Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
The present invention pertains to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2A serotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggreagation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. The present invention also relates to the methods for the treatment of 5-HT 2A serotonin receptor associated disorders in combination with other pharmaceutical agents administered separately or together.
1. An isolated compound of Formula (Ia):
or a pharmaceutically acceptable salt, hydrate or solvate thereof;
wherein:
X is O or S;
Vis O or NH;
W is C 1-4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C 1-3 alkyl, C 1-4 alkoxy, carboxy, cyano, C 3-7 cycloalkyl, C 1-3 haloalkyl, halogen, oxo and imino, wherein said C 1-3 alkyl is optionally substituted with C 1-3 alkylsulfonyl;
Z is absent;
R 1 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-7 cycloalkyl;
R 2 is selected from the group consisting of H, C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, C 2-8 dialkylsulfonamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide;
R 3 is selected from the group consisting of H, C 2-6 alkenyl, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C 2-6 alkenyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 3-7 cycloalkyl, heteroaryl and phenyl groups are optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-5 acyl, C 1-5 acyloxy, C 2-6 alkenyl, C 1-4 alkoxy, C 1-8 alkyl, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-4 alkylcarboxamide, C 2-6 alkynyl, C 1-4 alkylsulfonamide, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, C 1-4 alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6 cycloalkyl, C 2-6 dialkylcarboxamide, halogen, C 1-4 haloalkoxy, C 1-4 haloalkyl, C 1-4 haloalkylsulfinyl, C 1-4 haloalkylsulfonyl, C 1-4 haloalkylthio, hydroxyl, nitro and sulfonamide;
R 4a is H;
R 4b is H, C 1-12 acyl, carbo-C 1-6 -alkoxy, or C(═O)O-aryl, wherein said C 1-12 acyl, carbo-C 1-6 -alkoxy, and —C(═O)O-aryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-6 alkylcarboxamide, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkylimino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, halogen, nitro, and phenyl;
or R 4b is —C(═O)OCR a R b OC(═O)R c , wherein R a , R b and R c are each independently selected from H, or C 1-6 alkyl;
R 5 , R 6 and R 7 are each selected independently from the group consisting of H, C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, C 2-8 dialkylsulfonamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, heterocyclyl, hydroxyl, thiol, and nitro;
and
R 8 is phenyl optionally substituted with substituents selected independently from the group consisting of C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 2-8 dialkylcarboxamide, C 2-8 dialkylsulfonamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, heteroaryl, heterocyclyl, hydroxyl, thiol, nitro, phenoxy and phenyl, wherein said C 2-6 alkenyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkylimino, C 2-8 dialkylamino, heteroaryl, heterocyclyl, phenyl, and phenoxy, and each said substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, heterocyclyl, hydroxyl, thiol and nitro.
2. The isolated compound according to claim 1 having Formula (Ic), or a pharmaceutically acceptable salt, hydrate or solvate thereof:
3. The isolated compound according to claim 1 , wherein X is O and V is O.
4. The isolated compound according to claim 1 , wherein W is —CH 2 CH 2 — optionally substituted with 1 to 2 substituents selected independently from the group consisting of C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 haloalkyl, oxo and imino, wherein said C 1-3 alkyl is optionally substituted with C 1-3 alkylsulfonyl.
5. The isolated compound according to claim 1 , wherein W is —CH 2 CH 2 —.
6. The isolated compound according to claim 1 , wherein R 1 is C 1-6 alkyl.
7. The isolated compound according to claim 1 , wherein R 1 is —CH 3 .
8. The isolated compound according to claim 1 , wherein R 2 is H.
9. The isolated compound according to claim 1 , wherein R 3 is H, Cl, or Br.
10. The isolated compound according to claim 1 , wherein R 4a and R 4b are both H.
11. The isolated compound according to claim 1 , wherein R 4a is H, and R 4b is C 1-12 acyl.
12. The isolated compound according to claim 1 , wherein R 4a is H, and R 4b is carbo-C 1-6 -alkoxy.
13. The isolated compound according to claim 1 , wherein R 4a is H, and R 4b is —C(═O)OCR a R b OC(═O)R c , wherein R a , R b and R c are each independently selected from H or CH 3 .
14. The isolated compound according to claim 1 , wherein R 5 , R 6 , and R 7 are each H.
15. The isolated compound according to claim 1 , wherein R 8 is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected independently from the group consisting of C 1-6 acyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-8 dialkylamino, cyano, C 3-7 cycloalkyloxy, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, and heteroaryl, wherein said C 1-6 alkyl is optionally substituted with heterocyclyl.
16. The isolated compound according to claim 1 , wherein R 8 is selected from the group consisting of phenyl, 2-chloro-phenyl, 3-methyl-phenyl, 4-chloro-phenyl, 2,4-difluoro-phenyl, 3,4-difluoro-phenyl, 2-methoxy-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 3,4-dichloro-phenyl, 2-methyl-phenyl, 4-trifluoromethyl-phenyl, 2-ethoxy-phenyl, 3-chloro-phenyl, 3-trifluoromethyl-phenyl, 3,4-dimethoxy-phenyl, 2-trifluoromethyl-phenyl, 3-fluoro-4-methoxy-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, 2,6-difluoro-phenyl, 3-methoxy-phenyl, and 4-methyl-phenyl.
17. The isolated compound according to claim 1 , wherein R 8 is selected from the group consisting of 2-morpholin-4-yl-phenyl, 3-dimethylamino-phenyl, 3-methoxy-phenyl, 4-dimethylamino-phenyl, 4-trifluoromethoxy-phenyl, 2-dimethylamino-phenyl, 4-cyano-phenyl, 3-cyclopentyloxy-4-methoxy-phenyl, 4-methoxy-3-methyl-phenyl, 4-methoxy-2-methyl-phenyl, 4-ethyl-phenyl, 4-thiophen-2-yl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl, 4-fluoro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 4-methoxy-phenyl, 3-ethoxy-phenyl, 2-fluoro-4-methoxy-phenyl, 4-fluoro-3-methoxy-phenyl, 4-isopropoxy-phenyl, 3,5-difluoro-phenyl, 4-trifluoromethyl-phenyl, 2,6-difluoro-4-methoxy-phenyl, 3-trifluoromethyl-phenyl, 4-methoxy-3-trifluoromethyl-phenyl, 4-bromo-phenyl, 3-methoxy-4-methyl-phenyl, 3-methoxy-2-methyl-phenyl, 4-chloro-phenyl, 2-bromo-5-methoxy-phenyl, 2-fluoro-3-methoxy-phenyl, 4-bromo-3-methyl-phenyl, 2,4-difluoro-phenyl, 3-chloro-phenyl, 2-cyano-phenyl, 4-methyl-phenyl, 5-methoxy-2-(2,2,2-trifluoro-ethoxy)-phenyl, phenyl, 2,4,5-trifluoro-3-methoxy-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-bromo-4-methoxy-phenyl, 3-fluoro-5-trifluoromethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 3-bromo-phenyl, 3-fluoro-4-methoxy-phenyl, 3-cyano-phenyl, 2,6-difluoro-phenyl, 4-methoxy-3,5-dimethyl-phenyl, 3-chloro-4-methoxy-phenyl, 3,4,5-trimethoxy-phenyl, 2-fluoro-5-methoxy-phenyl, 3-trifluoromethoxy-phenyl, 4-acetylamino-phenyl, 3-fluoro-4-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl, 3-fluoro-4-trifluoromethyl-phenyl, 3,4-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 4-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-phenyl, 2-methoxy-phenyl, and 4-acetyl-phenyl.
18. The isolated compound according to claim 1 having Formula (IIa), or a pharmaceutically acceptable salt, hydrate or solvate thereof::
wherein:
W is —CH 2 CH 2 — optionally substituted with 1 to 2 substituents selected independently from the group consisting of C 1-3 alkyl, C 3-7 cycloalkyl, C 1-3 haloalkyl, oxo and imino, wherein said C 1-3 alkyl is optionally substituted with C 1-3 alkylsulfonyl;
R 3 is H or halogen;
R 4b is H, C 1-12 acyl, or carbo-C 1-6 -alkoxy, wherein said C 1-5 acyl, and carbo-C 1-6 -alkoxy are each optionally substituted with halogen;
or
R 4b is —C(═O)OCR a R b OC(═O)R c , wherein R a , R b and R c are each independently selected from H, or C 1-6 alkyl; and
R 8 is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected independently from the group consisting of C 1-6 acyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-8 dialkylamino, C 1-6 alkylthio, cyano, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phenyl, and phenoxy, wherein said C 1-6 alkyl and phenyl are each optionally substituted with 1 substituent selected from heterocyclyl and halogen.
19. The isolated compound according to claim 1 having Formula (IIa), or a pharmaceutically acceptable salt, hydrate or solvate thereof:
wherein:
W is —CH 2 CH 2 —optionally substituted with 1 to 2 substituents selected independently from the group consisting of —CH 3 , cyclohexyl, —CH 2 CH 2 S(═O) 2 CH 3 , cyclohexylmethyl, isopropyl, t-butyl, oxo and imino;
R 3 is H, Cl, or Br;
R 4b is H; and
R 8 is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected independently from the group consisting of C 1-6 acyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-8 dialkylamino, C 1-6 alkylthio, cyano, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, heteroaryl, heterocyclyl, hydroxyl, phenyl, and phenoxy, wherein said C 1-6 alkyl and phenyl are each optionally substituted with 1 substituent selected from heterocyclyl and halogen.
20. The isolated compound according to claim 1 having Formula (IIa), or a pharmaceutically acceptable salt, hydrate or solvate thereof:
wherein:
W is —CH 2 CH 2 —optionally substituted with 1 to 2 substituents selected independently from the group consisting of —CH 3 , cyclohexyl, —CH 2 CH 2 S(═O) 2 CH 3 , cyclohexylmethyl, isopropyl, t-butyl, oxo and imino;
R 3 is H, Cl, or Br;
R 4b is is H; and
R 8 is selected from the group consisting of phenyl, 2-chloro-phenyl, 3-methyl-phenyl, 4-chloro-phenyl, 2,4-difluoro-phenyl, 3,4-difluoro-phenyl, 2-methoxy-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 3,4-dichloro-phenyl, 2-methyl-phenyl, 4-trifluoromethyl-phenyl, 2-ethoxy-phenyl, 3-chloro-phenyl, 3-trifluoromethyl-phenyl, 3,4-dimethoxy-phenyl, 2-trifluoromethyl-phenyl, 3-fluoro-4-methoxy-phenyl, 4-methoxy-phenyl, 4-fluoro-phenyl, 2,6-difluoro-phenyl, 3-methoxy-phenyl, and 4-methyl-phenyl.
21. The isolated compound according to claim 1 having Formula (IIa), or a pharmaceutically acceptable salt, hydrate or solvate thereof:
wherein:
W is —CH 2 CH 2 —;
R 3 is H, Cl, or Br;
R 4b is H; and
R 8 is selected from the group consisting of 2-morpholin-4-yl-phenyl, 3-dimethylamino-phenyl, 3-methoxy-phenyl, 4-dimethylamino-phenyl, 4-trifluoromethoxy-phenyl, 2-dimethylamino-phenyl, 4-cyano-phenyl, 3-cyclopentyloxy-4-methoxy-phenyl, 4-methoxy-3-methyl-phenyl, 4-methoxy-2-methyl-phenyl, 4-ethyl-phenyl, 4-thiophen-2-yl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl, 4-fluoro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 4-methoxy-phenyl, 3-ethoxy-phenyl, 2-fluoro-4-methoxy-phenyl, 4-fluoro-3-methoxy-phenyl, 4-isopropoxy-phenyl, 3,5-difluoro-phenyl, 4-trifluoromethyl-phenyl, 2,6-difluoro-4-methoxy-phenyl, 3-trifluoromethyl-phenyl, 4-methoxy-3-trifluoromethyl-phenyl, 4-bromo-phenyl, 3-methoxy-4-methyl-phenyl, 3-methoxy-2-methyl-phenyl, 4-chloro-phenyl, 2-bromo-5-methoxy-phenyl, 2-fluoro-3-methoxy-phenyl, 4-bromo-3-methyl-phenyl, 2,4-difluoro-phenyl, 3-chloro-phenyl, 2-cyano-phenyl, 4-methyl-phenyl, 5-methoxy-2-(2,2,2-trifluoro-ethoxy)-phenyl, phenyl, 2,4,5-trifluoro-3-methoxy-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-bromo-4-methoxy-phenyl, 3-fluoro-5-trifluoromethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 3-bromo-phenyl, 3-fluoro-4-methoxy-phenyl, 3-cyano-phenyl, 2,6-difluoro-phenyl, 4-methoxy-3,5-dimethyl-phenyl, 3-chloro-4-methoxy-phenyl, 3,4,5-trimethoxy-phenyl, 2-fluoro-5-methoxy-phenyl, 3-trifluoromethoxy-phenyl, 4-acetylamino-phenyl, 3-fluoro-4-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl, 3-fluoro-4-trifluoromethyl-phenyl, 3,4-difluoro-phenyl, 2-chloro-6-fluoro-phenyl, 4-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-phenyl, 2-methoxy-phenyl, and 4-acetyl-phenyl.
