Title of Invention

CCR5 ANTAGONISTS OF FORMULA II

Abstract

The present invention relates to a novel CCRS antagonist compound , represented by the structural formula II and to a pharmaceutical composition for the treatment of HIV, solid organ transplant rejection, graft V. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis. The invention also relates to a combination of CCR5 antagonists of the invention in combination with antiviral agents useful in the treatment of HIV or agents useful in the treatment of inflammatory diseases.

Full Text

PIPERAZINE DERIVATIVES USEFUL AS CCR5 AhTTAGONISTS BACKGROUND The present invention relates to piperazine derivatives useful as selective CCR5 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds. The invention also relates to the use of a combination of a CCR5 antagonist of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a CCR-5 antagonist of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v, host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis. The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and while recent advances in drug therapies have been successful in stowing the progression of AIDS, there is still a need to find a safer, more efficient, less expensive way to control the virus. It has been reported that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates In vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. The present invention relates to small molecules which are CCR5 antagonists. CCR-5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease. Related piperazine derivatives which are muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer's disease are disclosed in US patents 5,883,096; 6,037,352; 5,889,006. A-M. Vandamme et al., Antiviral Chemistn/ & Chemotherapy. 9:187-203 (1998) disclose current clinical treatments of HlV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy ("HAART'); HAART involves various combinations of nucleoside reverse transcriptase Inhibitors ("NRTI"), non-nucleoside reverse transcriptase inhibitors ("NNRTI") and HIV protease inhibitors ("PI"). In compliant drug-naive patients, 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 usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority. SUMMARY OF THE INVENTION or a pharmaceutically acceptable salt thereof, wherein R is RQ-phenyl, R^-pyridyl, RMhiophenyl or R^-naphthyl; R^ is hydrogen or CrCe alkyl; The present invention relates to the treatment of HIV comprising administering to a mammal in need of such treatment an effective amount of a CCR5 antagonist represented by the structural formula I: R2 is R9, R10, Rii-pheny(; R9. R^O. R^'-substituted 6-membered heteroaryl; R^, R'lO, Rii-substituted 6-membered heteroaryl N-oxide; R"'2, Ri3-substituted 5-membered heteroaryi; naphthyl; fluorenyl; R'^ « R^' R'^ ' '9;p^ -C-heteroaryi diphenylmethyi R or R R3 is hydrogen, d-Ce alkyl, (CrC6)aIkoxy(CrC6)alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(Ci-C6)alkyl, RS-phenyl, R8-phenyl(Ci-C6)alkyl, R8-naphthyl, R^-naphthyl(Ci-C6)alkyl, R8-heteroaryl or R8-heteroaryl(Ci-C6)alkyl; R^, R5, R' and R^^ are independently selected from the group consisting of hydrogen and (CrC6)-alkyl; RS is hydrogen, Ci-Ce alkyl or CZ-CQ alkenyl; R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, -CF3, CF3O-, CH3C(0)-, -CN, CH3SO2-, CF3SO2-, Ri'^-phenyl, Ri^^benzyi, CH3C(=NOCH3), CH3C(=NOCH2CH3), ^ ^^^ ,-NH2,-NHCOCF3, -NHC0NH(Ci-C6 alkyl), -NHC0(Ci-C6 alkyl). -NHS02(Ci-C6 alkyl), O A —N X S-membered heteroaryl and ^—' , wherein X is -0-, -NH- or -N(CH3)-; R9 and R'o are independently selected from the group consisting of (CrC6)alkyl, halogen, -NR^'R', -OH, -CF3, -OCH3, -0-acyl, -OCF3 and -Si(CH3)3; RII is R9, hydrogen, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CH=NOR^^, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, -N(R')C0NR'^R'^ -NHCONH(chloro-(Ci-C6)alkyl), -NHCONH((C3- Ci)CycloalkyI(Ci-C6)alkyl), -NHC0(Ci-C6)alkyl, -NHCOCF3, -NHS02N{(Cr C6)alkyl)2, -NHS02(Ci-C6)alkyl, -N(S02CF3)2, -NHC02(C,-C6)a!kyI, C3-C10 cycloalkyl. -SR^°, -S0R^°, -S02R^°, -S02NH(Ci^C6 alkyl), -OSOsCCi- C6)a!kyl, -OSO2CF3, hydroxy(Ci-C5)alky!, -CON R'^R'^ -C0N(CH2CH2-0- CH3)2, -0C0NH(Ci-C6)alkyl, -COaR'^ -Si(CH3)3 or-B(OC(CH3)2)2; R12 js (Ci-C6)alkyl, -NH2 or R^^-phenyl; R''^ is 1 to 3 substituents independently selected from the group consisting of hydrogen, (CrCs) alkyl, -CF3, -CO2R17, -CN, (Ci-C6)alkoxy and halogen; R'^S and R^^ are independently selected from the group consisting of hydrogen and CrCe alkyl, or R^^ and R^^ together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms; R^^, R^® and R^^ are independently selected from the group consisting of H and d-Ce alkyl; and R^^ is Ci-Ce alkyl or phenyl. Preferred are compounds of formula I wherein R is R^ -phenyl or R8-naphthyl, especially wherein R^ is a single substituent, and especially wherein the R8 substituent is in the 4-position; For R8-phenyl, preferred R8 substituents are -CF3, -OCF3, CH3SO2-, CH3CO-, CH3C(=NOCH3)-. Br and I. For R8-naphthyl, R8 is preferably Ci-Cealkoxy. Also preferred are compounds of formula I wherein R3 is hydrogen, (Ci-Ce) alkyl, R8-phenyl. R8-benzyi or R8-pyridyl; more preferred definitions for R3 are methyl, ethyl, phenyl, benzyl and pyridyl. R"" is preferably hydrogen. For compounds of formula I, R^ is preferably hydrogen or methyl, especially methyl. R'* is preferably methyl; R^ and R^ are each preferably hydrogen. In compounds of formula I, R2 is preferably R^, R^o, R^i-phenyl, R9, RIO. Rii-pyridyl or an N-oxide thereof, or R9, R^O, R^i-pyrimidyl. When R2 is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R^ and R^o substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule and the R"'"' substituent can be attached to any of the remaining unsubstituted carbon ring members, for example as shown in the following structures: '\A/U and Preferred R^ and R^o substituents are: (CrC6)alkyl, especially methyl; halogen, especially chloro or bromo, -OH and -NH2. When R2 is phenyl, R^"" is preferably hydrogen or -OH; when R2 is pyridyl, R"'"' is preferably hydrogen; and when R2 is pyrimidyl, R^^ is preferably hydrogen, methyl or phenyl. Examples of particularly preferred R2 groups are as follows: Me^^A^Me Me^^^^A^OH Me^A^^NHo "^^^^NAv^Me C!^..,^^ OH ^'YT'^^' Meyl^Me Meyi^Me MeY^^Me ^'Vj ^' Br Br Me^.x^sv-MeCI'-.v-^^ Br-.A^Br TJ 1J 1J N N N N Me^^xL^Me Me..^^Me Me,.^^Me 6 6 O N^N N^N N^N Me Ph Also claimed are novel CCR5 antagonist compounds represented by the structural formula II R^ R^ or a pharmaceutically acceptable salt thereof, wherein (1) Ra is RSa.phenyl, RSb-pyhdyl, R8b-thiophenyl or R8-naphthyl; R' is hydrogen or C)-CQ alkyl; R2 is R9, R10, R11.phenyl; R9, R^O, R11-substituted 6-membered heteroaryl; R9, Rio, R^^-substituted 6-membered heteroaryl N-oxide; Ri2 Ri3.substituted 5-membered heteroaryl; naphthyl; fluorenyl; R^^ _ .R^^ R^' —C—i^ —C—heteroaryl diphenyimethyl, R'^ or R^^ ; R3 is hydrogen, Ci-Ce alkyl, (CrC6)alkoxy(Ci-C6)alkyl, C3-C10 cycloalkyi, C3-C10 cycloalkyKCi-CeJalkyI, R8-phenyl, R8-phenyl(Ci-C6)alkyl, R8-naphthyl, R^-naphthyl(Ci-C6)alkyl, RS-heteroan/l or R8-heteroaryl(Ci-C6)alkyl; R'^, R5, R7 and R^3 are independently selected from the group consisting of hydrogen and (CrCel-alkyI; RS is hydrogen, C^-Ce alkyl or C2-C5 alkenyl; R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen. CrCe alkyl, C-i-Cs alkoxy, -CF3. CF3O-, CH3C(0)-, 'CN, CH3SO2-, CF3SO2-, R^^-phenyl, R^^.benzyl, CH3CHNOCH3), CH3C(=NOCH2CH3), ^ SO2 ,-NHs,-NHCOCF3, -NHC0NH(CI-C6 alkyl), -NHC0(Ci-C6 alkyl), -NHS02(Ci-C6 alkyl), O S-membered heteroaryl and ^^—^ , wherein X is -0-, -NH- or -N(CH3)-; RSa is 1 to 3 substituents independently selected fronn the group consisting of hydrogen, halogen. -CF3, CF3O-, -CN, CF3SO2-, R^'^-phenyl, O A —N X -NHCOCF3, 5-membered heteroaryl and ^—^ , wherein X is as defined above; RSb is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, -CF3, CF3O-. CHsCP)-. -CN, CF3SO2-, Ri4.benzyl, CH3C(=NOCH3), CH3C(=NOCH2CH3), ° SO2 _ O A —N X -NHCOCF3, 5-mGnnbered heteroaryl and ^—' , wherein X is as defined above; R9 and R'^o are independently selected from the group consisting of (CrC6)alkyl, halogen, -NR"R", -OH, -CF3, -OCH3, -0-acyl, -OCF3 and -Si(CH3)3; R^' is R9, hydrogen, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CH=NOR^^, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, -N(R'^)C0NR'^R'^ -NHCONH(chloro-(Ci-C6)a!kyl), -NHCONH((C3-Ci)CycloalkyI(Ci-C6)alkyl), -NHC0(Ci-C6)alkyl, -NHCOCF3, -NHS02N((Ci-C6)alkyl)2, -NHS02(Ci-C6)alkyl, -N(S02CF3)2, -NHC02(CrC6)alkyl, C3-C10 cycloalkyi, -SR^°, -SOR^°, -SOaR^^, -S02NH(CrC6 alkyl), -OSOslCi-C6)alkyl, -OSO2CF3, hydroxy(Ci-C6)alkyl, -CON R'^R'^ -CON(CH2CH2-0- CH3)2, -0C0NH(CrC6)alkyl, -C02R'^ -Si(CH3)3 or-B(OC(CH3)2)2; R12 is (CrC6)alkyl, -NH2 or Ri^-phenyl; R''* is 1 to 3 substituents independently selected from the group consisting of hydrogen. (Ci-Cs) alkyl, -CF3, -CO2R17, -CN, (Ci-C6)alkoxy and halogen; R^5 and R'*^ are independently selected from the group consisting of hydrogen and Ci-Ce alkyl, or B^^ and R^6 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms; R^ , R^^ and R"*^ are independently selected from the group consisting of H and C-.-Ce alkyl; and R is Ci-Cg alkyl or phenyl; or (2) R^ is R8-phenyl, R^-pyridyl or R8-thiophenyI; R^' ^ R^^ R' —C—^ -y) -^C—heteroaryl R2 is fluorenyl, diphenylmethyl, R or R ; and R\ R3, R4, R5, R6^ R7^ R8^ R9^ RIO^ RII^ R12, R13^ R14^ R15^ R16, R'\ R'«, R^^ and R^' are as defined in (1). Preferred compounds of formula II are those defined in (1). More preferred are those of formula 11(1) wherein R^ is R^^-phenyl or R8-naphthyl, wherein R8a is -CF3, CF3O- or halogen and R^ is CrCe alkoxy. The R^^ or R8 substituent is preferably a single substituent; it is especially preferred that the R^a or R8 substituent is in the 4-pos(tion. Also preferred are compounds of formula 11(1) wherein R3 is hydrogen, (CrCe) alkyl, R8-phenyl. R^-benzyl or R8-pyridyl; more preferred definitions for R3 are methyl, ethyl, phenyl, benzyl and pyridyl. R' is preferably hydrogen. For compounds of formula 11(1), R^ is preferably hydrogen or methyl, especially methyl, R^ is preferably methyl; R5 and R"^ are each preferably hydrogen. R2 in formula 11(1) is preferably as defined for formula I, i.e., R^, R^^, R^i'phenyl. R9, R^O, R^i-pyridyl or an N-oxide thereof, or R9, R^O, R1^-pyrimidyl, wherein the R^, R"^*^, R^"'-substitution is as defined above for preferred compounds of formula I. Another aspect of the invention is a pharmaceutical composition for treatment of HIV comprising an effective amount of a CCR5 antagonist of formula II in combination with a pharmaceutically acceptable carrier. Another aspect of the invention is a pharmaceutical composition for treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising an effective amount of a CCR5 antagonist of formula II in combination with a pharmaceutically acceptable carrier. Yet another aspect of this invention is a method of treatment of HIV comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula II. Another aspect of the invention is a method of treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula I or II. Still another aspect of this invention is the use of a CCR5 antagonist of formula 1 or I! of this invention in combination with one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus for the treatment of AIDS. Still another aspect of this invention is the use of a CCR5 antagonist of formula I or II of this invention in combination with one or more other agents useful in the treatment of solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. The CCR5 and antiviral or other agents which are components of the combination can be administered in a single dosage form or they can be administered separately; a kit comprising separate dosage forms of the actives is also contemplated. DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below unless otherwise indicated. Alkyl represents straight and branched carbon chains and contains from one to six carbon atoms. Alkenyl represents Ca-Ce carbon chains having one or two unsaturated bonds, provided that two unsaturated bonds are not adjacent to each other. Substituted phenyl means that the phenyl group can be substituted at any available position on the phenyl ring. Acyl means a radical of a carboxylic acid having the formula alkyl-C(O)-, aryl-C(O)-, aralkyl-C(O)-, (C3'C7)cycloalkyl-C(0)-, (C3-C7)cycloalkyl-(Ci-C6)alkyl-C(0)-, and heteroaryl-C(O)-, wherein alkyl and heteroaryl are as defined herein; aryl is R'^'^-phenyl or R^'^-naphthyl; and aralkyi is aryl-(CrC6)alkyl, wherein aryl is as defined above. Heteroaryl represents cyclic aromatic groups of 5 or 6 atoms or bicyclic groups of 11 to 12 atoms having 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(3) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms. For 6-membered heteroaryl rings, carbon atoms can be substituted by R^, R*"^ or R^^ groups. Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyhdyl and 4-pyridyl. Typical 6-membered heteroaryl groups are pyridyt, pyrimidinyl, pyrazinyl, pyridazinyl and the N-oxides thereof. For 5-membered heteroaryl rings, carbon atoms can be substituted by R'^^ or Ri3 groups. Typical 5-membered heteroaryl rings are furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl and isoxazolyl. 5-Membered rings having one heteroatom can be joined through the 2- or 3- position; 5-membered rings having two heteroatoms are preferably joined through the 4-position. Bicyclic groups typically are benzo-fused ring systems derived from the heteroaryl groups named above, e.g. quinolyl, phthalazinyl, quinazolinyl, benzofuranyl, benzothienyl and indolyl. Preferred points of substitution for6-membered heteroaryl rings at R2 are described above. When R^ is a 5-membered heteroaryl group, the R"'^ and R"^^ substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule, and R^2 is preferably alkyl; however, if a heteroatom is adjacent to the carbon joining the ring to the rest of the molecule (i,e., as in 2-pyrrolyI), R^^ is preferably attached to a carbon ring member adjacent to the carbon joining the ring to the rest of the molecule. Halogen represents fluoro, chloro, bromo and iodo. One or more, preferaby one to four, antiviral agents useful in anti-HIV-1 therapy may be used in combination with a 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 and the antiviral agent or agents may be administered simultaneously or sequentially as separate dosage forms. The antiviral agents contemplated for use in combination with the compounds of the present invention comprise nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transchptase inhibitors, protease inhibitors and other antiviral drugs listed below not falling within these classifications. In particular, the combinations known as HAART (Highly Active Antiretroviral Therapy) are contemplated for use in combination with the CCR5 antagonists of this invention. The term "nucleoside and nucleotide reverse transcriptase inhibitors" ("NRTr s) as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV-I reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-1 RNA into proviral HIV^l DNA, Typical suitable NRTIs include zidovudine (AZT) available under the RETROVIR tradename from Glaxo-Wellcome Inc., Research Tnangle, NC 27709; didanosine (ddl) available under the VIDEX tradename from Bristol-Myers Squibb Co., Princeton, NJ 08543; zaicitabine (ddC) available under the HIVID tradename from Roche Pharmaceuticals, Nutley, NJ 07110; stavudine (d4T) available under the ZERIT trademark from Bristol-Myers Squibb Co., Princeton, NJ 08543; lamivudine (3TC) available under the EPIVIR tradename from Glaxo-Weilcome Research Tnangle, NC 27709; abacavir (1592U89) disclosed in WO96/30025 and available under the 2IAGEN trademark from Glaxo-Wellcome Research Triangle, NC 27709; adefovir dipivoxil [bis(POM)-PMEA] available under the PREVON tradename from Gilead Sciences, Foster City, CA 94404; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533 and under development by Bristol-Myers Squibb. Princeton, NJ 08543; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH-10619) under development by Biochem Pharma, Laval, Quebec H7V, 4A7, Canada; emitricitabine [(-)-FTC] licensed from Emory University under Emory Univ. U.S. Patent No. 5,814,639 and under development by Triangle Pharmaceuticals, Durham, NC 27707; beta-L-FD4 (also called beta-L'D4C and named beta-L-2\ 3'-dideoxy-5-fluoro-cytidene) licensed by Yale University to Vion Pharmaceuticals, New Haven CT 06511; DAPD, the purine nucleoside, (-)'beta-D-2,6,-diamino-purine dioxolane disclosed in EP 0656778 and licensed by Emory University and the University of Georgia to Triangle Pharmaceuticals, Durham. NC 27707; and lodenosine (FddA), 9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, a acid stable purine-based reverse transcriptase inhibitor discovered by the NIH and under development by U.S. Bioscience Inc, West Conshohoken, PA 19428. , The term "non-nucleoside reverse transcriptase inhibitors" ("NNRTPs) as used herein means non-nucleosides that inhibit the activity of HIV-1 reverse transcriptase. Typical suitable NNRTIs include nevirapine (BI-RG-587) available under the VIRAMUNE tradename from Boehringer Ingelheim. the manufacturer for Roxane Laboratories, Columbus, OH 43216; delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia & Upjohn Co,, Bridgewater NJ 08807; efavirenz (DMP-256) a benzoxazin-2-one disclosed in WO94/03440 and available under the SUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, DE 19880-0723; PNU-142721, a furopyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater NJ 08807; AG-1549 (formerly Shionogi # S-1153); 5-(3,5-dichlorophenyl)- thio-4-isopropyM-(4-pyridyl)methyl-IH-imida2ol-2-ylmethyl carbonate disclosed in WO 96 /10019 and under clinical development by Agouron Pharmaceuticals, Inc., LaJolla CA 92037-1020; MKC'442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyI)-(2,4{1H,3H)-pyrimidinedione) discovered by Mitsubishi Chemical Co. and under development by Triangle Pharmaceuticals, Durham, NC 27707; and (+)-calanolide A (NSC-675451) and B, coumarin derivatives disclosed in NIH U.S. Patent No. 5.489,697, licensed to Med Chem Research, which is co-developing (+) calanolide A with Vita-Invest as an orally administrable product. The term "protease inhibitor" ("PI") as used herein means inhibitors of the HIV'1 protease, an erizyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyprotelns), into the individual functional proteins found in infectious HIV-1. HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN(available from Merck) as well as nonpeptide protease inhibitors e.g., VIRACEPT (available from Agouron). Typical suitable Pis include saquinavir (Ro 31-8959) available in hard gel capsules under the INVIRASE tradename and as soft gel capsules under the FORTOUASE tradename from Roche Pharmaceuticals, Nutley, NJ 07110-1199; ritonavir (ABT-538) available under the NORVIR tradename from Abbott Laboratories, Abbott Park, IL 60064; indinavir (MK-639) available under the CRIXIVAN tradename from Merck & Co., Inc., West Point, PA 19486-0004; nelfnavir (AG-1343) available under the VIRACEPT tradename from Agouron Pharmaceuticals, Inc., LaJolla CA 92037-1020; amprenavir (141W94), tradename AGENERASE, a non¬peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, MA 02139-4211 and available from Glaxo-Wellcome, Research Triangle, NC under an expanded access program; lasinavir (BMS-234475) available from Bristol-Myers Squibb, Princeton, NJ 08543 (originally discovered by Novartis, Basel, Switzerland {CGP-61755); DMP-450, a cyclic urea discovered by Dupont and under development by Triangle Pharmaceuticals; BMS-2322623, an azapeptide under development by Bristol-Myers Squibb, Princeton, NJ 08543, as a 2nd-generation HlV-1 PI; ABT-378 under development by Abbott, Abbott Park, !L 60064; and AG-1549 an orally active imidazole carbamate discovered by Shionogi (Shionogi #S-1153) and underdevelopment by Agouron Pharmaceuticals, Inc., LaJolla CA 92037-1020. