces Strecker amine as a yellow colored syrup. The syrup is dissolved in THF (40 ml) and 3 mol (7 ml, 21 mmol) CH3MgBr is added to the solution. The mixture was stirred overnight at room temperature, then cooled to 0 C and added saturated NH4CI and water. The development of the extraction reaction with EtOAc is followed by silica gel chromatography

They give the piperazino-piperidine product (1.78 g, yield 81% Rf = 0.52, EtOAc/hexanes, 1:2).

Step 2: Process the product of Step 1 in the manner described in Example 11, Step 6, to obtain the title compound. Melting point 190 C (decomposition); HRMS (HCI hint): Found 560.2145.

Using a similar procedure, prepare compounds of the formula:

<img file="SA2180B1_D0093.tif" />

Where R2 is as specified in the table:

<img file="SA2180B1_D0094.tif" />

Example 13

<img file="SA2180B1_D0095.tif" />

Step 1: To a solution of the product protected with N-BOC from Example 11, Step 4 (250 mg, 0.581 mmol) in DMF (2.5 mL), add CuCl (1 g, 10.1 mmol). The suspension was stirred under N2 for 24 hours at 110 C. When the mixture is cooled to room temperature, NH4OH is added and the solution gradually turns a bright blue color. The development of the extractive reaction with EtOAc gives a mixture of -chloro substituted piperazine and a BOC derivative thereof. After treating the mixture with TFA (5 mL) in CH2CI2 (2 mL) for 2 hours, the solvent was evaporated and NaOH (3 M) was added. The development of the extraction reaction with EtOAc gives pure piperazine (110 mg) 79%) as a yellow colored syrup.

Step 2: Process the product of Step 1 in a similar way to Example 11, Steps 5 and 6, to obtain the title compound. Melting point 180°C (decomposition); HRMS (as HCI salt); Existing 454.2617.

Using a similar procedure, prepare compounds of the formula:

<img file="SA2180B1_D0096.tif" />

Where R10 and R9 are as specified in the table:

<img file="SA2180B1_D0097.tif" />

Using the product of Step 1 in Procedure Example 21, prepare the compounds of the formula:

<img file="SA2180B1_D0098.tif" />

Where R2 is as specified in the table:

<img file="SA2180B1_D0099.tif" />

<img file="SA2180B1_D0100.tif" />

Step 1: To a solution of the product protected with N-BOC from Example 11, step (5 g, 0.12 mol) in DMF (20 mL), add CuCN (20.8 g, 0.23 mol). The suspension was stirred under N2 for 22 hours at 110°C. After cooling the mixture to room temperature, NH4OH is added and the solution gradually turns a bright blue color. The development of the extractive reaction with EtOAc followed by silica gel column chromatography yielded a cyano derivative (2.29 g, 60% yield, Rf = 0.5, EtOAc/hexanes, 1:4), a carboxamide derivative (0.95 g, yield 23.6). %, Rf= 0.2, CH3OH/CH2CI2, 10:1) and the unsubstituted derivative (85 mg, 2.4%, Rf 0.75, EtOAc/hexanes, 1:2).

Step 2: The BOC group on the cyano compound from step 1 is first removed under acidic conditions and the resulting amine is converted to the title compound following the procedure of Example 11, steps 5 and 6. HRMS (as HCl salt): present ≥445.497

<img file="SA2180B1_D0101.tif" />

Step 1: To a solution of the product protected with N-BOC from Example 11, Step 4 (1.4 g, 3.26 mmol) CuCl and (1.61 g, 16.3 mmol) in CH3OH at 0°C add NaBH4 (3.69 g, 97.6 dmol) slowly. A black precipitate is formed. The mixture is warmed to room temperature and stirred overnight. The precipitate is removed by filtration and the CH3OH is removed by vacuum. Progression of the extraction reaction with EtOAc gives the desired compound (1 g, 100% yield, Rf = 0.55, EGAc/hexanes, 5:1) as a syrup.

Step 2: The BOC group on the product of step 1 is transformed under acidic conditions, and the resulting amine is transformed into the title compound by following the procedure of Example 11, steps 5 and 6, point

fusion 195 C; HRMS (as HCl salt): Found 420.3016. Using a similar procedure, prepare the following compound:

<img file="SA2180B1_D0102.tif" />

HRMS (as HCI salt): found −1.4426

<img file="SA2180B1_D0103.tif" />

Step 1: To a solution of the product protected with N-BOC from Example 11, Step 4 (2.5 g, 5.8 mmol) in benzene add phenyl boric acid (1.068 g, 13.8 mmol), Na2CO3 2 Mg(14 ml) and tettakis(tri-phenyl

phosphine)palladium (0.67 g, 0.58 mmol). Stir the mixture again

Steam condensation throughout the night. The development of the extractive reaction with EtOAc followed by silica gel epoch chromatography yielded a phenyl derivative (1037 g, yield 62% Rf

= 0.5, EtOAc/hexane' 1:5) as syrup.

Step 2: The BOC group on the product of Step 1 is removed under acidic conditions and the resulting amine is converted to the title compound following the procedure of Example 11, steps 5 and 6. Melting point 190°C; HRMS (as HCl salt): Present: 9 496.331. Using a similar procedure, prepare compounds of the formula:

<img file="SA2180B1_D0104.tif" />

Where R2 is as specified in the table:

<img file="SA2180B1_D0105.tif" />

*Free base

<img file="SA2180B1_D0106.tif" />

Step 1: The product protected with N-BOC from Example 11, Step 4 (800 mg, 1.88 mmol) is dissolved in dry THF and brought to a temperature of -78°C. N2 Add butyl lithium (2.5 mol, 0.832 ml solution, 2 mmol) and stir the mixture for 10 minutes at -78°C. The solution is then dropped into P-chlorobenzyl aldehyde (234 mg, 2.07 mmol) in THF at -78 C. The mixture was stirred for 30 minutes at -78°C, then gradually warmed to room temperature. Saturated NH4CI is added to the mixture and the extraction reaction with EtOAc followed by silica gel column chromatography gives the desired alcohol (30 mg, 3.6% yield, Rf = 0.5, EtOAc/hexanes, 2:1) as a yellow colored syrup.

Step 2: Stir for 2 hours with conditions to recondense the vapor Step 1 solution of alcohol (40 mg, 0.09 mmol), triethylsilane (52 mg, 0.45 mmol), TFA (5 ml) in CH2C12 (5 ml). After removing CH2CI2, triethylsilane TFA and under reduced pressure, a NaOH solution (3 M) is added to the remaining syrup. The development of the extraction reaction with EtOAc gives the chlorobenzyl derivative (20 mg, 68% yield) as a yellow colored syrup.

Step 3: The product of Step 2 is converted to the title compound by following the procedure of Example 11, Steps 5 and 6. Melting point 170 C (decomposition); HRMS (as HCl salt): Present: 544.3101.

