US 2007/0179196 A1 · Hiv integrase inhibitors

Abstract

Hydroxy (tetra- or hexa-)hydronaphthyridine dione compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: (I) wherein a, R,1?, R,2?, R,3?, R,4? and R,5? are defined herein. The 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.

A compound according to claim 20 which is a compound of Formula II, or a pharmaceutically acceptable salt thereof:

wherein:
bond in the ring is a single bond or a double bond;
X1 and X2 are each independently:
(1) —H,
(2) —C1-6alkyl,
(3) —OH
(4) —O—C1-6 alkyl,
(5) —C1-6 haloalkyl,
(6) —O—C1-6 haloalkyl,
(7) halogen,
(8) —CN,
(9) —N(Ra)Rb,
(10) —C(═O)N(Ra)Rb,
(11) —SRa,
(12) —S(O)Ra,
(13) SO2Ra,
(14) —N(Ra)SO2Rb,
(15) —N(Ra)SO2N(Ra)Rb,
(16) —N(Ra)C(═O)Rb,
(17) —N(Ra)C(═O)—C(═O)N(Ra)Rb,
(18) —HetA,
(19) —C(═O)—HetA, or
(20) HetB;
wherein each HetA is independently a C4-5 azacycloalkyl or a C3-4 diazacycloalkyl, either of which is optionally substituted with 1 or 2 substituents each of which is independently oxo or C1-6 alkyl;
and with the proviso that when HetA is attached to the rest of the compound via the —C(═O)— moiety, the HetA is attached to the —C(═O)— via a ring N atom;
and
each HetB 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;
or alternatively X1 and X2 are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy;
X3 is:
(1) —H,
(2) —C1-6 alkyl,
(3) —O—C1-6 alkyl,
(4) —C1-6 haloalkyl,
(5) —O—C1-6 haloalkyl, or
(6) halogen;
R4 is:
(1) —C1-6 alkyl,
(2) —CO2Ra,
(3) —C(═O)N(Ra)Rb,
(4) —C(═O)—N(Ra)—(CH2)2-3—ORb,
(5) —N(Ra)C(═O)Rb,
(6) —N(Ra)SO2Rb,
(7) —C3-6 cycloalkyl, which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, —C1-6 alkyl, —CF3, —O—C1-6 alkyl, or —OCF3,
(8) —HetK,
(9) —C(═O)—HetK,
(10) —C(═O)N(Ra)—HetK,
(11) —C(═O)N(Ra)—(CH2)0-2—(C3-6 cycloalkyl), wherein the cycloalkyl is optionally substituted with from 1 to 4 substituents each of which is independently halogen, —C1-6 alkyl, —CF3, —O—C1-6 alkyl, or —OCF3, or
(12) —C(═O)N(Ra)—CH2-phenyl, wherein the phenyl is optionally substituted with from 1 to 4 substituents each of which is independently —C1-6 alkyl, —O—C1-6 alkyl, —CF3, —OCF3, or halogen;
(13) —HetL,
(14) —C(═O)N(Ra)Rc, or
(15) halogen;
wherein HetK is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein the heterocyclic ring is optionally substituted with (i) from 1 to 4 substituents each of which is independently —C1-6 alkyl, oxo, halogen, —C(═O)N(Ra)Rb, —C(═O)C(═O)N(Ra)Rb, —C(═O)Ra, —CO2Ra, —SO2Ra, or —SO2N(Ra)Rb and (ii) from zero to 1 C3-6 cycloalkyl;
and with the proviso that when HetK is attached to the rest of the compound via the —C(═O)— moiety, the HetK is attached to the —C(═O)— via a ring N atom;
wherein HetL is 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 —C1-6 alkyl or —OH;
R5 is:
(1) —H,
(2) —C1-6 alkyl,
(3) —C3-6 cycloalkyl,
(4) —(CH2)1-2—C3-6 cycloalkyl,
(5) —CH2-phenyl wherein the phenyl 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, or —O—C1-6 haloalkyl,
(6) —(CH2)1-2—HetD, wherein HetD is a 4- to 7-membered saturated heterocyclic ring containing from 1 to 2 heteroatoms independently selected from 1 to 2 N atoms, from zero to 1 O atom and from zero to 1 S atom, wherein the heterocyclic ring is attached to the rest of the molecule via a ring N atom, and the heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, —C(═O)N(Ra)Rb, —C(═O)Ra, —CO2Ra, —SO2Ra, or —SO2N(Ra)Rb,
(7) phenyl which is optionally substituted with from 1 to 4 substituents each of which is independently —C1-6 alkyl, —O—C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 haloalkyl, —OH, halogen, —CN, —NO2, —C(═O)Ra, —CO2Ra, —SO2Ra, —N(Ra)C(═O)—C1-6 haloalkyl, —N(Ra)C(═O)Rb, —N(Ra)C(═O)N(Ra)Rb, —N(Ra)CO2Rb, —N(Ra)SO2Rb, —C(═O)N(Rd)Re, or —SO2N(Rd)Re;
(8) 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 —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, or —OH,
(9) C1-6 alkyl substituted with —O—C1-6 alkyl, —CN, —N(Ra)Rb, —C(═O)N(Ra)Rb, —C(═O)Ra, —CO2Ra, —SO2Ra, or —SO2N(Ra)Rb, or
(10) —C1-6 haloalkyl;
each Ra is independently H or C1-6 alkyl;
each Rb is independently H or C1-6 alkyl;
Rc is C1-6 haloalkyl or C1-6 alkyl substituted with —CO2Ra, —SO2Ra, —SO2N(Ra)Rb, or N(Ra)Rb;
and
each Rd and Re are independently H or C1-6 alkyl, or together with the N atom to which they are 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, wherein the S is optionally oxidized to S(O) or S(O)2, and wherein the saturated heterocyclic ring is optionally 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, —C(═O)Ra, —CO2Ra, —SO2Ra, or —SO2N(Ra)Rb.

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Hiv integrase inhibitors

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Hiv integrase inhibitors

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Abstract

Claims20