HIV Protease Inhibiting Compounds

Abstract

A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.

What is claimed is: 
     
         1 . A compound having formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt form or a stereoisomer thereof, wherein: 
         R A  is selected from the group consisting of —N(H)C(O)R 8 , —O(R a ),—N(R b )S(O) 2 R a , —N(R b )alkylN(R b )S(O) 2 R a , —N(R b )alkylN(R b )C(O)OR a , and -alkylS(O) 2 R a ; 
         R 1  is alkyl; 
         R 2  is alkyl; 
         R 3  is arylalkyl, wherein the aryl moiety of the arylalkyl is independently substituted with R 3a ; 
         R 3a  is heteroaryl selected from the group consisting of thiazolyl, and pyridyl, wherein each R 3a  is substituted with 0 or 1 substituents independently selected from the group consisting of alkyl and alkoxy; 
         R 4  is H and R 5  is OR 16 , or R 5  is H and R 4  is OR 16 , or R 4  and R 5  are —OR 16 ; 
         R 16  is hydrogen or R 15 ; 
         R 6  is arylalkyl, wherein the aryl moiety of the arylalkyl is independently substituted with 0 or 1 substituents independently selected from the group consisting of R 6a ; 
         R 6a  is pyridyl; 
         R 7  is —N(R b )C(O)OR a , alkyl or tetrahydrofuranyl, wherein the alkyl is independently substituted with 0 or 1 substituents independently selected from the group consisting of —OR a , —OC(O)R a , —SR a , —SOR a , —SO 2 R a , —N(R a )C(O)NR a R b , —C(O)NR a R b , —C(O)OR a  and R 7a ; 
         R 7a  is heteroaryl selected from the group consisting of thiazolyl and pyridyl; 
         R 8  is —OR a , —N(R b )C(O)OR a , -alkylOR a , -alkylOC(O)R a , or —O-alkylC(O)R a ; 
         R 15  is —P(O)(OH) 2 , or -alkyl-O—P(O)(OH) 2 ; 
         R a  and R b  at each occurrence are independently selected from the group consisting of hydrogen, alkyl, aryl and pyridyl, wherein each R a  and R b , at each occurrence, is independently substituted with 0 or 1 substituent independently selected from the group consisting of alkyl and R c ; and 
         R 1  is aryl or pyridyl. 
       
     
     
         2 . The compound of  claim 1 , wherein
 R A  is —N(H)C(O)R 8 ;   R 8  is —OR a ; and   R a  is alkyl.   
     
     
         3 . The compound of  claim 1 , wherein R 3  is arylalkyl substituted with pyridyl. 
     
     
         4 . The compound of  claim 1 , wherein R 4  is H, R 5  is OR 16 , and R 16  is hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein R 6  is unsubstituted arylalkyl. 
     