<img file="SA2180B1_D0107.tif" />

Step 1: To a solution of the 4-piperidinyl derivative protected with N-BOC of the cyano compound of Example 14, Step 1 (510 mg, 1.24 mmol) in Et2O (4 ml) add CH3MgBr 3 mol (4 ml) dropwise. Stir the mixture and re-condense the steam overnight. After cooling the solution on an ice bath, add 12 m HCl (4 ml) and stir the mixture on a steam bath for two hours. Cool the solution to room temperature and blot the solid NaOH pellets until the pH becomes &lt;10. Progression of the extraction reaction with CH3OH/EtOAc (3:1) yields the desired methyl ketone (249 mg,

61% productivity as syrup.

Step 2: The product of Step 1 is processed according to the standard DEC peptide coupling procedure in Example 11, Step 6, to obtain the title compound. Melting point: 210 C; HRMS (as HCl salt): Found: 483.2522. Using a similar procedure, prepare the following compound:

<img file="SA2180B1_D0108.tif" />

Melting point 210 C (decomposition); HRMS (as HCl salt): presence 463.3088.

<img file="SA2180B1_D0109.tif" />

Step 1: To a solution of product Example 22 (140 mg, 0.29 mmol) in CH30H (10 ml) EtOH (1 ml) add NH2OCH3HCI (738 mg, 8.84 mmol) NaOAc (725 mg, 8. 84 mmol). The suspension was stirred at 40°C overnight, the solvents were evaporated and water was added to the residue. The development of the extraction reaction with EtOAc followed by silcia gel chromatography generated the title compound (99 mg, 68% yield, Rf = 0.38, CH30H/CH2C12, 1:20). HRMS (as tartrate salt) calculated for M+H)+ C31H45N4O2) 505.3543; Existing 505.3542.

Using a similar procedure, prepare compounds of the formula:

<img file="SA2180B1_D0110.tif" />

Where R2, R6, R8 are as specified in the table:

<img file="SA2180B1_D0111.tif" />

<img file="SA2180B1_D0112.tif" />

Dissolve the free piperazino-piperidine from Example 11; Step 6 (1.7 g, 3.3 mmol) in CHCl3 (30 mL = stock solution A). Add 250 μL of stock solution A (0.027 mmol) to a slurry of 0.15 g (about 0.14 mmol) of carbodiimide bound to resin (prepared by reacting Argopore-Cl resin with l-(3-dimethylaminopropyl)-3- Ethylcarbodiimide in DMF at 100°C in DMF (1.5 mL) in a polyethylene SPE cartridge. Add to this mixture 75 μl of a 1 mol solution of 5-methyl-3-phenylisoxazole-4-carboxylic.

acid in DMF (0.075 mmol), HOBT (24 μl of a 1 mol solution in DMF). Shake this mixture for 14 hours, filter and add 0.1 g of Amberlyst-15 resin (0.47 mmol) to the filtrate. Shake the resin for 1 to 2 hours, filter and wash twice with each of the following solvents, THF, CH2CI2 and CH3OH, then wash with THF and CH2CI2. Treat the resin with NH3 2 mol in CH3OH (once for 30 minutes and once for 5 minutes). The filtrate is combined and concentrated under low pressure to produce the title compound. LCMS present +MH = 59901 (calculated molecular weight 598); Rf TLC = 0.74 (NH4OH/CH3OH/CH2Cl2 (95/5/0.5)).

<img file="SA2180B1_D0113.tif" />

Using the above procedure with suitable carboxylic acids the following compounds are given:

Where R2 is as specified in the table:

<img file="SA2180B1_D0114.tif" />

<img file="SA2180B1_D0115.tif" />

<img file="SA2180B1_D0116.tif" />

Step 1: First, the BOC group on the cyano compound in Example 14, Step 1, is removed under acidic conditions and the resulting amine (1.59 g, 6.96 mmol) is transformed, -1

tert-butoxycarbonyl-4-piperidone(1.66 g, 8.35 mmol) Ti(oiPr)4

(2.18 g, 7.66 mmol) in CH2CI2 at room temperature overnight. Add Et2AICN 1 mol (8.35 ml 8.35 mmol),

The mixture was stirred overnight at room temperature and the solvent evaporated. Saturated NaHCO3 is added to the residue and the extraction reaction with EtOAc followed by column chromatography yields Strecker amine as a syrup with a smaller color (76.1 g, 58% yield; Rf = 0.7, EtOAc/hexanes, 1:2).

Step 2: Step 1 amine (200 mg, 0.46 mmol) is dissolved in anhydrous THF (2 ml) and dropwise add 3 mol CH3MgBr (0.76 ml, 2.29 mmol). The mixture was stirred at room temperature overnight and then cooled to 0°C. Saturated NH4CI (10 mL) is added and a precipitate appears. Add water (40 milliliters) and the precipitate disappears. The extraction reaction phase with EtOAc followed by column chromatography gave the desired ipso-methyl derivative (169 mg, 86% yield, Rf = 0.53, EtOAc/hexanes, 2:1).

Step 3: Process the product of Step 2 in the manner described in Example 11, Step 6; Let's get the address component. Melting point 198°C (decomposition); HRMS (as HCl salt): Found 460.3079.

Using a similar procedure, prepare compounds of the formula:

<img file="SA2180B1_D0117.tif" />

Where R2 is as specified in the table:

<img file="SA2180B1_D0118.tif" />

Step 1: Treat the Strecker amine from Example 21, Step 1 (380 mg, 0.87 mmol) with CH3MgBr (2.9 ml, 8.7 mmol) in Et2O (5 ml) with vapor recondensation conditions throughout the night. Cool the mixture on ice and add water (5 ml) dropwise. Add 12m HCl (6 ml) and stir the mixture for two hours on a steam bath. After cooling the mixture on ice, NaOH is added until the pH of the solution becomes &gt;10. Progression of the extraction reaction with EtOAc yields the free amine as a syrup (3.7 mg, 100% yield).

<img file="SA2180B1_D0119.tif" />

Step 2: The product of Step 1 is converted to the title compound following the peptide conjugation procedure described in Example 11, Step 6. Melting point 80-85 C; Found HRMS: 476.3271.

Using a similar procedure, prepare compounds of the formula:

<img file="SA2180B1_D0120.tif" />

Where R2 is as specified in the table:

<img file="SA2180B1_D0121.tif" />

<img file="SA2180B1_D0122.tif" />

<img file="SA2180B1_D0123.tif" />

Step 1: Mix together ethyl diacetoacetate (93.4 g), CS2CO3 (185 g), CH3CN (550 mL), using a stirrer. Add CH3CN (50 ml) and cool the resulting mixture to 0 C. Add methyl trifluoromethane sulfonate (88.6 g) dropwise and after addition, remove the cooling bath. The mixture was stirred for 1 hour at room temperature, filtered, and the salts were washed with Et2O (2 × 50 mL). The organic extractives were combined and Et2o (300 ml) was added. The resulting mixture was filtered, the filter cake was washed with Et2O (2 x 100 ml), the Et2O extractants were combined and evaporated to half their volume. Cool the solution in an ice bath and wash once with cold (0 C) NaOH (pH = 11). The Et2O layer is dried on MgSO4, filtered and evaporated to give the desired product as a smaller color liquid (64.7 g) with a yield of 65%, which is used directly in the next step.