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607. Hydroxyurea (Droxia), a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T-cells, was discovered at the NCI is underdevelopment by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine. IL-2 is disclosed in Ajinomoto EP-OI42268 , Takeda EP-0176299, and Chiron U, S. Patent Nos. RE 33653, 4530787, 4569790, 4604377, 4748234, 4752585, and 4949314 is available under the PROLEUKIN (aldesleukin) tradename from Chiron Corp,, Emeryville, CA 94608-2997 as a lyophilized powder for IV infusion or sc administration upon reconstitution and dilution with water; a dose of about 1 to about 20 million lU/day, sc is preferred; a dose of about 15 million lU/day, sc is more preferred. IL-12 is disclosed in W096/25171 and is available from Roche Pharmaceuticals, Nutley, NJ 07110-1199 and American Home Products, Madison. NJ 07940; a dose of about 0.5 microgram/kg/day to about 10 microgram/kg/day, sc is preferred, Pentafuside (DP-178, T-20) a 36-amino acid synthetic peptide,disclosed in U.S. Patent No.5,464,933 licensed from Duke University to Trimeris which is developing pentafuside in collaboration with Duke University; pentafuside acts by inhibiting fusion of HIV-1 to target membranes. Pentafuside (3-100 mg /day) is given as a continuous sc infusion or injection together with efavirenz and 2 Pi's to HIV-1 positive patients refractory to a triple combination therapy; use of 100 mg/day is preferred. Yissum Project No. 11607, a synthetic protein based on the HIV -1 Vif protein, is under preclinical development by Yissum Research Development Co., Jerusalem 91042 , Israel. Ribavirin, 1-B-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from iCN Pharmaceuticals, Inc., Costa Mesa, CA; its manufacture and formulation are described in U.S. Patent No. 4,211.771. The term "anti-HIV-1 therapy'* as used herein means any anti-HIV-1 drug found useful for treating HIV-1 infections in man alone, or as part of multidrug combination therapies, especially the HAART triple and quadruple combination therapies. Typical suitable known anti-HIV-1 therapies include, but are not limited to multidrug combination therapies such as (i) at least three anti-HIV-1 drugs selected from two NRTIs, one PI, a second PI, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from , NNRTls and Pis, Typical suitable HAART - multidrug combination therapies 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 NRTIs , one PI and a second PI or one NNRTI. In treatment of naive patients, it is preferred to start anti-HIV-1 treatment with the triple combination therapy; the use of two NRTIs and one PI is preferred unless there is intolerance to Pis. Drug compliance is essential. The 004"^ and HIV-1-RNA plasma levels should be monitored every 3-6 months. Should viral toad plateau, a fourth drug,e.g., one PI or one NNRTI could be added. See the table below wherein typical therapies are further described: ANTI-HIV-1 MULTI DRUG COMBINATION THERAPIES A. Triple Combination Therapies 1. TwoNRTIs^ +one Pl^ 2. Two NRTIs^ + one NNRTI^ B. Quadruple Combination Therapies'^ Two NRTIs + one PI -h a second PI or one NNRTI C. ALTERNATIVES:^ Two NRTr One NRTI^ + one Pl^ Two PIs^ ± one NRTr or NNRTI^ One Pl^ + one NRTf + one NNRTI^ FOOTNOTES TO TABLE 1. One of the following: zidovudine + lamivudine; zidovudine + didanosine; stavudine + lamivudine; stavudine + didanosine; zidovudine + zaicitabine 2. Indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules. 3- Nevirapine or delavirdine. 4. See A-M. Vandamne at a! Antiviral Chemistry & Chemotherapy 9:187 at p 193-197 and Figures 1 +2. 5. Alternative regimens are for patients unable to take a recommended regimen because of compliance problems or toxicity, and for those who fail or relapse on a recommended regimen. Double nucleoside combinations may lead to HIV- resistance and clinical failure In many patients. 6. Most data obtained with saquinavir and ritonavir (each 400 mg bid). 7. Zidovudine, stavudine or didanosine, Agents known in the treatment of rheumatoid arthritis, transplant and graft v. host disease, inflammatory bowel disease and multiple sclerosis which can be administered in combination with the CCR5 antagonists of the present invention are as follows: solid organ transplant rejection and graft v, host disease: immune suppressants such as cyclosporine and lnterleukin-10 (IL-10), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids; inflammatory bowel disease: IL-10 (see US 5,368,854), steroids and azulfidine; rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil; multiple sclerosis: interferon-beta, interferon-alpha, and steroids. Certain compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers and rotamers)-The invention contemplates all such isomers both in pure form and in admixture. Including racemic mixtures. Certain compounds will be acidic in nature, e,g. those compounds which possess a carboxyl or phenolic hydroxy! group. These compounds may form pharmaceuticaliy acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceuticaliy acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. Certain basic compounds also form pharmaceuticaliy acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric. succinic, ascorbic, maleic. methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. 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, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are othenA/ise equivalent to their respective free base forms for purposes of the invention. All such acid and base salts are intended to be 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 purposes of the invention. Compounds of the invention can be made by the procedures known in the art, for example by the procedures described in the following reaction schemes, by the methods described in the examples below, and by using the methods described in W096/26196 and WO98/05292. The following solvents and reagents may be referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); 1-hydroxy-benzotriazole (HOBT); m-chioroperbenzoic acid (MCPBA); triethylamine (EtsN); diethyl ether (Et20); dimethylsulfoxide (DMSO); and 1-(3' dimethylaminopropyI)-3'ethyl carbodiimide hydrochloride (DEC). RT is room temperature, and TLC is thin-layer chromatography. Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl, Ph is phenyl, and Ac is acetyl. Scheme 1 R^N^ NH R^ R' R^ R' R-^N-^ _^ R^N-^ -1^ lA R^ R' R3 R^ ^.\ . X R N 5 -iU "' '? ... CN 8 k^NBoc 9 l^NBoc R^ R^ R^N IB 10 '^ NH Reagents and conditions: a: R'^CH(OS02CF3)C02CH3, base (e.g., K2CO3); b: CICH2COCI; c: NH3; d: NaBH4-BF3; e: N-Boc-4-piperidone, NaBH(0Ac)3; f: CF3CO2H; g: acylation; h: N-Boc-4-piperidone, Ti(0PM)4, Et2AICN; i: CH3MgBr. In Scheme 1, a benzylamine (1), wherein R and R^ are as defined above and R^ is hydrogen, is converted via (2) and (3) to the diketopiperazine (4), wherein R'* is as defined above, which is reduced to the piperazine (5). Depending upon the desired R substituent, this is processed in two ways. Reductive amination gives (6), which can be deprotected to (7) and finally acylated to the compounds of formula lA wherein R^ and R are H; alternatively, a modified Strecker reaction on (5) gives the aminonitrile (8), which, after treatment with methyl Grignard to give (9), deprotection to (10) and final N^acylation affords the compounds of formula IB wherein R5 is H and R^ is methyl. Acylation of (7) and (10) is carried out under standard conditions, e.g., with a compound R^COOH and reagents such as DEC and HOBT. Use of a chiral compound of formula 1, e.g., (S)-methyl 4-substituted benzylamine, and a chiral lactate in step a, e.g., methyl (R)-lactate triflate, will result in chiral compounds of formulas lA and IB. R^ HN NBoc R' R^ R N ■*- 14 N^ R' R' R-'^N 5a NH Scheme 2 11 ID R^ R OH 12 R N ^N 9a y-.R' R^ R OSO2CH3 v^. k^NBoc NBoc e-g IC Reagents: j: oxaborazolidine, BH3; k; CH3SO2CI, base; I: CF3CO2H. In Scheme 2, the compounds are prepared by an alkylation process on a pre-formed piperazine derivative. For example, preferred compounds with the S,S stereochemistry may be obtained in this way by chiral reduction of a ketone (11) to the alcohol (12), activation as the mesylate, and displacement with inversion by treatment with a suitable piperazine, which may either be mono-protected, in which case final elaboration requires deprotection followed by the steps described in (e) - (g) in Scheme 1 to obtain IC, or may be elaborated prior to the displacement step, in which case the final steps are (f) and (g) (deprotection and acylation) as in Scheme 1 to obtain ID. N Scheme 3 HN 1^4 R' RCHO N ■tr- NaBH(0Ac)3 "X^NBoc R 15 N R' R' CFaCOsH; ^ amide formation NBoc For compounds where R3 and R"' are each H, either the alkylation route of Scheme 2 or a reductive amination method as typified in Scheme 3 can be used. Scheme 4 ,4 R' HN ,N RR^CHCI . Nal, base 'N^NBOC R^ R-^N R' N R' N-deblocking; amide formation NBOC For diaryl compounds, wherein R and R3 are each aryl, an alkylation method as typified in Scheme 4 is preferrred. Scheme 5 CH3 NC CH3 I NaNfTMSls; CH3CH2 CH3 ^ CHsCHsl ^-^3^ 1 1. MgBrj, NaBH(0Ac)3 NC ^^3 XT L^ -^ fTY^N-S CFsO"-^^ 'x^NBoc 2. separate isomers CF O""^^ ^ k^NBoc CH3 Piperazines of formula 14, especially tfiose wherein R3 is C2-C6 alkyl or benzyl, may also be obtained by a process wherein the R portion is introduced as shown above by an alkylation-decyanation sequence. The reaction is exemplified for compounds wherein R is CFaO-phenyl, R' is hydrogen, R^ is ethyl and R^ is methyl, but using appropriate starting materials, other compounds of formula 14 can be similarly prepared. Scheme 6 m^ R-^N^" ^U 17 O 19 20 Reagents: m: BOC2O, base; n: R^MgBr; o: CCI3CO2H, NaBHaCN; p: CF3CO2H; q: NaBH4. BF3. As shown in Scheme 6, compounds bearing an additional alkyl group at R^ on the piperazine ring may be prepared from the diketopiperazine intermediates (4) of Scheme 1. (4) is activated by conversion to the N(t-butoxycarbonyl) compound (17); addition of a Grignard reagent and sequential reduction, deprotection and lactam reduction provides (21), which can be used to prepare compounds of formula I in the manner described for intermediate (5) in Scheme 1. Scheme 7 } N NH P-CIC6H4H2C- ' Many piperazines wherein R is R8-phenyl (or their Boc derivatives) shown in Scheme 1 can be obtained from a common intermediate, wherein RS is L Several examples are shown in the above scheme, wherein R^ is converted to CI, CN, -C{0)NH2, H, Ph and P-CIC6H4CH2-. Detailed procedures for these conversions are provided in the examples below. The resultant piperazine or BOC-piperazine is then treated as shown in Scheme 1. OH "XT CH2O Some compounds of the invention may be obtained by a Mannich method, as shown in the specific example of Scheme 8. Compounds useful in this invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. Example 1 ^N^ A. R^ = 2.6-Me2'CsH3 ^^Y^ B. R^ = 2-Me-5-NH2-C6H3 R Step 1 : Stir methyl R-lactate (5.0 g) in CH2CI2 (40 ml) at -70° C and add trfluoromethanesulfonic anhydride (7,6 ml), then 2,6-lutidine (7.8 ml). Remove the cooling, stir 0.5h, wash with 2N HCI and add the organic solution to (S)-melhyl 4-bromobenzylamine (9.0 g) and K2CO3 (11.2 g) in water (60 ml). Stir 20h at RT, dry the organic phase over K2CO3, evaporate and chromatograph on silica gel with Et20-CH2Cl2 to give the desired product (7.50 g) as a thick oil. Step 2: Retlux the product of step 1 (7.5 g) in 1,2-dichloroethane (40 ml) and CICH2COCI (5,0 ml) for 5h, then evaporate and use the resultant residue directly in the next step. Step 3: Stir the product of step 2 in DMSO (80 ml), water (10 ml) and Nal (8 g), cool in ice, add cone. NH4OH solution (15 ml) and stir to RT for 20h. Add water (200 ml) dropwise, collect the solid, wash well with water and dry at 70° C/ 5 mm to give the diketopiperazine, suitable for the next step. Step 4: Stir a mixture of the product of step 3 (6.8 g), 1,2-dimethoxyethane (60 ml) and NaBH4 (3.4 g) under N2, add BF3-OEt2 (6.8 ml) dropwise, then heat at 100° C for 10h. Cool and add CH3OH (20 ml) dropwise, followed by cone. HCi (30 ml). Heat at 100° C for 1h„ cool, basify with excess 2N NaOH and extract with EtOAc. Dry over K2CO3 and evaporate to obtain the piperazine (5.85 g), suitable for the next step. Step 5: Stir for 20h. at RT a mixture of the product of step 4 (5.48 g), N-Boc-4-piperidinone (4.32 g), HOAc (1.15 ml), CH2CI2 (80 ml) and sodium triacetoxy-borohydride (NaBH(0Ac)3) (8.3 g). Add excess aqueous Na2C03 solution slowly, stir for 0.5h, separate and filter the organic phase through a pad of silca gel, washing with 10:1 CH2Cl2-Et20 to elute all of the product. Evaporate and dissolve the residue in Et20 (100 ml). Stir and add a 4M solution of HCI in 1,4-dioxane (10 ml) dropwise. Collect the solid, wash with EtaO, and stir with CH2CI2 and excess aqueous NaOH. Dry the organic phase over K2CO3 and evaporate to obtain the desired product (5.45 g). Step 6: Stir at RT for 2h a mixture of the product of step 5 (1,5 g) and TFA (4 ml). Evaporate, dissolve in CH2CI2 and wash with excess 1N NaOH solution. Dry over K2CO3 and evaporate to obtain the product (1.15 g). Compound 1A: Following the standard procedure, react the product of step 6 with 2,6-dimethylben2oyl chloride in CH2CI2 and aqueous NaOH, and convert the product to the hydrochloride. Mp 185-192° C (decomposition). HRMS found: 498,2130; MH" Calc; 498.2120, Compound IB: Following the standard procedure, couple the product of step 6 with 2-amino-6-methylbenzoic acid using HOBT and DEC with diisopropyiethylamine in DMF, purify the amide by preparative TLC and convert to the hydrochloride. Mp 188-196° C (decomposition). HRMS found: 499.2069; MH^ Calc: 499.2072. Compound 1C: Following the above method, couple the product of step 6 with 2-amino-6-chlorobenzoic acid and convert after purification to the hydrochloride. Mp 192-200°C (decomposition). HRMS found: 519.1530; MH*Calc: 519.1526. Example 2 A. R^ = 2,6-Me2C6H3 B. R^ = 2-NH2-6-CI-C6H3 C. R^ = 2-Me-6-OH-C6H3 D. R^ = 2-Me-6-NH2C6H3 Step 1: Stir the product of Example 1, step 4 (1.00 g), N-t-butoxycarbonyl-4-piperidinone (0.77 g) and titanium (IV) isopropoxide (Ti(0iPr)4) (1.00 g) for 20h at RT in CH2CI2 (15 ml), reflux for 3h and cool to RT. Add diethylaluminum cyanide (Et2AICN) (4.2 ml of 1M toluene solution) and the stir for 5 days at RT under dry N2. Workup in CH2Cl2-aq. NaOH, dry and evaporate the organic phase and chromatograph on silica gel with CH2CI2-CH3OH (100:1) to obtain the desired product (0.72 g). Step 2: React the product of step 1 (0.70 g) in dry THF (15 ml) under N2 with CHsMgBr (4 ml of 3M Et20 solution) at RT for 20h. Workup in EtOAc- water and filter the organic phase through silica gel, washing with EtOAc. Evaporate to obtain the desired product (0.65 g). Step 3: Deprotect the product of step 2 with TFA according to the procedure described in Example 1, step 6. Compound 2A: React the product of step 3 with dimethylbenzoyi chloride as described in Example 1 and convert to the.HCI salt. Mp 180-187'C (decomposition). HRMS Found: 512.2272; MH* Calc: 512.2276. Compound 2B: React the product of step 3 with 2-amino-6-chlorobenzoic acid as described in Example 1, purify the crude product by preparative TLC and convert to the HCI salt. Mp 195-200° C (decomposition). HRMS Found: 535.1662; MH* Calc: 535.1652. Compound 2C: React the product of step 3 with 2-hydroxy-6-methylbenzoic acid as described in Example 1, purify the crude product by preparative TLC and convert to the HCI salt. Mp 206-210°C (decomposition). HRMS Found: 514.2067; MH* Calc: 514.2069. Compound 2D: React the product of step 3 with 2-amino-6-methylbenzoic acid using a procedure similar to that described in Example 1, purify the crude product by preparative TLC and convert to the HOI salt. Mp 202-209'C (decomposition). HRMS Found: 513.2227; MH* Gale: 513.2229. Example 3 A. R^= 2,6-di'Me-CsH3 B. R^ = 2-NH2-6-Cl'C5H3 C. R^ = 2.4-di-Me-3-pyrtdyl Step 1: Reflux and stir a mixture of S-alanine methyl ester hydrochloride (14 g), anhydrous NaaCOs (60 g), dry CH3CN (125 ml), chlorodiphenylmethane (22.3 g) and Nal (5 g) for 6 hr. Cool, add ice-HgO and extract with Et20 (350 ml, then 50 ml). Combine the Et20 extracts and wash with portions of IN aq. HCl: 200 ml, 100 ml, then 4 x 10 ml. Combine the aqueous acid extracts, stir and add excess Na2C03 in small poprtions until the mixture is basic. Extract with Et20, dry over MgS04 and evaporate to obtain the N-diphenylmethyl compound (23.2 g). Step 2: Reflux all of the above compound with CICH2COCI (10 ml) in dichloroethane (60 ml) for 4 h. Evaporate, and co-evaporate with toluene (20 ml). Dissolve the residue in CH2CI2 (200 ml), stir for 0.5 h with activated carbon (10 g), filter and evaporate. Stir the residue with ice cooling in DMSO (200 ml) and gradually add concentrated aqueous NH3 (100 ml), then Nal (10 g). Stir at RT for 20 hr. Add iced water (500 ml), collect the solid, wash well with water, then with several small portions of a 10:1 hexane-Et20 mixture, and dry at 50° C with high vacuum to obtain the solid diketopiperazine (15.5 g). Recrystallise a small sample from CH2CI2-hexanes: mp 186-188' C; [a]o^^ = +272.6°. Step 3: Stir the product of step 2 (4,0 g) in dimethoxyethane (40 ml) and NaBH4 (1.6 g) under N2 and add BFs-OEta (3.2 ml) slowly. Reflux for 20 h. Cool and add CH3OH (10 mi) dropwise. then cone. HCl (15 ml). Reflux for 2 h., and work up in excess 2N aq. NaOH and extract with CH2CI2. Dry over K2CO3 and evaporate. Chromatograph on silica, eluting with CH2CI2-CH3OH mixtures, and finally with 5:1:0.1 v/v/v CH2Cl2:CH30H:NH40H. Combine and evaporate the product fractions to obtain the desired product (1.95 g) as a pale yellow gum. Step 4: Stir a mixture of the product of step 3 (0,50 g), N-allyloxycarbonyl-4-piperidone (0.40 g), CH2CI2 (5 ml) and NaBH(0Ac)3 (0. 70 g) at RT for 20 h. Work up in CH2CI2 and excess aq, NaOH, dry over MgS04, evaporate and isolate the product by preparative TLC, eluting with 10% Et20 in CH2CI2, to obtain the desired compound (0.80 g) as an oil. contaminated with a small amount of starting ketone, but suitable for the next step. Step 5: Stir a mixture of the product of step 4 (0.80 g), CH3CN (20 ml), water (5 ml) and pipehdine (1.5 ml). Add tri(4-sulfophenyl)phosphine (0.072 g) and palladium (II) acetate (0.02 g) and stir at RT under N2 for 2 h. Work up with aqueous NaOH, extract with 5:1 v/vtoluene:CH2Cl2, dry over K2CO3 and evaporate to obtain a yellow oil, suitable for acylation. Compound 3A: Stir and reflux a mixture of the product of step 5 (0.10 g), N-(2,6-dimethoxybenzoyl)-4-piperidinone (0.10 g), CH2CI2 (2 ml) and NaBH(0Ac)3 (0,15 g) for 2.5 h., cool, and work up with CH2CI2 and aqueous NaOH. Dry over MgS04, evaporate and isolate the major product by preparative TLC, eluting with 3:1 v/v Et20:CH2Cl2^ Precipitate the hydrochoride to obtain the desired compound as the HCI salt (0.13 g). Mp 173-177° C (decomposition). HRMS Found: 482.3175; MH*Catc: 482.3171. Compound 3B: Couple the product of step 5 with 2-amino-6-chloroben2oic acid using DEC-HOBT as described in Example 1, isolate the product by PTLC and precipitate the hydrochloride to give compound 3B. Mp 188-IGS^'C (decomposition). HRMS Found: 503.2557; MH^ Calc: 503.2578. Compound 3C: Couple the product of step 5 with 2,4-dimethylnicotinic acid using DEC-HOBt as described above, isolate the product by PTLC and precipitate the hydrochloride to give compound 3C. Mp 180-188° C (decomposition). HRMS Found: 483.3114; MH* Calc: 483.3124. Using procedures similar to those described above, the following compounds were prepared: 3 3D: Mp. B5-89°C; HRMS (MH+) found: 495.3343 .