     
         6 . The compound of  claim 1 , wherein R 7  is alkyl. 
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt form, or a stereoisomer thereof, selected from the group consisting of:
 methyl (1S,4R,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-(methylsulfonyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1R,4S,6S,7S,10S)-4-benzyl-10-tert-butyl-6-hydroxy-1-[1-methyl-1-(methylsulfanyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1R,4S,6S,7S,10S)-4-benzyl-10-tert-butyl-6-hydroxy-1-[1-methyl-1-(methylsulfonyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S)-1-[({(1S,3S,4S)-4-({(2S)-3,3-dimethyl-2-[(phenoxyacetyl)amino]butanoyl}amino)-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;   methyl (1S,4S,6S,7S,10S)-7-benzyl-1,10-ditert-butyl-6-hydroxy-2,9,12-trioxo-4-[4-(2-pyridinyl)benzyl]-14-oxa-3,8,11-triazapentadec-1-ylcarbamate;   methyl (1S)-1-[({(1S,3S,4S)-4-{[(2S)-3,3-dimethyl-2-({[(6-methyl-3-pyridinyl)oxy]acetyl}amino)butanoyl]amino}-3-hydroxy-5-phenyl-1-[4-(2-pyridinyl)benzyl]pentyl}amino)carbonyl]-2,2-dimethylpropylcarbamate;   3-pyridinylmethyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   benzyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methyl-3-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(5-methyl-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-7-[4-(5-methyl-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-((R)-methylsulfinyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[1-methyl-1-((S)-methylsulfinyl)ethyl]-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(3-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4-[4-(4-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   1,2,5,6-tetradeoxy-2,5-bis({(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoyl}amino)-1,6-bis[4-(2-pyridinyl)phenyl]-D-iditol;   methyl (1S,4R,5R,7R,10S)-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-4,7-bis[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-7-benzyl-1,10-ditert-butyl-5-hydroxy-4-[4-(6-methoxy-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-7-[4-(6-methoxy-2-pyridinyl)benzyl]-2,9,12-trioxo-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-disec-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-[(3R)-tetrahydro furan-3-yl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(1,3-thiazol-2-yl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[(1S)-1-methylpropyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-3-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-methyl-3-(methylsulfonyl)propanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-di-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-4-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2S)-2-hydroxy-3,3-dimethylbutanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;   methyl (1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-12,12-dioxido-2,9-dioxo-4-(4-pyridin-2-ylbenzyl)-12-thia-3,8,11-triazamidec-1-ylcarbamate;   methyl (1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[(methylthio)methyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1R,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-[(methylsulfonyl)methyl]-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S)-1-({[(1S,3S,4S)-3-hydroxy-4-{[(2R)-2-hydroxy-3-methyl-3-(methylsulfonyl)butanoyl]amino}-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-isobutyl-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-1-(2-amino-2-oxo ethyl)-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl 2-{[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}-1-[(methoxycarbonyl)amino]-2-oxo ethylcarbamate;   methyl (1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-2,9,12,14-tetraoxo-4-(4-pyridin-2-ylbenzyl)-15-oxa-3,8,11,13-tetraazahexadec-1-ylcarbamate;   methyl (1S,4S,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-14,14-dimethyl-2,9,12,15-tetraoxo-4-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazahexadec-1-ylcarbamate;   7S,8S,10S,13S)-7-benzyl-4,13-di-tert-butyl-8-hydroxy-2,5,12,15-tetraoxo-10-(4-pyridin-2-ylbenzyl)-16-oxa-3,6,11,14-tetraazaheptadec-1-yl acetate;   methyl (1S)-1-({[(1S,3S,4S)-4-{[(2S)-2-(glycoloylamino)-3,3-dimethylbutanoyl]amino}-3-hydroxy-5-phenyl-1-(4-pyridin-2-ylbenzyl)pentyl]amino}carbonyl)-2,2-dimethylpropylcarbamate;   6S,7S,9S,12S)-6-benzyl-3-[(tert-butoxycarbonyl)amino]-12-tert-butyl-7-hydroxy-2,2-dimethyl-4,11,14-trioxo-9-(4-pyridin-2-ylbenzyl)-15-oxa-5,10,13-triazahexadec-1-yl acetate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-1-(2-hydroxy-1,1-dimethylethyl)-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-1-{[(aminocarbonyl)amino]methyl}-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(pyridin-2-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-10-tert-butyl-5-hydroxy-2,9,12-trioxo-7-(4-pyridin-2-ylbenzyl)-1-(1,3-thiazol-4-ylmethyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   (3S,6S,7S,9S,12S)-6-benzyl-12-tert-butyl-7-hydroxy-3-[(methoxycarbonyl)amino]-2,2-dimethyl-4,11,14-trioxo-9-(4-pyridin-2-ylbenzyl)-15-oxa-5,10,13-triazahexadec-1-yl acetate;   methyl (1S,4R,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-15,15-dioxido-2,9-dioxo-4-(4-pyridin-2-ylbenzyl)-15-thia-3,8,11,14-tetraazahexadec-1-ylcarbamate;   methyl (1S,4R,6S,7S,10S)-7-benzyl-1,10-di-tert-butyl-6-hydroxy-2,9,15-trioxo-4-(4-pyridin-2-ylbenzyl)-16-oxa-3,8,11,14-tetraazaheptadec-1-ylcarbamate;   methyl (5S,8S,10S,11S,14S)-11-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15-methyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oate;   methyl (5S,8S,10S,11S,14S)-11-benzyl-5-tert-butyl-10-hydroxy-14-[(methoxycarbonyl)amino]-15,15-dimethyl-3,6,13-trioxo-8-(4-pyridin-2-ylbenzyl)-2-oxa-4,7,12-triazahexadecan-16-oate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-(phosphonooxy)-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-7-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-4-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[(phosphonooxy)methoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate;   methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-bis(tert-butyl)-2,9,12-trioxo-5-[1-(phosphonooxy)ethoxy]-7-(4-pyridin-2-ylbenzyl)-13-oxa-3,8,11-triazatetradec-1-ylcarbamate; and   methyl (1S)-3-amino-1-({[(1S,2S,4S)-1-benzyl-2-hydroxy-4-{[N-(methoxycarbonyl)-3-methyl-L-valyl]amino}-5-(4-pyridin-2-ylphenyl)pentyl]amino}carbonyl)-2,2-dimethyl-3-oxopropylcarbamate.   
     
     
         8 . The compound of  claim 7  wherein the compound is methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate, or a pharmaceutically acceptable salt form, or stereoisomer thereof. 
     