Step 2: Mix together at room temperature the product of step 1 (64.2 g), sodium ethoxide in ethanol (commercial solution; 21% by weight; 113 g), ethanol (587 ml), formamidine acetate (36.2 g). After heating and re-condensing the steam for 4 hours, the mixture is cooled to room temperature, the resulting precipitate is removed by filtration, and the ethanol is removed by vacuum. The resulting liquid is divided between CH2CI2 and water and the aqueous layer is extracted with CH2C12 (150 x 3 ml). The CH2C12 extracts were diluted over MgSO4, filtered and rocked to give a dark crude liquid (50.7 g) which was purified by silica gel chromatography (980 mg; 1:4 EtOAc:hexanes as filtrate). After mixing the appropriate fractions, the desired product (28.5 g) is isolated with a yield of 46% and used directly in the next step.

Step 3: Mix together the product of step 2 (28.1 g), NaOH (6.72 g), water (65 ml), EtOH (130 ml) at room temperature and heat with re-condensing steam for one hour. The resulting solution is cooled to room temperature and the volatiles are removed by vacuum until a thick paste is obtained. Add water (20 ml), cool the mixture to 0°C and add dropwise

Concentrated HCl (14.3 ml) while stirring. The resulting white precipitate was collected by filtration, washed with ice water (2 x 10 ml) and air dried with suction for 30 minutes. The resulting white solid is treated with toluene (2 x 20 ml), the solvent is removed by vacuum at 50°C and then vacuum dried (1 mmHg pressure) for 18 hours. The desired product (14.9 g) is isolated as a white solid with a yield of 463, melting point: 176-178 C. Calculated elemental analysis for C7H8N2O2: C, 55.26%; H, 5.3%; N, 18.41%. Present: C, 55.13%; H, 5.44%; N, 18.18%.

A second amount of the product is isolated by evaporating the aqueous filter material (from above) until dry and adding water (20 milliliters). The resulting mixture was stirred for 5 minutes at room temperature, cooled in an ice bath, and the resulting precipitate was collected by filtration. The resulting solid is washed with ice water (5 x 2 milliliters) and dried according to the above description to give the product (4.68 g) as a yellow, buttery solid to give a combined yield of 83%.

Step 4: Mix together the product of Example 4, Step 6 (trihydrochloride form; 5.4 g), DMF (11.3 ml), HOBt (3.07 g), diisopropyl ethyl amine (12.3 ml) and the product of Step 3 (3.45 g) and add DEC (4.35 g) in portions within 15 minutes. The resulting mixture was heated for 18 hours at 45°C, cooled to room temperature, diluted with EtOAc (80 mL) and washed with 2 N NaOH (25 mL). The aqueous layer was extracted with EtOAc (25 x 3 ml), the organic extractives were combined, washed with saline, dried with Na2SO4, filtered and evaporated. The resulting crude oil was purified by silica gel chromatography (170 g; 19:76:5Et3N:EtOAc:hexanes as filter material). After steaming the parts

Accordingly, the free base form of the title compound (5.21 g) is isolated as a light-coloured foam with a yield of 91%.

Step 5: To a cold (0 C) solution of the free base of step 4 (2 g) and EtOAc (2 ml) add HCl (3 ml of a 4 mol solution in 1,4-dioxane). The resulting mixture was warmed to room temperature, diluted with Et2O (20 ml), filtered, washed with Et2O (2 x 20 ml), air dried with suction for 10 minutes and then vacuumed (1 mm pressure).

mercury) at 90°C for 5 hours to give the title compound (2.3 g) as a white solid with a yield of 97%. Melting point: 159-162 C0

Calculated elemental analysis of C27H36N5OF3.2HCI.0.5H2O: 55.38%; H,

6.71%; N, 11.96%; Cl, 12.11%. Present: C, 55.19%; H, 6.69%; N, 11.75%; Cl, 11.45%.

Additional pyrimidine derivative compounds are prepared using similar procedures:

<img file="SA2180B1_D0124.tif" />

Step 1: Process the product of Example 23, Step 1 in the same manner as in Example 23, Step 2, by substituting acetamidine hydrochloride (2.03 g) for formamidine acetate. The amounts of the reagents are: product of Example 23, Step 1 (4 g), ethanol (20 mL), sodium ethoxide, and in ethanol (commercial solution; 21% by weight; 8.03 g). After extraction and purification as described above, the product (1.7 g) is isolated as a colorless liquid with a yield of 41%, which is used directly in the next step.

Step 2: Treat the product of Step 1 (1.7 g) in the same manner as Example 23, Step 3, using ethanol (5 mL), water (5 mL), NaOH (1 g). After extraction and purification as described above, the product (12.* g) is isolated as a white solid with a yield of 48, which is used directly in the next step.

Step 3: The product of Example 4, Step 6 (0.05 g) and the product of Step 2 (as above) (0.28 g) are subjected to the same reaction conditions as in Example 23, Step 4, using HOBt (20 mg), DEC (45 mg), diisopropylethylamine (40 mg) and DMF (1.5 ml). After extraction and purification as described above, the product is converted into HC1 salt using...

The procedure specified in Example 23, Step 5, is to give the title compound (77 mg) as a white solid with a yield of 497 in the two steps. The melting point is 185-190 C.

<img file="SA2180B1_D0125.tif" />

Step 1: The product of Example 23, Step 1 is treated in the same procedure as Example 23, Step 2, by substituting benzamidine hydrochloride (3.35 g) for formamidine acetate. The amounts of the reagents are: product of Example 23, Step 1 (4 g), ethanol (20 mL) and sodium ethoxide in ethanol (commercial solution; 421 by weight; 8.03 g). After extraction and purification as described above, the product (4.5 g) is isolated as a liquid with a yield of 82% which is used in the immediate next step.

Step 2: Treat the product of Step 1 (4.5 g) in the same manner as Example 23, Step 3, using ethanol (10 mL), water (10 mL), NaOH (2 g). After extraction and purification as described above, the product (3 g) is isolated as a white solid with a yield of 477, which is used directly in the next step.

Step 3: The product of Example 4, Step 6 (75 mg), and the product of Step 2 (as above) (39 mg) are subjected to the same reaction conditions as in Example 23, Step 4, using HOBt (35 mg), DEC (53 mg), diisopropylethylamine (100 mg) and DMF (2 ml). After extraction and purification as described above, the product is converted to its HC1 salt using the procedure specified in Example 23, Step 5 to give the title compound (98 mg) as a white solid with a yield of 79% in both steps. Melting point 250-253 C

<img file="SA2180B1_D0126.tif" />

Step 1: Dissolve the product of Example 23, Step 2 (528 mg) in CH2CI2 (5 mL) and add meta-chloroperbenzoic acid (mCPBA) (600 mg) in 3 parts at room temperature. The resulting mixture was stirred for 24 hours at room temperature and CH2CI2 (2 ml) mCPBA (200 mg) was added. After 3 hours, the mixture was poured onto a silica gel column (40 g) and filtered with 1:1 EtOAc:hexanes and then 1:10 CH30H:CH2C12. After evaporating the appropriate fractions, the product (512 mg) separates as a white, waxy solid with a yield of 89%, which is used directly in the next step.