-^ I H3C M ° CH3 3E. t^p 170-175=0 "3^W^N^CH3 3F; Mp. 180-185°C Example 4 F3C O NH2 step 1: A solution of 4-trifluoromethyl acetophenone (1.88 g; 10 mmol) in dry THF (10 ml) was cooled in an ice bath and treated with freshly prepared solid (S)-2-methyl oxaborolidine (0.54g; 2 mmol). After 10 min., a solution of 2M borane-methyl sulfide complex (3 ml; 6 mmol) in THF was added dropwise over 5 min. TLC at the end of 30 min. showed that the starting material had been converted to a more polar product. The reaction was quenched with about 5 ml of CH3OH carefully until effervescence stopped; volatiles were removed in vacuo. The residue was dissolved in CH2CI2 and washed with IN HCI. water, 10% NaHCOa solution and brine. Concentration in vacuo gave 2g of a yellow gum. Flash silica gel chromatography (FSGC) using 10-20% EtOAc in hexanes furnished the desired chiral alcohol (1.6 g; 84%) as a colorless oil. TLC Rf = 0.6 in 25% EtOAc:hexanes. Step 2: To a solution of the product of step 1(1.55g; 8.16 mmol) in 10 ml of CH2CI2 cooled in an ice bath were added Bi^N (2.3 ml; 16.32 mmol) and CH3SO2CI (0.87 ml; 10.6 mmol) to form a turbid white solution. The reaction was quenched with water and the organic product was extracted with CH2CI2, washing with water, IN HCI, 10% NaHC03 solution and brine. Concentration in vacuo gave the chiral mesylate (2.1 g; 96%) as a pale yellow oil. TLC Rf = 0.6 in 25% EtOAc:hexanes. Step 3: A solution of the product of step 2 (2.1g; 7.8 mmol), the N-BOC protected 2(S)-methyl piperazine (1.56g; 7.8 mmol - prepared from the reaction of commercial 2(S)-methyl piperazine with N-(tert-butoxy- carbonyioxy)phthalimide) and 2,2,6,6-tetramethyl piperidine (1.34 mi; 8 mmol) in 14 ml of dry CN3CN were heated at reflux until TLC indicated complete disappearance of the mesylate (16 h). The reaction mixture was cooled to RT, diluted with CH2CI2 (50 ml) and washed with water (3 x 100 ml) and brine. The organic extract was dried over solid MgS04 and then concentrated to obtain 2.8 g of a yellow gum. FSGC (20% EtOAc in hexanes) sen/ed to isolate the desired (S,S)-diastereomer (1,5g; 52%) and its benzylic epimer, the (R,S)-diastereomer (0.5g; 17%) for a combined 69% yield. TLC Rf = 0.75 (S,S) and 0.56 (R,S) in 25% EtOAc:hexanes. Step 4: TFA (6 ml) was added to a solution of the product of step 3 in 12 ml of CH2CI2 and the resulting yellow-orange solution was stirred at RT for 8 h. The reaction was quenched by adding IN NaOH solution to adjust the pHtolO. Extractive work up in CH2CI2 gave 1.1 g of a yellow syrup. FSGC using 10% CH3OH in CH2CI2 removed the less polar impurity and gradient elution with 1% EtsN in 10% CH30H:CH2Cl2 was needed to etute the desired free amine of the (S,S) diastereomer. Yield = 0.9g (75%). TLC Rf = 0.5 in 10% CH30H:CH2Cl2. Step 5: A colorless solution of the product of step 4 (0.9g; 3.3 mmol), 4-piperidinone (0,86g; 4.3 mmol), NaB(0Ac)3H (1.05g; 4.95 mmol) and glacial AcOH (80 |al) in 8 ml of CH2CI2 was stirred at ambient temperature for a day. TLC indicated absence of starting material. The reaction mixture was diluted with 50 ml of CH2CI2, washed with IN NaOH solution, water (2 x) and brine. The CH2CI2 extract was dried over anhydrous MgS04 and concentrated to obtain 1.7g of yellow oil. FSGC (25% acetone in hexanes) was used to isolate the pure product (1.3g; 86%) as a white foam. TLC Rf = 0.6 in 25% acetone/hexanes. Step 6: TFA (5 ml) was added to a solution of the product of step 5 (1.3g; 2.87 mmol) in CH2CI2 (10 ml) and the resulting yellow orange solution was stirrred at RT for 7 h. The reaction was quenched with 1N NaOH solution and the pH was adjusted to 10. The organic product was extracted into 50 ml of CH2CI2 and washed with water, then bhne and dried over MgS04. Concentration gave the free amine (0.98g; 98%) as a yellow syrup. TLC Rf = 0.1 in 25% acetone/hexanes. Step 7: The product of step 6 (0.78g; 2.21 mmol), DEC (0.65g; 3.4 mmol), HOST (0,46g; 3.4 mmol) and 2-amino-6-chloro benzoic acid (0.51 g; 2.9 mmol) were dissolved in 8 ml of CH2CI2 to which was added diisopropylethyl amine (0.7 ml) and the mixture was stirred at ambient temperature for 16h. TLC analysis showed absence of starting material and formation of two over-lapping spots of medium polarity (rotomers of the hindered amide) as the major product. The crude product (1.3g) was isolated by extractive work up and purified through FSGC using 25% acetone in CH2CI2 as eluant to give the title compound (0.88g; 80%) as a pale yellow foam. TLC Rt = 0.45 and 0,5 in 25% acetoneiCHaCIa- A solution of hydrogen chloride in Et20 (1fv1; 3 ml) was added to a solution of the title compound free base (0.76g; 1.54 mmol) in CH2CI2 (5ml) to obtain an instantaneous white precipitate. After stirring at RT for 2 h, the vojatiles were removed on a rotary evaporator and the white residue was suspended in dry toluene (3x10 ml) and azeotroped. The white solid thus obtained was suspended in dry Et20 containing 10% EtOAc, stirred for 30 min, filtered and washed with Et20 (100 ml). The HCI salt of the title compound was dried under high vacuum to yield an off-white solid (0,88g; 95%). Mp: 205-210^ C. The product of step 6 was converted to other amides (4A-4E) as described in step 7 using the appropriate carboxylic acids. Physical data for compounds 4-4E having the following structures is as follows: R 8 k,N N^R- o wherein R8 and R2 are as defined in the table: Ex. R8 R2 Mp r C) HRMS(MH1 CF3 205-210 509.2295 4A CF3 192-195 489.2841 4B CF3 203-206 490.2681 4C CF3 186-190 488.2902 4D CF3 207-210 489.2851 4E 4F CF3 CF3 -^^ ~i .N-'O 1'^^ ,-^N 152 505 490.2796 Example 5 k^NBOC + F.CO F,CO F3C0 ^,^^-., HN NBOC XJ _=^ 24 DMF/TMP/100 C 25a 1:1 NBOC F3CO 25a F3CO iO^i Ex, 5 A solution of the racemic benzyl chloride 24 (1,26g, 5.62 mmol) which was prepared freshly from the corresponding carbinol, the 2(S)-methyl piperazine (1.12g, 5.62 mmol) and 2,2,6,6-tetramethyl piperidine (TMP) (1.9 ml, 11.2 mmol) were dissolved in dry DMF (2 ml) and heated to 100-110'C (internal temp.) for 10 h. TLC analysis showed absence of 24 and formation of two well-separated products. The mixture was diluted with water and the organics were extracted into Et20. The organic extract was washed with saturated NH4CI and brine and concentrated in vacuo to obtain 2 g of crude product. Flash chromatography on silica gel and elution first with 25% EtsO-hexane followed by 25% EtOAc-hexane gave -0.5 grams of 25a and --0.5 grams of 25b respectively (-45% combined yield). TLC Rf = 0.6 (for 25a) and 0.4 (for 25b) in 25% EtOAc-hexanes. Purified 25a was treated as described previously to obtain the final products 5 to 5F having the formula . F3CO 4^ R' ^N r 0 wherein R2 is as defined in the table: 0, Ex. R2 mp ro HRMS 208-212 519.2958 5A 198-203 535.2913 5B 233 (sharp) 539.2390 5C ^ CI 190 575,1800 5D ^ 253 ■ 558.1887 5E 99 202 519.2964 5F V?' 190 535.2901 5G 198-203 ~^ 5H ^r 205-210 "■^ Example 6 n Step 1: Y 0 R' ^^CHO F3CO .F3CO 28a. {S,S)-Diastereomer 28b. (R,S)-Diastereomer F3CO 27 HN NBOC 26 Ti(0iPr)4 / EtaAICN 1) NaHMDS/Et-l 2) Na{0Ac)3BH MgBrj : EtaO / CH3CN A mixture of the aldehyde 26 (3,9g, 20.5 mmol), the 2(S)"methyl-N-BOC-piperazine (4.1 g, 20.5 mmol) and Ti(0iPr)4 (6.1 mL; 20.5 mmol) in 40 ml of CH2CI2 was stirred at RT for 24 h. Et2AICN was introduced and stirred for an additonal day. The reaction mixture was processed as described before to obtain 4.71 grams (58%) of the cyano amine 27 after FSGC (TLC Rf = 0.45/0.5 for diastereomers seen with 25% Et20-hexanes as solvent). Step 2: Sodium hexamethyldisilazide (1M; 3.1 ml) was added to a solution of 27 (1g; 2.5 mmol) in dry THF cooled in a dry ice/acetone bath. The resulting bright yellow solution was treated with CH3CH2I (7.5 mmol; 0,6 ml). The dry ice bath was removed and the reaction was stirred at ambient temperature for 15 min. followed by gentle warming in a warm water bath (40°C) for 30 min. TLC indicated two well-separated spots. Standard extractive work up and purification by FSGC gave two alkylated compounds (combined yield: 0.7g; 70%). TLC Ri = 0.6 and 0.4 (25% EtOAc/hexanes). Step 3: The product of step 2 was stirred with NaBH(0Ac)3 (2x) and MgBr2:OEt2 (1x) in CH3CN for a day. The reaction mixture was quenched with water, the organics were extracted into EtOAc and processed to obtain 0.8 grams of crude product. FSGC (25% EtOAc-hexanes) gave -0.4 grams of each diastereomer (combined yield ^100%). TLC Rf = 0.55 (28a) and 0.45 (28b) in 25% EtOAc-hexanes. Step 4: Compound 28a (S.S-diastereomer) was processed through the usual 5 step sequence to complete the synthesis of compounds of Example 6, 6A and SB with an ipso-methyl group as well as compounds 6C and 6D which lack the ipso-methyl group; F,CO L.; T o Ex, R6 R2 mp (°C) MS (MH") CH 204 549.5 6A CH^ 253 589.4 6B CH 260 534.4 6C H 225 520.4 6D H 215 575.4 Example 7 The synthesis of compounds with an alky! or arylsulfonyl R8 group at the para position started with the corresponding para-substituted acetophenone which was treated as in Example 4, steps 1-6 to obtain the sulfone containing compounds of Example 7 havng the formula: R' O wherein R8 and R2 are as defined in the table: Ex. R8 R2 Mp r c) HRMS (MH*) 7 H3CSO2- 220-225 498.2790 7A H3CSO2- NH2 212-215 519.2197 7B ca, 62 190 (dec.) 604.2861 7C 02 NH2 178 (dec.) 625.2246 7D ca, ,/ NH- 170 (dec.) 605.2799 7E ca, ^ o- 170 (dec.) 609.2540 7F 200 (dec.) 612.2336 7G ca 02 Cl-yS-CI 158 (dec.) 644.1735 7H H3CSO2- 197 (dec.) 514.2847 Example 8 F^C O Step 1: A solution of the product of Example 4, step 4 (1,25g; 4.5 mmol), N-BOC-4-piperidinone (0.91 g; 4.6 mmol) and (Ti(0iPr)4) (1.4 ml; 4.6 mmol) in 10 ml of CH2CI2 was stirred at ambient temperature for 24 h. The reaction mixture was then treated with Et2AICN (5.5 ml; 1M solution in toluene) and stirring continued for 20 h. The reaction mixture was diluted with EtOAc and stirred with saturated NaHCOs solution (10 min.) and the layers were separated as much as possible. The turbid (from inseparable aqueous layer) organic layer was treated with excess celite and filtered, washing the filtercake with EtOAc. The filtrate layers were separated and the organic layer was washed with water and brine, dried over anhydrous MgS04 and concentrated to obtain 2.16g (98%) of an amber gum. Step 2: The Strecker amine from step 1 (2.16g) was dissolved in dry THF, cooled in an ice bath and treated with CHsMgBr (7.5 ml of a 3M solution in Et20). After 1 h, the ice bath was removed and the yellow, heterogeneous reaction mixture was stirred at RT for 18h, The reaction was quenched with saturated NH4CI solution, diluted with water and extracted with CH2CI2. Concentration gave 2,2 g of a yellow gum which was purified by FSGC, eluting the major product away from more polar impurities using a 1:1 mixture of CH2Cl2:EtOAc. The ipso-methyl compound was isolated as ayellowgum (1,85g; 88%). TLC Rf = 0,5 in 1:1 Et20:hexanes. Step 3: TFA (6 ml) was added to a solution of the product of step 2 (1.5g; 3.2 mmol) in 10 ml of CH2CI2 and stirred at 25^ C for 2 h. The reaction was quenched with IN NaOH solution to a pH of 9-10 and processed by extraction into CH2CI2 to obtain 1.2 g of crude product. FSGC using 1:1 CH2Cl2:EtOAc removed all the less polar impurities and gradient elution with 10% CH3OH in CH2CI2 and finally with 10% (ca. 7N-NH3) CH3OH in CH2CI2 led to the isolation of the free piperidine as a yellow gum (1.07g; 90%). TLC Rt = 0,2 in 10% CH30H:CH2Cl2. Step 4: A solution of the product of step 3 (1.03g; 2.8 mmol), 2,4-dimethyl nicotinic acid (0.42g; 2.8 mmol), DEC (0.8g; 4.2 mmol). HOBT (0.57g; 4.2 mmol) and diisopropyl ethyl amine (1ml; 5.6 mmol) in CH2CI2 (15 ml) was stirred at 25^" C for 24 h. The reaction mixture was diluted with CH2CI2 (25 ml), washed with water, 10% NaHC03 solution and brine, then concentrated to obtain 1.6g of crude oil. FSGC of this material using gradient elution with 10% acetone-CH2Cl2 followed by 2-5% CH3OH in CH2CI2 gave the title compound (1 The free base of the title compound (1g; 2 mmol) isolated above was dissolved in a 1:1 mixture of EtOAc:Et20 (8 ml) and a fresh solution of hydrogen chloride in EtaO (6.1 ml of a 1M solution) was added, instantly forming a white precipitate. After stirring at 25° C for 1h. the volatiles were removed in vacuo. The product was suspended in Et20 and filtered, washing the filtrate with EtaO. The HCI salt of the title compound thus obtained was dried in vacuo (1.1g; mp. 213-215'C). HRMS (MH+) 503.2997. The following amides 8A-8E were prepared in a similar manner from the product of step 3 using appropriate acids, and compounds 8F-8H, wherein the R8-substituent is a p-methyl sulfonyi group were similarly prepared. wherein R8 and R2 are as defined In the table: 0 Ex. R8 R2 Mp r c) HRMS (MH^) 8A CF3 216 503.3021 8B CF3 222-224 504.2850 8C CF3 262-263 502.3039 8D CF3 NHj 216-218 523.2466 8E CF3 210-212 519.2970 8F -SO2CH3 201-205 512.2955 8G -SO2CH3 NH2 217-221 533.2355 8H -SO2CH3 216-219 514.2736 81 -CF3 195-198 8J 8K -CF3 -CF3 CI C! CK/^/Cl CI 250-255 223-226 528.1791 576.1562 8L -CF3 >245 528.2439 8M -CF3 Br 176-181 570.1739 8N -CF3 Br-^...-^^Br Br 218-223 708.0040 80 -CF3 CI 215-220 522.2507 8P -CF3 Br 208-212 566.1987 8Q -CF3 Br CI 190-194 586.1442 8R 'CF3 CI 255-257 526.2243 Using procedures described following the table, compounds 8S-8EE of the structure 11 F3C o ' were prepared, wherein R" is defined in the table: Ex. R11 Mp (° C) HRMS (MH*) 8S -OH 210-220 (2xHCI salt) 518.2997 8T -OC(0)NHCH3CH3 205-210 (2xHCI salt) 589.3374 8U -0S0^CH3 165-171 (2xHCI salt) 596.2757 BV ^-^N*-o- 199-204 (2xHCl salt) 595.3254 8W -CHO 88-92 530.2985 8X -CH=NH-0CH3 202-205 (2xHCl salt) 559.3260 8Y -CHF, >245 (dec) (2xHCl salt) 552.3020 82 -NH-C(0)-NH-CH,CH3 214-219 (2xHCI salt) 588.3521 8AA -NH, 92-98 517.3154 8BB -NHSO^CH.CH, 205-211 (2xHCI salt) 609.3078 8CC -F 212-217 (2xHCl salt) 520.2949 8DD -CI 235-238 (2xHCI salt) 536.2663 SEE -Br 237-240 (2xHCI salt) 580.2141 8S: The tri-hydrochloride salt of the product of Example 8, step 3 (75 mg. 0,16 mmol), EDC (61 mg, 0.32 mmoi), HOBT (49 mg, 0.32 mmol), iPr^NEt (0.16 ml, 0.96 mmol), and 2.6-dimethyl-4-hydroxy-benzoic acid (53 mg, 0,32 mmol) were taken up in CH^CI^ and stirred at 25 °C for 20 h. The solution was concentrated. Purification via preparative TLC (EtOAc, 5103) gave the title compound as a yellow oil. m.p. (2xHCI salt) 210-220 ""C. HRMS (MK) calcd. for C^H3AN3F3, 518,2994; Found, 518,2997. 8T: 8S (100 mg, 0.19 mmol), ethyl isocyanate (0.05 ml, 0.58 mmol), and Et3N (0.13 ml, 0,95 mmol) were taken up in CH^CIj and stirred at 25 °C for 16 h. The solution was diluted with CH^Cl^ and washed with 1 N NaOH. The organic layer was dried (Na^SOJ, filtered, and concentrated. Purification via preparative TLC (2/1 EtOAc/hexanes, SiO^) gave the title compound as a yellow oil. 8U: 8S (250 mg, 0.48 mmol), methane sulfonyl anhydride (250 mg, 1.44 mmol), and NaH (38 mg, 60 wt% in oil) were taken up in THF and stirred at 25 °C for 20 h. The solution was diluted with EtOAc and washed with sat'd NaHC03. The organic layer was dried (Na^SOJ, filtered, and concentrated. Purification via preparative TLC (1/1 EtOAc/hexanes, SiO^) gave the title compound as a yellow oil (280 mg, 98%), 8V; The tri-hydrochloride salt of the product of Example 8, step 3 (50 mg, 0,1 mmol), EDC (38 mg, 0,2 mmol). HOBT (27 mg, 0.2 mmol), iPr.NEt (0.07 ml, 0.4 mmol), and 2,6-dimethyl'4'(4-pyridyl'N'Oxide)-benzoic acid (73 mg. 0.3 mmol) (see preparation below) were taken up in CH^CI^ and stirred at 25 ^C for 19 h. The solution was concentrated. Purification via preparative TLC (2/1 acetone/hexanes, SiO^) gave 8V as a yellow oil (23 mg, 39%). Preparation of 2,6-dimethyl-4-(4-pyridyl"N-oxide) benzoic acid HO.C^ Mel Me0.cA ^^'^^^^^^^ MeO.cO. Tf,0 OH -"^^'^^OBn H2 .A^ MeOaCvJv. 4-pyridyl boronic acid MeOaC A^oTf Pd(PPh3)4 MeOaCY^ HO2C NaOH Step A: 4-Benzyloxy-2,6-dimethyl benzoic acid (8.7 g, 34 mmol; Thea, S. etal Journal of the American Chemical Society ^985, 50, 1867), Mel (3.2 ml, 51 mmol), and Cs2C03 (17 g, 51 mmol) were allowed to stir in DMF at 25 °C for 17 h. The solution was filtered and partitioned between Et^O and water. The aqueous layer was extracted with Et^O, The combined Et^O layers were washed with HjO and brine. The organic layer was dried (MgSOJ, filtered, and concentrated. Purification via flash chromatography (10/1 hexanes/Et^O, SiO^) gave 8,6 g (94 %) of the methyl ester as a colorless oil. Step B: The benzyl protected phenol (8.5 g, 32 mmol) and Pd/C (750 mg, 10 wt % Pd) were taken up in CH3OH. The solution was charged with 50 psi Hj and shaken in a Parr apparatus at 25 °C for 17h. The solution was filtered (Celite). Concentration gave 5.6 g (98 %) of the phenol as a white solid. Step C: The phenol (3.5 g, 19.4 mmol) and iPr.NEt (3.76 g, 29.1 mmol) were dissolved in CH.CI^ at 0 °C. Triflic anhydride (Tfp) (4.2 ml, 25.2 mmol) was added dropwise to the solution at 0 °C. The solution was warmed to 25 "C and stirred at that temperature for 4.5 h. The solution was diluted with CH^Cl^ and washed with sat NaHCOj. The aqueous layer was extracted with CH^CI^. The combined organic layers were dried over Na.SO,. Filtration and concentration gave the crude aryl triflate. Purification via flash chromatography (10/1, hexanes/Et^O, SIO^) gave 5.7 g (94 %) of the triflate as a yellow oil. Step D: The triflate (1g, 3.2 mmol). 4-pyridyl boronic acid (1.2 g, 9.6 mmo!), Pd(PPh3), (370 mg, 0.32 mmol), and Na,C03 (1 g, 9.6 mmol) were taken up in DME/H,0 (4/1, 25 ml). The solution was heated to 90 °C (oil bath) under N^ fori 8 h. The solution was partitioned between EtOAc and H^O. The aqueous layer was extracted with EtOAc. The combined EtOAc layers were dried (Na^SOJ. Filtration and concentration gave a dark brown oil. Purification via flash chromatography (3/1 hexanes/EtOAc, StO^) gave 770 mg (100 %) of the pyridyl derivative as an orange oil. Step E: The pyridyl derivative (390 mg, 1.6 mmol) and mCPBA (550 mg, 3.2 mmol) were dissolved in CHfil^. The solution was stirred at 25 °C for 18 h. The solution was diluted with CH^CI^ and washed with 1 N NaOH, The organic layer was dried (Na^SOJ. Filtration and concentration gave 400 mg (97 %) of the N-oxide as an orange oil. HRMS (fvlH*) calcd. for C.^H^AN, 258.1130; Found, 258.1131. Step F: The methyl ester (400 mg, 1.6 mmol) was taken up in 5 mi of 3 N NaOH and 2 ml of EtOH. The solution was heated at reflux for 20 h. The solution was concentrated. The residue was treated with cone. HCI. The resulting solid was filtered and washed with water and brine. After drying under high vacuum, the free acid (377 mg, 100 %) was obtained as a tan solid, m.p. >225'C(decomp). HRMS (MK) calcd. for C,,H,,03N, 244.0974; Found, 244.0981. 