US 6,476,054 B1Granted

Cyclic amine modulators of chemokine receptor activity

AssigneeMerck & Co., Inc.

InventorsCharles G. Caldwell, Paul E. Finke, Malcolm Maccoss, Sander G. Mills, Bryan Oates, Dooseop Kim, Shankaran Kothandaraman, Liping Wang

Life of this patent

Estimating the term…

Abstract

The present invention is directed to cyclic amines of the formula I: (wherein R1, R2, R3, m and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.

Claims27

Dependent claims

A compound of the formula I:

wherein:
R1 is selected from a group consisting of:
linear or branched C1-8 alkyl, linear or branched C2-8 alkenyl, wherein the C1-8 alkyl or C2-8 alkenyl is optionally mono, di, tri or tetra substituted, where the substituents are independently selected from:
(a) hydroxy,
(b) oxo,
(c) cyano,
(d) halogen which is selected from F, Cl, Br, and I,
(e) trifluoromethyl,
(f) phenyl
(g) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(1′) phenyl,
(2′) hydroxy,
(3′) C1-6 alkyl,
(4′) cyano,
(5′) halogen,
(6′) trifluoromethyl,
(7′) —NR6COR7,
(8′) —NR6CO2R7,
(9′) —NR6CONHR7,
(10′) —NR6S(O)jR7, wherein j is 1 or 2,
(11′) —CONR6R7,
(12′) —COR6,
(13′) —CO2R6,
(14′) —OR6,
(15′) —S(O)kR6, wherein k is 0, 1 or 2,
(h) —NR6R7,
(i) —NR6COR7,
(j) —NR6CO2R7,
(k) —NR6CONHR7,
(l) —NR6S(O)j-R7,
(m) —CONR6R7,
(n) —COR7,
(o) —CO2R7,
(p) —OR7,
(q) —S(O)kR7,
(r) —NR6CO-heteroaryl,
(s) —NR6S(O)j-heteroaryl, and
(t) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1′) benzimidazolyl,
(2′) benzofuranyl,
(3′) benzoxazolyl,
(4′) furanyl,
(5′) imidazolyl,
(6′) indolyl,
(7′) isooxazolyl,
(8′) isothiazolyl,
(9′) oxadiazolyl,
(10′) oxazolyl,
(11′) pyrazinyl,
(12′) pyrazolyl,
(13′) pyridyl,
(14′) pyrimidyl,
(15′) pyrrolyl,
(16′) quinolyl,
(17′) tetrazolyl,
(18′) thiadiazolyl,
(19′) thiazolyl,
(20′) thienyl, and
(21′) triazolyl,
wherein the heteroaryl is unsubstituted or mono di or tri-substituted, where the substituents are independently selected from:
(a″) phenyl,
(b″) hydroxy;
(c″) oxo,
(d″) cyano,
(e″) halogen,
(f″) C1-6 alkyl, and
(g″) trifluoromethyl;
with the proviso that R1 bears at least one substituent which is —NR6COR7;
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6 alkyl,
(4) substituted C1-6 alkyl, where the substituents are independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) halogen,
(e) trifluoromethyl,
(f) —N(R4)(R5), wherein R4 and R5 are independently selected from hydrogen, C1-6 alkyl, and C1-6 alkyl substituted with C5-8 cycloalkyl,
(g) —N(R4)—CO—O—(R5), and
(h) —N(R4′)—CO—N(R4)(R5), wherein R4′ is selected from the definitions of R4,
(5) —O—C1-6 alkyl, and
(6) phenyl;
R3 is selected from the group consisting of:
(1) —N(R8)—CO—O—(C1-6 alkyl)-Ar, and
(2) —N(R8)—CO—O—R*;
