Non-nucleoside reverse transcriptase inhibitors

Abstract

Heteroaromatic compounds of Formula I: are HIV reverse transcriptase inhibitors, wherein R 1 , R 2 , R 3 , R 4 and R 5 are defined herein. The compounds of Formula I and their pharmaceutically acceptable salts are useful in the inhibition of HIV reverse transcriptase, the prophylaxis and treatment of infection by HIV and in the prophylaxis, delay in the onset or progression, and treatment of AIDS. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is C 1-10  alkyl, CycA, or AryA; 
 CycA is C 3-8  cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, C 1-6  alkyl, OH, O—C 1-6  alkyl, C 1-6  haloalkyl, or O—C 1-6  haloalkyl; 
 AryA is aryl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
 (i) from zero to 6 substituents are each independently:
 (1) C 1-6  alkyl, 
 (2) C 1-6  haloalkyl, 
 (3) C 1-6  alkyl substituted with from 1 to 3 substituents each of which is independently OH, O—C 1-6  alkyl, O—C 1-6  haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B , 
 (4) C 2-6  alkenyl, 
 (5) C 2-6  alkenyl substituted with from 1 to 3 substituents each of which is independently OH, O—C 1-6  alkyl, O—C 1-6  haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B , 
 (6) C 2-6  alkynyl, 
 (7) C 2-6  alkynyl substituted with from 1 to 3 substituents each of which is independently OH, O—C 1-6  alkyl, O—C 1-6  haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B , 
 (8) O—C 1-6  alkyl, 
 (9) O—C 1-6  haloalkyl, 
 (10) OH, 
 (11) halogen, 
 (12) CN, 
 (13) NO 2 , 
 (14) N(R A )R B , 
 (15) C(O)N(R A )R B , 
 (16) C(O)R A , 
 (17) C(O)—C 1-6  haloalkyl, 
 (18) C(O)OR A , 
 (19) OC(O)N(R A )R B , 
 (20) SR A , 
 (21) S(O)R A , 
 (22) S(O) 2 R A , 
 (23) S(O) 2 N(R A )R B , 
 (24) N(R A )S(O) 2 R B , 
 (25) N(R A )S(O) 2 N(R A )R B , 
 (26) N(R A )C(O)R B , 
 (27) N(R A )C(O)N(R A )R B , 
 (28) N(R A )C(O)—C(O)N(R A )R B , or 
 (29) N(R A )CO 2 R B , and 
 
 (ii) from zero to 2 substituents are each independently:
 (1) CycQ, 
 
 (2) AryQ,
 (3) HetQ, 
 (4) HetR, 
 (5) J-CycQ, 
 (6) J-AryQ, 
 (7) J-HetQ, 
 (8) J-HetR, 
 (9) C 1-6  alkyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR, 
 (10) C 2-6  alkenyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR, or 
 (11) C 2-6  alkynyl substituted with CycQ, AryQ, HetQ, HetR, J-CycQ, J-AryQ, J-HetQ, or J-HetR; 
 
 
 each CycQ is independently C 3-8  cycloalkyl or C 5-8  cycloalkenyl, wherein the cycloalkyl or cycloalkenyl is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, C 1-6  alkyl, OH, O—C 1-6  alkyl, C 1-6  haloalkyl, or O—C 1-6  haloalkyl; 
 each AryQ is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 5 substituents each of which is independently halogen, CN, NO 2 , C 1-6  alkyl, C 1-6  haloalkyl, OH, O—C 1-6  alkyl, O—C 1-6  haloalkyl, N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , SO 2 R A , SO 2 N(R A )R B , or SO 2 N(R A )C(O)R B ; 
 each HetQ is independently a heteroaryl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, C 1-6  alkyl, C 1-6  haloalkyl, OH, O—C 1-6  alkyl, O—C 1-6  haloalkyl, N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SO 2 R A , N(R A )C(O)N(R A )R B , or N(R A )CO 2 R B ; 
 each HetR is independently a 4- to 7-membered, saturated or unsaturated, non-aromatic heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O) 2 , and wherein the saturated or unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C 1-6  alkyl, OH, oxo, O—C 1-6  alkyl, C 1-6  haloalkyl, O—C 1-6  haloalkyl, C(O)N(R A )R B , C(O)R A , CO 2 R A , or SO 2 R A ; 
 each J is independently:
 (i) O, 
 (ii) S, 
 (iii) S(O), 
 (iv) S(O) 2 , 
 (v) O—C 1-6  alkylene, 
 (vi) S—C 1-6  alkylene, 
 (vii) S(O)—C 1-6  alkylene, 
 (viii) S(O) 2 —C — 6 alkylene, 
 (ix) N(R A ), or 
 (x) N(R A )—C 1-6  alkylene; 
 
