Compositions comprising CRAC inhibitors and corticosteroids and methods of use thereof

文档序号：156815 发布日期：2021-10-26 浏览：24次中文

阅读说明：本技术 包含crac抑制剂和皮质类固醇的组合物及其使用方法 (Compositions comprising CRAC inhibitors and corticosteroids and methods of use thereof ) 是由 S·维司瓦纳德哈 S·K·V·S·瓦卡兰卡于 2019-09-13 设计创作，主要内容包括：本公开涉及通过施用至少一种钙释放激活钙(CRAC)调节剂(例如CRAC抑制剂)和至少一种皮质类固醇治疗自身免疫性、呼吸道和/或炎性疾病或病症(例如银屑病、类风湿性关节炎或COPD)的方法。(The present disclosure relates to methods of treating autoimmune, respiratory, and/or inflammatory diseases or disorders (e.g., psoriasis, rheumatoid arthritis, or COPD) by administering at least one calcium release-activated calcium (CRAC) modulator (e.g., CRAC inhibitor) and at least one corticosteroid.)

1. A method of treating an autoimmune, respiratory and/or inflammatory disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of (i) a CRAC modulator and (ii) a corticosteroid.

2. The method of claim 1, wherein the CRAC modulator is a CRAC inhibitor.

3. The method of claim 1, wherein the CRAC modulator is

(i) A compound of formula (I)

Or a tautomer, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein

Ring Hy represents

Ring Hy is optionally substituted with R' ";

R¹and R²Are the same or different and are selected from CH₃、CH₂F、CHF₂、CF₃Substituted or unsubstituted C_(3-5)Cycloalkyl radical, CH₂-OR^a、CH₂-NR^aR^bAnd COOH;

ring Ar represents:

t, U, V and W are the same or different and are independently selected from CR^aAnd N;

Z¹、Z²and Z³Are the same or different and are selected from CR^a、CR^aR^bO, S and-NR^aProvided that Z is¹、Z²And Z³Represents O, S or-NR^a；

L₁And L₂Together represent-NH-C (═ X) -, -NH-S (═ O)_q-C (═ X) NH-, -NH-CR' R "-or-S (═ O)_qNH-；

A is absent or selected from- (CR' R ") -, O, S (═ O)_qC (═ X) and-NR^a；

Each occurrence of R 'and R' is the same OR different and is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, -OR^a、-COOR^a、-S(＝O)_q-R^a、-NR^aR^b、–C(＝X)-R^aSubstituted or unsubstituted C_(1-6)Alkyl, substituted or unsubstituted C_(1-6)Alkenyl, substituted or unsubstituted C_(1-6)Alkynyl and substituted or unsubstituted C_(3-5)Cycloalkyl, or R' and R ", together with the common atoms to which they are attached, may be joined to form a saturated 3-6 membered carbocyclic ring; it may optionally comprise one or more of the same or different and selected from O, NR^aAnd a heteroatom of S;

r' "is selected from hydrogen, hydroxy, cyano, halogen, -OR^a、-COOR^a、-S(＝O)_q-R^a、-NR^aR^b、–C(＝X)-R^aSubstituted or unsubstituted C_(1-6)Alkyl, substituted or unsubstituted C_(1-6)Alkenyl, substituted or unsubstituted C_(1-6)Alkynyl and substituted or unsubstituted C_(3-5)A cycloalkyl group;

each occurrence of X is independently selected from O, S and-NR^a；

Cy is selected from the group consisting of substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R^aand R^bIs the same OR different at each occurrence and is selected from the group consisting of hydrogen, nitro, hydroxy, cyano, halogen, -OR^c、-S(＝O)_q-R^c、–C(＝Y)-R^c、-CR^cR^d-C(＝Y)-R^c、-CR^cR^d-Y-CR^cR^d-、-C(＝Y)-NR^cR^d-、-NRR^d-C(＝Y)-NR^cR^d-、-S(＝O)_q-NR^cR^d-、-NR^cR^d-S(＝O)_q-NR^cR^d-、-NR^cR^d-NR^cR^d-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, optionally substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, or when R is^aAnd R^bWhen bonded directly to the same atom, they may be linked to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include one or more of the same or different and is selected from O, NR^cAnd a heteroatom of S;

