Tricyclic delta-opioid modulators

A compound of Formula (I):

• wherein:
• G is independently selected from —C(Z)N(R1)R2, phenyl, or a heterocycle selected from the group consisting of imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl, imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl, pyrimidinyl, triazinyl, isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl, and pyridinyl;
• wherein phenyl and the heterocycles of G are optionally substituted with one to three substituents independently selected from the group consisting of C1-8alkanyl, C1-8alkanyloxy, hydroxy(C1-8)alkanyl, carboxy(C1-8)alkanyl, C1-8alkanylcarbonylamino, halogen, hydroxy, cyano, oxo, thioxo, amino, C1-6alkanylamino, di(C1-6alkanyl)amino, C1-8alkanylthio, aminocarbonyl, aminothiocarbonyl, C1-8alkanylaminocarbonyl, di(C1-8alkanyl)aminocarbonyl, and C1-6alkanyloxycarbonylamino;
• provided that when G is pyridin-3-yl or thien-3-yl and R3 is hydrogen, R4 is not hydrogen;
• and provided that when G is N,N-diethylaminocarbonyl and R3 is methyl, R4 is not hydrogen;
• and provided that when G is N,N-diethylaminocarbonyl and R3 is hydrogen, R4 is not α′-chloro;
• R1 is hydrogen or C1-4alkanyl;
• R2 is selected from the group consisting of hydrogen;
• C1-4alkanyl;
• phenyl;
• and C1-6cycloalkanyl;
• wherein C1-4alkanyl is optionally substituted with one to three substituents independently selected from the group consisting of phenyl, amino, C1-6alkanylamino, di(C1-6alkanyl)amino, C1-4alkanyloxy, hydroxy, fluoro, chloro, cyano, aminocarbonyl, C1-8alkanylaminocarbonyl, di(C1-8alkanyl)aminocarbonyl, and phenoxy;
• and wherein any phenyl-containing substituent of R2 and C1-6cycloalkanyl substituents of R2 are optionally substituted with one to three substituents independently selected from the group consisting of C1-8alkanyl, C1-8alkanyloxy, trifluoromethyl, phenyl, fluoro, hydroxy, C1-8alkanylthio, C1-8alkanylsulfonyl, and C1-8alkanylsulfonylamino;
• or R1 and R2 taken together with the nitrogen to which they are attached form a 5-7 membered heterocycloalkyl wherein said heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of C1-8alkanyl, hydroxy(C1-8)alkanyl, and hydroxy;
• R3 is selected from the group consisting of hydrogen, C1-8alkanyl, C2-8alkenyl, C2-8alkynyl, C1-8alkanyloxy(C1-8)alkanyl, C1-8alkanylthio(C1-8)alkanyl, hydroxyC1-8alkanyl, thioformyl, phenylimino(C1-8)alkanyl, phenyl(C1-8)alkanyl, and heteroaryl(C1-8)alkanyl wherein heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl;
• wherein phenyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkanyloxy and hydroxy;
• or optionally, when phenyl and heteroaryl are optionally substituted with two substituents attached to adjacent carbon atoms, the two substituents together form a single fused moiety;
• wherein the moiety is selected from —O(CH2)1-3O—;
• R4 is one to three substituents independently selected from the group consisting of hydrogen, C1-6alkanyl, C1-6alkanyloxy, C6-10arylamino wherein aryl is optionally substituted with one to three substitutents independently selected from the group consisting of C1-6alkanyl, C1-6alkoxy, halogen, and hydroxy, formylamino, pyridinylamino, aminocarbonyl, C1-6alkanylaminocarbonyl, C1-6alkanylcarbonylamino, halogen, hydroxy, C6-10aryl, chromanyl, chromenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrazolyl, thiazolyl, and thienyl;
• R5 is one to two substituents independently selected from the group consisting of hydrogen and halogen;
• A is CH2CH2;
• Y is O;
• Z is O, NH, N(C1-6alkanyl), N(OH), N(OC1-6alkanyl), or N(phenyl);
• and
• enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

