HIV integrase inhibitors

1. A compound of Formula I, or an individual enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

Z is N—R 9 ;

R 1 is —CH 2 —R J , and R J is phenyl which is optionally substituted with from 1 to 4 substituents each of which is independently:

(1) —C 1-4 alkyl,

(2) —O—C 1-4 alkyl,

(3) —C 1-4 haloalkyl,

(4) —O—C 1-4 haloalkyl,

(5) halo,

(6) —CN,

(7) —N(R A )R B ,

(8) —C(═O)N(R A )R B ,

(9) —S(═O)R A ,

(10) —SO 2 R A ,

(11) —N(R A )SO 2 R B ,

(12) —N(R A )SO 2 N(R A )R B ,

(13) —N(R A )C(═O)R B , or

(14) —N(R A )C(═O)—C(═O)N(R A )R B ;

R 2 and R 4 are each independently:

(1) —H,

(2) —C 1-6 alkyl, which is optionally substituted with —OH, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —CN, —N(R A )R B , —C(═O)N(R A )R B , —C(═O)R A , —CO 2 R A , —S(O) n R A , —SO 2 N(R A )R B , —N(R A )C(═O)R B , —N(R A )CO 2 R B , —N(R A )SO 2 R B , —N(R A )SO 2 N(R A )R B , —N(R A )C(═O)N(R A )R B , or —OC(═O)N(R A )R B ,

(3) —C 1-6 haloalkyl,

(4) CycA,

(5) AryA,

(6) HetC, or

(7) —C 1-6 alkyl substituted with CycA, AryA, or HetC;

R 3 and R 5 are both H;

R 6 is:

(1) —H,

(2) —C 1-6 alkyl,

(3) —C 1-6 fluoroalkyl,

(4) CycA,

(5) AryA, or

(6) —C 1-6 alkyl substituted with AryA;

R 7 is H or —C 1-6 alkyl;

R 8 is:

(1) —H,

(2) —C 1-6 alkyl,

(3) —CO 2 R A ,

(4) —C(═O)N(R A )R B ,

(5) —R K ,

(6) —C(═O)—R K ,

(7) —C(═O)N(R A )—R K , or

(8) —C(═O)N(R A )—C 1-6 alkylene-R K ;

or alternatively R 7 and R 8 together with the carbon atom to which they are both attached form a 3- to 7-membered saturated carbocyclic ring;

R 9 is:

(1) —H,

(2) —C 1-6 alkyl,

(3) —C 1-6 fluoroalkyl,

(4) CycA, or

(5) —C 1-6 alkyl substituted with CycA, AryA, or HetC;

each n is independently an integer equal to zero, 1, or 2;

each R A is independently H or C 1-6 alkyl;

each R B is independently H or C 1-6 alkyl;

each R K is independently CycA, AryA, or HetC;

each CycA is independently a C 3-8 cycloalkyl, which is optionally substituted with from 1 to 4 substituents each of which is halogen, —OH, —C 1-6 alkyl, —C 1-6 haloalkyl, —O—C 1-6 alkyl, or —O—C 1-6 haloalkyl;

each AryA is independently phenyl, which is optionally substituted with from 1 to 5 substituents each of which is independently —C 1-6 alkyl, —C 1-6 alkylene-OH, —C 1-6 alkylene-O—C 1-6 alkyl, —C 1-6 alkylene-O—C 1-6 haloalkyl, —C 1-6 alkylene-N(R A )R B , —C 1-6 alkylene-C(═O)N(R A )R B , —C 1-6 alkylene-C(═O)R A , —C 1-6 alkylene-CO 2 R A , —C 1-6 alkylene-S(O) n R A , —O—C 1-6 alkyl, —C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —OH, halo, —N(R A )R B , —C(═O)N(R A )R B , —C(═O)R A , —CO 2 R A , —S(O) n R A , or —SO 2 N(R A )R B ; and

each HetC is independently a saturated or unsaturated heterocyclic ring which is:

(i) a saturated heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, azetidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl, thiadiazinanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl,

(ii) a mono-unsaturated heterocyclic ring selected from mono-unsaturated counterparts of the saturated rings in (i), or

(iii) an aromatic heterocyclic ring selected from the group consisting of pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl,

wherein the heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is halogen, —C 1-6 alkyl, —C 1-6 haloalkyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, OH, or oxo.

2. The compound according to claim 1 , or an individual enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

3. A compound according to claim 1 , which is a compound of Formula IIa, or an individual enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

X 1 and X 2 are each independently —H, —C 1-4 alkyl, —O—C 1-4 alkyl, —C 1-4 haloalkyl, —O—C 1-4 haloalkyl, halo, —CN, —N(R A )R B , —C(═O)N(R A )R B , or —S(O) n R A ;

R 2 and R 4 are each independently —H, —C 1-4 alkyl, —C 1-4 fluoroalkyl, C 3-6 cycloalkyl, phenyl, or benzyl;

R 6 is H, —C 1-4 alkyl, —CF 3 , cyclopropyl, phenyl or benzyl;

R 7 is H or —C 1-4 alkyl;