8W; 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) and iPrNEt (2 ml, 11 mmol) were subjected to the standard coupling conditions. Purification via flash chromatography (2/1 hexanes/EtOAc, SiO^) gave 898 mg (61 %) of 8W as a yellow foam. Preparation of 2.6'dimethvl-4-formvl benzoic acid tBut^OacJ^ Tf^O tButylO^cU,,^ ^^^^^^3)4 OH ,.'''\;:;^^i ^O"^^ nBuaSn -^-^ 2. QMS XACHO ^CHO Step A: 4-Hydroxy-2,6-dimethyl-benzoic acid, tert-butyl ester (6.4 g, 29 mmol) and iPr^NEt (5.6 g, 43 mmol) were taken up in CKCI^ and cooled to 0 'C. Tfp (5.8 ml, 34 mmol) was added slowly to the solution at 0 'C. The solution was stirred at 0 'C for 3 h. The solution was partitioned between sat. NaHC03 and CH^CI^. The aqueous layer was extracted with CH^CI^. The combined organic layers were dried (Na^SOJ. Filtration and concentration gave a brown oil. Purification via flash chromatography (20/1 hexanes/EtjO, SiO^) gave 7.99 g (82 %) of the triflate as a yellow solid. Step.B: The triflate (5 g, 15 mmol), LiCI (1.25 g, 30 mmol), Pd(PPh3), (340 mg, 0.3 mmol), and vinyl tributyl tin (4.5 ml, 16 mmol) were taken up in THF under N^. The solution was heated at 70 °C for 16 h. The solution was partitioned between EtOAc and sat. KF. The mixture was filtered. The organic layer was separated, and the aqueous layers were extracted with EtOAc. The combined organic layers were dried (MgSOJ. Filtration and concentration gave a yellow oil. Purification via flash chromatography (20/1 hexanes/EtjO. SiO^) gave 1.96 g (57 %) of the olefin as a yellow oil. Step C: The olefin (0.6 g, 2.6 mmol) was taken up in CH^CI^/MeOH (1/1). The solution was cooled to -78 ""C. Ozone was bubbled through the solution until a dark blue color persisted. The reaction was quenched with dimethyl sulfide. The reaction was concentrated to furnish the aldehyde as an oil. Step D: The tert-butyl ester (650 mg, 2.8 mmol) and TFA (3 ml) were taken up in CHjClj and stirred at 25 °C for 19 h. Concentration of the solution gave the acid as a beige solid. 8X: 8W (100 mg, 0.19 mmol), H,NOMe-HCI (28 mg, 0.34 mmol), NaOAc (32 mg, 0.46 mmol) were taken up in MeOH. The solution was stirred at 25 *'Cfor17h. The solution was concentrated. The residue was partitioned between CH^CIj and 1 N NaOH. The aqueous layer was extracted with CH2CI2. The combined organic layers were dried (Na^SOJ. Filtration and concentration gave the crude product. Purification via preparative TLC (1/1 hexanes/EtOAc, SiO^) gave 85 mg (84 %) of 8X. 8Y: 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, 0.15 mmol) were subjected to the standard coupling conditions (EDC/HOBT/ iPr^NEt). Purification via preparative TLC (2/1 hexanes/EtOAc, SiO^) gave 64 mg (73 %) of 8Y. Preparation of 4-difluoromethvl-2.6-dimethvl benzoic acid tButylOaC^ [Bis(2-methoxyethyl)amino]- tButyl02C XA CHO sulfur trifluoride TFA Step A: The aldehyde (400 mg, 1.7 mmol), [bis(2-methoxyethyl)amino]-sulfur trifluoride (640 mg, 2.9 mmol), and EtOH (0.02 ml, 0.34 mmol) were taken up 1,2-dichloroethane and stirred at 65 "C for 6 h and at 25 "C for 19 h. The solution was quenched with sat. NaHC03. The aqueous layer was extracted with CH^CIj. The combined organic layers were dried (NaSOJ. Filtration and concentration gave the crude product. Purification via preparative TLC (10/1 hexanes/Et^O, SiOJ gave 210 mg (50 %) of the difluoro derivative. Step B: The tert-butyl ester (210 mg. 0.82 mmol) and HCI (2.1 ml of 4 M in dioxane, 8.2 mmol) were taken up in MeOH. The solution was stirred at 45 "C for 20 h. The solution was concentrated to obtain the acid as a white solid. 1)(CF3CO)20 2)Br2 8Z: The tri-hydrochloride salt of the product of Example 8, step 3 (811 mg, 1.7 mmol) and 4-[(ethylamino)carbonylamino]-2,6-dimethyl benzoic acid (400 mg, 1.7 mmol) (see preparation below) were subjected to the standard coupling conditions (EDC/HOBT/iPrjNEt). Purification via flash chromatography (1/1 hexanes/acetone, SiO^) gave 803 mg (81 %) of 8Z as a foam. Preparation of 4-f(ethvlamino)carbonvlamino]-2,6-dimethvl benzoic acid NHC(0)CF3 1)MeLi 2) sec-BuLi 3) B0C2O ethyl isocyanate tButylOaC NHC(0)CF3 NaOH \^^..-T5^NH2 CuCl tButylOsC'y'^ HO2C H H tButylOgC'y*'^ ° I HCI Step A: 3,5-Dimethyl aniline (18.5 ml, 149 mmol) was taken up in CH^CIj, The solution was cooled in a water bath. Trifluoroacetic anhydride (29.5 ml, 209 mmol) was added slowly to the solution. After the addition, the solution was stirred at 25 °C for 15 minutes. Bromine (7,3 ml, 142 mmol) was added slowly to the solution while maintaining the RT water bath. The solution was stirred at 25 'C for 3.5 h. The solution was quenched with 10%Na^S2O3. The aqueous layer was extracted with CH^CIj. The combined organic layers were dried (MgSOJ, treated with activated carbon and filtered. Concentration gave an orange solid. Purification via recrystallization (hexanes/Et^O) gave two crops (34 g total, 77%) of the brominated derivative as a white solid. Step B: The aryl bromide (17 g, 57 mmol) was taken up in THF and cooled-to -78 °C under N^. Methyllithium/LiBr (54 ml of a 1.5 M solution in Et^O, 80 mmol) was added slowly to the solution at -78 'C. After 5 min of stirring, sec-BuLJ (62 ml of a 1.3 M in cyclohexane, 80 mmol) was added slowly to the reaction solution at -78 'C. After 5 min, di-t-butyl dicarbonate (22.5g. 103 mmol) in THF was added to the solution at -78 °C. The solution was warmed to 25 "^C. After 30 min, the reaction mixture was partitioned between water and CH^CIj. The aqueous layer was extracted with CH^CI^. The combined organic layers were dried (MgSOJ. Filtration and concentration gave a yellow solid. Purification via flash chromatography (1/1 to 1/4 hexanes/CH^CI,, SiOJ gave 13.1 g (72 %) of the tert-butyl ester as an off-white solid. Step C: The trifluoro-acetamide (1.0 g, 31 mmol) and NaOH (2,5 g, 62 mmol) were taken up in MeOH/Hp (3/1) and heated at 60 °C for 3 h. The solution was partitioned between CH^CIj and water. The aqueous layer was extracted with CH^CI^. The combined organic layers were washed with water and dried (Na^SOJ. Filtration and concentration gave 6.4 g (93 %) of the aniline as an orange solid. Step D: The aniline (1 g, 4.5 mmol), ethyl isocyanate (0.4 ml, 5 mmol), and CuCI (90 mg, 0.9 mmol) were taken up in DMF at 0 °C. The solution was warmed to 25 °C and stirred at that temperature for 2h. The solution was partitioned between EtOAc and 10 % NH.OH. The aqueous layer was extracted with EtOAc. The combined layers were washed with brine and dried (MgSOJ. Filtration and concentration gave a yellow solid. Purification via flash chromatography (3/1 to 1/1 hexanes/EtOAc, SiOJ gave 904 mg (69 %) of the urea as a yellow solid. Step E: The tert-butyl ester (900 mg, 3.1 mmol) and 4 M HCI in dioxane (3 ml) were taken up in iPrOH and heated at 45 'C for 3.5 h and at 25 °C for 16.5 h. The solution was concentrated under reduced pressure. The residue was partitioned between Et^O and 1 N NaOH. The aqueous, basic layer was extracted with Et^O. The aqueous layer was cooled to 0 °C and acidified with cone. HCI (pH = 1-2). The aqueous layer was extracted with EtOAc, The combined EtOAc layers were dried (Na^SOJ. Filtration and concentration gave the 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 4-amino-2,6-dimethyl benzoic acid (710 mg, 4.3 mmol) (see preparation below) were subjected to the standard coupling conditions (EDC/HOBT/iPr^NEt). Purification via flash chromatography (2/1 hexanes/acetone, SiO^) gave 1J6 g (52 %) of 8AA as a yellow foam. Preparation of 4-amino-2.6-dimethvl benzoic acid \pY'^'^2 HCI YV*^*^^ The tert'butyl ester (950 mg, 4.3 mmol) and HCI (11 ml, 4 M in dioxane) were taken up in MeOH at heated at 45 T for 20 h. The solution was concentrated to obtain the acid (710 mg) in quantitative yield, 8BB: 8AA (100 mg, 0.19 mmol) and ethane sulfonyl chloride (0.02 ml, 0.21 mmol) were taken up in pyridine and stirred at 25 *"€ for 19 h. The solution was concentrated. The residue was partitioned between 1 N NaOH and CHjClj. The aqueous layer was extracted with CH^Clj. The combined organic layers were dried (Na^SOJ. Filtration and concentration gave a brown oil. Purification via preparative TLC (2/1 hexanes/acetone, SIO^) gave 100 mg (86 %) of 8BB as a coloriess oil. 8CC: The trihydrochloride salt of the product of Example 8, step 3 (127 mg, 0.27 mmol) and 4-fluoro-2,6-dimethyl benzoic acid (58 mg, 0.35 mmol) (see preparation below) were coupled according to the general procedure (EDC/HOBT/iPr^NEt). Purification via preparative TLC (2/1 hexanes/ EtOAc, SiOJ gave 8CC as a coloriess oil (87 mg bis-HCI salt, 54 %). Preparation of 4-fluoro-2.6'dimethvl benzoic acid MeOsC^ MeOsC^ HO2C y 4-Amino-2,6-dimethyl benzoic acid (200 mg, 1.1 mmol) and NOBF, (196 mg, 1.7 mmol) were heated in 1,2-dichlorobenzene at 100'C for 30 min. The solution was cooled and diluted with MeOH and water. A few pellets (2-3) of KOH were added, and the solution was heated at reflux for 16 h. The solution was concentrated. The residue was partitioned between Et^O and 1 N NaOH. The aqueous layer was extracted with Et^O. The aqueous layer was cooled to 0 ""C and acidified with cone. HCI (pH = 1-2). The aqueous layer was extracted with CH^CIj. The organic layers were dried (Na^SOJ, Filtration and concentration gave 58 mg (31 %) of the acid as a tan solid. 8DD: The trihydrochloride salt of the product of Example 8, step 3 (150 mg, 0.31 mmol) and 4-chloro-2,6-dimethyl benzoic acid (76 mg, 0.41 mmol) (see preparation below) were coupled according to the general procedure (EDC/HOBT/iPr^NEt). Purification via preparative TLC (4/1 hexanes/ acetone, SiO^) gave 8DD as a colorless oil. Preparation of 4-chloro-2.6-dimethvl benzoic acid "'0^=^ ,8u„l nitrite MeO^CY "°== T 4-Amino-2,6-dimethyl benzoic acid (172 mg, 0.96 mmol) and CuCI^ (155 mg. 1.15 mmol) were taken up in CH3CN at 0 'C. Tert-butyl nitrite (0.17 ml, 1,4 mmol) was added to the solution at 0 °C. The solution was warmed to 25 'C and then at 65 'C for 45 min. The solution was partitioned between EtsO and water. The aqueous layer was extracted with Et^O. The combined organic layers were washed with brine and dried (MgSOJ. Filtration and concentration gave the methyl ester. The methyl ester was hydrolyzed as described above for the fluoro derivative (KOH). After extractive workup, 4-chloro-2,6-dimethyl benzoic acid (158 mg. 89 %) was obtained as a yellow solid. SEE: The trihydrochloride salt of the product of Example 8, step 3 (180 mg, 0.38 mmol) and 4-bromo-2.6-dimethyl benzoic acid (95 mg. 0.41 mmol) (see preparation below) were coupled according to the general procedure (EDC/HOBT/iPr,NEt). Purification via preparative TLC (4/1 hexanes/ acetone, SiO^) gave BEE as a colorless oil (140 mg bis-HCI salt, 56 %). Preparation of 4-bromo-2.6-dimethvl benzoic acid tButylOacJ^ Pd(PPh3)4 ^ tButy(02cJ^ ^>^^2 HOgC ^^^OTf Me3Sn-SnMe3 '^^SnMe3 2) TFA ^—Br Step A: The triflate (500 mg, 1.48 mmol), hexamethylditin (0.31 mmol, 1.48 mmol), LiCI (377 mg. 8,9 mmol), and Pd(PPh3), (171 mg, 0.15 mmol) were heated in THF (70 °C) under N^ for 21 h. The solution was partitioned between Et^O and pH = 7 buffer (NH.OAc). The aqueous layer was extracted with Et^O. The combined Et^O layers were washed with brine and dried (Na^SOJ. Filtration and concentration gave the crude aryl stannane as a yellow semisolid. Step B: The aryl stannane (0.74 mmol) was taken up in CH.CIj at 0 "C. Bromine (0.7 ml of 1 M Br^ in CH^Cy was added to the solution. The solution was stirred at 0 'C for 30 min. The solution was diluted with CH^CIj and washed with 10 % Na^S^Oj. The aqueous layer was extracted with CHjClj. The combined organic layers were dried (Na^SOJ. The solution was filtered. TFA (2 ml) was added to the solution, and the solution was stirred at 25 "C for 17 h. The solution was concentrated. The residue was partitioned between Etp and 1 N NaOH. The aqueous layer was extracted with EtjO. The aqueous layer was cooled to 0 "C and acidified with cone. HCI (pH = 1-2). The aqueous layer was extracted with CH^CIj. The combined organic layers were dried (Na^SOJ. Filtration and concentration gave 100 mg (59 %) of the acid as a white solid. Using procedures described following the table, compounds 8FF-8HH of the structure O CI were prepared, wherein R" is defined in the table: Ex. R11 Mp C C) HRMS (MM*) 8FF -OCH3 217-220 (2xHCl salt) 572.2048 8GG -OH 198-204 (2xHCl salt) 558.1898 8HH ^^N*-^ 200-205 (2xHCl salt) 635.2172 8FF: The trihydrochloride salt of the product of Example 8, step 3 (100 mg, 0.21 mmol) and 2,6-dichloro-4-methoxy-benzoic acid (140 mg, 0.63 mmol) were coupled according to the general procedure (EDC/HOBT/iPr^NEt). Purification via preparative TLC (3/1 hexanes/EtOAc, SiOj) gave BFF as a colorless oil (27 mg, 23 %). 8GG: The trihydrochloride salt of the product of Example 8, step 3 (330mg, 0.7 mmol) and 2,6-dichloro-4-hydroxy-benzoic acid (290 mg, 1.4 mmol) (see preparation below) were coupled according to the general procedure (EDC/HOBT/iPr,NEt), Purification via preparative TLC (1/1 hexanes/ EtOAc, SiO,) gave BGG as a colorless oil (75 mg, 19 %). Preparatiion of 2.6-dichloro-4-hvdroxv-benzoic acid Yj BBr3 Tj CI CI 2,6-Dichloro-4'methoxy-ben2oic acid (500 mg, 2.3 mmol) was taken up in CHjClj and cooled to -78 °C, BBrj (6.9 ml of a 1 M solution in CH^Cg was added to the solution at -78 ""C. The solution was warmed to 25 'C and stirred at that temperature for 16 h. The solution was quenched with 3 N NaOH, The aqueous layer was extracted with CH2CI2. The aqueous layer was cooled (0 "C) and acidified with cone. HCI (pH = 1-2). The aqueous layer was extracted with CHjCI^. The combined organic layers were dried (Na^SOJ. Filtration and concentration gave the crude phenol which was used without further purification. 8HH: The trihydrochloride salt of the product of Example 8, step 3 (96 mg, 0.2 mmol) and 2,6-dichloro-4-(4-pyridyl-N-oxide)-ben2oic acid (55 mg, 0.2 mmol) (see preparation below) were coupled according to the general procedure (EDC/HOBT/iPrjNEt). Purification via preparative TLC (1/5 hexanes/acetone, SiO^) gave 8HH as a colorless oil (54 mg, 43 %). Preparation of 2.6-dichloro-4-(4-pvridvl-N-oxide) benzoic add Cl-Y-^CI 4-pyridyl boronic acid ^' "^ ^ t-ButylOaC 1)mCPBA 2)TFA 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), and CsF (540 mg, 3.6 mmol) were taken up in NMP and heated at 100 'C under N^ (16 h). The solution was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine and dried (Na^SOJ. Filtration and concentration gave the crude product. Purification via preparative TLC (1/1 hexanes/EtOAc, SiO^) gave 68 mg (12 %) of the pyridyl ester. The tert-butyl ester was converted into the acid as done previously for the dimethyl derivative (a. mCPBA /b. TFA). Using suitable starting materials and the procedures described for examples 8S to 8HH, the compounds of the following structure were prepared: FaC ^N O R 11 ,11 wherein R is defined in the table Ex. R' m.p. CO HRMS(MH') calc. HRMS (MH-) found 811 •OCH, 236-240 532.3151 532.3166 8JJ -CH, >260 516.3202 516.3213 8KK V>^EJ^ 186-190 603.3522 603.3513 8LL ,sO 202-208 579.3311 579.3303 8MM \A^N 210-216 579.3311 579.3311 8NN o \^^^- 195-203 595.3260 595.3256 800 .o > 230 (dec) 578.3358 578.3368 8PP H 135-140 617.3679 617.3671 8QQ H H 205-215 602.3682 602.3722 8RR CH,OH > 235 (dec) 532.3151 532.3124 8SS .0 206-212 580.3263 580.3258 8TT >P 198-204 579.3311 579.3315 8UU 231-236 580.3263 580.3252 8VV H -^ 201 -207 613.2977 613.2981 3WW o -!-0-^-CF3 0 215-220 650.2487 650-2497 8XX 8YY 0 II —N-S-CH3 O 198-201 210-214 545.3103 595.2930 545.3098 595..2921 8ZZ CHJ 245 534.3108 534,311/ BAB 5 ^ 202-205 624.3195 624.3204 SAC 0 O 208-213 559.3260 559.3263 H H3 y-H SAD 8AE 'N NH2 H 0 H 215-220 215-220 560.3212 573.3416 550.3220 573.3424 8AF A' H Me 215-220 559.3260 559.3257 SAG 205-209 602.3682 602.3672 H H 8AH /I H H ,Me 186-192 574,3369 574.3378 8AI 8AJ >^N'^N'^ H H O X N(CH2CH20Me)2 200-206 165-173 616.3838 661.3941 615.3844 661.3949 8AK CN 240-250 527.2998 527.2991 SAL -/N ...1 N" H H 211-215 622.3136 622.3129 SAM y-uK H H 170-174 616.3838 616.3836 SAN 192-196 614.3682 614.3690 H H V All melting points were done on the bis hydrochloride salts (2xHCI) except 8PP was performed on the free base Using derivatives of the triflate intermediate described in 82 in procedures similar to those described above and following the table for 8AO-8AQ, the compounds of the following structure were prepared: F3C' ^ ^Ni-^ YY"' wherein R^' is defined in the table Ex. R" m.p. CO SAO -CN 240-250 SAP -CONHEt 215-220 8AQ -N(CH,)CONHEt 186-203 8AR -CONH, 200-208 8AS -CONHCH, 215-220 BAT -CON{CH,CH,OCH,), 165-173 BAU -CON(Et), 170-180 8AV -N(CH,)CONHCH, 198-210 BAW -NHCH, 190-200 8AX -N(CH,)CONH, 190-220 8A0: C02tBu OSO2CF3 2n(CN)2 Pd(PPh3). C02tBu COsH s;^^ Ex. 8. step 3 DEC/HOBt 8A0 Step 1: The triflate intermediate (see 8W) (0.4 g), Zn(CN)3 (0.2 g), Pd(PPh3), (0.3 g) and DMF (1.5 ml) were heated at 80 °C for 17 h. The reaction was cooled to RT, diluted with EtOAc and saturated aqueous NaHCO^. The EtOAc layer was removed, washed with water, dried with brine and evaporated to give a crude oil which was purified by preparative plate chromatography (2000 ^M silica plates; 8:1 hexanes: EtOAc eluant), to give, after isolation of the appropriate band, the cyano intermediate (0.2 g) in 77% yield. Step 2: The product of Step 1 (0.2 g) was dissolved in MeOH (1.5 ml) and HCI (4M solution in 1,4-dioxane; 2 ml) was added. The resulting solution was stirred at 50 °C for 3 h and evaporated. This crude intermediate (0-038 g) and the product of Example 8, Step 3 (65 mg; trihydrochloride fomri) were treated in the same fashion as Example 8, Step 4, using DMF (2 ml), HOBt (45 mg), DEC (60 mg) and diisopropyl ethyl amine (0.1 ml) to give, after isolation and purification, the free base form of SAO, which was converted to its HCI salt (45 mg) in 95% yield. SAP: -v^^^^ 1. oxaly! chloride >^ JL ^ cy R cton *; NaCl02 TT^V^ ^ ^V^=::M^ hx. B, blep3 COptBu C02tBu CO2H SAP 2. H2NEt \^ DEC/HOBt CHO CO2H 3- HCI CONHEt Step 1: 2,6-Dimethyl-4-formy! benzoic acid (1.96 g) (see 8W) was dissolved in t-butanol (94 ml) and 2-methyl-2-butene (24 ml). A solution of NaCIOj (6.89 g), NaH^PO, monohydrate (8.17 g) and water (45 ml) was added dropwise to the first solution. After complete addition, the pH was adjusted to 3 and two layers resulted. The organic layer was removed and evaporated to give intermediate acid (1.80 g) as a white crystalline solid, which was used without purification. Step 2: To a solution of the product of Step 1 (0.62 g), CH^CI^ (5 ml) and DMF (1 drop) was added oxalyl chloride (0.31 ml) and the resulting solution was stirred for 10 min, at which time a second portion of oxalyl chloride (0.30 ml) was added. The reaction was stirred for 10 min, toluene was added and the mixture was evaporated to dryness. CH^CI^ (10 ml) and EtNHj (1 ml) were added and the reaction was stirred for 2 days, then partitioned between brine and CH^CI^. The CH^CI^ layer was evaporated and HCI (4 ml of a 4 M solution in 1,4-dioxane) was added. The resulting solution was stirred for 3 h and evaporated to give a solid which was washed with Et^O and collected to give the amide intermediate (0.13 g) in 24%yield- Step 3: The product of Example 8, Step 3 (60 mg; trihydrochloride form) and the product of step 2 (35 mg) were treated in the same fashion as Example 8, Step 4 to give, after work up and purification, SAP as the free base form, which was converted to the HCI salt (50 mg) in 62% yield. 