A compound of Formula (I):

• wherein:
• G is selected from —C(Z)N(R1)R2, phenyl, or a heterocycle selected from the group consisting of imidazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl, imidazolinyl, thienyl, pyrazolyl, pyrimidinyl, triazinyl, isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl, and pyridinyl;
• wherein phenyl and the heterocycles of G are optionally substituted with one to three substituents independently selected from the group consisting of C1-4alkanyl, C1-4alkanyloxy, hydroxy(C1-4)alkanyl, carboxy(C1-4)alkanyl, C1-4alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, amino, C1-6alkanylamino, di(C1-6alkanyl)amino, C1-8alkanylthio, aminocarbonyl, aminothiocarbonyl, C1-8alkanylaminocarbonyl, and di(C1-8alkanyl)aminocarbonyl;
• provided that when G is pyridin-3-yl or thien-3-yl and R3 is hydrogen, R4 is not hydrogen;
• and provided that when G is N,N-diethylaminocarbonyl and R3 is methyl, R4 is not hydrogen;
• and provided that when G is N,N-diethylaminocarbonyl and R3 is hydrogen, R4 is not α′-chloro;
• R1 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl;
• R2 is selected from the group consisting of hydrogen, C1-4alkanyl, phenyl, and C1-6cycloalkanyl;
• wherein C1-4alkanyl is optionally substituted with one to three substituents independently selected from the group consisting of phenyl, C1-4alkanyloxy, hydroxy, fluoro, aminocarbonyl, C1-8alkanylaminocarbonyl, di(C1-8alkanyl)aminocarbonyl, and phenoxy;
• and wherein any phenyl-containing substituent of R2 is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkanyl, C1-6alkanyloxy, fluoro, hydroxy, and C1-6alkanylthio;
• or R1 and R2 taken together with the nitrogen to which they are attached form pyrrolidinyl or piperidinyl ring wherein said pyrrolidinyl or piperidinyl is optionally substituted with a substituent selected from the group consisting of C1-3alkanyl and hydroxy;
• R3 is selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl, methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and heteroaryl(C1-8)alkanyl wherein the heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl;
• wherein the phenyl in any phenyl-containing substituent is optionally substituted with one hydroxyl group;
• R4 is one to two substituents independently selected from the group consisting of hydrogen, C1-4alkanyl, C1-4alkanyloxy, halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy;
• R5 is hydrogen;
• A is CH2CH2;
• Y is O;
• Z is O, NH, or N(OH);
• and
• enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

A compound of Formula (I):

• wherein:
• G is selected from —C(Z)N(R1)R2, 2-methylcarbonylaminophenyl, 2-aminocarbonyl-phenyl, 1H-tetrazol-4-yl, 2-methyl-tetrazol-5-yl, 4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 4H-[1,2,4]-oxadiazol-5-thioxo-3-yl, 4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl, or pyridin-3-yl;
• provided that when G is pyridin-3-yl and R3 is hydrogen, R4 is not hydrogen;
• and provided that when G is N,N-diethylaminocarbonyl and R3 is methyl, R4 is not hydrogen;
• and provided that when G is N,N-diethylaminocarbonyl and R3 is hydrogen, R4 is not α′-chloro;
• R1is hydrogen, methyl, or ethyl;
• R2 is selected from the group consisting of hydrogen, C1-4alkanyl and phenyl;
• wherein C1-4alkanyl is optionally substituted with one to three substituents independently selected from the group consisting of phenyl, C1-4alkanyloxy, hydroxy, fluoro, and phenoxy;
• and wherein any phenyl-containing substituent of R2 is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkanyl, C1-6alkanyloxy, fluoro, and hydroxy;
• or R1 and R2taken together with the nitrogen to which they are attached form a pyrrolidinyl or piperidinyl ring wherein said pyrrolidinyl or piperidinyl is optionally substituted with a substituent selected from C1-3alkanyl or hydroxy;
• R3 is selected from the group consisting of hydrogen, methyl, allyl, 2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl, methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and heteroaryl(C1-8)alkanyl wherein the heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl;
• wherein the phenyl in any phenyl-containing substituent is optionally substituted with one hydroxyl group;
• R4 is one to three substituents independently selected from the group consisting of hydrogen, C1-4alkanyl, C1-4alkanyloxy, halogen, phenyl, furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy;
• R5 is hydrogen;
• A is CH2CH2;
• Y is O;
• Z is O or NH;
• and
• enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.

