Pyrrolopyrimidine compounds and their uses

Abstract

The disclosed compounds relate to treatments and therapies for protein kinase-associated disorders. There is also a need for compounds useful in the treatment or prevention or amelioration of one or more symptoms of cancer, transplant rejections, and autoimmune diseases. Furthermore, there is a need for methods for modulating the activity of protein kinases, such as CDK1, CDK2, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, using the compounds provided herein.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, wherein 
         X is CR 9 , or N; 
         R 1  is C 1-8 alkyl, CN, C(O)OR 4  or CONR 5 R 6 , a 5-14 membered heteroaryl group, or a 3-14 membered cycloheteroalkyl group; 
         R 2  is C 1-8 alkyl, C 3-14 cycloalkyl, or a 5-14 membered heteroaryl group, and wherein R 2  may be substituted with one or more C 1-8 alkyl, or OH; 
         L is a bond, C 1-8 alkylene, C(O), or C(O)NR 10 , and wherein L may be substituted or unsubstituted; 
         Y is H, R 11 , NR 12 R 13 , OH, or Y is part of the following group 
       
       
         
           
           
               
               
           
         
       
       where Y is CR 9  or N;
 where 0-3 R 8  may be present, and R 8  is C 1-8 alkyl, oxo, halogen, or two or more R 8  may form a bridged alkyl group; 
 W is CR 9 , or N; 
 R 3  is H, C 1-8 alkyl, C 1-8 alkylR 14 , C 3-14 cycloalkyl, C(O)C 1-8  alkyl, C 1-8 haloalkyl, C 1-8 alkylOH, C(O)NR 14 R 15 , C 1-8 cyanoalkyl, C(O)R 14 , C 0-8 alkylC(O)C 0-8 alkylNR 14 R 15 , C 0-8 alkylC(O)OR 14 , NR 14 R 15 , SO 2 C 1-8 alkyl, C 1-8 alkylC 3-14 cycloalkyl, C(O)C 1-8 alkylC 3-14 cycloalkyl, C 1-8 alkoxy, or OH which may be substituted or unsubstituted when R 3  is not H. 
 R 9  is H or halogen; 
 R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  are each independently selected from H, C 1-8 alkyl, C 3-14  cycloalkyl, a 3-14 membered cycloheteroalkyl group, a C 6-14  aryl group, a 5-14 membered heteroaryl group, alkoxy, C(O)H, C(N)OH, C(N)OCH 3 , C(O)C 1-3 alkyl, C 1-8 alkylNH 2 , C 1-6  alkylOH, and wherein R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , and R 13 , R 14 , and R 15  when not H may be substituted or unsubstituted; 
 m and n are independently 0-2; and 
 Wherein L, R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , and R 13 , R 14 , and R 15  may be substituted with one or more of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-14 cycloalkyl, 5-14 membered heteroaryl group, C 6-14 aryl group, a 3-14 membered cycloheteroalkyl group, OH, (O), CN, alkoxy, halogen, or NH 2 . 
 
     
     
         2 . The compound of formula I according to  claim 1  wherein R 3  is H, C 1-8 alkyl, C 3-14 cycloalkyl, C(O)C 1-8  alkyl, C 1-8 alkylOH, C 1-8 cyanoalkyl, C 0-8 alkylC(O)C 0-8 alkylNR 14 R 15 , C 0-8 alkylC(O)OR 14 , NR 14 R 15 , C 1-8 alkylC 3-14 cycloalkyl, C(O)C 1-8 alkylC 3-14 cycloalkyl, C 0-8 alkoxy, C 1-8 alkylR 14 , C 1-8 haloalkyl, or C(O)R 14 , which may be substituted with one or more of OH, CN, F, or NH 2 , and wherein R 14  and R 15  are each independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl, alkoxy, C(O)C 1-3 alkyl, C 1-8 alkylNH 2 , or C 1-6 alkylOH. 
     
     
         3 . The compound of formula I according to  claim 1  wherein R 3  is H, C 1-8 alkyl, or C 1-8 alkylOH. 
     
     
         4 . The compound of formula I according to  claim 1  wherein Y is H, OH, or Y is part of the following group 
       
         
           
           
               
               
           
         
       
       where Y is N and W is CR 9 , or N;
 where 0-2 R 8  may be present, and R 8  is C 1-8 alkyl, oxo, or two or more R 8  may form a bridged alkyl group. 
 
     
     
         5 . The compound of formula I according to  claim 1  wherein L is a bond, C 1-8 alkylene, or C(O)NH, or C(O). 
     
     
         6 . The compound of formula I according to  claim 1  wherein R 2  is C 3-14 cycloalkyl. 
     
     
         7 . The compound of formula I according to  claim 1  wherein R 2  is cyclopentane. 
     
     
         8 . The compound of formula I according to  claim 1  wherein R 1  is CN, C(O)OR 4 , CONR 5 R 6 , or a 5-14 membered heteroaryl group. 
     
     
         9 . The compound of formula I according to  claim 1  wherein R 1  is CONR 5 R 6 , and R 5  and R 6  are C 1-8 alkyl. 
     
     
         10 . The compound of formula I according to  claim 1  wherein X is CR 9 . 
     
     
         11 . The compound of formula I according to  claim 1  wherein one X is N and the other X is CR 9 . 
     