R^cand R^dMay be the same or different at each occurrence and is selected from the group consisting of hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, or when two R's are present^cAnd/or R^dWhen the substituents are directly bonded to the same atom, they may be linked to form a substituted or unsubstituted saturated or unsaturated 3-to 10-membered ring, which may optionally contain one or more heteroatoms which may be the same or different and are selected from O, NH and S;

each occurrence of Y is independently selected from O, S and-NR^a(ii) a And

each occurrence of q independently represents 0, 1 or 2; or

(ii)

CM2489；

CM4620；

N- (5- (6-chloro-2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) pyrazin-2-yl) -2-fluoro-6-methylbenzamide;

n- [4- [3, 5-bis (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl ] -4-methyl-1, 2, 3-thiadiazole-5-carboxamide (YM-58483);

2, 6-difluoro-N- {5- [ 4-methyl-1- (5-methylthiazol-2-yl) -1,2,5, 6-tetrahydro-pyridin-3-yl ] -pyrazin-2-yl } -benzamide (RO 2959);

2, 6-difluoro-N- (1- (4-hydroxy-2- (trifluoromethyl) benzyl) -1H-pyrazol-3-yl) benzamide (GSK-7975A);

2, 6-difluoro-N- (1- (2-phenoxybenzyl) -1H-pyrazol-3-yl) benzamide (GSK 5503A);

n- (2',5' -dimethoxy [1,1' -biphenyl ] -4-yl) -3-fluoro-4-pyridinecarboxamide (Synta 66),

or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1-3, wherein the CRAC modulator is a compound of formula (IA)

Or a tautomer, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein

R¹And R²Are each cyclopropyl, or R¹And R²One is CF₃And the other is cyclopropyl;

t is CF or N, and U, V, W is independently CH, CF or N;

L₁and L₂Together represent-NH-C (═ X) -, -NH-S (═ O)_q-, -C (═ X) NH-or-S (═ O)_qNH-or-NH-CR' R "-;

a is absent or selectedFrom- (CR 'R') -and-NR^a；

Each occurrence of R 'and R' is the same or different and is independently selected from hydrogen or substituted or unsubstituted C_(1-6)Alkyl, or R 'and R' may be combined to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, which may optionally include one or more of the same or different and is selected from O, NR^aAnd a heteroatom of S;

r' "is selected from hydrogen or halogen;

each occurrence of X is independently selected from O, S and-NR^a；

Cy is selected from

R^aIndependently for each occurrence of (A) is selected from hydrogen, nitro, hydroxy, cyano, halogen, -OR^c、-S(＝O)_q-R^c、-NR^cR^d、C(＝Y)-R^c、-CR^cR^d-C(＝Y)-R^c、-CR^cR^d-Y-CR^cR^d-、-C(＝Y)-NR^cR^d-、-NRR^d-C(＝Y)-NR^cR^d-、-S(＝O)_q-NR^cR^d-、-NR^cR^d-S(＝O)_q-NR^cR^d-、-NR^cR^d-NR^cR^d-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;

R^cand R^dMay be the same or different at each occurrence and is independently selected from the group consisting of hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitutedSubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, or when two R's are present^cAnd/or R^dWhen the substituents are directly bonded to the same atom, they may be linked to form a substituted or unsubstituted saturated or unsaturated 3-to 10-membered ring, which may optionally contain one or more heteroatoms which may be the same or different and are selected from O, NH and S; each occurrence of Y is independently selected from O, S and-NR^a(ii) a And

each occurrence of q independently represents 0, 1 or 2.

