Patent Publication Number: US-8114879-B2

Title: Piperazine derivatives useful as CCR5 antagonists

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of U.S. Ser. No. 10/668,862, filed Sep. 23, 2003, which is a divisional of U.S. Ser. No. 10/061,011, filed Jan. 30, 2002, now U.S. Pat. No. 6,689,765 B2, which is a divisional of U.S. Ser. No. 09/562,814, filed May 1, 2000, now U.S. Pat. No. 6,391,865 B1, which claims the benefit of U.S. Provisional Application Ser. No. 60/132,509, filed May 4, 1999. 
    
    
     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 slowing 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&#39;s disease are disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006. 
     A-M. Vandamme et al.,  Antiviral Chemistry  &amp;  Chemotherapy,  9:187-203 (1998) disclose current clinical treatments of HIV-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 
     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: 
                         
or a pharmaceutically acceptable salt thereof, wherein
 
     R is R 8 -phenyl, R 8 -pyridyl, R 8 -thiophenyl or R 8 -naphthyl; 
     R 1  is hydrogen or C 1 -C 6  alkyl; 
     R 2  is R 9 ,R 10 ,R 11 -phenyl; R 9 ,R 10 ,R 11 -substituted 6-membered heteroaryl; R 9 ,R 10 ,R 11 -substituted 6-membered heteroaryl N-oxide; R 12 ,R 13 -substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl 
     
       
         
         
             
             
         
       
     
     R 3  is hydrogen, C 1 -C 6  alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, C 3 -C 10  cycloalkyl, C 3 -C 10  cycloalkyl(C 1 -C 6 )alkyl, R 8 -phenyl, R 8 -phenyl(C 1 -C 6 )alkyl, R 8 -naphthyl, R 8 -naphthyl(C 1 -C 6 )alkyl, R 8 -heteroaryl or R 8 -heteroaryl(C 1 -C 6 )alkyl; 
     R 4 , R 5 , R 7  and R 13  are independently selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl; 
     R 6  is hydrogen, C 1 -C 6  alkyl or C 2 -C 6  alkenyl; 
     R 8  is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —CF 3 , CF 3 O—, CH 3 C(O)—, —CN, CH 3 SO 2 —, CF 3 SO 2 —, R 14 -phenyl, R 14 -benzyl, CH 3 C(═NOCH 3 ), CH 3 C(═NOCH 2 CH 3 ), 
                         
—NH 2 , —NHCOCF 3 , —NHCONH(C 1 -C 6  alkyl), —NHCO(C 1 -C 6  alkyl), —NHSO 2 (C 1 -C 6  alkyl), 5-membered heteroaryl and
 
                         
wherein X is —O—, —NH— or —N(CH 3 )—;
 
     R 9  and R 10  are independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, —NR 17 R 18 , —OH, —CF 3 , —OCH 3 , —O-acyl, —OCF 3  and —Si(CH 3 ) 3 ; 
     R 11  is R 9 , hydrogen, phenyl, —NO 2 , —CN, —CH 2 F, —CHF 2 , —CHO, —CH═NOR 17 , pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R 17 )CONR 18 R 19 , —NHCONH(chloro-(C 1 -C 6 )alkyl), —NHCONH((C 3 -C 1 )cycloalkyl(C 1 -C 6 )alkyl), —NHCO(C 1 -C 6 )alkyl, —NHCOCF 3 , —NHSO 2 N((C 1 -C 6 )alkyl) 2 , —NHSO 2 (C 1 -C 6 )alkyl, —N(SO 2 CF 3 ) 2 , —NHCO 2 (C 1 -C 6 )alkyl, C 3 -C 10  cycloalkyl, —SR 20 , —SOR 20 , —SO 2 R 20 , —SO 2 NH(C 1 -C 6  alkyl), —OSO 2 (C 1 -C 6 )alkyl, —OSO 2 CF 3 , hydroxy(C 1 -C 6 )alkyl, —CONR 17 R 18 , —CON(CH 2 CH 2 —O—CH 3 ) 2 , —OCONH(C 1 -C 6 )alkyl, —CO 2 R 17 , —Si(CH 3 ) 3  or —B(OC(CH 3 ) 2 ) 2 ; 
     R 12  is (C 1 -C 6 )alkyl, —NH 2  or R 14 -phenyl; 
     R 14  is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, —CF 3 , —CO 2 R 17 , —CN, (C 1 -C 6 )alkoxy and halogen; 
     R 15  and R 16  are independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl, or R 15  and R 16  together are a C 2 -C 5  alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms; 
     R 17 , R 18  and R 19  are independently selected from the group consisting of H and C 1 -C 6  alkyl; and 
     R 20  is C 1 -C 6  alkyl or phenyl. 
     Preferred are compounds of formula I wherein R is R 8 -phenyl or R 8 -naphthyl, especially wherein R 8  is a single substituent, and especially wherein the R 8  substituent is in the 4-position. For R 8 -phenyl, preferred R 8  substituents are —CF 3 , —OCF 3 , CH 3 SO 2 —, CH 3 CO—, CH 3 C(═NOCH 3 )—, Br and I. For R 8 -naphthyl, R 8  is preferably C 1 -C 6  alkoxy. Also preferred are compounds of formula I wherein R 3  is hydrogen, (C 1 -C 6 )alkyl, R 8 -phenyl. R 8 -benzyl or R 8 -pyridyl; more preferred definitions for R 3  are methyl, ethyl, phenyl, benzyl and pyridyl. R 1  is preferably hydrogen. For compounds of formula I, R 6  is preferably hydrogen or methyl, especially methyl. R 4  is preferably methyl; R 5  and R 7  are each preferably hydrogen. 
     In compounds of formula I, R 2  is preferably R 9 ,R 10 ,R 11 -phenyl, R 9 ,R 10 ,R 11 -pyridyl or an N-oxide thereof, or R 9 ,R 10 ,R 11 -pyrimidyl. When R 2  is pyridyl, it is preferably 3- or 4-pyridyl, and when pyrimidyl, it is preferably 5-pyrimidyl. The R 9  and R 10  substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule and the R 11  substituent can be attached to any of the remaining unsubstituted carbon ring members, for example as shown in the following structures: 
     
       
         
         
             
             
         
       
     
     Preferred R 9  and R 10  substituents are: (C 1 -C 6 )alkyl, especially methyl; halogen, especially chloro or bromo, —OH and —NH 2 . When R 2  is phenyl, R 11  is preferably hydrogen or —OH; when R 2  is pyridyl, R 11  is preferably hydrogen; and when R 2  is pyrimidyl, R 11  is preferably hydrogen, methyl or phenyl. Examples of particularly preferred R 2  groups are as follows: 
     
       
         
         
             
             
         
       
     
     Also claimed are novel CCR5 antagonist compounds represented by the structural formula II 
                         
or a pharmaceutically acceptable salt thereof, wherein
     (1) R a  is R 8a -phenyl, R 8b -pyridyl, R 8b -thiophenyl or R 8 -naphthyl;   

     R 1  is hydrogen or C 1 -C 6  alkyl, 
     R 2  is R 9 ,R 10 ,R 11 -phenyl; R 9 ,R 10 ,R 11 -substituted 6-membered heteroaryl; R 9 ,R 10 ,R 11 -substituted 6-membered heteroaryl N-oxide; R 12 ,R 13 -substituted 5-membered heteroaryl; naphthyl; fluorenyl; diphenylmethyl, 
     
       
         
         
             
             
         
       
     
     R 3  is hydrogen, C 1 -C 6  alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, C 3 -C 10  cycloalkyl, C 3 -C 10  cycloalkyl(C 1 -C 6 )alkyl, R 8 -phenyl, R 8 -phenyl(C 1 -C 10 )alkyl, R 8 -naphthyl, R 8 -naphthyl(C 1 -C 6 )alkyl, R 8 -heteroaryl or R 8 -heteroaryl(C 1 -C 6 )alkyl; 
     R 4 , R 5 , R 7  and R 13  are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl; 
     R 6  is hydrogen, C 1 -C 6  alkyl or C 2 -C 6  alkenyl; 
     R 8  is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 1 -C 6  alkoxy, —CF 3 , CF 3 O—, CH 3 (O)—, —CN, CH 3 SO 2 —, CH 3 SO 2 —, R 14 -phenyl, R 14 -benzyl, CH 3 C(═NOCH 3 ), CH 3 C(═NOCH 2 CH 3 ), 
                         
—NH 2 , —NHCOCF 3 , —NHCONH(C 1 -C 6  alkyl), —NHCO(C 1 -C 6  alkyl), —NHSO 2 (C 1 -C 6  alkyl), 5-membered heteroaryl and
 
                         
wherein X is —O—, —NH— or —N(CH 3 )—;
 
     R 8a  is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CF 3 , CF 3 O—, —CN, CF 3 SO 2 —, R 14 -phenyl, —NHCOCF 3 , 5-membered heteroaryl and 
                         
wherein X is as defined above;
 
     R 8b  is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, —CF 3 , CF 3 O—, CH 3 C(O)—, —CN, CF 3 SO 2 —, R 14 -benzyl, CH 3 C(═NOCH 3 ), CH 3 C(═NOCH 2 CH 3 ), 
                         
—NHCOCF 3 , 5-membered heteroaryl and
 
                         
wherein X is as defined above;
 
     R 9  and R 10  are independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, —NR 17 R 18 , —OH, —CF 3 , —OCH 3 , —O-acyl, —OCF 3  and —Si(CH 3 ) 3 ; 
     R 11  is R 9 , hydrogen, phenyl, —NO 2 , —CN, —CH 2 F, —CHF 2 , —CHO, —CH═NOR 17 , pyridyl, pyridyl N-oxide, pyrimidinyl, pyrazinyl, —N(R 17 )CONR 18 R 19 , —NHCONH(chloro-(C 1 -C 6 )alkyl), —NHCONH((C 3 -C 1 )cycloalkyl(C 1 -C 6 )alkyl), —NHCO(C 1 -C 6 )alkyl, —NHCOCF 3 , —NHSO 2 N((C 1 -C 6 )alkyl) 2 , —NHSO 2 (C 1 -C 6 )alkyl, —N(SO 2 CF 3 ) 2 , —NHCO 2 (C 1 -C 6 )alkyl, C 3 -C 10  cycloalkyl, —SR 20 , —SOR 20 , —SO 2 R 20 , —SO 2 NH(C 1 -C 6  alkyl), —OSO 2 (C 1 -C 6 alkyl, —OSO 2 CF 3 , hydroxy(C 1 -C 6 )alkyl, —CONR 17 R 18 , —CON(CH 2 CH 2 —O—CH 3 ) 2 , —OCONH(C 1 -C 6 )alkyl, —COR 17 , —Si(CH 3 ) 3  or —B(OC(CH 3 ) 2 ) 2 ; 
     R 12  is (C 1 -C 6 )alkyl, —NH 2  or R 14 -phenyl; 
     R 14  is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, —CF 3 , —CO 2 R 17 , —CN, (C 1 -C 6 )alkoxy and halogen, 
     R 15  and R 16  are independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl, or R 15  and R 16  together are a C 2 -C 5  alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms; 
     R 17 , R 18  and R 19  are independently selected from the group consisting of H and C 1 -C 6  alkyl; and 
     R 20  is C 1 -C 6  alkyl or phenyl; or
     (2) R a  is R 8 -phenyl, R 8 -pyridyl or R 8 -thiophenyl;   

     R 2  is fluorenyl, diphenylmethyl, 
     
       
         
         
             
             
         
       
     
     and R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19  and R 20  are as defined in (1). 
     Preferred compounds of formula II are those defined in (1). 
     More preferred are those of formula II (1) wherein R a  is R 8a -phenyl or R 8 -naphthyl, wherein R 8a  is —CF 3 , CF 3 O— or halogen and R a  is C 1 -C 6  alkoxy. The R 8a  or R 8  substituent is preferably a single substituent; it is especially preferred that the R 8a  or R 8  substituent is in the 4-position. Also preferred are compounds of formula II (1) wherein R 3  is hydrogen, (C 1 -C 6 ) alkyl, R 8 -phenyl. R 8 -benzyl or R 8 -pyridyl; more preferred definitions for R 3  are methyl, ethyl, phenyl, benzyl and pyridyl. R 1  is preferably hydrogen. For compounds of formula II (1), R 6  is preferably hydrogen or methyl, especially methyl. R 4  is preferably methyl; R 5  and R 7  are each preferably hydrogen. 
     R 2  in formula II (1) is preferably as defined for formula I, i.e., R 9 ,R 10 ,R 11 -phenyl, R 9 ,R 10 ,R 11 -pyridyl or an N-oxide thereof, or R 9 , R 10 , R 11 -pyrimidyl, wherein the R 9 ,R 10 ,R 11 -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 It. 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 I or II 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 C 2 -C 6  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)—, (C 3 -C 7 )cycloalkyl-C(O)—, (C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl-C(O)—, and heteroaryl-C(O)—, wherein alkyl and heteroaryl are as defined herein: aryl is R 14 -phenyl or R 14 -naphthyl; and aralkyl is aryl-(C 1 -C 6 )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(s) 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 9 , R 10  or R 11  groups. Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Typical 6-membered heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the N-oxides thereof. For 5-membered heteroaryl rings, carbon atoms can be substituted by R 12  or R 13  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 for 6-membered heteroaryl rings at R 2  are described above. When R 2  is a 5-membered heteroaryl group, the R 12  and R 13  substituents are preferably attached to carbon ring members adjacent to the carbon joining the ring to the rest of the molecule, and R 12  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-pyrrolyl), R 12  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, preferably 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 transcriptase 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” (“NRTI”s) as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV-1 reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-1 RNA into proviral HIV-1 DNA. 
     Typical suitable NRTIs include zidovudine (AZT) available under the RETROVIR tradename from Glaxo-Wellcome Inc., Research Triangle, N.C. 27709; didanosine (ddI) available under the VIDEX tradename from Bristol-Myers Squibb Co., Princeton, N.J. 08543; zalcitabine (ddC) available under the HIVID tradename from Roche Pharmaceuticals, Nutley, N.J. 07110; stavudine (d4T) available under the ZERIT trademark from Bristol-Myers Squibb Co., Princeton, N.J. 08543, lamivudine (3TC) available under the EPIVIR tradename from Glaxo-Wellcome Research Triangle, N.C. 27709; abacavir (1592U89) disclosed in WO96/30025 and available under the ZIAGEN trademark from Glaxo-Wellcome Research Triangle, N.C. 27709; adefovir dipivoxil [bis(POM)-PMEA] available under the PREVON tradename from Gilead Sciences, Foster City, Calif. 94404; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533 and under development by Bristol-Myers Squibb, Princeton, N.J. 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. Pat. No. 5,814,639 and under development by Triangle Pharmaceuticals, Durham, N.C. 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 Conn. 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, N.C. 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” (“NNRTI”s) 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, Ohio 43216; delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia &amp; Upjohn Co., Bridgewater N.J. 08807; efavirenz (DMP-266) a benzoxazin-2-one disclosed in WO94/03440 and available under the SUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, Del. 19880-0723; PNU-142721, a furopyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater N.J. 08807; AG-1549 (formerly Shionogi # S-1153); 5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbonate disclosed in WO 96/10019 and under clinical development by Agouron Pharmaceuticals, Inc., LaJoila Calif. 92037-1020; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione) discovered by Mitsubishi Chemical Co. and under development by Triangle Pharmaceuticals, Durham, N.C. 27707; and (+)-calanolide A (NSC-675451) and B, coumarin derivatives disclosed in NIH U.S. Pat. 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 enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), 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, N.J. 07110-1199, ritonavir (ABT-538) available under the NORVIR tradename from Abbott Laboratories, Abbott Park, Ill. 60064; indinavir (MK-639) available under the CRIXIVAN tradename from Merck &amp; Co., Inc., West Point, Pa. 19486-0004; nelfnavir (AG-1343) available under the VIRACEPT tradename from Agouron Pharmaceuticals, Inc., LaJolia Calif. 92037-1020; amprenavir (141W94), tradename AGENERASE, a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, Mass. 02139-4211 and available from Glaxo-Wellcome, Research Triangle, N.C. under an expanded access program; lasinavir (BMS-234475) available from Bristol-Myers Squibb, Princeton, N.J. 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, N.J. 08543, as a 2nd-generation HIV-1 PI; ABT-378 under development by Abbott, Abbott Park, Ill. 60064; and AG-1549 an orally active imidazole carbamate discovered by Shionogi (Shionogi #S-1153) and under development by Agouron Pharmaceuticals, Inc., LaJolla Calif. 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 NCl is under development 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-0142268, Takeda EP-0176299, and Chiron U.S. Pat. Nos. RE 33653, 4,530,787, 4,569,790, 4,604,377, 4,748,234, 4,752,585, and 4,949,314 is available under the PROLEUKIN (aldesleukin) tradename from Chiron Corp., Emeryville, Calif. 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 IU/day, sc is preferred; a dose of about 15 million IU/day, sc is more preferred. IL-12 is disclosed in WO96/25171 and is available from Roche Pharmaceuticals, Nutley, N.J. 07110-1199 and American Home Products, Madison, N.J. 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. Pat. 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&#39;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-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; its manufacture and formulation are described in U.S. Pat. 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, NNRTIs and PIs. Typical suitable HAART—multidrug combination therapies include: 
     (a) triple combination therapies such as two NRTIs and one Pt; or (b) two NRTIs and one NNRTI, and (c) quadruple combination therapies such as two NRTIs, one PI and a second Pt 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 CD4 +  and HIV-1-RNA plasma levels should be monitored every 3-6 months. Should viral load 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. 
                 Two NRTIs 1  + one PI 2   
               
