US 9,790,231 B2Granted

Chromane and chromene derivatives and their use as CRAC modulators

AssigneeLupin Limited

InventorsNageswara Rao Irlapati, Kiran Chandrashekhar Kulkarni, Vijay Pandurang Karche, Gokul Keruji Deshmukh, Neelima Sinha, Venkata P. Palle, Rajender Kumar Kamboj

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Abstract

The invention relates to compounds of Formula (I) and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine for the treatment of diseases, disorders associated with the modulation of calcium release-activated calcium (CRAC) channel. The invention also relates to pharmaceutical compositions containing such compounds in treating diseases disorders associated with calcium release-activated calcium (CRAC) channel modulators.

Claims8

Dependent claims

A compound having the Formula (I):

wherein,
A and B are independently CR3 or N;
ring R is Formula (i);
L is selected from —NR8C(O)—, —C(O)NR8—and —NR8CH2—;
X is CR or N where R is selected from hydrogen, halogen or substituted or unsubstituted alkyl;
R1, which may be same or different at each occurrence, is independently selected from halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and haloalkyl;
R2, which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, haloalkyl, —NR9R10, —COOR8 and —CONR9R10;
each of R3 is independently selected from hydrogen, halogen and substituted or unsubstituted alkyl;
R4 and R5, which may be same or different and are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl and —NR9R10;
or
R4 and R5 together with the carbon atom to which they are attached form oxo (C═O);
one of R6 and R7 is alkyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl and the other is selected from hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, —NR9R10, substituted or unsubstituted cycloalkyl, —COOR8 and —CONR9R10;
or R6 and R7 together with the carbon atom to which they are attached may form substituted or unsubstituted 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring;
R8 is hydrogen or substituted or unsubstituted alkyl;
R9 and R10, which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, and substituted or unsubstituted cycloalkyl;
or R9 and R10, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 5 to 7 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds;
Ra and Rb, which may be same or different and are independently selected from hydrogen, cyano, hydroxyalkyl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, haloalkoxy, substituted or unsubstituted cycloalkyl, —NR9R10, —COORS and —CONH2;
‘n’ is an integer ranging from 1 to 3, both inclusive;
and
‘p’ is an integer ranging from 0 to 2, both inclusive;
or a pharmaceutically acceptable salt thereof.

18 more elements

A compound which is selected from:

