US 7,459,452 B2 · Dihydroxypyrimidine carboxamide inhibitors of HIV integrase

Abstract

4,5-Dihydroxypyrimidine-6-carboxamides of formula: are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein R1, R2, R3 and R4 are defined herein. These compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment 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. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.

A method for treating infection by HIV or for treating or delaying the onset of AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof;
wherein
R1 is
(1) —H,
(2) —C1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —C(═O)—C0-6 alkyl-N(RaRb), N(Ra)—C(═O)—C0-6 alkyl-N(RbRc), —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), —N(Ra)—C(═O)Rb,
—N(Ra)C(═O)N(RbRc), —N(Ra)C(═O)C(═O)N(RbRc), or —N(Ra)C(═O)ORb,
(3) —O—C1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —C(═O)—C0-6 alkyl-N(RaRb), N(Ra)—C(═O)—C0-6 alkyl-N(RbRc), —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), or —N(Ra)—C(Rb)═O,
(4) —Rk,
(5) —C1-6 alkyl-Rk, wherein the alkyl is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C 1-6 alkyl, —O—C1-6 haloalkyl, —N(RaRb), —N(Ra)CO2Rb, —N(Ra)C(═O)—C0-6 alkyl-N(RbRc), or —N(Ra)—C2-6 alkyl-OH with the proviso that the —OH is not attached to the carbon alpha to N(Ra),
(6) —C2-5 alkenyl—Rk,
(7) —C2-5 alkynyl-Rk,
(8) —C0-6 alkyl—O—C0-6 alkyl-Rk,
(9) —C0-6 alkyl-S(O)n—C0-6 alkyl-Rk,
(10) —O—C1-6 alkyl-Rk,
(11) —O—C1-6 alkyl-O—C1-6 alkyl-Rk,
(12) —O—C1-6 alkyl-S(O)nRk,
(13) —C0-6 alkyl-N(Ra)—Rk,
(14) —C0-6 alkyl-N(Ra)—C1-6 alkyl-Rk,
(15) —C0-6 alkyl-N(Ra)—C1-6 alkyl-ORk,
(16) —C0-6 alkyl-C(═O)—Rk,
(17) —C0-6 alkyl-C(═O)N(Ra)—C0-6 alkyl-Rk,
(18) —C0-6 alkyl-N(Ra)C(═O)—C0-6 alkyl-Rk,
(19) —C0-6 alkyl-N(Ra)C(═O)—O—C0-6 alkyl-Rk,
(20) —C1-6 alkyl which is:
(i) substituted with aryl or —O-aryl, wherein the aryl is optionally substituted with one or more substituents each of which is independently halogen, —OH, —C1-6 alkyl, —C1-6 alkyl-ORa, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, methylenedioxy attached to two adjacent carbon atoms, or aryl;
(ii) substituted with —Rk, —C1-6 alkyl-Rk, —N(Ra)—C(═O)—C0-6 alkyl-Rk, —C0-6 alkyl-N(Ra)—C0-6 alkyl-Rk, —C0-6 alkyl—O—C0-6 alkyl-Rk, or —C0-6 alkyl-N(Ra)—C(═O)—C0-6 alkyl-Rk;
and
(iii) optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C1-6 alkyl, —O—C1-6 haloalkyl, or —N(RaRb), or
(21) —C1-6 alkyl, substituted with —O—C1-6 alkyl, and with a substituent selected from the group consisting of —N(Ra)C(═O)Rkand —N(Ra)C 1-6 alkyl-Rk,
R2 is —H or —C 1-6 alkyl which is optionally substituted with one or more substituents each of which is independently
(1) halogen,
(2) —OH,
(3) —CN,
(4) —O—C1-6 alkyl,
(5) —O—C1-6 haloalkyl,
(6) —C(═O)Ra,
(7) —CO2Ra,
(8) —SRa,
(9) —S(═O)Ra,
(10) —N(RaRb),
(11) —C(═O)N(RaRb),
(12) —N(Ra)—C(═O)—C1-6 alkyl-N(RbRc),
(13) —SO2Ra,
(14) —N(Ra)SO2Rb,
(15) —SO2N(RaRb),
(16) —N(Ra)—C(Rb)═O,
(17) —C3-8 cycloalkyl,
(18) aryl, wherein the aryl is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C0-6 alkyl-N(RaRb), or —C1-6 alkyl substituted with a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently —C1-6 alkyl, oxo, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
or
(19) a 5- to 8-membered monocyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S;