Ar is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyrimidyl,
(4) naphthyl,
(5) furyl,
(6) pyrryl,
(7) thienyl,
(8) isothiazolyl,
(9) imidazolyl,
(10) benzimidazolyl,
(11) tetrazolyl,
(12) pyrazinyl,
(13) quinolyl,
(14) isoquinolyl,
(15) benzofuryl,
(16) isobenzofuryl,
(17) benzothienyl,
(18) pyrazolyl,
(19) indolyl,
(20) isoindolyl,
(21) purinyl,
(22) isoxazolyl,
(23) thiazolyl,
(24) oxazolyl,
(25) triazinyl, and
(26) benzthiazolyl,
(27) benzoxazolyl,
(28) imidazopyrazinyl,
(29) triazolopyrazinyl,
(30) naphthyridinyl,
(31) furopyridinyl,
(32) thiopyranopyrimidyl and the 5-oxide and 5-dioxide thereof,
(33) pyridazinyl,
(34) quinazolinyl,
(35) pteridinyl,
(36) triazolopyrimidyl,
(37) triazolopyrazinyl,
(38) thiapurinyl,
(39) oxapurinyl, and
(40) deazapurinyl,
wherein Ar items (1) to (40) are unsubstituted or mono or di-substituted, where the substituents are independently selected from:
(a) C1-6 alkyl, unsubstituted or substituted with a substituent selected from:
(1′) oxo,
(2′) hydroxy,
(3′) —OR7,
(4′) phenyl,
(5′) trifluoromethyl, and
(6′) phenyl or mono, di or tri-substituted phenyl, where the substituents are independently selected from:
hydroxy, cyano, halogen, and trifluoromethyl,
(b) halogen,
(c) —OC1-6 alkyl,
(d) trifluoromethyl,
(e) hydroxy,
(f) —NO2,
(g) —(CH2)pS(O)k—(C1-6 alkyl), wherein p is 0, 1 or 2,
(h) —(CH2)pS(O)j-NH2,
(i) —(CH2)pS(O)j-NH(C1-6 alkyl),
(j) —(CH2)pS(O)j-NHR6,
(k) —(CH2)pS(O)j-NR6—(C1-6 alkyl),
(l) —(CH2)pCONH2,
(m) —(CH2)pCONH—(C1-6 alkyl),
(n) —(CH2)pCONHR6,
(o) —(CH2)pCONR6—(C1-6 alkyl),
(p) —(CH2)pCO2H,
(q) —(CH2)pCO2—(C1-6 alkyl),
(r) —(CH2)pNR6R7,
(s) —(CH2)pNH—C(O)—C1-6 alkyl,
(t) —(CH2)pNH—C(O)—NH2,
(u) —(CH2)pNH—C(O)—NHC1-6 alkyl
(v) —(CH2)pNH—C(O)—N(C1-6-alkyl)2,
(w) —(CH2)pNH—S(O)k-C1-6 alkyl,
(x) —(CH2)pN(C1-3 alkyl)-C(O)—N(diC1-6 alkyl),
(y) —(CH2)p-heteroaryl, —C(O)-heteroaryl or —(CH2)p—O-heteroaryl , wherein the heteroaryl is selected from the group consisting of:
(1′) benzimidazolyl,
(2′) benzofuranyl,
(3′) benzothiophenyl,
(4′) benzoxazolyl,
(5′) furanyl,
(6′) imidazolyl,
(7′) indolyl,
(8′) isooxazolyl,
(9′) isothiazolyl,
(10′) oxadiazolyl,
(11′) oxazolyl,
(12′) pyrazinyl,
(13′) pyrazolyl,
(14′) pyridyl,
(15′) pyrimidyl,
(16′) pyrrolyl,
(17′) quinolyl,
(18′) tetrazolyl,
(19′) thiadiazolyl,
(20′) thiazolyl,
(21′) thienyl,
(22′) triazolyl,
(23′) dihydrobenzimidazolyl,
(24′) dihydrobenzofuranyl,
(25′) dihydrobenzothiophenyl,
(26′) dihydrobenzoxazolyl,
(27′) dihydrofuranyl
(28′) dihydroimidazolyl,
(29′) dihydroindolyl,
(30′) dihydroisooxazolyl,
(31′) dihydroisothiazolyl,
(32′) dihydrooxadiazolyl,
(33′) dihydropyrazinyl,
(34′) dihydropyrazolyl,
(35′) dihydropyridinyl,
(36′) dihydropyrimidinyl,
(37′) dihydroquinolinyl,