2,6-Difluoro-N-(4-(2,2,6-trimethyl-4-oxochroman-7-yl)phenyl)benzamide,
N-(4-(6-Ethyl-2,2-dimethyl-4-oxochroman-7-yl)phenyl)-2,6-difluorobenzamide,
N-(2,6-Difluorophenyl)-4-(2,2,6-trimethyl-4-oxochroman-7-yl)benzamide,
2,6-Difluoro-N-(5-(2,2,6-trimethyl-4-oxochroman-7-yl)pyrazin-2-yl)benzamide,
N-(5-(6-Ethyl-2,2-dimethyl-4-oxochroman-7-yl)pyrazin-2-yl)-2,6-difluorobenzamide,
2,6-Difluoro-N-(5-(2,2,6-trimethyl-4-oxochroman-7-yl)pyrazin-2-yl)benzamide,
2,6-Difluoro-N-(5-(2,2,8-trimethylchroman-7-yl)pyrazin-2-yl)benzamide,
2-Chloro-6-fluoro-N-(4-(6-methylspiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)benzamide,
2-Fluoro-6-methyl-N-(4-(6-methylspiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)benzamide,
2-Fluoro-6-methyl-N-(4-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)benzamide,
2-Chloro-6-fluoro-N-(4-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)benzamide,
2-Fluoro-N-(4-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)benzamide,
N-(2,6-Difluorophenyl)-4-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)benzamide,
7-(4-((2-Fluoro-6-methylbenzyl)amino)phenyl)-6-methylspiro[chroman-2,1′-cyclobutan]-4one,
2,6-Difluoro-N-(4-(5-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-6-yl)phenyl)benzamide,
2,6-Difluoro-N-(4-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)benzamide,
2,6-Difluoro-N-(4-(7-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-6-yl)phenyl)benzamide,
2,6-Difluoro-N-(4-(7-methylspiro[chroman-2,1′-cyclobutan]-6-yl)phenyl)benzamide,
2,6-Difluoro-N-(4-(8-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)benzamide,
N-(4-(6-Ethyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)-2,6-difluorobenzamide,
7-(4-(2,6-Difluorobenzyl)amino)phenyl)-6-methylspiro[chroman-2,1′-cyclobutan]-4-one,
2,6-Difluoro-N-(4-(6-methylspiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)benzamide,
2,6-Difluoro-N-(4-(8-methylspiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)benzamide,
N-(4-(6-Ethylspiro[chroman-2,1′-cyclobutan]-7-yl)phenyl)-2,6-difluorobenzamide,
2,6-Difluoro-N-(4-(4-hydroxy-6-methylspiro[chroman-2,1′-cyclobutan]-7-yl) phenyl)benzamide,
2,6-Difluoro-N-(5-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)pyridin-2yl)benzamide,
2,6-Difluoro-N-(6-(2,2,6-trimethyl-4-oxochroman-7-yl)pyridin-3-yl)benzamide,
N-(6-(6-Ethyl-2,2-dimethyl-4-oxochroman-7-yl)pyridin-3-yl)-2,6-difluoro benzamide,
2,6-Difluoro-N-(6-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)pyridin-3yl)benzamide,
2,6-Difluoro-N-(4-(2,2, 8-trimethyl-4-oxochroman-7-yl)phenyl)benzamide,
2,6-Difluoro-N-(5-(2,2,8-trimethyl-4-oxochroman-7-yl)pyrazin-2-yl)benzamide,
2,6-Difluoro-N-(4-(4-hydroxy-2,2, 8-trimethylchroman-7-yl)phenyl)benzamide,
7-(4-((2, 6-Difluorobenzyl)amino)phenyl)-2,2, 6-trimethylchroman-4-one,
7-(5-((2, 6-Difluorobenzyl)amino)pyrazin-2-yl)-2,2, 6-trimethylchroman-4-one,
7-(6-((2, 6-Difluorobenzyl)amino)pyridin-3 -yl)-2,2,6-trimethylchroman-4-one,
2,6-Difluoro-N-(5-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)pyrazin-2-yl)benzamide,
2,6-Difluoro-N-(6-(2,2,8-trimethyl-4-oxochroman-7-yl)pyridin-3-yl)benzamide,
7-(5-((2,6-Difluorobenzyl)amino)pyrazin-2-yl)-6-methylspiro[chroman-2,1′-cyclobutan]-4-one,
7-(6-((2,6-Difluorobenzyl)amino)pyridin-3-yl)-6-methylspiro[chroman-2,1′-cyclobutan]-4-one,
7-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-6-methylspiro[chroman-2,1′-cyclobutan]-4-one,
N-(5-(6-Ethyl-4-oxospiro [chroman-2,1′-cyclobutan]-7-yl)pyrazin-2-yl)-2,6-difluoro benzamide,
N-(3,5-Difluoropyridin-4-yl)-4-(6-ethyl-2,2-dimethyl-4-oxochroman-7-yl)benzamide,
N-(3,5-Difluoropyridin-4-yl)-4-(2,2,6-trimethyl-4-oxochroman-7-yl)benzamide,
4-(6-Methyl-4-oxospiro [chroman-2,1′-cyclobutan]-7-yl)-N-(3-methylpyridin-4-yl)benzamide,
Methyl 7-(5-(2,6-difluoro benzamido)pyrazin-2-yl)-2,6-dimethyl-4-oxochroman-2-carboxylate,
7-(5 -(2,6-Difluorobenzamido)pyrazin-2-yl)-2,6-dimethyl-4-oxochroman-2-carboxamide,
7-(5-(2,6-Difluorobenzamido)pyrazin-2-yl)-2,6-dimethyl-4-oxochroman-2-carboxylic acid,
N-(4-(6-Ethyl-4-hydroxy-2,2-dimethylchroman-7-yl)phenyl)-2,6-difluoro benzamide,
N-(4-(6-Ethyl-2,2-dimethylchroman-7-yl)phenyl)-2,6-difluorobenzamide,
N-(3,5-Difluoropyridin-4-yl)-4-(6-ethyl-2,2-dimethylchroman-7-yl)benzamide,
N-(3,5-Difluoropyridin-4-yl)-4-(2,2,6-trimethylchroman-7-yl)benzamide,
2,6-Difluoro-N-(4-(2-(hydroxymethyl)-2,6-dimethyl-4-oxochroman-7-yl)phenyl) benzamide,
2,6-Difluoro-N-(5-(2-(hydroxymethyl)-2,6-dimethyl-4-oxochroman-7-yl)pyrazin-2-yl)benzamide,
2,6-Difluoro-N-(6-(2-(hydroxymethyl)-2,6-dimethyl-4-oxochroman-7-yl)pyridin-3-yl)benzamide,
2,6-Difluoro-N-(5-(2-(hydroxymethyl)-2,6-dimethyl-4-oxochroman-7-yl)pyridin-2-yl)benzamide,
N-(5-(2,2-Bis(hydroxymethyl)-6-methyl-4-oxochroman-7-yl)pyrazin-2-yl)-2,6-difluorobenzamide,
N-(6-(2,2-Bis(hydroxymethyl)-6-methyl-4-oxochroman-7-yl)pyridin-3-yl)-2,6-difluorobenzamide,
N-(5-(2,2-Bis(hydroxymethyl)-6-methyl-4-oxochroman-7-yl)pyridin-2-yl)-2,6-difluorobenzamide,
N-(4-(6-Ethyl-2-(hydroxymethyl)-2-methyl-4-oxochroman-7-yl)phenyl)-2,6-difluorobenzamide,
2,6-Difluoro-N-(4-(2,2,8-trimethylchroman-7-yl)phenyl)benzamide,
2,6-Difluoro-N-(4-(4-hydroxy-2,2,6-trimethylchroman-7-yl)phenyl)benzamide,
2,6-Difluoro-N-(5-(4-hydroxy-6-methylspiro[chroman-2,1′-cyclobutan]-7-yl)pyrazin-2-yl)benzamide,
N-(4-(4-(Dimethylamino)-2,2,6-trimethylchroman-7-yl)phenyl)-2,6-difluoro benzamide,
N-(5-(6-Ethyl-2,2-dimethyl-4-oxochroman-7-yl)pyridin-2-yl)-2,6-difluorobenzamide,
N-(3,5-Difluoropyridin-4-yl)-4-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)benzamide,
N-(3,5-Dichloropyridin-4-yl)-4-(6-methyl-4-oxospiro[chroman-2,1′-cyclobutan]-7-yl)benzamide,
N-(3,5-Difluoropyridin-4-yl)-4-(6-methylspiro[chroman-2,1′-cyclobutan]-7-yl)benzamide,
N-(3,5-Dichloropyridin-4-yl)-4-(6-methylspiro[chroman-2,1′-cyclobutan]-7-yl)benzamide,
2,6-Difluoro-N-(4-(2-(hydroxymethyl)-2,8-dimethyl-4-oxochroman-7-yl)phenyl)benzamide,
2,6-difluoro-N-(4-(2-(hydroxymethyl)-2,8-dimethylchroman-7-yl) phenyl)benzamide,
2,6-Difluoro-N-(5-(2-(hydroxymethyl)-2,6dimethylchroman-7-yl)pyrazin-2-yl)benzamide,
N-(2,6-Difluorophenyl)-4-(6-methylspiro[chroman-2,1′-cyclobutan]-7-yl)benzamide,
2,6-Difluroro-N-(4-(1′-methyl-4-oxospiro[chroman-2,4′-piperidin]-6-yl)phenyl)benzamide,
N-(4-(1′,6-Dimethyl-4-oxospiro[chroman-2,4′-piperiden]-7-yl)phenyl)-2,6-difluorobenzamide,
2,6-Difluoro-N-(4-(6methyl-4-oxospiro[chroman-2,4′-piperidin]-7-yl)phenyl)benzamide hydrochloride,
2,6-Difluoro-N-(4-(6′-methyl-4′-oxospiro[azetidine-3,2′-chroman]-7′-yl)phenyl)benzamide hydrochloride,
N-(4-(1,6′-Dimethyl-4′-oxospiro[azetidine-3,2′-chroman]-7′-yl)phenyl)-2,6-difluorobenzamide,
2,6-Difluoro-N-(5-(6-methyl-4-oxospiro[chroman-2,3′-oxetan]-7-yl)pyrazin-2-yl)benzamide,
2,6-Difluoro-N-(6-(6-methyl-4-oxospiro[chroman-2,3′-oxetan]-7-yl)pyridin-3-yl)benzamide,
2,6-Difluoro-N-(5-(6-methyl-4-oxospiro[chroman-2,3′-oxetan]-7-yl)pyridin-2-yl)benzamide and
N-(4-(6-Ethyl-4-oxospiro[chroman-2,3′-oxetan]-7-yl)phenyl)-2,6-difluorobenzamide or a pharmaceutically acceptable salt thereof.

