US2005176718A1PendingUtilityA1
Aza- and polyaza-naphthalenyl carboxamides useful as HIV integrase inhibitors
Priority: Oct 12, 2000Filed: Feb 11, 2005Published: Aug 11, 2005
Est. expiryOct 12, 2020(expired)· nominal 20-yr term from priority
Inventors:Neville J. AnthonyRobert GomezSteven D. YoungMelissa EgbertsonJohn S. WaiLinghang ZhuangMark W. EmbreyLekhanh O. TranJeffrey MelamedH. Marie LangfordJames P. Guare, Jr.Thorsten E. FisherSamson M. JollyMichelle KuoDebra S. PerlowJennifer J. BennettTimothy Funk
A61P 31/00A61P 31/12A61P 31/18C07D 471/04
47
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Claims
Abstract
Aza- and polyaza-naphthalenyl carboxamide derivatives including certain quinoline carboxamide and naphthyridine carboxamide derivatives are described. These compounds are inhibitors of HIV integrase and inhibitors of HIV replication, and are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, as compounds or pharmaceutically acceptable salts, or 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.
Claims
exact text as granted — not AI-modified1 - 10 . (canceled)
11 . A pharmaceutical composition comprising an effective amount of a compound of Formula (V-A):
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein:
Q 2 is
(1) —H,
(2) methyl,
(3) ethyl,
(4) CF 3 ,
(5) methoxy,
(6) ethoxy
(7) —OCF 3
(8) halo selected from —F, —Cl and —Br,
(9) —CN,
(10) —CH 2 OH,
(11) —CH 2 OCH 3
(12) —(CH 2 ) 0-2 C(═O)CH 3 ,
(13) —(CH 2 ) 0-2 CO 2 CH 3 ,
(14) —SR a ,
(15) —N(R a ) 2 ,
(16) —(CH 2 ) 1-2 N(R a ) 2 ,
(17) —(CH 2 ) 0-2 C(═O)N(R a ) 2 ,
(18) —S—CH 2 —C(═O)N(R a ) 2 ,
(19) —O—CH 2 —C(═O)N(R a ) 2 ,
(20) —N(SO 2 R a )—CH 2 —C(═O)N(R a ) 2 ,
(21) —N(R a )—C(R a )═O,
(22) —C(═O)—N(R a )—(CH 2 ) 1-2 —C(═O)N(R a ) 2 ,
(23) —C(═O)—N(R a )—(CH 2 ) 1-2 OR a ,
(24) —C(═O)—N(R a )—(CH 2 ) 1-3 —N(R a ) 2 ,
(25) —SO 2 R a ,
(26) —N(R a )SO 2 R a ,
(27) —CH═CH—C(═O)—N(R a ) 2 ,
(28) —C≡C—CH 2 OR a ,
(29) —C≡C—CH 2 SR a ,
(30) —C≡C—CH 2 SO 2 R a ,
(31)
(32) —N(R a )—(CH 2 ) 1-3 SR a ,
(33) —N(R a )—(CH 2 ) 1-3 OR a ,
(34) —N(R a )—(CH 2 ) 1-3 N(R a ) 2 ,
(35) —N(R a )—(CH 2 ) 1-3 N(R a )—C(R a )═O,
(36) —N(R a )CH 2 —C(═O)N(R a ) 2 ,
(37) —N(R a )—C(═O)—C(═O)—N(R a ) 2 ,
(38) —N(R a )—C(═O)—N(R a ) 2 ,
(39) —N(R a )—(CH 2 ) 1-2 —CO 2 R a ,
(40) —N(R a )—C(═O)—N(R a )—(CH 2 ) 1-2 —C(═O)—N(R a ) 2 ,
(41) —N(R a )—C(═O)—(CH 2 ) 1-2 —C(═O)—N(R a ) 2 ,
(42) —N(R a )—SO 2 —N(R a ) 2 ,
(43) —R k ,
(44) —(CH 2 ) 1-4 R k ,
(45) —C═C—CH 2 R
(46) —O—R k ,
(47) —S—R k ,
(48) —SO 2 —R k ,
(49) —N(R c )—R k ,
(50) —N(R c )—(CH 2 ) 1-4 H substituted with one or two R k groups,
(51) —N(R c )—(CH 2 ) 1-4 OR k ,
(52) —C(═O)—R k ,
(53) —C(═O)N(R a )—R k ,
(54) —N(R a )—C(═O)—R k ,
(55) —C(═O)N(R a )—(CH 2 ) 1-4 R k , or
(56) —N(R a )—SO 2 R k ,
each of R 1 and R 2 is independently:
(1) —H,
(2) methyl,