               
                   
                 2. 
                 Two NRTIs 1  + one NNRTI 3   
               
            
           
           
               
               
            
               
                   
                 B. Quadruple Combination Therapies 4   
               
            
           
           
               
               
               
            
               
                   
                   
                 Two NRTIs + one PI + a second PI or one NNRTI 
               
            
           
           
               
               
            
               
                   
                 C. ALTERNATIVES: 5   
               
            
           
           
               
               
               
            
               
                   
                   
                 Two NRTI 1   
               
               
                   
                   
                 One NRTI 5  + one PI 2   
               
               
                   
                   
                 Two PIs 6  ± one NRTI 7  or NNRTI 3   
               
               
                   
                   
                 One PI 2  + one NRTI 7  + one NNRTI 3   
               
               
                   
               
               
                 FOOTNOTES TO TABLE 
               
               
                   1 One of the following: zidovudine + lamivudine; zidovudine + didanosine; stavudine + lamivudine; stavudine + didanosine; zidovudine + zalcitabine 
               
               
                   2 Indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules. 
               
               
                   3 Nevirapine or delavirdine. 
               
               
                   4 See A-M. Vandamne et al Antiviral Chemistry &amp; Chemotherapy 9: 187 at p 193-197 and FIGS. 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 Interleukin-10 (IL-10), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;   inflammatory bowel disease: IL-10 (see U.S. Pat. No. 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 hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. 
     Certain basic compounds also form pharmaceutically 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 otherwise 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 WO96/26196 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 (HOST); m-chloroperbenzoic acid (MCPSA); triethylamine (Et 3 N); diethyl ether (Et 2 O); dimethylsulfoxide (DMSO); and 1-(3-dimethylaminopropyl)-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. 
                                           
Reagents and conditions: a: R 4 CH(OSO 2 CF 3 )CO 2 CH 3 , base (e.g., K 2 CO 3 ); b: ClCH 2 COCl; c; NH 3 ; d: NaBH 4 —BF 3 ; e: N-Boc-4-piperidone, NaBH(OAc) 3 ; f: CF 3 CO 2 H; g: acylation; h: N-Boc-4-piperidone, Ti(OPr-i) 4 , Et 2 AlCN; i: CH 3 MgBr.
 
     In Scheme 1, a benzylamine (1), wherein R and R 3  are as defined above and R 1  is hydrogen, is converted via (2) and (3) to the diketopiperazine (4), wherein R 4  is as defined above, which is reduced to the piperazine (5). Depending upon the desired R 6  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 IA wherein R 5  and R 6  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 R 5  is H and R 6  is methyl. Acylation of (7) and (10) is carried out under standard conditions, e.g., with a compound R 2 COOH and reagents such as DEC and HOBT. Use of a chiral compound of formula I, 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 IA and IB. 
                         
Reagents: j: oxaborazolidine, BH 3 ; k: CH 3 SO 2 Cl, base; l: CF 3 CO 2 H.
 
     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. 
     
       
         
         
             
             
         
       
     
     For compounds where R 3  and R 1  are each H, either the alkylation route of Scheme 2 or a reductive amination method as typified in Scheme 3 can be used. 
     
       
         
         
             
             
         
       
     
     For diaryl compounds, wherein R and R 3  are each aryl, an alkylation method as typified in Scheme 4 is preferred. 
     
       
         
         
             
             
         
       
     
     Piperazines of formula 14, especially those wherein R 3  is C 2 -C 6  alkyl or benzyl, may also be obtained by a process wherein the 
                         
portion is introduced as shown above by an alkylation-decyanation sequence. The reaction is exemplified for compounds wherein R is CF 3 O-phenyl, R 1  is hydrogen, R 3  is ethyl and R 4  is methyl, but using appropriate starting materials, other compounds of formula 14 can be similarly prepared.
 
                         
Reagents: m: BOC 2 O, base, n: R 6 MgBr; o: CCl 3 CO 2 H, NaBH 3 CN; p: CF 3 CO 2 H; q: NaBH 4 , BF 3 .
 
     As shown in Scheme 6, compounds bearing an additional alkyl group at R 5  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. 
     
       
         
         
             
             
         
       
     
     Many piperazines wherein R is R 8 -phenyl (or their Boc derivatives) shown in Scheme 1 can be obtained from a common intermediate, wherein R 8  is 1. Several examples are shown in the above scheme, wherein R 8  is converted to Cl, CN, —C(O)NH 2 , H, Ph and p-ClC 6 H 4 CH 2 —. 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. 
     
       
         
         
             
             
         
       
     
     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 
     
       
         
         
             
             
         
       
         
         Step 1: Stir methyl R-lactate (5.0 g) in CH 2 Cl 2  (40 ml) at −70° C. and add trifluoromethanesulfonic anhydride (7.6 ml), then 2,6-lutidine (7.8 ml). Remove the cooling, stir 0.5 h, wash with 2N HCl and add the organic solution to (S)-methyl 4-bromobenzylamine (9.0 g) and K 2 CO 3  (11.2 g) in water (60 ml). Stir 20 h at RT, dry the organic phase over K 2 CO 3 , evaporate and chromatograph on silica gel with Et 2 O—CH 2 Cl 2  to give the desired product (7.50 g) as a thick oil. 
         Step 2: Reflux the product of step 1 (7.5 g) in 1,2-dichloroethane (40 ml) and ClCH 2 COCl (5.0 ml) for 5 h, 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 NaI (8 g), cool in ice, add conc. NH 4 OH solution (15 ml) and stir to RT for 20 h. 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 NaBH 4  (3.4 g) under N 2 , add BF 3 .OEt 2  (6.8 ml) dropwise, then heat at 100° C. for 10 h. Cool and add CH 3 OH (20 ml) dropwise, followed by conc. HCl (30 ml). Heat at 100° C. for 1 h., cool, basify with excess 2N NaOH and extract with EtOAc. Dry over K 2 CO 3  and evaporate to obtain the piperazine (5.85 g), suitable for the next step. 
         Step 5: Stir for 20 h. at RT a mixture of the product of step 4 (5.48 g), N-Boc-4-piperidinone (4.32 g), HOAc (1.15 ml), CH 2 Cl 2  (80 ml) and sodium triacetoxy-borohydride (NaBH(OAc) 3 ) (8.3 g). Add excess aqueous Na 2 CO 3  solution slowly, stir for 0.5 h, separate and filter the organic phase through a pad of silica gel, washing with 10:1 CH 2 Cl 2 -Et 2 O to elute all of the product. Evaporate and dissolve the residue in Et 2 O (100 ml). Stir and add a 4M solution of HCl in 1,4-dioxane (10 ml) dropwise. Collect the solid, wash with Et 2 O, and stir with CH 2 Cl 2  and excess aqueous NaOH. Dry the organic phase over K 2 CO 3  and evaporate to obtain the desired product (5.45 g). 
         Step 6: Stir at RT for 2 h a mixture of the product of step 5 (1.5 g) and TFA (4 ml). Evaporate, dissolve in CH 2 Cl 2  and wash with excess 1N NaOH solution. Dry over K 2 CO 3  and evaporate to obtain the product (1.15 g). 
         Compound 1A: Following the standard procedure, react the product of step 6 with 2,6-dimethylbenzoyl chloride in CH 2 Cl 2  and aqueous NaOH, and convert the product to the hydrochloride. Mp 185-192° C. (decomposition). HRMS found: 498.2130: MH +  Calc: 498.2120. 
         Compound 1B: Following the standard procedure, couple the product of step 6 with 2-amino-6-methylbenzoic acid using HOBT and DEC with diisopropylethylamine 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 
     
       
         
         
             
             
         
       
         
         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(OiPr) 4 ) (1.00 g) for 20 h at RT in CH 2 Cl 2  (15 ml), reflux for 3 h and cool to RT. Add diethylaluminum cyanide (Et 2 AlCN) (4.2 ml of 1M toluene solution) and the stir for 5 days at RT under dry N 2 . Workup in CH 2 Cl 2 -aq. NaOH, dry and evaporate the organic phase and chromatograph on silica gel with CH 2 CO 2 —CH 3 OH (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 N 2  with CH 3 MgBr (4 ml of 3M Et 2 O solution) at RT for 20 h. 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 dimethylbenzoyl chloride as described in Example 1 and convert to the HCl 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 HCl 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 HCl 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 HCl salt. Mp 202-209° C. (decomposition). HRMS Found: 513.2227, MH + . Calc: 513.2229. 
       
    
     EXAMPLE 3 
     
       
         
         
             
             
         
       
         
         Step 1: Reflux and stir a mixture of S-alanine methyl ester hydrochloride (14 g), anhydrous Na 2 CO 3  (60 g), dry CH 3 CN (125 ml), chlorodiphenylmethane (22.3 g) and NaI (5 g) for 6 hr. Cool, add ice-H 2 O and extract with Et 2 O (350 ml, then 50 ml). Combine the Et 2 O extracts and wash with portions of 1N aq. HCl: 200 ml, 100 ml, then 4×10 ml. Combine the aqueous acid extracts, stir and add excess Na 2 CO 3  in small portions until the mixture is basic. Extract with Et 2 O, dry over MgSO 4  and evaporate to obtain the N-diphenylmethyl compound (23.2 g). 
         Step 2: Reflux all of the above compound with ClCH 2 COCl (10 ml) in dichloroethane (60 ml) for 4 h. Evaporate, and co-evaporate with toluene (20 ml). Dissolve the residue in CH 2 Cl 2  (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 NH 3  (100 ml), then NaI (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-Et 2 O mixture, and dry at 50° C. with high vacuum to obtain the solid diketopiperazine (15.5 g). Recrystallise a small sample from CH 2 Cl 2 -hexanes: mp 186-188° C.; [α] D   20 +272.6°. 
         Step 3: Stir the product of step 2 (4.0 g) in dimethoxyethane (40 ml) and NaBH 4  (1.6 g) under N 2  and add BF 3 .OEt 2  (3.2 ml) slowly. Reflux for 20 h. Cool and add CH 3 OH (10 ml) dropwise, then conc. HCl (15 ml). Reflux for 2 h., and work up in excess 2N aq. NaOH and extract with CH 2 Cl 2 . Dry over K 2 CO 3  and evaporate. Chromatograph on silica, eluting with CH 2 Cl 2 —CH 3 OH mixtures, and finally with 5:1:0.1 v/v/v CH 2 Cl 2 :CH 3 OH:NH 4 OH. 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), CH 2 Cl 2  (5 ml) and NaBH(OAc) 3  (0.70 g) at RT for 20 h. Work up in CH 2 Cl 2  and excess aq. NaOH, dry over MgSO 4 , evaporate and isolate the product by preparative TLC, eluting with 10% Et 2 O in CH 2 Cl 2 , 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), CH 3 CN (20 ml), water (5 ml) and piperidine (1.5 ml). Add tri(4-sulfophenyl)phosphine (0.072 g) and palladium (11) acetate (0.02 g) and stir at RT under N 2  for 2 h. Work up with aqueous NaOH, extract with 5:1 v/v toluene:CH 2 Cl 2 , dry over K 2 CO 3  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), CH 2 Cl 2  (2 ml) and NaBH(OAc) 3  (0.15 g) for 2.5 h., cool, and work up with CH 2 Cl 2  and aqueous NaOH. Dry over MgSO 4 , evaporate and isolate the major product by preparative TLC, eluting with 3:1 v/v Et 2 O:CH 2 Cl 2 . Precipitate the hydrochloride to obtain the desired compound as the HCl salt (0.13 g). Mp 173-177° C. (decomposition). HRMS Found: 482.3175; MH + . Calc: 482.3171. 
         Compound 3B: Couple the product of step 5 with 2-amino-6-chlorobenzoic acid using DEC-HOBt as described in Example 1, isolate the product by PTLC and precipitate the hydrochloride to give compound 3B. Mp 188-195° C. (decomposition). HRMS Found: 503.2567; 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: 
     
       
         
         
             
             
         
       
     
     EXAMPLE 4 
     
       
         
         
             
             
         
       
         
