Compounds and compositions as itpkb inhibitors

Abstract

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or dysregulated B cell activities, particularly diseases or disorders that involve aberrant activation of inositol 1,4,5-trisphosphate 3-kinase B (ITPKb).

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein:
 n is selected from 0, 1, 2 and 3; 
 m is selected from 0, 1, 2 and 3; 
 up to 3 groups of Ring A selected from —CR 1 ═, —CR 2 ═ and —CR 5 ═ are optionally replaced with —N═; 
 
         R 1 , R 2  and R 5  are independently selected from hydrogen, hydroxy, halo, cyano, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, hydroxy-substituted-C 1-6 alkyl and cyano-substituted-C 1-6 alkyl; 
         R 3  and R 4 , together with the carbon atoms to which R 3  and R 4  are attached, form a 5 to 6 member heterocycle fused to ring A containing up to 4 radicals selected from O, C(O), S(O) 2 , CR 11 R 12  and NH; wherein each R 11  and R 12  are independently selected from hydrogen, C 1-3 alkyl, and halo-substituted-C 1-3 alkyl; or R 11  and R 12 , together with the carbon to which they are both attached, forms C 3-7 cycloalkyl; 
         R 6  and R 7  are independently selected from hydrogen, C 1-3 alkyl and halo-substituted-C 1-3 alkyl; or R 6  and R 7 , together with the carbon to which they are both attached, forms C 3-7 cycloalkyl; 
         R 8  is selected from C 1-6 alkyl, C 2-6 alkenyl, halo-substituted-C 1-6 alkyl and hydroxy-substituted-C 1-6 alkyl; or two R 8  groups can combine to form an alkyl bridge; or when two R 8  groups are attached to the same carbon atom, they, together with the carbon to which they are both attached, form C 3-7 cycloalkyl; 
         R 9  is selected from L 1 -C 6-10 aryl, L 1 -C 1-10 heteroaryl, C 1-6 alkyl, L 1 -C 3-12 cycloalkyl and L 1 -C 3-8 heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 9  can be optionally substituted with 1 to 3 radicals independently selected from halo, cyano, hydroxy, C 1-3 alkyl, halo-substituted-C 1-3 alkyl, cyano-substituted-C 1-3 alkyl, hydroxy-substituted-C 1-3 alkyl, —C(O)R 13 , —C(O)NR 13 R 14 ; wherein each R 13  and R 14  are independently selected from hydrogen and C 1-6 alkyl; 
         L 1  is a bond, C 1-3  alkyl or halo-substituted-C 1-3  alkyl; 
         Y is N or CR 10 ; 
         R 10  is selected from hydrogen, C 1-6 alkyl, —NR 15 R 16 , —NR 15 C(O)R 16  and —C(O)NR 15 R 16 ; wherein each R 15  and R 16  are independently selected from hydrogen, C 1-6 alkyl, C 6-10 aryl, C 1-10 heteroaryl, C 3-12 cycloalkyl and C 3-8 heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl can be optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 1-6  alkoxy and halo-substituted-C 1-6 alkoxy; 
         and the pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 n is selected from 1 and 2;   m is selected from 0, 1 and 2;   up to 3 groups of Ring A selected from —CR 1 ═, —CR 2 ═ and —CR 5 ═ are optionally replaced with —N═   R 1 , R 2  and R 5  are hydrogen;   R 6  and R 7  are hydrogen;   R 8  is selected from C 1-6 alkyl, halo-substituted-C 1-6 alkyl and hydroxy-substituted-C 1-6 alkyl; or two R 8  groups can combine to form an alkyl bridge; or when two R 8  groups are attached to the same carbon, they, together with the carbon to which they are both attached, form C 3-7 cycloalkyl;   R 9  is selected from L 1 -C 6-10 aryl, L 1 -C 1-10 heteroaryl, C 1-6 alkyl, L 1 -C 3-12 cycloalkyl and L 1 -C 3-8 heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R 9  can be optionally substituted with 1 to 3 radicals independently selected from halo, cyano, hydroxy, C 1-3 alkyl, halo-substituted-C 1-3 alkyl, cyano-substituted-C 1-3 alkyl, hydroxy-substituted-C 1-3 alkyl, —C(O)R 13 , —C(O)NR 13 R 14 ; wherein each R 13  and R 14  are independently selected from hydrogen and C 1-6 alkyl;   L 1  is a bond or C 1-3 alkyl;   Y is CR 10 , and   R 10  is hydrogen.   
     
     
         3 . The compound of  claim 2 , wherein the 5 to 6 member heterocycle fused to ring A formed from R 3  and R 4 , together with the carbon atoms to which R 3  and R 4  are attached, is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3 , wherein R 8  is selected from methyl, ethyl, trifluoromethyl, difluoromethyl, fluoromethyl and hydroxy-methyl; or two R 8  groups can combine to form an alkyl bridge selected from methyl, ethyl and propyl; or two R 8  groups are attached to the same carbon, they, together with the carbon to which they are both attached, form cyclopropyl. 
     
