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 independently selected from CR 9 and N;
R 2 is 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, 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 heteroalkyl, 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, or optionally substituted heteroaryl;
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 ;
Y is CR 9 ; 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, CF 3 , 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 compound having the structure of Formula (III):
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 ;
R 2 is 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, 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 heteroalkyl, 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 F, Cl, Br, I, —CN, —NO 2 , —OH, —OCF 3 , —OR 5 , optionally substituted aryl, optionally substituted O-aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 4 , —S(═O) 2 N(R 5 ) 2 , —N(R 5 )S(═O) 2 N(R 5 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 4 , —S(═O) 2 NHC(═O)R 4 , —N(R 5 ) 2 , —N(R 5 )C(═O)R 5 , —N(R 5 )C(═O)N(R 5 ) 2 , —N(R 5 )C(═O)OR 4 , —CO 2 R 5 , —C(═O)R 5 , —OC(═O)R 4 , —OC(═O)N(R 5 ) 2 , —CON(R 5 ) 2 , —SR 5 , —S(═O)R 4 , and —S(═O) 2 R 4 ;
n is an integer selected from 0-3;
each R 4 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
R 5 and R 7 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
R 6 is selected from H, F, 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 4 heterocycloalkyl, optionally substituted aryl, optionally substituted O-aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 4 , —S(═O) 2 N(R 5 ) 2 , —N(R 5 )S(═O) 2 N(R 5 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 4 , —S(═O) 2 NHC(═O)R 4 , —N(R 5 ) 2 , —N(R 5 )C(═O)R 4 , —N(R 5 )C(═O)N(R 5 ) 2 , —N(R 5 )C(═O)OR 4 , —CO 2 R 5 , —C(═O)R 5 , —OC(═O)R 4 , —OC(═O)N(R 5 ) 2 , —CON(R 5 ) 2 , —SR 5 , —S(═O)R 4 , and —S(═O) 2 R 4 ;
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.
15 . 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.
16 . A method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof according to claim 1 .
17 . A method of modulating store-operated calcium (SOC) channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with the compound or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof according to claim 1 .
18 . The method of claim 17 , wherein the disease, disorder or condition in a mammal is selected from diseases/disorders involving inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, organ transplant rejection, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, psoriasis, multiple sclerosis, Sjogren's syndrome, and autoimmune diseases or disorders.