(3) ethyl,
(4) CF 3 ,
(5) methoxy,
(6) ethoxy
(7) —OCF 3
(8) halo selected from —F and —Cl,
(9) —CN,
(10) —CH 2 OR a ,
(11) —CO 2 R a ,
(12) —SR a ,
(13) —N(R a ) 2 ,
(14) —(CH 2 ) 1-3 N(R a ) 2 ,
(15) —SO 2 R a ,
(16) —R k ,
(17) —(CH 2 ) 1-3 R k ,
(18) —O—R k , or
(19) —O—(CH 2 ) 1-3 R k ;
each R a is independently —H or —C 1-4 alkyl;
each R c is independently —H, —C 1-4 alkyl, or —(CH 2 ) 1-3 N(R a ) 2 ;
each R k is independently:
(1) phenyl which is unsubstituted or substituted with from 1 to 4 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) phenyl,
(g) —S—CH 3 ,
(h) —CN,
(i) —OH,
(j) phenyloxy
(k) —N(R a ) 2 ,
(l) —(CH 2 ) 1-3 N(R a ) 2 ,
(m) —R t ,
(n) —(CH 2 ) 0-3 C(═O)N(R a ) 2 , and
(O) —(CH 2 ) 0-3 C(═O)R a ;
(2) —C 3-6 Cycloalkyl,
(3) a 5- or 6-membered heteroaromatic ring selected from thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, and pyridazinyl, wherein the heteroaromatic ring is unsubstituted or substituted on nitrogen or carbon with 1 Or 2 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) —S—C 1-6 alkyl,
(g) —CN,
(h) —OH,
(i) —N(R a ) 2 ,
(j) —C 1-6 alkyl-N(R a ) 2 ,
(k) —R t ,
(l) oxo,
(m) —(CH 2 ) 0-3 C(═O)N(R a ) 2 , and
(n) —(CH 2 ) 0-3 C(═O)R a ;
(4) a 5- or 6- or 7-membered saturated heterocyclic ring selected from piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, thiadiazepanyl, dithiazepanyl, diazepanyl, and thiadiazinanyl; and wherein the heterocyclic ring is unsubstituted or substituted with 1 to 4 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) —CN,
(g)═O,
(h) phenyl,
(i) benzyl,
(j) phenylethyl,
(k) —OH,
(l) —(CH 2 ) 0-3 C(═O)N(R a ) 2 ,
(m) —(CH 2 ) 0-3 C(═O)R a ,
(n) N(R a )—C(═O)R a ,
(O) N(R a )—CO 2 R a ,
(p) (CH 2 ) 1-3 N(R a )—C(═O)R a ,
(q) N(R a ) 2 ,
(r) (CH 2 ) 1-3 N(R a ) 2 ,
(s) SO 2 R a ,
(t) —(CH 2 ) 0-3 C(═O)R t ,
(u) —R t ,
(v) —N(R a )R t , and
(w) —(CH 2 ) 1-3 R t ; and
(5) an 8- to 10-membered heterobicyclic ring selected from indolyl, benzotriazolyl, benzoimidazolyl, imidazo[4,5-b]pyridinyl, dihydroimidazo[4,5-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, dihydropyrazolo[4,3-c]pyridinyl, tetrahydropyrazolo[4,3-c]pyridinyl, pyrrolo[1,2-a]pyrazinyl, dihydropyrrolo[1,2-a]pyrazinyl, tetrahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, and 1,2,3,4tetrahydro-1,8-naphthyridinyl, wherein the bicyclic ring is unsubstituted or substituted with 1 Or 2 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) —CN,
(g) ═O, and
(h) —OH;
R t is selected from pyrrolidinyl, pyrazolidinyl, imidazolinyl, piperidinyl, piperazinyl, pyrrolyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, and pyradizinyl; any one of which is unsubstituted or substituted with 1 Or 2 Substituents independently selected from —F, —Cl, —Br, oxo, methyl, and methoxy;
or a pharmaceutically acceptable salt thereof.