     
         12 . The compound of formula I according to  claim 1  wherein X is CR 9  and Y is 
       
         
           
           
               
               
           
         
       
       where m and n are 1, and Y and W are N. 
     
     
         13 . A method of treating a disease, disorder or syndrome associated with CDK 4 inhibition, said method comprising administering a compound according to  claim 1  or its prodrug or pharmaceutical composition comprising the compound of formula I or its prodrug and pharmaceutically acceptable excipients to a subject in need thereof. 
     
     
         14 . The method of treating as claimed in  claim 13 , wherein the disease, disorder or syndrome is hyperproliferative in a subject, wherein subject is an animal including humans, selected from a group comprising cancer and inflammation. 
     
     
         15 . A method of inhibiting a cyclin dependent kinase (e.g. cdk-4), which method comprises contacting the kinase with a kinase-inhibiting compound according to  claim 1 . 
     
     
         16 . A method of modulating a cellular process (for example cell division) by inhibiting the activity of a cyclin dependent kinase using a compound according to  claim 1 . 
     
     
         17 . A compound according to  claim 1  for use in the prophylaxis or treatment of a disease state as described herein. 
     
     
         18 . The use of a compound according to  claim 1  for the manufacture of a medicament, wherein the medicament is for any one or more of the uses defined herein. 
     
     
         19 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         20 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier in a form suitable for oral administration. 
     
     
         21 . A compound of formula I(a): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 50  is CONR 54 R 55 , or CN; 
         R 51  is C 3-14 cycloalkyl which may be unsubstituted or substituted by C 1-3 alkyl, or OH; 
         Z is CH or N; and 
         V is NR 56  or CHR 57 ; 
         R 54  and R 55  are independently H, C 1-3 alkyl, 
         R 52 , R 53 , R 56 , and R 57  are independently H, C 1-8 alkyl, C 3-14 cycloalkyl, C 1-8 haloalkyl, NR 58 R 59 , C(O)OR 60 , C(O)C 1-8 alkyl, C 0-8 alkylC(O)C 0-8 alkyl-NR 61 R 62 , C 1-8 alkoxy, C 1-8 alkylOR 63 , C(O)-5-14cycloheteroalkyl group, C 3-14 cycloalkyl group, each of which when not H may be substituted by one or more of C 1-8 alky, OH, or CN; 
         R 58 , R 59 , R 60 , R 61 , R 62 , and R 63  are H or C 1-8 alkyl. 
       
     
     
         22 . A compound selected from:
 7-Cyclopentyl-2-[5-(3-methyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carbonitrile;   7-Cyclopentyl-2-{5-[4-(2-fluoro-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-(4-dimethylamino-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   2-[5-(4-Carbamoylmethyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   2-{5-[4-(2-Amino-acetyl)-piperazin-1-yl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   2-[5-(3-Amino-pyrrolidin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(2-methoxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[4-(2-hydroxyethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-((R)-3-methyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-((S)-3-methylpiperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-(3-methylpiperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(3-hydroxypropyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(pyrrolidine-1-carbonyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-((S)-2,3-dihydroxypropyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-(5-{4-[2-(2-hydroxyethoxy)-ethyl]-piperazin-1-yl}-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(2-hydroxy-1-methylethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{6-[4-(2-hydroxyethyl)-piperazin-1-yl]-pyridazin-3-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(2,3-dihydroxypropyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-((R)-2,3-dihydroxypropyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-(4-dimethylamino-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;   7-Cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-(4-dimethylaminopiperidine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-(1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-((S)-3-methylpiperazin-1-ylmethyl)-pyridin-2-ylamino]-7H pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-((S)-2-hydroxypropyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-((R)-2-hydroxypropyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide;   7-Cyclopentyl-2-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-(4-isopropyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(4-methyl-pentyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[6-(4-isopropyl-piperazin-1-yl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(2-hydroxy-2methylpropyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-(3,3-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]oct-3-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-(4-ethyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-(4-cyclopentyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[(R)-4-(2-hydroxyethyl)-3-methyl-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[(S)-4-(2-hydroxyethyl)-3-methyl-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(2-hydroxyethyl)-piperazin-1-ylmethyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(2-dimethylaminoacetyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(2-ethyl-butyl)piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   2-{5-[4-(2-Cyclohexyl-acetyl)piperazin-1-yl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-{5-[4-(3-cyclopentyl-propionyl)-piperazin-1-yl]-pyridin-2-ylamino}7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[5-(4-isobutylpiperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3d]pyrimidine-6-carboxylic acid dimethylamide;   {4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl]-piperazin-1-yl}-acetic acid methyl ester;   7-Cyclopentyl-2-{5-[4-(2-isopropoxyethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   {4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl]-piperazin-1-yl}-acetic acid ethyl ester;   4-(6-{7-Cyclopentyl-6-[(2-hydroxy-ethyl)methyl-carbamoyl]-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino}-pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester;   7-Cyclopentyl-2-{5-[4-(2-methyl-butyl)piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   7-Cyclopentyl-2-[1′-(2-hydroxy-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[3,4′]bipyridinyl-6-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide;   {4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]piperazin-1-yl}-acetic acid; and   2-{4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazin-1-yl}-propionic acid; or pharmaceutically acceptable salts thereof.