5. The method of any one of claims 1-3, wherein the CRAC modulator is a compound of formula (IB)

Or a tautomer, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein

R¹And R²Are each cyclopropyl, or R¹And R²One is CF₃And the other is cyclopropyl;

t, U, V and W are the same or different and are independently selected from CR^aAnd N;

-CH₂-，-CHMe-，

a is absent or selected from

Cy is selected from the following bicyclic rings: substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

R^aand R^bIs the same OR different at each occurrence and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, -OR^c、-S(＝O)_q-R^c、-NR^cR^d、–C(＝Y)-R^c、-CR^cR^d-C(＝Y)-R^c、-CR^cR^d-Y-CR^cR^d-、-C(＝Y)-NR^cR^d-、-NRR^d-C(＝Y)-NR^cR^d-、-S(＝O)_q-NR^cR^d-、-NR^cR^d-S(＝O)_q-NR^cR^d-、-NR^cR^d-NR^cR^d-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, or when R is^aAnd R^bWhen bonded directly to the same atom, they may be linked to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include one or more of the same or different and is selected from O, NR^cAnd a heteroatom of S;

R^cand R^dMay be the same or different for each occurrence and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, or when two R's are present^cAnd/or R^dWhen the substituents are bonded directly to the same atom, they may beLinked to form a substituted or unsubstituted saturated or unsaturated 3-to 10-membered ring, which may optionally contain one or more heteroatoms which are the same or different and are selected from O, NH and S;

each occurrence of X is independently selected from O, S and-NR^a；

Each occurrence of Y is independently selected from O, S and-NR^a(ii) a And

each occurrence of q independently represents 0, 1 or 2.

6. The method of any one of claims 1-5, wherein R¹And R²Are each cyclopropyl, or R¹And R²One is CF₃And the other is cyclopropyl.

7. The method of any one of claims 1-6, wherein Hy is

8. The method of any one of claims 1-7, wherein ring Ar is selected from

9. The method of any one of claims 1-8, wherein L₁And L₂Together represent-NH-C (═ X) -or-C (═ X) -NH-.

10. The method of any one of claims 1-9, wherein Cy is selected from the group consisting of

11. The method of any one of claims 1-10, wherein Cy is selected from the group consisting of

12. The method of any of claims 1-11, wherein the CRAC modulator is selected from the group consisting of

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -4-methyl-1, 2, 3-thiadiazole-5-carboxamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -4-methylthiazole-5-carboxamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2, 4-dimethylthiazole-5-carboxamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -5-methylisoxazole-4-carboxamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -3, 5-dimethylisoxazole-4-carboxamide

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] benzamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2-methylbenzamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2, 6-difluorobenzamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2, 3-difluorobenzamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl-3- (methylsulfonyl) benzamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -4- (methylsulfonyl) benzamide

2-chloro-N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -5- (methylthio) benzamide

2-chloro-N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl) -5- (methylsulfonyl) benzamide

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] nicotinamide hydrochloride

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] isonicotinamide hydrochloride

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -3-fluoroisonicotinamide

3, 5-dichloro-N- (4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl) isonicotinamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -4-methylpyrimidine-5-carboxamide

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2-phenylacetamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2- (4-fluorophenyl) acetamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -1-phenylcyclopropanecarboxamide

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2- (pyridin-2-yl) acetamide

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2- (pyridin-3-yl) acetamide

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2- (pyridin-4-yl) acetamide

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2- (piperazin-1-yl) acetamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2-morpholinoacetamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] benzenesulfonamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] -4-methyl-1, 2, 3-thiadiazole-5-carboxamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] -4-methylthiazole-5-carboxamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] -3, 5-dimethylisoxazole-4-carboxamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] -2-methylbenzamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] -2, 3-difluorobenzamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] -2, 6-difluorobenzamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] nicotinamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] isonicotinamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] -4-methylpyrimidine-5-carboxamide

N- [4- (4-chloro-3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] -4-methyl-1, 2, 3-thiadiazole-5-carboxamide

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -4-methyl-1, 2, 3-thiadiazole-5-carboxamide

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -4-methylthiazole-5-carboxamide

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -2, 4-dimethylthiazole-5-carboxamide

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -3, 5-dimethylisoxazole-4-carboxamide

6- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) -N-o-tolylnicotinamide

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -2-fluorobenzamide

N- [6- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -2, 3-difluorobenzamide