12 . The pharmaceutical composition according to claim 11 , wherein in the compound of Formula (V-A), or a pharmaceutically acceptable salt thereof, R 1 is H or F, and R 2 is H or —SO 2 CH 3 , with the proviso that R 1 and R 2 are not both H.
13 . The pharmaceutical composition according to claim 12 , wherein the compound of Formula (V-a) is a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof:
14 . The pharmaceutical composition according to claim 12 , wherein in the compound of Formula (V-A), or a pharmaceutically acceptable salt thereof,
Q 2 is:
(1) —C(═O)N(R a ) 2 ,
(2) —CH 2 C(═O)N(R a ) 2 ,
(3) —CH 2 CH 2 C(═O)N(R a ) 2 ,
(4) —S—CH 2 —C(═O)N(R a ) 2 ,
(5) —O—CH 2 —C(═O)N(R a ) 2 ,
(6) —N(R a )—C(R a )═O,
(7) —N(SO 2 R a )—CH 2 —C(═O)N(R a ) 2 ,
(8) —N(R a )—C(═O)—C(═O)—N(R a ) 2 ,
(9) —N(R a )SO 2 R a ,
(10) —CH═CH—C(═O)—N(R a ) 2 ,
(11) —N(R a )CH 2 —C(═O)N(R a ) 2 ,
(12) —N(R a )—C(═O)—N(R a ) 2 ,
(13) —R k ,
(14) —(CH 2 ) 1-3 R k , or
(15) —N(R c )—(CH 2 ) 1-3 R k ,
each R a is independently —H or —C 1-4 alkyl; each R c is independently —H or —C 1-4 alkyl; and R k is a saturated heterocyclic ring selected from piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, pyrazolidinyl, hexahydropyrimidinyl, 1,2-thiazinanyl, 1,4-thiazepanyl, 1,2,5-thiadiazepanyl, 1,5,2-dithiazepanyl, 1,4-diazepanyl, and 1,2,6-thiadiazinanyl, wherein the heterocyclic ring is unsubstituted or substituted with 1 to 4 Substituents independently selected from:
(a) methyl or ethyl,
(b) ═O,
(c) —C(═O)N(R a ) 2 ,
(d) —CH 2 C(═O)N(R a ) 2 ,
(e) —C(═O)R a , or
(f) —SO 2 R a .
15 . The pharmaceutical composition according to claim 14 , wherein in the compound of Formula (V-A), or a pharmaceutically acceptable salt thereof,
Q 2 is:
(1) —C(═O)N(R a ) 2 ,
(2) —CH 2 C(═O)N(R a ) 2 ,
(3) —CH 2 CH 2 C(═O)N(R a ) 2 ,
(4) —S—CH 2 —C(═O)N(R a ) 2 ,
(5) —O—CH 2 —C(═O)N(R a ) 2 ,
(6) —N(SO 2 R a )—CH 2 —C(═O)N(R a ) 2 ,
(7) —N(R a )—C(═O)—C(═O)—N(R a ) 2 ,
(8) —N(R a )SO 2 R a ,
(9) —CH═CH—C(═O)—N(R a ) 2 ,
(10) —N(R a )CH 2 —C(═O)N(R a ) 2 ,
(11) —N(R a )—C(═O)—N(R a ) 2 ,
(12) —R k ,
(13) —(CH 2 ) 1-2 R k , or
(14) —NH—(CH 2 ) 1-2 R k ;
each R a is independently methyl, ethyl, or isopropyl; and R k is a saturated heterocyclic ring selected from piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, pyrazolidinyl, hexahydropyrimidinyl, 1,2-thiazinanyl, 1,4-thiazepanyl, 1,2,5-thiadiazepanyl, 1,5,2-dithiazepanyl, 1,4-diazepanyl, and 1,2,6-thiadiazinanyl, wherein the heterocyclic ring is unsubstituted or substituted with 1 to 4 Substituents independently selected from:
(a) methyl or ethyl,
(b) ═O,
(c) —C(═O)NH 2 ,
(d) —C(═O)CH 3 , or
(e) —SO 2 CH 3 .