         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 (0.54 g; 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 CH 3 OH carefully until effervescence stopped; volatiles were removed in vacuo. The residue was dissolved in CH 2 Cl 2  and washed with 1N HCl, water, 10% NaHCO 3  solution and brine. Concentration in vacuo gave 2 g 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 R f =0.6 in 25% EtOAc:hexanes. 
         Step 2: To a solution of the product of step 1 (1.55 g; 8.16 mmol) in 10 ml of CH 2 Cl 2  cooled in an ice bath were added Et 3 N (2.3 ml; 16.32 mmol) and CH 3 SO 2 Cl (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 CH 2 Cl 2 , washing with water, 1N HCl, 10% NaHCO 3  solution and brine. Concentration in vacuo gave the chiral mesylate (2.1 g; 96%) as a pale yellow oil. TLC R f =0.6 in 25% EtOAc:hexanes. 
         Step 3: A solution of the product of step 2 (2.1 g; 7.8 mmol), the N—BOC protected 2(S)-methyl piperazine (1.56 g 7.8 mmol—prepared from the reaction of commercial 2(S)-methyl piperazine with N-(tert-butoxy-carbonyloxy)phthalimide) and 2,2,6,6-tetramethyl piperidine (1.34 ml; 8 mmol) in 14 ml of dry CN 3 CN were heated at reflux until TLC indicated complete disappearance of the mesylate (16 h). The reaction mixture was cooled to RT, diluted with CH 2 Cl 2  (50 ml) and washed with water (3×100 ml) and brine. The organic extract was dried over solid MgSO 4  and then concentrated to obtain 2.8 g of a yellow gum. ESGC (20% EtOAc in hexanes) served to isolate the desired (SS)-diastereomer (1.5 g; 52%) and its benzylic epimer, the (R,S)-diastereomer (0.5 g; 17%) for a combined 69% yield. TLC R f =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 CH 2 Cl 2  and the resulting yellow-range solution was stirred at RT for 8 h. The reaction was quenched by adding 1N NaOH solution to adjust the pH to 10. Extractive work up in CH 2 Cl 2  gave 1.1 g of a yellow syrup. FSGC using 10% CH 3 OH in CH 2 Cl 2  removed the less polar impurity and gradient elution with 1% Et 3 N in 1004 CH 3 OH:CH 2 Cl 2  was needed to elute the desired free amine of the (S,S) diastereomer. Yield=0.9 g (75%). TLC R f =0.5 in 10% CH 3 OH:CH 2 Cl 2 . 
         Step 5: A colorless solution of the product of step 4 (0.9 g; 3.3 mmol), 4-piperidinone (0.86 g; 4.3 mmol), NaB(OAc) 3 H (1.05 g; 4.95 mmol) and glacial AcOH (80 μl ) in 8 ml of CH 2 Cl 2  was stirred at ambient temperature for a day. TLC indicated absence of starting material. The reaction mixture was diluted with 50 ml of CH 2 Cl 2 , washed with 1N NaOH solution, water (2×) and brine. The CH 2 Cl 2  extract was dried over anhydrous MgSO 4  and concentrated to obtain 10.7 g of yellow oil. FSGC (25% acetone in hexanes) was used to isolate the pure product (1.3 g; 86%) as a white foam. TLC R f =0.6 in 25% acetone/hexanes. 
         Step 6: TFA (5 ml) was added to a solution of the product of step 5 (1.3 g; 2.87 mmol) in CH 2 Cl 2  (10 ml) and the resulting yellow orange solution was stirred 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 CH 2 Cl 2  and washed with water, then brine and dried over MgSO 4 . Concentration gave the free amine (0.98 g; 98%) as a yellow syrup. TLC R f =0.1 in 25% acetone/hexanes. 
         Step 7: The product of step 6 (0.78 g; 2.21 mmol), DEC (0.65 g; 3.4 mmol), HOBT (0.46 g; 3.4 mmol) and 2-amino-6-chloro benzoic acid (0.51 g; 2.9 mmol) were dissolved in 8 ml of CH 2 Cl 2  to which was added diisopropylethyl amine (0.7 ml) and the mixture was stirred at ambient temperature for 16 h. 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 (1.3 g) was isolated by extractive work up and purified through FSGC using 25% acetone in CH 2 Cl 2  as eluant to give the title compound (0.88 g; 80%) as a pale yellow foam. TLC R f =0.45 and 0.5 in 25% acetone:CH 2 Cl 2 . 
       
    
     A solution of hydrogen chloride in Et 2 O (1M; 3 ml) was added to a solution of the title compound free base (0.76 g; 1.54 mmol) in CH 2 Cl 2  (5 ml) to obtain an instantaneous white precipitate. After stirring at RT for 2 h, the volatiles were removed on a rotary evaporator and the white residue was suspended in dry toluene (3×10 ml) and azeotroped. The white solid thus obtained was suspended in dry Et 2 O containing 10% EtOAc, stirred for 30 min, filtered and washed with Et 2 O (100 ml). The HCl salt of the title compound was dried under high vacuum to yield an off-white solid (0.88 g; 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: 
                         
wherein R 8  and R 2  are as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 R 8   
                 R 2   
                 Mp (° C.) 
                 HRMS (MH + ) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 4 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 205-210 
                 509.2295 
               
               
                   
               
               
                 4A 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 192-195 
                 489.2841 
               
               
                   
               
               
                 4B 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 203-206 
                 490.2681 
               
               
                   
               
               
                 4C 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 186-190 
                 488.2902 
               
               
                   
               
               
                 4D 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 207-210 
                 489.2851 
               
               
                   
               
               
                 4E 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 152 
                 505 
               
               
                   
               
               
                 4F 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 490.2796 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 5 
     
       
         
         
             
             
         
       
     
     A solution of the racemic benzyl chloride 24 (1.26 g, 5.62 mmol) which was prepared freshly from the corresponding carbinol, the 2(S)-methyl piperazine (1.12 g, 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 Et 2 O. The organic extract was washed with saturated NH 4 Cl and brine and concentrated in vacuo to obtain 2 g of crude product. Flash chromatography on silica gel and elution first with 25% Et 2 O-hexane followed by 25% EtOAc-hexane gave ˜0.5 grams of 25a and ˜0.5 grams of 25b respectively (˜45% combined yield). TLC R f =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. 
                         
wherein R 2  is as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                 Ex. 
                 R 2   
                 mp (° C.) 
                 HRMS 
               
               
                   
               
             
            
               
                   
                 5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 208-212 
                 519.2958 
               
               
                   
               
               
                   
                 5A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 198-203 
                 535.2913 
               
               
                   
               
               
                   
                 5B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 233 (sharp) 
                 539.2390 
               
               
                   
               
               
                   
                 5C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190 
                 575.1800 
               
               
                   
               
               
                   
                 5D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 253 
                 558.1887 
               
               
                   
               
               
                   
                 5E 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 202 
                 519.2964 
               
               
                   
               
               
                   
                 5F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190 
                 535.2901 
               
               
                   
               
               
                   
                 5G 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 198-203 
                 — 
               
               
                   
               
               
                   
                 5H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 205-210 
                 — 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 6 
     
       
         
         
             
             
         
       
         
         Step 1: 
       
    
     
       
         
         
             
             
         
       
     
     A mixture of the aldehyde 26 (3.9 g, 20.5 mmol), the 2(S)-methyl-N-BOC-piperazine (4.1 g, 20.5 mmol) and Ti(OiPr) 4  (6.1 mL; 20.5 mmol) in 40 ml of CH 2 Cl 2  was stirred at RT for 24 h. Et 2 AlCN was introduced and stirred for an additional day. The reaction mixture was processed as described before to obtain 4.71 grams (58%) of the cyano amine 27 after FSGC (TLC R f =0.45/0.5 for diastereomers seen with 25% Et 2 O-hexanes as solvent).
     Step 2: Sodium hexamethyldisilazide (1M; 3.1 ml) was added to a solution of 27 (1 g; 2.5 mmol) in dry THF cooled in a dry ice/acetone bath. The resulting bright yellow solution was treated with CH 3 CH 2 I (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: 0.7 g; 70%). TLC R f =0.6 and 0.4 (25% EtOAc/hexanes).   Step 3: The product of step 2 was stirred with NaBH(OAc) 3  (2×) and MgBr 2 :OEt 2  (1×) in CH 3 CN 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 R f =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 6B with an ipso-methyl group as well as compounds 6C and 6D which lack the ipso-methyl group:   

     
       
         
           
               
            
               
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. 
                 R 6   
                 R 2   
                 mp (° C.) 
                 MS (MH + ) 
               
               
                   
               
               
                 6 
                 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 204 
                 549.5 
               
               
                   
               
               
                 6A 
                 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 253 
                 589.4 
               
               
                   
               
               
                 6B 
                 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 260 
                 534.4 
               
               
                   
               
               
                 6C 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 225 
                 520.4 
               
               
                   
               
               
                 6D 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 215 
                 575.4 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 7 
     The synthesis of compounds with an alkyl or arylsulfonyl R 8  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 having the formula: 
                         
wherein R 8  and R 2  are as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 R 8   
                 R 2   
                 Mp (° C.) 
                 HRMS (MH + ) 
               
               
                   
               
             
            
               
                 7 
                 H 3 CSO 2 — 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 220-225 
                 498.2790 
               
               
                   
               
               
                 7A 
                 H 3 CSO 2 — 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 212-215 
                 519.2197 
               
               
                   
               
               
                 7B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190 (dec.) 
                 604.2861 
               
               
                   
               
               
                 7C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 178 (dec.) 
                 625.2246 
               
               
                   
               
               
                 7D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 170 (dec.) 
                 605.2799 
               
               
                   
               
               
                 7E 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 170 (dec.) 
                 609.2540 
               
               
                   
               
               
                 7F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 200 (dec.) 
                 612.2336 
               
               
                   
               
               
                 7G 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 158 (dec.) 
                 644.1735 
               
               
                   
               
               
                 7H 
                 H 3 CSO 2 — 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 197 (dec.) 
                 514.2847 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 8 
     
       
         
         
             
             
         
       
         
         Step 1: A solution of the product of Example 4, step 4 (1.25 g; 4.6 mmol), N—BOC-4-pipendinone (0.91 g; 4.6 mmol) and (Ti(OiPr) 4 ) (1.4 ml, 4.6 mmol) in 10 ml of CH 2 CO 2  was stirred at ambient temperature for 24 h. The reaction mixture was then treated with Et 2 AlCN (5.5 ml; 1M solution in toluene) and stirring continued for 20 h. The reaction mixture was diluted with EtOAc and stirred with saturated NaHCO 3  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 MgSO 4  and concentrated to obtain 2.16 g (98%) of an amber gum. 
         Step 2: The Strecker amine from step 1 (2.16 g) was dissolved in dry THF, cooled in an ice bath and treated with CH 3 MgBr (7.5 ml of a 3M solution in Et 2 O). After 1 h, the ice bath was removed and the yellow, heterogeneous reaction mixture was stirred at RT for 18 h. The reaction was quenched with saturated NH 4 Cl solution, diluted with water and extracted with CH 2 Cl 2 . 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 CH 2 Cl 2 :EtOAc. The ipso-methyl compound was isolated as a yellow gum (1.85 g; 88%). TLC R f =0.5 in 1:1 Et 2 O:hexanes. 
         Step 3: TFA (6 ml) was added to a solution of the product of step 2 (15 g; 3.2 mmol) in 10 ml of CH 2 Cl 2  and stirred at 25° C. for 2 h. The reaction was quenched with 1N NaOH solution to a pH of 9-10 and processed by extraction into CH 2 Cl 2  to obtain 1.2 g of crude product. FSGC using 1:1 CH 2 Cl 2 :EtOAc removed all the less polar impurities and gradient elution with 10% CH 3 OH in CH 2 Cl 2  and finally with 10% (ca. 7N—NH 3 ) CH 3 OH in CH 2 Cl 2  led to the isolation of the free piperidine as a yellow gum (1.07 g; 90%). TLC R f =0.2 in 10% CH 3 OH:CH 2 Cl 2 . 
         Step 4: A solution of the product of step 3 (1.03 g; 2.8 mmol), 2,4-dimethyl nicotinic acid (0.42 g; 2.8 mmol), DEC (0.8 g; 4.2 mmol), HOBT (0.57 g; 4.2 mmol) and diisopropyl ethyl amine (1 ml; 5.6 mmol) in CH 2 Cl 2  (15 ml) was stirred at 25° C. for 24 h. The reaction mixture was diluted with CH 2 Cl 2  (25 ml), washed with water, 10% NaHCO 3  solution and brine, then concentrated to obtain 1.6 g of crude oil. FSGC of this material using gradient elution with 10% acetone-CH 2 Cl 2  followed by 2-5% CH 3 OH in CH 2 Cl 2  gave the title compound (1.1 g; 80%) as a white foam. TLC R f =0.45 in 5% CH 3 OH—CH 2 Cl 2 . 
       
    
     The free base of the title compound (1 g; 2 mmol) isolated above was dissolved in a 1:1 mixture of EtOAc:Et 2 O (8 ml) and a fresh solution of hydrogen chloride in Et 2 O (6-1 ml of a 1M solution) was added, instantly forming a white precipitate After stirring at 25° C. for 1 h, the volatiles were removed in vacuo, The product was suspended in Et 2 O and filtered, washing the filtrate with Et 2 O. The HCl salt of the title compound thus obtained was dried in vacuo (1.1 g; 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 R 8 -substituent is a p-methyl sulfonyl group were similarly prepared. 
                         
wherein R 8  and R 2  are as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 R 8   
                 R 2   
                 Mp (° C.) 
                 HRMS (MH + ) 
               
               
                   
               
             
            
               
                 8A 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 216 
                 503.3021 
               
               
                   
               
               
                 8B 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 222-224 
                 504.2850 
               
               
                   
               
               
                 8C 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 262-263 
                 502.3039 
               
               
                   
               
               
                 8D 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 216-218 
                 523.2466 
               
               
                   
               
               
                 8E 
                 CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 210-212 
                 519.2970 
               
               
                   
               
               
                 8F 
                 —SO 2 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 201-205 
                 512.2955 
               
               
                   
               
               
                 8G 
                 —SO 2 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 217-221 
                 533.2355 
               
               
                   
               
               
                 8H 
                 —SO 2 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 216-219 
                 514.2736 
               
               
                   
               
               
                 8I 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195-198 
                 — 
               
               
                   
               
               
                 8J 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 250-255 
                 528.1791 
               
               
                   
               
               
                 8K 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 223-226 
                 576.1562 
               
               
                   
               
               
                 8L 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 &gt;245  
                 528.2439 
               
               
                   
               
               
                 8M 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 176-181 
                 570.1739 
               
               
                   
               
               
                 8N 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 218-223 
                 708.0040 
               
               
                   
               
               
                 8O 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 215-220 
                 522.2507 
               
               
                   
               
               
                 8P 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 208-212 
                 566.1987 
               
               
                   
               
               
                 8Q 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190-194 
                 586.1442 
               
               
                   
               
               
                 8R 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 255-257 
                 526.2243 
               
               
                   
               
            
           
         
       
     
     Using procedures described following the table, compounds 8S-8EE of the structure 
                         
were prepared, wherein R 11  is defined in the table:
 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 R 11   
                 Mp (° C.) 
                 HRMS (MH + ) 
               
               
                   
               
             
            
               
                 8S 
                 —OH 
                 210-220 
                 518.2997 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                 8T 
                 —OC(O)NHCH 2 CH 3   
                 205-210 
                 589.3374 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                 8U 
                 —OSO 2 CH 3   
                 165-171 
                 596.2757 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                   
               