N- [6- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -2, 6-difluorobenzamide

N- [6- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] nicotinamide dihydrochloride

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] isonicotinamide

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -3-fluoroisonicotinamide

3, 5-dichloro-N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } isonicotinamide

3, 5-dichloro-N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] isonicotinamide

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -4-methylpyrimidine-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -4-methyl-1, 2, 3-thiadiazole-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -4-methylthiazole-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -N, 4-dimethylthiazole-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2, 4-dimethylthiazole-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -5-methylisoxazole-4-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -3, 5-dimethylisoxazole-4-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -1-methyl-1H-imidazole-2-carboxamide

N- {4- [ 3-cyclopropyl-5- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -4-methyl-1H-imidazole-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2-methylbenzamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2, 3-difluorobenzamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2, 6-difluorobenzamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -3- (methylsulfonyl) benzamide

2-chloro-N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -5- (methylthio) benzamide

2-chloro-N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -5- (methylsulfonyl) benzamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } pyridine-4-carboxamide hydrochloride

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -3-fluoroisonicotinamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -4-methylpyrimidine-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2, 4-dimethylpyrimidine-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2- (4-fluorophenyl) acetamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2- (pyridin-2-yl) acetamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2- (pyridin-3-yl) acetamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2- (pyridin-4-yl) acetamide

4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -N- [ (4-methylthiazol-5-yl) methyl ] aniline

1- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -3- (4-methyl-1, 2, 3-thiadiazol-5-yl) urea

1- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -3- (4-methylthiazol-5-yl) urea

1- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -3- (4-methylpyrimidin-5-yl) urea

4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -N- (4-methylthiazol-5-yl) benzamide

4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -N- (2, 6-difluorophenyl) benzamide

N- {4- [ 4-chloro-5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -4-methylthiazole-5-carboxamide

N- {4- [ 4-chloro-5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2- (pyridin-2-yl) acetamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -4-methyl-1, 2, 3-thiadiazole-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -4-methylthiazole-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -5-methylisoxazole-4-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -3, 5-dimethylisoxazole-4-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -2-methylbenzamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -2, 3-difluorobenzamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -2, 6-difluorobenzamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } nicotinamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } isonicotinamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -3-fluoroisonicotinamide

3, 5-dichloro-N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } isonicotinamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -4-methylpyrimidine-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -N, 4-dimethylpyrimidine-5-carboxamide

N- {4- [ 4-chloro-5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -4-methyl-1, 2, 3-thiadiazole-5-carboxamide

N- {4- [ 4-chloro-5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -2- (pyridin-2-yl) acetamide

1- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -3- (4-methylpyrimidin-5-yl) urea

N- {4- [5) -cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] 3-fluorophenyl } -2, 6-dichlorobenzamide

4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -N- (2, 3-difluorophenyl) -3-fluorobenzamide

4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -N- (2, 6-difluorophenyl) -3-fluorobenzamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -4-methyl-1, 2, 3-thiadiazole-5-carboxamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -4-methylthiazole-5-carboxamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -3, 5-dimethylisoxazole-4-carboxamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2-methylbenzamide

2-chloro-N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } benzamide

N- (6- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) pyridin-3-yl) -2-fluorobenzamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2, 3-difluorobenzamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2, 6-difluorobenzamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } picolinamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -3-methylpyridine amide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } nicotinamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2-methylnicotinamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } isonicotinamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -3-fluoroisonicotinamide

3, 5-dichloro-N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } isonicotinamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -4-methylpyrimidine-5-carboxamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2- (pyridin-2-yl) acetamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2- (pyridin-4-yl) acetamide

N- {4- [ 4-chloro-5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -4-methylpyrimidine-5-carboxamide

1- {6- [ 3-cyclopropyl-5- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -3- (4-methylthiazol-5-yl) urea

6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -N- (2, 3-difluorophenyl) nicotinamide

6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -N- (2, 6-difluorophenyl) nicotinamide

N- {6- [ 4-chloro-5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -4-methylthiazole-5-carboxamide

N- {2- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyrimidin-5-yl } -2, 6-difluorobenzamide