8AQ: COstBu C02tBu C02tBu CO2H '"^" --^ni^Yr ^^YV— 8AQ 2. Me2S04 NHs NHMe NMeCONHEt NMeCONHEt Step 1: To a solution of the amine intermediate (2 g) (see 8Z) was added NaH (0.4 g of a 60% oil dispersion). The resulting suspension was stirred for 15 min and Me^SO, was added. After heating at reflux for 1.5 h, the reaction was cooled to RT, poured into saturated NH.CI aqueous solution and extracted with Et^O. After evaporation, the crude reaction mixture was chromatographed on silica gel, eluting with 4:1 hexanes:EtOAc, to give, after evaporation of the appropriate fractions, the methylamine intermediate (0.8 g) in 38% yield. Step2: The product of Step 1 (0.12 g). THF (5 ml) and EtNCO (54 mg) were heated at reflux for 17 h. EtNCO (54 mg) and 1,4-dioxane (2 ml) were added and the resulting solution was heated in a sealed tube at 65 °C for 17 h. The solution was cooled, evaporated and purified by preparative plate chromatography (silica gel; 25% EtOAciCH^Cy, to give the desired product (0.1 g) as a crystalline solid in 64% yield. Step 3: The product of Step 2 (0.1 g) was treated in the same fashion as Example 8, Step 3 (p 28) to give the desired intermediate (0.08 g) which was 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) were treated in the same fashion as Example 8, Step 4, to give, after work up and purification, 8AQ as the free base form, which was converted to the HCI salt (65 mg) in 62% yield. Using procedures described above and employing commercially available acids, compounds 8AY'8BT of the structure were prepared, wherein R'° and R" are defined in the table: Ex. plO R" Mp {° C) SAY -CH, H 205-208 8AZ F H 250-255 8BA CI H 215-217 SBC -CH, Br 228-231 8BD -CH3 ^"CN 194-198 8BE CI CI 240-241 8BF CI F 268-270 SBG Br H 210-213 8BH CI Br 213-217 8BI Br F 176-181 8BJ 1 H 184-190 8BK -CF, F 204-209 8BL F F 268-270 8BM CI NK 215-220 8BN H F 258-260 8B0 H Br 238-240 8BP H CI 235-240 8BQ Br CI 190-194 8BR CH3CH2" H 211-214 8BS -Si(CH3)3 H 230-240 8BT CI NO2 275-280 Using procedures similar to those described above, the following compounds were prepared: f R^ ,8 r,3 r^6 wherein R , R , R and R are as defined in the table: Ex. R 3 R- R' R' MP r c) 8BU -CF: CH3 -CH: H3C N^ 195-220 8BV -CF: CH3 -CH: F3C N^ 80-85 8BW -CF: CH3 -CH3 »' 212-217 8BX -CF: CH3 -CH: ,::^'' 235-238 8BY -CF- CH3 -CH: B(OC(CH3)2); 195-200 8B2 -CF- CH. -CH: Br 237-240 N 8CA -CF: GH3 'CH2CH3 N 179-181 N 11 N 8CB -CF: -CH2CH3 200-202 8CD -CF3 "^= -CH2CH3 "Y^NHCONHEt 199-205 8CE H GH3 -CH3 P9 206-210 8CF -CF3 ^ -CH3 235-239 O NH2 Step 1: A solution of 4-N-BOC-2(S)-methyl piperazine (1,5g; 7.5 mmol), 4-methoxy-benzyl chloride (1.1 ml; 8.1 mmol) and diisopropyl ethyl amine (1.5 ml) in dry CH3CN were heated at reflux for 5 h. The reaction mixture was cooled to RT and volatiles were removed in vacuo. The residue was dissolved in CH2CI2 (30 ml) and washed with water and brine. Concentration gave the crude product, which was purified by FSGC (10% EtOAc-hexanes) to obtain 2.1g (88%) of product as a pale yellow liquid. TFA (6 ml) was added to a solution of the above compound (2Jg; 6.56 mmol) in 12 ml of CH2CI2 and the mixture stirred at 25° C for 1.5 h. The reaction was quenched with IN NaOH and adjusted to pH 10. Extractive work-up in CH2CI2 furnished the desired product (1.4g; 97%) as a colorless gum. Step 2: A mixture of the product of step 1 (1.4g; 6.36 mmol), N-BOC-4-piperidinone (1.27g; 6,4 mmol) and Ti(0iPr)4 (1.9 ml; 6.4 mmol) was stirred at 25° C for 24h. A 1M solution of Et2AICN in toluene (7,6 ml) was added to the reaction mixture and the mixture stirred at ambient temperature for another day. The Strecker amine thus formed was worked-up and isolated (27g; 100%) as described in Example 8, step 2. TLC Rf = 0.3 in 25% EtOAc-CH2Cl2. The Strecker amine (2.7g; 6.3 mmol) was dissolved in 15 ml of dry THF at 0° C and CHsMgBr (3M in EtaO; 10.5 ml) was added to it. After 1 h, the ice bath was removed and the reaction allowed to proceed at RT for 15 h. TLC analysis of the heterogeneous reaction mixture showed no change from the starting material; the mixture was warmed at 60° C for 5 h with no observed change in TLC behavior. The reaction mixture was quenched with saturated NH4CI and organic products extracted into CH2CI2. FSGC of the crude product (2.7g) using 15% acetone-hexanes as the eluant provided the desired ipso-methyl compound as a colorless gum (2.3g; 87%). Step 3: The product of step 2 (1.7g; 4.08 mmol), ammonium formate (1.4g-22 mmol) and 10% palladium on carbon (0.4g) were mixed in 20 ml of CH3OH and heated at reflux for 5 h. The reaction mixture was filtered through celite and volatiles were removed. The residue was dissolved in CH2CI2 and washed with 10% NaOH solution, water and brine. Concentration in vacuo gave l.lg (92%) of pale yellow gum. Step 4: A solution of the product of step 3 (0.12g; 0.4 mmol), p-trifluoro-methyl benzyl bromide (O.lg; 0.4 mmol) and diisopropyl ethyl amine (0.1 ml) in dry CH3CN was gently warmed (60-70" C) for 16 h. The mixture was cooled and organic product isolated via extractive work-up in CH2CI2. FSGC (10-30% Et20-CH2Cl2; Rf = 0.4) yielded the major product as a colorless film (0.12g; 68%). Treatment of the above product (in CH2CI2) with TFA (1 ml) for 1 h followed by basification and standard work-up provided the desired compound (0.09g; 96%) as a colorless film. Step 5: The product of step 4 (0.045g; 0.13 mmol) and 6-chloro anthraniiic acid (0.022g; 0.13 mmol) were coupled as described in Example 1 and after work-up and FSGC (5% CH3OH in CH2CI2) the title compound was isolated as a colorless film (0.058g; 90%). The HCI salt of the title compound was prepared in the usual manner by the reaction of the free base with 1M HCI-Et20 and processing the precipitate to obtain a beige solid (0.066g). Using a similar procedure, the product of step 3 was converted to other compounds, first by alkylation of the piperazine nitrogen with the appropriate halide, followed by deprotection and coupling of the piperidinyl portion with the appropriate acid to form the amides of general structure: Y o wherein R and R2 are as defined in the table: Ex. R R2 Mp r c) HRMS (MH*) 9A F.C NHj 246-249 509.2293 9B F,c 204-208 488.2895 9C 247-249 546.1978 9D 249-251 567.1407 9E FiCO 206-209 504.2848 9F F^CO NH- 244-247 525.2242 9G ■v.. 0 201-204 484.2630 9H v., ^JD- NH2 222-226 505.2039 91 i^" MeO N 226-229 451.3060 9J M NH2 229-232 472.2474 9K 268-271 455.2577 9L NH2 212-216 476.1975 9M M 229-232 450.3126 9N H3C 246-251 434.3168 90 F,C % 192-205 9P "K^ 185-196 — 9Q OH 202-210 9R P^c-^ OH 203-206 9S .cO- 1 w 190-205 — 9T .COJO^' vV • 180-205 ~ 9U .c-O" CI 258-262 *v Using a similar procedure described below, compounds wherein R is 4-ethoxynaphthyl were also prepared: Steps 1-3: See Example 9. Step 4A: 4-Hydroxynaphthaldehyde (0.86g) and K2CO3 (1.38g, 2 equiv,) in CH3CN (35 ml) were treated with CH3CH2I (0.80 ml, 2 equiv.). and the resulting mixture was stirred at RT for 20 h. The reaction mixture was concentrated in vacuo, the residue treated with EtOAc, and the mixture filtered. The filtrate was partitioned with H2O. The dried (MgS04) EtOAc was concentrated in vacuo to give an orange-brown residue (0.89g). This residue was placed on preparative thin layer plates (10, 1000[i), and eluted with CH2CI2 to give the title compound (0.82g). Step 4: Under argon, the products of step 3 (0,270g; 0.95 mmol) and step 4A (0.571 g; 2.9 mmol) in CH2CI2 (25 ml) were stirred at RT for 30 min. Na(0Ac)3BH (0,506g; 3,4 mmol) was added. After 19 h, the reaction mixture was quenched with dilute NaOH. The aqueous layer was washed with CH2CI2 (3X). The combined CH2CI2 solution was washed with H2O (3X) and then brine. The dried (MgS04) CH2CI2 solution was concentrated to -50 mL Amberlyst 15 (4,5 meq/g: 2.4g; 11.025 mmeq) was added. After 19 h, additional Amberlyst 15 (2.3g) was added. After? h, the resin was washed with CH2CI2 (5X). THF (5X). THF:H20 (5X), H2O (5X), CH3OH (5X) and CH2CI2 (5X). The resin was eluted with 2M NH3 in CH3OH (300 ml) (3X), followed by concentration in vacuo to give an amber oil (0.215g). The crude material was placed on preparative thin layer plates (4, lOOO^i), and eluted with CH2Cl2:2tVl NH3 in CH3OH (9:1) to give an amber oil (0.125g, 36%). Step 5: Using the appropriate carboxylic acid in the procedure of Example 9, step 5, the following compounds were prepared: CHaCHjO O CH3 gy LCMS found M+H = 531 HPLC* Retention time 5.52 min. CH3CH2O O CH3 9^ LCMS found M+H = 516; HPLC* Retention time 5.66 min. *HPLC: VYDAC 218TP5405 column; gradient 5-95% B over 10 min hold 2 min; Soln A 0.1% TFA/H^O, Soln B 0.1% TFA/CH3CN at 245 nm. Using a similar procedure wherein the starting piperazine does not have the methyl substituent, the following compound was prepared: fJ'^ CH3 k.Nj;^H3C N^ O CH3 (^) 9X: M.p. 250 =C Example 10 10 A. R® = NH2; R'"=CI B. R® = NH2; R^° = CH3 C. R®, R'° = CH3, CH3 Step 1: A solution of 4-N-BOC-2(S)-methyl piperazine (0.4g; 2 mmol), p-iodobenzaldehyde (0.46g; 2 mmol) and NaBH(0Ac)3 (0.65g; 3 mmol) in 6 ml of CH2CI2 was heated at gentle reflux for 14 h. The contents were cooled, diluted with 30 ml of CH2CI2 and washed with 1N NaOH solution. water and brine to isolate an yellow oil (0.8g). FSGC (25% EtOAc-hexane) afforded the desired product (0.66g; 79%) as a colorless film. TLC R( = 0.6 in 25% EtOAc-hexane The BOC protecting group was removed from the product (0.66g; 1.58 mmol) by treatment with TFA (1 ml) in CH2CI2 (2 ml). Following standard work up, the mono-alkylated piperazine (0.5g; 100%) was obtained as a colorless gum. Step 2: NaBH(0Ac)3 (0.63g; 3 mmol) and two drops of AcOH were added to a solution of the product of step 1 (0.5g; 1.58 mmol) and N-BOC-piperidinone (O.Sg; 3 mmol) in 5 ml of CH2CI2 and the resulting solution was stirred at ambient temperature for 16 h. After the usual work up and FSGC, the desired product (0.6g; 76%) was obtained as a colorless oil. TLC R, = 0.4 in 25% acetone-CH2Cl2. The free piperidine {0.38g; 79%) was prepared from the N-BOC protected compound (0.6g; 1.2 mmol) by treatment with TFA (2 ml) in CH2CI2 (5 ml). Compound 10A: The coupling of 6-chloro anthranilic acid (0.065g; 0.38 mmol) with the product of step 2 (0.127g; 0.32 mmol) in the presence of DEC (0.092g; 0.48 mmol), HOBT (0.065g; 0.48 mmol) and diisopropylethyl amine (0.1 ml), followed by product isolation, were carried out as described previously. This procedure furnished the compound 10A (0.13g; 73%) as a colorless film. TLC R, = 0.5 / 0.45 for a pair of rotomers in 2% CH3OH- CH2CI2. The HCI salt of the title compound was prepared in the usual manner. Mp: 198-202° C; HRMS (MH*) = 553.1231. Compound 108: Coupling the product of step 2 with 6-methyl anthranilic acid gave compound 108 (HCI salt) in 73% yield. Mp: 197-200° C; HRMS (MH*) = 533.1774. Compound IOC: 2,6-DimethyI benzoic acid was coupled to the product of step 2 to obtain the amide IOC (HCI salt) in 50% yield. Mp: 202-205° C; HRMS (MH*) = 532.1826. Example 11 Step 1: (S)-Methylbenzylamine (27 ml, 0.2 mol) in CH2CI2 (50 ml) was dropped into ice-cold trifiuoroacetic anhydride (40 ml) in CH2CI2 (200 mi) within 15 min. The mixture was stirred at RT for 1 h, then cooled in an ice water bath, iodine was added (27 g, 0.106 mol) and then [bis(trifluoro-acetoxy)iodo]-benzene (25 g, 0.058 mol). After being stirred at RT overnight in the dark, more [bis(trifluoroacetoxy)iodo]benzene (24 g, 0.056 mol) was added and the mixture was stirred at RT for one more day. The mixture was diluted with CH2CI2 (500 ml) and ice-cold Na2S03 (10% aqueous, 500 ml) and stirred for 0.5 h. The organic layer was separated and washed with NaHCOa, filtered through a short silica gel column and washed with CH2CI2 (500 ml). After CH2CI2 was evaporated, Et20 (125 ml) was added and the mixture stirred for 10 min, Hexanes (600 ml) was added gradually to the Et20 solution and the mixture was stirred for 0.5 h. The precipitate was collected and washed with hexanes. The white solid was dried at RT and iodo compound (36.5 g, 53% yield, Rf = 0.7, EtOAc/hexanes, 1:3) was obtained. Step 2: The product of step 1 (11.2 g, 0.033 mol) was dissolved in CH3OH (200 ml) and NaOH (15 g, 0.375 mol) in water (100 ml) was added dropwise. The mixture was stirred at RT for 2.5 h. After the CH3OH was evaporated, the aqueous layer was extracted with Et20 (3x100 ml) and the combined organic portion was washed with brine, dried over Na2S04, filtered and concentrated to give a free amine. Methyl-fl-lactate (4,08 g, 0.039 mol) was dissolved in CH2CI2 (40 ml) and the mixture was stirred and cooled in acetone-C02 to -78° C under N2 atmosphere. Trifluoromethane sulfonic anhydride (10.2 g, 0.036 mmol) and then 2,6-lutidine (6.27 g, 0,059 mol) were added and the mixture was stirred for 5 min at -78° C. The mixture was warmed to RT and stirred for 30 min. More CH2CI2 was added to the mixture and the solution was washed with 2N HCI. The freshly prepared amine from above was added to the trifiate solution followed by K2CO3 (18 g, 0.132 mol) in water (20 ml). The mixture was stirred at RT overnight. Extractive work-up with CH2CI2 followed by silica gel column chromatography gave a secondary amine (8.27 g, 75% yield, Rf = 0.65, hexanes/EtOAc, 3:1) as a yellow syrup. Step 3: The amine of step 2 (17.3 g, 0.052 mol) was dissolved in dichloroethane (100 ml) and CICH2COCI (117.2 g, 82 ml, 1.04 mol). The mixture was stirred under reflux condition for 3 h. Both the solvent and CICH2COCI were removed under vacuum. The remaining yellow syrup was dissolved in DMSO (40 ml) at 0°C and Nal (5.2 g, 0.035 mol) and NH4OH (56 ml, 1.04 mol) were added. The reaction mixture was stirred 0° C for 30 min., warmed up to RT and stirred overnight. Water (100 ml) was added to the mixture and the precipitate was filtered and washed with water. The white solid obtained was dried in air to give the diketopiperazine (14.3 g, 77% yield, Rf = 0.56, hexanes/ EtOAc, 3:1). Step 4: The diketopiperazine of step 3 (14.3 g, 0.04 mol) was dissolved in dimethoxy ethane (200 ml) and NaBH4 (15.1 g, 0.4 mol) and BFa-OEtj (34 g, 29.5 ml, 0.24 mol) were added to the solution. The mixture was stirred under reflux conditions for 3 h and then cooled to about 0° C on a ice bath. CH3OH (500 ml) and then concentrated HCI (300 ml) were added slowly to the mixture. The solution was stirred for 20 min. at RT and then under reflux conditions for 45 min. The mixture was concentrated and NaOH was added until the pH was more than 10. Extractive work up with EtOAc gave the desired piperazine as a yellow syrup (12.9 g, 98% yield). Step 5: The product of step 4 (1.9 g, 5.79 mmol) , N-BOC-4-piperidone (5.73 g, 28.8 mmol), NaBH(0Ac)3 (6.1 g, 28,8 mmol) and 2M AcOH (5.76 ml, 11.52 mmol) were combined in CH2CI2 (150 ml) and the mixture was stirred overnight. After the solvent was removed, NaOH (3N) was added and extractive work up with EtOAc followed by silica gel chromatography afforded pure piperazino-piperidine (2.21 g, 75% yield, Rf = 0.18, hexanes/EtOAc, 1:1) as a syrup. Step 6: The product of step 5 (1.9 g, 3.7 mmol) was dissolved in CH2CI2 (10 ml) and TFA (10 ml) was added. The mixture was stirred at RT for 2 h. After the removal of the solvent and TFA under reduced pressure, NaOH solution (3N) was added to the remaining syrup and extractive work up with EtOAc gave the free piperazino-piperidine (1.3 g, 85% yield) as a yellow syrup. To a solution of the free piperazino-piperidine (200 mg, 0.484 mmol) in CH2CI2 (2 ml) were added 2,6-dimethylbenzoic acid (150 mg, 0.99 mmol), DEC (191 mg, 0.99 mmol) and HOST (135 mg, 0.99 mmol). The mixture was stirred at RT overnight and then the solvent was removed under reduced pressure. NaOH solution (3N) was added to the remaining syrup and extractive work up with EtOAc followed by column chromatography afforded the title compound (210 mg, 80% yield, Rf = 0.37, CH2CI2/CH3OH, 20:1). HRMS (as the HOI) calcd for C27H37N3OI (M+H") 546.1981, found 546.1965. Mp: 190° 0 (dec). Using a similar procedure, compounds of the formula were prepared, wherein R^ and R^*^ are as defined in the table: Ex R9 Rio Mp(°C) HRMS 11A -CH3 -NH2 198 (dec.) 547.1928 11B -CI -NH2 203 (dec.) 567.1395 11C -OH -OH 200 (dec.) 550.1555 11D -OCH3 -OCH3 200 (dec.) 578.1860 Example 12 Step 1: To the solution of the product of Example 11, step 4 (1.4 g. 4.2 mmol) and 1'tert-butoxycarbonyl-4*piperidone (0.93 g, 4.67 mmol) in CH2CI2 was added Ti(0iPr)4 (1.19 g, 4.2 mmol) and the mixture was stirred at RT overnight. 1M Et2AICN (5.04 ml, 5.04 mmol) was added, the mixture was stirred overnight at RT and the solvent was evaporated. Saturated NaHCOs was added to the residue and extractive work up with EtOAc gave the Strecker amine as a yellow syrup. The syrup was dissolved in THF (40 ml) and 3M CHsMgBr (7 ml, 21 mmol) was added to the solution. The mixture was stirred at RT overnight, then cooled to O^C and saturated NH4CI and water was added. Extractive work up with EtOAc followed by silica gel chromatography gave the piperazino-piperidine product (1,78 g, 81%yield. Rt = 0.52. hexanes/EtOAc, 2:1). Step 2: Treat the product of step 1 in the manner described in Example 11, Step 6, to obtain the title compound. Mp. 190° C (dec); HRMS (as the HClsalt): found 560.2145. Using a similar procedure, compounds of the formula were prepared, wherein R2 is as defined in the table: Ex R2 mp(°C) HRMS 12A H^^, 145 (dec.) 581.1537 12B HsNyLxHs 150 (dec.) 561.2083 12c HaCvJvXHs 208 (dec.) 561.2096 12D 206 (dec.) 562.1944 12E H3CSJY^H3 190 (dec.) 577.2029 12F N 245 (dec.) 601.1006 12G OH 218 (dec.) 577.2029 12H 5 195 (dec.) 617.0945 121 116 (dec.) 562.2048 Step 1: To a solution of the N-BOC protected product of Example 11. step 4 (250 mg, 0.581 mmol) in DMF (2.5 ml), CuCI (1 g, 10.1 mmol) was added. The suspension was stirred under N2 at 110° C for 24 h. After the mixture was cooled to RT, NH4OH was added and the solution gradually turned bright blue. Extractive work up with EtOAc gave a mixture of the chloro-substituted piperazine and its BOC derivative. After treating the mixture with TFA (5 ml) in CH2CI2 (2 ml) for 2 h, the solvent was evaporated and NaOH (3N) was added. Extractive work up with EtOAc afforded the pure piperazine (110 mg, 79%) as a yellow syrup. Step 2: The product of step 1 was treated in a manner similar to Example 11, steps 5 and 6, to obtain the title compound. Mp. 180° C (dec); HRf\/1S (as the HCI salt): found 454.2617. Using a similar procedure, compounds of the formula N Cl were prepared, wherein R9 and R^o are as defined in the table: Ex R9 RIO Mp(°C) HRMS 13A -CH3 -NH2 200 (dec.) 455.2577 13B -CI -NH2 200 (dec.) 475.2023 13C -CI -CI 187 (dec.) 494.1536 Using the product of step 1 in the procedure of Example 12, compounds of the formula N N-CI were prepared, wherein R2 is as defined in the table: Ex R2 Mpr'C) HRMS 13D XT 197 (dec.) 468.2779 13E H.N^ 205 (dec.) 489.2184 13F H2N,X^CH3 210 (dec.) 469.2734 13G 195 (dec.) 470.2689 13H N 260 (dec.) 509.1634 131 H3CyJ>yCH3 200 (dec.) 485.2688 Example 14 }—\ /— Step 1: To a solution of the N-BOC protected product of Example 11, step 4 (5 g. 0.012 moi) in DMF (20 ml), CuCN (20.8 g, 0.23 mol) was added. The suspension was stirred under N2 at 110°C for 22 h. After the mixture was cooled to RT, NH4OH was added and the solution gradually turned bright blue. Extractive work up with EtOAc followed by silica gel column chromatography gave the cyano derivative (2.29 g, 60% yield, Rf = 0.5, hexanes/EtOAc, 4:1), the carboxamide derivative (0.95 g, 23,6% yield, Rf = 0.2, CH2CI2/CH3OH, 10:1) and the unsubstituted derivative (85 mg. 2,4% yield, Rf = 0.75, hexanes/EtOAc. 