Step 2: Dissolve the product of step 1 in CH3OH (1.8 mL) and add a 1 mol solution of Na2CO3 (1.5 mL). After stirring for 36 hours at room temperature, the resulting mixture was evaporated until dry, toluene (2 milliliters) was added and the mixture was evaporated until dry. The resulting raw solid (153 mg) is used directly in the next step without purification.

Step 3: The product of Example 4, Step 6 (94 mg) and the product of Step 2 (as above) (76 mg) are subjected to the same reaction conditions as in Example 23, Step 4, using HOBt (92 mg), DEC (130 mg) , diisopropylethylamine (0.14 ml), DMF (0.25 ml). After extraction and purification by preparative thin layer chromatography (1000 μmol silica plate; 95:5 Et3N:EtOAc as eluting material), the free base form of the title compound (52 mg) is isolated as a foam in 40% yield. Calculated HRMS: +MH for C27H37N5O2F3: 520.2899; Size: 0520.2908

Step 4: The Step 3 product (52 mg) is subjected to the reaction conditions as in Example 23, Step 5, using EtOAc (1 mL) HCI and 4 mol D-1,4 solution

dioxane; 75 microliters) to give, after the reaction progresses, the title compound (44.5 mg) as a white solid with a yield of 76%. Melting point: Decomposition above 161 Celsius. Using similar procedures, also prepare compounds of the formula:

<img file="SA2180B1_D0127.tif" />

Where R8a and R11 are as specified in the table:

<img file="SA2180B1_D0128.tif" />

Example 24

Method A:

<img file="SA2180B1_D0129.tif" />

Step 1: To stannane (0.39 g, 0.95 mmol) in DMF (10 ml) add 2-chloro-4-fluoroiodobenzene (0.73 g, 2.86 mmol), Cul (0.19 g, 1.05 tetrakis(triphenylphosphine)palladium(O) and (0.11 g, 0.95 mmol). Stir the reaction for 21 hours at room temperature. The reaction mixture was added to Et2O and the heterogeneous solution was filtered through a celite filler, and washed with EtOAc. The filtered material is washed with water and saline solution and dried (MgSO4). Filtration and vacuum evaporation of the solvent yielded a residue which was previously adsorbed on the silica gel. Purification with hexane/EtOAc 4% silica gel chromatography yields arylacrylate (0.19 g, 78%), which is used directly in the next step.

Step 2: To trimethylsulfoxonium iodide (0.18 g, 0.81 mmol) in DMSO (1.6 ml) add potassium tert-butoxide (0.09 g, 0.81 mmol). The reaction mixture was stirred for 1 hour at room temperature, at which time arylacrylate (0.19 g, 0.74 mM) in DMSO (1.6 mL) was added. Stir the reaction mixture for 5 hours at room temperature and add water. The mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried (MgSO4). Filtering and vacuuming the solvent yielded arylcyclopropyl ester which was used directly by raising it in CH2CI2 (3 mL) and adding TFA (0.5 mL). The reaction mixture was stirred for 15 hours at room temperature and then concentrated by vacuum to give arylcyclopropylcarboxylic acid (0.14 g, 91% - two steps). Without further purification, carboxylic acid is coupled to the product of Example 8, Step 3, using the procedure of Example 8, Step 4, to obtain compound 24a as the HCl salt. M+H (HRMS): Found: 566.2561.

Method B:

<img file="SA2180B1_D0130.tif" />

To2-fluorophenylacetonitrile(0.8 g, 5.92 mmol),

Benzyltriethylammonium chloride (0.03 g, 0.12 mmol) 1-bromo- and 2-chloroethane (1.7 g, 11.9 mmol) Add 50% aqueous NaOH (3.5 ml). Stir the reaction for 21 hours at 45°C and add ethylene glycol (3 ml). The reaction is then warmed to 100°C and stirred for 7 hours. Upon cooling to room temperature, dilute the reaction with water and wash with EtOAc. Acidification of the aqueous layer to a pH of 2-3 with 6 mAqueous HCl. The acidic solution is extracted with Et2O. The combined Et2O extracts are washed with water and brine and dried (MgSO4). Filtering and vacuuming the solvent yielded a pale yellow solid (1.06 g, 99%). Combine arylcyclopropyl acid with the product of Example 8, Step 3, using the procedure of Example 8, Step 4 to obtain compound 24b as a salt (M+H (HRMS .HCl): 532.2949).

Using similar procedures, compounds of the formula are prepared:

<img file="SA2180B1_D0131.tif" />

As specified in the table:

<img file="SA2180B1_D0132.tif" />

Wherever it is

<img file="SA2180B1_D0133.tif" />

<img file="SA2180B1_D0134.tif" />

<img file="SA2180B1_D0135.tif" />

Mix together cyclopropyl carboxaldehyde (3.4 ml), S-methyl N-BOC piperazine (8.28 ml), CH2CI2 (82 ml) and Ti(0iPr)4 (15.8 ml) and stir at room temperature for 23 hours, then cool. Bring the resulting solution to 0 C and add Et2AlCN (1 mol in toluene; 62.1 mL). Stir the solution for 5 hours at room temperature, add a mixture of KF (20 g) and Celite (10 g), then carefully add EtOAc (120 ml) and water (120 ml). The resulting slurry was stirred for 15 minutes, filtered, washed with EtOAc (35 x 3 ml) and removed the EtOAc layer, washed with brine, dried over Na2SO4, filtered and evaporated to give the required medium (12 g) which was used directly in the next step.

<img file="SA2180B1_D0136.tif" />

To a low-C solution of 4-iodobenzotrifluoride (40 g) THF (52 ml) add isopropyl magnesium chloride (2 mol in Et20; 74 ml). The resulting solution was stirred for one hour at room temperature and then added to a 0°C solution of the step 1 product (10 g) THF and (26 ml) within 10 minutes. The reaction solution was warmed to room temperature, stirred overnight and EtOAc (50 ml) was added. After stirring for 10 minutes, add 2 m NaOH (50 ml) and stir the resulting mixture for 30 minutes, filter and wash the salts with EtOAc (20 x 3 ml). The combined EtOAc extracts were washed with brine, dried over Na2S04, filtered and evaporated to give the crude product (28 g) as a gold-coloured oil which was purified by silica gel chromatography (1 kg), filtering with EtOAc:hexanes (8:1). The two diastereomeric products are combined as one fraction (15.9 g) and further purified by column chromatography as described above to give intermediate A (Rf = 0.47 in 4:1 EtOAc:hexanes; 5.34 g), which is contaminated with an unidentified impurity. (The second diastereomer B (Rf = 0.29 also collects in 4:1 EtOAc:hexanes)).