16 - 36 . (canceled)
37 . The pharmaceutical composition according to claim 11 , wherein the compound of Formula (V-A) is 5-(1,1-dioxido-1,2-thiazinan-2-yl)-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide, or a pharmaceutically acceptable salt thereof.
38 . 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 the pharmaceutical composition according to claim 11 .
39 . 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 the pharmaceutical composition according to claim 37 .
40 . A method for inhibiting HIV integrase in a subject in need thereof which comprises administering to the subject the pharmaceutical composition according to claim 11 .
41 . A method for inhibiting HIV integrase in a subject in need thereof which comprises administering to the subject the pharmaceutical composition according to claim 37 .
42 . 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 an effective amount of a compound of Formula (V-A), or a pharmaceutically acceptable salt thereof:
wherein:
Q 2 is
(1) —H,
(2) methyl,
(3) ethyl,
(4) CF 3 ,
(5) methoxy,
(6) ethoxy
(7) —OCF 3
(8) halo selected from —F, —Cl and —Br,
(9) —CN,
(10) —CH 2 OH,
(11) —CH 2 OCH 3
(12) —(CH 2 ) 0-2 C(═O)CH 3 ,
(13) —(CH 2 ) 0-2 CO 2 CH 3 ,
(14) —SR a ,
(15) —N(R a ) 2 ,
(16) —(CH 2 ) 1-2 N(R a ) 2 ,
(17) —(CH 2 ) 0-2 C(═O)N(R a ) 2 ,
(18) —S—CH 2 —C(═O)N(R a ) 2 ,
(19) —O—CH 2 —C(═O)N(R a ) 2 ,
(20) —N(SO 2 R a )—CH 2 —C(═O)N(R a ) 2 ,
(21) —N(R a )—C(R a )═O,
(22) —C(═O)—N(R a )—(CH 2 ) 1-2 —C(═O)N(R a ) 2 ,
(23) —C(═O)—N(R a )—(CH 2 ) 1-2 OR a ,
(24) —C(═O)—N(R a )—(CH 2 ) 1-3 —N(R a ) 2 ,
(25) —SO 2 R a ,
(26) —N(R a )SO 2 R a ,
(27) —CH═CH—C(═O)—N(R a ) 2 ,
(28) —C≡C—CH 2 OR a ,
(29) —C≡C—CH 2 SR a ,
(30) —C≡C—CH 2 SO 2 R a ,
(31)
(32) —N(R a )—(CH 2 ) 1-3 SR a ,
(33) —N(R a )—(CH 2 ) 1-3 OR a ,
(34) —N(R a )—(CH 2 ) 1-3 N(R a ) 2 ,
(35) —N(R a )—(CH 2 ) 13N(R a )—C(R a )═O,
(36) —N(R a )CH 2 —C(═O)N(R a ) 2 ,
(37) —N(R a )—C(═O)—C(═O)—N(R a ) 2 ,
(38) —N(R a )—C(═O)—N(R a ) 2 ,
(39) —N(R a )—(CH 2 ) 1-2 —CO 2 R a ,
(40) —N(R a )—C(═O)—N(R a )—(CH 2 ) 1-2 —C(═O)—N(R a ) 2 ,
(41) —N(R a )—C(═O)—(CH 2 ) 1-2 —C(═O)—N(R a ) 2 ,
(42) —N(R a )—SO 2 —N(R a ) 2 ,
(43) R k ,
(44) —(CH 2 ) 1-4 R k ,
(45) —C≡C—CH 2 R k ,
(46) —O—R k ,
(47) —S—R k ,
(48) —SO 2 —R k ,
(49) —N(R c )—R k ,
(50) —N(R c )—(CH 2 ) 1-4 H substituted with one or two R k groups,
(51) —N(R c )—(CH 2 ) 1-4 OR k ,
(52) —C(═O)—R k ,
(53) —C(═O)N(R a )—R k ,
(54) —N(R a )—C(═O)—R k ,
(55) —C(═O)N(R a )—(CH 2 ) 1-4 R k , or
(56) —N(R a )—SO 2 R k ,
each of R 1 and R 2 is independently:
(1) —H,
(2) methyl,
(3) ethyl,
(4) CF 3 ,
(5) methoxy,
(6) ethoxy
(7) —OCF 3
(8) halo selected from —F and —Cl,
(9) —CN,