78 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound having the Formula (I):

wherein,
A and B are independently CR3 or N;
ring R is Formula (i);
L is selected from —NR8C(O)—, —C(O)NR8—and —NR8CH2—;
X is CR or N where R is selected from hydrogen, halogen or substituted or unsubstituted alkyl;
R1, which may be same or different at each occurrence, is independently selected from halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and haloalkyl;
R2, which may be same or different at each occurrence, is independently selected from halogen, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, haloalkyl, —NR9R10, —COOR8 and —CONR9R10;
each of R3 is independently selected from hydrogen, halogen and substituted or unsubstituted alkyl;
R4 and R5, which may be same or different and are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl and —NR9R10;
or
R4 and R5 together with the carbon atom to which they are attached form oxo (C═O);
one of R6 and R7 is alkyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl and the other is selected from hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl, —NR9R10, substituted or unsubstituted cycloalkyl, —COOR8 and —CONR9R10;
or R6 and R7 together with the carbon atom to which they are attached may form substituted or unsubstituted 3 to 7 membered carbocyclic ring or 4 to 7 membered heterocyclic ring;
R8 is hydrogen or substituted or unsubstituted alkyl;
R9 and R10, which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, and substituted or unsubstituted cycloalkyl;
or R9 and R10, together with the nitrogen atom to which they are attached, may form a substituted or unsubstituted, saturated or unsaturated 5 to 7 membered cyclic ring, wherein the unsaturated cyclic ring may have one or two double bonds;
Ra and Rb, which may be same or different and are independently selected from hydrogen, cyano, hydroxyalkyl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, haloalkoxy, substituted or unsubstituted cycloalkyl, —NR9R10, —COORS and —CONH2;
‘n’ is an integer ranging from 1 to 3, both inclusive;
and
‘p’ is an integer ranging from 0 to 2, both inclusive;
or a pharmaceutically acceptable salt thereof.

18 more elements