2:1). Step 2: The BOC group on the cyano compound of step 1 was first removed under acidic conditions and the resultant amine was converted to the title compound following the procedure of Example 11, steps 5 and 6. HRMS (as the HCI salt): found 445.4970. Example 15 Step 1: To a solution of the N-BOC protected product of Example 11, step 4 (1.4 g, 3,26 mmol) and CuCI (1,61 g, 16.3 mmol) in CH3OH at 0^ C was added NaBH4 (3.69 g, 97.6 mmol) slowly. A black precipitate was formed. The mixture was warmed to RT and stirred overnight. The precipitate was removed by celite filtration and CH3OH was removed under vacuum. Extractive work up with EtOAc afforded the desired compound (1g, 100% yield, Rf == 0.55, hexanes/EtOAc, 5:1) as a syrup. Step 2: The BOC group on the product of step 1 was removed under acidic conditions and the resultant amine was converted to the title compound following the procedure of Example 11, steps 5 and 6. Mp. 195°C; HRMS (as the HCI salt): found 420.3016. Using a similar procedure, the following compound is prepared: HRMS (as the HCI salt): found 441.2426 Example 16 Step 1: To a solution of the N-BOC protected product of Example 11, step 4 (2.5 g, 5.8 mmol) in benzene were added phenyl boric acid (1.68 g, 13.8 mmol), 2M Na2C03 (14 ml) and tetrakis(tri-phenyl phosphine) palladium (0.67 g, 0.58 mmol). The mixture was stirred under reflux overnight. Extractive work up with EtOAc followed by silica gel column chromatography gave the phenyl derivative (1.37g, 62% yield, Rt = 0.5, hexane/EtOAc, 5:1) as a syrup. Step 2: The BOC group on the product of step 1 was removed under acidic conditions and the resultant amine was converted to the title compound following the procedure of Example 11, steps 5 and 6. Mp. 190' C; HRMS (as the HCI salt): found 496,3319. Using a similar procedure, compounds of the formula were prs Sch 223254 223255 275666 pared, wherein R2 is as defined in the table: Ex R2 Mp (° C) HRMS 16A H,.^C, 190 (dec.) 517.2754 16B H2N,X.CH3 65-70* 497.3287 16C 190 (dec.) 498.3225 * tree base Example 17 CI step 1: The N-BOC protected product of Example 11, step 4 (800 mg, 1.88 mmol) was dissolved in dry THF and the temperature was brought to -78° C under N2. Butyl lithium (2.5 M solution, 0.832 ml, 2 mmol) was added and the mixture was stirred at -78° C for 10 min. The solution then was dropped into p-chlorobenzyl aldehyde (234 mg, 2.07 mmol) in THF at -78° C. The mixture was stirred for 30 min. at -78° C, then gradually warmed up to RT. Saturated NH4CI was added to the mixture and extractive work up with EtOAc followed by silica gel column chromatography gave the desired alcohol (30 mg, 3.6% yield, Rf = 0.5, hexanes/EtOAc, 2:1) as a yellow syrup. Step 2: A solution of alcohol of step 1 (40 mg, 0.090 mmol), triethylsilane (52 mg, 0.45 mmol) and TFA (5 ml) in CH2CI2 (5 ml) was stirred under reflux conditions for 2 h. After CH2CI2, triethylsilane and TFA were removed under reduced pressure, NaOH solution (3N) was added to the remaining synjp. Extractive work up with EtOAc afforded the chlorobenzyl derivative (20 mg, 68% yield) as a yellow syrup.. Step 3: The product of step 2 was converted to the title compound following the procedure of Example 11, steps 5 and 6. Mp. 170° C (dec); HRMS (as the HCI salt): found 544.3101. Example 18 H2N Step 1: To a solution of the N-BOC protected 4-piperidinyl derivative of the cyano compound of Example 14, step 1 (510 mg, 1.24 mmol) in Et20 (4 ml) was added 3M CHaMgBr (4 ml) in a dropwise manner. The mixture was stirred under reflux overnight. After the solution was cooled on ice-bath, 12N HCI (4 ml) was added and the mixture was stirred on a steam bath for 2 h. The solution was cooled to RT and solid NaOH pellets were added until the pH was more than 10. Extractive work up with EtOAc/CHaOH (3:1) afforded the desired methyl ketone (249 mg, 61% yield) as a syrup. Step 2: The product of step 1 was treated according to the standard DEC peptide coupling procedures of Example 11, step 6, to obtain the title compound. Mp, 210°C; HRMS (as the HCI salt): found 483.2522. Using a similar procedure, the following compound is prepared: I 18A Mp. 210°C(dec.); HRMS (as the HCI salt): found 463.3088 Example 19 step 1: To a solution of the product of Example 22 (140 mg, 0.29 mmol) in CH3OH (10 ml) and EtOH (1 ml) were added NHaOCHs-HCI (738 mg, 8.84 mmol) and 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. Extractive work up with EtOAc followed by silica gel chromatography generated the title compound (99 mg, 68% yield, Rf = 0.38, CH2CI2/CH3OH, 20:1). HRMS (as the tartrate) calc'd. for C31H45N4O2 (M+H") 505.3543; found 505,3542. Using a similar procedure, compounds of the formula R' were prepared, wherein R8. R6 and R2 are as defined in the table: Ex R8 R6 R2 mpro HRMS 19A H3C— pCHa H 194 (dec.) 512.2785 19B H3C— ^0CH3 -./■■"■ C H XT 150 (dec.) 492.3344 19C NOCH2CH3 H3C-C—1 H 506.3494 19D H3C—c—1 -CH3 H3Cyi-yXH3 180 (dec.) 508.3296 19E H3C—C—} -CH3 195 (dec.) 493.3291 Dissolve the free piperazino-piperidine of Example 11, step 6 (1.7 g, 3.3 mmol) in CHCI3 (30ml; = Stock solution A). Add 250 ul of stock solution A (0.027 mmol) to a slurry of 0.15 g (- 0.14 mmol) of resin bound cardodiimide (prepared by reacting Argopore-CI resin with 1-(3-dimethyl-aminopropyl)3-ethyl carbodiimide in DMF at 100° C in DMF (1.5ml) in a polyethylene SPE cartridge. To this mixture add 75ul of a 1 M solution of 5-methyl-3-phenylisoxazole-4-carboxylic acid in DMF (0.075 mmol), and HOBT (24 ul of a 1M solution in DMF). Shake this mixture for 14 h, filter and add 0.1 g of Amberlyst-15 resin (0.47 mmol) to the filtrate. Shake for 1 to 2 h, filter and wash the resin twice with each of the following solvents THF, CH2CI2 and CH3OH, then wash with THF and CH2CI2. Treat the resin with 2M NH3 in CH3OH (1 time for 30 min, and 1 time for 5 min). Combine and concentrate the filtrates under reduced pressure to afford the title compound. LCMS found MH*= 599.1 (calculated MW 598); TLC Rt = 0.74 (CH2CI2/CH3OH/NH4OH (95/5/0.5)). Using the procedure above with the appropriate carboxylic acids gave the following compounds k.N r^ o wherein R2 is as defined in the table: Ex. R2 LCMS results TLC Rf values 20A F. V MH^ = 600.1 Rt = 6.56 min. 0.92 20B H,N CI MH+ = 601.1 Rt = 5.69 min. 0.63 20C CH, MH+ = 560.1 Rt = 5.77 min. 0.60 20D H3C CH3 MH+ = 588,1 Rt = 6.61 min 0.66 20E v9 MH+ = 604.1 Rt = 5.60 min. 0.87 20F 20G H3C0J; 0CH3 MH+ = 658.2 Rt = 5.69 min. MH+ = 606.1 Rt = 6.17 min. 0.86 0.43 20H MH+ = 568.1 Rt = 5.67 min. 0.57 201 MH+ = 586.1 Rt = 6.02 min. 0.63 20J T> MH+ = 558.1 Rt = 5.35 min 0.33 20K CH- MH+ = 546.1 Rt = 5.37 min, 0.52 Example 21 ^Y^,XK Step 1: The BOC group on the cyano compound of Example 14, step 1, was first removed under acidic conditions and the resulting amine (1.59 g, 6.96 mmol), 1-fert-butoxycarbonyl-4-piperidone (1.66g, 8.35 mmol) and Tj(0iPr)4 (2.18 g, 7.66 mmol) in CH2CI2 were stirred at RT overnight. 1M Et2AICN (8.35 ml, 8.35 mmol) was added, the mixture was stirred overnight at RT and the solvent was evaporated. Saturated NaHCOa was added to the residue and extractive work up with EtOAc followed by column chromatography gave the Strecker amine as a yellow syrup (1.76 g, 58% yield, Rf = 0.70, Hexanes/EtOAc, 2:1). Step 2: The amine of Step 1 (200 mg, 0.46 mmol) was dissolved in anhydrous THF (2 ml) and 3M CHaMgBr (0.76 ml, 2.29 mmol) was added dropwise. The mixture was stirred at RT overnight and then cooled to CC. Saturated NH4CI (10 ml) was added and a precipitate appeared. Water (40 ml) was addded and the precipitate disappeared. Extractive work up with EtOAc followed by column chromatography gave the desired ipso-methyl derivative (169 mg, 86% yield, R, = 0.53, Hexanes/EtOAc, 2:1). Step 3: The product of step 2 was treated in the manner described in Example 11, Step 6, to obtain the title compound. Dec. 198°C; HRMS (as the HCI salt): found 460.3079. Using a similar procedure, compounds of the formula xr-N^N^N-^a^ were prepared, wherein R2 is as defined in the table: Ex R2 Mp (°C) HRMS 21A 205 (dec.) 480.2532 218 65-75* • Mp for the free amine 475.3033 21c 0^. 250 (dec.) 500.1992 21D 195 (dec.) 461.3019 step 1: The Strecker amine from Example 21, step 1 (380 mg, 0.87 mmo') was treated with CHsMgBr (2.9 ml, 8.7 mmol) in EtaO (5 ml) under reflux conditions overnight. The mixture was cooled on ice and water (5 ml) was added dropwise. 12N HCi (6 ml) was added and the mixture was stirred on a steam bath for 2 h. After the mixture was cooled on ice, NaOH was added until the pH of the solution was above 10. Extractive work up with EtOAc afforded a free amine as a syrup (307 mg, 100% yield). Step 2: The product of step 1 was converted to the title compound following the peptide coupling procedure described in Example 11, step 6. Mp. 80-85° C; HRMS found 476.3271. Using a similar procedure, compounds of the formula were prepared, wherein R^ is as defined in the table: Ex. R2 Mp CC) HRMS 22A 195 (dec.) 493.3172 22B 200 (dec.) 478.3178 N F,C Example 23 A, 0 ' HCI salt Steps 1-3: O 0 COsEt CO2H O NaOH 1. CS2CO3 aq acetate N^.^N N-^^N formamidine OCH: ^ CO^Et -^ COaEt Step 1: Ethyl diacetoacetate (93.4 g), CS2CO3 (185 g) and CH3CN (550 ml) were mixed together, using an overhead mechanical stirrer. CH3CN (50 ml) was added and the resulting mixture was cooled to 0°C. Methyl trifluoromethane sulfonate (88.6 g) was added dropwise and after addition, the cooling bath was removed. The mixture was stirred for 1 h at RT, filtered, and the salts were washed with EtgO (2 X 50 ml). The organic extracts were combined and Et20 (300 ml) was added. The resulting mixture was filtered, the filter cake was washed with Et20 (2 X 100 ml), the Et20 extracts were combined and evaporated to half volume. The solution was cooled in an ice bath and washed'once with cooled (0°C) 2 N NaOH (pH = 11). The Et20 layer was dried over MgS04, filtered and evaporated to give the desired product as a yellow liquid (64.7 g) in 65% yield, which was used directly in the next step. Step 2: The product of step 1 (64.2 g), sodium ethoxide in ethanol (commercial solution; 21 wt%; 113 g) ethanol (587 ml) and formamidine . acetate (36.2 g) were mixed together at RT. After refluxing for 4 h, the mixture was cooled to RT, the resulting precipitate was filtered off and the ethanol was removed under vacuum. The resulting liquid was partitioned between water and CH2CI2 and the aqueous layer was extracted with CH2CI2 (3 X 150 ml). The CH2CI2 extracts were dried over MgS04, filtered and evaporated to give a dark crude liquid (50.7 g) which was purified by silica gel chromatography (980 g; 4:1 hexanes:EtOAc as eluant). After evaporation of the appropriate fractions, the desired product (28.5 g) was isolated in 46% yield and used directly in the next step. Step 3: The product of step 2 (28.1 g), NaOH (6.72 g), water (65 ml) and EtOH (130 ml) were mixed together at RT and heated at reflux for 1h. The resulting solution was cooled to RT and the volatile materials were removed in vacuo until a thick paste resulted. Water (20 ml) was added, the mixture was cooled to OX and cone. HCI (14.3 ml) was added dropwise with stirring. The resulting white precipitate was collected by filtration, washed with ice water (2X10 ml) and air dried with suction for 30 min. The resulting white solid was treated with toluene (2 x 20 ml), the solvent was removed in vacuo at 50°C and then dried under vacuum (1 mm Hg) for 18 h. The desired product (14.9 g) was isolated as a white solid in 63% yield, mp: 176-178°C. Elemental analysis of C7H8N2O2: calc'd C 55.26%, H 5.30%, N 18.41%; found: C 55.13%, H 5.44%, N 18.18%. A second crop of product was isolated by evaporation of the aqueous filtrate (from above) to dryness and addition of water (20 ml). The resulting mixture was stirred at RT for 5 min, cooled in an ice bath and the precipitate formed was collected by filtration. The resulting solid was washed with ice water (2X5 ml) and dried as described above to give the product (4.68 g) as a cream colored solid to give a combined yield of 83%. Step 4: The product of Example 4, step 6 (trihydrochloride form; 5.4 g), DMF(11.3 ml), HOBt(3.07g), diisopropyl ethyl amine (12.3 ml) and the product of step 3 (3.45 g) were mixed together and DEC (4.35 g) was added in portions over 15 min. The resulting mixture was heated at 45°C for 18 h, cooled to RT, diluted with EtOAc (80 ml) and washed with 2 N NaOH (25 ml). The aqueous layer was extracted with EtOAc (3 x 25 ml), the organic extracts were combined, washed with brine, dried over Na2S04, filtered and evaporated. The resulting crude oil was purified by silica gel chromatography (170 g; 76:19:5 hexanes:EtOAc:Et3N as eluant). After evaporation of the appropriate fractions, the free base form of the title compound (5.21 g) was isolated as a light colored foam in 91% yield. Step 5: To a cooled (O'^C) solution of the free base of step 4 (2,00 g) and EtOAc (20 ml) was added HCI (3.0 ml of a 4.0 M solution in 1,4-dioxane). The resulting mixture was warmed to RT, diluted with Et20 (20 ml), filtered, washed with EtaO (2 X 20 ml), air dried with suction for 10 min and then under vacuum (1 mm Hg) at 90'C for 5 h to give the title compound (2.30 g) as a white solid in 97% yield, mp: 159-162X, Elemental analysis of C27H36N5OF3»2HCI'0,5H2O: calc'd: C 55.38%. H 6.71%, N 11.96%, CI 12.11%; found: C 55.19%, H 6.69%, N 11.75%, CI 11.45%. Additional pyrimidine derivative-compounds were made using similar procedures: (TV^N^ CH3 F3C-^ ^NI^H3C N^CH3 O CH3 HCI salt 23A Steps 1-2: . COsEt 9^2H 0 c, CH 3 CO,B " N^^ t Step 1: The product of Example 23, step 1 was treated in the same manner as in Example 23, step 2, substituting acetamidine hydrochloride (2.03 g) for formamidine acetate. The amounts of the reagents were: product of Example 23, step 1 (4.0 g), ethanol (20 ml) and sodium ethoxide in ethanol (commercial solution; 21 wt%; 8.03 g). After extraction and purification as described above, the product was isolated (1.7 g) as a colorless liquid in 41% yield, which was used directly in the next step. Step 2: The product of step 1 (1.7 g) was treated in the same manner as Example 23, step 3, using ethanol (5 ml), water (5 ml) and NaOH (1.0 g). After extraction and purification as described above, the product was isolated (0.12 g) as a white solid in 8% yield, which was used directly in the next step. Step 3: The product of Example 4, step 6 (0.05 g), and the product of step 2 (immediately above) (0.028 g) were subjected to the same reaction conditions as in Example 23, step 4, using HOBt (20 mg), DEC (45 mg), diisopropyl ethylamine (40 mg) and DMF (1.5 ml). After extraction and purification as described above, the product was converted to its HCI salt using the procedure outlined for Example 23, step 5 to give the title compound (77 mg) as a white solid in 97% yield over the two steps, mp: 185-190°C. F.C HCI salt 23B Steps 1-2: 0 C02Et CO2H OCH3 HN^NH^.HCI ^ "^ -^^^^^ COsEt Step 1: The product of Example 23, step 1 was treated in the same as in Example 23, step 2, substituting benzamidine hydrochloride (3.35 g) for formamidine acetate. The amounts of the reagents were: product of Example 23, step 1 (4.0 g), ethanol (20 ml) and sodium ethoxide in ethanol (commercial solution; 21 wt%; 8.03 g). After extraction and purification as described above, the product was isolated (4.5 g) as a liquid in 82% yield which was used directly in the next step. Step 2: The product of step 1 (4.5 g) was treated in the same manner as Example 23, step 3, using ethanol (10 ml), water (10 ml) and NaOH (2.0 g), After extraction and purification as described above, the product was isolated (3.0 g) as a white solid in 77% yield which was used directly in the next step. Step 3: The product of Example 4, step 6 (75 mg), and the product of step 2 (immediately above) (39 mg) were subjected to the same reaction conditions as in Example 23, step 4, using HOBt (35 mg), DEC (53 mg), diisopropyl ethylamine (100 mg) and DMF (2 ml). After extraction and purification as described above, the product was converted to its HCI salt using the procedure outlined for Example 23, step 5 to give the title compound (98 mg) as a white solid in 96% yield over the two steps. mp:250'253°C. CH3 HCI salt 23C Steps 1-2: EtO^O EtO^O HOwjO vV mCPB_A ^ 1 ^ Na2C03 Step 1: The product of Example 23, step 2 (528 mg) was dissolved in CH2CI2 (5.0 ml) and meta-chloroperbenzoic acid (mCPBA) (600 mg) was added in three portions at RT. The resulting mixture was stirred at RT for 24 h and CH2CI2 (2 ml) and mCPBA (200 mg) were added. After 3 h. the mixture was poured onto a silica gel column (40 g) and eluted with 1:1 hexanes:EtOAc and then 10:1 CH2Cl2:CH30H. After evaporation of the appropriate fractions, the product was isolated (512 mg) as a waxy white solid in 89% yield, which was used directly in the next step. Step 2: The product of step 1 was dissolved in CH3OH (1.8 ml) and a solution of 1.0 M Na2C03 (1,5 ml) was added. After stirring at RT for 36 h, the resulting mixture was evaporated to dryness, toluene (2 ml) was added and the mixture was evaporated to dryness. The resulting crude solid (153 mg) was 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 (immediately above) (76 mg) were subjected to the same reaction conditions as in Example 23, step 4, using HOBt (92 mg), DEC (130 mg), diisopropyl ethylamine (0.14 ml) and DMF (0,25 ml). After extraction and purification by preparative thin layer chromatography (1000 laM silica plate; 95:5 EtOAc:Et3N eluant), the free base form of the title compound was isolated (52 mg) as a foam in 40% yield. HRMS: calc'd: MH"^: C27H37N5O2F3: 520.2899; measured: 520.2908. Step 4: The product of step 3 (52 mg) was subjected to the reaction conditions in Example 23, step 5. using EtOAc (1.0 ml) and HCI (4.0 M solution in 1,4-dioxane; 75 ^Il) to give, after work up, the title compound (44.5 mg) as a white solid in 76% yield, mp: decompostion above 161°C Using similar procedures, the compounds of the formula O CH3 were also prepared, wherein R^ and R" are as defined in the table: Ex. R"^ R n m-P. (°C) 23D -CF, -OH 175-185 23E -CF. -OCH 169-173 23F zCF, -NH, 200-210 23G -CF, -NHCONHEt 184-190 23H iCF, -CF, 83-86 231 •CF3 154-159 23J -CF, -SCH, 176 (dec) 23K -OCF. -CH, 205-210 23L -OCF, Ph 239-242 23M -OCF, -OCH, 200-210 23N -OCF, -OH 185-191 Example 24 Arylcyclopropylamides Method A: O I F.C OH k^N^O CI step 1: To the stannane (0.39 g, 0.95 mmol) in DMF (10 ml) was added the 2-chloro-4-fluoroiodoben2ene (0.73 g, 2.86 mmol), Cul (0.19 g, 1.05 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.11 g, 0.095 mmol) BusSn '4i Stale Coupling Me Me X^ k^N^f^ o I ■ (Cn3)2SCn2 + — 24A ;/. TFA, CH2CI2 The reaction was stirred at RT under N^ for 21 h. The reaction mixture was added to Et^O and the heterogeneous solution filtered through a bed of celite, washing with EtOAc. The filtrate was washed with water and brine and dried (MgSOJ, Filtration and evaporation of the solvent in vacuo afforded a residue that was preadsorbed on silica gel. Purification by silici gel chromatography (4% EtOAc/hexane) yielded the arylacrylate (0.19 g, 78%), which was used directly in the next step. Step 2: To trimethylsulfoxonium iodide (0.18 g, 0.81 mmol) in DMSO (1.6 ml) was added potassium fe/t-butoxide (0.09 g, 0.81 mmol). The reaction mixture was stirred at RT for 1 h, at which time the arylacrylate (0.19 g, 0.74 mmol) in DMSO (1.6 ml) was added. The reaction mixture was stirred at RT for 5 h and water was added. The mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried (MgSOJ. Filtration and evaporation of the solvent in vacuo afforded the arylcyclopropyl ester that was used directly by taking up into CH^CIg (3 ml) and adding TFA (0.5 ml). The reaction mixture was stirred at RT for 15 h and then concentrated in vacuo to afford the arylcyclopropylcarboxylic acid (0.14 g, 91%-2 steps). Without further purification, the carboxylic acid was coupled to the product of example 8, step 3, using the procedure of Example 8, step 4 to obtain 24A as the HCI salt. HRMS (M+H): found 566.2561. Method B: i. B,.