Claims for Patent: 8,685,980

Summary for Patent: 8,685,980

Title:	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.
Inventor(s):	Gilbert Ebai Besong, Christopher Thomas Brain, Clinton Alan Brooks, Miles Stuart Congreve, Claudio Dagostin, Guo He, Ying Hou, Steven Howard, Yue Li, Yipin Lu, Paul Neil Mortenson, Troy D. Smith, Moo Je Sung, Steven John Woodhead, Wojciech Wrona, Bharat Lagu
Assignee:	Astex Therapeutics Ltd, Novartis Pharmaceuticals Corp
Application Number:	US13/060,154
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,685,980
Patent Claims:	1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein X is CR9; R1 is CONR5R6, and R5 and R6 are C1-8alkyl; R2 is C3-14cycloalkyl; L is a bond, C1-8alkylene, C(O), or C(O)NH, and wherein L may be substituted or unsubstituted; Y is H, R11, NR12R13, OH, or Y is part of the following group where Y is CR9 or N; where 0-3 R8 may be present, and R8 is C1-8alkyl, oxo, halogen, or two or more R8 may form a bridged alkyl group; W is CR9, or N; R3 is H, C1-8alkyl, C1-8alkylR14, C3-14cycloalkyl, C(O)C1-8 alkyl, C1-8haloalkyl, C1-8alkylOH, C(O)NR14R15, C1-8cyanoalkyl, C(O)R14, C0-8alkylC(O)C0-8alkylNR14R15, C0-8alkylC(O)OR14, NR14R15, SO2C1-8alkyl, C1-8alkylC3-14cycloalkyl, C(O)C1-8alkylC3-14cycloalkyl, C1-8alkoxy, or OH which may be substituted or unsubstituted when R3 is not H; R9 is H or halogen; R11, R12, R13, R14, and R15 are each independently selected from H, C1-8alkyl, C3-14 cycloalkyl, a 3-14 membered cycloheteroalkyl group, a C6-14 aryl group, a 5-14 membered heteroaryl group, alkoxy, C(O)H, C(NH)OH, C(NH)OCH3, C(O)C1-3alkyl, C1-8alkylNH2, and C1-6alkylOH, and wherein R11, R12, and R13, R14, and R15 when not H may be substituted or unsubstituted; m and n are independently 0-2; and wherein L, R3, R11, R12, and R13, R14, and R15 may be substituted with one or more of C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-14cycloalkyl, 5-14 membered heteroaryl group, C6-14aryl group, a 3-14 membered cycloheteroalkyl group, OH, (O), CN, alkoxy, halogen, or NH2. 2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 wherein R3 is H, C1-8alkyl, C3-14cycloalkyl, C(O)C1-8 alkyl, C1-8alkylOH, C1-8cyanoalkyl, C0-8alkylC(O)C0-8alkylNR14R15, C0-8alkylC(O)OR14, NR14R15, C1-8alkylC3-14cycloalkyl, C(O)C1-8alkylC3-14cycloalkyl, C1-8alkylR14, C1-8haloalkyl, or C(O)R14, which may be substituted with one or more of OH, CN, F, or NH2, and wherein R14 and R15 are each independently selected from H, C1-8alkyl, C3-14cycloalkyl, alkoxy, C(O)C1-3alkyl, C1-8alkylNH2, or C1-6alkylOH. 3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 wherein R3 is H, C1-8alkyl, or C1-8alkylOH. 4. The compound of formula I or a pharmaceutically acceptable salt thereof according claim 1 wherein Y is H, OH, or Y is part of the following group , where Y is N and W is CR9, or N; where 0-2 R8 may be present, and R8 is C1-8alkyl, oxo, or two or more R8 may form a bridged alkyl group. 5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 wherein R2 is cyclopentane. 6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 wherein Y is where m and n are 1, and Y and W are N. 7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 8. A compound of formula I(a): I(a) or a pharmaceutically acceptable salt thereof, wherein: R50 is CONR54R55; R51 is C3-14cycloalkyl which may be unsubstituted or substituted by C1-3alkyl, or OH; Z is CH or N; and V is NR56 or CHR57; R54 and R55 are both methyl; and R52, R53R56, and R57 are H. 9. A compound selected from: 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-(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]-7Hpyrrolo[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-(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-1-7H-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-{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[3.2.4]oct-3-ylmethyl)-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; 7-Cyclopentyl-2-{5-[4-(2-isopropoxyethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7Hpyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-(2-methyl-butyl)piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; and 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; or a pharmaceutically acceptable salt thereof. 10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3 wherein R3 is H, methyl, ethyl, propyl, isopropyl, CH2OH, or CH2CH2OH. 11. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein m is 2 and n is 1. 12. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R8 is methyl, ethyl, propyl, butyl, oxo, or two R8 can form a bridged group. 13. The compound according to claim 1 wherein L is a bond an Y is not H; or a pharmaceutically acceptable salt thereof. 14. The compound according to claim 1 wherein L is a bond and Y is where m and n are 1 or 2, and Y and W are N; or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 14 wherein R3 is H, methyl, ethyl, propyl, or isopropyl, or CH2OH, or CH2CH2OH; or a pharmaceutically acceptable salt thereof.