Novel modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer

Abstract

Disclosed are novel calcium release-activated calcium (CRAC) channel inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods of treatment using them. The present disclosure also relates to methods for treating non-small cell lung cancer (NSCLC) with CRAC inhibitors, and to methods for identifying therapeutics for treating and of diagnosing cancer.

1 . A compound of formula 
       
         
           
           
               
               
           
         
       
       or a tautomer, prodrug, N-oxide, pharmaceutically acceptable ester or pharmaceutically acceptable salt thereof, wherein
 Ring Hy represents 
 
       
         
           
           
               
               
           
         
       
       optionally substituted with R′″;
 R 1  and R 2  are the same or different and are independently selected from CH 3 , CH 2 F, CHF 2 , CF 3 , substituted or unsubstituted C (3-5) cycloalkyl, CH 2 —OR a , CH 2 —NR a R b , CN and COOH with the proviso that; 
 a) both R 1  and R 2  at the same time do not represent CF 3 , 
 b) both R 1  and R 2  at the same time do not represent CH 3 , 
 c) when R 1  is CF 3  then R 2  is not CH 3  and 
 d) when R 1  is CH 3  then R 2  is not CF 3 ; 
 Ring Ar represents: 
 
       
         
           
           
               
               
           
         
         T, U, V and W are the same or different and are independently selected from CR a  and N; 
         Z 1 , Z 2  and Z 3  are the same or different and are independently selected from CR a , CR a R b , O, S and —NR a , with the proviso that at least one of Z 1 , Z 2  and Z 3  represents O, S or —NR a ; 
         L 1  and L 2  together represent —NH—C(═X)—, —NH—S(═O) q —, —C(═X)NH—, or —S(═O) q NH— or —NH—CR′R″—; 
         A is absent or selected from —(CR′R″)—, O, S(═O) q , C(═X) and —NR a ; 
         R′ and R″ are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, —OR a , —COOR a , —S(═O) q —R a , —NR a R b , —C(═X)—R a , substituted or unsubstituted C (1-6)  alkyl group, 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″ may be joined to form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR a  and S; 
         R′″ is selected from hydrogen, hydroxy, cyano, halogen, —OR a , —COOR a , —S(═O) q —R a , —NR a R b , —C(═X)—R a , substituted or unsubstituted C (1-6)  alkyl group, substituted or unsubstituted C (1-6)  alkenyl, substituted or unsubstituted C (1-6)  alkynyl, and substituted or unsubstituted C (3-5) cycloalkyl. 
         each occurrence of X is independently selected from O, S and —NR a ; 
         Cy is a bicyclic ring selected from substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
         each occurrence of R a  and R b  are the same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, —OR c , —S(═O) q —R c , —NR c R d , —C(═Y)—R c , —CR c R d —C(═Y)—R c , —CR c R d —Y—CR c R d —, —C(═Y)—NR c R d —, —NRR d —C(═Y)—NR c R d —, —S(═O) q —NR c R d —, —NR c R d —S(═O) q —NR c R d —, —NR c R d —NR c R d —, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocylyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, or when R a  and R b  are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR c  and S; 
         each occurrence of R c  and R d  may be same or different and are 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 cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or when two R c  and/or R d  substitutents are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which are the same or different and are selected from O, NH and S; 
         each occurrence of Y is selected from O, S and —NR a ; and 
         each occurrence of q independently represents 0, 1 or 2; 
       
       with Proviso (e) that the compound of formula (I) is not:
 N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-methyl-3-(trifluoromethyl)-1H-Thieno[2,3-c]pyrazole-5-carboxamide or N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-Pyrazolo[1,5-a]pyrimidine-2-carboxamide. 
 
     
     
         2 . A compound of  claim 1 , wherein Hy is 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound of  claim 2 , wherein Hy is 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound of  claim 3 , wherein Hy is 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound of  claim 1 , wherein Ar is 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound of  claim 6 , wherein Ar is 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound of  claim 1 , wherein L 1  and L 2  together represent —NH—C(═O)—, —NH—S(═O) q —, —C(═O)NH— or —NH—CH 2 —. 
     