^^, PTC, 50% NaOH 45 °C N //. ethylene glycol, 100 °C quantitative F To the 2-fluorophenylacetonitrile (0,80 g, 5.92 mmol), benzyltriethyl-ammonium chioride (0.03 g, 0.12 mmol), and 1-bromo-2-chloroethane (1.70 g, 11.9 mmoi) was added 50% aqueous NaOH (3,5 ml). The reaction was stirred at 45 °C for 21 h and ethylene glycol was added (3 ml). The reaction was then warmed to 100 °C and stirred for 7 h. Upon cooling to RT, the reaction was diluted with water and washed with EtOAc. The aqueous layer was acidified to pH 2-3 with aqueous 6N HCI. The acidified solution was extracted with Et^O. The combined Et^O extracts were washed with water and brine and dried (MgSOJ. Filtration and evaporation of the solvent in vacuo afforded a pale yellow solid (1.06 g, 99%). The arylcyclopropyl acid was coupled to the product of example 8, step 3, using the procedure of Example 8, step 4 to obtain 24B as the HCI salt, HRMS (M+H): found 532.2949. Using similar procedures, the compounds of the formula Me Me F,C k.N^^ LN-^° 14 ^ / R were prepared, wherein is as defined in the table: Ex. HRMS (M+H) m.p. (°C) 24C ,JO ~~ 240-245 24D ,ja° >225 24E ^^0CH3 172-176 24F ,ja'"^ 225-230 24G CI >225 24H .-O^OCH, 544.3151 241 ,ja" 592.2150 24J ,i7' 532.2956 24K ,jr^ 539.3003 24L yXr^* 558.2949 24M 0 572.3107 24N ^^0, 582.2910 ^" 240 ,xy"' 582.2910 24P ,Xs 520.2609 ^ — 24Q ^A^N 515.2991 Example 25 N N^ F3C O Step 1: . Ti{OiPr)4 /P>CHO y ! "? Pt_AinM NC I J m\ k.NBOC 2. EtaAiCN ^^ k_NBOC Cyclopropyl carboxaldehyde (3.4 ml), S-methyl N-BOC piperazine (8.28 g), CHjClj (82 ml) and Ti(OiPr), (15.80 ml) were mixed together and stirred at RT for 23 h, then the resulting solution was cooled to 0 °C and Et^AICN (1.0 M in toluene; 62.1 ml) was added. The solution was stirred for 5 h at RT. A mixture of KF (20 g) and Celite (10 g) was added, followed by cautious addition of EtOAc (120 ml) and water (120 ml). The resulting slurry was stirred for 15 min, filtered, washed with EtOAc (3 X 35 ml) and the EtOAc layer was removed, washed with brine, dried over Na^SO,, filtered and evaporated to give the desired intermediate (12.0 g) which was used directly in the next step. Step 2: NC^^'S, F,C- FX To a O'C solution of A-iodobenzotrifluoride (40 g) and THF (52 ml) was added isopropyl magnesium chloride (2.0 M in Et^O; 74 ml). The resulting solution was stirred at RT for 1 h and then added to a 0 °C solution of the product of step 1 (10.0 g) and THF (26 ml) over 10 min. The reaction solution was warmed to RT, stirred overnight and EtOAc (50 ml) was added. After stirring for 10 min, 2 N NaOH (50 ml) was added and the resulting mixture was stirred for 30 min, filtered and the salts were washed with EtOAc (3 X 20 ml). The combined EtOAc extracts were washed with brine, dried over NajSO^, filtered and evaporated to give the crude product (28 g) as a gold oil which was chromatographed on silica gel (1 kg), eluting with hexanes;EtOAc (8:1), Two diastereomeric products were collected as a single fraction (15,9 g) and further purified by column chromatography as described above to give intermediate A (R^=0,47 in 4:1 hexanes:EtOAc; 5.34 g), which was contaminated with an unidentified impurity. (The second diastereomer B (R^=0,29 in 4:1 hexanes:EtOAc ) was also collected.) Step 3: ^i^^ Dowex ^^N-^ yj> k^NBOC CH2CI2 Cj k.NH F3C F3C To a solution of A from Step 2 (3.96 g) and CH^CI^ (120 ml) was added DOWEX 50X2-100 ion exchange resin (15 g) and the resulting mixture was shaken for 2.5 h at RT. The resin was filtered off and washed with CHjClj (2 X 40 ml). The resin was treated with 7 N NH, in CH3OH (30 ml), the resin was filtered off and this procedure was repeated two times. The CH3OH extracts were combined and evaporated. The resulting oil was treated with tolueneiCHjClj (1:1; 15 ml) and evaporated to give the piperazine intermediate (0.80 g) as a clear oil. HRMS: calc'd: M K: CeHj,N,F3:299.1735; measured:299.1748. Step 4: 1. Ti(0iPr)4/ oK NBOC 2. EtjAlCN 3. CHgMgBr p Q' .—to. ■^ The product of Step 3 (0.57 g) was treated in the same fashion as Example 8, Step 1, using N-BOC 4-piperidone (0.42 g), CHjCIj (3.84 ml), Ti(OiPr), (3.39 ml), Et^AlCN (2.88 ml) and CHjMgBr (3.0 M in Et^O; 3.2 ml) to give the desired product (0.78 g) as a clear oil in 82 % yield. Step 5: The product of Step 4 (0.12 g) was treated withAcOHiCHjCIj (3:1, v:v; 1.4 ml) followed by BFjEt^O (0.14 ml). After stirring for 1 h, the resulting solution was diluted with CH2CI2 (10 ml), cooled to 0°C and the pH was adjusted to 10 with solid NaOH. Water (2 ml) was added and the CH^CIj layer was removed. After further extraction (2X10 mi) with CHjClj, the organic layer was washed with water, brine, dried over Na^SO,. filtered and evaporated to give the free piperidine (80 mg) in 81 % yield. Step 6: The product of Step 5 (57 mg) was treated in the same fashion as in Example 8, Step 4, using DMF (0.30 ml), HOBt (41 mg), DEC (57 mg). diisopropyl ethyl amine (0.08 ml) and 4,6-dimethyI 5-pyrimidine carboxylic acid (43 mg); the reaction was stirred at 45X for 5 h. Purification of the crude oil was carried out by preparative plate chromatography (silica adsorbent; 2000 fxM; 76:19:5 EtOAc;hexanes:Et3N as eluant) to give, after elution of the desired band (1:1 CH^CIjiMeOH) and concentration of solvent, the title compound (70 mg) as a clear oil in 93% yield. The HCI salt was prepared as described for Example 8, Step 4 (78 mg) in 100% yield. mp:147-149'C. Using a similar procedure, the following compound was prepared: "^ - NHCONHB O 25A F,C Example 26 Ph Step 1: CN I NBOC The desired compound was prepared in a manner similar to Example 25, Step 1, using p-trifluoromethyl benzaldehyde (20 g) instead of cyclopropyl carboxaldehyde, to give, after work up, a mixture of diastereomers (22.7 g) in 59% yield. Step 2: ^^^ JL NaNn"MS)2/THF/-78oC L^ ? To a -70°C solution of the product of step 1 (1.9 g) and THF (15 ml) was added NaHMDS (1.0 M in THF; 7.5 ml) followed by benzyl bromide (2 ml). The cooling bath was removed and the resulting solution was stirred for 45 min. Concentrated NH.OH (10 ml) was added and the reaction was stirred for 30 min. The resulting mixture was partitioned between water and CHjClj, the CHjClj extracts were removed and evaporated and the crude oil was purified by column chromatography (silica gel; 2:1 hexanesiCHjClj; 10:1 to 7:1 hexanes:EtOAc as eluant) to give, after evaporation of the appropriate fractions, a mixture of intermediates (1.92 g) as a yellow foam. Step 3: ^^I^ NaBH(QAc)3 pJ-^X^ . rrN-S B A The mixture of Step 2 (1.91 g), CH^CN (35 ml), sodium triacetoxy borohydride (4.0 g) and magnesium bromide etherate (2.25 g) were mixed and stirred at RT for 70 h. Water (25 ml) was added and then, gradually, a solution of NajCO, (10 g) in water (50 ml). After extraction with EtOAc (2 X 50 ml), drying and evaporation of the organic layer, the resulting oil was purified by preparative plate chromatography (5 X 2000 mM silica plates; 6:1 hexanes:EtOAc as eluant). The less polar band was removed, treated with 1:1 methanol:CHjClj, filtered and evaporated to give intermediate A (0.84 g) as a white foam. HRMS: calc'd: M H*: C25H,3O2NjF3:449.2407; measured:4492416. Step 4: The product of Step 3 (0.81 g) was treated in the same fashion as in Example 8, Step 3, using TFA (5 ml) and CH^CI^ (10 ml), to give, after work up, the free piperazine (0.60 g) as a clear gum. HRMS: calc'd: M H': CeoH^jN.F,: 349.1892; measured:349.1894. Step 5: The product of Step 4 (0.39 g) was treated in the same fashion as in Example 8, Step 1, using N-BOC 4-piperidone (0.25 g), CH^CI^ (8 ml), Ti(OiPr), (0.40 mg), Et^AICN (2 ml) and CHjMgBr (3.0 M in Et^O; 1.5 ml) to give the desired BOC-protected piperidinyl intermediate (0.44 g) as a dear oil in 72 % yield. HRMS: calc'd: MH*: C3,H,AN3F3:546.3307; measured:546.3315. Step 6: The product of step 5 (0.43 g) was treated in the same fashion as in Example 8, Step 3, using TFA (3 ml), CH.CI^ (2 ml) and water (0.2 ml) to give, after work up, the free piperidinyl intermediate (0.37 g) as a clear oil. step 7: The product of step 6 (50 mg) was treated in the same fashion as in Example 8. Step 4. using CH^CI, (3 ml). HOBt (28 mg), DEC (40 mg). diisopropyl ethyl amine (42 mg) and 4,6-dimethyl 5-pyrimidine carboxylic acid (24 mg); the reaction was stirred at RT for 2 days. Using the procedure described in Example 8, Step 4, the HCI salt of the title compound was prepared (59 mg) in 91% yield (from the product of Step 5). M.p:187-196°C. HRMS: calc'd: MH^ C^H,,ONsF3:580.3263; measured:580.3263. Using a similar procedure, compounds of the formula .3 R R 8a iSa t-,3 were prepared, wherein R , R and R are as defined in the table: Ex. R 8a R^ R' Mp (°C) 26B -CF3 O- ^ >^^^^ VN 86-92 26C -CF3 O. N ^-VN 83-90 26D -CF3 O. V /PV-OH 195-205 26E -CF3 o. VV-NHCONHEt 118-125 N 26F -0CF3 o. X'VOCHa 175-185 26G -0CF3 O- 180-190 26H -0CF3 o. // N 220-230 261 26J -0CF3 -0CF3 N ^-VN rvci 195-210 190-200 26K -0CF3 O. "7? 180-205 rv-oH 26 L -0CF3 O- 230-240 26M -0CF3 o. 60-65 26N -OCRS O. 65-68 260 -0CF3 O- "i»v. 60-62 /r= N 26P -CF3 i 256-258 26Q -CF3 CI t>>- .-^:> 254-256 (dec) ^ 26R -CF3 ^ ^-^:> 249-250 (dec) Example 27 on3on2 ff CH3Cn2 o Step 1: FX Et O^ OH 4*-Trifluoromethyl)propiophenone (2.02 g, 0.01 mol) and (S)*2-methyl-CBS-oxazaborolidine (1M in THF) (2.0 ml, 0.002 mol) in THF (10 ml) was cooled in an ice-bath and borane-methyl sulfide complex (2M in THF) (3 ml, 0.006 mol) was added dropwise to the mixture. The mixture was stirred for 30 min at 0° C and CH3OH was added slowly until no bubbles appeared. The solvents were removed under reduced pressure and HCI solution (1N) was added to the mixture. EtOAc extractive work up followed by silica gel chromatography afforded the alcohol (1 Al g) in 72% yield. Step 2: A solution of the product of Step 1 (4.32 g, 0.021 mo!) and Et3N (5.9 ml. 0.042 mol) in CH^Cl^ (20 ml) was cooled to 0' C in ice bath and CH3SO2CI (2.13 ml, 0.028 mol) was added dropwise. The mixture was stirred at 0° C for 1 h and the ice bath was removed. Water was added to the mixture and CH^CI^ extractive work up afforded the mesylate (5.99 g) in quantitative yield. Steo 3: The product of Step 2 (5.93 g, 0.021 mol) and 1-terf-butoxy- carbonyl-3S-methyl piperazine (4.2 g, 0.021 mol) were dissolved in anhydrous CH^CN (20 ml) and oven-dry K^COg (4.35 g. 0.032 mol) was added to the solution. The mixture was stirred under reflux for 2 days, then diluted with water. EtOAc extractive work up followed by silica gel chromatography gave the desired product (3.16 g) in 39% yield. Step 4: TFA (10 ml) was added to a solution of the product of Step 3(1.15 g, 2.59 mmol) in CH2CI2 (5 ml) and the mixture was stirred at RT for 2 h, then concentrated under reduced pressure. NaOH (3N) was added to the residue and extractive work up with EtOAc gave the desired amine in quantitative yield. Step 5: The product of Step 4 and 1-/e/t-butoxycarbonyl-4-piperidone (0,94 g, 4.74 mmol) were treated with Ti(OiPr),, Et^AICN and CH3MgBr in a manner similar to that described in Example 8, step 1, to obtain the desired product (1.09 g) in 87% yield (from the amine of Step 4). Step 6: TFA (4 ml) was added to a solution of the product of Step 5 (0.76 mg, 1.57 mmol) in CH2CI3 (2 ml) and the mixture was stirred at RT for 2 h before it was concentrated under reduced pressure. NaOH (3N) was added to the residue and extractive work up with EtOAc gave the desired amine in quantitative yield. Step 7: The amine of Step 6 and 4,6-dimethylpynmidine 5-carboxylic acid (0.36 g, 2.35 mmol), were coupled as described in Example 8, Step 4, to obtain the title compound (0.58 g) in 72% yield. M.p. 160; HRMS (MH*) found: 518.3123. Using a similar procedure, compounds of the formula iV^ A - 0 were prepared wherein Z. R . R and R are as defined in the table below H Ex. Z R' R ^ N Me 27A R' VAA^ N^N Dec.(0°C) 185 HRMS 491.2744 27B 27C N N Me Me H Me '-'Vu ^>V\, O 190 190 506.2729 505.2898 N^N 27D N Me Me ^^\r\j O 200 520.2902 27E CH Et Me O 197 533.3097 27F CH Et Me »-nj\^ OH 215 532.3147 27G CH Et Me vAAy NHCOCF3 230 627.3145 27H CH Et Me 210 602.3678 NHCONHEt 271 CH Et Me '^Xr^j 215 531.3305 NH. 27J CH Et Me 215 593.3470 27K CH Et Me "N 0 195 609.3424 27L CH Et Me N(S02CF3)2 170 745.2308 27M N n-Pr Me 204 533.3207 27N N n-Pr Me NHCONHEt 210 617.3798 270 N n-Pr Me 202 531.3304 U 27P N n-Pr Me A 165 543.3311 27Q N n-Pr Me 225 584.3205 27R N n-Pr Me 0 195 548.3217 Using similar procedures, the following compounds were also prepared: 27S: M.p. 236 °C NHCONHEt 27T: M.p. 213 °C Example 28 F.C A O Steps 1-4: CN I „ ^ PN . 1)H2/Pd-C/1 atm. ^.Jk JL NaHMDS/-78° ^^1 -—= *- P^C^J k.NBOC ^ .XX^ONBOC 2) NaB(0Ac)3H/ ^^^ Allyl bromide / RT "^3^ MgBrj: OEts N^ 1) Separate diastereomers ^3C 2) Reductive Amination p Q^^^ ^NX^ Ipso-cyanation k^NBOC 3)CH3MgBr/THF/A Step 1: The cyano amine was prepared from p-trifluoromethyl benzaldehyde and 2(S)-methyl-4-(tert-butoxycarbonyl) piperazine exactly as describedin Example 6, Step 1, Step 2: A solution of the cyano amine 2 (2,5 g; 6,53 mmol) in 30 ml of dry THF was placed under a blanket of Nj and cooled to -78° C, This solution was treated with a solution of sodium hexa-methyl disilazide in THF (1M; 26 ml) followed after 5 min with neat allyl bromide (6 ml). Upon removal of the bath and letting the reaction mixture warm to RT (-1h), it changed from a yellow solution to dark reddish brown solution. The reaction was quenched with saturated NH.CI solution and the product extracted with EtOAc, washed with water, brine and dried. Concentration in vacuo afforded a brown semi solid. FSGC of this material using 25% Et^O in hexane as eluant gave 2,5 grams (92%) of the desired product as an amber gum (TLC R, = 0,65, 0.6 for two overlapping spots). Step 3: A solution of the product of Step 2 (2.4g) in CH3OH was treated with 10% Pd/C (0.2g) and placed under a balloon of H^ gas. After stirring at RT for 4 h, the catalyst was removed via filtration through cellte. Concentration of the filtrate yielded an amber gum. The a-propyl nitrile obtained above was dissolved in CH^CN (12 ml). Magnesium bromide etherate (2.1 g; 8,14 mmol) and sodium triacetoxy borohydride (3.44 g; 16.2 mmol) were added and the reaction mixture was stirred at RT overnight. The reaction was quenched with water and rendered basic with saturated NaHCOa- The organic products were extracted with EtOAc and processed to obtain ~ 2 g of crude material. FSGC (10-25% EtjO in hexane) served to isolate two diasteromeric products (1.7g total; 79% for two steps): (S, S)-Diastereomer (A); TLC R, = 0.6 (25% Et,0-Hexane). 0.9 g of a colorless gum. (R, S)-Diastereomer (B): TLC R, = 0.5 (25% Et,0-Hexane). 0.8 g of a colorless gum. Step 4: Removal of the BOC-protecting group from the intermediate A was accomplished by treatment with TFA in CHjCI,. The isolated free piperazine (0.68g; 2.3 mmol), N-(tert-butoxycarbonyI)-4-piperidinone (0.45g; 2.3 mmol) and Ti(OiPr), ( 0.7 mL; 2.5 mmol) were dissolved in 10 ml of CHjClj and stirred overnight. EtjAICN (1M in toluene; 2.7 ml) was introduced into the reaction mixture and the resultant solution was stirred for a day. The reaction was diluted with EtOAc and quenched with water. Celite was added to aid in the filtration of titanium and aluminum salts. The biphasic filtrate was washed with water, brine and dried. Concentration in vacuo yielded 1.1 g of a yellow gum (TLC R, = 0.55 in 25% EtOAc-hexane). The resultant ipso-cyano compound was dissolved in dry THF (8 ml) and treated with a solution of CH^MgBr (3M in Et^O; 6 ml) and stirred overnight at RT. The reaction flask was placed in a cold water bath and carefully quenched with saturated NH.CI solution. The organic product was extracted with EtOAc and washed with water and brine. Concentration to a crude product which was purified by rapid FSGC (10-25% EtOAc in hexane) gave the BOC-piperidinyl compound as a pale yellow gum (l.lg; 100%). TLC R, = 0.6 in 25% EtOAc-hexane. Step 5: The BOC-protecting group on the piperidine nitrogen in the product of Step 4 was removed by treatment with TFA in CH^CIj. Basification with 1 M NaOH and processing in CH^Cl^ afforded the unprotected piperidine in 90% yield. This intermediate was coupled (EDCI, HOBt) to aryl and heteroaryl carboxylic acids to obtain the amides exemplified in the following table: F-,C wherein R^ is as defined in the table: Ex. 28A Mp (° C) HRMS (MHl 249 Calculated: 532.3263 Found: 532.3268 28B 59 Calculated: 547.3260 Found: 547.3278 28C 246 Calculated: 530.3358 Found: 530.3372 28D 239 Calculated: 542.3358 Found: 542.3361 28E 258 Calculated: 583.3260 Found: 583.3272 N-0 28F 102 Calculated: 623.3573 Found: 623.3572 28G ■0-un 216 Calculated: 545.3467 Found: 545.3459 28H ^' 217 Calculated: 546.3307 Found: 546.3309 28 .^.t"' 223 Calculated: 616.3838 Found: 616.3848 Using similar procedures, the following compounds were prepared: ,8 r-»3 wherein R°, R^ and R are as defined in the table: Ex. R« R^ R^ Mp r c) 28J -CF3 a^ 195-220 28K -CF3 a, N^^NHCONHEt 105-115 28L CH3CONH- ^ vV 177-180 28M -CF3 CF3 vV 224-232 Using 3-fluoro benzyl bromide or chloride in place of benzyl bromide in the procedure of Example 28, steps 1-4 (processing isomer B in step 3), then using the process of Example 1, step 5, followed by the process of Example 26, steps 6*7, the following compound was prepared (HCI salt): FaC O ' 28N: m.p. 185-193 °C Example 29 HsCO^ F3C R' Steps 1-3: Q ^J\ NaOMe / CH3OH ^..^^Tl^oMe JD^ RT/ 55% MeO^ F-,C m-CPBA F,C HN NBOC CH2CI2 / RT F3C OMs V-v MsCi 0°C F3C ^- NBOC /L^ k^NBOC F.qC CH3CN /A p ^' 83% for 2 steps ^ Stepi: Solid m-CPBA was added to a solution of p-trifluorometliyl styrene (3g; 17.4 mmol) in 30 ml of CH.CIj and stirred at RT for 20 h. About 20 ml of a saturated solution of NaHCOjWas added and stirred at RT for 2 h. The mixture was diluted with 20 ml of CHjCljand the organic product extracted into the CH^CI^ layer. The organic extract was processed to obtain the crude product. FSGC gave 3g (90%) of the desired epoxide as a colorless oil. TLC R, ^ 0.8 (25% EtOAc in hexane). Step 2: Freshly prepared NaOCH3 (0.6g; 10,6 mmol) was added to a solution of the product of Step 1 (2g; 10.6 mmol) in 20 ml of anhydrous CH3OH. After stirring at RT for a day, CH3OH was removed in vacuo. The residue was dissolved in CH^CIj and washed with water and brine. Concentration, followed by FSGC, furnished 1,3 g (55%) of the carbinol as a colorless oil (R, = 0.3 50% Et^O in hexane). Step 3: The carbinol of Step 2 (1.3g; 5.9 mmol) was dissolved in CH^CI^ and cooled in an ice bath. Sequential treatment with Et3N (1.7 ml; 12 mmol) and CH3SO2CI (0.6 ml; 7.7 mmol) and stirring for 30 min formed the mesylate. The product was extracted by standard work up (yield = 100%). The mesylate (1.76g; 5.9 mmol) and 2(S)-methyl-4-(tert-butoxycarbonyl) piperazine (2.4 g; 12 mmol) were dissolved in 5 ml of CH3CN and heated to reflux for 19 h. The reaction mixture was cooled to RT and directly subjected to flash chromatography on silica gel. Eluting with 25%, then 50% Et^O in hexane served to isolate the diastereomeric products A and B (Total yield = 86%). A: R, = 0.5 (50% Et^O in hexane). Light yellow gum (0.9g; 42%) B; R, = 0.4 (50% Et,0 in hexane). Amber gum (1.13g;44%) Step 4: Reductive amination of the free piperazine dervied from A (0.9g; 2.2 mmol) with N-BOC-piperidin-4-one with the installation of the ipso-methyl group was carried out as described in Example 1, step 4. to obtain the BOC-protected piperidinyl compound (0.87g; 92%). R, = 0.3 (50% EtOAc in hexane). Step 5: The BOC protecting group was removed from the piperidine nitrogen via TFA, and the resultant compound was coupled with acids using the EDCI / HOBt method as described in Example 8, step 4, to obtain the compounds shown in the following table: F3C k^N Y^ wherein R^ is as shown in the table: Ex. R' Mp (° C) HRMS (MK) 29A 163 Calculated: 534.3056 Found: 534.3050 29B .