US 6,723,730 B2 · Capsaicin receptor ligands

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
A is absent or is selected from the group consisting of O, S, NRA, NRACRBRB′, CRBRB′NRA, —CRA═CRB—, and C3H4;
where RA, RB, and RB′ are independently selected at each occurrence from hydrogen or alkyl;
Z is oxygen or sulfur;
each R3 and R4 independently
(a) selected from the group consisting of hydrogen;
halogen;
hydroxy;
amino;
cyano;
nitro;
—COOH;
—CHO, optionally substituted alkyl;
optionally substituted alkenyl;
optionally substituted alkynyl;
optionally substituted alkoxy;
optionally substituted alkylthio;
optionally substituted alkyl ketone;
optionally substituted alkylester;
optionally substituted alkylsulfinyl;
optionally substituted alkylsulfonyl;
optionally substituted mono- or di-alkylcarboxamide;
optionally substituted —S(O)nNHalkyl;
optionally substituted —S(O)nN(alkyl)(alkyl);
optionally substituted —NHC(═O)alkyl;
optionally substituted —NC(═O)(alkyl)(alkyl);
optionally substituted —NHS(O)nalkyl;
optionally substituted —NS(O)n(alkyl)(alkyl);
optionally substituted saturated heterocyclic ring or partially unsaturated heterocycle of from 5 to 8 atoms, which saturated heterocyclic ring or partially unsaturated heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, and S;
optionally substituted aryl having from 1 to 3 rings;
or optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms per ring independently selected from the group consisting of N, O, and S;
or
(b) joined to a R3 and R4 not attached to the same carbon may be joined to form an optionally substituted aryl ring, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is optionally substituted, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is optionally substituted and contains 1, 2, or 3 heteroatoms selected from N, O, and S;
Ar1 is selected from the group consisting of:
(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimdyl, pyrazinyl, benzimidazolyl naphthyl, indolyl, isoindolyl, benzfuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazoly, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with R5;
and
(b) bicyclic oxygen-containing groups of the formula:
optionally mono-, di-, or trisubstituted with R5, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to 8 ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;
Ar2 is selected from the group consisting of:
(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolyl, furanyl thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimdyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazoly, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with R5;
and
(b) bicyclic oxygen-containing groups of the formula:
optionally mono-, di-, or trisubstituted with R5, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to 8 ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;
R5 is independently selected at each occurence from the group consisting of halogen, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6, C2-6alkynyl substituted with 0-2 R6, C1-6alkoxy and Y;
R6 is independently selected at each occurence from the group consisting of halogen, hydroxy, cyano C1-4alkyl, C1-4alkoxy, —S(O)n(C1-4alkyl), halo(C1-4)alkly, halo(C1-4)alkoxy, CO(C1-4alkyl), CONH(C1-4alkyl), CON(C1-4alkyl1) (C1-4alkyl2) where alkyl1 and alkyl2 may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —XR7, and Y;
X is independently selected at each occurence from the group consisting of —CH2—, —CHR8—, —O—, —S(O)n—, —NH—, —NR8—, —C(═O)—, —C(═O)O—, —C(═O)NH—, —C(═O)NR8—, —S(O)nNH—, —S(O)nNR8—, NHC(═O)—, —NR8C(═O)—, —NHS(O)n—, and —NR8S(O)n—;
R7 and R8 are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubsitituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —O(alkyl), —NH(alkyl), —N(alkyl)(alkyl), —NHC(O)(alkyl), —N(alkyl)C(O)(alkyl), —NHS(O)n(alkyl), —S(O)n(alkyl), —S(O)nNH(alkyl), —S(O)nN(alkyl3)(alkyl4) where alkyl3 and alkyl4 are opitionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′;
Y and Y′ are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, mono- or dialkylamino, and alkylthio;
wherein said 3- to 8-memberered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S;
n is independently chosen at each occurrence from 0, 1, and 2.