 R 2  and R 3  are each independently:
 (1) H, 
 (2) C 1-6  alkyl, 
 (3) C 1-6  haloalkyl, 
 (4) C 1-6  alkyl substituted with from 1 to 3 substituents each of which is independently OH, O—C 1-6  alkyl, O—C 1-6  haloalkyl, CN, NO 2 , N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , S(O) 2 N(R A )R B , N(R A )C(O)R B , N(R A )CO 2 R B , N(R A )S(O) 2 R B , N(R A )S(O) 2 N(R A )R B , OC(O)N(R A )R B , N(R A )C(O)N(R A )R B , or N(R A )C(O)C(O)N(R A )R B , 
 (5) O—C 1-6  alkyl in which the alkyl is optionally substituted with OH, O—C 1-6  alkyl, O—C 1-6  haloalkyl, CN, N(R A )R B , C(O)N(R A )R B , C(O)R A , CO 2 R A , SR A , S(O)R A , S(O) 2 R A , or S(O) 2 N(R A )R B , 
 (6) O—C 1-6  haloalkyl, 
 (7) halogen, 
 (8) CN, 
 (9) NO 2 , 
 (10) N(R A )R B , 
 (11) C(O)N(R A )R B , 
 (12) C(O)R A , 
 (13) C(O)—C 1-6  haloalkyl, 
 (14) C(O)OR A , 
 (15) OC(O)R A , 
 (16) OC(O)N(R A )R B , 
 (17) SR A , 
 (18) S(O)R A , 
 (19) S(O) 2 R A , 
 (20) S(O) 2 N(R A )R B , 
 (21) N(R A )S(O) 2 R B , 
 (22) N(R A )S(O) 2 N(R A )R B , 
 (23) N(R A )C(O)R B , 
 (24) N(R A )C(O)N(R A )R B , 
 (25) N(R A )C(O)—C(O)N(R A )R B , 
 (26) N(R A )CO 2 R B , 
 (27) N(R C )R D , 
 (28) C(O)N(R C )R D , 
 (29) OC(O)N(R C )R D , 
 (30) S(O) 2 N(R C )R D , 
 (31) N(R A )S(O) 2 N(R C )R D , 
 (32) N(R A )C(O)N(R C )R D , 
 (33) N(R A )C(O)—C(O)N(R C )R D , 
 (34) C 3-8  cycloalkyl, 
 (35) O—C 3-8  cycloalkyl, 
 (36) AryX, or 
 (37) HetX;
 wherein AryX independently has the same definition as AryQ, and HetX independently has the same definition as HetQ; 
 
 
 R 4  is H, C 1-6  alkyl, AryZ, HetZ, halogen, CN, or C 1-6  fluoroalkyl; 
 AryZ independently has the same definition as AryQ; 
 HetZ independently has the same definition as HetQ; 
 R 5  is H or C 1-6  alkyl; 
 each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; 
 each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered heterobicyclic, fused ring system containing from 1 to 6 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O) 2 ; 
 each R A  is independently H or C 1-6  alkyl; 
 each R B  is independently H or C 1-6  alkyl; and 
 each pair of R C  and R D  together with the nitrogen to which they are both attached form a 4- to 7-membered saturated or unsaturated, non-aromatic ring which optionally contains a heteroatom in addition to the N to which R C  and R D  are attached, wherein the additional heteroatom is selected from N, O, and S; wherein the ring is optionally substituted with 1 or 2 substituents each of which is independently C 1-6  alkyl, C(O)R A , C(O)OR A , C(O)N(R A )R B , or S(O) 2 R A ; and wherein the optional S in the ring is optionally in the form of S(O) or S(O) 2 , 
 excluding 3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile and pharmaceutically acceptable salts thereof. 
 
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein AryA is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 3 substituents each of which is independently:
 (1) C 1-4  alkyl,   (2) C 1-4  haloalkyl,   (3) C 2-4  alkenyl,   (4) C 2-4  alkenyl substituted with CN,   (5) O—C 1-4  alkyl,   (6) O—C 14  haloalkyl,   (7) OH,   (8) halogen,   (9) CN,   (10) NO 2 ,   (11) N(R A )R B ,   (12) C(O)N(R A )R B ,   (13) C(O)R A ,   (14) CO 2 R A ,   (15) SR A ,   (16) S(O)R A ,   (17) SO 2 R A ,   (18) SO 2 N(R A )R B ,   (19) SO 2 N(R A )C(O)R B , or   (20) CycQ, with the proviso that no more than 2 of the substituents are CycQ;
 wherein: 
   each CycQ is C 3-7  cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1 to 3 substituents, each of which is independently halogen, C 1-4  alkyl, OH, O—C 1-4  alkyl, C 1-4  haloalkyl, or O—C 1-4  haloalkyl; and   any R A  or R B  which is part of AryA is H or C 1-4  alkyl.   
     
