5-HT receptor ligands and uses thereof

A pharmaceutical composition comprising

• (1) a compound of Formula (IA)
• 15
• wherein
• Y is nitrogen;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• at least one of R1a, R1b , R1d, and R1e is independently selected from the group consisting of halogen, nitro, amino, (C1-C4)alkylamino, cyano, —C(O)NH2, (C1-C4)alkyl, halo-substituted(C1-C4)alkyl, (C1-C4) alkoxy, and halo-substituted(C1-C4)alkoxy, or R1a and R1b taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R1a taken together with R2a or R2b forms a five- or six-membered, fully saturated fused ring;
• R1c is hydrogen;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, partially or fully saturated (C3-C6)cycloalkyl, or one of which taken together with R1a forms a five- or six-membered, fully saturated fused ring;
• n is 0, 1, or 2;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, or (C1-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C1-C4)alkoxy, (C1-C4)alkoxy-carbonyl, or (C3-C4)alkenyl;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt;
• and
• (2) a pharmaceutically acceptable excipient, diluent, or carrier

A pharmaceutical composition comprising (1) a compound of Formula (IB)

• 17
• wherein
• Y is N;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• R1a, R1b, R1c, R1d and R1e are each independently hydrogen, halogen, nitro, cyano, amino, (C1-C4)alkylamino, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, —C(O)NH2, R1a and R1b taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R1a taken together with R2a or R2b forms a five- or six-membered, fully saturated, fused ring;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, partially or fully saturated (C3-C6)cycloalkyl, or one of which taken together with R1a forms a five- or six-membered, fully saturated fused ring;
• n is 0, 1, or 2;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, (C0-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C1-C4)alkoxy, (C1-C4)alkoxy-carbonyl, or (C3-C4)alkenyl;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt;
• (2) an antiobesity agent;
• and
• (3) a pharmaceutically acceptable excipient, diluent, or carrier.

A method for treating a 5-HT2 receptor-mediated disease, condition, or disorder in an animal comprising the step of administering to said animal a therapeutically effective amount of a compound of Formula of (IB)

• 18
• wherein
• Y is N;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• R1a, R1b, R1c, R1d and R1e are each independently hydrogen, halogen, nitro, cyano, amino, (C1-C4)alkylamino, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, —C(O)NH2, R1a and R1b taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R1a taken together with R2a or R2b forms a five- or six-membered, fully saturated, fused ring;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, partially or fully saturated (C3-C6)cycloalkyl, or one of which taken together with R1a forms a five- or six-membered, fully saturated fused ring;
• n is 0, 1, or 2;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C1-C4)alkoxy, (C1-C4)alkoxy-carbonyl, or (C3-C4)alkenyl;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt.

A pharmaceutical kit comprising

• (a) a dosage form comprising a compound of Formula (IB)
• 19
• wherein
• Y is N;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• R1a, R1b, R1c, R1d and R1e are each independently hydrogen, halogen, nitro, cyano, amino, (C1-C4)alkylamino, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, —C(O)NH2, R1a and R1b taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R1a taken together with R2a or R2b forms a five- or six-membered, fully saturated, fused ring;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, partially or fully saturated (C3-C6)cycloalkyl, or one of which taken together with R1a forms a five- or six-membered, fully saturated fused ring;
• n is 0, 1, or 2;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C1-C4)alkoxy, (C1-C4)alkoxy-carbonyl, or (C3-C4)alkenyl;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt;
• and
• (b) instructions describing a method of using said dosage form to treat or prevent a 5-HT2 receptor-mediated disease, condition, or disorder.

A pharmaceutical kit comprising

• (a) a first unit dosage form comprising
• (i) a compound of Formula (IB)
• 20
• wherein
• Y is N;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• R1a, R1b, R1c, R1d and R1e are each independently hydrogen, halogen, nitro, cyano, amino, (C1-C4)alkylamino, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, —C(O)NH2, R1a and R1b taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R1a taken together with R2a or R2b forms a five- or six-membered, fully saturated, fused ring;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, partially or fully saturated (C3-C6)cycloalkyl, or one of which taken together with R1a forms a five- or six-membered, fully saturated fused ring;
• n is 0, 1, or 2;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C1-C4)alkoxy, (C1-C4)alkoxy-carbonyl, or (C3-C4)alkenyl;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt;
• and
• (ii) a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof;
• b) a second dosage form comprising
• (i) at least one additional pharmaceutical agent selected from the group consisting of an apo-B/MTP inhibitor, an MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β3 adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a cannabinoid 1 receptor antagonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti-related protein, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or reverse agonist, and a neuromedin U receptor agonist;
• and
• (ii) a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof;
• and
• c) a container.

A method for treating or preventing a 5-HT2 receptor-mediated disease, condition, or disorder comprising administering to an animal in need of such treatment

• a) a therapeutically effective amount of a compound of Formula (IB)
• 21
• wherein
• Y is N;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• R1a, R1b, R1c, R1d and R1e are each independently hydrogen, halogen, nitro, cyano, amino, (C1-C4)alkylamino, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, —C(O)NH2, R1a and R1b taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R1a taken together with R2a or R2b forms a five- or six-membered, fully saturated, fused ring;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, partially or fully saturated (C3-C6)cycloalkyl, or one of which taken together with R1a forms a five- or six-membered, fully saturated fused ring;
• n is 0,1, or 2;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C1-C4)alkoxy, (C1-C4)alkoxy-carbonyl, or (C3-C4)alkenyl;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt;
• and
• b) a therapeutically effective amount of at least one additional pharmaceutical agent selected from the group consisting of an apo-B/MTP inhibitor, an MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β3 adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a cannabinoid 1 receptor antagonist, a melanin concentrating hormone antagonist, leptin, a leptin analog, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a Neuropeptide-Y antagonist, a thyromimetic agent, dehydroepiandrosterone or an analog thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, a urocortin binding protein antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, an AGRP, a ghrelin receptor antagonist, a histamine 3 receptor antagonist or reverse agonist, and a neuromedin U receptor agonist.

