US 2011/0257162 A1 · HIV INTEGRASE INHIBITORS

Abstract

Compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: wherein m, n, X, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 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.

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

wherein:
X is N(RK);
RK is:
(1) H,
(2) C1-6 alkyl,
(3) C1-6 alkyl substituted with T, wherein T is CO2RA, CN, SO2RA, N(RD)RE, C(O)N(RD)RE, N(RA)—C(O)C(O)—N(RD)RE, N(RA)—C(O)RB, N(RA)—SO2RB, N(RA)—SO2N(RD)RE, or N(RA)—CO2RB,
(4) C1-6 haloalkyl,
(5) C(O)RA,
(6) C(O)—C1-6 haloalkyl,
(7) CO2RA,
(8) C(O)—U,
(9) C(O)—C1-6 alkylene-U,
(10) C(O)N(RD)RE,
(11) C(O)—C1-6 alkylene-N(RD)RE,
(12) C(O)C(O)—U,
(13) C(O)C(O)—C1-6 alkylene-U,
(14) C(O)C(O)—N(RD)RE,
(15) C(O)C(O)—C1-6 alkylene-N(RD)RE,
(16) SO2RA,
(17) SO2—U,
(18) SO2—C1-6 alkylene-U,
(19) SO2N(RD)RE,
(20) CycB,
(21) C1-6 alkyl substituted with U, or
(22) C1-6 alkyl substituted with C(O)N(RA)—C1-6 alkylene-U,
wherein U is CycB, AryB, or HetB;
m and n are each 1;
R1 is:
(1) H,
(2) C1-6 alkyl,
(3) C1-6 haloalkyl,
(4) C1-6 alkyl substituted with V, wherein V is OH, O—C1-6 alkyl, O—C1-6 haloalkyl, SRA, S(O)RA, SO2RA, N(RD)RE, C(O)N(RD)RE, N(RA)—C(O)C(O)—N(RD)RE, N(RA)—C(O)RE, N(RA)—SO2RB, N(RA)—C1-6 alkylene-SO2RB, N(RA)C(O)—C1-6 alkylene-SO2RB, N(RA)—SO2N(RD)RE, N(RA)—CO2RB, or N(RA)—C(O)N(RD)RE,
(5) C1-6 alkyl substituted with W, wherein W is CycA, AryA, HetA, O—C1-6 alkylene-CycA, O—C1-6 alkylene-AryA, O—C1-6 alkylene-HetA, S(O)j—C1-6 alkylene-CycA, S(O)j—C1-6 alkylene-AryA, S(O)j—C1-6 alkylene-HetA, N(RA)—C(O)-AryA, or N(RA)—C(O)-HetA,
(6) N(RA)—SO2RB,
(7) N(RA)—SO2N(RD)RE,
(8) N(RA)—CO2RB,
(9) N(RD)RE,
(10) N(RC)RA,
(11) N(RA)—C(O)RB,
(12) N(RC)—C(O)RA,
(13) S(O)jRF,
(14) ORF,
(16) CycA,
(17) AryA,
(18) HetA,
(19) N(RA)—C(O)-CycA,
(20) N(RA)—C(O)-AryA,
(21) N(RA)—C(O)-HetA,
(22) N(RA)—C(O)—N(RD)RE,
(23) N(RC)—C(O)-CycA,
(24) N(RC)—C(O)-AryA,
(25) N(RC)—C(O)-HetA,
(26) N(RC)—C(O)—N(RD)RE,
(27) N(RA)—C(O)C(O)-CycA,
(28) N(RA)—C(O)C(O)-AryA,
(29) N(RA)—C(O)C(O)-HetA,
(30) N(RA)—C(O)C(O)—N(RD)RE,
(31) N(RC)—C(O)C(O)-CycA,
(32) N(RC)—C(O)C(O)-AryA,
(33) N(RC)—C(O)C(O)-HetA, or
(34) N(RC)—C(O)C(O)—N(RD)RE;
each j is independently an integer equal to zero, 1, or 2;
R2 is H or C1-6 alkyl;
or alternatively R1 and R2 together with the ring carbon atom to which they are both attached form (i) a 3- to 7-membered saturated carbocyclic ring or (ii) a 4- to 7-membered saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S, where independently each N is optionally substituted with C1-6 alkyl and each S is optionally oxidized to S(O) or S(O)2;
each R3 is independently H or C1-6 alkyl, and each R4 is independently H or C1-6 alkyl;
or alternatively R3 and R4 attached to the same carbon atom together form oxo or thioxo;
each R5 is independently H or C1-6 alkyl, and each R6 is independently H or C1-6 alkyl;
or alternatively R5 and R6 attached to the same carbon atom together form oxo or thioxo;
R7 is H or C1-6 alkyl;
R8 is H or C1-6 alkyl;
or alternatively R7 and R8 together form oxo or thioxo;
R9 is H or C1-6 alkyl;
R10 is C1-6 alkyl substituted with CycC, AryC or HetC;
each RA is independently H or C1-6 alkyl;
each RB is independently H or C1-6 alkyl;
RC is C1-6 alkyl substituted with CycA, AryA, or HetA;
or alternatively, when R1 includes the N(RC) moiety, RC and RK together with (i) the N atom to which RK is attached, (ii) the N atom to which RC, is attached, (iii) the ring carbon to which R1 is attached, and (iv) the 1 ring carbon atom between X and the ring carbon to which R1 is attached, join to form a fused 5- to 7-membered diazacycloalkyl ring, wherein the portion of the fused ring obtained from RC and RK is a 1- to 4-membered methylene chain optionally substituted with oxo or C1-6 alkyl;
each RD and RE are each independently H or C1-6 alkyl, or together with the nitrogen to which they are both attached form a 4- to 7-membered saturated heterocyclic ring optionally containing a heteroatom in addition to the nitrogen attached to RD and RE selected from N, O, and S, where the S is optionally oxidized to S(O) or S(O)2, and wherein the saturated heterocyclic ring is optionally substituted with 1 or 2 substituents each of which is independently C1-6 alkyl or S(O)2—C1-6 alkyl;