47 more elements

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
A is absent or is selected from the group consisting of O, S, NRA, CRBRB′, NRACRBRB′, CRB RB′NRA, —CRA═CRB—, and C3H4;
where RA, RB, and RB′ are independently selected at each occurrence from hydrogen or alkyl;
each R3 and R4 is independently;
(a) selected from the group consisting of hydrogen;
halogen;
hydroxy;
amino;
cyano;
nitro;
—COOH;
—CHO, optionally substituted alkyl;
optionally substituted alkenyl;
optionally substituted alkynyl;
optionally substituted alkoxy;
optionally substituted mono or dialkylamino;
optionally substituted alkylthio;
optionally substituted alkyl ketone;
optionally substituted alkylester;
optionally substituted alkylsulfinyl;
optionally substituted alkylsulfonyl;
optionally substituted mono- or di-alkylcarboxamide;
optionally substituted —S(O)nNHalkyl;
optionally substituted —S(O)nN(alkyl)(alkyl);
optionally substituted —NHC(═O)alkyl;
optionally substituted —NC(═O)(alkyl)(alkyl);
optionally substituted —NHS(O)nalkyl;
optionally substituted —NS(O)n(alkyl)(alkyl);
optionally substituted saturated heterocyclic ring or partially unsaturated heterocycle of from 5 to 8 atoms, which saturated heterocyclic ring or partially unsaturated heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, and S;
optionally substituted aryl having from 1 to 3 rings;
or optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms per ring independently selected from the group consisting of N, O, and S;
or
(b) joined to a R3 and R4 not attached to the same carbon to form an optionally substituted aryl ring, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is optionally substituted, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is optionally substituted and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;
Ar1 is selected from the group consisting of:
(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolyl, furanyl thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazoly, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl;
wherein Ar1 is optionally mono-, di-, or trisubstituted with R5, and Ar2 is optionally mono-, di-, or trisubstituted with R9;
Ar1 is selected from the group consisting of:
cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrim1dyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazoly, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl;
wherein Ar1 is optionally mono-, di-, or trisubstituted with R5, and Ar2 is optionally mono-, di-, or trisubstituted with R9;
and
(b) groups of the formula:
optionally mono-, di-, or trisubstituted with R5, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to 8 ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;
R5 is independently selected at each occurence from the group consisting of cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alky substituted with 0-2 R6, alkenyl substituted with 0-2 R6, alkynyl substituted with 0-2 R6, alkoxy and Y;
R9 is independently selected at each occurrence from the group consisting of nitro, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 R6, alkenyl substituted with 0-2 R6, alkynyl substituted with 0-2 R6, alkoxy substituted with 0-2 R6, and Y;
R6 is independently selected at each occurrence from the group consisting of halogen , hydroxy, cyano, alkyl, alkoxy, —S(O)n(alkyl), haloalkyl, haloalkoxy, CO(alkyl), CONH(alkyl), CON(alkyl1)(alkyl2) where alkyl1 and alkyl2 may be joined to from a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —XR7, and Y;
X is independently selected at each occurence from the group consisting of —CH2—, —CHR8—, —O—, —S(O)n—, —NH—, —NR8—, —C(═O)—, —C(═O)O—, —C(═O)NH—, —C(═O)NR8—, —S(O)nNH—, —S(O)nNR8—, NHC(═O)—, —NR8C(═O)—, —NHS(O)n—, and —NR8S(O)n—;
R7 and R8 are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubstituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —O(alkyl), —NH(alkyl), —N(alkyl)(alkyl), —NHC(O)(alkyl), —N(alkyl)C(O)(alkyl), —NHS(O)n(alkyl), —S(O)n(alkyl), —S(O)nNH(alkyl), —S(O)nN(alkyl3)(alkyl4) where alkyl3 and alkyl4 are opitionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′;
Y and Y′ are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, mono- or dialkylamino, and alkylthio;
wherein said 3- to 8-memberered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S;
n is independently chosen at each occurrence from 0, 1, and 2.

