5-HT2C receptor agonists and compositions and methods of use

Patent metadata

Field	Value
Publication number	US-10836764-B2
Application number	US-201716326522-A
Country	US
Kind code	B2
Filing date	Aug 18, 2017
Priority date	Aug 19, 2016
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

The present invention relates to compounds of Formula A and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2C receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a 5-HT 2C receptor-mediated disorder, such as, weight management, inducing satiety, and decreasing food intake, and for preventing and treating obesity, antipsychotic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, tobacco/nicotine dependence, drug addiction, alcohol addiction and the like, obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders, urinary incontinence, psychiatric disorders (including schizophrenia, anorexia nervosa, and bulimia nervosa), Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorders (including parkinsonism and antipsychotic-induced movement disorder), hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea. Also provided are compositions comprising a compound herein, optionally in combination with a supplemental agent.

First claim

What is claimed is:

1. A compound selected from compounds of Formula A, and pharmaceutically acceptable salts, solvates, and hydrates thereof:

wherein
n is 1 or 2;
each of R 6 , R 7 , and R 8 is independently selected from hydrogen and C 1 -C 6 alkyl;
R 9 is hydrogen or C 1 -C 6 alkyl;
X 2 is N or CR 2 ;
X 3 is N or CR 3 ;
X 4 is N or CR 4 ;
wherein each of R 1 , R 2 , R 3 , and R 4 is independently selected from:
a) hydrogen;
b) C 1 -C 6 alkyl optionally substituted with one or more groups each independently selected from:
C 6 -C 10 aryl optionally substituted with halogen;
C 1 -C 6 alkoxy optionally substituted with 3- to 8-membered heterocycloalkyl;
C 3 -C 8 cycloalkyl;
OH;
CN;
3- to 8-membered heterocycloalkyl;
5- to 10-membered heteroaryl; and
halogen;
c) C 2 -C 6 alkenyl;
d) C 3 -C 5 cycloalkyl;
e) 5- to 10-membered heteroaryl optionally substituted with halogen;
f) C 6 -C 10 aryl optionally substituted with one or more groups each independently selected from halogen, C 1 -C 6 alkoxy optionally substituted with halogen, and C 1 -C 6 alkyl optionally substituted with halogen,
wherein the C 6 -C 10 aryl is optionally fused to a heterocyclic ring;
g) CONHC 1 -C 6 alkyl optionally substituted with halogen;
h) NH(CO)R 5 , wherein R 5 is selected from C 1 -C 6 alkoxy, C 1 -C 6 alkyl optionally substituted with C 6 -C 10 aryl, C 6 -C 10 aryl optionally substituted with halogen, 3- to 8-membered heterocycloalkyl, and C 3 -C 8 cycloalkyl;
i) halogen; and
j) C 1 -C 6 alkylthio;

wherein at least one but not more than two of X 2 , X 3 and X 4 are N, and either
(i) only one of X 2 , X 3 and X 4 is N and at least one of R 1 , R 2 , R 3 , and R 4 is hydrogen; or
(ii) only X 2 and X 4 are N.

2. The compound of claim 1 , wherein n is 1.

3. The compound of claim 1 , wherein n is 2.

4. The compound of claim 1 , wherein R 1 is hydrogen.

5. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl.

6. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl substituted with C 6 -C 10 aryl, C 6 -C 10 aryl that is substituted with halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy that is substituted with 3- to 8-membered heterocycloalkyl, C 3 -C 8 cycloalkyl, OH, CN, 3- to 8-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or halogen.

7. The compound of claim 1 , wherein R 1 is C 6 -C 10 aryl optionally substituted with one or more groups each independently selected from halogen, C 1 -C 6 alkoxy optionally substituted with halogen, and C 1 -C 6 alkyl optionally substituted with halogen, wherein the C 6 -C 10 aryl is optionally fused to a heterocyclic ring.

8. The compound of claim 1 , wherein R 1 is CONHC 1 -C 6 alkyl, CONHC 1 -C 6 alkyl substituted with halogen, halogen, or C 1 -C 6 alkylthio.

9. The compound of claim 1 , wherein R 1 is NH(CO)R 5 , wherein R 5 is selected from the group consisting of: C 1 -C 6 alkoxy, C 1 -C 6 alkyl optionally substituted with C 6 -C 10 aryl, C 6 -C 10 aryl optionally substituted with halogen, 3- to 8-membered heterocycloalkyl, and C 3 -C 8 cycloalkyl.

10. The compound of claim 1 , wherein R 1 is selected from the group consisting of: benzo[d][1,3]dioxol-5-yl, methylcarbamoyl, hydrogen, 2-chlorobenzamido, 3-(trifluoromethoxy)phenyl, benzyl, 2-methoxyethyl, pentyl, pentan-2-yl, ethyl, isopropyl, butyl, propyl, isobutyl, 3-fluorobenzyl, 2-fluorobenzyl, methyl, isopentyl, methoxymethyl, cyclohexylmethyl, neopentyl, cyclobutyl(hydroxy)methyl, (ethoxycarbonyl)amino, 2-phenylacetamido, butyramido, thiophen-2-yl, cyclohexyl, 4-fluorobenzyl, pyrrolidine-1-carboxamido, (tetrahydro-2H-pyran-2-yl)methyl, ((tetrahydro-2H-pyran-4-yl)methoxy)methyl, 2-(trifluoromethyl)phenyl, 4-methoxyphenyl, bromo, cyclobutylmethyl, 2,3-difluorobenzamido, benzamido, (2,2-difluoroethyl)carbamoyl, cyclopropanecarboxamido, 2-cyanoethyl, pyridin-2-ylmethyl, but-2-en-1-yl, isopropoxymethyl, 5-chloropyridin-2-yl, cyclopentyl, cyclobutyl, chloro, cyclopropyl, 3,3,3-trifluoropropyl, phenethyl, and cyclopentylmethyl.