R 8 is —H, —C 1-4 alkyl, —CO 2 —C 1-4 alkyl, —C(═)NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, HetE, —C(═O)-HetE, or —C(═O)N(R A )—(CH 2 ) 1-2 -HetF; wherein

HetE is a saturated heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, azetidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl, thiadiazinanyl, tetrahydropyranyl, tetrahydrothiopyranyl and dioxanyl, wherein the saturated heterocyclic is optionally substituted with from 1 to 3 substituents each of which is independently oxo or C 1-4 alkyl; and with the proviso that the saturated heterocyclic is attached to the —C(═O)— via a ring N atom; and

HetF is a heteroaromatic ring selected from the group consisting of pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl and thiadiazolyl, wherein the heteroaromatic ring is optionally substituted with 1 or 2 substituents each of which is independently a C 1-4 alkyl;

or alternatively R 7 and R 8 together with the carbon atom to which they are both attached form a 3- to 6-membered saturated carbocyclic ring;

R 9 is —H, —C 1-4 alkyl, —CH 2 CF 3 , —C 3-6 cycloalkyl, —CH 2 —C 3-6 cycloalkyl, or —CH 2 -phenyl;

each R A is independently H or C 1-4 alkyl; and

each R B is independently H or C 1-4 alkyl.

4. A compound according to claim 3 , or an individual enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

X 1 and X 2 are each independently H, fluoro, chloro, methyl, trifluoromethyl, methoxy, CN, —SO 2 CH 3 , —C(═O)NH(CH 3 ), or —C(═O)N(CH 3 ) 2 ;

R 2 and R 4 are both H;

R 6 is H, methyl, cyclopropyl, or phenyl;

R 7 is H or methyl;

R 8 is —H, —C 1-4 alkyl, —CO 2 —C 1-4 alkyl, —C(═O) NH(C 1-4 alkyl), —C(═O)N(C 1-4 alkyl) 2 , C 3-6 cycloalkyl, HetF, —C(═O)-HetE, or —C(═O)N(R A )—(CH 2 ) 1-2 -HetF; wherein

HetE is selected from the group consisting of:

 wherein the asterisk * denotes the point of attachment to the —C(═O) moiety; and

HetF is selected from the group consisting of pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, pyridyl, pyrimidinyl, and pyrazinyl;

or alternatively R 7 and R 8 together with the carbon atom to which they are both attached form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and

R 9 is H, methyl, ethyl, n-propyl, isopropyl, —CH 2 CF 3 , cyclopropyl, or —CH 2 -cyclopropyl.

5. A compound, according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

2-(4-fluorobenzyl)-8-hydroxy-5,5,6-trimethyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

(+)-2-(4-fluorobenzyl)-8-hydroxy-5,5,6-trimethyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

(−)-2-(4-fluorobenzyl)-8-hydroxy-5,5,6-trimethyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

2-(4-fluorobenzyl)-8-hydroxy-6-methyl-4a-phenyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

(+)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-4a-phenyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

(−)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-4a-phenyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

5-(tert-butyloxycarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione, and diastereomers and enantiomers thereof;

5-ethyl-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione, and diastereomers and enantiomers thereof;

6-(cyclopropylmethyl)-2-(4-fluorobenzyl)-8-hydroxy-5,5-dimethyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

5-(dimethylaminocarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione, and diastereomers and enantiomers thereof

2-(3-chloro-4-fluorobenzyl)-8-hydroxy-5,5,6-trimethyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

(+)-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-5,5,6-trimethyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

(−)-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-5,5,6-trimethyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

6′-(4-fluorobenzyl)-4′-hydroxy-2′-methyl-6′,7′,8′,8a′-tetrahydro-2′ H-spiro[cyclopentane-1,1′-[2,6]naphthyridine]-3′,5′-dione;

(+)-6′-(4-fluorobenzyl)-4′-hydroxy-2′-methyl-6′,7′,8′,8a′-tetrahydro-2′ H-spiro[cyclopentane-1,1′-[2,6]naphthyridine]-3′,5′-dione;

(−)-6′-(4-fluorobenzyl)-4′-hydroxy-2′-methyl-6′,7′,8′,8a′-tetrahydro-2′ H-spiro[cyclopentane-1,1′-[2,6]naphthyridine]-3′,5′-dione;

2-(3,4-difluorobenzyl)-8-hydroxy-5,5,6-trimethyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

6′-(4-fluorobenzyl)-4′-hydroxy-2′-methyl-6′,7′,8′,8a′-tetrahydro-2′ H-spiro[cyclobutane-1,1′-[2,6]naphthyridine]-3′,5′-dione;

5-[(2-methylpropyl)aminocarbonyl]-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione, and diastereomers and enantiomers thereof;

5-(tert-butylaminocarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione, and diastereomers and enantiomers thereof;

5-[(2-pyridylmethyl)aminocarbonyl]-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione, and diastereomers and enantiomers thereof

5-(pyrimidin-2-yl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione, and diastereomers and enantiomers thereof;

2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-cyclopropyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione;

(+)-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-cyclopropyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione; and

(−)-2-(3-chloro-4-fluorobenzyl)-8-hydroxy-6-cyclopropyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione.

6. A pharmaceutical composition comprising a compound according to claim 1 , or an individual enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.