47 more elements

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
G, Q, T, and W are the same or different and are selected from the group consisting of N, CH, and CR5, wherein T or W or both is N;
A is absent or is selected from the group consisting of O, S, NRA, CRBRB′, NRACRBRB′, CRB RB′NRA, —CRA═CRB—, and C3H4;
where RA, RB, and RB′ are independently selected at each occurrence from hydrogen alkyl;
Z is oxygen or sulfur;
each R3 and R4 is independently
(a) selected from the group consisting of hydrogen;
halogen;
hydroxy;
amino;
cyano;
nitro;
—COOH;
—CHO, optionally substituted C1-6alkyl;
optionally substituted C2-6alkenyl;
optionally substituted C2-6alkynyl;
optionally substituted C1-6alkoxy;
optionally substituted mono or di(C1-6)alkylamino;
optionally substituted C1-6alkylthio;
optionally substituted C1-6alkyl ketone;
optionally substituted C1-6alkylester;
optionally substituted C1-6alkylsulfinyl;
optionally substituted C1-6alkylsulfonyl;
optionally substituted mono- or di(C1-6)alkylcarboxamide;
optionally substituted —S(O)nNHC1-6alkyl;
optionally substituted —S(O)nN(C1-6alkyl)(C1-6alkyl);
optionally substituted —NHC(═O)C1-6alkyl;
optionally substituted —NC(═O)(C1-6alkyl)(C1-6alkyl);
optionally substituted —NHS(O)nC1-6alkyl;
optionally substituted —NS(O)n(C1-6alkyl)(C1-6alkyl);
optionally substituted saturated heterocyclic ring or partially unsaturated heterocycle of from 5 to 8 atoms, which saturated heterocyclic ring or partially unsaturated heterocycle contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;
optionally substituted aryl having from 1 to 3 rings;
and optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms per ring independently selected from the group consisting of N, O, and S;
or
(b) joined to a R3 and R4 not attached to the same carbon may be joined to form an optionally substituted aryl ring;
a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is optionally substituted;
or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is optionally substituted and contains 1, 2, or 3 heteroatoms selected from N, O, and S;
R5 represents 1 to 3 substituents independently selected at each occurrence from the group consisting of cyano, hydroxy, amino, C3-6 alkyl substituted with 0-2 R6, C2-6 alkenyl substituted with 0-2 R6, C2-6 alkynyl substituted with 0-2 R6, C3-6alkoxy, —NH(C1-6alkyl) substituted with 0-2 R6, —N(C1-6alkyl)(C1-6alkyl) where each alkyl is independently substituted with 0-2 R6, —XR7, and Y;
R9 represents 0 to 3 substituents and is independently selected at each occurrence from the group consisting of halogen, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6, C2-6alkynyl substituted with 0-2 R6, C1-6alkoxy substituted with 0-2 R6;
and Y;
R6 is independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy, —S(O)n(C1-4alkyl), halo(C1-4)alkyl, halo(C1-4) alkoxy, CO(C1-4alkyl), CONH(C1-4alkyl), CON(C1-4alkyl1)(C1-4alkyl2) where alkyl1 and alkyl2 may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —XR7, and Y;
X is independently selected at each occurrence from the group consisting of —CH2—, —CHR8—, —O—, —S(O)n—, —NH—, —NR8—, —C(═O)—, —C(═O)O—, —C(═O)NH—, —C(═O)NR8—, —S(O)nNH—, —S(O)nNR8—, NHC(═O)—, —NR8C(═O)—, —NHS(O)n—, and —NR8S(O)n—;
R7 and R8 are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubsitituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —O(C1-4alkyl), —NH(C1-4alkyl), —N(C1-4alkyl)(C1-4alkyl), —NHC(O)(C1-4alkyl), —N(C1-4alkyl)C(O)(C1-4alkyl), —NHS(O)n(C1-4alkyl), —S(O)n(C1-4alkyl), —S(O)nNH(C1-4alkyl), —S(O)nN(C1-4alkyl3)(C1-4alkyl4) where C1-4alkyl3 and C1-4alkyl4 are opitionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′;
Y and Y′ are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C1-4alklyl, C1-4alkoxy, halo(C1-4)alklyl, halo(C1-4)alkoxy, mono- or di(C1-4)alklylamino, and C1-4alklthio;
wherein said 3- to 8-membered heterocyclic group contain one or more heteroatom(s) independently selected from N, O, and S;
and
n is independently chosen at each occurrence from 0, 1, and 2.