               
                 8V 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 199-204 (2xHCl salt) 
                 595.3254 
               
               
                   
               
               
                 8W 
                 —CHO 
                 88-92 
                 530.2985 
               
               
                 8X 
                 —CH═NH—OCH 3   
                 202-205 
                 559.3260 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                 8Y 
                 —CHF 2   
                 &gt;245 (dec) 
                 552.3020 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                 8Z 
                 —NH—C(O)—NH—CH 2 CH 3   
                 214-219 
                 588.3521 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                 8AA 
                 —NH 2   
                 92-98 
                 517.3154 
               
               
                 8BB 
                 —NHSO 2 CH 2 CH 3   
                 205-211 
                 609.3078 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                 8CC 
                 —F 
                 212-217 
                 520.2949 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                 8DD 
                 —Cl 
                 235-238 
                 536.2663 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                 8EE 
                 —Br 
                 237-240 
                 580.2141 
               
               
                   
                   
                 (2xHCl salt) 
               
               
                   
               
            
           
         
       
         
         8S: The tri-hydrochloride salt of the product of Example 8, step 3 (75 mg, 0.16 mmol), EDC (61 mg, 0.32 mmol), HOST (49 mg, 0.32 mmol), iPr 2 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 2 Cl 2  and stirred at 25° C. for 20 h. The solution was concentrated. Purification via preparative TLC (EtOAc, SiO 2 ) gave the title compound as a yellow oil. m.p. (2×HCl salt) 210-220° C. HRMS (MH + ) calcd. for C 29 H 39 O 2 N 3 E 3 , 518.2994. Found, 518.2997. 
         8T: 8S (100 mg, 0.19 mmol), ethyl isocyanate (0.05 ml, 0.58 mmol), and Et 3 N (0.13 ml, 0.95 mmol) were taken up in CH 2 Cl 2  and stirred at 25° C. for 16 h. The solution was diluted with CH 2 Cl 2  and washed with 1 N NaOH. The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated. Purification via preparative TLC (211 EtOAc/hexanes, SiO 2 ) 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&#39;d NaHCO 3 . The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated. Purification via preparative TLC (1/1 EtOAc/hexanes, SiO 2 ) 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 2 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 2 Cl 2  and stirred at 25° C. for 19 h. The solution was concentrated. Purification via preparative TLC (2/1 acetone/hexanes, SiO 2 ) gave 8V as a yellow oil (23 mg, 39%). 
       
    
     Preparation of 2,6-dimethyl-4-(4-pyridyl-N-oxide) benzoic acid 
     
       
         
         
             
             
         
       
         
         Step A: 4-Benzyloxy-2,6-dimethyl benzoic acid (8.7 g, 34 mmol; Thea, S. et al  Journal of the American Chemical Society  1985, 50, 1867), MeI (3.2 ml, 51 mmol), and Cs 2 CO 3  (17 g, 51 mmol) were allowed to stir in DME at 25° C. for 17 h, The solution was filtered and partitioned between Et 2 O and water. The aqueous layer was extracted with Et 2 O. The combined Et 2 O layers were washed with H 2 O and brine. The organic layer was dried (MgSO 4 ), filtered, and concentrated. Purification via flash chromatography (10/1 hexanes/Et 2 O, SiO 2 ) 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 CH 3 OH. The solution was charged with 50 psi H 2  and shaken in a Parr apparatus at 25° C. for 17 h. 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 2 NEt (3.76 g, 29.1 mmol) were dissolved in CH 2 Cl 2  at 0° C. Triflic anhydride (Tf 2 O) (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 2 Cl 2  and washed with sat NaHCO 3 . The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried over Na 2 SO 4 . Filtration and concentration gave the crude aryl triflate. Purification via flash chromatography (10/1, hexanes/Et 2 O, SIO 2 ) gave 5.7 g (94%) of the triflate as a yellow oil. 
         Step D: The triflate (1 g, 3.2 mmol), 4-pyridyl boronic acid (1.2 g, 9.6 mmol), Pd(PPh 3 ) 4  (370 mg, 0.32 mmol), and Na 2 CO 3  (1 g, 9.6 mmol) were taken up in DME/H 2 O (4/1, 25 ml). The solution was heated to 90° C. (oil bath) under N 2  for 18 h. The solution was partitioned between EtOAc and H 2 O. The aqueous layer was extracted with EtOAc. The combined EtOAc layers were dried (Na 2 SO 4 ). Filtration and concentration gave a dark brown oil. Purification via flash chromatography (3/1 hexanes/EtOAc, SiO 2 ) 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 CH 2 Cl 2 . The solution was stirred at 25° C. for 18 h. The solution was diluted with CH 2 Cl 2  and washed with 1N NaOH. The organic layer was dried (Na 2 SO 4 ). Filtration and concentration gave 400 mg (97%) of the N-oxide as an orange oil. HRMS (MH + ) calcd. for C 15 H 16 O 3 N, 258.1130; Found, 258.1131. 
         Step F: The methyl ester (400 mg, 1.6 mmol) was taken up in 5 ml 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 conc. HCl. 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.&gt;225° C. (decomp). HRMS (MH + ) calcd. for C 14 H 14 O 3 N, 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 (111 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 2 ) gave 898 mg (61%) of SW as a yellow foam. 
       
    
     Preparation of 2,6-dimethyl-4-formyl benzoic acid 
     
       
         
         
             
             
         
       
         
         Step A: 4-Hydroxy-2,6-dimethyl-benzoic acid, tert-butyl ester (6.4 g, 29 mmol) and iPr 2 NEt (5.6 g, 43 mmol) were taken up in CH 2 Cl 2  and cooled to 0° C. Tf 2 O (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. NaHCO 3  and CH 2 Cl 2 . The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ). Filtration and concentration gave a brown oil. Purification via flash chromatography (20/1 hexanes/Et 2 O, SiO 2 ) gave 7.99 g (82%) of the triflate as a yellow solid. 
         Step B: The triflate (5 g, 15 mmol), LiCl (1.25 g, 30 mmol), Pd(PPh 3 ) 4  (340 mg, 0.3 mmol), and vinyl tributyl tin (4.5 ml, 16 mmol) were taken up in THF under N 2 . 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 (MgSO 4 ). Filtration and concentration gave a yellow oil. Purification via flash chromatography (20/1 hexanes/Et 2 O, SiO 2 ) 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 2 Cl 2 /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 CH 2 Cl 2  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 2 NOMe-HCl (28 mg, 0.34 mmol), NaOAc (32 mg, 0.46 mmol) were taken up in MeOH, The solution was stirred at 25° C. for 17 h. The solution was concentrated. The residue was partitioned between CH 2 Cl 2  and 1 N NaOH. The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ). Filtration and concentration gave the crude product. Purification via preparative TLC (1/1 hexanes/EtOAc, SiO 2 ) 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, 0.16 mmol) were subjected to the standard coupling conditions (EDC/HOBT/iPr 2 NEt). Purification via preparative TLC (2/1 hexanes/EtOAc, SiO 2 ) gave 64 mg (73%) of 8Y. 
       
    
     Preparation of 4-difluoromethyl-2,6-dimethyl benzoic acid 
     
       
         
         
             
             
         
       
         
         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. NaHCO 3 . The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (NaSO 2 ). Filtration and concentration gave the crude product. Purification via preparative TLC (10/1 hexanes/Et 2 O, SiO 2 ) gave 210 mg (50%) of the difluoro derivative. 
         Step B: The tert-butyl ester (210 mg, 0.82 mmol) and HCl (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. 
         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/Pr 2 NEt). Purification via flash chromatography (1/1 hexanes/acetone, SiO 2 ) gave 803 mg (81%) of 8Z as a foam. 
       
    
     Preparation of 4-[(ethylamino)carbonylamino]-2,6-dimethyl benzoic acid 
     
       
         
         
             
             
         
       
         
         Step A: 3,5-Dimethyl aniline (18.5 ml, 149 mmol) was taken up in CH 2 Cl 2 . 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 2 S 2 O 3 . The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (MgSO 4 ), treated with activated carbon and filtered. Concentration gave an orange solid. Purification via recrystallization (hexanes/Et 2 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 2 . Methyllithium/LiBr (54 ml of a 1.5 M solution in Et 2 O, 80 mmol) was added slowly to the solution at −78° C. After 5 min of stirring, sec-BuLi (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 (22.5 g, 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 2 Cl 2 . The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (MgSO 4 ). Filtration and concentration gave a yellow solid. Purification via flash chromatography (1/1 to 1/4 hexanes/CH 2 Cl 2 , SiO 2 ) gave 13.1 g (72%) of the tert-butyl ester as an off-white solid. 
         Step C: The trifluoro-acetamide (10 g, 31 mmol) and NaOH (2.5 g, 62 mmol) were taken up in MeOH/H 2 O (3/1) and heated at 60 (C for 3 h. The solution was partitioned between CH 2 Cl 2  and water. The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were washed with water and dried (Na 2 SO 4 ). 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 CuCl (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 2 h. The solution was partitioned between EtOAc and 10% NH 4 OH. The aqueous layer was extracted with EtOAc. The combined layers were washed with brine and dried (MgSO 4 ). Filtration and concentration gave a yellow solid. Purification via flash chromatography (3/1 to 1/1 hexanes/EtOAc, SiO 2 ) 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 HCl 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 2 O and 1 N NaOH. The aqueous, basic layer was extracted with Et 2 O. The aqueous layer was cooled to 0° C. and acidified with conc. HCl (pH=1-2). The aqueous layer was extracted with EtOAc. The combined EtOAc layers were dried (Na 2 SO 4 ). 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 2 NEt). Purification via flash chromatography (2/1 hexanes/acetone, SiO 2 ) gave 1.16 g (52%) of 8AA as a yellow foam. 
       
    
     Preparation of 4-amino-2,6-dimethyl benzoic acid 
     
       
         
         
             
             
         
       
     
     The tert-butyl ester (950 mg, 4.3 mmol) and HCl (11 ml, 4 M in dioxane) were taken up in MeOH at heated at 45° C. 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° C. for 19 h. The solution was concentrated. The residue was partitioned between 1 N NaOH and CH 2 Cl 2 . The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ). Filtration and concentration gave a brown oil. Purification via preparative TLC (211 hexanes/acetone, SIO 2 ) gave 100 mg (86%) of 8BB as a colorless 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 2 NEt). Purification via preparative TLC (2/1 hexanes/EtOAc, SiO 2 ) gave 8CC as a colorless oil (87 mg bis-HCl salt, 54%).   

     Preparation of 4-fluoro-2,6-dimethyl benzoic acid 
     
       
         
         
             
             
         
       
     
     4-Amino-2,6-dimethyl benzoic acid (200 mg, 1.1 mmol) and NOBF 4  (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 2 O and 1 N NaOH. The aqueous layer was extracted with Et 2 O. The aqueous layer was cooled to 0° C. and acidified with conc. HCl (pH=1-2), The aqueous layer was extracted with CH 2 Cl 2 . The organic layers were dried (Na 2 SO 4 ). 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 2 NEt). Purification via preparative TLC (4/1 hexanes/acetone, SiO 2 ) gave 8DD as a colorless oil.   

     Preparation of 4-chloro-2,6-dimethyl benzoic acid 
     
       
         
         
             
             
         
       
     
     4-Amino-2,6-dimethyl benzoic acid (172 mg, 0.96 mmol) and CuCl 2  (155 mg, 1.15 mmol) were taken up in CH 3 CN 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 Et 2 O and water. The aqueous layer was extracted with Et 2 O. The combined organic layers were washed with brine and dried (MgSO 4 ). 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.
     8EE: 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 2 NEt). Purification via preparative TLC (4/1 hexanes/acetone, SiO 2 ) gave 8EE as a colorless oil (140 mg bis-HCl salt, 56%).   

     Preparation of 4-bromo-2,6-dimethyl benzoic acid 
     
       
         
         
             
             
         
       
         
         Step A: The triflate (500 mg, 1.48 mmol), hexamethylditin (0.31 mmol, 1.48 mmol), LiCl (377 mg, 8.9 mmol), and Pd(PPh 3 ) 4  (171 mg, 0.15 mmol) were heated in THF (70° C.) under N 2  for 21 h. The solution was partitioned between Et 2 O and pH =7 buffer (NH 4 OAc). The aqueous layer was extracted with Et 2 O. The combined Et 2 O layers were washed with brine and dried (Na 2 SO 4 ). 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 2 Cl 2  at 0° C. Bromine (0.7 ml of 1 M Br 2  in CH 2 Cl 2 ) was added to the solution. The solution was stirred at 0° C. for 30 min. The solution was diluted with CH 2 Cl 2  and washed with 10% Na 2 S 2 O 3 . The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ). The solution was filtered. TFA (2 ml) was added to the solution, and the solution was stirred at 25° C. for 17 hi The solution was concentrated. The residue was partitioned between Et 2 O and 1 N NaOH. The aqueous layer was extracted with Et 2 O. The aqueous layer was cooled to 0° C. and acidified with conc. HCl (pH=1-2). The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ). 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 
                         
were prepared, wherein R 11  is defined in the table:
 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 R 11   
                 Mp (° C.) 
                 HRMS (MH + ) 
               
               
                   
               
             
            
               
                 8FF 
                 —OCH 3   
                 217-220 
                 572.2048 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                 8GG 
                 —OH 
                 198-204 
                 558.1898 
               
               
                   
                   
                 (2xHCl salt) 
                   
               
               
                   
               
               
                 8HH 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 2 NEt). Purification via preparative TLC (3/1 hexanes/EtOAc, SiO 2 ) gave 8FF as a colorless oil (27 mg, 23%). 
         8GG: The trihydrochloride salt of the product of Example 8, step 3 (330 mg, 0.7 mmol) and 2,6-dichloro-4-hydroxy-benzoic acid (290 mg, 1.4 mmol) (see preparation below) were coupled according to the general procedure (EDC/HOBT/iPr 2 NEt). Purification via preparative TLC (1/1 hexanes/EtOAc, SiO 2 ) gave 8GG as a colorless oil (75 mg, 19 h). 
       
    
     Preparation of 2,6-dichloro-4-hydroxy-benzoic acid 
     
       
         
         
             
             
         
       
     
     2,6-Dichloro-4-methoxy-benzoic acid (500 mg, 2.3 mmol) was taken up in CH 2 CO 2  and cooled to −78° C. BBr 3  (6.9 ml of a 1 M solution in CH 2 Cl 2 ) 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 CH 2 Cl 2 . The aqueous layer was cooled (0° C.) and acidified with conc. HCl (pH=1-2). The aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were dried (Na 2 SO 4 ). 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)-benzoic acid (55 mg, 0.2 mmol) (see preparation below) were coupled according to the general procedure (EDC/HOBT/iPr 2 NEt). Purification via preparative TLC (1/5 hexanes/acetone, SiO 2 ) gave 8HH as a colorless oil (54 mg, 43%).   