22. The isolated compound according to claim 1 , wherein said compound is selected from the group consisting of:
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-morpholin-4-yl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-dimethylamino-benzamide;
N-[4-((R)-2-Amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-dimethylamino-benzamide;
N-[4-((R)-2-Amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-dimethylamino-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-cyano-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-cyclopentyloxy-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-methyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-2-methyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-methyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-ethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-thiophen-2-yl-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(1,1,2,2-tetrafluoro-ethoxy)-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-trifluoromethyl-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-ethoxy-benzamide;
N-[4-((S)-2-Amino-4-methanesulfonyl-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-isopropoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3,5-difluoro-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;
N-[4-((S)-2-Amino-3-methyl-butoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-4-methoxy-benzamide;
N-[4-((R)-2-Amino-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-bromo-benzamide;
{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-2-methyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-4-methyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-2-methyl-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-bromo-5-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-3-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-bromo-3-methyl-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide;
N-[4-Carbamoylmethoxy-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-cyano-benzamide;
N-[4-Carbamoylmethoxy-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethoxy-benzamide;
N-[4-Carbamimidoylmethoxy-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methyl-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-5-methoxy-2-(2,2,2-trifluoro-ethoxy)-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4,5-trifluoro-3-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-trifluoromethyl-benzamide;
N-[4-(2-Acetylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-bromo-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-5-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-5-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-4-methyl-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-bromo-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-2-methyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-cyano-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-thiophen-2-yl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3,5-dimethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3,4,5-trimethoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2,6-difluoro-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-bromo-5-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-5-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-bromo-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-3-methoxy-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethoxy-benzamide;
N-[4-((S)-2-Amino-propoxy)-3- (4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-methoxy-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-bromo-benzamide;
N-[4-((S)-2-Amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;
4-Acetylamino-N-[4-(2-amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-cyclopentyloxy-4-methoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-methyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-benzamide;
N-[4-((S)-2-Amino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-methyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-chloro-4-fluoro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-chloro-3-fluoro-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3,4-difluoro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-chloro-6-fluoro-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-4-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-benzamide;
N-[4-(2-Amino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3,5-difluoro-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethoxy-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-methoxy-3,5-dimethyl-benzamide;
N-[4-(2-Amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-methoxy-benzamide;
4-Acetyl-N-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide;
N-[4-(2-Amino-2-methyl-propoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;
{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid 4-nitro-phenyl ester;
N-[4-[2-((S)-2-Acetylamino-4-methylsulfanyl-butyrylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;
{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid 2-chloro-ethyl ester;
{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid ethyl ester;
{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid 2-dimethylamino-ethyl ester;
N-[4-[2-(2-Dimethylamino-acetylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide;
Acetic acid 1-{2-[-(3-methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethylcarbamoyloxy}-ethyl ester;
N-[4-(2-Hexanoylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide; and
{2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester;
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
23. A pharmaceutical composition comprising a compound of Formula (Ia):
or a pharmaceutically acceptable salt, hydrate or solvate thereof;
wherein:
X is O or S;
V is O or NH;
W is C 14 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C 1-3 alkyl, C 14 alkoxy, carboxy, cyano, C 3-7 cycloalkyl, C 1-3 haloalkyl, halogen, oxo and imino, wherein said C 1-3 alkyl is optionally substituted with C 1-3 alkylsulfonyl;
Z is absent;
R 1 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-7 cycloalkyl;
R 2 is selected from the group consisting of H, C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, C 2-8 dialkylsulfonamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide;
R 3 is selected from the group consisting of H, C 2-6 alkenyl, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C 2-6 alkenyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 3-7 cycloalkyl, heteroaryl and phenyl groups are optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-5 acyl, C 1-5 acyloxy, C 2-6 alkenyl, C 1-4 alkoxy, C 1-8 alkyl, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-4 alkylcarboxamide, C 2-6 alkynyl, C 1-4 alkylsulfonamide, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, C 1-4 alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6 cycloalkyl, C 2-6 dialkylcarboxamide, halogen, C 1-4 haloalkoxy, C 1-4 haloalkyl, C 1-4 haloalkylsulfinyl, C 1-4 haloalkylsulfonyl, C 1-4 haloalkylthio, hydroxyl, nitro and sulfonamide;
R 4a is H;
R 4b is H, C 1-12 acyl, carbo-C 1-6 -alkoxy, or C(═O)O-aryl, wherein said C 1-12 acyl, carbo-C 1-6 -alkoxy, and —C(═O)O-aryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-6 alkylcarboxamide, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkylimino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, halogen, nitro, and phenyl;
or R 4b is —C(═O)OCR a R b OC(═O)R c , wherein R a , R b and R c are each independently selected from H, or C 1-6 alkyl;
R 5 , R 6 and R 7 are each selected independently from the group consisting of H, C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, C 2-8 dialkylsulfonamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, heterocyclyl, hydroxyl, thiol, and nitro; and
R 8 is phenyl optionally substituted with substituents selected independently from the group consisting of C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 2-8 dialkylcarboxamide, C 2-8 dialkylsulfonamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, heteroaryl, heterocyclyl, hydroxyl, thiol, nitro, phenoxy and phenyl, wherein said C 2-6 alkenyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkylimino, C 2-8 dialkylamino, heteroaryl, heterocyclyl, phenyl, and phenoxy, and each said substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, heterocyclyl, hydroxyl, thiol and nitro,
or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
24. An isolated compound that is N-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
25. A pharmaceutical composition comprising N-[4-(2-amino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.