     
         3 . A compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, wherein AryA is phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently:
 (1) C 1-4  alkyl,   (2) C 1-4  haloalkyl,   (3) O—C 1-4  alkyl,   (4) halogen,   (5) CN,   (6) S—C 1-4  alkyl, or   (7) CycQ, with the proviso that no more than one substituent is CycQ, and wherein CycQ is C 3-7  cycloalkyl.   
     
     
         4 . A compound according to  claim 3 , or a pharmaceutically acceptable salt thereof, wherein the phenyl is optionally substituted with from 1 to 2 substituents each of which is independently:
 (1) CH 3 ,   (2) CF 3 ,   (3) CHF2,   (4) CH 2 CF 3 ,   (5) OCH 3 ,   (6) Cl,   (7) Br,   (8) F,   (9) CN,   (10) SCH 3 , or   (11) cyclopropyl, with the proviso that no more than one substituent is cyclopropyl.   
     
     
         5 . A compound according to  claim 4 , or a pharmaceutically acceptable salt thereof, wherein the phenyl is a 3,5-di-substituted phenyl. 
     
     
         6 . A compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein the 3,5-di-substituted phenyl is 3-chloro-5-cyanophenyl. 
     
     
         7 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
 R 2  and R 3  are each independently   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         V is H, CH 3 , C(O)CH 3 , C(O)OCH 3 , or S(O) 2 CH 3 ; and 
         R 4  is H, C 1-4  alkyl, Cl, Br, F, CN, or C 1-4  fluoroalkyl. 
       
     
     
         8 . A compound according to  claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
 R 2  is:
 (1) C 1-4  alkyl, 
 (2) C 1-4  haloalkyl, 
 (3) O—C 1-4  alkyl, 
 (4) O—C 1-4  halooalkyl, 
 (5) halogen, 
 (6) S—C 1-4  alkyl, or 
 (7) C 3-7  cycloalkyl; 
   R 3  is:
 (1) H, 
 (2) C 1-4  alkyl, 
 (3) C 1-4  haloalkyl, 
 (4) O—C 1-4  alkyl, 
 (5) O—C 1-4  haloalkyl, 
 (6) halogen, 
 (7) S—C 1-4  alkyl, or 
 (8) C 3-7  cycloalkyl; and 
   R 4  is H.   
     
     
         9 . A compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
 R 2  is:
 (1) C 1-4  alkyl, 
 (2) C 1-4  fluoroalkyl, 
 (3) O—C 1-4  alkyl, 
 (4) O—C 1-4  fluoroalkyl, 
 (5) Cl, 
 (6) Br, 
 (7) F, 
 (8) S—C 1-4  alkyl, or 
 (9) C 3-6  cycloalkyl; and 
   R 3  is:
 (1) C 1-4  alkyl, 
 (2) C 1-4  fluoroalkyl, 
 (3) O—C 1-4  alkyl, 
 (4) O—C 1-4  fluoroalkyl, 
 (5) Cl, 
 (6) Br, 
 (7) F, 
 (8) S—C 1-4  alkyl, or 
 (9) C 3-6  cycloalkyl. 
   
     
     
         10 . A compound according to  claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
 R 2  is:
 (1) CH 3 , 
 (2) CF 3 , 
 (3) CF 2 CH 3 , 
 (4) CH 2 CF 3 , 
 (5) OCH 3 , 
 (6) OCF 3 , 
 (7) Cl, 
 (8) Br, 
 (9) F, 
 (10) SCH 3 , or 
 (11) cyclopropyl; and 
   R 3  is:
 (1) H, 
 (2) CH 3 , 
 (3) CF 3 , 
 (4) CF 2 CH 3 , 
 (5) CH 2 CF 3 , 
 (6) OCH 3 , 
 (7) OCF 3 , 
 (8) Cl, 
 (9) Br, 
 (10) F, 
 (11) SCH 3 , or 
 (12) cyclopropyl. 
   
     
     
         11 . A compound according to  claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 3  is H, Cl, Br, or F. 
     
     
         12 . A compound according to  claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 2  is:
 (1) CF 3 ,   (3) Cl, or   (5) Br.   
     
     
         13 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is H or C 1-4  alkyl. 
     
     
         14 . A compound according to  claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 5  is H or C 1-3  alkyl. 
     
     
         15 . A compound according to  claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 5  is H, CH 3 , or CH 2 CH 3 . 
     
