US 2010/0168097 A1 · Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

Compounds of Formula I: Formula (I); are HIV reverse transcriptase inhibitors, wherein R1, R2, R3, R4 and R5 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, 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.

A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:
R1 is:
(1) halogen,
(2) CN,
(3) NO2,
(4) C(O)RA,
(5) C(O)ORA,
(6) C(O)N(RA)RB,
(7) SRA,
(8) S(O)RA,
(9) S(O)2RA,
(10) S(O)2N(RA)RB,
(11) N(RA)RB,
(12) N(RA)S(O)2RB,
(13) N(RA)C(O)RB,
(14) N(RA)C(O)ORB,
(15) N(RA)S(O)2N(RA)RB,
(16) OC(O)N(RA)RB,
(17) N(RA)C(O)N(RA)RB,
(18) C1-6 alkyl,
(19) C1-6 haloalkyl,
(20) C2-6 alkenyl,
(21) C2-6 alkynyl,
(22) OH,
(23) O—C1-6 alkyl,
(24) O—C1-6 haloalkyl,
(25) C1-6 alkyl substituted with OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, or N(RA)C(O)N(RA)RB,
(26) CycA,
(27) AryA,
(28) HetA,
(29) HetR,
(30) C1-6 alkyl substituted with CycA, AryA, HetA, or HetR,
(31) J-CycA,
(32) J-AryA,
(33) J-HetA, or
(34) J-HetR;
J is:
(1) O,
(2) S,
(3) S(O),
(4) S(O)2,
(5) O—C1-6 alkylene,
(6) S—C1-6 alkylene,
(7) S(O)—C1-6 alkylene,
(8) S(O)2—C1-6 alkylene,
(9) N(RA),
(10) N(RA)—C1-6 alkylene,
(11) C(O),
(12) C(O)—C1-6 alkylene,
(13) C(O)—C1-6 alkylene-O,
(14) C(O)N(RA),
(15) C(O)N(RA)—C1-6 alkylene,
(16) C(O)N(RA)—C1-6 alkylene-C(O)O, or
(17) C(O)N(RA)S(O)2;
CycA is C3-8 cycloalkyl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
(i) from zero to 6 substituents are each independently:
(1) halogen,
(2) CN
(3) C1-6 alkyl,
(4) OH,
(5) O—C1-6 alkyl,
(6) C1-6 haloalkyl, or
(7) O—C1-6 haloalkyl, and
(ii) from zero to 2 substituents are each independently:
(1) CycE,
(2) AryE,
(3) O-AryE,
(4) HetE,
(5) HetF, or
(6) C1-6 alkyl substituted with CycE, AryE, O-AryE, HetE, O-HetE, or HetF;
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) C1-6 alkyl,
(2) C1-6 alkyl substituted with OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(3) O—C1-6 alkyl,
(4) C1-6 haloalkyl,
(5) O—C1-6 haloalkyl,
(6) OH,
(7) halogen,
(8) CN,
(9) NO2,
(10) N(RA)RB,
(11) C(O)N(RA)RB,
(12) C(O)RA,
(13) C(O)—C1-6 haloalkyl,
(14) C(O)ORA,
(15) OC(O)N(RA)RB,
(16) SRA,
(17) S(O)RA,
(18) S(O)2RA,
(19) S(O)2N(RA)RB,
(20) N(RA)S(O)2RB,
(21) N(RA)S(O)2N(RA)RB,
(22) N(RA)C(O)RB,
(23) N(RA)C(O)N(RA)RB,
(24) N(RA)C(O)—C(O)N(RA)RB, or
(25) N(RA)CO2RB, and
(ii) from zero to 2 substituents are each independently:
(1) CycE,
(2) AryE,
(3) O-AryE,
(4) HetE,
(5) HetF, or
(6) C1-6 alkyl substituted with CycE, AryE, O-AryE, HetE, O-HetE, or HetF;
HetA is heteroaryl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
(i) from zero to 6 substituents are each independently:
(1) C1-6 alkyl,
(2) C1-6 alkyl substituted with OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, S(O)2RA, S(O)2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S(O)2RB, N(RA)S(O)2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB,
(3) C1-6 alkyl substituted with from 2 to 4 OH,
(4) O—C1-6 alkyl,
(5) C1-6 haloalkyl,
(6) O—C1-6 haloalkyl,
(7) OH,
(8) oxo,
(9) halogen,
(10) CN,
(11) NO2,
(12) N(RA)RB,
(13) C(O)N(RA)RB,
(14) C(O)RA,
(15) C(O)—C1-6 haloalkyl,
(16) C(O)ORA,
(17) OC(O)N(RA)RB,
(18) SRA,
(19) S(O)RA,
(20) S(O)2RA,
(21) S(O)2N(RA)RB,
(22) N(RA)S(O)2RB,
(23) N(RA)S(O)2N(RA)RB,
(24) N(RA)C(O)RB,
(25) N(RA)C(O)N(RA)RB,
(26) N(RA)C(O)—C(O)N(RA)RB, or