(10) —CH 2 OR a ,
(11) —CO 2 R a ,
(12) —SR a ,
(13) —N(R a ) 2 ,
(14) —(CH 2 ) 1-3 N(R a ) 2 ,
(15) —SO 2 R a ,
(16) —R k ,
(17) —(CH 2 ) 1-3 R k ,
(18) —O—R k , or
(19) —O—(CH 2 ) 1-3 R k ;
each R a is independently —H or —C 1-4 alkyl;
each R c is independently —H, —C 1-4 alkyl, or —(CH 2 ) 1-3 N(R a ) 2 ;
each R k is independently:
(1) phenyl which is unsubstituted or substituted with from 1 to 4 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) phenyl,
(g) —S—CH 3 ,
(h) —CN,
(i) —OH,
(j) phenyloxy
(k) —N(R a ) 2 ,
(l) —(CH 2 ) 1-3 N(R a ) 2 ,
(m) —R t ,
(n) —(CH 2 ) 0-3 C(═O)N(R a ) 2 , and
(O)—(CH 2 ) 0-3 C(═O)R a ;
(2) —C 3-6 Cycloalkyl,
(3) a 5- or 6-membered heteroaromatic ring selected from thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, and pyridazinyl, wherein the heteroaromatic ring is unsubstituted or substituted on nitrogen or carbon with 1 Or 2 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) —S—C 1-6 alkyl,
(g) —CN,
(h) —OH,
(i) —N(R a ) 2 ,
(j) —C 1-6 alkyl-N(R a ) 2 ,
(k) —R t ,
(l) oxo,
(m) —(CH 2 ) 0-3 C(═O)N(R a ) 2 , and
(n) —(CH 2 ) 0-3 C(═O)R a ;
(4) a 5- or 6- or 7-membered saturated heterocyclic ring selected from piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, thiadiazepanyl, dithiazepanyl, diazepanyl, and thiadiazinanyl; and wherein the heterocyclic ring is unsubstituted or substituted with 1 to 4 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) —CN,
(g) ═O,
(h) phenyl,
(i) benzyl,
(j) phenylethyl,
(k) —OH,
(l) —(CH 2 ) 0-3 C(═O)N(R a ) 2 ,
(m) —(CH 2 ) 0-3 C(═O)R a ,
(n) N(R a )—C(═O)R a ,
(O) N(R a )—CO 2 R a ,
(p) (CH 2 ) 1-3 N(R a )—C(═O)R a ,
(q) N(R a ) 2 ,
(r) (CH 2 ) 1-3 N(R a ) 2 ,
(s) SO 2 R a ,
(t) —(CH 2 ) 0-3 C(═O)R t ,
(u) —R t ,
(v) —N(R a )R t , and
(w) —(CH 2 ) 1-3 R t ; and
(5) an 8- to 10-membered heterobicyclic ring selected from indolyl, benzotriazolyl, benzoimidazolyl, imidazo[4,5-b]pyridinyl, dihydroimidazo[4,5-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, dihydropyrazolo[4,3-c]pyridinyl, tetrahydropyrazolo[4,3-c]pyridinyl, pyrrolo[1,2-a]pyrazinyl, dihydropyrrolo[1,2-a]pyrazinyl, tetrahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, and 1,2,3,4-tetrahydro-1,8-naphthyridinyl, wherein the bicyclic ring is unsubstituted or substituted with 1 Or 2 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) —CN,
(g)═O, and
(h) —OH; and
R t is selected from pyrrolidinyl, pyrazolidinyl, imidazolinyl, piperidinyl, piperazinyl, pyrrolyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, and pyradizinyl; any one of which is unsubstituted or substituted with 1 Or 2 Substituents independently selected from —F, —Cl, —Br, oxo, methyl, and methoxy.
