Claims for Patent: 9,416,136

Summary for Patent: 9,416,136

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 Besong, Christopher Thomas Brain, Clinton A Brooks, Miles Stuart Congreve, Claudio Dagostin, Guo He, Ying Hou, Steven Howard, Yue Li, Yipin Lu, Paul Mortenson, Troy Smith, Moo Je Sung, Steven Woodhead, Wojciech Wrona, Bharat Lagu
Assignee:	Astex Therapeutics Ltd, Novartis Pharmaceuticals Corp
Application Number:	US14/158,358
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,416,136
Patent Claims:	1. A method for the treatment of cancer by inhibiting cyclin-dependent kinase 4 comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject in need 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, 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; 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 C1-6 alkylOH; R9 is H or halogen; m and n are independently 0-2; and wherein L 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 method according to claim 1 wherein R3 is H, C1-8alkyl, or C1-8alkylOH, or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1 wherein R2 is cyclopentane; or a pharmaceutically acceptable salt thereof. 4. The method according to claim 1 wherein Y is where m and n are 1, and Y and W are N; or a pharmaceutically acceptable salt thereof. 5. A method for the treatment of cancer by inhibiting cyclin-dependent kinase 4 comprising administering a compound of formula I(a), or a pharmaceutically acceptable salt thereof, to a subject in need thereof: 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, R53 R56, and R57 are H. 6. A method for the treatment of cancer by inhibiting cyclin-dependent kinase 4 comprising administering a compound to a subject in need of thereof wherein the compound is 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]-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[3.2.1]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-acetyppiperazin-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. 7. The method according to claim 2 wherein R3 is H, methyl, ethyl, propyl, isopropyl, CH2OH, or CH2CH2OH; or a pharmaceutically acceptable salt thereof. 8. The method according to claim 1 wherein m is 2 and n is 1; or a pharmaceutically acceptable salt thereof. 9. The method according to claim 1 wherein R8 is methyl, ethyl, propyl, butyl, oxo, or two R8 can form a bridged group; or a pharmaceutically acceptable salt thereof. 10. The method according to claim 1 wherein L is a bond an Y is not H; or a pharmaceutically acceptable salt thereof. 11. The method 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. 12. The method according to claim 11 wherein R3 is H, methyl, ethyl, propyl, isopropyl, CH2OH or CH2CH2OH; or a pharmaceutically acceptable salt thereof. 13. The method according to claim 1 wherein the cancer is breast carcinoma. 14. The method according to claim 1 wherein the cancer is colon carcinoma. 15. The method according to claim 1 wherein the cancer is lung carcinoma. 16. The method according to claim 1 wherein the cancer is acute lymphoblastic leukemia. 17. The method according to claim 1 wherein the cancer is chronic myelogenous leukemia. 18. The method according to claim 1 wherein the cancer is melanoma. 19. The method according to claim 1 wherein the cancer is a tumor of mesenchymal origin. 20. The method according to claim 1 wherein the cancer is pancreatic cancer. 21. The method according to claim 1 wherein the cancer is prostate cancer. 22. The method according to claim 1 wherein the cancer is non-small-cell lung cancer. 23. The method according to claim 1 wherein the cancer is mantle cell lymphoma.