<img file="SA2180B1_D0137.tif" />

To a solution of compound A in step 2 (3.96 g) CH2C12 and (120 ml) resin replace DOWEX 50 The resin is treated with 7 mm NH in CH3OH (30 milliliters), the resin is removed by filtration, and this procedure is repeated twice. The CH3OH extracted substances are combined and the resulting oil is treated with CH2Cl2:toluene (1:1; 15 milliliters) and evaporated to give the intermediate piperazine (0). 8 g) as pure oil. : Calculated HRMS: +Ci6H21N2F3 :MH: 299.1735; Size:

٢٩٩.١٧٤٨.

<img file="SA2180B1_D0138.tif" />

Process the product of Step 3 (57.0 g) in the same manner as Example 8, Step 1, using -N BOC 4-piperidone (0.42 g), CH2CI2 (3.84 ml), 4(Ti(OiPr) (3.39 ml), Et2AlCN (2.88 ml), CH3MgBr (3 mol in Et2O; 3.2 ml) to give the desired product. (0.78 g) as pure oil with a yield of 82% Step 5: Treat the product of step 4 (0.12 g) with CH2CI2:AcOH (1:3v:v;1.4

ml) then BF3Et2O (0.14 ml). After stirring for one hour, dilute the resulting solution with CH2CI2 (10 mL), cool to 0 C and adjust the pH to 10 with

NaOH is solid. Water (2 ml) is added and the CH2CI2 layer is removed. After additional (2 x 10 ml) with CH2C12, the organic layer is washed with water, brine, dried over Na2S04, filtered and evaporated to give free piperidine (80 mg) with a yield of 81%.

Step 6: Process the product of Step 5 (57 mg) in the same manner as in Example 8, Step 4, using DMF (0.3 ml), HOBt (41 mg), DEC (57 mg),

diisopropylethylamine (0.08 ml) 4,6-dimethyl 5-pyrimidine carboxylic acid and

(43 mg); Stir the reaction for 5 hours at 45°C. The crude oil is purified by preparatory plate chromatography (silica absorbent; 2000 μmol; 5:19:76 Et3N:hexanes:EtOAc as filter) to give, after filtering, the desired package (1:1

(MeOH:CH2CI2) and solvent concentration, the title compound (70 mg) as pure oil with a yield of 93%.

Prepare HCl salt as described in Example 8, Step 4 (78 mg) in 100% yield. a point

Melting: 147-149 C

Using a similar procedure, prepare the following compound:

<img file="SA2180B1_D0139.tif" />

Melting point &gt;188 (decomposition).

<img file="SA2180B1_D0140.tif" />

<img file="SA2180B1_D0141.tif" />

The desired compound is prepared in a manner similar to Example 25, step 1, using p-trifluoromethyl benzaldehyde (20 g) instead of cyclopropyl carboxaldehyde, to give, after reaction progression, a mixture of diastereomers (22.7 g) with a yield of 59%.

<img file="SA2180B1_D0142.tif" />

To a -70°C solution of the step 1 product (1.9 g) and THF (15 ml) Add NaHMDS (1 mol in THF; 7.5 ml) followed by benzyl bromide (2 milliliters). Remove the cooling bath and stir the resulting solution for 45 minutes. Added

Concentrate NH4OH (10 ml) and stir the reaction for 30 minutes. The resulting mixture was divided between CH2CI2 and water, the CH2CI2 extracts were removed and evaporated, and the crude oil was purified by column chromatography (silica gel; 1:2 CH2Cl2:hexanes; 1:10 to 7:1 EtOAc:hexanes as clarifier) ​​to give, after evaporation of the appropriate fractions, a mixture of Intermediate material (1.92 g) as foam

In smaller colour.

<img file="SA2180B1_D0143.tif" />

Mix the mixture of step 2 (1.91 g), CH3CN (35 ml), sodium triacetoxy borohydride (4 g), magnesium bromide etherate (2.25 g) and stir for 7 hours at room temperature. Add water (25 ml) and then, gradually, a solution of Na2CO3 (10 g) in water (50 ml). After extraction with EtOAc (50 ml x 2), drying and evaporation of the organic layer, the resulting oil was purified by preparatory dish chromatography (5×2000 mM silica dishes; 6:1 EtOAc:hexanes as filtration material). The exponent beam was depolarized, treated with CH2CI2:methanol 1:1, filtered and heated to give a medium (0.84

g) as white foam. HRMS: Calculated: C25H29o2N2F3 :NH: 449.2407; Size: 449.2416.

Step 4: The product of Step 3 (0.81 g) is treated in the same manner as in Example 8, Step 3, with TFA (5 mL) CH2CI2 (10 mL) to give, after reaction progression, free piperazine (0.6 g) as pure gum. HRMS: Calculated: C20H23N2F3:MH: 349.1892; Size: 349.1894.

Step 5: Process the product of Step 4 (0.39 g) in the same manner as in Example 8, Step 1, using N-BOC 4-piperidone (0.25 g), CH2CI2 (8 mL), 4(Ti(OiPr) (0.4 mg) , Et2AlCN (2 mL) CH3MgBr (3 mol in Et2O; 1.5 mL) to give the protected piperidinyl intermediate with the required BOC (0.44 g) as pure oil with a yield of 72%: Calculated HRMS: C31H42O2N3F3: MH: 546.3307; : 546.3315.

Step 6: The product of Step 5 (0.43 g) is treated in the same way as in Example 8, Step 3, using TFA (3 ml), CH2CI (2 ml) and water (0.2 ml) to give, after reaction progression, the free piperidinyl intermediate (37 0 g) as pure oil.

Step 7: Treat the product of Step 6 (50 mg) in the same manner as in Example 8, Step 4, using CH2CI2 (3 ml), HOBt (28 mg), DEC (40 mg), diisopropyl ethyl amine (42 mg) 4,6 -dimethyl 5-pyrimidine caboxylic acid (24 mg); The reaction was stirred for two days at room temperature. Using the procedure described in Example 8, Step 4, prepare the HCl salt of the title compound (59 mg) in 91% yield (from the product of Step 5). Melting point: 187-196 Celsius. HRMS: Calculated: MH:+C33H40ON5F3: 580.3263; Size: 580.3263.

Using a similar procedure, prepare compounds of the formula:

<img file="SA2180B1_D0144.tif" />

Where R3, R8a and R2 are as specified in the table:

<img file="SA2180B1_D0145.tif" />

<img file="SA2180B1_D0146.tif" />

Step 1:

<img file="SA2180B1_D0147.tif" />

<img file="SA2180B1_D0148.tif" />

Quenched 4'-(trifluoromethyl)propiophenone (2.02 g, 0.01 mol) and -2-(s)methyl-CBS-oxazaborolidine (1 mol in THF) (2 mL, 0.002 mol

gram) in THF (10 ml) in an ice bath and add to the mixture dropwise -borane methyl sulfide complex (2 mol in THF) (3 ml, 0.006 mol). Stir the mixture for 30 minutes at 0°C and add CH3OH slowly until the bubbles disappear. The solvents are removed under reduced pressure and HC1 solution (1 M) is added to the mixture. The development of the extraction reaction with EtOAc followed by silica gel chromatography gave alcohol (1.47 g) with a yield of 72%.