N- {4- [5- (fluoromethyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -4-methylthiazole-5-carboxamide

N- {4- [5- (difluoromethyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -4-methylthiazole-5-carboxamide

3, 5-dichloro-N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] isonicotinamide

N- (2-chloro-6-fluorophenyl) -4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorobenzamide

N- {2- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyrimidin-5-yl } -4-methylthiazole-5-carboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3, 5-difluorophenyl } -4-methylpyrimidine-5-carboxamide

{4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -1-phenylcyclobutanecarboxamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -4-methyloxazole-5-carboxamide

N- {2- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyrimidin-5-yl } -4-methylpyrimidine-5-carboxamide

4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluoro-N- (4-methylpyrimidin-5-yl) benzamide and

n- {4- [ 3-cyclopropyl-5- (difluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -2, 6-difluorobenzamide;

n- {4- [ 5-cyclopropyl-3- (difluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -2, 6-difluorobenzamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -1H-benzo [ d ] imidazole-6-carboxamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -1H-benzo [ d ] [1,2,3] triazole-6-carboxamide

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] quinoline-6-carboxamide hydrochloride

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] quinoxaline-6-carboxamide

2- (1H-benzo [ d ] imidazol-1-yl) -N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] acetamide

2- (1H-benzo [ d ] [1,2,3] triazol-1-yl) -N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] acetamide

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2- (1H-indol-3-yl) acetamide

N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2- (imidazo [1,2-a ] pyridin-2-yl) acetamide hydrochloride

N- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2- (quinolin-6-yl) acetamide:

n- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) phenyl ] -2- (quinolin-6-yl) acetamide hydrochloride

2- (1H-benzo [ d ] [1,2,3] triazol-1-yl) -N- (4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl) acetamide

Hydrochloric acid N- [4- (3, 5-dicyclopropyl-1H-pyrazol-1-yl) -3-fluorophenyl ] -2- (quinolin-6-yl) acetamide

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] quinoline-6-carboxamide dihydrochloride

N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] quinoxaline-6-carboxamide

2- (1H-benzo [ d ] [1,2,3] triazol-1-yl) -N- [6- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] acetamide

N- [6- (3, 5-Bicyclopropyl-1H-pyrazol-1-yl) pyridin-3-yl ] -2- (quinolin-6-yl) acetamide dihydrochloride

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } quinoline-6-carboxamide hydrochloride

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } quinoxaline-6-carboxamide

2- (1H-benzo [ d ] imidazol-1-yl) -N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } acetamide

2- (1H-benzo [ d ] [1,2,3] triazol-1-yl) -N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } acetamide

2- (2H-benzo [ d ] [1,2,3] triazol-2-yl) -N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } acetamide

2- (3H- [1,2,3] triazolo [4,5-b ] pyridin-3-yl) -N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } acetamide

(S) -2- (3H- [1,2,3] triazolo [4,5-b ] pyridin-3-yl) -N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } propanamide

2- (6-amino-9H-purin-9-yl) -N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } acetamide

N- (4- (5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) -2- (1, 3-dimethyl-2, 6-dioxo-2, 3-dihydro-1H-purin-7 (6H) -yl) acetamide

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl) phenyl) -2- (imidazo [1,2-a ] pyridin-2-yl) acetamide hydrochloride

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2- (quinolin-6-yl) acetamide hydrochloride

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } -2- (quinolin-6-yl) propanamide hydrochloride

N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } -1H-benzo [ d ] [1,2,3] triazole-6-carboxamide

2- (1H-benzo [ d ] [1,2,3] triazol-1-yl) -N- {4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluorophenyl } acetamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -1H-benzo [ d ] [1,2,3] triazole-5-carboxamide

2- (1H-benzo [ d ] [1,2,3] triazol-1-yl) -N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } acetamide

2- (2H-benzo [ d ] [1,2,3] triazol-2-yl) -N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } acetamide

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2- (quinolin-6-yl) acetamide hydrochloride

2- (1H-benzo [ d ] [1,2,3] triazol-1-yl) -N- {6- [ 4-chloro-5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } acetamide

4- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] -3-fluoro-N- (quinolin-6-methyl) benzamide hydrochloride and

1- [4- (3, 5-bicyclopropyl-1H-pyrazol-1-yl) phenyl ] -3- (quinolin-6-yl) urea,

and pharmaceutically acceptable salts thereof.