     Preparation of 2,6-dichloro-4-(4-pyridyl-N-oxide) benzoic acid 
     
       
         
         
             
             
         
       
     
     2,4,6-Trichloro benzoic acid, tert-butyl ester (500 mg, 1.8 mmol), 4-pyridyl boronic acid (270 mg, 2.16 mmol), Pd(PCy 3 ) 2 Cl 2  (130 mg, 0.18 mmol), and CsF (540 mg, 3.6 mmol) were taken up in NMP and heated at 100° C. under N 2  (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 2 SO 4 ). Filtration and concentration gave the crude product, Purification via preparative TLC (1/1 hexanes/EtOAc, SiO 2 ) 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: 
                         
wherein R 11  is defined in the table
 
                                                         HRMS (MH + )   HRMS (MH + )       Ex.   R 11     m.p. (° C.)   calc.   found                                                    8II   —OCH 3     236-240   532.3151   532.3166       8JJ   —CH 3     &gt;260   516.3202   516.3213               8KK                         186-190   603.3522   603.3513               8LL                         202-208   579.3311   579.3303               8MM                         210-216   579.3311   579.3311               8NN                         196-203   595.3260   595.3256               8OO                         &gt;230 (dec)   578.3358   578.3368               8PP                         135-140   617.3679   617.3671               8QQ                         205-215   602.3682   602.3722               8RR   CH 2 OH   &gt;235 (dec)   532.3151   532.3124               8SS                         206-212   580.3263   580.3258               8TT                         198-204   579.3311   579.3315               8UU                         231-236   580.3263   580.3252               8VV                         201-207   613.2977   613.2981               8WW                         215-220   650.2487   650.2497               8XX                         198-201   545.3103   545.3098               8YY                         210-214   595.2930   595..2921               8ZZ   CH 2 F   &gt;245   534.3108   534.3117               8AB                         202-205   624.3195   624.3204               8AC                         208-213   559.3260   559.3263               8AD                         215-220   560.3212   560.3220               8AE                         215-220   573.3416   573.3424               8AF                         215-220   559.3260   559.3257               8AG                         205-209   602.3682   602.3672               8AH                         186-192   574.3369   574.3378               8AI                         200-206   616.3838   616.3844               8AJ                         165-173   661.3941   661.3949               8AK   CN   240-250   527.2998   527.2991               8AL                         211-215   622.3136   622.3129               8AM                         170-174   616.3838   616.3836               8AN                         192-196   614.3682   614.3690                    
All melting points were done on the bis hydrochloride salts (2×HCl) except 8PP was performed on the free base
 
     Using derivatives of the triflate intermediate described in 8Z in procedures similar to those described above and following the table for 8AO-8AQ, the compounds of the following structure were prepared: 
                         
wherein R 11  is defined in the table
 
     
       
         
           
               
               
               
               
             
               
                   
                   
               
               
                   
                 Ex. 
                 R 11   
                 m.p. (° C.) 
               
               
                   
                   
               
             
            
               
                   
                 8AO 
                 —CN 
                 240-250 
               
               
                   
                 8AP 
                 —CONHEt 
                 215-220 
               
               
                   
                 8AQ 
                 —N(CH 3 )CONHEt 
                 186-203 
               
               
                   
                 8AR 
                 —CONH 2   
                 200-208 
               
               
                   
                 8AS 
                 —CONHCH 3   
                 215-220 
               
               
                   
                 8AT 
                 —CON(CH 2 CH 2 OCH 3 ) 2   
                 165-173 
               
               
                   
                 8AU 
                 —CON(Et) 2   
                 170-180 
               
               
                   
                 8AV 
                 —N(CH 3 )CONHCH 3   
                 198-210 
               
               
                   
                 8AW 
                 —NHCH 3   
                 190-200 
               
               
                   
                 8AX 
                 —N(CH 3 )CONH 2   
                 190-220 
               
               
                   
                   
               
            
           
         
       
         
         8AO: 
       
    
     
       
         
         
             
             
         
       
         
         Step 1: The triflate intermediate (see 8W) (0.4 g), Zn(CN) 2  (0.2 g), Pd(PPh 3 ) 4  (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 3 . 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 μM 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 HCl (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 form) 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 purifications the free base form of 8AO, which was converted to its HCl salt (45 mg) in 95% yield. 
         8AP: 
       
    
     
       
         
         
             
             
         
       
         
         Step 1: 2,6-Dimethyl-4-formyl benzoic acid (1.96 g) (see 8W) was dissolved in t-butanol (94 ml) and 2-methyl-2-butene (24 ml). A solution of NaClO 2  (6.89 g), NaH 2 PO 4  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 2 Cl 2  (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 2 Cl 2  (10 ml) and EtNH 2  (1 ml) were added and the reaction was stirred for 2 days, then partitioned between brine and CH 2 Cl 2 . The CH 2 Cl 2  layer was evaporated and HCl (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 2 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, 8AP as the free base form, which was converted to the HCl salt (50 mg) in 62% yield. 
         8AQ: 
       
    
     
       
         
         
             
             
         
       
         
         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 2 SO 4  was added. After heating at reflux for 1.5 h, the reaction was cooled to RT, poured into saturated NH 4 Cl aqueous solution and extracted with Et 2 O. After evaporation, the crude reaction mixture was chromatographed on silica get, eluting with 4:1 hexanes:EtOAc, to give, after evaporation of the appropriate fractions, the methylamine intermediate (0.8 g) in 38% yield. 
         Step 2: 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% EtOAc:CH 2 Cl 2 ), 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 HCl 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 10  and R 11  are defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                 Ex. 
                 R 10   
                 R 11   
                 Mp (° C.) 
               
               
                   
               
             
            
               
                   
                 8AY 
                 —CH 3   
                 H 
                 205-208 
               
               
                   
                 8AZ 
                 F 
                 H 
                 250-255 
               
               
                   
                 8BA 
                 Cl 
                 H 
                 215-217 
               
               
                   
                 8BC 
                 —CH 3   
                 Br 
                 228-231 
               
               
                   
               
               
                   
                 8BD 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 194-198 
               
               
                   
               
               
                   
                 8BE 
                 Cl 
                 Cl 
                 240-241 
               
               
                   
                 8BF 
                 Cl 
                 F 
                 268-270 
               
               
                   
                 8BG 
                 Br 
                 H 
                 210-213 
               
               
                   
                 8BH 
                 Cl 
                 Br 
                 213-217 
               
               
                   
                 8BI 
                 Br 
                 F 
                 176-181 
               
               
                   
                 8BJ 
                 I 
                 H 
                 184-190 
               
               
                   
                 8BK 
                 —CF 3   
                 F 
                 204-209 
               
               
                   
                 8BL 
                 F 
                 F 
                 268-270 
               
               
                   
                 8BM 
                 Cl 
                 NH 2   
                 215-220 
               
               
                   
                 8BN 
                 H 
                 F 
                 258-260 
               
               
                   
                 8BO 
                 H 
                 Br 
                 238-240 
               
               
                   
                 8BP 
                 H 
                 Cl 
                 235-240 
               
               
                   
                 8BQ 
                 Br 
                 Cl 
                 190-194 
               
               
                   
                 8BR 
                 CH 3 CH 2 — 
                 H 
                 211-214 
               
               
                   
                 8BS 
                 —Si(CH 3 ) 3   
                 H 
                 230-240 
               
               
                   
                 8BT 
                 Cl 
                 NO 2   
                 275-280 
               
               
                   
               
            
           
         
       
     
     Using procedures similar to those described above, the following compounds were prepared: 
                         
wherein R 8 , R 3 R 6  and R 2  are as defined in the table:
 
     
       
         
           
               
               
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 R 8   
                 R 3   
                 R 6   
                 R 2   
                 Mp (° C.) 
               
               
                   
               
             
            
               
                 8BU 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195-220 
               
               
                   
               
               
                 8BV 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 80-85 
               
               
                   
               
               
                 8BW 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 212-217 
               
               
                   
               
               
                 8BX 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 235-238 
               
               
                   
               
               
                 8BY 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195-200 
               
               
                   
               
               
                 8BZ 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 237-240 
               
               
                   
               
               
                 8CA 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 2 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 179-181 
               
               
                   
               
               
                 8CB 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 2 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 200-202 
               
               
                   
               
               
                 8CD 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 2 CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 199-205 
               
               
                   
               
               
                 8CE 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 206-210 
               
               
                   
               
               
                 8CF 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 235-239 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 9 
     
       
         
         
             
             
         
       
         
         Step 1: A solution of 4-N—BOC-2(S)-methyl piperazine (1.5 g; 7.5 mmol), 4-methoxy-benzyl chloride (1.1 ml; 8.1 mmol) and diisopropyl ethyl amine (1.5 ml) in dry CH 3 CN 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 CH 2 Cl 2  (30 ml) and washed with water and brine. Concentration gave the crude product, which was purified by FSGC (10% EtOAc-hexanes) to obtain 2.1 g (88%) of product as a pale yellow liquid. 
       
    
     TFA (6 ml) was added to a solution of the above compound (2.1 g; 6.56 mmol) in 12 ml of CH 2 Cl 2  and the mixture stirred at 25° C. for 1.5 h. The reaction was quenched with 1N NaOH and adjusted to pH 10. Extractive work-up in CH 2 Cl 2  furnished the desired product (1.4 g; 97%) as a colorless gum.
     Step 2: A mixture of the product of step 1 (1.4 g; 6.36 mmol), N-BOC-4-piperidinone (1.27 g; 6.4 mmol) and Ti(OiPr) 4  (1.9 ml; 6.4 mmol) was stirred at 25° C. for 24 h. A 1M solution of Et 2 AlCN 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 (2.7 g; 100%) as described in Example 8, step 2. TLC R f =0.3 in 25% EtOAc—CH 2 Cl 2 .   

     The Strecker amine (2.7 g; 6.3 mmol) was dissolved in 15 ml of dry THF at 0° C. and CH 3 MgBr (3M in Et 2 O; 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 NH 4 Cl and organic products extracted into CH 2 Cl 2 . FSGC of the crude product (2.7 g) using 15% acetone-hexanes as the eluant provided the desired ipso-methyl compound as a colorless gum (2.3 g; 87%).
     Step 3: The product of step 2 (1.7 g; 4.08 mmol), ammonium formate (1.4 g; 22 mmol) and 10% palladium on carbon (0.4 g) were mixed in 20 ml of CH 3 OH and heated at reflux for 5 h. The reaction mixture was filtered through celite and volatiles were removed. The residue was dissolved in CH 2 Cl 2  and washed with 1.0% NaOH solution, water and brine. Concentration in vacuo gave 1.1 g (92%) of pale yellow gum.   Step 4: A solution of the product of step 3 (0.12 g; 0.4 mmol), p-trifluoro-methyl benzyl bromide (0.1 g; 0.4 mmol) and diisopropyl ethyl amine (0.1 ml) in dry CH 3 CN was gently warmed (60-70° C.) for 16 h. The mixture was cooled and organic product isolated via extractive work-up in CH 2 Cl 2 . FSGC (10-30% Et 2 O—CH 2 Cl 2 ; R f =0.4) yielded the major product as a colorless film (0.12 g; 68%).   

     Treatment of the above product (in CH 2 Cl 2 ) with TFA (1 ml) for 1 h followed by basification and standard work-up provided the desired compound (0.099; 96%) as a colorless film.
     Step 5: The product of step 4 (0.045 g; 0.13 mmol) and 6-chloro anthranilic acid (0.022 g; 0.13 mmol) were coupled as described in Example 1 and after work-up and FSGC (5% CH 3 OH in CH 2 Cl 2 ) the title compound was isolated as a colorless film (0.058 g; 90%).   

     The HCl salt of the title compound was prepared in the usual manner by the reaction of the free base with 1M HCl-Et 2 O and processing the precipitate to obtain a beige solid (0.066 g). 
     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: 
                         
wherein R and R 2  are as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 R 
                 R 2   
                 Mp (° C.) 
                 HRMS (MH + ) 
               
               
                   
               
             
            
               
                 9A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 246-249 
                 509.2293 
               
               
                   
               
               
                 9B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 204-208 
                 488.2895 
               
               
                   
               
               
                 9C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 247-249 
                 546.1978 
               
               
                   
               
               
                 9D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 249-251 
                 567.1407 
               
               
                   
               
               
                 9E 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 206-209 
                 504.2848 
               
               
                   
               
               
                 9F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 244-247 
                 525.2242 
               
               
                   
               
               
                 9G 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 201-204 
                 484.2630 
               
               
                   
               
               
                 9H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 222-226 
                 505.2039 
               
               
                   
               
               
                 9I 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 226-229 
                 451.3060 
               
               
                   
               
               
                 9J 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 229-232 
                 472.2474 
               
               
                   
               
               
                 9K 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 268-271 
                 455.2577 
               
               
                   
               
               
                 9L 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 212-216 
                 476.1975 
               
               
                   
               
               
                 9M 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 229-232 
                 450.3126 
               
               
                   
               
               
                 9N 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 246-251 
                 434.3168 
               
               
                   
               
               
                 9O 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 192-205 
                 — 
               
               
                   
               
               
                 9P 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 185-196 
                 — 
               
               
                   
               
               
                 9Q 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 202-210 
                 — 
               
               
                   
               
               
                 9R 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 203-206 
                 — 
               
               
                   
               
               
                 9S 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190-205 
                 — 
               
               
                   
               
               
                 9T 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 180-205 
                 — 
               
               
                   
               
               
                 9U 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 258-262 
                 — 
               
               
                   
               
            
           
         
       
     
     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 (0.86 g) and K 2 CO 3  (1.38 g, 2 equiv.) in CH 3 CN (35 ml) were treated with CH 3 CH 2 I (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 H 2 O. The dried (MgSO 4 ) EtOAc was concentrated in vacuo to give an orange-brown residue (0.89 g). This residue was placed on preparative thin layer plates (10, 1000μ), and eluted with CH 2 Cl 2  to give the title compound (0.82 g).   Step 4: Under argon, the products of step 3 (0.270 g; 0.95 mmol) and step 4A (0.571 g; 2.9 mmol) in CH 2 Cl 2  (25 ml) were stirred at RT for 30 min. Na(OAc) 3 BH (0.506 g; 3.4 mmol) was added. After 19 h, the reaction mixture was quenched with dilute NaOH. The aqueous layer was washed with CH 2 Cl 2  (3×). The combined CH 2 Cl 2  solution was washed with H 2 O (3×) and then brine. The dried (MgSO 4 )CH 2 Cl 2  solution was concentrated to ˜50 ml. Amberlyst 15 (4.5 meq/g: 2.4 g; 11.025 mmeq) was added. After 19 h, additional Amberlyst 15 (2.3 g) was added. After 7 h, the resin was washed with CH 2 Cl 2  (5×), THF (5×), THF:H 2 O (5×), H 2 O (5×), CH 3 OH (5×) and CH 2 Cl 2  (5×). The resin was eluted with 2M NH 3  in CH 3 OH (300 ml) (3×), followed by concentration in vacuo to give an amber oil (0.215 g). The crude material was placed on preparative thin layer plates (4, 1000μ), and eluted with CH 2 Cl 2 :2M NH 3  in CH 3 OH (9:1) to give an amber oil (0.125 g, 36%).   Step 5: Using the appropriate carboxylic acid in the procedure of Example 9, step 5, the following compounds were prepared:   

     
       
         
         
             
             
         
       
     
     LCMS found M+H=531; HPLC* Retention time 5.52 min. 
     