RF is C1-6 alkyl, or alternatively, when R1 is SRF or ORF, RF and RK together with (i) the N atom to which RK is attached, (ii) the S or O atom to which RF is attached, (iii) the ring carbon to which R1 is attached, and (iv) the 1 ring carbon atom between X and the ring carbon to which R1 is attached, join to form a fused 5- to 7-membered oxyazacycloalkyl or thioazacycloalkyl ring, wherein the portion of the fused ring obtained from RF and RK is a 1- to 4-membered methylene chain;
each CycA is independently C3-8 cycloalkyl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
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, or
(4) C1-6 alkyl substituted with CycD, AryD, or HetD;
CycB and CycC each independently have the same definition as CycA;
each AryA is independently 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, 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) CycD,
(2) AryD,
(3) HetD, or
(4) C1-6 alkyl substituted with CycD, AryD, or HetD;
AryB and AryC each independently have the same definition as AryA;
each HetA is independently 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, 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) 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) S(O)2RA,
(20) S(O)2N(RA)RB,
(21) N(RA)S(O)2RB,
(22) N(RA)S(O)2N(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, or
(4) C1-6 alkyl substituted with CycD, AryD, or HetD;
HetB and HetC each independently have the same definition as HetA;
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 halogen, C1-6 alkyl, C1-6 haloalkyl, O—C1-6 alkyl, O—C1-6 haloalkyl, or hydroxy;
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;
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;
and provided that:
when RK is:
(1) H,
(2) C1-6 alkyl,
(3) C1-6 alkyl substituted with T, wherein T is CO2RA, CN, SO2RA, N(RD)RE, C(O)N(RD)RE, or N(RA)—C(O)RB,
(4) C1-6 haloalkyl,
(5) C(O)RA,
(6) C(O)—C1-6 haloalkyl,
(8) C(O)—U and U is AryB or HetB,
(9) C(O)—C1-6 alkylene-U
(10) C(O)N(RD)RE,
(11) C(O)—C1-6 alkylene-N(RD)RE,
(14) C(O)C(O)—N(RD)RE (except when RD and RE together with the N to which they are both attached form a saturated heterocyclic ring),
(16) SO2RA, or
(18) SO2—C1-6 alkylene-U;
then R1 is:
(4) C1-6 alkyl substituted with V, wherein V is S(O)RA, N(RA)—C(O)C(O)—N(RD)RE, N(RA)—SO2RB, N(RA)—C1-6 alkylene-SO2RB, N(RA)C(O)—C1-6 alkylene-SO2RB, N(RA)—SO2N(RD)RE, N(RA)—CO2RB, or N(RA)—C(O)N(RD)RE when N(RA)—C(O)N(RD)RE is other than NH—C(O)NH2,
(5) C1-6 alkyl substituted with W, wherein W is O—C1-6 alkylene-CycA, O—C1-6 alkylene-AryA, O—C1-6 alkylene-HetA, S(O)j—C1-6 alkylene-CycA, S(O)j—C1-6 alkylene-AryA, S(O)j—C1-6 alkylene-HetA, N(RA)—C(O)-AryA, or N(RA)—C(O)-HetA,
(7) N(RA)—SO2N(RD)RE when RD and RE together with the N to which they are both attached form an optionally substituted saturated heterocyclic ring,
(10) N(RC)RA when RC and RK are involved in the formation of an optionally substituted fused diazacycloalkyl ring,
(12) N(RC)—C(O)RA when RC and RK are involved in the formation of an optionally substituted fused diazacycloalkyl ring,
(13) S(O)jRF when RF and RK are involved in the formation of a fused thioazacycloalkyl ring,
(14) ORF when RF and RK are involved in the formation of a fused oxyazacycloalkyl ring,
(16) CycA,
(21) N(RA)—C(O)-HetA,
(22) N(RA)—C(O)—N(RD)RE when RD and RE together with the N to which they are both attached form an optionally substituted saturated heterocyclic ring,
(23) N(RC)—C(O)-CycA when RC and RK are involved in the formation of an optionally substituted fused diazacycloalkyl ring,
(24) N(RC)—C(O)-AryA when RC and RK are involved in the formation of an optionally substituted fused diazacycloalkyl ring,
(25) N(RC)—C(O)-HetA,
(26) N(RC)—C(O)—N(RD)RE when (i) RD and RE together with the N to which they are both attached form a optionally substituted saturated heterocyclic ring or (ii) RC and RK are involved in the formation of an optionally substituted fused diazacycloalkyl ring),
(27) N(RA)—C(O)C(O)-CycA,
(28) N(RA)—C(O)C(O)-AryA,
(29) N(RA)—C(O)C(O)-HetA,
(30) N(RA)—C(O)C(O)—N(RD)RE,
(31) N(RC)—C(O)C(O)-CycA,
(32) N(RC)—C(O)C(O)-AryA,
(33) N(RC)—C(O)C(O)-HetA, or
(34) N(RC)—C(O)C(O)—N(RD)RE.

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Hiv integrase inhibitors

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Hiv integrase inhibitors

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Abstract

Claims17