     
         8 . A compound of  claim 7 , wherein L 1  and L 2  together represent —NH—C(═O)—, —C(═O)NH— or S(═O) q NH— —NH—CH 2 —. 
     
     
         9 . A compound of  claim 1 , wherein A is absent or is selected from —(CR′R″)- or —NR a    
     
     
         10 . A compound of  claim 9 , wherein A is —CH 2 — or —CHMe-, —(CR′R″)—, where R′ and R″ are joined to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, which may optionally include one or more heteroatoms which are the same or different and are selected from O, NR a  and S; 
     
     
         11 . A compound of  claim 9 , wherein A is —NH—, CH 2 — —CHMe-, 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound of  claim 1 , wherein Cy is 
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound of  claim 12 , wherein Cy is 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound of  claim 12 , wherein Cy is 
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound of formula (IA) 
       
         
           
           
               
               
           
         
       
       or a tautomer, prodrug, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein
 R 1  and R 2  are the same or different and are independently selected from CH 3 , CH 2 F, CHF 2 , CF 3 , substituted or unsubstituted C (3-5)  cycloalkyl, CH 2 —OR a , CH 2 —NR a R b , CN and COOH with the proviso that; 
 a) both R 1  and R 2  at the same time do not represent CF 3 , 
 b) both R 1  and R 2  at the same time do not represent CH 3 , 
 c) when R 1  is CF 3  then R 2  is not CH 3  and 
 d) when R 1  is CH 3  then R 2  is not CF 3 ; 
 T, U, V and W are the same or different and are independently selected from CR a  and N; 
 L 1  and L 2  together represent —NH—C(═X)—, —NH—S(═O) q —, —C(═X)NH—, or —S(═O) q NH— or —NH—CR′R″—; 
 A is absent or selected from —(CR′R″)—, O, S(═O) q , C(═X) and —NR a ; 
 each occurrence of R′ and R″ are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, —OR a , —COOR a , —S(═O) q —R a , —NR a R b , —C(═X)—R a , substituted or unsubstituted C (1-6)  alkyl group, 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″ may be joined to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR a  and S; 
 R″′ is selected from hydrogen, hydroxy, cyano, halogen, —OR a , —COOR a , —S(═O) q —R a , —NR a R b , —C(═X)—R a , substituted or unsubstituted C (1-6)  alkyl group, substituted or unsubstituted C (1-6)  alkenyl, substituted or unsubstituted C (1-6)  alkynyl, and substituted or unsubstituted C (3-5) cycloalkyl; 
 each occurrence of X is independently selected from O, S and —NR a ; 
 Cy is a bicyclic ring selected from substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
 each occurrence of R a  and R b  are the same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, —OR c , —S(═O) q —R c , —NR c R d , —C(═Y)—R c , —CR c R d —C(═Y)—R c , —CR c R d —Y—CR c R d —, —C(═Y)—NR c R d —, —NRR d —C(═Y)—NR c R d —, —S(═O) q —NR c R d —, —NR c R d —S(═O) q —NR c R d —, —NR c R d —NR c R d —, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocylyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, or when R a  and R b  substitutent are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR c  and S; 
 each occurrence of R c  and R d  may be same or different and are 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 cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or when two R c  and/or R d  substitutents are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which are the same or different and are selected from O, NH and S; 
 each occurrence of Y is selected from O, S and —NR a ; and 
 each occurrence of q independently represents 0, 1 or 2, 
 
       with Proviso (e) that the compound of formula (I) is not:
 N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-methyl-3-(trifluoromethyl)-1H-Thieno[2,3-c]pyrazole-5-carboxamide or N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-Pyrazolo[1,5-a]pyrimidine-2-carboxamide. 
 
     
     
         16 . A compound of  claim 15 , wherein
 L 1  and L 2  together represent —NH—C(O)—; and   Cy is a bicyclic ring selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.   
     