     
         16 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  and X 2  are each independently:
 (1) H, 
 (2) C 1-4  alkyl, 
 (3) C 1-4  haloalkyl, 
 (4) C 2-4  alkenyl, 
 (5) C 2-4  alkenyl substituted with CN, 
 (6) OH, 
 (7) O—C 1-4  alkyl, 
 (8) O—C 1-4  haloalkyl, 
 (9) halogen, 
 (10) CN, 
 (11) NO 2 , 
 (12) N(R A )R B , 
 (13) C(O)N(R A )R B , 
 (14) C(O)R A , 
 (15) CO 2 R A , 
 (16) SR A , 
 (17) S(O)R A , 
 (18) SO 2 R A , 
 (19) SO 2 N(R A )R B , 
 (20) SO 2 N(R A )C(O)R B , or 
 (21) CycQ; wherein: 
 each CycQ is C 3-7  cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1 to 3 substituents, each of which is independently halogen, C 1-4  alkyl, OH, O—C 1-4  alkyl, C 1-4  haloalkyl, or O—C 1-4  haloalkyl; 
 
 R 2  and R 3  are each independently: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each V is independently H, CH 3 , C(O)CH 3 , C(O)OCH 3 , or S(O) 2 CH 3 ; 
         R 5  is H or C 1-4  alkyl; 
         each R A  is independently H or C 1-4  alkyl; and 
         each R B  is independently H or C 1-4  alkyl. 
       
     
     
         17 . A compound according to  claim 16 , or a pharmaceutically acceptable salt thereof, wherein:
 X 1  and X 2  are each independently:
 (1) C 1-4  alkyl, 
 (2) C 1-4  fluoroalkyl, 
 (3) O—C 1-4  alkyl, 
 (4) halogen, 
 (5) CN, 
 (6) S—C 1-4  alkyl, or 
 (7) CycQ; 
 and provided that
 (i) no more than one substituent is CycQ, and wherein CycQ is C 3-7  cycloalkyl; and 
 (ii) at least one of X 1  and X 2  is other than H; 
 
   R 2  is:
 (1) C 1-4  alkyl, 
 (2) C 1-4  fluoroalkyl, 
 (3) O—C 1-4  alkyl, 
 (4) O—C 1-4  fluoroalkyl, 
 (5) halogen, 
 (6) S—C 1-4  alkyl, or 
 (7) C 3-7  cycloalkyl; 
   R 3  is:
 (1) H, 
 (2) C 1-4  alkyl, 
 (3) C 1-4  haloalkyl, 
 (4) O—C 1-4  alkyl, 
 (5) O—C 1-4  fluoroalkyl, 
 (6) halogen, 
 (7) S—C 1-4  alkyl, or 
 (8) C 3-7  cycloalkyl; and 
   R 5  is H or C 1-3  alkyl.   
     
     
         18 . A compound according to  claim 17 , or a pharmaceutically acceptable salt thereof, wherein:
 X 1  and X 2  are each independently:
 (1) Cl, 
 (2) Br, 
 (3) F, 
 (4) CN, 
 (5) CH 3 , 
 (6) CHF 2 , 
 (7) CF 3 , 
 (8) OCH 3 , 
 (9) SCH 3 , or 
 (10) cyclopropyl, with the proviso that no more than one substituent is cyclopropyl. 
   R 2  is:
 (1) CH 3 , 
 (2) CF 3 , 
 (3) CF 2 CH 3 , 
 (4) CH 2 CF 3 , 
 (5) OCH 3 , 
 (6) OCF 3 , 
 (7) Cl, 
 (8) Br, 
 (9) F, 
 (10) SCH 3 , or 
 (11) cyclopropyl; 
   R 3  is:
 (1) H, 
 (2) CH 3 , 
 (3) CF 3 , 
 (4) CF 2 CH 3 , 
 (5) CH 2 CF 3 , 
 (6) OCH 3 , 
 (7) OCF 3 , 
 (8) Cl, 
 (9) Br, 
 (10) F, 
 (11) SCH 3 , or 
 (12) cyclopropyl; and 
   R 5  is H, CH 3 , or CH 2 CH 3 .   
     
     
         19 . A compound according to  claim 18 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound according to  claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 3  is H, Cl, Br or F. 
     
     
         21 . A compound according to  claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 5  is CH 3  or CH 2 CH 3 . 
     
     
         22 . A compound according to  claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 3  is H. 
     
     
         23 . A compound of Formula I according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         24 . A pharmaceutical composition comprising an effective amount of the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         25 . A method for the prophylaxis or treatment of infection by HIV or for the prophylaxis, treatment, or delay in the onset of AIDS in a subject in need thereof which comprises administering to the subject an effective amount of the compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method of  claim 25 , further comprising administering to the subject a second HIV antiviral agent selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors. 
     
     
         27 . (canceled)