wherein the heterocycle is optionally substituted with one or more substituents each of which is independently —C1-6 alkyl, —O—C1-6 alkyl, oxo, phenyl, or naphthyl;
R3 is —H or —C1-6 alkyl;
R4 is
(1) H,
(2) C1-6 alkyl which is optionally substituted with one or more substituents each of which is independently halogen, —OH, O—C1-6 alkyl, —O—C1-6 haloalkyl, —NO2, —N(RaRb), —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —SO2Ra, or —N(Ra)CO2Rb,
(3) C1-6 alkyl which is optionally substituted with one or more substituents each of which is independently halogen, —OH, or O—C1-4 alkyl, and which is substituted with 1 or 2 substituents each of which is independently:
(i) C3-8 cycloalkyl,
(ii) aryl,
(iii) a fused bicyclic carbocycle consisting of a benzene ring fused to a C5-7 cycloalkyl,
(iv) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S,
(v) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or
(vi) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic,
(4) C2-5 alkynyl optionally substituted with aryl,
(5) C3-8 cycloalkyl optionally substituted with aryl,
(6) aryl,
(7) a fused bicyclic carbocycle consisting of a benzene ring fused to a C5-7 cycloalkyl,
(8) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S,
(9) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or
(10) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic;
wherein
each aryl in (3)(ii) or the aryl in (4), (5) or (6) or each fused carbocycle in (3)(iii) or the fused carbocycle in (7) is optionally substituted with one or more substituents each of which is independently halogen, —OH, —C1-6 alkyl, —C1-6 alkyl-ORa, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —CN, —NO2, —N(RaRb), —C1-6 alkyl-N(RaRb), —C(═O)N(RaRb), —C(═O)Ra, —CO2Ra, —C1-6 alkyl-CO2Ra, —OCO2Ra, —SRa, —S(═O)Ra, —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), —N(Ra)C(═O)Rb, —N(Ra)CO2Rb, —C1-6 alkyl-N(Ra)CO2Rb, aryl, —C1-6 alkyl-aryl, —O-aryl, or —C0-6 alkyl-het wherein het is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, and het is optionally fused with a benzene ring, and is optionally substituted with one or more substituents each of which is independently —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, or —CO2Ra;
each saturated heterocyclic ring in (3)(iv) or the saturated heterocyclic ring in (8) is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, aryl, or a 5- or 6- membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
and
each heteroaromatic ring in (3)(v) or the heteroaromatic ring in (9) or each fused bicyclic heterocycle in (3)(vi) or the fused bicyclic heterocycle in (10) is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C 1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, aryl, or —C 1-6 alkyl-aryl;
or alternatively R3 and R4 together with the N to which both are attached form a C3-7 azacycloalkyl which is optionally substituted with one or more substituents each of which is independently —C1-6 alkyl or oxo;
each Ra, Rb, Rc, and Rd is independently —H or —C1-6 alkyl;
Rkis carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more substituents each of which is independently
(1) halogen,
(2) —OH,
(3) —CN,
(4) —C1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —C(═O)—(CH2)0-2N(RaRb), N(Ra)—C(═O)—(CH2)0-2N(RbRc), —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), or —N(Ra)—C(Rb)═O,
(5) —O—C1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —C(═O)—(CH2)0-2N(RaRb), N(Ra)—C(═O)—(CH2)0-2N(RbRc), —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), or —N(Ra)—C(Rb)═O,