wherein the heteroaryl group of items (1′) to (37′) is unsubstituted, or mono, di or tri-substituted, where the substituents are selected from:
(a′) hydrogen,
(b′) C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, where the substituents are selected from:
hydrogen and hydroxy,
(c′) hydroxy,
(d′) oxo,
(e′) —OR6,
(f′) halogen,
(g′) trifluoromethyl,
(h′) nitro,
(i′) cyano,
(j′) —NHR6,
(k′) —NR6R7,
(l′) —NHCOR6,
(m′) —NR6COR7,
(n′) —NHCO2R6,
(o′) —NR6CO2R7,
(p′) —NHS(O)jR6,
(q′) —NR6S(O)jR7,
(r′) —CONR6R7,
(s′) —COR6,
(t′) —CO2R6, and
(u′) —S(O)jR6;
R* is selected from the group consisting of:
(1) substituted C1-6 alkyl or C5-8 cycloalkyl, where the substituents are independently selected from:
(a) phenyl and
(b) mono, di or tri-substituted phenyl, where the substituent is independently selected from:
(1′) hydroxy,
(2′) C1-3 alkyl,
(3′) cyano,
(4′) halogen,
(5′) trifluoromethyl, and
(6′) C1-3 alkyloxy,
(2) phenyl, and
(3) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6 alkyl,
(c) C1-6 alkoxy
(d) cyano,
(e) halogen, and
(f) trifluoromethyl;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl,
(3) substituted C1-6 alkyl, where the substituents are independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) cyano,
(e) halogen,
(f) trifluoromethyl, and
(g) C5-8 cycloalkyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6 alkyl,
(c) cyano,
(d) halogen, and
(e) trifluoromethyl;
R7 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl or C5-8 cycloalkyl,
(3) substituted C1-6 alkyl or C5-8 cycloalkyl, where the substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the substituent is independently selected from:
(1′) hydroxy,
(2′) C1-3 alkyl,
(3′) cyano,
(4′) halogen,
(5′) trifluoromethyl, and
(6′) C1-3 alkyloxy,
(c) hydroxy,
(d) oxo,
(e) cyano,
(f) halogen, and
(g) trifluoromethyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6 alkyl,
(c) C1-6 alkoxy
(d) cyano,
(e) halogen, and
(f) trifluoromethyl;
or R6 and R7 may be joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or di-substituted, the substituents independently selected from:
(1) hydroxy,
(2) oxo,
(3) cyano,
(4) halogen,
(5) trifluoromethyl,
R8 is selected from the group consisting of:
(1) C2-10 alkenyl,
(2) C2-10 alkynyl,
(3) heteroaryl,
(4) substituted C1-10 alkyl, C2-10 alkenyl or C1-10 alkynyl, where the substituents are independently selected from:
(a) C3-4 cycloalkyl,
(b) hydroxy,
(c) C1-6 alkyloxy,
(d) cyano,
(e) heteroaryl,
(f) halogen,
(g) trifluoromethyl,
(h) —CO2H,
(i) —SO3H,
(j) —CO2R6,
(k) —CONR6R7,
(l) —NR4CONR6R7,
(m) —NR4CO2R6,
(n) —NR4COR6, and
(o) —SR4;
m is an integer selected from 0, 1 and 2,
n is an integer selected from 0, 1 and 2,
and pharmaceutically acceptable salts thereof.

