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. ##STR00001##
Inventor(s):	Besong; Gilbert (Cambridge, GB), Brain; Christopher Thomas (Cambridge, MA), Brooks; Clinton A (Beaufort, NC), Congreve; Miles Stuart (Cambridge, GB), Dagostin; Claudio (Cambridge, GB), He; Guo (Cambridge, MA), Hou; Ying (Cambridge, MA), Howard; Steven (Cambridge, GB), Li; Yue (Shanghai, CN), Lu; Yipin (Emeryville, CA), Mortenson; Paul (Cambridge, GB), Smith; Troy (Cambridge, MA), Sung; Moo Je (Cambridge, MA), Woodhead; Steven (Cambridge, GB), Wrona; Wojciech (Waltham, MA), Lagu; Bharat (Cambridge, MA)
Assignee:	Novartis AG (Basel, CH) Astex Therapeutics, Ltd. (Cambridge, GB)
Application Number:	14/158,358
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: ##STR00254## wherein X is CR.sup.9; R.sup.1 is CONR.sup.5R.sup.6, and R.sup.5 and R.sup.6 are C.sub.1-8alkyl; R.sup.2 is C.sub.3-14cycloalkyl; L is a bond, C.sub.1-8alkylene, 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 ##STR00255## where Y is N and W is CR.sup.9, or N; where 0-2 R.sup.8 may be present, and R.sup.8 is C.sub.1-8alkyl, oxo, or two or more R.sup.8 may form a bridged alkyl group; R.sup.3 is H, C.sub.1-8alkyl, C.sub.3-14cycloalkyl, C(O)C.sub.1-8 alkyl, C.sub.1-8alkylOH, C.sub.1-8cyanoalkyl, C.sub.0-8alkylC(O)C.sub.0-8alkylNR.sup.14R.sup.15, C.sub.0-8alkylC(O)OR.sup.14, NR.sup.14R.sup.15, C.sub.1-8alkylC.sub.3-14cycloalkyl, C(O)C.sub.1-8alkylC.sub.3-14cycloalkyl, C.sub.1-8alkylR.sup.14, C.sub.1-8haloalkyl, or C(O)R.sup.14, which may be substituted with one or more of OH, CN, F, or NH.sub.2 , and wherein R.sup.14 and R.sup.15 are each independently selected from H, C.sub.1-8alkyl, C.sub.3-14cycloalkyl, alkoxy, C(O)C.sub.1-3alkyl, C.sub.1-8alkylNH.sub.2, or C.sub.1-6 alkylOH; R.sup.9 is H or halogen; m and n are independently 0-2; and wherein L may be substituted with one or more of C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-14cycloalkyl, 5-14 membered heteroaryl group, C.sub.6-14aryl group, a 3-14 membered cycloheteroalkyl group, OH, (O), CN, alkoxy, halogen, or NH.sub.2. 2. The method according to claim 1 wherein R.sup.3 is H, C.sub.1-8alkyl, or C.sub.1-8alkylOH, or a pharmaceutically acceptable salt thereof. 3. The method according to claim 1 wherein R.sup.2 is cyclopentane; or a pharmaceutically acceptable salt thereof. 4. The method according to claim 1 wherein Y is ##STR00256## 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: ##STR00257## or a pharmaceutically acceptable salt thereof, wherein: R.sup.50 is CONR.sup.54R.sup.55; R.sup.51 is C.sub.3-14cycloalkyl which may be unsubstituted or substituted by C.sub.1-3alkyl, or OH; Z is CH or N; and V is NR.sup.56 or CHR.sup.57; R.sup.54 and R.sup.55 are both methyl; and R.sup.52, R.sup.53 R.sup.56, and R.sup.57 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-pyrrol- o[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']bipyrazin- yl-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-py- rrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-((S)-3-methylpiperazin-1-yl)-pyridin-2-ylamino]-7H-pyr- rolo[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-y- lamino}-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-ylamin- o}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-(2,3-dihydroxypropyl)-piperazin-1-yl]-pyridin-2-yla- mino}-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-p- yrrolo[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-ylami- no]-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-yla- mino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-((R)-2-hydroxypropyl)-piperazin-1-yl]-pyridin-2-yla- mino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyr- rolo[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-py- rrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]oct-3-ylmethyl)-pyridin-2-yla- mino]-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-p- yrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-(1'-isopropyl-1',2',3',4',5',6'-hexahydro-[3,4']bipyridin- yl-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]pyridi- n-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]pyridi- n-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-(2-hydroxyethyl)-piperazin-1-ylmethyl]-pyridin-2-yl- amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-(2-dimethylaminoacetyl)-piperazin-1-yl]-pyridin-2-y- lamino}-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-cyclopent- yl-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-pyrro- lo[2,3d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-{5-[4-(2-isopropoxyethyl)-piperazin-1-yl]pyridin-2-ylamin- o}-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']b- ipyridinyl-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 R.sup.3 is H, methyl, ethyl, propyl, isopropyl, CH.sub.2OH, or CH.sub.2CH.sub.2OH; 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 R.sup.8 is methyl, ethyl, propyl, butyl, oxo, or two R.sup.8 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 ##STR00258## 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 R.sup.3 is H, methyl, ethyl, propyl, isopropyl, CH.sub.2OH or CH.sub.2CH.sub.2OH; 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.