Step 2: Cool to 0°C in an ice bath a solution of step 1 product (4.32 g, 0.021 mol) Et3N (5.9 mL, 0.042 mol) in CH2CI2 (20 mL) and add CH3SO2C1 (2.13 mL) dropwise. , 0.028 mol). Stir the mixture for an hour at 0°C and remove the ice bath. Water is added to the mixture and a CH2CI2 extraction reaction develops to produce mesylate (5.99 g) with quantitative yield.

Step 3: The product of step 2 (5.93 g, 0.021 mol) 1-tert-butoxycarbonyl-3S-methyl piperazine (4.2 g, 0.021 mol) is dissolved in anhydrous CH3CN (20 mL) and added to the dried K2CO3 solution. In stove (4.35 g, 0.032 mol). Stir the mixture and re-condense the steam for two days, then dilute it with water. The development of an EtOAc extraction reaction followed by silica gel chromatography gave the desired product (3.16 g) with a yield of 39%.

Step 4: Add TFA (10 ml) to a solution of the product of step 3 (1.15 g, 2.59 mmol) in CH2CI2 (5 ml) and stir the mixture for 2 hours at room temperature, then concentrate under reduced pressure. NaOH (3 m) is added to the residue and the extraction reaction with EtOAc produces the required amine in quantitative yield. Step 5: Treat the product of Step 4, l-tert-butoxycarbonyl-4-piperidone (0.94 g, 4.74 mmol) with 4(CH3MgBr) and Ti(OiPr, Et2AlCN) in a manner similar to the method described in Example 8, Step 1, to obtain on the desired product (1.09 g) with a yield of 87% (from amine step 4).

Step 6: Add TFA (4 ml) to a solution of the product of step 5 (0.76 mg, 1.57 mmol) in CH2CI2 (2 ml) and stir the mixture for 2 hours at

Room temperature before concentrating under reduced pressure. NaOH (3 m) is added to the residue and the extraction reaction with EtOAc produces the required amine in quantitative yield.

Step 7: Combine the amine Step 6 4,6-dimethylpyrimidine 5-carboxylic acid (36.0 g, 2.35 mmol), as described in Example 8, Step 4, to obtain the title compound (58.0 g) in 72% yield. . Melting point 160 C; MH+ (HRMS) located: 518.3123.

Using a similar procedure, prepare compounds of the formula:

<img file="SA2180B1_D0149.tif" />

Where R6, R3, Z and R2 are as specified in the table below:

<img file="SA2180B1_D0150.tif" />

<img file="SA2180B1_D0151.tif" />

Using similar procedures, also prepare the following compounds:

<img file="SA2180B1_D0152.tif" />

<img file="SA2180B1_D0153.tif" />

<img file="SA2180B1_D0154.tif" />

<img file="SA2180B1_D0155.tif" />

Step 1: Prepare cyano amine from 2(S)-methyl-4-and p-trifluoromethyl benzaldehyde tert-butoxycarbonyl)piperazine exactly as described in Example 6, Step 1.

Step 2: A solution of cyano amine 2 (2.5 g; 6.53 mmol) is placed in 30 mL of dry THF under an N2 atmosphere and cooled to -78 C. This solution is treated with a solution of sodium hexa-methyl disilazide in THF (1 mol; 26 mL) followed after 5 minutes by pure allyl bromide (6 mL). When the bath is removed and the reaction mixture is allowed to warm to room temperature (about 1 hour), the solution changes from yellow to dark reddish brown. The reaction was quenched with a saturated NH4CI solution and the product was extracted with EtOAc, washed with water, brine and dried. Concentration by suction produces a brownish semi-solid substance. The FSGC of this material using 25% Et2O in hexane as the filter material gives

2.5 g (92%) of the desired product is a smaller amber color (Rf TLC = 0.65, 6.0 for two overlapping spots).

Step 3: A solution of the product of step 2 (2.4 g) is treated in CH3OH with 10% Pd/C (0.2 g) and placed under a blanket of H2 gas. After stirring for 4 hours at room temperature, the catalyst is removed by filtration through celite. The concentration of the filtrate produces colored gum

Smaller amber.

The α-propyl nitrile obtained above is dissolved in CH3CN (12 mL). Add magnesium bromide eherate (2.1 g; 8.14 mmol) and sodium triacetoxy borohydride (3.44 g; 16.2 mmol) and stir the reaction mixture overnight at room temperature. The reaction quenches with water and becomes basic with saturated NaHCO3. Organic products are extracted with EtOAc and processed to obtain approximately 2 g of raw material. FSGC (10-25% EtO in hexane) leads to the isolation of two diasteromeric products (total 7.1 g; 79% from two steps):

S,S)-Diastereomer) (a): Rf TLC = 0.6 (25% Hexane-Et2O). 0.9 g of colorless glue 0

R,S)-Diastereomer) (b): Rf TLC = 0.5 (25% Hexane-Et25). 0.8 g of

Colorless glue.

Step 4: The BOC protecting group is removed from intermediate A by treatment with TFA in CH2C12. Dissolve the separated free piperazine (0.68 g; 2.3 mmol), -N tert-butoxy carbonyl)-4-piperidinone (0.45 g; 2.3 mmol), Ti(OiPr)4, and (0 .7 ml; 2.5 mmol) in 10 ml CH2C12 and stir overnight. Et2AlCN (1 mol in toluene; 2.7 mL) was introduced into the reaction mixture and the resulting solution was stirred for 1 day. The reaction is reduced with EtOAc and quenched with water. Celite is added to help filter out titanium and aluminum salts. The bi-phase filtrate is washed with water, solution. Salt and dry. Vacuum concentration yields 1.1 g of smaller colored gum (RfTLC = 0.55 in 25% hexane-EtOAc).

The resulting ipso-cyano complex was dissolved in dry THF (8 ml) and treated with CHMgBr solution (3 mol in 6 ml Et2O) and stirred overnight at room temperature. Place the reaction flask in a cold water bath and carefully quench it with a saturated NH4CI solution. The organic product was extracted with EtOAc and washed with water and brine. Concentration to a crude product which is then raised by rapid FSGC analysis (10-25% EtOAc in hexane) yields BOC-piperidinyl as a pale yellow gum (1.1 g; 100%). Rf TLC = 0.6 in 25% hexane-EtOAc.