(6) —NO2,
(7) oxo,
(8) ethylenedioxy, spiro substituted on a ring carbon in a saturated ring of Rk,
(9) —C(═O)Ra,
(10) —CO2Ra,
(11) —SRa,
(12) —S(═O)Ra,
(13) —N(RaRb),
(14) —C(═O)N(RaRb),
(15) —C(═O)—C1-6 alkyl-N(RaRb),
(16) —N(Ra)C(═O)Rb,
(17) —SO2Ra,
(18) —SO2N(RaRb),
(19) —N(Ra)SO2Rb,
(20) —Rm,
(21) —C1-6 alkyl-Rm, wherein the alkyl is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —N(Ra)CO2Rb, —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), or —N(Ra)—C(Rb)═O,
(22) —C0-6 alkyl-N(Ra)—C0-6 alkyl-Rm,
(23) —C0-6 alkyl—O—C0-6 alkyl-Rm,
(24) —C0-6 alkyl-S—C0-6 alkyl-Rm,
(25) —C0-6 alkyl-C(═O)—C0-6 alkyl-Rm,
(26) —C(═O)—O—C0-6 alkyl-Rm,
(27) —C(═O)N(Ra)—C0-6 alkyl-Rm,
(28) —N(Ra)C(═O)—Rm,
(29) —N(Ra)C(═O)—C 1-6 alkyl-Rm, wherein the alkyl is optionally substituted with one or more sub stituents each of which is independently halogen, —OH, —CN, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C 1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —N(Ra)CO2Rb, —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), or —N(Ra)—C(Rb)═0,
(30) —N(Ra)—C(═O)—N(Rb)—C0-6 alkyl-Rm,
(31) —N(Ra)—C(═O)—O—C0-6 alkyl-Rm, or
(32) —N(Ra)—C(═O)—N(Rb)—SO2—C0-6 alkyl-Rm;
carbocycle in Rk is (i) a C3 to C8 monocyclic, saturated or unsaturated ring, (ii) a C7 to C 12 bicyclic ring system, or (iii) a C11 to C16 tricyclic ring system, wherein each ring in (ii) or (iii) is independent of or fused to the other ring or rings and each ring is saturated or unsaturated;
heterocycle in Rk is (i) a 4- to 8-membered, saturated or unsaturated monocyclic ring, (ii) a 7- to 12-membered bicyclic ring system, or (iii) an 11 to 16-membered tricyclic ring system;
wherein each ring in (ii) or (iii) is independent of or fused to or bridged with or spiro to the other ring or rings and each ring is saturated or unsaturated;
the monocyclic ring, bicyclic ring system, or tricyclic ring system contains from 1 to 6 heteroatoms selected from N, O and S and a balance of carbon atoms;
and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally be oxidized, and any one or more of the nitrogen heteroatoms is optionally quatemized;
each Rm is independently C3-8 cycloalkyl;
aryl;
a 5- to 8-membered monocyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S;
or a 9- to 10-membered bicyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S;
wherein any one or more of the nitrogen and sulfur heteroatoms in the monocyclic or bicyclic heterocycle is optionally oxidized and any one or more of the nitrogen heteroatoms is optionally quatemized;
and wherein
the cycloalkyl or the aryl is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —N(RaRb), aryl, or —C1-6 alkyl-aryl;
and
the monocyclic or bicyclic heterocycle is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl optionally substituted with —O—C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, aryl, —C1-6 alkyl-aryl, —C(═O)-aryl, —CO2-aryl, —CO2—C 1-6 alkyl-aryl, a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
and
each n is independently an integer equal to zero, 1 or 2.

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Dihydroxypyrimidine carboxamide inhibitors of HIV integrase

Life of this patent

Dihydroxypyrimidine carboxamide inhibitors of HIV integrase

Life of this patent

Abstract

Claims18