A method of increasing lean meat content in an edible animal comprising the step of administering to said edible animal a lean meat increasing amount of a compound of Formula (IB)

• 22
• wherein
• Y is N;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• R1a, R1b, R1c, R1d and R1e are each independently hydrogen, halogen, nitro, cyano, amino, (C1-C4)alkylamino, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, —C(O)NH2, R1a and R1b taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R1a taken together with R2a or R2b forms a five- or six-membered, fully saturated, fused ring;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, partially or fully saturated (C3-C6)cycloalkyl, or one of which taken together with R1a forms a five- or six-membered, fully saturated fused ring;
• n is 0,1, or 2;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C0-C4)alkoxy, (C1-C4)alkoxy-carbonyl, or (C3-C4)alkenyl;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt.

A compound of Formula (IC)

• 23
• wherein
• Y is N;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• Q is a heteroaryl group selected from the group consisting of pyridin-2-yl, pyridin-3-yl, furan-3-yl, furan-2-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, quinolin-2-yl, quinolin-3-yl, isoquinolin-3-yl, benzofuran-2-yl, benzofuran-3-yl, isobenzofuran-3-yl, benzothiophen-2-yl, benzothiophen-3-yl, indol-2-yl, indol-3-yl, 2H-imidazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,3,4-thiadiazoi-2-yl, 1,3,4-thiadiazol-5-yl, and 1,2,4-oxathiazol-3-yl, where the heteroaryl group is optionally substituted with one to three substituents independently selected from halo, (C1-C4)alkyl, cyano, nitro, amino, (C1-C4)alkylamino, or (C1-C4)alkyoxy;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, or partially or fully saturated (C3-C6)cycloalkyl;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, or (C1-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C1-C4)alkoxy, (C1-C4)alkoxy-carbonyl, or (C3-C4)alkenyl;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt.

A method for treating female sexual dysfunction (FSD) comprising the step of administering to a female in need thereof a therapeutically effective amount of a compound of Formula (IA).

• 24
• wherein
• Y is nitrogen;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• at least one of R1a, R1b, R1d, and R1e is independently selected from the group consisting of halogen, nitro, amino, (C1-C4)alkylamino, cyano, —C(O)NH2, (C1-C4)alkyl, halo-substituted(C1-C4)alkyl, (C1-C4) alkoxy, and halo-substituted(C1-C4)alkoxy, or R1a and R1b taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R1a taken together with R2a or R2b forms a five- or six-membered, fully saturated fused ring;
• R1c is hydrogen;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, partially or fully saturated (C3-C6)cycloalkyl, or one of which taken together with R1a forms a five- or six-membered, fully saturated fused ring;
• n is 0, 1, or 2;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, or (C0-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C1-C4)alkoxy, (C1-C4)alkoxy-carbonyl, (C3-C4)alkenyl, or an amino-protecting group;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt.

A method for treating male erectile dysfunction (MED) comprising the step of administering to a male in need thereof a therapeutically effective amount of a compound of Formula (IA).

• 25
• wherein
• Y is nitrogen;
• X and Z are each independently CR, where R for each occurrence is hydrogen, halogen, (C1-C4)alkyl, amino, or (C1-C4)alkylamino;
• W is oxy, thio, amino, (C1-C4)alkylamino, or acetylamino;
• at least one of R1a, R1b, R1d, and R1e is independently selected from the group consisting of halogen, nitro, amino, (C1-C4)alkylamino, cyano, —C(O)NH2, (C1-C4)alkyl, halo-substituted(C1-C4)alkyl, (C1-C4) alkoxy, and halo-substituted(C1-C4)alkoxy, or R1a and R1b taken together form a five- or six-membered, aromatic or partially or fully saturated fused ring, or R1a taken together with R2a or R2b forms a five- or six-membered, fully saturated fused ring;
• R1c is hydrogen;
• R2a and R2b are each independently hydrogen, (C1-C4)alkyl, partially or fully saturated (C3-C6)cycloalkyl, or one of which taken together with R1a forms a five- or six-membered, fully saturated fused ring;
• n is 0, 1, or 2;
• R3a and R3b are each independently hydrogen, halogen, (C1-C4)alkyl, or (C1-C4)alkyl substituted with hydroxy, fluoro, or (C1-C4)alkoxy;
• R4 is hydrogen, hydroxy, (C1-C4)alkyl, (C1-C4)alkyl substituted with hydroxy or cyano, (C1-C4)alkylcarbonyl, (C1-C4)alkoxy, (C1-C4)alkoxy-carbonyl, (C3-C4)alkenyl, or an amino-protecting group;
• a nitrogen oxide thereof, a prodrug of said compound or said nitrogen oxide;
• a pharmaceutically acceptable salt of said compound, said nitrogen oxide, or said prodrug, or a solvate or hydrate of said compound, said nitrogen oxide, said prodrug, or said salt.