     
         17 . A compound of formula (IA-II) 
       
         
           
           
               
               
           
         
       
       or a tautomer, prodrug, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein
 R 1  and R 2  are the same or different and are independently selected from CH 3 , CH 2 F, CHF 2 , CF 3 , substituted or unsubstituted C (3-5) cycloalkyl, CH 2 —OR a , CH 2 —NR a R b , CN and COOH with the proviso that both R 1  and R 2  at the same time do not represent CF 3 ; 
 T, U, V and W are the same or different and are independently selected from CR a  and N; 
 A is absent or selected from —(CR′R″)—, O, S(═O) q , C(═X) and —NR a ; 
 R′ and R″ are the same or different and are independently selected from hydrogen, hydroxy, cyano, halogen, —OR a , —COOR a , —S(═O) q —R a , —NR a R b , —C(═X)—R a , substituted or unsubstituted C (1-6)  alkyl group, 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″ may be joined to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR a  and S; 
 R′″ is selected from hydrogen, hydroxy, cyano, halogen, —OR a , —COOR a , —S(═O) q —R a , —NR a R b , —C(═X)—R a , substituted or unsubstituted C (1-6)  alkyl group, substituted or unsubstituted C (1-6)  alkenyl, substituted or unsubstituted C (1-6)  alkynyl, and substituted or unsubstituted C (3-5)  cycloalkyl. 
 each occurrence of X is independently selected from O, S and —NR a ; 
 Cy is a C (8-13)  bicyclic substituted or unsubstituted heteroaryl; 
 each occurrence of R a  and R b  are the same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, —OR c , —S(═O) q —R c , —NR c R d , —C(═Y)—R c , —CR c R d —C(═Y)—R c , —CR c R d —Y—CR c R d —, —C(═Y)—NR c R d —, —NRR d —C(═Y)—NR c R d —, —S(═O) q —NR c R d —, —NR c R d —S(═O) q —NR c R d —, —NR c R d —NR c R d —, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocylyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, or when R a  and R b  are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR c  and S; 
 each occurrence of R c  and R d  may be same or different and are 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 cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or when two R c  and/or R d  substitutents are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include one or more heteroatoms which are the same or different and are selected from O, NH and S; 
 Y is selected from O, S and —NR a ; and 
 each occurrence of q independently represents 0, 1 or 2. 
 
       with the proviso that the compound of formula (I) does not include
 N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-methyl-3-(trifluoromethyl)-1H-Thieno[2,3-c]pyrazole-5-carboxamide or N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-Pyrazolo[1,5-a]pyrimidine-2-carboxamide. 
 
     
     
         18 . A compound of  claim 15 , wherein both R 1  and R 2  represent cyclopropyl. 
     
     
         19 . A compound of  claim 15 , wherein one of R 1  and R 2  is CF 3  and the other is independently cyclopropyl, CH 2 F or CHF 2 . 
     
     
         20 . A compound of  claim 15 , wherein T, U, V, and W are independently CH, CF or N. 
     
     
         21 . A compound of  claim 20 , wherein T is CF or N and each of U, V and W is CH. 
     
     
         22 . A compound of  claim 20 , wherein each of T and V is independently CF or N and each of U and W is CH. 
     
     
         23 . A compound of  claim 15 , wherein L 1  and L 2  together represent —NH—C(═O)—, —NH—S(═O) q —, —C(═O)NH— or —NH—CH 2 —; 
     
     
         24 . A compound of  claim 15 , wherein A is absent, —NH—, or —CH 2 —. 
     
     
         25 . A compound of  claim 24 , wherein A is —CH 2 —. 
     
     
         26 . A compound of  claim 15 , wherein Cy is selected from 
       
         
           
           
               
               
           
         
       
     
     
         27 . A compound of  claim 15 , wherein Cy is 
       
         
           
           
               
               
           
         
       
     
     
         28 . A compound of  claim 17 , wherein Cy is selected from 
       
         
           
           
               
               
           
         
       
     
     
         29 . A compound of formula (IA-III) 
       
         
           
           
               
               
           