43 . The method according to claim 42 , wherein in the compound of Formula (V-A), or a pharmaceutically acceptable salt thereof, R 1 is H or F, and R 2 is H or —SO 2 CH 3 , with the proviso that R 1 and R 2 are not both H.
44 . The method according to claim 43 , wherein the compound of Formula (V-A) is a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof:
45 . The method according to claim 43 , wherein in the compound of Formula (V-A), or a pharmaceutically acceptable salt thereof,
Q 2 is:
(1) —C(═O)N(R a ) 2 ,
(2) —CH 2 C(═O)N(R a ) 2 ,
(3) —CH 2 CH 2 C(═O)N(R a ) 2 ,
(4) —S—CH 2 —C(═O)N(R a ) 2 ,
(5) —O—CH 2 —C(═O)N(R a ) 2 ,
(6) —N(R a )—C(R a )═O,
(7) —N(SO 2 R a )—CH 2 —C(═O)N(R a ) 2 ,
(8) —N(R a )—C(═O)—C(═O)—N(R a ) 2 ,
(9) —N(R a )SO 2 R a ,
(10) —CH═CH—C(═O)—N(R a ) 2 ,
(11) —N(R a )CH 2 —C(═O)N(R a ) 2 ,
(12) —N(R a )—C(═O)—N(R a ) 2 ,
(13) —R k ,
(14) —(CH 2 ) 1-3 R k , or
(15) —N(R c )—(CH 2 ) 1-3 R k ,
each R a is independently —H or —C 1-4 alkyl; each R c is independently —H or —C 1-4 alkyl; and R k is a saturated heterocyclic ring selected from piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, pyrazolidinyl, hexahydropyrimidinyl, 1,2-thiazinanyl, 1,4-thiazepanyl, 1,2,5-thiadiazepanyl, 1,5,2-dithiazepanyl, 1,4-diazepanyl, and 1,2,6-thiadiazinanyl, wherein the heterocyclic ring is unsubstituted or substituted with 1 to 4 Substituents independently selected from:
(a) methyl or ethyl,
(b) ═O,
(c) —C(═O)N(R a ) 2 ,
(d) —CH 2 C(═O)N(R a ) 2 ,
(e) —C(═O)R a , or
(f) —SO 2 R a .
46 . The method according to claim 45 , wherein the compound of Formula (V-A) is 5-(1,1-dioxido-1,2-thiazinan-2-yl)-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide, or a pharmaceutically acceptable salt thereof.
47 . A method for inhibiting HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula (V-A), or a pharmaceutically acceptable salt thereof:
wherein:
Q 2 is
(1) —H,
(2) methyl,
(3) ethyl,
(4) CF 3 ,
(5) methoxy,
(6) ethoxy
(7) —OCF 3
(8) halo selected from —F, —Cl and —Br,
(9) —CN,
(10) —CH 2 OH,
(11) —CH 2 OCH 3
(12) —(CH 2 ) 0-2 C(═O)CH 3 ,
(13) —(CH 2 ) 0-2 CO 2 CH 3 ,
(14) —SR a ,
(15) —N(R a ) 2 ,
(16) —(CH 2 ) 1-2N(R a ) 2 ,
(17) —(CH 2 ) 0-2 C(═O)N(R a ) 2 ,
(18) —S—CH 2 —C(═O)N(R a ) 2 ,
(19) —O—CH 2 —C(═O)N(R a ) 2 ,
(20) —N(SO 2 R a )—CH 2 —C(═O)N(R a ) 2 ,
(21) —N(R a )—C(R a )═O,
(22) —C(═O)—N(R a )—(CH 2 ) 1-2 —C(═O)N(R a ) 2 ,
(23) —C(═O)—N(R a )—(CH 2 ) 1-2 OR a ,
(24) —C(═O)—N(R a )—(CH 2 ) 1-3 —N(R a ) 2 ,
(25) —SO 2 R a ,
(26) —N(R a )SO 2 R a ,
(27) —CH═CH—C(═O)—N(R a ) 2 ,
(28) —C≡C—CH 2 OR a ,
(29) —C≡C—CH 2 SR a ,
(30) —C≡C—CH 2 SO 2 R a ,
(31)
(32) —N(R a )—(CH 2 ) 1-3 SR a ,
(33) —N(R a )—(CH 2 ) 1-3 OR a ,
(34) —N(R a )—(CH 2 ) 1-3 N(R a ) 2 ,