307 more elements

A method for blocking the entry of HIV into target cells of a patient in need thereof comprising administering to the patient a compound of Formula I:

or a pharmaceutically acceptable salt thereof, in an amount effective to block HIV from binding to surface receptors of target cells;
wherein:
R1 is selected from a group consisting of:
linear or branched C1-8 alkyl, linear or branched C2-8 alkenyl, wherein the C1-8 alkyl or C2-8 alkenyl is optionally mono, di, tri or tetra substituted, where the substituents are independently selected from:
(a) hydroxy,
(b) oxo,
(c) cyano,
(d) halogen which is selected from F, Cl, Br, and I,
(e) trifluoromethyl,
(f) phenyl
(g) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(1′) phenyl,
(2′) hydroxy,
(3′) C1-6 alkyl,
(4′) cyano,
(5′) halogen,
(6′) trifluoromethyl,
(7′) —NR6COR7,
(8′) —NR6CO2R7,
(9′) —NR6CONHR7,
(10′) —NR6S(O)jR7, wherein j is 1 or 2,
(11′) —CONR6R7,
(12′) —COR6,
(13′) —CO2R6,
(14′) —OR6,
(15′) —S(O)kR6, wherein k is 0, 1 or 2,
(h) —NR6R7,
(i) —NR6COR7,
(j) —NR6CO2R7,
(k) —NR6CONHR7,
(l) —NR6S(O)j-R7,
(m) —CONR6R7,
(n) —COR7,
(o) —CO2R7,
(p) —OR7,
(q) —S(O)kR7,
(r) —NR6CO-heteroaryl,
(s) —NR6S(O)j-heteroaryl, and
(t) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1′) benzimidazolyl,
(2′) benzofuranyl,
(3′) benzoxazolyl,
(4′) furanyl,
(5′) imidazolyl,
(6′) indolyl,
(7′) isooxazolyl,
(8′) isothiazolyl,
(9′) oxadiazolyl,
(10′) oxazolyl,
(11′) pyrazinyl,
(12′) pyrazolyl,
(13′) pyridyl,
(14′) pyrimidyl,
(15′) pyrrolyl,
(16′) quinolyl,
(17′) tetrazolyl,
(18′) thiadiazolyl,
(19′) thiazolyl,
(20′) thienyl, and
(21′) triazolyl,
wherein the heteroaryl is unsubstituted or mono di or tri-substituted, where the substituents are independently selected from:
(a″) phenyl,
(b″) hydroxy,
(c″) oxo,
(d″) cyano,
(e″) halogen,
(f′) C1-6 alkyl,and
(g″) trifluoromethyl;
with the proviso that R1 bears at least one substituent which is —NR6COR7;
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6 alkyl,
(4) substituted C1-6 alkyl, where the substituents are independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) halogen,
(e) trifluoromethyl,
(f) —N(R4)(R5), wherein R4 and R5 are independently selected from hydrogen, C1-6 alkyl, and C1-6 alkyl substituted with C5-8 cycloalkyl,
(g) —N(R4)—CO—O—(R5), and
(h) —N(R4′)—CO—N(R4)(R5), wherein R4′ is selected from the definitions of R4,
(5) —O—C1-6 alkyl, and
(6) phenyl;
R3 is selected from the group consisting of:
(1) —N(R8)—CO—O—(C1-6 alkyl)-Ar, and
(2) —N(R8)—CO—O—R7;
Ar is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyrimidyl,
(4) naphthyl,
(5) furyl,
(6) pyrryl,
(7) thienyl,
(8) isothiazolyl,
(9) imidazolyl,
(10) benzimidazolyl,
(11) tetrazolyl,
(12) pyrazinyl,
(13) quinolyl,
(14) isoquinolyl,
(15) benzofuryl,
(16) isobenzofuryl,
(17) benzothienyl,
(18) pyrazolyl,
(19) indolyl,
(20) isoindolyl,
(21) purinyl,
(22) isoxazolyl,
(23) thiazolyl,
(24) oxazolyl,
(25) triazinyl, and
(26) benzthiazolyl,
(27) benzoxazolyl,
(28) imidazopyrazinyl,
(29) triazolopyrazinyl,
(30) naphthyridinyl,
(31) furopyridinyl,
(32) thiopyranopyrimidyl and the 5-oxide and 5-dioxide thereof,
(33) pyridazinyl,
(34) quinazolinyl,
(35) pteridinyl,
(36) triazolopyrimidyl,
(37) triazolopyrazinyl,
(38) thiapurinyl,
(39) oxapurinyl, and
(40) deazapurinyl,
wherein Ar items (1) to (40) are unsubstituted or mono or di-substituted, where the substituents are independently selected from:
(a) C1-6 alkyl, unsubstituted or substituted with a substituent selected from:
(1′) oxo,
(2′) hydroxy,
(3′) —OR7,
(4′) phenyl,
(5′) trifluoromethyl, and
(6′) phenyl or mono, di or tri-substituted phenyl, where the substituents are independently selected from:
hydroxy, cyano, halogen, and trifluoromethyl,
(b) halogen,
(c) —OC1-6 alkyl,
(d) trifluoromethyl,
(e) hydroxy,
(f) —NO2,
(g) —(CH2)pS(O)k—(C1-6 alkyl), wherein p is 0, 1 or 2,
(h) —(CH2)pS(O)j-NH2,
(i) —(CH2)pS(O)j-NH(C1-6 alkyl),
(j) —(CH2)pS(O)j-NHR6,
(k) —(CH2)pS(O)j-NR6—(C1-6 alkyl),
(l) —(CH2)pCONH2,
(m) —(CH2)pCONH—(C1-6 alkyl),
(n) —(CH2)pCONHR6,
(o) —(CH2)pCONR6—(C1-6 alkyl),
(p) —(CH2)pCO2H,
(q) —(CH2)pCO2—(C1-6 alkyl),
(r) —(CH2)pNR6R7,
(s) —(CH2)pNH—C(O)—C1-6 alkyl,
(t) —(CH2)pNH—C(O)—NH2,
(u) —(CH2)pNH—C(O)—NHC1-6 alkyl,
(v) —(CH2)pNH—C(O)—N(C1-6 alkyl)2,
(w) —(CH2)pNH—S(O)k-C1-6 alkyl,
(x) —(CH2)pN(C1-3 alkyl)-C(O)—N(diC1-6 alkyl),
(y) —(CH2)p-heteroaryl, —C(O)-heteroaryl or —(CH2)p—O-heteroaryl, wherein the heteroaryl is selected from the group consisting of:
(1′) benzimidazolyl,
(2′) benzofuranyl,
(3′) benzothiophenyl,
(4′) benzoxazolyl,
(5′) furanyl,
(6′) imidazolyl,
(7′) indolyl,
(8′) isooxazolyl,
(9′) isothiazolyl,
(10′) oxadiazolyl,
(11′) oxazolyl,
(12′) pyrazinyl,
(13′) pyrazolyl,
(14′) pyridyl,
(15′) pyrimidyl,
(16′) pyrrolyl,
(17′) quinolyl,
(18′) tetrazolyl,
(19′) thiadiazolyl,
(20′) thiazolyl,
(21′) thienyl,
(22′) triazolyl,
(23′) dihydrobenzimidazolyl,
(24′) dihydrobenzofuranyl,
(25′) dihydrobenzothiophenyl,
(26′) dihydrobenzoxazolyl,
(27′) dihydrofuranyl
(28′) dihydroimidazolyl,
(29′) dihydroindolyl,
(30′) dihydroisooxazolyl,
(31′) dihydroisothiazolyl,
(32′) dihydrooxadiazolyl,
(33′) dihydropyrazinyl,
(34′) dihydropyrazolyl,
(35′) dihydropyridinyl,
(36′) dihydropyrimidinyl,
(37′) dihydroquinolinyl,
wherein the heteroaryl group of items (1′) to (37′) is unsubstituted, or mono, di or tri-substituted, where the substituents are selected from:
(a′) hydrogen,
(b′) C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, where the substituents are selected from:
hydrogen and hydroxy,
(c′) hydroxy,
(d′) oxo,
(e′) —OR6,
(f′) halogen,
(g′) trifluoromethyl,
(h′) nitro,
(i′) cyano,
(j′) —NHR6,
(k′) —NR6R7,
(l′) —NHCOR6,
(m′) —NR6COR7,
(n′) —NHCO2R6,
(o′) —NR6CO2R7,
(p′) —NHS(O)jR6,
(q′) —NR6S(O)jR7,
(r′) —CONR6R7,
(s′) —COR6,
(t′) —CO2R6, and
(u′) —S(O)jR6;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl,
(3) substituted C1-6 alkyl, where the substituents are independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) cyano,
(e) halogen,
(f) trifluoromethyl, and
(g) C5-8 cycloalkyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6 alkyl,
(c) cyano,
(d) halogen, and
(e) trifluoromethyl;
R7 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl or C5-8 cycloalkyl,
(3) substituted C1-6 alkyl or C5-8 cycloalkyl, where the substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the substituent is independently selected from:
(1′) hydroxy,
(2′) C1-3 alkyl,
(3′) cyano,
(4′) halogen,
(5′) trifluoromethyl, and
(6′) C1-3 alkyloxy,
(c) hydroxy,
(d) oxo,
(e) cyano,
(f) halogen, and
(g) trifluoromethyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6 alkyl,
(c) C1-6 alkoxy
(d) cyano,
(e) halogen, and
(f) trifluoromethyl;
or R6 and R7 may be joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or di-substituted, the substituents independently selected from:
(1) hydroxy,
(2) oxo,
(3) cyano,
(4) halogen,
(5) trifluoromethyl,
R8 is selected from the group consisting of:
(1) C2-10 alkenyl,
(2) C2-10 alkynyl,
(3) heteroaryl,
(4) substituted C1-10 alkyl, C2-10 alkenyl or C2-10 alkynyl, where the substituents are independently selected from:
(a) C3-4 cycloalkyl,
(b) hydroxy,
(c) C1-6 alkyloxy,
(d) cyano,
(e) heteroaryl,
(f) halogen,
(g) trifluoromethyl,
(h) —CO2H,
(i) —SO3H,
(j) —CO2R6,
(k) —CONR6R7,
(l) —NR4CONR6R7,
(m) —NR4CO2R6,
(n) —NR4COR6, and
(o) —SR4;
m is an integer selected from 0, 1 and 2, and
n is an integer selected from 0, 1 and 2.

289 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/690,622Filed 17 Oct 2000 · division
Priority: 2 Feb 1998
Granted: 5 Nov 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
C07D 211/56
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 211/58
Nitrogen atoms: attached in position 4
C07D 233/56
Having two double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms or radicals containing only…

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Application60/073,446Us provisional application · filed 2 Feb 1998
Application09/241,486Parent of this division · filed 1 Feb 1999
US 6,140,349 AParent of this division
US 6,476,054 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula I:

wherein:
R1 is selected from a group consisting of:
linear or branched C1-8 alkyl, linear or branched C2-8 alkenyl, wherein the C1-8 alkyl or C2-8 alkenyl is optionally mono, di, tri or tetra substituted, where the substituents are independently selected from:
(a) hydroxy,
(b) oxo,
(c) cyano,
(d) halogen which is selected from F, Cl, Br, and I,
(e) trifluoromethyl,
(f) phenyl
(g) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(1′) phenyl,
(2′) hydroxy,
(3′) C1-6 alkyl,
(4′) cyano,
(5′) halogen,
(6′) trifluoromethyl,
(7′) —NR6COR7,
(8′) —NR6CO2R7,
(9′) —NR6CONHR7,
(10′) —NR6S(O)jR7, wherein j is 1 or 2,
(11′) —CONR6R7,
(12′) —COR6,
(13′) —CO2R6,
(14′) —OR6,
(15′) —S(O)kR6, wherein k is 0, 1 or 2,
(h) —NR6R7,
(i) —NR6COR7,
(j) —NR6CO2R7,
(k) —NR6CONHR7,
(l) —NR6S(O)j-R7,
(m) —CONR6R7,
(n) —COR7,
(o) —CO2R7,
(p) —OR7,
(q) —S(O)kR7,
(r) —NR6CO-heteroaryl,
(s) —NR6S(O)j-heteroaryl, and
(t) heteroaryl, wherein heteroaryl is selected from the group consisting of:
(1′) benzimidazolyl,
(2′) benzofuranyl,
(3′) benzoxazolyl,
(4′) furanyl,
(5′) imidazolyl,
(6′) indolyl,
(7′) isooxazolyl,
(8′) isothiazolyl,
(9′) oxadiazolyl,
(10′) oxazolyl,
(11′) pyrazinyl,
(12′) pyrazolyl,
(13′) pyridyl,
(14′) pyrimidyl,
(15′) pyrrolyl,
(16′) quinolyl,
(17′) tetrazolyl,
(18′) thiadiazolyl,
(19′) thiazolyl,
(20′) thienyl, and
(21′) triazolyl,
wherein the heteroaryl is unsubstituted or mono di or tri-substituted, where the substituents are independently selected from:
(a″) phenyl,
(b″) hydroxy;
(c″) oxo,
(d″) cyano,
(e″) halogen,
(f″) C1-6 alkyl, and
(g″) trifluoromethyl;
with the proviso that R1 bears at least one substituent which is —NR6COR7;
R2 is selected from the group consisting of:
(1) hydrogen,
(2) hydroxy,
(3) C1-6 alkyl,
(4) substituted C1-6 alkyl, where the substituents are independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) halogen,
(e) trifluoromethyl,
(f) —N(R4)(R5), wherein R4 and R5 are independently selected from hydrogen, C1-6 alkyl, and C1-6 alkyl substituted with C5-8 cycloalkyl,
(g) —N(R4)—CO—O—(R5), and
(h) —N(R4′)—CO—N(R4)(R5), wherein R4′ is selected from the definitions of R4,
(5) —O—C1-6 alkyl, and
(6) phenyl;
R3 is selected from the group consisting of:
(1) —N(R8)—CO—O—(C1-6 alkyl)-Ar, and
(2) —N(R8)—CO—O—R*;
Ar is selected from the group consisting of:
(1) phenyl,
