Tetrahydro-4H-pyrido[1,2-a] pyrimidines useful as HIV integrase inhibitors

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

• wherein
• R1, R12, and each R16 are independently H, NR2R5, OR2, SR2, SOR2, SO2R2, SO2NR2R5, OC(O)NR2R5, R11, C1-6 alkyl, substituted alkyl, SR18, SO2R18, or N[SO2N(C1-6 alkyl)2]R18;
• wherein substituted alkyl is C1-6 alkyl substituted with O—C1-6 alkyl, C3-8 cycloalkyl, or aryl, wherein the cycloalkyl is optionally substituted with from 1 to 3 C1-6 alkyl groups and the aryl is optionally substituted with from 1 to 5 substituents each of which is independently C1-6 alkyl, O—C1-6 alkyl, CF3, OCF3, halo, CN, or NO2;
• with the proviso that no more than one of R1, R12 and R16 is other than H, C1-6 alkyl, or substituted alkyl;
• R2 is
• 1) H, or
• 2) C1-6 alkyl which is optionally substituted with aryl, C3-8 cycloalkyl, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
• R5 is
• 1) H,
• 2) C1-6 alkyl, optionally substituted at any carbon atom with halogen, aryl, SO2—C1-6 alkyl, N(C1-6 alkyl)2, or SO2NRuRv, wherein Ru and Rv are each independently a C1-6 alkyl group or Ru and Rv together with the N to which they are attached form a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and from zero to 3 heteroatoms in addition to the N atom to which Ru and Rv are attached, wherein the additional heteroatoms are independently selected from N, O and S, and in which any ring S atom is optionally oxidized to SO or SO2, and wherein the heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently a C1-6 alkyl group,
• 3) C(O)C1-6 alkyl, where the alkyl is optionally substituted at any carbon atom with halogen, aryl, SO2—C1-6 alkyl, N(C1-16 alkyl)2, or SO2NRu*Rv*, wherein Ru* and Rv* independently have the same definition as Ru and Rv respectively as set forth above,
• 4) C(O)—C1-6 fluoroalkyl,
• 5) C(O)R7,
• 6) C(O)C(O)NR8R9,
• 7) SO2NR8R9,
• 8) SO2C1-6 alkyl, where the alkyl is optionally substituted at any carbon atom with halogen, aryl, SO2—C1-6 alkyl or N(C1-6 alkyl)2,
• 9) C(O)NR8R9,
• 10) SO2R7,
• 11) C(O)C(O)R10, where R10 is a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, and in which any ring S atom is optionally oxidized to SO or SO2, and wherein the heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently a C1-6 alkyl group,
• 12) C(O)O—C1-6 alkyl, or
• 13) SO2R20, wherein R20 is a saturated heterocyclic ring independently having the same definition as R10 set forth above;
• or alternatively R2 and R5 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and from zero to 3 heteroatoms in addition to the N atom to which R2 and R5 are attached, wherein the additional heteroatoms are independently selected from N, O and S, and in which any ring S atom is optionally oxidized to SO or SO2, and wherein the heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently a C1-6 alkyl group;
• R7 and R11 are each independently a 5- or 6-membered unsaturated heterocyclic ring or an unsaturated 9- or 10-membered heterobicyclic fused ring system, wherein the ring or bicyclic ring system contains from 1 to 4 heteroatoms independently selected from N, O and S, and in which any one or more of the N and S atoms is optionally oxidized, and wherein the ring is optionally substituted with from 1 to 3 substituents each of which is independently a C1-6 alkyl group;
• R8 and R9 are each independently selected from the group consisting of C1-6 alkyl and aryl;
• R14, R30, each R32, R34 and R36 are independently:
• (1) H,
• (2) C1-6 alkyl, or
• (3) C1-6 alkyl substituted with O—C1-6 alkyl, C3-8 cycloalkyl, or aryl,
• wherein the cycloalkyl is optionally substituted with from 1 to 3 C1-6 alkyl groups and the aryl is optionally substituted with from 1 to 5 substituents each of which is independently C1-6 alkyl, O—C1-6 alkyl, CF3, OCF3, halo, CN, or NO2;
• R18 is C1-6 alkyl substituted with C(O)NRwRx, wherein Rw and Rx are each independently a C1-6 alkyl group or Rw and Rx together with the N to which they are attached form a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and from zero to 3 heteroatoms in addition to the N atom to which Rw and Rx are attached, wherein the additional heteroatoms are independently selected from N, O and S, and wherein any of the ring S atoms is optionally oxidized to SO or SO2, and wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently a C1-6 alkyl group;
• R3 is H or C1-6 alkyl;
• R4 is
• 1) hydrogen,
• 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 (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 alkylene-ORa, C1-6 haloalkyl, O—C1-6 alkyl, O—C1-6 haloalkyl, CN, NO2, N(RaRb), —C1-6 alkylene-N(RaRb), C(O)N(RaRb), C(O)Ra, CO2Ra, —C1-6 alkylene-CO2Ra, OCO2Ra, SRa, S(O)Ra, SO2Ra, N(Ra)SO2Rb, SO2N(RaRb), N(Ra)C(O)Rb, N(Ra)CO2Rb, —C1-6 alkylene-N(Ra)CO2Rb, aryl, —C1-6 alkylene-aryl, O-aryl, or —C0-6 alkylene-HetA wherein HetA is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, and the heteroaromatic ring 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—C1-6alkyl, O—C1-6 haloalkyl, OH, 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, C1-6 haloalkyl, O—C1-6 alkyl, O—C1-6 haloalkyl, OH, aryl, or C1-6 alkylene-aryl;
• or alternatively R3 and R4 together with the nitrogen 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 and Rb is independently hydrogen or C1-6 alkyl;
• and
• n is an integer equal to 1.