     
         5 . The compound of  claim 4 , wherein R 9  is selected from C 3-7 cycloalkyl, C 4-7 heterocycloalkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl and furo[3,2-c]pyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl or furo[3,2-c]pyridin-4-ylis optionally substituted with 1 to 3 radicals independently selected from trifluoromethyl, cyano, bromo, chloro, hydroxy-methyl, methyl-carbonyl, methyl, amino-carbonyl, nitro, iodo, fluoro, methoxy-carbonyl, hydroxy, amino, carboxy and methoxy. 
     
     
         6 . The compound of  claim 1  selected from: 6-{4-[4-(5-trifluoromethyl-pyridin-2-yl)-[1,4]diazepan-1-ylmethyl]-1H-pyrazol-3-yl]-benzo[e][1,3]oxazine-2,4-dione; 6-(4-((4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl) methyl)-1H-pyrazol-3-yl)-3H-benzo[e][1,3]oxazine-2,4-dione; 6-(4-(((R)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl) methyl)-1H-pyrazol-3-yl)-3H-benzo[e][1,3]oxazine-2,4-dione; 6-(4-(((S)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl) methyl)-1H-pyrazol-3-yl)-3H-benzo[e][1,3]oxazine-2,4-dione; 6-(4-(((R)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydrobenzo[e][1,3]oxazin-2-one; 6-(4-((4-(5-(trifluoromethyl)pyridin-2-yl)-1,4-diazepan-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydrobenzo[e][1,3]oxazin-2-one; 7-(4-(((R)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)-1,2-dihydroisoquinolin-3(4H)-one; 7-(4-(((R)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)isoquinoline-1,3(2H,4H)-dione; 6-(4-44-(5-(trifluoromethyl)pyridin-2-yl)-1,4-diazepan-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2(1H)-one; 7-(4-((4-(5-(trifluoromethyl)pyridin-2-yl)-1,4-diazepan-1-yl)methyl)-1H-pyrazol-3-yl)-1,2-dihydroisoquinolin-3(4H)-one; and 6-(4-(((R)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2(1H)-one; (R)-6-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)benzo[d]oxazol-2(3H)-one; 6-(4-43-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; 6-(4-((4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-5-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)benzo[d]oxazol-2(3H)-one; 6-(4-((3-(5-(trifluoromethyl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; 6-(4-42-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; 6-(4-((3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; 6-(4-((3-(5-(trifluoromethyl)pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)-1H-pyrazol-3-yl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione; (S)-6-(4-43-(fluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; 6-(4-((4-(2,3-dimethylphenyl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione; 6-(4-((4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one; 6-(4-((4-(2,3-dimethylphenyl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)benzo[d]oxazol-2(3H)-one; (S)-6-(4-43-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-6-(4-((3-(trifluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (S)-6-(4-((3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-2-(2-methyl-4-((3-(2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)isonicotinonitrile; (R)-6-(4-((3-methyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-6-(4-((3-methyl-4-(5-methylpyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (S)-6-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-6-(4-((4-cyclohexyl-3-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-6-(5-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-2H-1,2,3-triazol-4-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-4,4-dimethyl-6-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; 6-(4-((4-(5-(trifluoromethyl)pyridin-2-yl)-4,7-diazaspiro[2.5]octan-7-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-6-(2-methyl-4-((3-(2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-1H-pyrazol-4-yl)methyl)piperazin-1-yl)nicotinonitrile; (R)-6-(4-((4-(5-chloropyridin-2-yl)-3-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (S)-1-((3-(2-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-yl)-1H-pyrazol-4-yl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-2-carboxylic acid; (S)-6-(4-((2-(hydroxymethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (S)-6-(4-((2-(fluoromethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-6-(4-((3-methyl-4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-6-(4-((4-(2-fluorobenzyl)-3-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-6-(4-((4-(4-chlorophenyl)-3-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (R)-6-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (S)-6-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (S)-6-(4-((3-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)benzo[d]oxazol-2(3H)-one, and (R)-6-(4-((3-methyl-4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one; (S)-6-(4-((4-cyclohexyl-3-methylpiperazin-1-yl)methyl)-1H-pyrazol-3-yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one. 
     
     
         7 . A method for modulating T and B lymphocyte development and function in a subject for the treatment of autoimmune diseases, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an agent which modulates the kinase activity or cellular level of an ITPKb molecule; thereby modulating B lymphocyte differentiation and function in a subject. 
     
     
         8 . The method of  claim 7  wherein the agent down-regulates the cellular level of the ITPKb molecule. 
     
     
         9 . The method of  claim 8  wherein the agent is a compound of  claim 1 . 
     
     
         10 . The method of  claim 9  wherein the agent inhibits the kinase activity of the ITPKb molecule. 
     
     
         11 . The method of  claim 10  wherein the subject is human and the ITPKb molecule is human ITPKβ. 
     
     
         12 . The method of  claim 11  in which the autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic anemia, and psoriasis. 
     
     
         13 . The method of  claim 11  wherein the subject suffers from B cell lymphoma.