HIV protease inhibitors

摘要

Compounds of Formula I are disclosed wherein R1, R2, R3A, R3B, R4A, R4B, R5A, R5B, R6A, R6B, R7, R8 and R9 are defined herein. The compounds encompassed by Formula I include compounds which are HIV protease inhibitors and other compounds which can be metabolized in vivo to HIV protease inhibitors. The compounds and their pharmaceutically acceptable salts are useful for the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment, or delay in the onset 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.;

主权项

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:
R1 is C1-6 alkyl, C1-6 fluoroalkyl, CycA, AryA, C1-6 alkyl substituted with CycA, HetA, C1-6 alkyl substituted with HetA, or C1-6 alkyl substituted with AryA; R2 is C(O)OH, C(O)NH2, C(O)NH—C1-6 alkyl, or CH(RJ)—Z, wherein:
Z is OH, NH2, or ORP;RJ is H, C1-6 alkyl, C1-6 fluoroalkyl, or C1-6 alkyl substituted with C3-5 cycloalkyl;RP is PO(OH)O−.M+; PO(O−)2.2M+; PO(O−)2.M2+; or C(O)RQ;M+ is a pharmaceutically acceptable monovalent counterion;M2+ is a pharmaceutically acceptable divalent counterion; andRQ is:
(1) C1-6 alkyl,(2) C3-6 cycloalkyl,(3) C1-6 alkyl substituted with C3-6 cycloalkyl,(4) O—C1-6 alkyl,(5) O—C1-6 alkyl substituted with O—C1-6 alkyl,(6) O—C1-6 fluoroalkyl,(7) C(O)O—C1-6 alkyl,(8) C(O)—C1-6 alkylene-N(H)—C1-6 alkyl,(9) C(O)—C1-6 alkylene-N(—C1-6 alkyl)2,(10) C1-6 alkyl substituted with C(O)O—C1-6 alkyl,(11) C1-6 alkyl substituted with C(O)OH,(12) C1-6 alkyl substituted with C(O)—C1-6 alkyl,(13) N(H)—C1-6 alkyl,(14) N(—C1-6 alkyl)2,(15) C1-6 alkyl substituted with NH2, N(H)—C1-6 alkyl, or N(—C1-6 alkyl)2,(16) AryA,(17) C1-6 alkyl substituted with AryA,(18) O—C1-6 alkyl substituted with AryA,(19) HetA,(20) C1-6 alkyl substituted with HetA,(21) O—C1-6 alkyl substituted with HetA,(22) HetB, or(23) O-HetB; R3A and R3B are each independently H, Cl, F, C1-6 alkyl, C1-6 fluoroalkyl, or C1-6 alkyl substituted with C3-6 cycloalkyl, wherein the cycloalkyl is unsubstituted, or substituted with from 1 to 4 substituents each of which is independently Cl, F, or C1-6 alkyl; R4A and R4B are each independently H, Cl, F, C1-6 alkyl, C1-6 fluoroalkyl, or C1-6 alkyl substituted with C3-6 cycloalkyl, wherein the cycloalkyl is unsubstituted, or substituted with from 1 to 4 substituents each of which is independently Cl, F, or C1-6 alkyl; R5A and R5B are each independently H, C1-6 alkyl, C1-6 fluoroalkyl, C1-6 alkyl substituted with OH, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or C1-6 alkyl substituted with C3-6 cycloalkyl, wherein the cycloalkyl is unsubstituted, or substituted with from 1 to 4 substituents each of which is independently Cl, F, or C1-6 alkyl; alternatively, R5A and R5B together with the carbon atom to which they are both attached form C3-6 cycloalkyl; and provided that at least one of R3A, R3B, R4A, and R4B is F or Cl; R6A is:wherein the asterisk (*) denotes the point of attachment to the rest of the compound;
R6B is H or C1-6 alkyl; alternatively, R6A and R6B together with the carbon to which they are attached form a C3-6 cycloalkyl which is unsubstituted, or substituted with phenyl, wherein the phenyl is unsubstituted, or substituted with from 1 to 3XB; each XB and each XC are independently selected from the group consisting of:
(1) C1-6 alkyl,(2) C3-6 cycloalkyl,(3) C1-6 haloalkyl,(4) OH,(5) O—C1-6 alkyl,(6) O—C1-6 haloalkyl,(7) O—C3-6 cycloalkyl,(8) SH,(9) S—C1-6 alkyl,(10) S—C1-6 haloalkyl,(11) S—C3-6 cycloalkyl,(12) halo,(13) CN,(14) NO2,(15) NH2,(16) N(H)—C1-6 alkyl,(17) N(—C1-6 alkyl)2,(18) N(H)C(O)—C1-6 alkyl,(19) N(H)CH(O),(20) CH(O),(21) C(O)—C1-6 alkyl,(22) C(O)OH,(23) C(O)O—C1-6 alkyl,(24) SO2H,(25) SO2—C1-6 alkyl; and(26) C1-6 alkyl substituted with:
(a) C1-6 haloalkyl,(b) OH(c) O—C1-6 alkyl,(d) O—C1-6 haloalkyl,(e) O—C3-6 cycloalkyl,(f) SH,(g) S—C1-6 alkyl,(h) halo,(i) CN,(j) NO2,(k) NH2,(l) N(H)—C1-6 alkyl,(m) N(—C1-6 alkyl)2,(n) C(O)—C1-6 alkyl,(o) C(O)OH,(p) C(O)O—C1-6 alkyl, or(q) SO2—C1-6 alkyl; T is O, S, S(O), or SO2; m is an integer equal to 0, 1, 2, or 3; n is an integer equal to 0, 1, 2, or 3; R7 is H, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkyl substituted with C3-6 cycloalkyl, or C(O)—RK; R8 is H or C1-6 alkyl; RK is:
(1) C1-6 alkyl,(2) C3-6 cycloalkyl,(3) C1-6 alkyl substituted with C3-6 cycloalkyl,(4) O—C1-6 alkyl,(5) O—C1-6 alkyl substituted with O—C1-6 alkyl,(6) O—C1-6 fluoroalkyl,(7) C(O)O—C1-6 alkyl,(8) C1-6 alkyl substituted with C(O)O—C1-6 alkyl,(9) C1-6 alkyl substituted with C(O)OH,(10) C1-6 alkyl substituted with C(O)—C1-6 alkyl,(11) N(H)—C1-6 alkyl,(12) N(—C1-6 alkyl)2,(13) C1-6 alkyl substituted with NH2, N(H)—C1-6 alkyl, or N(—C1-6 alkyl)2,(14) AryA,(15) C1-6 alkyl substituted with AryA,(16) O—C1-6 alkyl substituted with AryA,(17) HetA,(18) C1-6 alkyl substituted with HetA,(19) O—C1-6 alkyl substituted with HetA,(20) HetB,(21) O-HetB, or(22) O—C1-6 alkyl substituted with HetB; R9 is AryQ or HetQ; AryQ is an aryl which is independently phenyl or naphthyl, wherein the phenyl or naphthyl is unsubstituted, or substituted with from 1 to 4XA each of which is independently:
(1) C1-6 alkyl,(2) C3-6 cycloalkyl,(3) C1-6 haloalkyl,(4) OH(5) O—C1-6 alkyl,(6) O—C1-6 haloalkyl,(7) O—C3-6 cycloalkyl,(8) SH,(9) S—C1-6 alkyl,(10) S—C1-6 haloalkyl,(11) S—C3-6 cycloalkyl,(12) halo,(13) CN,(14) NO2,(15) NH2,(16) N(H)—C1-6 alkyl,(17) N(—C1-6 alkyl)2,(18) N(H)C(O)—C1-6 alkyl,(19) N(H)CH(O),(20) CH(O),(21) C(O)—C1-6 alkyl,(22) C(O)OH,(23) C(O)O—C1-6 alkyl,(24) SO2H,(25) SO2—C1-6 alkyl, or(26) C1-6 alkyl substituted with:
(a) C3-6 cycloalkyl,(b) C1-6 haloalkyl,(c) OH(d) O—C1-6 alkyl,(e) O—C1-6 haloalkyl,(f) O—C3-6 cycloalkyl,(g) SH,(h) S—C1-6 alkyl,(i) S—C1-6 haloalkyl,(j) S—C3-6 cycloalkyl,(k) halo,(l) CN,(m) NO2,(n) NH2,(o) N(H)—C1-6 alkyl,(p) N(—C1-6 alkyl)2,(q) N(H)C(O)—C1-6 alkyl,(r) N(H)CH(O),(s) CH(O),(t) C(O)—C1-6 alkyl,(u) C(O)OH,(v) C(O)O—C1-6 alkyl,(w) SO2H, or(x) SO2—C1-6 alkyl; HetQ is a heteroaryl which 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, and wherein at least one of the rings is aromatic, each N in a ring is optionally in the form of an oxide, and each S is optionally S(O) or S(O)2; and wherein the heteroaryl is unsubstituted, or substituted with from 1 to 4XA substituents each of which is independently as set forth in the definition of AryQ; CycA is a C3-7 cycloalkyl which is unsubstituted, or substituted with from 1 to 4 substituents each of which is independently Cl, F, or C1-6 alkyl; each AryA is an aryl which is independently phenyl or naphthyl, wherein the phenyl or naphthyl is unsubstituted, or substituted with from 1 to 4YB wherein each YB independently has the same definition as XB; each HetA is a heteroaryl which is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (ii) is a fused, 9- or 10-membered heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, and wherein at least one of the rings is aromatic, each N in a ring is optionally in the form of an oxide, and each S is optionally S(O) or S(O)2; wherein the heteroaromatic ring (i) or the heterobicyclic ring (ii) is unsubstituted, or substituted with from 1 to 4 YC wherein each YC independently has the same definition as XB; each HetB 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 unsubstituted, or 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)NH2, C(O)N(H)—C1-6 alkyl, C(O)N(—C1-6 alkyl)2, C(O)H, C(O)—C1-6 alkyl, CO2H, CO2—C1-6 alkyl, SO2H, or SO2—C1-6 alkyl.