A compound of Formula (I):

• wherein:
• G is —C(Z)N(R1)R2, C6-10aryl, or a heterocycle selected from the group consisting of imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl, imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl, pyrimidinyl, triazinyl, furyl, indazolyl, indolyl, indolinyl, isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, and pyridinyl;
• wherein aryl and the heterocycles of G are optionally substituted with one to three substituents independently selected from the group consisting of C1-8alkanyl, C2-8alkenyl, C2-8alkynyl, C1-8alkanyloxy, hydroxy(C1-8)alkanyl, carboxy(C1-8)alkanyl, C1-8alkanylcarbonylamino, halogen, hydroxy, cyano, nitro, oxo, thioxo, amino, C1-6alkanylamino, di(C1-6alkanyl)amino, C1-8alkanylthio, C1-8alkanylsulfonyl, C1-8alkanylsulfonylamino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, C1-8alkanylaminocarbonyl, di(C1-8alkanyl)aminocarbonyl, and C1-6alkanyloxycarbonylamino;
• R1 is a substituent selected from the group consisting of hydrogen, C1-8alkanyl, C2-8alkenyl, and C2-8alkynyl;
• R2 is a substituent selected from the group consisting of hydrogen;
• C1-8alkanyl;
• C2-8alkenyl;
• C2-8alkynyl;
• C6-10aryl;
• and
• C1-8cycloalkanyl;
• wherein C1-8alkanyl is optionally substituted with one to three substituents independently selected from the group consisting of phenyl, amino, C1-6alkanylamino, di(C1-6alkanyl)amino, C1-6alkanyloxy, thioC1-6alkanyloxy, hydroxy, fluoro, chloro, cyano, aminocarbonyl, C1-8alkanylaminocarbonyl, di(C1-8alkanyl)aminocarbonyl, C1-6alkanyloxycarbonyl, and aryloxy;
• and wherein any aryl-containing substituents and C1-8cycloalkanyl substituents of R2 are optionally substituted with one to three substituents independently selected from the group consisting of C1-8alkanyl, C2-8alkenyl, C2-8alkynyl, C1-8alkanyloxy, trifluoromethyl, trifluoromethoxy, phenyl, halogen, cyano, hydroxy, C1-8alkanylthio, C1-8alkanylsulfonyl, and C1-8alkanylsulfonylamino;
• or R1 and R2 taken together with the nitrogen to which they are attached form a 5-7 membered cycloheteroalkyl optionally substituted with one to three substituents independently selected from the group consisting of C1-8alkanyl, hydroxy(C1-8)alkanyl, hydroxy, amino, C1-6alkanylamino, di(C1-6alkanyl)amino, and halogen;
• R3 is a substituent selected from the group consisting of hydrogen, C1-8alkanyl, halo1-3(C1-8)alkanyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkanyl, cycloalkanyl(C1-8)alkanyl, C1-8alkanyloxy(C1-8)alkanyl, C1-8alkanylthio(C1-8)alkanyl, hydroxyC1-8alkanyl, C1-8alkanyloxycarbonyl, halo1-3(C1-8)alkanylcarbonyl, formyl, thioformyl, carbamimidoyl, phenylimino(C1-8)alkanyl, phenyl(C1-8)alkanyl, phenyl(C1-8)alkenyl, phenyl(C1-8)alkynyl, naphthyl(C1-8)alkanyl and heteroaryl(C1-8)alkanyl wherein the heteroaryl is selected from the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl, indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl;
