Compounds that modulate intracellular calcium
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 method of alleviating, abating, or ameliorating the symptoms of rheumatoid arthritis, asthma, psoriasis, arthritis, ulcerative colitis, rejection of skin transplant, or renal transplantation in a mammal comprising administering to the mammal a compound or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof having the structure of Formula (VIA):
wherein:
R′ 1 is
L 2 is —NH—C(═O)—, or —C(═O)NH—;
X is CR 3 or N;
Y is independently selected from CR 9 or N;
R 2 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 4 alkyleneC 2 -C 8 heterocycloalkyl, aryl, heteroaryl, fused aryl or fused heteroaryl; wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 4 alkyleneC 2 -C 8 heterocycloalkyl, aryl, heteroaryl, fused aryl or fused heteroaryl is optionally substituted with at least one R 3 ;
R 3 is independently selected from H, F, D, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 5 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted O-aryl, optionally substituted heteroaryl,
n is an integer selected from 0-2;
R 9 is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 5 , —OCF 3 , C 1 -C 6 carbonylalkyl, or —CF 3 ; or two R 9 attached to the same carbon atom form an oxetane ring;
R 10 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 5 , —OCF 3 , C 1 -C 6 carbonylalkyl, or —CF 3 ; and
R 5 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl.
2. The method of claim 1 wherein R′ 1 is
L 2 is —NH—C(═O)—, or —C(═O)NH—;
X is CR 3 ;
Y is CR 9 ; and
R 2 is aryl optionally substituted with at least one R 3 .
3. The method of claim 2 wherein aryl is phenyl.
4. The method of claim 3 wherein phenyl is substituted with at least one R 3 selected from Cl, Br, F, I, CF 3 , C 1 -C 6 alkyl, or OC 1 -C 6 alkyl.
5. The method of claim 4 wherein C 1 -C 6 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl.
6. The method of claim 4 wherein phenyl is substituted with at least one R 3 selected from Cl, Br, F, and I.
7. The method of claim 4 wherein phenyl is substituted with at least one F.
8. The method of claim 2 wherein R 10 is a halogen.
9. The method of claim 1 wherein R 2 is heteroaryl substituted with at least one R 3 .
10. The method of claim 9 wherein heteroaryl is selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyranyl, thiadiazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzimidazolyl, quinolyl, pteridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazolothiazolyl, quinoxazinyl, and indolizinyl.
11. The method of claim 10 wherein heteroaryl is pyridyl.
12. The method of claim 9 wherein heteroaryl is substituted with at least one R 3 selected from Cl, Br, F, I, CF 3 , C 1 -C 6 alkyl, or OC 1 -C 6 alkyl.
13. The method of claim 12 wherein heteroaryl is substituted with at least one R 3 selected from Cl, Br, F, and I.
14. The method of claim 13 wherein heteroaryl is substituted with at least one F.
15. The method of claim 1 wherein the compound is selected from
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.