       
         
         
             
             
         
       
     
     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 2 O, Soln B 0.1% TFA/CH 3 CN at 245 nm. 
     Using a similar procedure wherein the starting piperazine does not have the methyl substituent, the following compound was prepared; 
     
       
         
         
             
             
         
       
     
     EXAMPLE 10 
     
       
         
         
             
             
         
       
         
         Step 1: A solution of 4-N—BOC-2(S)-methyl piperazine (0.4 g; 2 mmol), p-iodobenzaldehyde (0.46 g; 2 mmol) and NaBH(OAc) 3  (0.65 g; 3 mmol) in 6 ml of CH 2 Cl 2  was heated at gentle reflux for 14 h. The contents were cooled, diluted with 30 ml of CH 2 Cl 2  and washed with 1N NaOH solution, water and brine to isolate an yellow oil (0.8 g). FSGC (25% EtOAc-hexane) afforded the desired product (0.66 g; 79° f) as a colorless film. TLC R f =0.6 in 25% EtOAc-hexane 
       
    
     The BOC protecting group was removed from the product (0.66 g; 1.58 mmol) by treatment with TFA (1 ml) in CH 2 Cl 2  (2 ml). Following standard work up, the mono-alkylated piperazine (0.5 g; 100%) was obtained as a colorless gum.
     Step 2: NaBH(OAc) 3  (0.63 g; 3 mmol) and two drops of AcOH were added to a solution of the product of step 1 (0.5 g; 1.58 mmol) and N—BOC-piperidinone (0.6 g; 3 mmol) in 5 ml of CH 2 Cl 2  and the resulting solution was stirred at ambient temperature for 16 h. After the usual work up and FSGC, the desired product (0.6 g; 76%) was obtained as a colorless oil. TLC R f =0.4 in 25% acetone-CH 2 Cl 2 .   

     The free piperidine (0.38 g; 79%) was prepared from the N—BOC protected compound (0.6 g; 1.2 mmol) by treatment with TFA (2 ml) in CH 2 Cl 2  (5 ml).
     Compound 10A: The coupling of 6-chloro anthranilic acid (0.065 g; 0.38 mmol) with the product of step 2 (0.127 g; 0.32 mmol) in the presence of DEC (0.092 g; 0.48 mmol), HOBT (0.065 g; 0.48 mmol) and diisopropylethyl amine (0.1 ml), followed by product isolation, were carried out as described previously. This procedure furnished the compound 10A (0.139; 73%) as a colorless film. TLC R f =0.5/0.45 for a pair of rotomers in 2% CH 3 OH—CH 2 Cl 2 .   

     The HCl salt of the title compound was prepared in the usual manner. Mp: 198-202° C.; HRMS (MH + ))=53.1231.
     Compound 10B: Coupling the product of step 2 with 6-methyl anthranilic acid gave compound 10B (HCl salt) in 73% yield. Mp: 197-200° C.; HRMS (MH + )=533.1774.   Compound 10C: 2,6-Dimethyl benzoic acid was coupled to the product of step 2 to obtain the amide 10C(HCl salt) in 50% yield. Mp: 202-205° C.; HRMS (MH + )=532.1826.   

     EXAMPLE 11 
     
       
         
         
             
             
         
       
         
         Step 1: (S)-Methylbenzylamine (27 ml, 0.2 mol) in CH 2 Cl 2  (50 ml) was dropped into ice-cold trifluoroacetic anhydride (40 ml) in CH 2 Cl 2  (200 ml) 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 CH 2 Cl 2  (500 ml) and ice-cold Na 2 SO 3  (10% aqueous, 500 ml) and stirred for 0.5 h. The organic layer was separated and washed with NaHCO 3 , filtered through a short silica gel column and washed With CH 2 Cl 2  (500 ml). After CH 2 Cl 2  was evaporated, Et 2 O (125 ml) was added and the mixture stirred for 10 min. Hexanes (600 ml) was added gradually to the Et 2 O 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, R f =0.7, EtOAc/hexanes, 1:3) was obtained. 
         Step 2: The product of step 1 (11.2 g, 0.033 mol) was dissolved in CH 3 OH (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 CH 3 OH was evaporated, the aqueous layer was extracted with Et 2 O (3×100 ml) and the combined organic portion was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give a free amine. 
       
    
     Methyl-R-lactate (4.08 g, 0.039 mol) was dissolved in CH 2 Cl 2  (40 ml) and the mixture was stirred and cooled in acetone-CO 2  to −78° C. under N 2  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 CH 2 Cl 2  was added to the mixture and the solution was washed with 2N HCl. The freshly prepared amine from above was added to the triflate solution followed by K 2 CO 3  (18 g, 0.132 mol) in water (20 ml). The mixture was stirred at RT overnight. Extractive work-up with CH 2 Cl 2  followed by silica gel column chromatography gave a secondary amine (8.27 g, 75% yield, R f =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 ClCH 2 COCl (117.2 g, 82 ml, 1.04 mol). The mixture was stirred under reflux condition for 3 h. Both the solvent and ClCH 2 COCl were removed under vacuum, The remaining yellow syrup was dissolved in DMSO (40 ml) at 0° C. and NaI (5.2 g, 0.035 mol) and NH 4 OH (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, R f =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 NaBH 4  (15.1 g, 0.4 mol) and BF 3 .OEt 2  (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. CH 3 OH (500 ml) and then concentrated HCl (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(OAc) 3  (6.1 g, 28.8 mmol) and 2M AcOH (5.76 ml, 11.52 mmol) were combined in CH 2 Cl 2  (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, R f =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 CH 2 Cl 2  (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 CH 2 Cl 2  (2 ml) were added 2,6-dimethylbenzoic acid (150 mg, 0.99 mmol), DEC (191 mg, 0.99 mmol) and HOBT (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, R f =0.37, CH 2 Cl 2 /CH 3 OH, 20:1). HRMS (as the HCl) calcd for C 27 H 37 N 3 OI (M+H + ) 546.1981, found 546.1965. Mp; 190° C. (dec.).   

     Using a similar procedure, compounds of the formula 
                         
were prepared, wherein R 9  and R 10  are as defined in the table:
 
     
       
         
           
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Ex 
                 R 9   
                 R 10   
                 Mp (° C.) 
                 HRMS 
               
               
                   
                   
               
             
            
               
                   
                 11A 
                 —CH 3   
                 —NH 2   
                 198 (dec.) 
                 547.1928 
               
               
                   
                 11B 
                 —Cl 
                 —NH 2   
                 203 (dec.) 
                 567.1395 
               
               
                   
                 11C 
                 —OH 
                 —OH 
                 200 (dec.) 
                 550.1555 
               
               
                   
                 11D 
                 —OCH 3   
                 —OCH 3   
                 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 CH 2 CO 2  was added Ti(OiPr) 4  (1.19 g, 4.2 mmol) and the mixture was stirred at RT overnight. 1M Et 2 AlCN (5.04 ml, 5.04 mmol) was added, the mixture was stirred overnight at RT and the solvent was evaporated. Saturated NaHCO 3  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 CH 3 MgBr (7 ml, 21 mmol) was added to the solution. The mixture was stirred at RT overnight, then cooled to 0° C. and saturated NH 4 Cl and water was added. Extractive work up with EtOAc followed by silica gel chromatography gave the piperazino-piperidine product (1.78 g, 81% yield, R f  =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 HCl salt): found 560.2145. 
       
    
     Using a similar procedure, compounds of the formula 
                         
were prepared, wherein R 2  is as defined in the table.
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                 Ex 
                 R 2   
                 mp (° C.) 
                 HRMS 
               
               
                   
               
             
            
               
                   
                 12A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 145 (dec.) 
                 581.1537 
               
               
                   
               
               
                   
                 12B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 150 (dec.) 
                 561.2083 
               
               
                   
               
               
                   
                 12C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 208 (dec.) 
                 561.2096 
               
               
                   
               
               
                   
                 12D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 206 (dec.) 
                 562.1944 
               
               
                   
               
               
                   
                 12E 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190 (dec.) 
                 577.2029 
               
               
                   
               
               
                   
                 12F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 245 (dec.) 
                 601.1006 
               
               
                   
               
               
                   
                 12G 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 218 (dec.) 
                 577.2029 
               
               
                   
               
               
                   
                 12H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195 (dec.) 
                 617.0945 
               
               
                   
               
               
                   
                 12I 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 116 (dec.) 
                 562.2048 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 13 
     
       
         
         
             
             
         
       
         
         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), CuCl (1 g, 10.1 mmol) was added. The suspension was stirred under N 2  at 110° C. for 24 h. After the mixture was cooled to RT, NH 4 OH 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 CH 2 Cl 2  (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.); HRMS (as the HCl salt): found 454.2617. 
       
    
     Using a similar procedure, compounds of the formula 
                         
were prepared, wherein R 9  and R 10  are as defined in the table.
 
     
       
         
           
               
               
               
               
               
               
             
               
                   
                   
               
               
                   
                 Ex 
                 R 9   
                 R 10   
                 Mp (° C.) 
                 HRMS 
               
               
                   
                   
               
             
            
               
                   
                 13A 
                 —CH 3   
                 —NH 2   
                 200 (dec.) 
                 455.2577 
               
               
                   
                 13B 
                 —Cl 
                 —NH 2   
                 200 (dec.) 
                 475.2023 
               
               
                   
                 13C 
                 —Cl 
                 —Cl 
                 187 (dec.) 
                 494.1536 
               
               
                   
                   
               
            
           
         
       
     
     Using the product of step 1 in the procedure of Example 12, compounds of the formula 
                         
were prepared, wherein R 2  is as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                 Ex 
                 R 2   
                 Mp (° C.) 
                 HRMS 
               
               
                   
               
             
            
               
                   
                 13D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 197 (dec.) 
                 468.2779 
               
               
                   
               
               
                   
                 13E 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 205 (dec.) 
                 489.2184 
               
               
                   
               
               
                   
                 13F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 210 (dec.) 
                 469.2734 
               
               
                   
               
               
                   
                 13G 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195 (dec.) 
                 470.2689 
               
               
                   
               
               
                   
                 13H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 260 (dec.) 
                 509.1634 
               
               
                   
               
               
                   
                 13I 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 mol) in DMF (20 ml), CuCN (20.8 g, 0.23 mol) was added. The suspension was stirred under N 2  at 110° C. for 22 h. After the mixture was cooled to RT, NH 4 OH 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, R f =0.5, hexanes/EtOAc, 4.1), the carboxamide derivative (0.95 g, 23.6% yield, R f =0.2, CH 2 Cl 2 /CH 3 OH, 10:1) and the unsubstituted derivative (85 mg, 2.4% yield, R f =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 HCl 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 CuCl (1.61 g, 16.3 mmol) in CH 3 OH at 0° C. was added NaBH 4  (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 CH 3 OH was removed under vacuum. Extractive work up with EtOAc afforded the desired compound (1 g, 100% yield, R f =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 HCl salt): found 420.3016. 
     Using a similar procedure, the following compound is prepared: 
     
       
         
         
             
             
         
       
     
     HRMS (as the HCl 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 Na 2 CO 3  (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 (1.37 g, 62% yield, R f =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 HCl salt): found 496.3319. 
     Using a similar procedure, compounds of the formula 
                         
were prepared, wherein R 2  is as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                 Sch 
                 Ex 
                 R 2   
                 Mp (° C.) 
                 HRMS 
               
               
                   
               
             
            
               
                 223254 
                 16A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190 (dec.) 
                 517.2754 
               
               
                   
               
               
                 223255 
                 16B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 65-70* 
                 497.3287 
               
               
                   
               
               
                 2?5666 
                 16C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190 (dec.) 
                 498.3225 
               
               
                   
               
               
                 *free base 
               
            
           
         
       
     
     EXAMPLE 17 
     
       
         
         
             
             
         
       
         
         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 N 2 . 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 NH 4 Cl 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, R f =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 CH 2 Cl 2  (5 ml) was stirred under reflux conditions for 2 h. After CH 2 Cl 2 , triethylsilane and TFA were removed under reduced pressure, NaOH solution (3N) was added to the remaining syrup. 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 HCl salt): found 544.3101. 
       
    
     EXAMPLE 18 
     
       
         
         
             
             
         
       
         
         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 Et 2 O (4 ml) was added 3M CH 3 MgBr (4 ml) in a dropwise manner. The mixture was stirred under reflux overnight. After the solution was cooled on ice-bath, 12N HCl (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/CH 3 OH (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 HCl salt): found 483.2522. 
       
    
     Using a similar procedure, the following compound is prepared: 
     
       
         
         
             
             
         
       
     
     Mp. 210° C. (dec.); HRMS (as the HCl salt): found 463.3088 
     EXAMPLE 19 
     
       
         
         
             
             
         
       
         
         Step 1: To a solution of the product of Example 22 (140 mg, 0.29 mmol) in CH 3 OH (10 ml) and EtOH (1 ml) were added NH 2 OCH 3 .HCl (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, R f =0.38, CH 2 Cl 2 /CH 3 OH, 20:1). HRMS (as the tartrate) calc&#39;d. for C 31 H 45 N 4 O 2  (M+H + ) 505.3543; found 505.3542. 
       