44 more elements

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
A is selected from the group consisting of a single bond, S, NRA, NRACHRB, CHRBNRA, —CRA═CRB—, and C3H4;
where RA and RB are independently selected at each occurrence from the group consisting of hydrogen and alkyl;
each R3 and R4 is independently
(a) selected from the group consisting of hydrogen;
halogen;
hydroxy;
amino;
cyano;
nitro;
—COOH;
—CHO, optionally substituted alkyl;
optionally substituted alkenyl;
optionally substituted alkynyl;
optionally substituted alkoxy;
optionally substituted mono or dialkylamino;
optionally substituted alkylthio;
optionally substituted alkyl ketone;
optionally substituted alkylester;
optionally substituted alkylsulfinyl;
optionally substituted alkylsulfonyl;
optionally substituted mono- or di-alkylcarboxamide;
optionally substituted —S(O)nNHalkyl;
optionally substituted —S(O)nN(alkyl)(alkyl);
optionally substituted —NHC(═O)alkyl;
optionally substituted —NC(═O)(alkyl)(alkyl);
optionally substituted —NHS(O)nalkyl;
optionally substituted —NS(O)n(alkyl)(alkyl);
optionally substituted saturated heterocyclic ring or partially unsaturated heterocycle of from 5 to 8 atoms, which saturated heterocyclic ring or partially unsaturated heterocycle contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;
optionally substituted aryl having from 1 to 3 rings;
and optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms per ring independently selected from the group consisting of N, O, and S;
or
(b) joined to a R3 or R4 not attached to the same carbon to form an optionally substituted aryl ring;
a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is optionally substituted;
or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is optionally substituted and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;
R5 represents 0-3 substituents independently selected at each occurrence from the group consisting of cyano, nitro, haloalkyl, haloalkoxy, C2-6 alkenyl substituted with 0-2 R6, and C2-6 alkynyl substituted with 0-2 R6;
R9 represents 0-3 substituents independently selected at each occurrence from the group consisting of bromo, haloalkyl, haloalkoxy, hydroxy, C2-6 alkyl substituted with 0-2 R6, C2-6 alkenyl substituted with 0-2 R6, C2-6 alkynyl substituted with 0-2 R6, and C2-6 alkoxy;
R6 is independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy, —S(O)n(alkyl), haloalkyl, haloalkoxy, CO(alkyl), CONH(alkyl), CON(alkyl1)(alkyl2) where alkyl1 and alkyl2 may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —XR7, and Y;
X is independently selected at each occurrence from the group consisting of —CH2—, —CHR8—, —O—, —S(O)n—, —NH—, —NR8—, —C(═O)—, —C(═O)O—, —C(═O)NH—, —C(═O)NR8—, —S(O)nNH—, —S(O)nNR8—, NHC(═O)—, —NR8C(═O)—, —NHS(O)n—, and —NR8S(O)n—;
R7 and R8 are independently selected at each occurrence from straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 3 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 3 to 8 carbon atoms is unsubstituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —O(alkyl), —NH(alkyl), —N(alkyl)(alkyl), —NHC(O)(alkyl), —N(alkyl)C(O)(alkyl), —NHS(O)n(alkyl), —S(O)n(alkyl), —S(O)nNH(alkyl), —S(O)nN(alkyl3)(alkyl4) where alkyl3 and alkyl4 are optionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′;
Y and Y′ are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, mono- or dialkylamino, and alkylthio;
wherein said 3- to 8-membered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S;
and
n is independently chosen at each occurrence from 0, 1, and 2.