• wherein phenyl, naphthyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkanyl, C2-6alkenyl, C1-6alkanyloxy, amino, C1-6alkanylamino, di(C1-6alkanyl)amino, C1-6alkanylcarbonyl, C1-6alkanylcarbonyloxy, C1-6alkanylcarbonylamino, C1-6alkanylthio, C1-6alkanylsulfonyl, halogen, hydroxy, cyano, fluoro(C1-6)alkanyl, thioureido, and fluoro(C1-6)alkanyloxy;
• alternatively, when phenyl and heteroaryl are optionally substituted with alkanyl or alkanyloxy substituents attached to adjacent carbon atoms, the two substituents can together form a fused cyclic alkanyl or cycloheteroalkanyl selected from the group consisting of —(CH2)3-5—, —O(CH2)2-4—, —(CH2)2-4O—, and —O(CH2)1-3O—;
• R4 is one to three substituents independently selected from the group consisting of hydrogen;
• C1-6alkanyl;
• C2-6alkenyl;
• C2-6alkynyl;
• aryl(C2-6)alkynyl;
• C1-6alkanyloxy;
• amino;
• C1-6alkanylamino;
• di(C1-6alkanyl)amino;
• C6-10arylamino wherein aryl is optionally substituted with one to three substitutents independently selected from the group consisting of C1-6alkanyl, C1-6alkoxy, halogen, and hydroxy;
• formylamino;
• pyridinylamino;
• C1-6alkanylcarbonyl;
• C1-6alkanylcarbonyloxy;
• C1-6alkanyloxycarbonyl;
• aminocarbonyl;
• C1-6alkanylaminocarbonyl;
• di(C1-6alkanyl)aminocarbonyl;
• C1-6alkanylcarbonylamino;
• C1-6alkanylthio;
• C1-6alkanylsulfonyl;
• halogen;
• hydroxy;
• cyano;
• hydroxycarbonyl;
• C6-10aryl;
• chromanyl;
• chromenyl;
• furanyl;
• imidazolyl;
• indazolyl;
• indolyl;
• indolinyl;
• isoindolinyl;
• isoquinolinyl;
• isothiazolyl;
• isoxazolyl;
• naphthyridinyl;
• oxazolyl;
• pyrazinyl;
• pyrazolyl;
• pyridazinyl;
• pyridinyl;
• pyrimidinyl;
• pyrrolyl;
• quinazolinyl;
• quinolinyl;
• quinolizinyl;
• quinoxalinyl;
• tetrazolyl;
• thiazolyl;
• thienyl;
• fluoroalkanyl;
• and fluoroalkanyloxy;
• or optionally, when R4 is two substituents attached to adjacent carbon atoms, the two substituents together form a single fused moiety, wherein the fused moiety is —(CH2)3-5—, —O(CH2)2-4—, —(CH2)2-4O—, —O(CH2)1-3O—, or —S—C(NH2)═N—;
• R5 is one to two substituents independently selected from the group consisting of hydrogen, C1-6alkanyl, C2-6alkenyl, C1-6alkanyloxy, amino, C1-6alkanylamino, di(C1-6alkanyl)amino, C1-6alkanylcarbonyl, C1-6alkanylcarbonyloxy, C1-6alkanyloxycarbonyl, C1-6alkanylaminocarbonyl, C1-6alkanylcarbonylamino, C1-6alkanylthio, C1-6alkanylsulfonyl, halogen, hydroxy, cyano, fluoro(C1-6)alkanyl and fluoro(C1-6)alkanyloxy;
• A is —(CH2)m—, wherein m is 2 or 3;
• Y is O;
• Z is O, S, NH, N(C1-6alkanyl), N(OH), N(OC1-6alkanyl), or N(phenyl);
• and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof.