3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto

Patent metadata

Field	Value
Publication number	US-10781180-B2
Application number	US-201816177672-A
Country	US
Kind code	B2
Filing date	Nov 1, 2018
Priority date	Nov 19, 2004
Publication date	Sep 22, 2020
Grant date	Sep 22, 2020

Abstract

The present invention also relates to the methods for the treatment of 5-HT2A serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.

First claim

What is claimed is:

1. A compound of Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;

wherein:
V is O, S, S(═O), S(═O) 2 , or NR 10 ;
W is C 1-4 alkylene optionally substituted with 1 to 8 substituents selected independently from the group consisting of C 1-3 alkyl, C 1-4 alkoxy, carboxy, cyano, C 1-3 haloalkyl, halogen, and oxo; or W is absent;
X is C(═O), C(═S), or absent;
Y is O, NR 11 , or absent;
Z is C 1-4 alkylene, or C 3-6 cycloalkylene, each optionally substituted with 1 to 8 substituents selected independently from the group consisting of C 1-3 alkyl, C 1-4 alkoxy, carboxy, cyano, C 1-3 haloalkyl, halogen, hydroxyl, and oxo; or 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 to 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 4 is heterobicyclic, heterocyclic, or heteroaryl each optionally substituted with substituents selected independently from the group consisting of C 1-6 acyl, C 1-12 acyloxy, C 2-6 alkenyl, C 1-4 alkoxy, C 1-6 alkoxycarbonylamino, C 1-6 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 3-7 cycloalkylcarbonyl, C 2-6 dialkylcarboxamide, formyl, halogen, C 1-4 haloalkoxy, C 1-4 haloalkyl, C 1-4 haloalkylsulfinyl, C 1-4 haloalkylsulfonyl, C 1-4 haloalkylthio, heteroaryl, hydroxyl, nitro, phenyl and sulfonamide; wherein said C 1-5 acyl, C 1-5 acyloxy, C 1-4 alkoxy, C 1-6 alkyl, C 1-4 alkylcarboxamide, amino, carbo-C 1-6 -alkoxy, and heteroaryl are each optionally substituted with substituents selected independently from the group consisting of C 1-6 alkyl, C 1-5 acyl, C 1-4 alkoxy, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-4 alkylcarboxamide, C 1-4 alkylsulfonyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6 cycloalkyl, halogen, C 1-4 haloalkoxy, C 1-4 haloalkyl, hydroxyl, and phenyl;
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, heterocyclic, hydroxyl, thiol, nitro, phenoxy, and phenyl;
R 8 is C 1-8 alkyl, C 2-6 alkenyl, aryl, C 3-7 cycloalkyl, or heteroaryl each 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 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, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent substituents together with said aryl or said heteroaryl form a C 5-7 cycloalkyl optionally comprising 1 to 2 oxygen atoms and optionally substituted with F, Cl or Br; and 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, heterocyclic, and phenyl are each optionally substituted with 1 to 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, hydroxyl, thiol and nitro; and
R 9 , R 10 , and R 11 are each independently H or C 1-8 alkyl;
provided that R 4 is a group other than an oxiranyl group.

2. The compound according to claim 1 having Formula (Ic):

3. The compound according to claim 1 , wherein V is O.

4. The compound according to claim 1 , wherein W is —CH 2 —, —CH 2 CH 2 —, —CH 2 C(═O)—, —CH 2 CH 2 CH 2 —, —C(CH 3 ) 2 C(═O)—, —CH 2 CH(CH 3 )—, —CH(CH 3 )CH 2 —, —C(CH 3 ) 2 CH 2 —, or —CH 2 C(CH 3 ) 2 —.

5. The compound according to claim 1 , wherein W is absent.

6. The compound according to claim 1 , wherein X is C(═O).

7. The compound according to claim 1 , wherein X is absent.

8. The compound according to claim 1 , wherein Y is NH, O or absent.

9. The compound according to claim 1 , wherein Z is absent, —CH 2 —, —CH(OH)—, —CF 2 —, —C(CH 3 ) 2 —, 1,1-cyclopropyl, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )—, or —C(═O)—.

10. The compound according to claim 1 , wherein R 1 is —CH 3 .

11. The compound according to claim 1 , wherein R 2 is H.

12. The compound according to claim 1 , wherein R 3 is H, F, Cl or Br.

13. The compound according to claim 1 , wherein R 4 is heterobicyclic, heterocyclic, or heteroaryl each optionally substituted with substituents selected independently from the group consisting of C 1-6 acyl, C 1-12 acyloxy, C 1-6 alkoxycarbonylamino, C 1-4 alkoxy, C 1-6 alkyl, C 1-4 alkylca

Assignees

• Arena Pharm Inc

Inventors

• Teegarden Bradley
• Xiong Yifeng
• Strah-Pleynet Sonja
• Jayakumar Honnappa
• Dosa Peter I
• Feichtinger Konrad
• Casper Martin
• Lehmann Juerg
• Jones Robert M
• Unett David J
• Choi Jin Sun Karoline

Classifications

• C07D231/12 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P9/12

  Antihypertensives · CPC title