41 more elements

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof exhibits an EC50 or Ki of 1 micromolar or less in a standard assay of capsaicin receptor mediated calcium mobilization;
and wherein
A is absent or is selected from the group consisting of O, S, NRA, NRACRBRB′, CRBRB′NRA, —CRA═CRB—, and C3H4;
where
RA, RB, and RB′ are independently selected at each occurrence from hydrogen and C1-6 alkyl;
Z is oxygen or sulfur;
each R3 and R4 is independently
(a) selected from the group consisting of hydrogen, halogen, cyano, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6;
C2-6alkynyl substituted with 0-2 R6;
C1-6alkoxy substituted with 0-2 R6, —NH(C1-6alkyl) substituted with 0-2 R6, —N(C1-6alkyl)(C1-6alkyl) where each C1-6alkyl is independently substituted with 0-2 R6, —XR7, and Y;
or
(b) joined to a R3 or R4 not attached to the same carbon to form an aryl ring substituted with 0-3 R6, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is substituted with 0-2 R6, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is substituted with 0-2 R6 and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;
Ar1 is selected from the group consisting of:
(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with R5;
and
(b) bicyclic oxygen-containing groups of the formula:
optionally mono-, di-, or trisubstituted with R5, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to S ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;
Ar2 is selected from the group consisting of:
(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with R5;
and
(b) bicyclic oxygen-containing groups of the formula:
optionally mono-, di-, or trisubstituted with R5, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to 8 ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;
R5 is independently selected at each occurrence from the group consisting of halogen, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6, C2-6alkynyl substituted with 0-2 R6, C1-6alkoxy and Y;
R6 is independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy, —S(O)n(C1-4alkyl), halo(C1-4)alkyl, halo(C1-4)alkoxy, CO(C1-4alkyl), CONH(C1-4alkyl), CON(C1-4alkyl1)(C1-4alkyl2) where alkyl1 and alkyl2 may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —XR7, and Y;
X is independently selected at each occurrence from the group consisting of —CH2—, —CHR8—, —O—, —S(O)n—, —NH—, —NR8—, —C(═O)—, —C(═O)O—, —C(═O)NH—, —C(═O)NR8—, —S(O)nNH—, —S(O)nNR8—, NHC(═O)—, —NR8C(═O)—, —NHS(═O)n—, and —NR8S(O)n—;
R7 and R8 are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubstituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —O(C1-4alkyl), —NH(C1-4alkyl), —NH(C1-4alkyl)(C1-4alkyl), —NHC(O)(C1-4alkyl), —NH(C1-4alkyl)C(O)(C1-4alkyl), —NHS(O)n(C1-4alkyl), —S(O)n(C1-4alkyl), —S(O)nNH(C1-4alkyl), —S(O)nN(C1-4alkyl3)(C1-4alkyl4) where C1-4alkyl3 and C1-4alkyl4 are optionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′;
Y and Y′ are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C1-4alkyl, C1-4alkoxy, halo(C1-4)alkyl, halo(C1-4)alkoxy, mono- or di(C1-4)alkylamino, and C1-4alkylthio;
wherein said 3- to 8-membered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S;
and
n is independently chosen at each occurrence from 0, 1, and 2.

27 more elements

A compound of the Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F:

or a pharmaceutically acceptable salt of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, wherein
A represents NH or O;
each R3 and R4 is independently
(a) selected from the group consisting of hydrogen, halogen, cyano, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6;
C2-6alkynyl substituted with 0-2 R6;
C1-6alkoxy substituted with 0-2 R6, —NH(C1-6alkyl) substituted with 0-2 R6, —N(C1-6alkyl)(C1-6alkyl) where each C1-6alkyl is independently substituted with 0-2 R6, —XR7, and Y;
or
(b) joined to a R3 or R4 not attached to the same carbon to form an aryl ring substituted with 0-3 R6, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is substituted with 0-2 R6, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is substituted with 0-2 R6 and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;
R5 represents from 1 to 3 substituents independently selected at each occurrence from the group consisting of halogen, cyano, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6, C2-6alkynyl substituted with 0-2 R6, C1-6alkoxy, —NH(C1-6alkyl) substituted with 0-2 R6, —N(C1-6alkyl)(C1-6alkyl) where each C1-6alkyl is independently substituted with 0-2 R6, —XR7, and Y;
R9 represents from 1 to 3 substituents independently selected at each occurrence from the group consisting of halogen, cyano, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6, C2-6alkynyl substituted with 0-2 R6, C1-6alkoxy substituted with 0-2 R6, and Y;
R6 is independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy, —S(O)n(C1-4alkyl), halo(C1-4)alkyl, halo(C1-4)alkoxy, CO(C1-4alkyl), CONH(C1-4alkyl), CON(C1-4alkyl1)(C1-4alkyl2) where alkyl1 and alkyl2 may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —XR7, and Y;
X is independently selected at each occurrence from the group consisting of —CH2—, —CHR8—, —O—, —S(O)n—, —NH—, —NR8—, —C(═O)—, —C(═O)O—, —C(═O)NH—, —C(═O)NR8—, and —NR8S(O)n—;
R7 and R8 are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubstituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —O(C1-4alkyl), —NH(C1-4alkyl), —N(C1-4alkyl)(C1-4alkyl), —NHC(O)(C1-4alkyl), —N(C1-4alkyl)C(O)(C1-4alkyl), —NHS(O)n(C1-4alkyl), —S(O)n(C1-4alkyl), —S(O)nNH(C1-4alkyl), —S(O)nN(C1-4alkyl3)(C1-4alkyl4) where C1-4alkyl3 and C1-4alkyl4 are optionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′;
Y and Y′ are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C1-4alkyl, C1-4alkoxy, halo(C1-4)alkyl, halo(C1-4)alkoxy, mono- or di(C1-4)alkylamino, and C1-4alkylthio;
wherein said 3- to 8-membered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S;
and
n is independently chosen at each occurrence from 0, 1, and 2.

