Fused pyrazole derivatives and methods of treatment of metabolic-related disorders thereof

A method of treating atherosclerosis in a human patient in need of such treatment comprising administering to said patient a compound of Formula (Ia):

• or a pharmaceutically acceptable salt, hydrate or solvate thereof, in an amount that is effective to treat atherosclerosis;
• or a pharmaceutical composition comprising the compound of Formula (Ia), or the pharmaceutically acceptable salt, hydrate or solvate thereof, in an amount that is effective to treat atherosclerosis in combination with a pharmaceutically acceptable carrier;
• wherein:
• X is N and Z is CR7, or X is CR7 and Z is N;
• R1 and R4 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, C1-6-alkylamido, amino-C1-6-alkylsulfonyl, C1-6-alkylthioamido, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol;
• R2 and R3 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, C1-6-alkylamido, amino-C1-6-alkylsulfonyl, C1-6-alkylthioamido, arylsulfinyl, arylsulfonyl, arylthio, carbamimidoyl, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, C1-6-dialkylamido, C1-6-dialkylthioamido, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, heterocyclic-oxy, heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C4-7 oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid and thiol;
• wherein said C1-6 alkyl is optionally substituted with substituents selected from the group consisting of C1-6 acyl, C1-6 acyloxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 haloalkoxy, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, nitro, phenoxy and phenyl;
• or
• R2 and R3 together with the carbon to which they are both bonded form a C3-6 cycloalkyl;
• R5 and R6 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol;
• and R7 is carbo-C1-6-alkoxy, carboxy or tetrazol-5-yl.

A method of treating dyslipidemia in a human patient in need of such treatment comprising administering to said patient a compound of Formula (Ia):

• or a pharmaceutically acceptable salt, hydrate or solvate thereof, in an amount that is effective to treat dyslipidemia;
• or a pharmaceutical composition comprising the compound of Formula (Ia), or the pharmaceutically acceptable salt, hydrate or solvate thereof, in an amount that is effective to treat dyslipidemia in combination with a pharmaceutically acceptable carrier;
• wherein:
• X is N and Z is CR7, or X is CR7 and Z is N;
• R1 and R4 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, C1-6-alkylamido, amino-C1-6-alkylsulfonyl, C1-6-alkylthioamido, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol;
• R2 and R3 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, C1-6-alkylamido, amino-C1-6-alkylsulfonyl, C1-6-alkylthioamido, arylsulfinyl, arylsulfonyl, arylthio, carbamimidoyl, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, C1-6-dialkylamido, C1-6-dialkylthioamido, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, heterocyclic-oxy, heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C4-7 oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid and thiol;
• wherein said C1-6 alkyl is optionally substituted with substituents selected from the group consisting of C1-6 acyl, C1-6 acyloxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 haloalkoxy, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, nitro, phenoxy and phenyl;
• or
• R2 and R3 together with the carbon to which they are both bonded form a C3-6 cycloalkyl;
• R5 and R6 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C3-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol;
• and R7 is carbo-C1-6-alkoxy, carboxy or tetrazol-5-yl.

A method of raising HDL in a human comprising administering to said human a therapeutically-effective amount of a compound of Formula (Ia):

• or a pharmaceutically acceptable salt, hydrate or solvate thereof;
• or a pharmaceutical composition comprising a therapeutically-effective amount of the compound of Formula (Ia), or the pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with a pharmaceutically acceptable carrier;
• wherein:
• X is N and Z is CR7, or X is CR7 and Z is N;
• R1 and R4 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, C1-6-alkylamido, amino-C1-6-alkylsulfonyl, C1-6-alkylthioamido, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol;
• R2 and R3 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, C1-6-alkylamido, amino-C1-6-alkylsulfonyl, C1-6-alkylthioamido, arylsulfinyl, arylsulfonyl, arylthio, carbamimidoyl, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, C1-6-dialkylamido, C1-6-dialkylthioamido, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, heterocyclic-oxy, heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C4-7 oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid and thiol;
• wherein said C1-6 alkyl is optionally substituted with substituents selected from the group consisting of C1-6 acyl, C1-6 acyloxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7cycloalkyloxy, C2-6 dialkylamino, C1-6 haloalkoxy, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, nitro, phenoxy and phenyl;
• or
• R2 and R3 together with the carbon to which they are both bonded form a C3-6 cycloalkyl;
• R5 and R6 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol;
• and R7 is carbo-C1-6-alkoxy, carboxy or tetrazol-5-yl.

A method of producing a pharmaceutical composition comprising admixing a compound of Formula (Ia):

• or a pharmaceutically acceptable salt, hydrate or solvate thereof,
• wherein:
• X is N and Z is CR7, or X is CR7 and Z is N;
• R1 and R4 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide;
• C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, C1-6-alkylamido, amino-C1-6-alkylsulfonyl, C1-6-alkylthioamido, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol;
• R2 and R3 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, C1-6-alkylamido, amino-C1-6-alkylsulfonyl, C1-6-alkylthioamido, arylsulfinyl, arylsulfonyl, arylthio, carbamimidoyl, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, C1-6-dialkylamido, C1-6-dialkylthioamido, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, heterocyclic-oxy, heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro, C4-7 oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid and thiol;
• wherein said C1-6 alkyl is optionally substituted with substituents selected from the group consisting of C1-6 acyl, C1-6 acyloxy, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C3-7 cycloalkyloxy, C2-6 dialkylamino, C1-6 haloalkoxy, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, nitro, phenoxy and phenyl;
• or
• R2 and R3 together with the carbon to which they are both bonded form a C3-6 cycloalkyl;
• R5 and R6 are each selected independently from the group consisting of H, C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylamino, C1-6 alkylcarboxamide, C1-6 alkylthiocarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylthioureyl, C1-6 alkylureyl, amino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-6 dialkylamino, C1-6 dialkylcarboxamide, C1-6 dialkylthiocarboxamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, heterocyclic, hydroxyl, nitro, sulfonamide and thiol;
• and R7is carbo-C1-6-alkoxy, carboxy or tetrazol-5-yl and a pharmaceutically acceptable carrier.