Compounds that modulate intracellular calcium
View Patent ↗Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of SOC channel activity.
1. A compound of Formula (I):
wherein:
A is C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl or heteroaryl wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, aryl or heteroaryl are independently optionally substituted with at least one R; or A is aryl or heteroaryl substituted with two R groups on adjacent carbon atoms wherein the two R groups and the carbon atoms to which they are attached form a C 4 -C 8 cycloalkyl or C 2 -C 8 heterocycloalkyl;
R is selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , —C═CH, —C═CR 3 , C 1 -C 6 alkylenealkyne, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, phenyl, —NHS(═O) 2 R 3 , S(═O) 2 N(R 4 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 3 , —S(═O) 2 NHC(═O)R 4 , N(R 4 ) 2 , —N(R 4 )C(═O)R 3 , —CO 2 R 4 , —C(═O)R 3 , —OC(═O)R 3 , —C(═O)N(R 4 ) 2 , —SR 3 , —S(═O)R 3 , and —S(═O) 2 R 3 ;
J is a bond, NHS(═O) 2 , S(═O) 2 N(R 4 ), —C(═O), —C(═O)NHS(═O) 2 , —S(═O) 2 NHC(═O), N(R 4 ), —N(R 4 )C(═O), —CO 2 , —C(═O), —OC(═O), —C(═O)N(R 4 ), —S, —S(═O), and —S(═O) 2 , C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, or C 2 -C 6 heterocycloalkylene, wherein C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, and C 2 -C 6 heterocycloalkylene is optionally substituted with at least one R;
Q is selected from hydrogen, F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 heterocycloalkyl, aryl, heteroaryl, —NHS(═O) 2 R 3 , S(═O) 2 N(R 4 ) 2 , —C(═O)CF 3 ; —C(═O)NHS(═O) 2 R 3 , —S(═O) 2 NHC(═O)R 4 , N(R 4 ) 2 , —N(R 4 )C(═O)R 3 , —CO 2 R 4 , —C(═O)R 3 , —OC(═O)R 3 , —C(═O)N(R 4 ) 2 , —SR 3 , —S(═O)R 3 , and —S(═O) 2 R 3 ;
R 1 is CO 2 R 2 , wherein R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, phenyl or benzyl;
Z is O, S, NH, N—CN, or CHNO 2 ;
X is W-L-B, or B wherein B is optionally substituted with at least one R;
W is NR 2 , O or a bond;
L is methylene, ethylene substituted with at least one R, C 3 -C 6 alkylene, C 2 -C 6 alkenylene, C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, or C 2 -C 6 heterocycloalkylene, wherein methylene, C 3 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, and C 2 -C 6 heterocycloalkylene is optionally substituted with at least one R;
B is C 3 -C 10 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl or heteroaryl;
each R 3 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
each R 4 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; or
a pharmaceutically acceptable salt, or N-oxide thereof.
2. The compound of claim 1 wherein R 2 and Q are both hydrogen.
3. The compound of claim 1 wherein R 4 is hydrogen.
4. The compound of claim 1 wherein Z is O.
5. The compound of claim 1 wherein J is a bond.
6. The compound of claim 1 wherein A is aryl.
7. The compound of claim 6 wherein aryl is phenyl.
8. The compound of claim 7 wherein phenyl is substituted with at least one R.
9. The compound of any of claim 8 wherein R is selected from F, Cl, Br, I, or C 1 -C 6 alkyl.
10. The compound of claim 1 wherein A is heteroaryl.
11. The compound of claim 10 wherein heteroaryl is substituted with at least one R.
12. The compound of claim 1 wherein X is B.
13. The compound of claim 11 wherein B is heteroaryl.
14. The compound of claim 13 wherein heteroaryl is selected from benzoxazole, benzothiazole, benzimidazole, pyrazolopyridine, imidazopyridine, benzoxadiazole, benzothiadiazole, and benzotriazole.
15. The compound of claim 13 wherein B is substituted with at least one R.
16. The compound of claim 15 wherein R is selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , C 1 -C 6 alkylenealkyne, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, and phenyl.
17. The compound of claim 12 wherein B is C 3 -C 8 cycloalkyl.
18. The compound of claim 12 wherein B is C 2 -C 8 heterocycloalkyl.
19. The compound of claim 12 wherein B is aryl.
20. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, excipient, carrier or binder thereof.
21. A method for treating an autoimmune disease, heteroimmune disease or condition, or inflammatory disease in a mammal comprising administering to the mammal a compound of claim 1 or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 wherein the autoimmune disease is inflammatory bowel disease, rheumatoid arthritis, myasthenia gravis, multiple sclerosis, Sjogren's syndrome, lupus erythematosus, psoriasis, osteoarthritis, scleroderma, and autoimmune hemolytic anemia.
23. The method of claim 22 wherein the disease, disorder or condition is rheumatoid arthritis.