(35) —N(R a )—(CH 2 ) 13N(R a )—C(R a )═O,
(36) —N(R a )CH 2 —C(═O)N(R a ) 2 ,
(37) —N(R a )—C(═O)—C(═O)—N(R a ) 2 ,
(38) —N(R a )—C(═O)—N(R a ) 2 ,
(39) —N(R a )—(CH 2 ) 1-2 —CO 2 R a ,
(40) —N(R a )—C(═O)—N(R a )—(CH 2 ) 1-2 —C(═O)—N(R a ) 2 ,
(41) —N(R a )—C(═O)—(CH 2 ) 1-2 —C(═O)—N(R a ) 2 ,
(42) —N(R a )—SO 2 —N(R a ) 2 ,
(43) —R k ,
(44) —(CH 2 ) 1-4 R k ,
(45) —C≡C—CH 2 R k ,
(46) —O—R k ,
(47) —S—R k ,
(48) —SO 2 —R k ,
(49) —N(R c )—R k ,
(50) —N(R c )—(CH 2 ) 1-4 H substituted with one or two R k groups,
(51) —N(R c )—(CH 2 ) 1-4 OR k ,
(52) —C(═O)—R k ,
(53) —C(═O)N(R a )—R k ,
(54) —N(R a )—C(═O)—R k ,
(55) —C(═O)N(R a )—(CH 2 ) 1-4 R k , or
(56) —N(R a )—SO 2 R k ,
each of R 1 and R 2 is independently:
(1) —H,
(2) methyl,
(3) ethyl,
(4) CF 3 ,
(5) methoxy,
(6) ethoxy
(7) —OCF 3
(8) halo selected from —F and —Cl,
(9) —CN,
(10) —CH 2 OR a ,
(11) —CO 2 R a ,
(12) —SR a ,
(13) —N(R a ) 2 ,
(14) —(CH 2 ) 1-3 N(R a ) 2 ,
(15) —SO 2 R a ,
(16) —R k ,
(17) —(CH 2 ) 1-3 R k ,
(18) —O—R k , or
(19) —O—(CH 2 ) 1-3 R k ;
each R a is independently —H or —C 1-4 alkyl;
each R c is independently —H, —C 1-4 alkyl, or —(CH 2 ) 1-3 N(R a ) 2 ;
each R k is independently:
(1) phenyl which is unsubstituted or substituted with from 1 to 4 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) phenyl,
(g) —S—CH 3 ,
(h) —CN,
(i) —OH,
(j) phenyloxy
(k) —N(R a ) 2 ,
(l) —(CH 2 ) 1-3 N(R a ) 2 ,
(m) —R t ,
(n) —(CH 2 ) 0-3 C(═O)N(R a ) 2 , and
(O)—(CH 2 ) 0-3 C(═O)R a ;
(2) —C 3-6 Cycloalkyl,
(3) a 5- or 6-membered heteroaromatic ring selected from thienyl, pyridyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, and pyridazinyl, wherein the heteroaromatic ring is unsubstituted or substituted on nitrogen or carbon with 1 Or 2 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) —S—C 1-6 alkyl,
(g) —CN,
(h) —OH,
(i) —N(R a ) 2 ,
(j) —C 1-6 alkyl-N(R a ) 2 ,
(k) —R t ,
(l) oxo,
(m) —(CH 2 ) 0-3 C(═O)N(R a ) 2 , and
(n) —(CH 2 ) 0-3 C(═O)R a ;
(4) a 5- or 6- or 7-membered saturated heterocyclic ring selected from piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, thiadiazepanyl, dithiazepanyl, diazepanyl, and thiadiazinanyl; and wherein the heterocyclic ring is unsubstituted or substituted with 1 to 4 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) —CN,
(g)═O,
(h) phenyl,
(i) benzyl,
(j) phenylethyl,
(k) —OH,
(l) —(CH 2 ) 0-3 C(═O)N(R a ) 2 ,
(m) —(CH 2 ) 0-3 C(═O)R a ,
(n) N(R a )—C(═O)R a ,
(O) N(R a )—CO 2 R a ,
(p) (CH 2 ) 13N(R a )—C(═O)R a ,
(q) N(R a ) 2 ,
(r) (CH 2 ) 13N(R a ) 2 ,
(s) SO 2 R a ,
(t) —(CH 2 ) 0-3 C(═O)R t ,
(u) R t ,
(v) —N(R a )R t , and
(w) —(CH 2 ) 1-3 R t ; and