13. The method of any of claims 1-11, wherein the CRAC modulator is selected from the group consisting of

CM2489；

CM4620；

N- (5- (6-chloro-2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) pyrazin-2-yl) -2-fluoro-6-methylbenzamide;

n- [4- [3, 5-bis (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl ] -4-methyl-1, 2, 3-thiadiazole-5-carboxamide (YM-58483);

2, 6-difluoro-N- {5- [ 4-methyl-1- (5-methylthiazol-2-yl) -1,2,5, 6-tetrahydro-pyridin-3-yl ] -pyrazin-2-yl } -benzamide (RO 2959);

2, 6-difluoro-N- (1- (4-hydroxy-2- (trifluoromethyl) benzyl) -1H-pyrazol-3-yl) benzamide (GSK-7975A);

2, 6-difluoro-N- (1- (2-phenoxybenzyl) -1H-pyrazol-3-yl) benzamide (GSK 5503A);

n- (2',5' -dimethoxy [1,1' -biphenyl ] -4-yl) -3-fluoro-4-pyridinecarboxamide (Synta 66);

n- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2-methylbenzamide;

n- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -3-fluoroisonicotinamide;

and pharmaceutically acceptable salts thereof.

14. The method of any of claims 1-13, the CRAC modulator is selected from

N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2-methylbenzamide;

n- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -3-fluoroisonicotinamide;

and pharmaceutically acceptable salts thereof.

15. The method of any one of claims 1-14, wherein the corticosteroid is selected from dexamethasone, betamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, fluticasone, triamcinolone, budesonide or cortisone prednisolone, methylprednisolone, naphthalenone, desflurane, lorasone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetate, clocortolone, methylprednisolone aceponate, dexamethasone palmitate, tiprednisolone, hydrocortisone aceponate, prednisolone dipropionate, alclometasone dipropionate, halometasone, sulfoheptylprednisolone, mometasone furoate monohydrate, mometasone furoate, rimexolone, prednisolone farnesol, ciclesonide, desoxypropionate ketone, fluticasone propionate, halobetamethasone dipropionate, prednisolone acetonide, prednisone propionate, halobetamethasone dipropionate, hydrocortisone dipropionate, and combinations thereof, Loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, 17-betamethasone valerate, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate, hydrocortisone propionate and pharmaceutically acceptable salts thereof.

16. The method of claim 15, wherein the corticosteroid is selected from the group consisting of dexamethasone, betamethasone, prednisolone, methylprednisolone, prednisone, hydrocortisone, fluticasone, mometasone furoate monohydrate, triamcinolone, budesonide, cortisone, and pharmaceutically acceptable salts thereof.

17. The method of any one of claims 15-16, wherein the corticosteroid is selected from dexamethasone, fluticasone, and pharmaceutically acceptable salts thereof.

18. The method of any one of claims 1-17, wherein the CRAC modulator is N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2-methylbenzamide and the corticosteroid is dexamethasone.

19. The method of any one of claims 1-17, wherein the CRAC modulator is N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2-methylbenzamide and the corticosteroid is fluticasone.

20. The method of any one of claims 1-17, wherein the CRAC modulator is N- {6- [ 5-cyclopropyl-3- (trifluoromethyl) -1H-pyrazol-1-yl ] pyridin-3-yl } -2-methylbenzamide and the corticosteroid is mometasone, mometasone furoate, or mometasone furoate monohydrate.

21. The method of any one of claims 1-20, wherein a therapeutically effective amount of (i) the CRAC modulator and a therapeutically effective amount of (ii) the corticosteroid are administered simultaneously as a combined preparation.

22. The method of any one of claims 1-20, wherein the therapeutically effective amount of (i) the CRAC modulator and the therapeutically effective amount of (ii) the corticosteroid are administered sequentially.