14 more elements

A compound of the Formula:

or a pharmaceutically acceptable salt thereof, wherein:
A is absent or is selected from the group consisting of O, S, NRA, CRBRB′, NRACRBRB′, CRBRB′NRA, —CRA═CRB—, and C3H4;
where RA, RB, and RB′ are independently selected at each occurrence from hydrogen and C1-6 alkyl;
each R3 and R4 is independently
(a) selected from the group consisting of hydrogen, halogen, cyano, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6;
C2-6alkynyl substituted with 0-2 R6;
C1-6alkoxy substituted with 0-2 R6, —NH(C1-6alkyl) substituted with 0-2 R6, —N(C1-6alkyl)(C1-6alkyl) where each C1-6alkyl is independently substituted with 0-2 R6, —XR7, and Y;
or
(b) joined to a R3 or R4 not attached to the same carbon to form an aryl ring substituted with 0-3 R6, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is substituted with 0-2 R6, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is substituted with 0-2 R6 and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;
R5 is selected from the group consisting of bromo, fluoro, iodo, halo(C1-6)alkyl, halo(C3-6)alkoxy, C3-6alkyl substituted with 0-3 R6, C2-6alkenyl substituted with 0-3 R6, C2-6alkynyl substituted with 0-3 R6, C3-6alkoxy, (C3-8cycloalkyl)C1-4alkyl, —NH(C1-6alkyl) substituted with 0-2 R, —N(C1-6alkyl)(C1-6alkyl) where each C1-6alkyl is substituted with 0-2 R6, Y, —(C═O)Y, —(CH2)Y, and —(CH(CN))Y;
R9 is selected from the group consisting of halogen, cyano, —N(SO2C1-6alkyl)(SO2C1-6alkyl), —SO2NH2, halo(C1-6)alkyl, halo(C1-6)alkoxy, C1-6alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6, C2-6alkynyl substituted with 0-2 R6, and C1-6alkoxy substituted with 0-2 R6;
R5B represents from 0 to 2 substituents independently selected at each occurrence from the group consisting of
(a) halogen, cyano, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, (C3-8cycloalkyl)C1-4alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6, C2-6alkynyl substituted with 0-2 R6, C1-6alkoxy, —NH(C1-6alkyl) substituted with 0-2 R6, —N(C1-6alkyl)(C1-6alkyl) where each C1-6alkyl is independently substituted with 0-2 R6, and Y;
and
(b) groups that are joined to R5 to form a C3-8cycloalkyl group or a saturated heterocyclic ring or partially unsaturated heterocycle, each of which is optionally substituted by from 1 to 5 substituents independently chosen from cyano, halogen, hydroxy, C1-4alkyl, C1-4alkoxy, —NH(C1-4alkyl), —N(C1-4alkyl)(C1-4alkyl) halo(C1-4)alkyl, and halo(C1-4)alkoxy, wherein the saturated heterocyclic ring or partially unsaturated heterocycle contains from 4 to 3 ring atoms of which 1, 2, or 3 are heteroatoms independently selected from N, O, and S;
R9B represents from 0 to 2 substituents independently selected at each occurrence from halogen, cyano, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl substituted with 0-2 R6, (C3-8cycloalkyl)C1-4alkyl substituted with 0-2 R6, C2-6alkenyl substituted with 0-2 R6, C2-6alkynyl substituted with 0-2 R6, C1-6alkoxy substituted with 0-2 R6, and Y;
R6 is independently selected at each occurrence from the group consisting of cyano, halogen, hydroxy, C1-4alkyl, C1-4alkoxy, —S(O)n(C1-4alkyl), halo(C1-4)alkyl, halo(C1-4)alkoxy, CO(C1-4alkyl), CONH(C1-4alkyl), CON(C1-4alkyl1)(C1-4alkyl2) where alkyl1 and alkyl2 may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —XR7, and Y;
X is independently selected at each occurrence from the group consisting of —CH2—, —CHR8—, —O—, —S(O)n—, —NH—, —NR8—, —C(═O)—, —C(═O)NH—, —C(═O)NH8—, —S(═O)nNH—, —S(O)nNR8—, NHC(═O)—, —NR8C(═O)—, —NHS(O)n—, and —NH8S(O)n—;
R7 and R8 are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —O(C1-4alkyl), NH(C1-4alkyl), —N(C1-4alkyl)(C1-4alkyl) —NHC(O)(C1-4alkyl), —N(C1-4alkyl)C(O)(C1-4alkyl) —NHS(O)n(C1-4alkyl), —S(O)n(C1-4alkyl), —S(O)nNH(C1-4alkyl), —S(O)nN(C1-4alkyl3)(C1-4alkyl4) where C1-4alkyl3 and C1-4alkyl4 are optionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′;
Y and Y′ are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C1-4alkyl, C1-4alkoxy, halo(C1-4)alkyl, halo(C1-4)alkoxy, mono- or di(C1-4)alkylamino, and C1-4alkylthio;
wherein said 3- to 8-membered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S;
and
n is independently chosen at each occurrence from 0, 1, and 2.