(27) N(RA)CO2RB, and
(ii) from zero to 2 substituents are each independently:
(1) CycE,
(2) AryE,
(3) O-AryE,
(4) HetE,
(5) HetF, or
(6) C1-6 alkyl substituted with CycE, AryE, O-AryE, HetE, O-HetE, or HetF;
HetR is (i) a 4- to 7-membered, saturated or mono-unsaturated 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 or (ii) a 6- to 10-membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing 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 mono-unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents, wherein:
(i) from zero to 4 substituents are each independently halogen, CN, C1-6 alkyl, OH, oxo, C(O)RA, CO2RA, S(O)RA, SRA, S(O)2RA, O—C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylene-CN, C1-6 alkylene-OH, or C1-6 alkylene-O—C1-6 alkyl;
and
(ii) from zero to 2 substituents are each independently CycE, AryE, HetE, HetF, or C1-6 alkyl substituted with CycE, AryE, HetE, or HetF;
R2 is:
(1) C1-6 alkyl,
(2) C1-6 haloalkyl,
(3) C1-6 alkyl substituted with OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, SO2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO2RB, N(RA)SO2N(RA)RB, OC(O)N(RA)RB, or N(RA)C(O)N(RA)RB,
(3) CycB,
(4) AryB,
(5) HetB,
(6) HetS,
(7) C1-6 alkyl substituted with CycB, AryB, HetB, or HetS,
(8) N(RA)—C1-6 alkyl,
(9) N(RA)—C1-6 alkyl, wherein the alkyl is substituted with OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, SO2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO2RB, N(RA)SO2N(RA)RB, OC(O)N(RA)RB, or N(RA)C(O)N(RA)RB, with the proviso that the OH, O—C1-6 alkyl, or O—C1-6 haloalkyl is not attached to the carbon in C1-6 alkyl that is directly attached to the rest of the molecule,
(10) N(RA)-CycB,
(11) N(RA)-AryB,
(12) N(RA)-HetB, or
(13) N(RA)—C1-6 alkyl, wherein the alkyl is substituted with CycB, AryB, HetB, or HetS;
CycB independently has the same definition as CycA;
AryB independently has the same definition as AryA;
HetB independently has the same definition as HetA;
HetS independently has the same definition as HetR;
R3 is HetC, wherein HetC independently has the same definition as HetA;
R4 is H, C1-6 alkyl, C(O)C1-6 alkyl, C(O)-CycD, C(O)-AryD, C(O)-HetD, or C(O)HetU;
CycD independently has the same definition as CycA;
AryD independently has the same definition as AryA;
HetD independently has the same definition as HetA;
HetU independently has the same definition as HetR;
R5 is H or independently has the same definition as R1;
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 bicyclic, fused ring system containing from 1 to 4 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 CycE is independently C3-8 cycloalkyl which is optionally substituted with a total of from 1 to 4 substituents, wherein:
(i) from zero to 4 substituents are each independently halogen, C1-6 alkyl, OH, O—C1-6 alkyl, C1-6 haloalkyl, or O—C1-6 haloalkyl, and
(ii) from zero to 2 substituents are each independently CycG, AryG, HetG, HetH, or C1-6 alkyl substituted with CycG, AryG, O-AryG, HetG, or HetH;
each AryE is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with a total of from 1 to 5 substituents, wherein:
(i) from zero to 5 substituents are each independently halogen, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, OH, O—C1-6 alkyl, O—C1-6 haloalkyl, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, SO2N(RA)RB, or SO2N(RA)C(O)RB, and