23. The method of claim 22, wherein the therapeutically effective amount of corticosteroid is administered prior to the therapeutically effective amount of the CRAC modulator.

24. The method of any one of claims 1-23, wherein the therapeutically effective amount of the CRAC modulator is administered from two times daily to once every three weeks, and the therapeutically effective amount of the corticosteroid is administered from two times daily to once every three weeks.

25. The method of any one of claims 1-24, wherein the autoimmune, respiratory and/or inflammatory disease or disorder is selected from asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis, psoriasis, arthritis, vasculitis, dermatitis, osteoarthritis, inflammatory muscle diseases, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allograft or xenograft (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, sjogren's syndrome, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, idiopathic Pulmonary Fibrosis (IPF), chronic recurrent hepatitis, primary biliary cirrhosis, allergic conjunctivitis, atopic dermatitis, and combinations thereof.

26. The method of any one of claims 1-25, wherein the autoimmune, respiratory and/or inflammatory disease or disorder is selected from asthma, rheumatoid arthritis, psoriasis and chronic obstructive pulmonary disease.

27. The method of any one of claims 1-26, wherein the CRAC modulator and the corticosteroid are each administered in about the following amounts

(i)0.01mg to about 1000 mg;

(ii)0.01mg to about 500 mg;

(iii)0.01mg to about 250 mg; or

(iv)0.01mg to about 100 mg.

28. The method of any one of claims 1-27, wherein

(a) The CRAC modulator is administered in an amount of about

(i)0.01mg to about 1000 mg;

(ii)10mg to about 500 mg;

(iii)50mg to about 250 mg; or

(iv)50mg to about 100 mg; and is

(b) The corticosteroid is administered in an amount of about 0.01mg to about 100 mg.

29. The method of any one of claims 1-28, wherein

(a) The CRAC modulator is administered in an amount from about 10mg to about 500 mg; and

(b) the corticosteroid is administered in an amount of about 0.01mg to about 100 mg.

30. The method of any one of claims 1-29, wherein the CRAC modulator and the corticosteroid are administered at a rate of about 1: 100 to about 100: 1 ratio.

31. A pharmaceutical composition comprising (i) a CRAC modulator, (ii) a corticosteroid, and (iii) optionally, a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

32. The pharmaceutical composition of claim 31, wherein the CRAC modulator is

(i) A compound of formula (I)

Or a tautomer, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein

Ring Hy represents

Ring Hy is optionally substituted with R';

R¹and R²Are the same or different and are selected from CH₃、CH₂F、CHF₂、CF₃Substituted or unsubstituted C_(3-5)Cycloalkyl radical, CH₂-OR^a、CH₂-NR^aR^bAnd COOH;

ring Ar represents:

t, U, V and W are the same or different and are independently selected from CR^aAnd N;

Z¹、Z²and Z³Are the same or different and are selected from CR^a、CR^aR^bO, S and-NR^aProvided that Z is¹、Z²And Z³Represents O, S or-NR^a；

L₁And L₂Together represent-NH-C (═ X) -, -NH-S (═ O)_q-C (═ X) NH-, -NH-CR' R "-or-S (═ O)_qNH-；

A is absent or selected from- (CR' R ") -, O, S (═ O)_qC (═ X) and-NR^a；

r' "is selected from hydrogen, hydroxy, cyano, halogen, -OR^a、-COOR^a、-S(＝O)_q-R^a、-NR^aR^b、–C(＝X)-R^aGet, getSubstituted or unsubstituted C_(1-6)Alkyl, substituted or unsubstituted C_(1-6)Alkenyl, substituted or unsubstituted C_(1-6)Alkynyl and substituted or unsubstituted C_(3-5)A cycloalkyl group;

each occurrence of X is independently selected from O, S and-NR^a

R^cand R^dMay be the same or different at each occurrence and is selected from the group consisting of hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitutedCycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, or when two R's are^cAnd/or R^dWhen the substituents are directly bonded to the same atom, they may be linked to form a substituted or unsubstituted saturated or unsaturated 3-to 10-membered ring, which may optionally contain one or more heteroatoms which may be the same or different and are selected from O, NH and S;

each occurrence of Y is independently selected from O, S and-NR^a(ii) a And

each occurrence of q independently represents 0, 1 or 2; or

(ii)