     
         9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound or combination of compounds of  claim 1 , or a pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition of  claim 9  wherein the compound is methyl (1S,4S,5S,7S,10S)-4-benzyl-1,10-ditert-butyl-5-hydroxy-2,9,12-trioxo-7-[4-(2-pyridinyl)benzyl]-13-oxa-3,8,11-triazatetradec-1-ylcarbamate, or a pharmaceutically acceptable salt form, stereoisomer, or combination thereof, and a pharmaceutically acceptable carrier. 
     
     
         11 . The pharmaceutical composition of  claim 9  wherein the composition further comprises one, two, three, four, five or six agents selected from the group consisting of a second HIV protease inhibitor, a HIV reverse transcriptase inhibitor, an HIV entry/fusion inhibitor, an HIV integrase inhibitor and an HIV budding/maturation inhibitor, and a pharmaceutically acceptable carrier. 
     
     
         12 . The pharmaceutical composition of  claim 11  wherein the second HIV protease inhibitor is selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684 and GW640385X;
 wherein the HIV reverse transcriptase inhibitor is selected from the group consisting of lamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083), DPC-961, MIV-150, TMC-120 and TMC-125; 
 wherein the HIV entry/fusion inhibitor is selected from the group consisting of enfuvirtide (T-20), T-1249, PRO 2000, PRO 542, PRO 140, AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D), TNX-355 and UK-427857; 
 wherein the HIV integrase inhibitor is selected from the group consisting of S-1360, zintevir (AR-177), L-870812 and L-870810; and 
 wherein the HIV budding/maturation inhibitor is PA-457. 
 
     
     
         13 . The pharmaceutical composition of  claim 11 , comprising ritonavir or a pharmaceutically acceptable salt form of ritonavir. 
     
     
         14 . A method for treating an HIV infection comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or combination of compounds of  claim 1 , or a pharmaceutically acceptable salt form, or stereoisomer thereof. 
     
     
         15 . A method for treating an HIV infection comprising administering to a patient in need of such treatment a pharmaceutical composition of  claim 9 . 
     
     
         16 . A process of preparing a compound of formula (XVIII) 
       
         
           
           
               
               
           
         
         wherein 
         X 1  is CH or N; 
         X 2  is CH or N; 
         X 3  is CH or N; provided only one of X 1 , X 2 , X 3  is N and the other two are CH; 
         R 112  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl heterocyle, aryl or heteroaryl; 
         wherein each R 112  is substituted with 0, 1 or 2 substituents independently selected from the group consisting of halo, —OR a′ , —SR a′ , —SOR a′ , —SO 2 R a′ , —NR a′ R b′ , —N(R b )C(O)R a′ —N(R b )C(O)OR a′ , —N(R b′ )C(═N)NR a′ R b′ , —N(R b )C(O)NR a′ R b′ , —C(O)NR a′ R b′ , —C(O)OR a′  and R 112a ; 
         R 112a  is cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl; wherein each R 112a  is substituted with 0, 1, 2, 3 or 4 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —SH, —S(alkyl), —SO 2 (alkyl), —N(H)C(O)alkyl, —N(alkyl)C(O)alkyl, —N(H)C(O)NH 2 , —N(H)C(O)N(H)(alkyl), —N(H)C(O)N(alkyl) 2 , —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , haloalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH 2 , -alkylN(H)(alkyl), -alkylN(alkyl) 2 , -alkylN(H)C(O)NH 2 , -alkylN(H)C(O)N(H)(alkyl), -alkylN(H)C(O)N(alkyl) 2 , -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH 2 , -alkylC(O)N(H)(alkyl) and -alkyl-C(O)N(alkyl) 2 ; 
         R 111  is C 1 -C 6  alkyl or phenylmethyl; and 
         R a′  and R b′  are each independently selected from the group consisting of hydrogen and alkyl. 
         wherein the process comprises the steps of: 
         (a) contacting a compound of formula (i) 
       
       
         
           
           
               
               
           
         
         with potassium tert-butoxide and n-butyl lithium in a first solvent; 
         (b) contacting a first base with ketonitrile of formula (ii) 
       
       
         
           
           
               
               
           
         
         wherein P 1  and P 2  are nitrogen protecting group and P 1  and P 2  can be the same or different, in the first solvent; 
         (c) contacting the product of step (b) with the product of step (a) to provide a compound of formula (iii) 
       
       
         
           
           
               
               
           
         
         (d) contacting the compound of formula (iii) with a first reducing agent and an acid in a second solvent; 
         (e) contacting the product of step (d) in the second solvent with a second reducing agent, to provide a compound of formula (iv); 
       
       
         
           
           
               
               
           
         
         (f) contacting the compound of formula (iv) with a hydrogen source and a catalyst in a third solvent to provide a compound of formula (v); 
       
       
         
           
           
               
               
           
         
         and 
         (g) contacting the compound of formula (v) with a compound of formula (vi), 
       
       
         
           
           
               
               
           
         
         a coupling reagent and a second base in a fourth solvent to provide the compound of formula (XVIII).