11. The compound of claim 1 , wherein X 2 is CR 2 .

12. The compound of claim 1 , wherein X 2 is CR 2 and R 2 is selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with C 6 -C 10 aryl, C 1 -C 6 alkyl substituted with C 1 -C 6 alkoxy, C 1 -C 6 alkyl substituted with C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl substituted with 3- to 8-membered heterocycloalkyl, C 3 -C 8 cycloalkyl, halogen, or C 1 -C 6 alkylthio.

13. The compound of claim 1 , wherein X 2 is CR 2 and R 2 is selected from the group consisting of: hydrogen, propyl, benzyl, 2-cyanoethyl, isopropoxymethyl, cyclohexylmethyl, (tetrahydro-2H-pyran-2-yl)methyl, cyclobutyl, chloro, and cyclopentylmethyl.

14. The compound of claim 1 , wherein X 3 is CR 3 .

15. The compound of claim 1 , wherein X 3 is CR 3 and R 3 is hydrogen or C 1 -C 6 alkylthio.

16. The compound of claim 1 , wherein X 3 is CR 3 and R 3 is selected from the group consisting of: hydrogen and methylthio.

17. The compound of claim 1 , wherein X 4 is CR 4 .

18. The compound of claim 1 , wherein X 4 is CR 4 and R 4 is hydrogen.

19. The compound of claim 1 , wherein R 6 is hydrogen.

20. The compound of claim 1 , wherein R 6 is C 1 -C 6 alkyl.

21. The compound of claim 1 , wherein R 6 is selected from the group consisting of: hydrogen and methyl.

22. The compound of claim 1 , wherein R 7 is hydrogen.

23. The compound of claim 1 , wherein R 8 is hydrogen.

24. The compound of claim 1 , wherein R 9 is hydrogen.

25. The compound of claim 1 , wherein R 9 is C 1 -C 6 alkyl.

26. The compound of claim 1 , wherein R 9 is selected from the group consisting of: hydrogen and methyl.

27. The compound of claim 1 , wherein:
R 1 is selected from the group consisting of: benzo[d][1,3]dioxol-5-yl, methylcarbamoyl, hydrogen, 2-chlorobenzamido, 3-(trifluoromethoxy)phenyl, benzyl, 2-methoxyethyl, pentyl, pentan-2-yl, ethyl, isopropyl, butyl, propyl, isobutyl, 3-fluorobenzyl, 2-fluorobenzyl, methyl, isopentyl, methoxymethyl, cyclohexylmethyl, neopentyl, cyclobutyl(hydroxy)methyl, (ethoxycarbonyl)amino, 2-phenylacetamido, butyramido, thiophen-2-yl, cyclohexyl, 4-fluorobenzyl, pyrrolidine-1-carboxamido, (tetrahydro-2H-pyran-2-yl)methyl, ((tetrahydro-2H-pyran-4-yl)methoxy)methyl, 2-(trifluoromethyl)phenyl, 4-methoxyphenyl, bromo, cyclobutylmethyl, 2,3-difluorobenzamido, benzamido, (2,2-difluoroethyl)carbamoyl, cyclopropanecarboxamido, 2-cyanoethyl, pyridin-2-ylmethyl, but-2-en-1-yl, isopropoxymethyl, 5-chloropyridin-2-yl, cyclopentyl, cyclobutyl, chloro, cyclopropyl, 3,3,3-trifluoropropyl, phenethyl, and cyclopentylmethyl;
X 2 is N, or X 2 is CR 2 and R 2 is selected from the group consisting of: hydrogen, propyl, benzyl, 2-cyanoethyl, isopropoxymethyl, cyclohexylmethyl, (tetrahydro-2H-pyran-2-yl)methyl, cyclobutyl, chloro, and cyclopentylmethyl;
X 3 is N, or X 2 is CR 3 and R 3 is selected from the group consisting of: hydrogen and methylthio;
X 4 is N, or X 4 is CR 4 and R 4 is hydrogen;
R 6 is selected from the group consisting of: hydrogen and methyl; and
R 9 is selected from the group consisting of: hydrogen and methyl.

28. The compound of claim 1 , wherein the c

Assignees

• Arena Pharm Inc

Inventors

• Semple Graeme
• Ren Albert S
• Schrader Thomas O
• Kasem Michelle
• Zhu Xiuwen

Classifications

• C07D471/14 Primary

  Ortho-condensed systems · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P3/00 Primary

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P25/34

  Tobacco-abuse · CPC title

• A61P25/32

  Alcohol-abuse · CPC title