(5) an 8- to 10-membered heterobicyclic ring selected from indolyl, benzotriazolyl, benzoimidazolyl, imidazo[4,5-b]pyridinyl, dihydroimidazo[4,5-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, dihydropyrazolo[4,3-c]pyridinyl, tetrahydropyrazolo[4,3-c]pyridinyl, pyrrolo[1,2-a]pyrazinyl, dihydropyrrolo[1,2-a]pyrazinyl, tetrahydropyrrolo[1,2-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, and 1,2,3,4-tetrahydro-1,8-naphthyridinyl, wherein the bicyclic ring is unsubstituted or substituted with 1 Or 2 Substituents independently selected from:
(a) halogen selected from —F, —Cl, and —Br,
(b) methyl or ethyl,
(c) —CF 3 ,
(d) methoxy,
(e) —OCF 3 ,
(f) —CN,
(g)═O, and
(h) —OH; and
R t is selected from pyrrolidinyl, pyrazolidinyl, imidazolinyl, piperidinyl, piperazinyl, pyrrolyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, and pyradizinyl; any one of which is unsubstituted or substituted with 1 Or 2 Substituents independently selected from —F, —Cl, —Br, oxo, methyl, and methoxy.
48 . The method according to claim 47 , wherein in the compound of Formula (V-A), or a pharmaceutically acceptable salt thereof, R 1 is H or F, and R 2 is H or —SO 2 CH 3 , with the proviso that R 1 and R 2 are not both H.
49 . The method according to claim 48 , wherein the compound of Formula (V-A) is a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof:
50 . The method according to claim 48 , wherein in the compound of Formula (V-A), or a pharmaceutically acceptable salt thereof,
Q 2 is:
(1) —C(═O)N(R a ) 2 ,
(2) —CH 2 C(═O)N(R a ) 2 ,
(3) —CH 2 CH 2 C(═O)N(R a ) 2 ,
(4) —S—CH 2 —C(═O)N(R a ) 2 ,
(5) —O—CH 2 —C(═O)N(R a ) 2 ,
(6) —N(R a )—C(R a )═O,
(7) —N(SO 2 R a )—CH 2 —C(═O)N(R a ) 2 ,
(8) —N(R a )—C(═O)—C(═O)—N(R a ) 2 ,
(9) —N(R a )SO 2 R a ,
(10) —CH═CH—C(═O)—N(R a ) 2 ,
(11) —N(R a )CH 2 —C(═O)N(R a ) 2 ,
(12) —N(R a )—C(═O)—N(R a ) 2 ,
(13) —R k ,
(14) —(CH 2 ) 1-3 R k , or
(15) —N(R c )—(CH 2 ) 1-3 R k ,
each R a is independently —H or —C 1-4 alkyl; each R c is independently —H or —C 1-4 alkyl; and R k is a saturated heterocyclic ring selected from piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isooxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, pyrazolidinyl, hexahydropyrimidinyl, 1,2-thiazinanyl, 1,4-thiazepanyl, 1,2,5-thiadiazepanyl, 1,5,2-dithiazepanyl, 1,4-diazepanyl, and 1,2,6-thiadiazinanyl, wherein the heterocyclic ring is unsubstituted or substituted with 1 to 4 Substituents independently selected from:
(a) methyl or ethyl,
(b) ═O,
(c) —C(═O)N(R a ) 2 ,
(d) —CH 2 C(═O)N(R a ) 2 ,
(e) —C(═O)R a , or
(f) —SO 2 R a .
51 . The method according to claim 50 , wherein the compound of Formula (V-A) is 5-(1,1-dioxido-1,2-thiazinan-2-yl)-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide, or a pharmaceutically acceptable salt thereof.Cited by (0)
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