         
       
       or a tautomer, prodrug, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein
 R 1  and R 2  are the same or different and are independently selected from CH 2 F, CHF 2 , CF 3 , cyclopropyl with the proviso that both R 1  and R 2  at the same time do not represent CF 3 ; 
 T and V are the same or different and are independently selected from CF and N; 
 each of U and V is CR a ; 
 L 1  and L 2  together represent —NH—C(═X)—, —NH—S(═O) q —, —C(═X)NH—, or —S(═O) q NH— or —NH—CR′R″—; 
 A is absent or selected from —(CR′R″)— and —NR a ; 
 each occurrence of R′ and R″ are the same or different and are independently selected from hydrogen or substituted or unsubstituted C (1-6)  alkyl group or R′ and R″ may be joined to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR a  and S; 
 R′″ is selected from hydrogen, or halogen 
 each occurrence of X is independently selected from O, S and —NR a ; 
 Cy is a bicyclic ring selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 
 each occurrence of R a  and R b  are the same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, —OR c , —S(═O) q —R c , —NR c R d , —C(═Y)—R c , —CR c R d —C(═Y)—R c , —CR c R d —Y—CR c R d —, —C(═Y)—NR c R d —, —NRR d —C(═Y)—NR c R d —, —S(═O) q —NR c R d —, —NR c R d —S(═O) q —NR c R d —, —NR c R d —NR c R d —, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocylyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, or when R a  and R b  substitutent are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR c  and S; 
 each occurrence of R c  and R d  may be same or different and are 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 cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or when two R c  and/or R d  substitutents are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which are the same or different and are selected from O, NH and S; 
 each occurrence of Y is selected from O, S and —NR a ; and 
 each occurrence of q independently represents 0, 1 or 2. 
 
     
     
         30 . A compound of  claim 29 , wherein one of R 1  and R 2  is CF 3  and the other is cyclopropyl. 
     
     
         31 . A compound of  claim 29 , wherein one of R 1  and R 2  is CF 3  and the other is CH 2 F, CHF 2 . 
     
     
         32 . A compound of  claim 29 , wherein both R 1  and R 2  represent cyclopropyl. 
     
     
         33 . A compound of  claim 29 , wherein T is CF or N. 
     
     
         34 . A compound of  claim 29 , wherein U, V, W are CH, CF or N. 
     
     
         35 . A compound of  claim 29 , wherein L 1  and L 2  together represent —NH—C(═O)—, C(═O)NH— or —NH—CH 2 —. 
     
     
         36 . A compound of  claim 29 , wherein A is absent, —NH—, or —CH 2 —. 
     
     
         37 . A compound of  claim 36 , wherein A is absent. 
     
     
         38 . A compound of  claim 36 , wherein A is —CH 2 —. 
     
     
         39 . A compound of  claim 36 , wherein A is —NH—. 
     
     
         40 . A compound of  claim 29 , wherein Cy is selected from 
       
         
           
           
               
               
           
         
       
     
     
         41 . A compound of  claim 40 , wherein Cy is 
       
         
           
           
               
               
           
         
       
     
     
         42 . A compound of formula (IA-IV) 
       
         
           
           
               
               
           
         
       
       or a tautomer, prodrug, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof, wherein
 R 1  and R 2  are the same or different and are independently selected from CH 2 F, CHF 2 , CF 3 , cyclopropyl with the proviso that both R 1  and R 2  at the same time do not represent CF 3 ; 
 T and V are the same or different and are independently selected from CH, CF and N; 
 each of U and V is CR a ; 
 L 1  and L 2  together represent —NH—C(═X)—, —NH—S(═O) q —, —C(═X)NH—, or —S(═O) q NH— or —NH—CR′R″—; 
 A is selected from —(CR′R″)— and —NR a ; 
 each occurrence of R′ and R″ are the same or different and are independently selected from hydrogen or substituted or unsubstituted C (1-6)  alkyl group or R′ and R″ may be joined to form a substituted or unsubstituted saturated or unsaturated 3-6 membered ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR a  and S; 
 R″′ is selected from hydrogen, or halogen; 
 each occurrence of X is independently selected from O, S and —NR a ; 
 Cy is a bicyclic substituted or unsubstituted heteroaryl; 
 each occurrence of R a  and R b  are the same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, —OR c , —S(═O) q —R c , —NR c R d , —C(═Y)—R c , —CR c R d —C(═Y)—R c , —CR c R d —Y—CR c R d —, —C(═Y)—NR c R d —, —NRR d —C(═Y)—NR c R d —, —S(═O) q —NR c R d —, —NR c R d —S(═O) q —NR c R d —, —NR c R d —NR c R d —, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocylyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, or when R a  and R b  substitutent are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR c  and S; 
 each occurrence of R c  and R d  may be same or different and are 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 cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or when two R c  and/or R d  substitutents are directly bound to the same atom, they may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which are the same or different and are selected from O, NH and S; 
 each occurrence of Y is selected from O, S and —NR a ; and 
 each occurrence of q independently represents 0, 1 or 2. 
 