(2) pyridyl,
(3) pyrimidyl,
(4) naphthyl,
(5) furyl,
(6) pyrryl,
(7) thienyl,
(8) isothiazolyl,
(9) imidazolyl,
(10) benzimidazolyl,
(11) tetrazolyl,
(12) pyrazinyl,
(13) quinolyl,
(14) isoquinolyl,
(15) benzofuryl,
(16) isobenzofuryl,
(17) benzothienyl,
(18) pyrazolyl,
(19) indolyl,
(20) isoindolyl,
(21) purinyl,
(22) isoxazolyl,
(23) thiazolyl,
(24) oxazolyl,
(25) triazinyl, and
(26) benzthiazolyl,
(27) benzoxazolyl,
(28) imidazopyrazinyl,
(29) triazolopyrazinyl,
(30) naphthyridinyl,
(31) furopyridinyl,
(32) thiopyranopyrimidyl and the 5-oxide and 5-dioxide thereof,
(33) pyridazinyl,
(34) quinazolinyl,
(35) pteridinyl,
(36) triazolopyrimidyl,
(37) triazolopyrazinyl,
(38) thiapurinyl,
(39) oxapurinyl, and
(40) deazapurinyl,
wherein Ar items (1) to (40) are unsubstituted or mono or di-substituted, where the substituents are independently selected from:
(a) C1-6 alkyl, unsubstituted or substituted with a substituent selected from:
(1′) oxo,
(2′) hydroxy,
(3′) —OR7,
(4′) phenyl,
(5′) trifluoromethyl, and
(6′) phenyl or mono, di or tri-substituted phenyl, where the substituents are independently selected from:
hydroxy, cyano, halogen, and trifluoromethyl,
(b) halogen,
(c) —OC1-6 alkyl,
(d) trifluoromethyl,
(e) hydroxy,
(f) —NO2,
(g) —(CH2)pS(O)k—(C1-6 alkyl), wherein p is 0, 1 or 2,
(h) —(CH2)pS(O)j-NH2,
(i) —(CH2)pS(O)j-NH(C1-6 alkyl),
(j) —(CH2)pS(O)j-NHR6,
(k) —(CH2)pS(O)j-NR6—(C1-6 alkyl),
(l) —(CH2)pCONH2,
(m) —(CH2)pCONH—(C1-6 alkyl),
(n) —(CH2)pCONHR6,
(o) —(CH2)pCONR6—(C1-6 alkyl),
(p) —(CH2)pCO2H,
(q) —(CH2)pCO2—(C1-6 alkyl),
(r) —(CH2)pNR6R7,
(s) —(CH2)pNH—C(O)—C1-6 alkyl,
(t) —(CH2)pNH—C(O)—NH2,
(u) —(CH2)pNH—C(O)—NHC1-6 alkyl
(v) —(CH2)pNH—C(O)—N(C1-6-alkyl)2,
(w) —(CH2)pNH—S(O)k-C1-6 alkyl,
(x) —(CH2)pN(C1-3 alkyl)-C(O)—N(diC1-6 alkyl),
(y) —(CH2)p-heteroaryl, —C(O)-heteroaryl or —(CH2)p—O-heteroaryl , wherein the heteroaryl is selected from the group consisting of:
(1′) benzimidazolyl,
(2′) benzofuranyl,
(3′) benzothiophenyl,
(4′) benzoxazolyl,
(5′) furanyl,
(6′) imidazolyl,
(7′) indolyl,
(8′) isooxazolyl,
(9′) isothiazolyl,
(10′) oxadiazolyl,
(11′) oxazolyl,
(12′) pyrazinyl,
(13′) pyrazolyl,
(14′) pyridyl,
(15′) pyrimidyl,
(16′) pyrrolyl,
(17′) quinolyl,
(18′) tetrazolyl,
(19′) thiadiazolyl,
(20′) thiazolyl,
(21′) thienyl,
(22′) triazolyl,
(23′) dihydrobenzimidazolyl,
(24′) dihydrobenzofuranyl,
(25′) dihydrobenzothiophenyl,
(26′) dihydrobenzoxazolyl,
(27′) dihydrofuranyl
(28′) dihydroimidazolyl,
(29′) dihydroindolyl,
(30′) dihydroisooxazolyl,
(31′) dihydroisothiazolyl,
(32′) dihydrooxadiazolyl,
(33′) dihydropyrazinyl,
(34′) dihydropyrazolyl,
(35′) dihydropyridinyl,
(36′) dihydropyrimidinyl,
(37′) dihydroquinolinyl,
wherein the heteroaryl group of items (1′) to (37′) is unsubstituted, or mono, di or tri-substituted, where the substituents are selected from:
(a′) hydrogen,
(b′) C1-6 alkyl, branched or unbranched, unsubstituted or mono or di-substituted, where the substituents are selected from:
hydrogen and hydroxy,
(c′) hydroxy,
(d′) oxo,
(e′) —OR6,
(f′) halogen,