CM2489；

CM4620；

N- (5- (6-chloro-2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) pyrazin-2-yl) -2-fluoro-6-methylbenzamide;

n- [4- [3, 5-bis (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl ] -4-methyl-1, 2, 3-thiadiazole-5-carboxamide (YM-58483);

2, 6-difluoro-N- {5- [ 4-methyl-1- (5-methylthiazol-2-yl) -1,2,5, 6-tetrahydro-pyridin-3-yl ] -pyrazin-2-yl } -benzamide (RO 2959);

2, 6-difluoro-N- (1- (4-hydroxy-2- (trifluoromethyl) benzyl) -1H-pyrazol-3-yl) benzamide (GSK-7975A);

2, 6-difluoro-N- (1- (2-phenoxybenzyl) -1H-pyrazol-3-yl) benzamide (GSK 5503A);

n- (2',5' -dimethoxy [1,1' -biphenyl ] -4-yl) -3-fluoro-4-pyridinecarboxamide (Synta 66);

or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition of any one of claims 31-32, wherein the CRAC modulator is a compound of formula (IA)

Or a tautomer, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein

R¹And R²Are each cyclopropyl, or R¹And R²One is CF₃And the other is cyclopropyl;

t is CF or N, and U, V, W is independently CH, CF or N;

L₁and L₂Together represent-NH-C (═ X) -, -NH-S (═ O)_q-, -C (═ X) NH-or-S (═ O)_qNH-or-NH-CR' R "-;

a is absent or selected from- (CR 'R') -and-NR^a；

r' "is selected from hydrogen or halogen;

each occurrence of X is independently selected from O, S and-NR^a；

Cy is selected from

R^aIndependently for each occurrence of (A) is selected from hydrogen, nitro, hydroxy, cyano, halogen, -OR^c、-S(＝O)_q-R^c、-NR^cR^d、C(＝Y)-R^c、-CR^cR^d-C(＝Y)-R^c、-CR^cR^d-Y-CR^cR^d-、-C(＝Y)-NR^cR^d-、-NRR^d-C(＝Y)-NR^cR^d-、-S(＝O)_q-NR^cR^d-、-NR^cR^d-S(＝O)_q-NR^cR^d-、-NR^cR^d-NR^cR^d-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkylAn alkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted heterocyclylalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heteroarylalkyl group;

R^cand R^dMay be the same or different for each occurrence and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, or when two R's are present^cAnd/or R^dWhen the substituents are directly bonded to the same atom, they may be linked to form a substituted or unsubstituted saturated or unsaturated 3-to 10-membered ring, which may optionally contain one or more heteroatoms which may be the same or different and are selected from O, NH and S;

each occurrence of Y is independently selected from O, S and-NR^a(ii) a And

each occurrence of q independently represents 0, 1 or 2.

34. The pharmaceutical composition of any one of claims 31-33, wherein the CRAC modulator is a compound of formula (IB)

Or a tautomer, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein

R¹And R²Are each cyclopropyl, or R¹And R²One is CF₃And the other is cyclopropyl;

t, U, V and W are the same or different and are independently selected from CR^aAnd N;

-CH₂-，-CHMe-，

a is absent or selected from

R^cand R^dMay be the same or different for each occurrence and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, or when two R's are present^cAnd/or R^dWhen the substituents are directly bonded to the same atom, they may be linked to form a substituted or unsubstituted saturated or unsaturated 3-to 10-membered ring, which may optionally contain one or more heteroatoms which may be the same or different and are selected from O, NH and S;

each occurrence of X is independently selected from O, S and-NR^a；

Each occurrence of Y is independently selected from O, S and-NR^a(ii) a And

each occurrence of q independently represents 0, 1 or 2.

35. The pharmaceutical composition of any one of claims 31-34, wherein the CRAC modulator is selected from