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US 7,741,315 B2Granted
HIV integrase inhibitors
AssigneeMerck Sharp & Dohme Corp.
InventorsJoseph P. Vacca, John S. Wai, Linda S. Payne, Richard C. A. Isaacs, Richard Pracitto
Life of this patent
Estimating the term…
Abstract
Tricyclic compounds of Formula (I) are inhibitors of HIV integrase and inhibitors of HIV replication: wherein bond a, ring A, R1, R2 and R3 are defined herein. The compounds are useful for the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment, or delay in the onset of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.
Claims12
A compound of Formula I, or a pharmaceutically acceptable salt thereof:
- wherein:
- bond in the ring is a single bond or a double bond;
- R1 is C1-6 alkyl, RJ, or C1-6 alkyl substituted with RJ, wherein RJ is CycA, AryA, HetA, or HetP;
- R2 is H or C1-6 alkyl;
- R3 is:
- (1) H,
- (2) halogen,
- (3) CN,
- (4) C1-6 alkyl,
- (5) C1-6 haloalkyl,
- (6) C1-6 alkyl substituted with OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, C(O)—N(RA)—C1-6 alkylene-ORB with the proviso that the N(RA) moiety and the ORB moiety are not both attached to the same carbon of the C1-6 alkylene moiety, SRA, S(O)RA, SO2RA, SO2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO2RB, N(RA)SO2N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB,
- (7) C(O)RA,
- (8) CO2RA,
- (9) C(O)N(RA)RB,
- (10) C(O)—N(RA)—C1-6 alkylene-ORB with the proviso that the N(RA) moiety and the ORB moiety are not both attached to the same carbon of the C1-6 alkylene moiety,
- (11) SRA,
- (12) S(O)RA,
- (13) SO2RA,
- (14) SO2N(RA)RB,
- (15) N(RA)RB,
- (16) N(RA)C(O)RB,
- (17) N(RA)C(O)ORB;
- (18) N(RA)C(O)N(RA)RB,
- (19) N(RA)C(O)C(O)N(RA)RB,
- (20) N(RA)SO2RB,
- (21) N(RA)SO2N(RA)RB,
- (22) OC(O)N(RA)RB, or
- (23) Y—RK, wherein:
- Y is a single bond, C1-6 alkylene, O, O—C1-6 alkylene, C1-6 alkylene-O, C(O), C(O)—C1-6 alkylene, C1-6 alkylene-C(O), C(O)—C1-6 alkylene-O, C(O)—C1-6 alkylene-O—C1-6 alkylene, C(O)N(RA), C(O)N(RA)—C1-6 alkylene, C1-6 alkylene-C(O)N(RA), C1-6 alkylene-C(O)N(RA)—C1-6 alkylene, S(O), S(O)2, S(O)—C1-6 alkylene, S(O)2—C1-6 alkylene, C1-6 alkylene-S(O), or C1-6 alkylene-S(O)2;
- and
- RK is CycB, AryB, HetB, or HetQ;
- or, as an alternative, when bond is a double bond, R2 and R3 together with the carbon atoms to which each is attached form:
- (i) a benzene ring which is optionally substituted with a total of from 1 to 4 substituents wherein (a) from zero to 4 substituents are each independently one of substituents (1) to (25) as defined in part (i) of the definition of AryA and (b) from zero to 2 substituents are each independently one of the substituents (1) to (6) as defined in part (ii) of the definition of AryA, or
- (ii) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with a total of from 1 to 3 substituents wherein (a) from zero to 3 substituents are each independently one of substituents (1) to (26) as defined in part (i) of the definition of HetA and (b) from zero to 2 substituents are each independently one of the substituents (1) to (6) as defined in part (ii) of the definition of HetA;
- ring A is an 8-membered, saturated or mono-unsaturated heterocyclic ring containing in addition to the nitrogen shared with the naphthyridine ring from 1 to 3 heteroatoms independently selected from N, O, and S, wherein 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 6 substituents, wherein:
- (i) from zero to 6 substituents are each independently:
- (1) halogen,
- (2) C1-6 alkyl,
- (3) C1-6 haloalkyl,
- (4) C1-6 alkyl substituted with OH, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, C(O)—N(RA)—C1-6 alkylene-ORB with the proviso that the N(RA) moiety and the ORB moiety are not both attached to the same carbon of the C1-6 alkylene moiety, SRA, S(O)RA, SO2RA, SO2N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO2RB, N(RA)SO2N(RA)RB, N(RA)C(O)N(RA)RB, OC(O)N(RA)RB, or OC(O)RA,
- (5) O—C1-6 alkyl,
- (6) O—C1-6 haloalkyl,
- (7) oxo,
- (8) C(RA)RB,
- (9) C(O)N(RA)RB,