     
     
         43 . A compound of  claim 42 , wherein one of R 1  and R 2  is CF 3  and the other is cyclopropyl. 
     
     
         44 . A compound of  claim 42 , wherein one of R 1  and R 2  is CF 3  and the other is CH 2 F, CHF 2 . 
     
     
         45 . A compound of  claim 42 , wherein both R 1  and R 2  represent cyclopropyl. 
     
     
         46 . A compound of  claim 42 , wherein T is CH, CF or N. 
     
     
         47 . A compound of  claim 46 , wherein T is CF. 
     
     
         48 . A compound of  claim 42 , wherein U, V, W are CH, CF or N. 
     
     
         49 . A compound of  claim 42 , wherein L 1  and L 2  together represent —NH—C(═O)—, C(═O)NH— or —NH—CH 2 —; 
     
     
         50 . A compound of  claim 42 , wherein A is —NH—, or —CH 2 —. 
     
     
         51 . A compound of  claim 49 , wherein A is —CH 2 —. 
     
     
         52 . A compound of  claim 49 , wherein A is —NH—. 
     
     
         53 . A compound of  claim 42 , wherein Cy is selected from 
       
         
           
           
               
               
           
         
       
     
     
         54 . A compound of  claim 53 , wherein Cy is selected from 
       
         
           
           
               
               
           
         
       
     
     
         55 . A compound of  claim 1 , wherein the compound is selected from:
 N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-1H-benzo[d]imidazole-6-carboxamide,   N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-1H-benzo[d][1,2,3]triazole-6-carboxamide,   N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]quinoline-6-carboxamide,   N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]quinoxaline-6-carboxamide,   2-(1H-benzo[d]imidazol-1-yl)-N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl) phenyl]acetamide,   2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-[4-(3,5-dicyclopropyl-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,   N-[4-(3,5-dicyclopropyl-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,   N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-2-(quinolin-6-yl)acetamide,   N-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)-3-fluorophenyl]-2-(quinolin-6-yl) acetamide,   N-[4-(4-chloro-3,5-dicyclopropyl-1H-pyrazol-1-yl)-3-fluorophenyl]-4-methyl-1,2,3-thiadiazole-5-carboxamide,   N-[6-(3,5-dicyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]quinoline-6-carboxamide,   N-[6-(3,5-dicyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]quinoxaline-6-carboxamide,   2-(1H-benzo[d][1,2,3]triazol-1-yl)-N-[6-(3,5-dicyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]acetamide,   N-[6-(3,5-dicyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]-2-(quinolin-6-yl)acetamide,   N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}quinoline-6-carboxamide,   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,   N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-(quinolin-6-yl)acetamide,   N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-(quinolin-6-yl)propanamide,   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,   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-ylmethyl) benzamide,   1-[4-(3,5-dicyclopropyl-1H-pyrazol-1-yl)phenyl]-3-(quinolin-6-yl)urea,   
       or a tautomer, prodrug, N-oxide, pharmaceutically acceptable ester, or pharmaceutically acceptable salt thereof. 
     
     
         56 - 66 . (canceled) 
     
     
         67 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         68 . The pharmaceutical composition of  claim 67 , further comprising one or more additional therapeutic agents selected from anti-inflammatory agent, anti-cancer agent immunosuppressive agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof. 
     
     
         69 - 101 . (canceled)