^OH 208 Calculated: 548.3100 Found: 548.3092 29C 101 Calculated: 549.3053 Found: 549.3057 29D 192 Calculated: 618.3631 Found: 618.3538 Example 30 J '61^ F3CO' R2 Step 1 Bt f F3CO F3C0^^ ^N k^NBoc bL_ Toluene Reflux A solution of p-trifluoromethoxy benzaldehyde (0.48 ml, 3.36 mmol), the piperidino-pipiperazine (I.OOg, 3.36 mmol) and benzotriazole (0.48g, 4.00 mmol) in dry toluene were heated at reflux for 6 h. The reaction mixture was cooled to RT and the solvent was removed in vacuo. Following NMR verification of the formation of the product, the product was used without further purification in the next step. Step 2: PrMgBr '4^ k^NBoc 60% F,CO F3CO Boc k B 2 : 1 To a solution of the product of Step 1 (1.15g, 1.97 mmol) in 20 ml of toluene was added a solution of n-propyl magnesium bromide (2M in Et^O, 1.1 ml) and the mixture stirred at RT for 15 h. The reaction mixture was quenched by pouring onto ice and saturated aqueous NH^CI solution. The aqueous layer was extracted with EtOAc, washed with 1M NaOH solution, water and brine. Concentration and purification by FSGC (20% EtOAc -hexane) provided the desired product A. Further elution with 30% EtOAc in hexane gave the (R, S) diastereomer B. Step 3: The amine A was treated with TFA in CH^CI^to remove the BOC-protecting group. Coupling of the free piperidine with acids using EDCI / HOBt provided compounds 30-30B in the following table; similar methods were used to prepare compounds 30C-L R aa ? 1 XTON Ex, R aa R' Mp C C) HRMS (MH*) found 30 -OCF3 n-Pr ^ 237 546.3314 30A -OCF3 n-Pr 241 548.3217 NH- 30B -OCF. n-Pr 219 632.3779 30C H ■O ^ 175-178 N.^N 30D H -O NH 177-189 30E H -O ^^1>CN 84-90 30F -CF. -O CF. 180-192 N.^N 30G -CF. -O 180-186 N^N 30H H -O 9^ "^ N 178-188 301 -OCF. -o 165-175 Mixture of diastereomers Example 31 ,N O A solution of the product of Example 12, step 2 (150 mg, 0,27 mmol), imidazole (27.4 mg, 0.403mmoi), 1,10-phenanthroiine (48 mg, 0.27 mmol), frans,frans-dibenzylideneacetone (6.28 mg, 0.027 mmol), copper (II) trifluoromethanesulfonate benzene complex (15 mg, 0.027 mmol) and Cs^COa (96-1 mg, 0,30 mmol) in xylene (2 ml) was stirred at 110° C for 5 days. The reaction mixture was cooled to RT and saturated NaHC03 was added. Extractive EtOAc work up followed by silica gel chromatography gave the title compound (70 mg, 52% yield). Dec. 215" C (HCI salt). HRMS calcd for C^H3gCIN30S (M+H+) 500.3389, found 500.3396. The following assays can be used to determine the CCR5 antagonistic activity of the compounds of the invention. CCR5 Membrane Binding Assay: A high throughput screen utilizing a CCR5 membrane binding assay identifies inhibitors of RANTES binding. This assay utilizes membranes prepared from NIH 3T3 cells expressing the human CCR5 chemokine receptor which have the ability to bind to RANTES, a natural ligand for the receptor. Using a 96-well plate format, membrane preparations are incubated with ^^251-RANTES in the presence or absence of compound for one hour. Compounds are serially diluted over a wide range of 0.001 ug/ml to 1 ug/ml and tested in triplicates. Reaction cocktails are harvested through glass fiber filters, and washed thoroughly. Total counts for replicates are averaged and data reported as the concentration required to inhibit 50 percent of total 125|. RANTES binding. Compounds with potent activity in the membrane binding assay are further characterized in secondary cell-based HIV-1 entry and replication assays, HIV-1 Entry Assay: Replication defective HIV-1 reporter virions are generated by cotransfection of a plasmid encoding the NL4-3 strain of HIV-1 (which has been modified by mutation of the envelope gene and introduction of a luciferase reporter plasmid) along with a plasmid encoding one of several HIV-1 envelope genes as described by Connor et al, Virology. 206 (1995), p. 935- 944. Following transfection of the two plasmids by calcium phosphate precipitation, the viral supernatants are harvested on day 3 and a functional viral titer determined. These stocks are then used to infect U87 cells stably expressing CD4 and the chemokine receptor CCR5 which have been preincubated with or without test compound. Infections are carried out for 2 hours at 37 °C, the cells washed and media replaced with fresh media containing compound. The cells are incubated for 3 days, Iysed and luciferase activity determined. Results are reported as the concentration of compound required to inhibit 50% of the luciferase activity in the control cultures. HIV'1 Reolication Assav: This assay uses primary peripheral blood mononuclear cells or the stable U87-CCR5 cell line to determine the effect of anti-CCR5 compounds to block infection of primary HIV-1 strains. The primary lymphocytes are purified from normal healthy donors and stimulated in vitro with PHA and IL-2 three days prior to infection. Using a 96-well plate format, cells are pretreated with drug for 1 hour at 37 °C and subsequently infected with an M-tropic HIV-1 isolates. Following infection, the cells are washed to remove residual inoculum and cultured in the presence of compound for 4 days. Culture supernatants are harvested and viral replication measured by determination of viral p24 antigen concentration. Calcium Flux Assav: Cells expressing the HIV coreceptor CCR5 are loaded with calcium sensitive dyes prior to addition of compound or the natural CCR5 ligand. Compounds with agonist properties will induce a calcium flux signal in the cell, while CCR5 antagonists are identified as compounds which do not induce signaling by themselves but are capable of blocking signaling by the natural ligand RANTES. GTPvS Binding Assav: A GTPyS binding assay measures receptor activation by CCR5 ligands. This assay measures the binding of 35s labeled-GTP to receptor coupled G-proteins that occurs as a result of receptor activation by an appropriate ligand. In this assay, the CCR5 ligand, RANTES, is incubated with membranes from CCR5 expressing cells and binding to the receptor activation (or binding) is determined by assaying for bound 3^5 label. The assay quantitatively determines if compounds exhibit agonist characteristics by inducing activation of the receptor or alternatively antagonist properties by measuring inhibition of RANTES binding in a competitive or non-competitive fashion. Chemotaxis Assav: The chemotaxis assay is a functional assay which characterizes the agonist vs. antagonist properties of the test compounds. The assay measures the ability of a non-adherent murine cell line expressing human CCR5 (BaF-550) to migrate across a membrane in response to either test compounds or natural ligands (i.e., RANTES, M1P-1B). Cells migrate across the permeable membrane towards compounds with agonist 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 CCR-5 receptors in inflammatory conditions has been reported in such publications as Immunology Letters. 57, (1997), 117-120 (arthritis); Clinical & Experimental Rheumatology. U (4) (1999), p. 419-425 (rheumatoid arthritis); Clinical & Exoerimental Immunology. 117 (2) (1999), p.237-243 (atopic dermatitis); international Journal of Immunopharmacolooy. 20 (11) (1998), p. 661-7 (psoriasis); Journal of Allergy & Clinical Immunology. 100 (6, Pt 2) (1997), p. S52-5 (asthma); and Journal of Immunology. 159 (6) (1997), p. 2962-72 (allergies). In the assay to determine inhibition of RANTES binding, compounds of the invention range in activity from a Ki of about 0.5 to about 1500 nM, with preferred compounds having a range of activity from about 0.5 to about 750 nM, more preferably about 0.5 to 300 nM, and most preferably about 0.5 to 50 nfvl. The results for preferred and representative compounds of formulas I and II in the test to determine inhibition of RANTES binding are given in the table below. In the table, "Ex. No." stands for "Example Number^ and "nM" stands for "nanomolar," Ex. No. Ki (nM) Inhibition of RANTES binding 3C 9.97 6C 30.0 6E 1.43 11 10.5 16 60 20A 1300 23 2.95 For preparing pharmaceutical compositions of the CCR5 antagonist compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e,g. magnesium carbonate, magnesium stearate. talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co,, Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. 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, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The CCR5 antagonist compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. Preferably the CCR5 antagonist compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 10 mg to about 500 mg, preferably from about 25 mg to about 300 mg, more preferably from about 50 mg to about 250 mg, and most preferably from about 55 mg to about 200 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be ' divided and administered in portions during the day as required. The amount and frequency of administration of the CCR5 antagonist compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 100 mg/day to about 300 mg/day. preferably 150 mg/day to 250 mg/day, more preferably about 200 mg/day, in two to four divided doses. The doses and dosage regimen of the NRTIs, NNRTIs. Pis and other agents will be determined by attending clinician in view of the approved doses and dosage regimen in the package insert or as set forth in the protocol taking into consideration the age, sex and condition of the patient and the severity of the HIV-1 infection. While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention. WHAT IS CLAIMED IS: 1, A compound represented by the structural formula II RSb is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, "CF3, CF3O-, CHaCCO)-, -CN, CF3S02% Ri4-benzyl, CH3C(=NOCH3), CH3C(=NOCH2CH3), ° O -NHCOCF3, 5-membered heteroaryl and "^—' , wherein X is as defined above; R9 and R'0 are independently selected from the group consisting of (CrC6)alky!. halogen, >NR"R", -OH, -CF3, -OCH3, -0-acyl, -OCF3 and -Si(CH3)3; RII is R9, hydrogen, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CH=NOR^^, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, -N(R'^)C0NR'^R'^ -NHCONH(chioro-(Ci-C6)alkyl), -NHCONH({C3-Ci)Cycloalkyl(CrC6)aIkyl), -NHC0(Ci-C6)alkyl, -NHCOCF3, -NHS02N({Ci-C6)alkyl)2. -NHS02(Ci-C6)aikyl, -NtSOsCFah, -NHC02(CrC6)alkyl, C3-C10 cycloalkyi, -SR^°, -SOR^°. -SOsR^. ■S02NH(CrC5 alkyl), -OSOaCCi-C6)alkyl, -OSO2CF3. hydroxy(Ci-C6)alkyl, -CON R^^R^^ -CON(CH2CH2-0- CH3}2, -0C0NH(CrC6)alkyl, -C02R'^ -Si(CH3)3 or -B(OC(CH3)2)2; R^2 is (Ci-C6)a!kyl, -NH2 or Ri-^-phenyl; R*"^ is 1 to 3 substituents independently selected from the group consisting of hydrogen, (Ci-Ce) alkyl, -CF3, 'CO2R17, -CN, (CrC6)alkoxy and halogen; Ris and R"'^ are independently selected from the group consisting of hydrogen and CrCe alkyl, or R'^ and Ri6 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms; R^^, R^^ and R^^ are independently selected from the group consisting of H and Ci-Ce alkyl; and R^° is CrCe alkyl or phenyl; or (2) Ra is R9-phenyl, R8-pyridyl or RS-thiophenyl; —C—yy --C—heteroaryl R2 is fiuorenyl, diphenylmethyl, R^^ or R and R^ R3, R^, R5. R6, R7, R8, R9^ RIO^ R11, R12^ R13^ R14 R15, R^6^ R'^^ R^'*^ R^5 ^^^ pj2o ^^^ ^g defined in (1). 2. A compound of claim 1 wherein RQ is R^^-phenyl or R8-naphthyl. 3. A compound of claim 2 wherein R^ is ^^ ', wherein R8a js CF3, CF3O-or halogen; or R^ is R' wherein R8 is CrCe alkoxy. *V\A* 4. A compound of claim 1 wherein R3 is hydrogen, (C-j-Ce) alkyl, RS-phenyi, R^-benzyl or R8-pyridyl. 5. A compound of claim 1 wherein R"' is hydrogen; R^ is hydrogen or methyl; R^ is methyl; and R5 and R"^ are each hydrogen. 6. A compound of claim 1 wherein R2 is R9, R^O, R^ ^-phenyl; R9, R^O, R^^-pyridyl or an N-oxide thereof; or R9, R^O^ Rii-pyrimidyl. 7. A compound of claim 6 wherein R2 is selected from the group consisting of 'W\, ■wv wherein R9 and R^O are selected from the group consisting of (Ci-C6)alkyl, halogen, -OH and -NH2. 8. A compound selected from the group consisting of those represented by the structural formula R' wherein R, R^, R6 and R^ are as defined in the following table: R R3 R6 R2 Br^-i PH3 H B'^-i CH3 -CH3 OH 0-? H FaC-OH PH3 H 'fi ffi-Q-i pH3 H FsCO-^-^ PH3 -CH3 FfiO-^~\—\ pHg -CH3 N Y 0 FsCO-^-l PH3 -CH3 H3C^JY^'^3 F3CO.QH H3C--. -CH3 H3C-y=k^H3 F3CO-Q-? HaC,^ -CH3 H3C.^Js^H3 F3CO-QH CH -CH3 HaCSOsH^^i PH3 H H 3Cs.^^x>^CH3 ^XXsc-O^ CH3 H H3C's,^^CH3 ^^OH pH3 -CH3 F3C-QH PH3 -CH3 H.^CH3 ^30-^^ PH3 -CH3 f3c-{y-\ CHs -CH3 H3CX.J^H3 0 H3CS02-^^J PH3 -CH3 F30OH H -CHs vW -0^ H -CHa WW F3C0-HQ-^ H -CHs H3CS02-Q>-| H -CH3 '^ H H ^-^ pH3 H WW H3CvJ^CH3 -0-^ PH3 -CH3 c^^-i pH3 H HaCyk^CHa CH^i PH3 -CH3 VW XT NC- ^^i pH3 H ^^ HaCyiYCHa H,c' v/ \^ CH3 H H3C>,^,,*L^H3 H^C NOCH i:H3 -CH3 vW H3C-^^^Y'^'^3 CH3CH20-Q— o H -CH3 *A.A- H3C^CH3 CH3CH2O-Q— H -CH3 H3Cv,^^*\^'^3 N.^,N F3CC^ CH3 •CH,CH3 'VIA H3 C--Y^s^s^ C H3 F3C^ •CH,CH, •\/V* FsCO^I •CH,CH3 •w* H 3C-Y?:K_^ C H 3 V NHCONHEt H r^ C ■»wtfr\^ C H: O H CH3 -CM. F3C iX. -CH. 'S/V H3C-Y!:^^^YCH3 N^N rF,G' -CH3 •VAA H3C-Y:S^Y'CH3 ^30^= CH3 -CH3 OAA H3 C "Y^i^v-^ C H 3 FX H'iC-»w^^\,^ C H; ^ N^-' CH3 -CM. -CH, NHCONHEt /T^ FaCO^:} F,C- k -CH. -CH, 'XAA H3C^Y=^:^^CH3 V NHCONHEt OyTVA F3C0-^ \ -CH3 H3C'v-;s:^^CH3 V NHCONHEt ^fi^y-i 1 -CH3 F3C^I 1 * -CH3 H3C-vj;??^CH3 V NHCONHEt F3C0-^ \ -CH, H3C-Y?:^^CH3 hc- 9. A pharmaceutical composition for the treatment of Human Immunodeficiency Virus, solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis, comprising an effective amount of a CCR5 antagonist of claim 1 in combination with a pharmaceutically acceptable carrier. 10- The use of a compound of claim 1 for the preparation of a medicament for treating Human Immunodeficiency Virus, solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis. 11. The use of a compound of claim 1 for the preparation of a medicament for combined use with one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus, 12. The use of claim 11 wherein the antiviral agent is selected from the group consisting of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. 13. The use of a compound of claim 1 for the preparation of a medicament for combined use with one or more agents for treating solid organ transplant rejection, graft v, host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. 14, The use of a CCR5 antagonist of formula I for the preparation of a medicament for treating Human Immunodeficiency Virus, solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowei disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis, wherein the CCR5 antagonist is represented by the structural formula I: I or a pharmaceutically acceptable salt thereof, wherein R is R8-phenyl, R^-pyridyl, R^-thiophenyl or R8-naphthyl; R1 is hydrogen or CrCe alkyl; R2 is R9. R'JO, Rii-phenyl; R9. R^o, Ri^-substituted 6-membered heteroaryl; R9, R10, R^i-substituted 6-membered heteroaryl N-oxide; R12, Ri3-substituted5-membered heteroaryl; naphthyl; fluorenyl; -9-0 —C—heteroaryl 1 R ^— 1 6 diphenylmethyl R or R R3 is hydrogen, d-Ce alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, C3-C10 cycloalkyi, C3-C10 cycloalkyl(Ci-C6)alkyl, R8-phenyl, R8-phenyl(Ci-C6)alkyi, R8-naphthyl. R°-naphthyl(Ci-C6)alkyl, R8-heteroaryl or R8-hetGroaryl(Ci-C6)alkyl; R^, R5, R^ and R^^ are Independently selected from the group consisting of hydrogen and (CrC6)-alkyl; R6 is hydrogen, Ci-Ce alkyl or C2-C6 alkenyl; R8 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C-\-CQ alkyl, Ci-Ce alkoxy, -CF3, CF3O-, CH3C(0)-, -CN, CH3SO2-, CF3SO2-, Ri4-phenyl, Ri^-benzyl, CH3C(=NOCH3), CH3C(=NOCH2CH3), ° SO2 ,-NH2,-NHCOCF3, -NHC0NH(Ci-C6 alkyl), -NHC0(Ci-C6 alkyl). -NHS02(Ci-C6 alkyl). O A —N X 5-membered heteroaryl and ^—' , wherein X is -0-, -NH- or -N(CH3)-; R9 and R"'0 are independently selected from the group consisting of (CrC6)alkyl, halogen, -NR"R", -OH, -CF3. -OCH3, -0-acyl, -OCF3 and -Si(CH3)3; RII is R9, hydrogen, phenyl. -NO2, -CN, -CH2F, -CHF2, -CHO, -CH=NOR^^, pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, -N(R^^)CONR'®R'^ -NHCONH(chloro-(CrC6)alkyl), -NHC0NH((C3- Ci)Cycloalkyl(Ci-C6)alkyl), -NHC0(C,-C6)alkyl, -NHCOCF3, -NHS02N((Ci- C6)alkyl)2, -NHS02(Ci-C6)alkyl, -N(S02CF3)2, -NHC02(CrC6)alkyl, C3-C10 cycloalkyi, -SR^°, -SOR^°, -S02R^, -S02NH(Ci-C6 alkyl), -0S02(Cr C6)alkyl, -OSO2CF3, hydroxy(Ci-C6)alkyl, -CON R'^R^^ -CON(CH2CH2-0- CH3)2, -0C0NH(Ci-C6)alkyl, -C02R^^ -Si(CH3)3 or-B(0C(CH3)2)2; R12 is (Ci-C6)alkyl, -NH2 or Ri^-phenyl; R^'* is 1 to 3 substituents independently selected from the group consisting of hydrogen, (Ci-Ce) alkyl, -CF3, -CO2R17, -CN, (CrC6)alkoxy and halogen; R'5 and R'lS are independently selected from the group consisting of hydrogen and CrCe alkyl, or RiS and R^^ together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms; R^ , R'° and R^^ are independently selected from the group consisting of H and Ci-Ce alkyl; and R^° is Ci-Ce alkyl or phenyl. 15. The use of claim 14 wherein R is R8-phenyl or R^-naphthyl. 16. The use of claim 15 wherein R is R'-A // 17. The use of claim 14 wherein Pfl is hydrogen, (Ci-Ce) alkyl, R8-phenyl, R8-benzyi or R8-pyhdyl. 18. The use of claim 14 wherein R^ is hydrogen and R^ is hydrogen or methyl. 'VUV 19. The use of claim 14 wherein R2 is R9, R^O, Rii-phenyl; R9, R^o, Rii-pyridyl or an N-oxide thereof, or R9, R^O, Rii-pyrimidyl. 20. The use of claim 19 wherein R2 is selected from the group consisting of 'WU R^° R' 10 wherein R9 and R^o are selected from the group consisting of (CrCelalkyI, halogen, -OH and -NHa^ 21. The use of claim 20 wherein R2 is phenyl or pyridyl and R'' is hydrogen, or wherein R2 is pyrimidyl and R^' is hydrogen, methyl or phenyl. 22. The use of claim 14 for the treatment of Human Immunodeficiency Virus, further comprising one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus. 23. The use of claim 22 wherein the antiviral agent is selected from the group consisting of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. 24. The use of claim 14 for the treatment of solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis, further comprising one or more other agents useful in the treatment of said diseases. 25. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat Human Immunodeficiency Virus which comprises in one container a pharmaceutical composition comprising an effective amount of a CCR5 antagonist of claim 14 in a pharmaceutically acceptable carrier, and in separate containers, one or more pharmaceutical composition comprising an effective amount of a antiviral or other agent useful in the treatment of Human Immunodeficiency Virus in a pharmaceutically acceptable carrier.

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