(g′) trifluoromethyl,
(h′) nitro,
(i′) cyano,
(j′) —NHR6,
(k′) —NR6R7,
(l′) —NHCOR6,
(m′) —NR6COR7,
(n′) —NHCO2R6,
(o′) —NR6CO2R7,
(p′) —NHS(O)jR6,
(q′) —NR6S(O)jR7,
(r′) —CONR6R7,
(s′) —COR6,
(t′) —CO2R6, and
(u′) —S(O)jR6;
R* is selected from the group consisting of:
(1) substituted C1-6 alkyl or C5-8 cycloalkyl, where the substituents are independently selected from:
(a) phenyl and
(b) mono, di or tri-substituted phenyl, where the substituent is independently selected from:
(1′) hydroxy,
(2′) C1-3 alkyl,
(3′) cyano,
(4′) halogen,
(5′) trifluoromethyl, and
(6′) C1-3 alkyloxy,
(2) phenyl, and
(3) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6 alkyl,
(c) C1-6 alkoxy
(d) cyano,
(e) halogen, and
(f) trifluoromethyl;
R6 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl,
(3) substituted C1-6 alkyl, where the substituents are independently selected from:
(a) phenyl,
(b) hydroxy,
(c) oxo,
(d) cyano,
(e) halogen,
(f) trifluoromethyl, and
(g) C5-8 cycloalkyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6 alkyl,
(c) cyano,
(d) halogen, and
(e) trifluoromethyl;
R7 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl or C5-8 cycloalkyl,
(3) substituted C1-6 alkyl or C5-8 cycloalkyl, where the substituents are independently selected from:
(a) phenyl,
(b) mono, di or tri-substituted phenyl, where the substituent is independently selected from:
(1′) hydroxy,
(2′) C1-3 alkyl,
(3′) cyano,
(4′) halogen,
(5′) trifluoromethyl, and
(6′) C1-3 alkyloxy,
(c) hydroxy,
(d) oxo,
(e) cyano,
(f) halogen, and
(g) trifluoromethyl,
(4) phenyl,
(5) mono, di or tri-substituted phenyl, where the substituents are independently selected from:
(a) hydroxy,
(b) C1-6 alkyl,
(c) C1-6 alkoxy
(d) cyano,
(e) halogen, and
(f) trifluoromethyl;
or R6 and R7 may be joined together to form a 5-, 6-, or 7-membered monocyclic saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and in which the ring is unsubstituted or mono or di-substituted, the substituents independently selected from:
(1) hydroxy,
(2) oxo,
(3) cyano,
(4) halogen,
(5) trifluoromethyl,
R8 is selected from the group consisting of:
(1) C2-10 alkenyl,
(2) C2-10 alkynyl,
(3) heteroaryl,
(4) substituted C1-10 alkyl, C2-10 alkenyl or C1-10 alkynyl, where the substituents are independently selected from:
(a) C3-4 cycloalkyl,
(b) hydroxy,
(c) C1-6 alkyloxy,
(d) cyano,
(e) heteroaryl,
(f) halogen,
(g) trifluoromethyl,
(h) —CO2H,
(i) —SO3H,
(j) —CO2R6,
(k) —CONR6R7,
(l) —NR4CONR6R7,
(m) —NR4CO2R6,
(n) —NR4COR6, and
(o) —SR4;
m is an integer selected from 0, 1 and 2,
n is an integer selected from 0, 1 and 2,
and pharmaceutically acceptable salts thereof.

307 more elements

Facts

Application

09/690,622Filed 17 Oct 2000 · division

Priority

2 Feb 1998

Granted

5 Nov 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
C07D 211/56
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 211/58
Nitrogen atoms: attached in position 4
C07D 233/56
Having two double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms or radicals containing only…