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 compound having the structure of Formula (VI):
wherein:
R′ 1 is
L 2 is —Z—C(R 12 ) 2 — or —C(R 12 ) 2 N(R 5 )—;
Z is O, S, S(O), or NR 5 ;
X is CR 3 or N;
Y is CR 9 ;
R 2 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, heteroaryl, fused aryl or fused heteroaryl; wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 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, —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, aryl, O-aryl, or heteroaryl wherein aryl, O-aryl, and heteroaryl are substituted with at least one Cl, Br, F, I, CF 3 , C 1 -C 6 alkyl, or OC 1 -C 6 alkyl;
n is an integer selected from 0-2;
R 9 is independently selected from H, D, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 5 , —OCF 3 , C 1 -C 6 carbonylalkyl, and —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, and —CF 3 ;
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;
R 12 is independently selected from H, D, halogen, —CN, —CF 2 H, CF 3 , C 1 -C 6 alkyl, —NH—C(O)R, and C(O)NHR 5 ;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
2. The compound of claim 1 wherein R′ 1 is;
X is CR 3 ;
and
R 2 is aryl optionally substituted with at least one R 3 .
3. The compound of claim 2 wherein aryl is substituted with at least one R 3 selected from Cl, Br, F, I, C 1 -C 6 alkyl, or OC 1 -C 6 alkyl.
4. The compound of claim 3 wherein aryl is substituted with at least one R 3 selected from Cl, Br, F, and I.
5. The compound of claim 4 wherein aryl is substituted with at least one F.
6. The compound of claim 2 wherein R 10 is a halogen.
7. The compound of claim 1 wherein R 2 is heteroaryl substituted with at least one R 3 .
8. The compound of claim 7 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.
9. The compound of claim 8 wherein heteroaryl is pyridyl.
10. The compound of claim 9 wherein heteroaryl is substituted with at least one R 3 selected from Cl, Br, F, and I.
11. The compound of claim 10 wherein heteroaryl is substituted with at least one F.
12. A compound selected from:
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
13. The compound of claim 1 having the structure of Formula (VIA):
14. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of claim 1 or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.