(ii) from zero to 2 substituents are each independently CycG, AryG, HetG, HetH, or C1-6 alkyl substituted with CycG, AryG, O-AryG, HetG, or HetH;
each HetE 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 fused heterobicyclic ring selected from 2,3-dihydrobenzo-1,4-dioxinyl and benzo-1,3-dioxolyl;
and wherein the heteroaromatic ring or the heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents wherein:
(i) from zero to 4 substituents are each independently halogen, C1-6 alkyl, C1-6 haloalkyl, O—C1-6 alkyl, O—C1-6 haloalkyl, OH, C(O)RA, CO2RA, SO2RA, N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)CO2RB, and
(ii) from zero to 2 substituents are each independently CycG, AryG, HetG, HetH, or C1-6 alkyl substituted with CycG, AryG, O-AryG, HetG, or HetH;
each HetF is independently a 4- to 7-membered, saturated or mono-unsaturated 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 mono-unsaturated heterocyclic ring is optionally substituted with a total of from 1 to 4 substituents, wherein:
(i) from zero to 4 substituents are each independently halogen, CN, C1-6 alkyl, OH, oxo, O—C1-6 alkyl, C1-6 haloalkyl, O—C1-6 haloalkyl, C(O)RA, CO2RA, or SO2RA, and
(ii) from zero to 2 substituents are each independently CycG, AryG, HetG, HetH, or C1-6 alkyl substituted with CycG, AryG, O-AryG, HetG, or HetH;
each CycG is independently C3-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, C1-6 alkyl, OH, O—C1-6 alkyl, C1-6 haloalkyl, or O—C1-6 haloalkyl;
each AryG 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, NO2, C1-6 alkyl, C1-6 haloalkyl, OH, O—C1-6 alkyl, O—C1-6 haloalkyl, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, SO2N(RA)RB, or SO2N(RA)C(O)RB;
each HetG is independently 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, and wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, C1-6 alkyl, C1-6 haloalkyl, O—C1-6 alkyl, O—C1-6 haloalkyl, OH, C(O)RA, CO2RA, SO2RA, N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)CO2RB;
each HetH is independently a 4- to 7-membered, saturated or mono-unsaturated 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 mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, CN, C1-6 alkyl, OH, oxo, O—C1-6 alkyl, C1-6 haloalkyl, O—C1-6 haloalkyl, C(O)RA, CO2RA, or SO2RA;
each RA is independently H or C1-6 alkyl;
and
each RB is independently H or C1-6 alkyl;
and with the proviso that:
(A) when R1 is halogen, R2 is AryB and AryB is unsubstituted phenyl or phenyl substituted with from 1 to 5 substituents each of which is independently halogen, NO2, CN, C1-4 alkyl, O—C1-4 alkyl, C1-4 alkylamino, sulfonamido, or C1-4 haloalkyl having to 3 halogen substituents, R4 is H, and R5 is H, then R3 is not (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, and wherein the heteroaromatic ring is unsubstituted or substituted with one or more substituents each of which is independently amino, C1-4 alkyl, C1-4 alkylamino, halogen, sulfonamido, CN, C3-5 cycloalkyl, or C1-4 haloalkyl having from 1 to 3 halogen substituents or (ii) 4,5,6,7-hexahydrobenzimidazol-2-yl.

192 more elements

Non-Nucleoside Reverse Transcriptase Inhibitors

Life of this patent

Non-Nucleoside Reverse Transcriptase Inhibitors

Life of this patent

Abstract

Claims19