    
     Using a similar procedure, compounds of the formula 
                         
were prepared, wherein R 8 , R 6  and R 2  are as defined in the table:
 
     
       
         
           
               
               
               
               
               
               
             
               
                   
               
               
                 Ex 
                 R 8   
                 R 6   
                 R 2   
                 mp (° C.) 
                 HRMS 
               
               
                   
               
             
            
               
                 19A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 194 (dec.) 
                 512.2785 
               
               
                   
               
               
                 19B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 150 (dec.) 
                 492.3344 
               
               
                   
               
               
                 19C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 506.3494 
               
               
                   
               
               
                 19D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 180 (dec.) 
                 508.3296 
               
               
                   
               
               
                 19E 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 —CH 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195 (dec.) 
                 493.3291 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 20 
     
       
         
         
             
             
         
       
     
     Dissolve the free piperazino-piperidine of Example 11, step 6 (1.7 g, 3.3 mmol) in CHCl 3  (30 ml; =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 (1.5 ml) in a polyethylene SPE cartridge. To this mixture add 75 ul of a 1 M solution of 5-methyl-3-phenylisoxazole-4-carboxylic acid in DM F (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 Amberdyst-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, CH 2 Cl 2  and CH 3 OH, then wash with THF and CH 2 Cl 2 . Treat the resin with 2M NH 3  in CH 3 OH (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 R f =0.74 (CH 2 Cl 2 /CH 3 OH/NNH 4 OH (95/5/0.5)). 
     Using the procedure above with the appropriate carboxylic acids gave the following compounds 
                         
wherein R 2  is as defined in the table:
 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                   
                 LCMS 
                 TLC 
               
               
                 Ex. 
                 R 2   
                 results 
                 R f  values 
               
               
                   
               
             
            
               
                 20A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 600.1 R t  = 6.56 min. 
                 0.92 
               
               
                   
               
               
                 20B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 601.1 R t  = 5.69 min. 
                 0.63 
               
               
                   
               
               
                 20C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 560.1 R t  = 5.77 min. 
                 0.60 
               
               
                   
               
               
                 20D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 588.1 R t  = 6.61 min. 
                 0.66 
               
               
                   
               
               
                 20E 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 604.1 R t  = 5.60 min. 
                 0.87 
               
               
                   
               
               
                 20F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 658.2 R t  = 5.69 min. 
                 0.86 
               
               
                   
               
               
                 20G 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 606.1 R t  = 6.17 min. 
                 0.43 
               
               
                   
               
               
                 20H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 568.1 R t  = 5.67 min. 
                 0.57 
               
               
                   
               
               
                 20I 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 586.1 R t  = 6.02 min. 
                 0.63 
               
               
                   
               
               
                 20J 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 558.1 R t  = 5.35 min. 
                 0.33 
               
               
                   
               
               
                 20K 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 MH +  = 546.1 R t  = 5.37 min. 
                 0.52 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 21 
     
       
         
         
             
             
         
       
         
         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-tert-butoxycarbonyl-4-piperidone (1.66 g, 8.35 mmol) and Ti(OiPr) 4  (2.18 g, 7.66 mmol) in CH 2 Cl 2  were stirred at RT overnight 1M Et 2 AlCN (8.35 ml, 8.35 mmol) was added, the mixture was stirred overnight at RT and the solvent was evaporated. Saturated NaHCO 3  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, R f =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 CH 3 MgBr (0.76 ml, 2.29 mmol) was added dropwise. The mixture was stirred at RT overnight and then cooled to 0° C. Saturated NH 4 Cl (10 ml) was added and a precipitate appeared. Water (40 ml) was added and the precipitate disappeared. Extractive work up with EtOAc followed by column chromatography gave the desired ipso-methyl derivative (169 mg, 86% yield, R f =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 HCl salt): found 460.3079. 
       
    
     Using a similar procedure, compounds of the formula 
                         
were prepared, wherein R 2  is as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                 Ex 
                 R 2   
                 Mp (° C.) 
                 HRMS 
               
               
                   
               
             
            
               
                   
                 21A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 205 (dec.) 
                 480.2532 
               
               
                   
               
               
                   
                 21B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 65-75* *Mp for the free amine 
                 476.3033 
               
               
                   
               
               
                   
                 21C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 250 (dec.) 
                 500.1992 
               
               
                   
               
               
                   
                 21D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195 (dec.) 
                 461.3019 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 22 
     
       
         
         
             
             
         
       
         
         Step 1: The Strecker amine from Example 21, step 1 (380 mg, 0.87 mmol) was treated with CH 3 MgBr (2.9 ml, 8.7 mmol) in Et 2 O (5 ml) under reflux conditions overnight. The mixture was cooled on ice and water (5 ml) was added dropwise. 12N HCl (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 2  is as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                 Ex. 
                 R 2   
                 Mp (° C.) 
                 HRMS 
               
               
                   
               
             
            
               
                   
                 22A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195 (dec.) 
                 493.3172 
               
               
                   
               
               
                   
                 22B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 200 (dec.) 
                 478.3178 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 23 
                         
Steps 1-3:
 
     
       
         
         
             
             
         
       
         
         Step 1; Ethyl diacetoacetate (93.4 g), Cs 2 CO 3  (185 g) and CH 3 CN (550 ml) were mixed together, using an overhead mechanical stirrer. CH 3 CN (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 Et 2 O (2×50 ml). The organic extracts were combined and Et 2 O (300 ml) was added. The resulting mixture was filtered, the filter cake was washed with Et 2 O (2×100 ml), the Et 2 O 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=111). The Et 2 O layer was dried over MgSO 4 , 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 CH 2 Cl 2  and the aqueous layer was extracted with CH 2 Cl 2  (3×150 ml). The CH 2 Cl 2  extracts were dried over MgSO 4 , filtered and evaporated to give a dark crude liquid (50.7 g) which was purified by silica gel chromatography (9.80 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 1 h. 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 0° C. and conc. HCl (14.3 ml) was added dropwise with stirring. The resulting white precipitate was collected by filtration, washed with ice water (2×10 ml) and air dried with suction for 30 min. The resulting white solid was treated with toluene (2×20 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 C 7 H 8 N 2 O 2 : calc&#39;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 (2×5 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 (3.07 g), 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 (3×25 ml), the organic extracts were combined, washed with brine, dried over Na 2 SO 4 , filtered and evaporated. The resulting crude oil was purified by silica gel chromatography (170 g; 76:19:5 hexanes:EtOAc:Et 3 N 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 (0° C.) solution of the free base of step 4 (2.00 g) and EtOAc (20 ml) was added HCl (3.0 ml of a 4.0 M solution in 1,4-dioxane). The resulting mixture was warmed to RT, diluted with Et 2 O (20 ml), filtered, washed with Et 2 O (2×20 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: 159-162° C.   

     Elemental analysis of C 27 H 36 N 5 OF 3 .2HCl.0.5H 2 O: calc&#39;d: C, 55.38%; H 6.71%; N, 11.96%; Cl, 12.11%; found: C 55.19%; H, 6.69%; N, 11.75%; Cl 11.45%. 
     Additional pyrimidine derivative-compounds were made using similar procedures: 
                         
Steps 1-2:
 
     
       
         
         
             
             
         
       
         
         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 HCl 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. 
       
    
                         
Steps 1-2:
 
     
       
         
         
             
             
         
       
         
         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 HCl 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. 
                         
Steps 1-2:
 
     
       
         
         
             
             
         
       
         
         Step 1: The product of Example 23, step 2 (528 mg) was dissolved in CH 2 Cl 2  (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 CH 2 Cl 2  (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 CH 2 Cl 2 :CH 3 OH. 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 CH 3 OH (1.8 ml) and a solution of 1.0 M Na 2 CO 3  (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 μM silica plate; 95:5 EtOAc:Et 3 N eluant), the free base form of the title compound was isolated (52 mg) as a foam in 40% yield. HRMS: calc&#39;d: M.H + : C 27 H 37 N 5 O 2 F 3 : 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 HCl (4.0 M solution in 1,4-dioxane; 75 μl) to give, after work up, the title compound (44.5 mg) as a white solid in 76% yield. mp: decomposition above 161° C. 
       
    
     Using similar procedures, the compounds of the formula 
                         
were also prepared, wherein R 8a  and R 11  are as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                   
                 Ex. 
                 R 8a   
                 R 11   
                 m.p. (° C.) 
               
               
                   
               
             
            
               
                   
                 23D 
                 —CF 3   
                 —OH 
                 175-185 
               
               
                   
                 23E 
                 —CF 3   
                 —OCH 3   
                 169-173 
               
               
                   
                 23F 
                 —CF 3   
                 —NH 2   
                 200-210 
               
               
                   
                 23G 
                 —CF 3   
                 —NHCONHEt 
                 184-190 
               
               
                   
                 23H 
                 —CF 3   
                 —CF 3   
                 83-86 
               
               
                   
               
               
                   
                 23I 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 154-159 
               
               
                   
               
               
                   
                 23J 
                 —CF 3   
                 —SCH 3   
                 &gt;176 (dec) 
               
               
                   
                 23K 
                 —OCF 3   
                 —CH 3   
                 205-210 
               
               
                   
                 23L 
                 —OCF 3   
                 Ph 
                 239-242 
               
               
                   
                 23M 
                 —OCF 3   
                 —OCH 3   
                 200-210 
               
               
                   
                 23N 
                 —OCF 3   
                 —OH 
                 185-191 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 24 
     Arylcyclopropylamides 
     Method A: 
     
       
         
         
             
             
         
       
         
         Step 1: To the stannane (0.39 g, 0.95 mmol) in DMF (10 ml) was added the 2-chloro-4-fluoroiodobenzene (0.73 g, 2.86 mmol), CuI (0.19 g, 1.05 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.11 g, 0.095 mmol). The reaction was stirred at RT under N 2  for 21 h. The reaction mixture was added to Et 2 O and the heterogeneous solution filtered through a bed of celite, washing with EtOAc. The filtrate was washed with water and brine and dried (MgSO 4 ). Filtration and evaporation of the solvent in vacuo afforded a residue that was preabsorbed on silica gel. Purification by silica 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 tert-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 (MgSO 4 ). Filtration and evaporation of the solvent in vacuo afforded the arylcyclopropyl ester that was used directly by taking up into CH 2 Cl 2  (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 HCl salt. HRMS (M+H): found 566.2561.
 
Method B:
 
       
    
     
       
         
         
             
             
         
       
     
     To the 2-fluorophenylacetonitrile (0.80 g, 5.92 mmol), benzyltriethyl-ammonium chloride (0.03 g, 0.12 mmol), and 1-bromo-2-chloroethane (1.70 g, 11.9 mmol) 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 HCl. The acidified solution was extracted with Et 2 O. The combined Et 2 O extracts were washed with water and brine and dried (MgSO 4 ). 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 HCl salt. HRMS (M+H): found 532.2949. 
     Using similar procedures, the compounds of the formula 
                         
were prepared, wherein
 
                         
is as defined in the table:
 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 HRMS (M + H) 
                 m.p. (° C.) 
               
               
                   
               
             
            
               
                 24C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 240-245 
               
               
                   
               
               
                 24D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 &gt;225 
               
               
                   
               
               
                 24E 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 172-176 
               
               
                   
               
               
                 24F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 225-230 
               
               
                   
               
               
                 24G 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 &gt;225 
               
               
                   
               
               
                 24H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 544.3151 
                 — 
               
               
                   
               
               
                 24I 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 592.2150 
                 — 
               
               
                   
               
               
                 24J 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 532.2956 
                 — 
               
               
                   
               
               
                 24K 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 539.3003 
                 — 
               
               
                   
               
               
                 24L 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 558.2949 
                 — 
               
               
                   
               
               
                 24M 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 572.3107 
                 — 
               
               
                   
               
               
                 24N 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 582.2910 
                 — 
               
               
                   
               
               
                 24O 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 582.2910 
                 — 
               
               
                   
               
               
                 24P 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 520.2609 
                 — 
               
               
                   
               
               
                 24Q 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 515.2991 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 25 
                         
Step 1:
 
     
       
         
         
             
             
         
       
     
     Cyclopropyl carboxaldehyde (3.4 ml), S-methyl N—BOC piperazine (8.28 g), CH 2 Cl 2  (82 ml) and Ti(OiPr) 4  (15.80 ml) were mixed together and stirred at RT for 23 h, then the resulting solution was cooled to 0° C. and Et 2 AlCN (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 (3×35 ml) and the EtOAc layer was removed, washed with brine, dried over Na 2 SO 4 , filtered and evaporated to give the desired intermediate (12.0 g) which was used directly in the next step. 
     Step 2: 
     
       
         
         
             
             
         
       
     
     To a 0° C. solution of 4-iodobenzotrifluoride (40 g) and THF (52 ml) was added isopropyl magnesium chloride (2.0 M in Et 2 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 (3×20 ml). The combined EtOAc extracts were washed with brine, dried over Na 2 SO 4 , 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 f =0.47 in 4:1 hexanes:EtOAc; 5.34 g), which was contaminated with an unidentified impurity. (The second diastereomer B (R f =0.29 in 4:1 hexanes:EtOAc) was also collected.) 
     Step 3: 
     
       
         
         
             
             
         
       
     
     To a solution of A from Step 2 (3.96 g) and CH 2 Cl 2  (120 ml) was added DOWEX 50×2-100 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 CH 2 Cl 2  (2×40 ml). The resin was treated with 7 N NH 3  in CH 3 OH (30 ml), the resin was filtered off and this procedure was repeated two times. The CH 3 OH extracts were combined and evaporated. The resulting oil was treated with toluene:CH 2 Cl 2  (1-1; 15 ml) and evaporated to give the piperazine intermediate (0.80 g) as a clear oil. HRMS: calc&#39;d: M.H + : C 16 H 21 N 2 F 3 :299.1735; measured: 299.1748. 
     Step 4: 
     
       
         
         
             
             
         
       
     
     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), CH 2 Cl 2  (3.84 ml), Ti(OiPr) 4  (3.39 ml), Et 2 AlCN (2.88 ml) and CH 3 MgBr (3.0 M in Et 2 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 with AcOH:CH 2 Cl 2  (3:1, v:v; 1.4 ml) followed by BF 3 .Et 2 O (0.14 ml). After stirring for 1 h, the resulting solution was diluted with CH 2 Cl 2  (10 ml), cooled to 0° C. and the pH was adjusted to 10 with solid NaOH. Water (2 ml) was added and the CH 2 Cl 2  layer was removed After further extraction (2×10 ml) with CH 2 Cl 2 , the organic layer was washed with water, brine, dried over Na 2 SO 4 , 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-dimethyl 5-pyrimidine carboxylic acid (43 mg); the reaction was stirred at 45° C. for 5 h Purification of the crude oil was carried out by preparative plate chromatography (silica adsorbent; 2000 μM; 76:19:5 EtOAc:hexanes:Et 3 N as eluant) to give, after elution of the desired band (1:1 CH 2 Cl 2 :MeOH) and concentration of solvent, the title compound (70 mg) as a clear oil in 93% yield The HCl 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: 
     
       
         
         
             
             
         
       
     
     EXAMPLE 26 
                         
Step 1:
 
     
       
         
         
             
             
         
       
     
     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: 
     
       
         
         
             
             
         
       
     
     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 4 OH (10 ml) was added and the reaction was stirred for 30 min. The resulting mixture was partitioned between water and CH 2 Cl 2 , the CH 2 Cl 2  extracts were removed and evaporated and the crude oil was purified by column chromatography (silica gel; 2:1 hexanes:CH 2 CO 2 ; 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: 
     
       
         
         
             
             
         
       
     
     The mixture of Step 2 (1.91 g), CH 3 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 Na 2 CO 3  (10 g) in water (50 ml). After extraction with EtOAc (2×50 ml), drying and evaporation of the organic layer, the resulting oil was purified by preparative plate chromatography (5×2000 mM silica plates; 6:1 hexanes:EtOAc as eluant). The less polar band was removed, treated with 1:1 methanol:CH 2 CO 2 , filtered and evaporated to give intermediate A (0.84 g) as a white foam. HRMS: calc&#39;d: M.H + : C 25 H 29 O 2 N 2 F 3 :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 2 Cl 2  (10 ml), to give, after work up, the free piperazine (0.60 g) as a clear gum. HRMS: cal&#39;d: M.H + : C 20 H 23 N 2 F 3 : 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 2 Cl 2  (8 ml), Ti(OiPr) 4  (0.40 mg), Et 2 AlCN (2 ml) and CH 13 MgBr (3.0 M in Et 2 O; 1.5 ml) to give the desired BOC-protected piperidinyl intermediate (0.44 g) as a clear oil in 72% yield. HRMS: calc&#39;d: M.H + : C 31 H 42 O 2 N 3 F 3 :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 2 Cl 2  (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 2 Cl 2  (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 HCl 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&#39;d: M H + : C 33 H 40 ON 5 F 3 : 580.3263; measured: 580.3263. 
     Using a similar procedure, compounds of the formula 
                         
were prepared, wherein R 8a , R 3  and R 2  are as defined in the table.
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 R 8a   
                 R 3   
                 R 2   
                 Mp (° C.) 
               
