IP Library › Granted Patent US 9,758,514

Granted Patent B2

US 9,758,514 · App. 14/539,470 · Granted Sep 12, 2017

Modulators of calcium release-activated calcium channel

Inventors: Meyyappan Muthuppalaniappan (Hyderabad, IN); Srikant Viswanadha (Hyderabad, IN); Gayatri S. Merikapudi (Hyderabad, IN); Swaroop K. Vakkalanka (La Chaux-de-Fonds, CH)

Assignee: RHIZEN PHARMACEUTICALS SA

C07D417/10 A61K31/415 A61K31/422 A61K31/427 A61K31/433 A61K31/4439 A61K31/455 A61K31/496 A61K31/506 A61K31/5377 A61K45/06 C07D207/327 C07D207/337 C07D231/12 C07D295/195 C07D401/04 C07D401/10 C07D401/12 C07D401/14 C07D403/04 C07D403/10 C07D403/12 C07D403/14 C07D413/10 C07D413/12 C07D413/14 C07D417/12 C07D417/14 C12N5/0634 C12N2500/46

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Quick Facts

Patent No.: US 9,758,514
App. No.: 14/539,470
Granted: Sep 12, 2017
Kind: B2

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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.

Claims (277)

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 selected from monocyclic substituted or unsubstituted cycloalkyl group, monocyclic substituted or unsubstituted heterocyclyl, monocyclic substituted or unsubstituted A aryl, and monocyclic 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;

wherein

when A is absent, L 1 and L 2 together represent —NH—C(═O)— and ring Ar represents

then Cy is not substituted or unsubstituted pyridyl, monocyclic substituted or unsubstituted cycloalkyl or monocyclic substituted or unsubstituted aryl; and

with the proviso that the compound of formula (I) does not include

N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-(difluoromethyl)-5-methyl-1H-Pyrazole-3-carboxamide;

N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-methyl-4-nitro-1H-Pyrazole-5-carboxamide;

N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-3-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-5-Isoxazolecarboxamide;

N-[4-[5-cyclopropyl-3-trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4,5-dihydro-3-(2-methoxyphenyl)-5-Isoxazole carboxamide;

N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2-[4-(1,1-dimethylethyl)phenyl]-Cyclopropanecarboxamide;

N-[4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-3-Pyridinecarboxamide;

N-[4-[3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-3-Pyridine carboxamide; or

N-benzyl-6-(3,5-dicyclopropyl-1H-pyrazol-1-yl) pyridazin-3-amine.

2. A compound of claim 1 , wherein Hy is selected from

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 selected from

6. A compound of claim 1 , wherein Ar is selected from

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 absent,

12. A compound of claim 1 , wherein Cy is

13. A compound of claim 12 , wherein Cy is selected from

14. A compound of claim 13 , wherein Cy is selected from

15. A compound of formula (IA)

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

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;

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

Cy is selected from monocyclic substituted or unsubstituted cycloalkyl group, monocyclic substituted or unsubstituted heterocyclyl, monocyclic substituted or unsubstituted aryl, and monocyclic 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 CR d —Y—CR c R d —, —C(═Y)—NR c R d —, —NR c R 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 Y is selected from O, S and —NR a ; and

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