Step 5: The BOC protecting group on the piperidine nitrogen in the product of step 4 is removed by treatment with TFA in 0CH2Cl2. The solution becomes basic with 1 mol NaOH and treated in CH2C12 to produce unprotected piperidine in 90% yield. This intermediate substance (HOBt, EDCl) is combined with heteroaryl carboxylic and aryl acids to obtain the amides represented in the following table:

<img file="SA2180B1_D0156.tif" />

Where R2 is as specified in the table:

<img file="SA2180B1_D0157.tif" />

<img file="SA2180B1_D0158.tif" />

Using similar procedures, prepare the following compounds:

<img file="SA2180B1_D0159.tif" />

Where R3, R8 and R2 are as specified in the table:

<img file="SA2180B1_D0160.tif" />

Using 3-fluoro benzyl bromide or chloride instead of benzyl bromide in Example Procedure 28, Steps 1-4 (preparing isomer B in Step 3), then using Example Procedure 1, Step 5, followed by Example Procedure 26, Steps 6-7, prepare The following compound (HC1 salt):

<img file="SA2180B1_D0161.tif" />

<img file="SA2180B1_D0162.tif" />

<img file="SA2180B1_D0163.tif" />

Step 1: Add solid m-CPBA to a solution of p-trifluoromethyl styrene (3 g; 17.4 mmol) in 30 mL CH2CI2 and stir for 20 hours at room temperature. Add about 20 mL of saturated NaHCO3 solution and stir for 2 hours at room temperature. Dilute the mixture with CH2C12 (20 mL) and extract the organic product into the CH2CI2 layer. The organic extracted material is processed to obtain the raw product. FSGC yields 3g (90%) of the required epoxide as a colorless oil. Rf TLC = 0.8 (25% EtOAc in hexane).

Step 2: Add freshly prepared NaOCH (0.6 g; 10.6 mmol) to a solution of the product of step 1 (2 g; 1.6 mmol) in 20 ml anhydrous CH3OH. After stirring for one day at room temperature, CH3OH was removed by vacuum. The residue is dissolved in CH2CI2 and washed with water and brine. In concentration, then FSGC, they give 1.3 g (55%) of carbinol as a colorless oil (Rf = 0.3, 50% Et2O in hexane).

Step 3: Step 2: Dissolve cabinol (1.3 g; 5.9 mM) in CH2CI2 and cool in an ice bath. Subsequent treatment with Et3N (1.7 mL; 2 1 mmol) and CHSO2CI (0.6 mL; 7.7 mmol) and stirring for 30 minutes gave mesylate. The product is extracted by standard reaction development (100% yield).

Dissolve mesylate (1.76 g; 5.9 mM) and 2(S)-methyl-4-(tert-butoxy)

carbonyl)piperazine (2.4 g; 12 mmol) in 5 mL CH3CN and heated with steam recondensation for 19 hours. The reaction mixture was cooled to room temperature and directly subjected to flash chromatography on silica gel. Filtration with 25% and then 50% Et2O in hexane is used to separate diastereomeric products A and B (total yield = 86%).

A: Rf = 0.5 (50% Et2O in hexane). Smaller, lighter colored gum (0.9 g; 42%).

B: Rf = 0.4 (50% Et2O in hexane). Amber yellow gum (1.13 g; 44%).

Step 4: The free piperazine derived from A (0.9 g; 2.2 mmol) is reductively aminoacylated with N-BOC-piperidin-4-one with the isomethyl group positioned as follows:

Description In Example 1, Step 4 let's obtain the piperidinyl compound protected with BOC (0.87 g; 92%).Rf = 0.3 (50% EtOAc in hexane).

Step 5: The BOC protecting group is removed from the piperidine nitrogen by TFA, and the resulting compound is coupled with acids using the HOBt/EDCI method as described in Example 8, Step 4, to obtain the compounds shown in the following table:

<img file="SA2180B1_D0164.tif" />

Where R2 is as shown in the table:

<img file="SA2180B1_D0165.tif" />

<img file="SA2180B1_D0166.tif" />

<img file="SA2180B1_D0167.tif" />

<img file="SA2180B1_D0168.tif" />

Heat for 6 hours with steam re-condensing a solution of p-trifluoromethoxy benzaldehyde (0.48 ml, 3036 mmol), piperidino-piperazine (1

g, 3.36 mmol) benzotriazole and (0.48 g, 4 mmol) in

dry toluene. The reaction mixture is cooled to room temperature and the solvent is removed by vacuum. Following NMR confirmation of product composition, the product is used in the next step without further purification.

<img file="SA2180B1_D0169.tif" />

To a solution of the product of step 1 (1.16 g, 1.97 mmol) in 20 ml toluene, add a solution of n-propyl magnesium bromide (2 mol in Et2O, 1.1 ml) and stir the mixture for 15 hours at room temperature. . The mixture quenches

Reaction by pouring on ice and a saturated aqueous NH4C1 solution. The aqueous layer was extracted with EtOAc, washed with 1 mM NaOH solution, water and brine. The focus

And purification by FSGC analysis (20%)

hexane-EtOAc) provide the desired product A. Further elution with 300% EtOAc in hexane gives R,S diastereomer b.

Step 3: Treat amine A with TFA at CH7CI7 to remove the BOC protecting group. Coupling of free piperidine with acids using HOBt/EDCI provides compounds 30-30b in the following table; Similar methods are used to prepare compounds 30C-I.

<img file="SA2180B1_D0170.tif" />

<img file="SA2180B1_D0171.tif" />

Diastereomers mixtures

<img file="SA2180B1_D0172.tif" />

Stir for 5 days at 110 C. Solution of product of example 12, step 2 (150 mg, 0.27 mmol), imidazole (27.4 mg, 0.403 mmol), 1,10-phenanthroline (48 mg, 0.27 mmol). (96.1 mg, 0.3 mmol) Gram) in xylene (2 ml). Cool the reaction mixture to room temperature and add saturated NaHCO3. The development of the EtOAc extraction reaction followed by silica gel chromatography gave the title compound (70 mg, yield 52%). Decomposition 215 C (HRMS salt.(HCl calculated for M+H) C29H39CIN3OS) 500.3389, found 500.3396.

The following tests may be used to determine the receptor antagonist activity of the compounds of the invention

CCR5.

CCR5 Membrane Binding Assay CCR5:

An aggressive internal screening using the CCR5 membrane binding assay identifies inhibitors of RANTES binding. This assay uses membranes prepared from NIH 3T3 cells. We demonstrate a human CCR5 chemokine receptor that has the ability to bind to RANTES, a natural ligand for the receptor. Using a 96-well plate format, membrane preparations of I125-RANTES are incubated in the presence or absence of compound for 1 hour. Compounds were serially diluted in bulk from 0.001 to 1 µg/ml and divided into three equal amounts. The reaction mixtures were collected through glass fiber filters and washed well. Total counts of binary amounts are averaged and data are reported as the concentration required to inhibit 50% total binding to I125-RANTES. Compounds with strong activity in the membrane association assay are further characterized in secondary cell-dependent HIV-1 entry and division assays.

