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 .- 18 . (canceled)
19 . A compound having the structure of Formula (XI) having the structure:
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 H, D, 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 S , —S(═O)R 4 , and —S(═O) 2 R 4 ;
n is an integer selected from 1-3;
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 S , —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.
20 . The compound of claim 19 having the structure of Formula (XIA):
21 . The compound of claim 20 , wherein R″ 1 is
22 . The compound of claim 21 wherein L 2 is —CH 2 N(H)—.
23 . The compound of claim 22 wherein R 2 is phenyl.
24 . The compound of claim 23 wherein R 2 is phenyl substituted with at least one R 3 selected from F, Cl, Br, I, —CN, —OH, —CF 3 , —OCF 3 , —OR 5 , —N(R 5 ) 2 , and C 1 -C 6 alkyl.
25 . The compound of claim 24 wherein R 6 is selected from —CF 3 , —OCF 3 , —OR 5 , C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl.
26 . The compound of claim 25 wherein R 7 is C 1 -C 6 alkyl.
27 . The compound of claim 26 wherein R 6 is —CF 3 and R 7 is —CH 3 .
28 . The compound of claim 27 wherein R 7 is C 1 -C 6 haloalkyl.
29 . The compound of claim 28 wherein R 6 is —CF 3 and R 7 is —CF 3 .
30 . The compound of claim 24 wherein R 2 is phenyl substituted with at least 2 substituents.
31 . The compound of claim 24 wherein R 2 is phenyl substituted with at least 3 substituents.
32 . The compound of claim 22 wherein R 2 is heteroaryl.
33 . The compound of claim 32 wherein heteroaryl is selected from thienyl, thianthrenyl, furyl, pyranyl, thiadiazolyl, benzothiadiazolyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolo-pyrimidinyl, triazolo-pyrimidinyl, imidazo-pyrimidinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, oxazolyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, and phenoxazinyl.
34 . The compound of claim 32 wherein R 2 is heteroaryl substituted with at least one R 3 selected from halogen, —OH, —CN, —NO 2 , —CF 3 , —OCF 3 , —OR 5 , —N(R 5 ) 2 , C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl.
35 . The compound of claim 34 wherein R 2 is pyridyl.
36 . A compound having the structure of Formula (VIII) having the structure:
wherein:
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 ;
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, and optionally substituted heteroaryl;
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 S , —S(═O)R 4 , and —S(═O) 2 R 4 ;
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 4 is independently selected from 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.
37 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of claim 19 or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.
38 . 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 a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof according to claim 19 .
39 . The method of claim 38 , 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.