               
                   
               
             
            
               
                 26B 
                 —CF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 86-92 
               
               
                   
               
               
                 26C 
                 —CF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 83-90 
               
               
                   
               
               
                 26D 
                 —CF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195-205 
               
               
                   
               
               
                 26E 
                 —CF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 118-125 
               
               
                   
               
               
                 26F 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 175-185 
               
               
                   
               
               
                 26G 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 180-190 
               
               
                   
               
               
                 26H 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 220-230 
               
               
                   
               
               
                 26I 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195-210 
               
               
                   
               
               
                 26J 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190-200 
               
               
                   
               
               
                 26K 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 180-205 
               
               
                   
               
               
                 26L 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 230-240 
               
               
                   
               
               
                 26M 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 60-65 
               
               
                   
               
               
                 26N 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 65-68 
               
               
                   
               
               
                 26O 
                 —OCF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 60-62 
               
               
                   
               
               
                 26P 
                 —CF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 256-258 
               
               
                   
               
               
                 26Q 
                 —CF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 254-256 (dec) 
               
               
                   
               
               
                 26R 
                 —CF3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 249-250 (dec) 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 27 
                         
Step 1:
 
     
       
         
         
             
             
         
       
     
     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 boranemethyl 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 CH 3 OH was added slowly until no bubbles appeared. The solvents were removed under reduced pressure and HCl solution (1N) was added to the mixture. EtOAc extractive work up followed by silica gel chromatography afforded the alcohol (1.47 g) in 72% yield.
     Step 2: A solution of the product of Step 1 (4.32 g, 0.021 mol) and Et 3 N (5.9 ml, 0.042 mol) in CH 2 Cl 2  (20 ml) was cooled to 0° C. in ice bath and CH 3 SO 2 Cl (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 2 Cl 2  extractive work up afforded the mesylate (5.99 g) in quantitative yield.   Step 3: The product of Step 2 (5.93 g, 0.021 mol) and 1-tert-butoxy-carbonyl-3S-methyl piperazine (4.2 g, 0.021 mol) were dissolved in anhydrous CH 3 CN (20 ml) and oven-dry K 2 CO 3  (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 CH 2 Cl 2  (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-tert-butoxycarbonyl-4-piperidone (0.94 g, 4.74 mmol) were treated with Ti(OiPr) 4 , Et 2 AlCN and CH 3 MgBr 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 CH 2 Cl 2  (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-dimethylpyrimidine 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 
                         
were prepared wherein Z, R 3 , R 6  and R 2  are as defined in the table below:
 
     
       
         
           
               
               
               
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                   
                   
                 Dec. 
                   
               
               
                 Ex. 
                 Z 
                 R 3   
                 R 6   
                 R 2   
                 (0° C.) 
                 HRMS 
               
               
                   
               
             
            
               
                 27A 
                 N 
                 Me 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 185 
                 491.2744 
               
               
                   
               
               
                 27B 
                 N 
                 Me 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190 
                 506.2729 
               
               
                   
               
               
                 27C 
                 N 
                 Me 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 190 
                 505.2898 
               
               
                   
               
               
                 27D 
                 N 
                 Me 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 200 
                 520.2902 
               
               
                   
               
               
                 27E 
                 CH 
                 Et 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 197 
                 533.3097 
               
               
                   
               
               
                 27F 
                 CH 
                 Et 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 215 
                 532.3147 
               
               
                   
               
               
                 27G 
                 CH 
                 Et 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 230 
                 627.3145 
               
               
                   
               
               
                 27H 
                 CH 
                 Et 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 210 
                 602.3678 
               
               
                   
               
               
                 27I 
                 CH 
                 Et 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 215 
                 531.3305 
               
               
                   
               
               
                 27J 
                 CH 
                 Et 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 215 
                 593.3470 
               
               
                   
               
               
                 27K 
                 CH 
                 Et 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195 
                 609.3424 
               
               
                   
               
               
                 27L 
                 CH 
                 Et 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 170 
                 745.2308 
               
               
                   
               
               
                 27M 
                 N 
                 n-Pr 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 204 
                 533.3207 
               
               
                   
               
               
                 27N 
                 N 
                 n-Pr 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 210 
                 617.3798 
               
               
                   
               
               
                 27O 
                 N 
                 n-Pr 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 202 
                 531.3304 
               
               
                   
               
               
                 27P 
                 N 
                 n-Pr 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 165 
                 543.3311 
               
               
                   
               
               
                 27Q 
                 N 
                 n-Pr 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 225 
                 584.3205 
               
               
                   
               
               
                 27R 
                 N 
                 n-Pr 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195 
                 548.3217 
               
               
                   
               
            
           
         
       
     
     Using similar procedures, the following compounds were also prepared: 
     
       
         
         
             
             
         
       
     
     EXAMPLE 28 
                         
Steps 1-4:
 
     
       
         
         
             
             
         
       
         
         Step 1: The cyano amine was prepared from p-trifluoromethyl benzaldehyde and 2(S)-methyl-4-(tert-butoxycarbonyl)piperazine exactly as described in 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 N 2  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 (˜1 h), it changed from a yellow solution to dark reddish brown solution. The reaction was quenched with saturated NH 4 Cl 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 2 O in hexane as eluant gave 2.5 grams (92%) of the desired product as an amber gum (TLC R f =0.65, 0.6 for two overlapping spots). 
         Step 3: A solution of the product of Step 2 (2.4 g) in CH 3 OH was treated with 10% Pd/C (0.2 g) and placed under a balloon of H 2  gas. After stirring at RT for 4 h, the catalyst was removed via filtration through celite. Concentration of the filtrate yielded an amber gum. 
       
    
     The α-propyl nitrite obtained above was dissolved in CH 3 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 NaHCO 3 . The organic products were extracted with EtOAc and processed to obtain ˜2 g of crude material. FSGC (10-25% Et 2 O in hexane) served to isolate two diasteromeric products (1.7 g total; 79% for two steps):
     (S,S)-Diastereomer (A): TLC R f =0.6 (25% Et 2 O-Hexane). 0.9 g of a colorless gum.   (R,S)-Diastereomer (B): TLC R f =0.5 (25% Et 2 O-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 CH 2 Cl 2 . The isolated free piperazine (0.68 g; 2.3 mmol), N-(tert-butoxycarbonyl)-4-piperidinone (0.45 g; 2.3 mmol) and Ti(OiPr) 4  (0.7 mL; 2.5 mmol) were dissolved in 10 ml of CH 2 Cl 2  and stirred overnight Et 2 AlCN (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 f =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 3 MgBr (3M in Et 2 O; 6 ml) and stirred overnight at RT. The reaction flask was placed in a cold water bath and carefully quenched with saturated NH 4 Cl 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 (1.1 g; 100%). TLC R f =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 2 Cl 2 . Basification with I M NaOH and processing in CH 2 Cl 2  afforded the unprotected piperidine in 90% yield. This intermediate was coupled (EDCl, HOBt) to aryl and heteroaryl carboxylic acids to obtain the amides exemplified in the following table:   

                         
wherein R 2  is as defined in the table:
 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 HRMS 
               
               
                 Ex. 
                 R 2   
                 Mp (° C.) 
                 (MH + ) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                 28A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 
               
               
                   
               
               
                 28F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 102 
                 Calculated: 623.3573 Found: 623.3572 
               
               
                   
               
               
                 28G 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 216 
                 Calculated: 545.3467 Found: 545.3459 
               
               
                   
               
               
                 28H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 217 
                 Calculated: 546.3307 Found: 546.3309 
               
               
                   
               
               
                 28I 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 223 
                 Calculated: 616.3838 Found: 616.3848 
               
               
                   
               
            
           
         
       
     
     Using similar procedures, the following compounds were prepared: 
                         
wherein R 8 , R 3  and R 2  are as defined in the table:
 
     
       
         
           
               
               
               
               
               
             
               
                   
               
               
                 Ex. 
                 R 8   
                 R 3   
                 R 2   
                 Mp (° C.) 
               
               
                   
               
             
            
               
                 28J 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 195-220 
               
               
                   
               
               
                 28K 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 105-115 
               
               
                   
               
               
                 28L 
                 CH 3 CONH— 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 177-180 
               
               
                   
               
               
                 28M 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 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 (HCl salt): 
     
       
         
         
             
             
         
       
     
     EXAMPLE 29 
                         
Steps 1-3:
 
     
       
         
         
             
             
         
       
         
         Step 1: Solid m-CPBA was added to a solution of p-trifluoromethyl styrene (3 g; 17.4 mmol) in 30 ml of CH 2 Cl 2  and stirred at RT for 20 h. About 20 ml of a saturated solution of NaHCO 3  was added and stirred at RT for 2 h. The mixture was diluted with 20 ml of CH 2 Cl 2  and the organic product extracted into the CH 2 Cl 2  layer. The organic extract was processed to obtain the crude product. FSGC gave 3 g (90%) of the desired epoxide as a colorless oil. TLC R f =0.8 (25% EtOAc in hexane), 
         Step 2: Freshly prepared NaOCH 3  (0.6 g; 10.6 mmol) was added to a solution of the product of Step 1 (2 g; 10.6 mmol) in 20 ml of anhydrous CH 3 OH. After stirring at RT for a day, CH 3 OH was removed in vacuo. The residue was dissolved in CH 2 Cl 2  and washed with water and brine. Concentration, followed by FSGC, furnished 1.3 g (55%) of the carbinol as a colorless oil (R f =0.3 50% Et 2 O in hexane). 
         Step 3: The carbinol of Step 2 (1.3 g; 5.9 mmol) was dissolved in CH 2 CO 2  and cooled in an ice bath. Sequential treatment with Et 3 N (1.7 ml; 12 mmol) and CH 3 SO 2 Cl (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 (1.76 g; 5.9 mmol) and 2(S)-methyl-4-(tert-butoxycarbonyl)piperazine (2.4 g; 12 mmol) were dissolved in 5 ml of CH 3 CN 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 2 O in hexane served to isolate the diastereomeric products A and B (Total yield=86%).
     A: R f =05 (50% Et 2 O in hexane). Light yellow gum (0.9 g; 42%)   B: R f =0.4 (50% Et 2 O in hexane). Amber gum (1.13 g; 44%)   Step 4; Reductive amination of the free piperazine derived from A (0.9 g; 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 (0.87 g; 92%). R f =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 EDCl/HOBt method as described in Example 8, step 4, to obtain the compounds shown in the following table:   

                         
wherein R 2  is as shown in the table:
 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                   
                   
                 HRMS 
               
               
                 Ex. 
                 R 2   
                 Mp (° C.) 
                 (MH + ) 
               
               
                   
               
             
            
               
                 29A 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 163 
                 Calculated: 534.3056 Found: 534.3050 
               
               
                   
               
               
                 29B 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 208 
                 Calculated: 548.3100 Found: 548.3092 
               
               
                   
               
               
                 29C 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 101 
                 Calculated: 549.3053 Found: 549.3057 
               
               
                   
               
               
                 29D 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 192 
                 Calculated: 618.3631 Found: 618.3638 
               
               
                   
               
            
           
         
       
     
     EXAMPLE 30 
                         
Step 1:
 
     
       
         
         
             
             
         
       
     
     A solution of p-trifluoromethoxy benzaldehyde (0.48 ml, 3.36 mmol), the piperidino-pipiperazine (1.00 g, 3.36 mmol) and benzotriazole (0.48 g, 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: 
     
       
         
         
             
             
         
       
     
     To a solution of the product of Step 1 (1.16 g, 1.97 mmol) in 20 ml of toluene was added a solution of n-propyl magnesium bromide (2M in Et 2 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 4 Cl 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 2 Cl 2  to remove the BOC-protecting group. Coupling of the free piperidine with acids using EDCl/HOBt provided compounds 30-30B in the following table; similar methods were used to prepare compounds 30C-I.   

     
       
         
           
               
            
               
                   
               
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 HRMS (MH + ) 
               
               
                 Ex. 
                 R 8a   
                 R 3   
                 R 2   
                 Mp (° C.) 
                 found 
               
               
                   
               
               
                 30 
                 —OCF 3   
                 n-Pr 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 237 
                 546.3314 
               
               
                   
               
               
                 30A 
                 —OCF 3   
                 n-Pr 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 241 
                 548.3217 
               
               
                   
               
               
                 30B 
                 —OCF 3   
                 n-Pr 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 219 
                 632.3779 
               
               
                   
               
               
                 30C 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 175-178 
                 — 
               
               
                   
               
               
                 30D 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 177-189 
                 — 
               
               
                   
               
               
                 30E 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 84-90 
                 — 
               
               
                   
               
               
                 30F 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 180-192 
                 — 
               
               
                   
               
               
                 30G* 
                 —CF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 180-186 
                 — 
               
               
                   
               
               
                 30H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 178-188 
                 — 
               
               
                   
               
               
                 30I* 
                 —OCF 3   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 165-175 
                 — 
               
               
                   
               
               
                 *Mixture of diastereomers 
               
            
           
         
       
     
     EXAMPLE 31 
     
       
         
         
             
             
         
       
     
     A solution of the product of Example 12, step 2 (150 mg, 0.27 mmol), imidazole (27.4 mg, 0.403 mmol), 1,10-phenanthroline (48 mg, 0.27 mmol), trans,trans-dibenzylideneacetone (6.28 mg, 0.027 mmol), copper (II) trifluoromethanesulfonate benzene complex (15 mg, 0.027 mmol) and Cs 2 CO 3  (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 NaHCO 3  was added. Extractive EtOAc work up followed by silica gel chromatography gave the title compound (70 mg, 52% yield). Dec. 215° C. (HCl salt). 
     HRMS calcd for C 29 H 39 ClN 3 OS (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  125 I-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 I-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, lysed 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 Replication Assay: 
     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 Assay: 
     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. 
     GTPγS Binding Assay: 
     A GTPγS binding assay measures receptor activation by CCR5 ligands. This assay measures the binding of  35 S 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  35 S 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 Assay: 
     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, MIP-1β). 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  &amp;  Experimental Rheumatology,  17 (4) (1999), p. 419-425 (rheumatoid arthritis);  Clinical  &amp;  Experimental Immunology,  117 (2) (1999), p. 237-243 (atopic dermatitis);  International Journal of Immunopharmacology,  20 (11) (1998), p. 661-7 (psoriasis);  Journal of Allergy  &amp;  Clinical Immunology,  100 (6, Pt 2) (1997), p. S52-5 (asthma); and  Journal of Immunology,  159 (6) (1997), p. 2962-72 (allergies). 
     In 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 nM. 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.” 
     
       
         
           
               
               
               
             
               
                   
                   
               
               
                   
                   
                 Ki (nM) 
               
               
                   
                   
                 Inhibition of 
               
               
                   
                 Ex. No. 
                 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&#39;s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa. 
     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.