20 more elements

A compound of the Formula:

or a pharmaceutically acceptable salt thereof, wherein:
A is absent or is selected from the group consisting of O, S, NRA, CRBRB′, NRACRBRB′, CRBRB′NRA, —CRA═CRB—, and C3H4;
where RA, RB, and RB′ are independently selected at each occurrence from hydrogen and C1-6 alkyl;
R3 and R4 are independently chosen at each occurrence from the group consisting of hydrogen, halogen, cyano, nitro, halo(C1-6)alkyl, halo(C1-6)alkoxy, hydroxy, amino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, —NH(C1-6alkyl), and —N(C1-6alkyl)(C1-6alkyl);
R5 is selected from the group consisting of halogen, halo(C1-6)alkyl, C3-6alkyl substituted with 0-3 R6, C2-6alkenyl substituted with 0-3 R6, (C3-8cycloalkyl)C1-4alkyl substituted with 0-3 R6, and Y;
R5B and R9B each represent from 0 to 2 substituents and are independently chosen from halogen, cyano, nitro, halo(C1-2)alkyl, halo(C1-2)alkoxy, amino, C1-4alkyl, and C1-2alkoxy;
R6 is independently selected at each occurrence from the group consisting of cyano, halogen, hydroxy, C1-4alkyl, C1-4alkoxy, —NH(C1-4alkyl), —N(C1-4alkyl)(C1-4alkyl) and Y;
Y is independently selected at each occurrence from C3-8 cycloalkyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl,morpholinyl, thiomorpholinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, and imidazolyl, each of which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C1-4alkyl, C1-4alkoxy, halo(C1-4)alkyl, halo(C1-4)alkoxy, mono- or di(C1-4)alkylamino, and C1-4alkylthio.

5 more elements

Capsaicin receptor ligands

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Capsaicin receptor ligands

Life of this patent

Abstract

Claims185