HIV-1 Entry Assay:

HIV-1 receptor viral bodies that lack cleavage are generated by co-reception of the gene carrier from the host from a plasmid encoding the 3-N14 strain of HIV-1 (which is modified by mutation of the packaging gene and insertion of the luciferase receptor plasmid) next to a plasmid encoding one of the HIV-1 envelope genes. HIV multiple as described by 206..Connor et al. Virology) (935-944 .1995), P). Following transgenic reception of the two plasmids by calcium phosphate precipitation from the host, the viral supernatants are collected on day 3 and a functional viral titer is determined. These stocks are then used to infect U87 cells stably expressing CD4 and CCR5 chemokine receptors, which are pre-incubated with or without test compound. Infections are carried out for two hours at 37°C, the cells are washed and the media is replaced with fresh media containing the compound. Cells were incubated for 3 days, lysed, and luciferase activity was determined. Results are reported as the concentration of compound required for 50% inhibition of luciferase activity in the comparative example cultures.

HIV-1 Replication Assay HIV Split Test:

This assay uses primary peripheral blood mononuclear cells or a stable U87-CCR5 cell line to determine the effect of anti-CCR5 compounds on inhibiting infection with primary HIV-1 strains. Primary lymphocytes were purified from normal healthy donors and cultured in vitro with PHA and IL-2 for 3 days before infection. Using a 96-well plate format, cells are pretreated with drug for 1 hour at 37°C and subsequently infected with separate membrane-bound HIV-1 material. After infection, cells were washed to remove residual inoculum and cultured in the presence of compound for 4 days. Culture supernatants are collected and virus division is measured by determining the concentration of viral p24 antigen.

Calcium Flux Assay calcium:

Cells expressing the CCR5 co-receptor were transfected with calcium-sensitive dyes before the addition of the natural CCR5 recombinant or ligand. Compounds with signal antagonist properties cause calcium influx into the cell, while CCR5 antagonists are identified as compounds that do not cause the signal themselves but have the ability to inhibit signaling by the natural ligand RANTES.

GTPγS binding test

:GTPγS Binding Assay

The GTPγS binding assay measures receptor activation by CCR5 ligands. This assay measures S35-tagged GTP binding to G proteins coupled to a receptor that occurs as a result of activation of the receptor with an appropriate ligand. In this assay, a RANTES ligand, CCR5, is incubated with membranes from cells expressing CCR5 and binding to the active receptor (or binding) is determined by the associated 35S tag. The test quantitatively determines whether compounds exhibit antagonistic properties by inducing receptor activation or alternatively antagonistic properties by measuring inhibition of RANTES binding in a competitive or noncompetitive manner. Chemotaxis Assay:

The chemotaxis test is a functional test that distinguishes the antagonistic versus antagonistic properties of test compounds. The assay measures the ability of a non-adherent mouse cell line expressing human CCR5 (550-BaF) to migrate across a membrane in response to either test compounds or natural ligands (i.e., MIP-lβ, RANTES). Cells migrate across the permeable membrane toward compounds that have antagonistic activity. Compounds that are antagonists not only fail to induce chemotaxis, but are also capable of inhibiting cell migration in response to known CCR5 ligands.

The role of CC chemokine receptors such as the 5-CCR receptor in inflammatory conditions is documented in such publications as:

Immunology Letters, 57, (1997), 117-120 (arthritis); Clinical &amp; Experimental Rheumatology, 17 (4) (1999), P. 419-425 (rheumatoid arthritis); Clinical &amp; Experimental Immunology, 117 (2) (1999), P. 237-243 (atopic dermatitis); International Journal of Immunopharmacology, 20 (11) (1998), P. 661-7 (psoriasis); Journal of Allergy &amp; Clinical Immunology, 100 (6, Pt 2) (1997), P. S52-5 (asthma); and Journal of Immunology, 159 (6) (1997), p. 2962-72 (allergies).

In a test to determine inhibition of binding, the compounds of the invention range in activity from about 0.5 to about 1500 nmol, and the range of activity of the compounds Ki is preferably from about 0.5 to about 750 nmol, the most preferable is about 0.5 to 300 nmol, and the best is about 0.5 to about 750 nmol. 50 nanoparticles. That results

Preferred and representative compounds of Formulas I and II in the test to determine binding inhibition are given in the table below. In Table No. &amp; Ex. Denoted by &amp;example number&amp; &amp;nM&amp;

It stands for &gt;nanomolecular&gt;

<img file="SA2180B1_D0173.tif" />

To prepare drug compositions of the CCR5 antagonist compounds described in this invention, the pharmaceutically acceptable, inert, carrier materials can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, sachets and suppositories. Our powders and tablets may consist of from about 5 to about 95% of the active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate; talc, sugar or lactose. Tablets, powders, sachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacturing various formulations may be found in:

(1990) Remington's Pharmaceutical Sciences, 18th Edition (A., Gennaro (ed.)

Mack Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. Examples include hydrocarbons, propylene glycol-water solutions, solutions for non-oral injection, or the addition of sweeteners and clouding agents to oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for administration into the nose.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, eg nitrogen.

Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for administration either orally or into the blood. These liquid forms include solutions, suspensions and emulsions.

The CCR5 antagonist compounds of the invention can also be delivered transdermally. Transdermal formulations may be in the form of creams, lotions, aerosols and/or emulsions and may be inserted into a transdermal patch or reservoir type structure such as is conventional in the art for this purpose. It is preferable to give the anti-CCR5 compound enterally.

Preferably, the medicinal preparation should be in the form of a single dose. In this form, the preparation is divided into unit doses of appropriate size containing appropriate amounts of the active ingredient, for example, an effective amount to achieve the desired purpose.

The amount of active compound in a unit dosage may be varied or adjusted at from about 10 mg to about 500 mg, preferably from about 25 mg to about 300 mg,

Most preferably from about 50 mg to about 250 mg, and most preferably from about 55 mg to about 200 mg, depending on the specific use.

The actual dose used may vary depending on the patient's needs and the severity of the condition to be treated. Determining the optimal dosage regimen for a particular situation is within the skill of the invention. For convenience, the total daily dose may be divided and given in parts during the day

as orderd .

The quantity and frequency of administration of the patented compounds and/or pharmaceutically acceptable salts thereof are regulated at the discretion of the treating physician, taking into account such factors as the age, condition and size of the patient in addition to the severity of the symptoms to be treated. A typical recommended daily dosage regimen for oral administration can range from about 100 mg/day to about 300 mg/day.

mg/day, preferably 150 mg/day to 250 mg/day, more preferably about 200 mg/day, in two or four divided doses.

Doses and dosage regimens for PIs, NNTIs, NRTIs and other factors are determined by the treating physician in light of the established doses and dosage regimen specified in the package insert or as stated in the protocol, taking into account the age, sex, condition of the patient and the severity of the injury.

HIV-1

While the present invention has been described in combination with particular embodiments described above, many alternatives, modifications and variations thereof will become apparent to those skilled in the art. All such alternatives, modifications and variations are within the scope and spirit of the present invention.