- (10) C(O)C(O)N(RA)RB,
- (11) C(O)RA,
- (12) CO2RA,
- (13) SRA,
- (14) S(O)RA,
- (15) SO2RA,
- (16) SO2N(RA)RB, or
- (17) OH, and
- (ii) from zero to 2 substituents are each Z—RL, wherein:
- each Z is independently a single bond, C1-6 alkylene, O, O—C1-6 alkylene, C1-16 alkylene-O, C(O), C(O)—C1-6 alkylene, C1-6 alkylene-C(O), C(O)—C1-6 alkylene-O, C(O)—C1-6 alkylene-O—C1-6 alkylene, C(O)N(RA), C(O)N(RA)—C1-6 alkylene, C1-6 alkylene-C(O)N(RA), C1-6 alkylene-C(O)N(RA)—C1-6 alkylene, S(O), S(O)2, S(O)—C1-6 alkylene, S(O)2—C1-6 alkylene, C1-6 alkylene-S(O), or C1-6 alkylene-S(O)2;
- and
- each RL is independently CycC, AryC, HetC, or HetR;
- each RA is independently H or C1-6 alkyl;
- each RB is independently H or C1-6 alkyl;
- CycA is a 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) CycD,
- (2) AryD,
- (3) HetD,
- (4) HetZ,
- (5) C1-6 alkyl substituted with CycD, AryD, HetD, or HetZ, or
- (6) C(O)—HetZ or C(O)C(O)-HetZ;
- CycB independently has the same definition as CycA;
- each CycC independently has the same definition as CycA;
- AryA is an aryl which is optionally substituted with a total of from 1 to 5 substituents, wherein:
- (i) from zero to 5 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, 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, 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) SO2RA,
- (19) SO2N(RA)RB,
- (20) N(RA)SO2RB,
- (21) N(RA)SO2N(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) CycD,
- (2) AryD,
- (3) HetD,
- (4) HetZ,
- (5) C1-6 alkyl substituted with CycD, AryD, HetD, or HetZ, or
- (6) C(O)-HetZ or C(O)C(O)—HetZ;
- AryB independently has the same definition as AryA;
- each AryC independently has the same definition as AryA;
- HetA is a heteroaryl which is optionally substituted with a total of from 1 to 5 substituents, wherein:
- (i) from zero to 5 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, 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, 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) oxo,
- (8) halogen,
- (9) CN,
- (10) NO2,
- (11) N(RA)RB,
- (12) C(O)N(RA)RB,
- (13) C(O)RA,
- (14) C(O)—C1-6 haloalkyl,
- (15) C(O)ORA,
- (16) OC(O)N(RA)RB,
- (17) SRA,
- (18) S(O)RA,
- (19) SO2RA,
- (20) SO2N(RA)RB,
- (21) N(RA)SO2RB,
- (22) N(RA)SO2N(RA)RB,
- (23) N(RA)C(O)RB,
- (24) N(RA)C(O)N(RA)RB,
- (25) N(RA)C(O)C(O)N(RA)RB, or
- (26) N(RA)CO2RB, and
- (ii) from zero to 2 substituents are each independently:
- (1) CycD,
- (2) AryD,
- (3) HetD,
- (4) HetZ,
- (5) C1-6 alkyl substituted with CycD, AryD, HetD, or HetZ, or
- (6) C(O)—HetZ or C(O)C(O)-HetZ;
- HetB independently has the same definition as HetA;
- each HetC independently has the same definition as HetA;
- HetP 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, C1-6 alkyl, C1-6 haloalkyl, O—C1-6 alkyl, O—C1-6 haloalkyl, oxo, C(O)N(RA)RB, C(O)C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, or SO2N(RA)RB, and
- (ii) from zero to 2 substituents are each independently CycD, AryD, HetD, or C1-6 alkyl substituted with CycD, AryD, HetD;
- HetQ independently has the same definition as HetP;
- each HetR independently has the same definition as HetP;
- each CycD is independently a 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, or C1-6 haloalkyl;
- each AryD is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (25) as set forth above in part (i) of the definition of AryA;
- each HetD is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently any one of the substituents (1) to (26) as set forth above in part (i) of the definition of HetA;
- each HetZ 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, wherein the saturated or mono-unsaturated heterocyclic 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, oxo, C(O)N(RA)RB, C(O)C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, or SO2N(RA)RB;
- each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic 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;
- and
- 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.
161 more elements
Dependencies are inferred from the claim text.