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. ##STR00001##
Inventor(s):	Besong; Gilbert Ebai (Bad Duerkheim, DE), Brain; Christopher Thomas (North Reading, MA), Brooks; Clinton Alan (Smyrna, GA), Congreve; Miles Stuart (Royston, GB), Dagostin; Claudio (Cambridge, GB), He; Guo (Lexington, MA), Hou; Ying (Belmont, MA), Howard; Steven (Cambridge, GB), Li; Yue (Shanghai, CN), Lu; Yipin (Dublin, CA), Mortenson; Paul Neil (Cambridge, GB), Smith; Troy D. (Nashua, NH), Sung; Moo Je (Belmont, MA), Woodhead; Steven John (San Diego, CA), Wrona; Wojciech (Waltham, MA), Lagu; Bharat (Acton, MA)
Assignee:	Novartis AG (Basel, CH) Astex Therapeutics, Ltd. (Cambridge, GB)
Application Number:	13/060,154
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,685,980
Patent Claims:	1. A compound of formula I: ##STR00253## or a pharmaceutically acceptable salt thereof, 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, R.sup.11, NR.sup.12R.sup.13, OH, or Y is part of the following group ##STR00254## where Y is CR.sup.9 or N; where 0-3 R.sup.8 may be present, and R.sup.8 is C.sub.1-8alkyl, oxo, halogen, or two or more R.sup.8 may form a bridged alkyl group; W is CR.sup.9, or N; R.sup.3 is H, C.sub.1-8alkyl, C.sub.1-8alkylR.sup.14, C.sub.3-14cycloalkyl, C(O)C.sub.1-8 alkyl, C.sub.1-8haloalkyl, C.sub.1-8alkylOH, C(O)NR.sup.14R.sup.15, C.sub.1-8cyanoalkyl, C(O)R.sup.14, 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, SO.sub.2C.sub.1-8alkyl, C.sub.1-8alkylC.sub.3-14cycloalkyl, C(O)C.sub.1-8alkylC.sub.3-14cycloalkyl, C.sub.1-8alkoxy, or OH which may be substituted or unsubstituted when R.sup.3 is not H; R.sup.9 is H or halogen; R.sup.11, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each independently selected from H, C.sub.1-8alkyl, C.sub.3-14 cycloalkyl, a 3-14 membered cycloheteroalkyl group, a C.sub.6-14 aryl group, a 5-14 membered heteroaryl group, alkoxy, C(O)H, C(NH)OH, C(NH)OCH.sub.3, C(O)C.sub.1-3alkyl, C.sub.1-8alkylNH.sub.2, and C.sub.1-6alkylOH, and wherein R.sup.11, R.sup.12, and R.sup.13, R.sup.14, and R.sup.15 when not H may be substituted or unsubstituted; m and n are independently 0-2; and wherein L, R.sup.3, R.sup.11, R.sup.12, and R.sup.13, R.sup.14, and R.sup.15 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 compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 wherein 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.1-6alkylOH. 3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 wherein R.sup.3 is H, C.sub.1-8alkyl, or C.sub.1-8alkylOH. 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 ##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. 5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 wherein R.sup.2 is cyclopentane. 6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 wherein Y is ##STR00256## 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): ##STR00257## I(a) 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.53R.sup.56, and R.sup.57 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-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-- 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-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-- 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-py- rrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.4]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]-pyrid- in-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]-pyrid- in-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}-7- H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; 2-{5-[4-(2-Cyclohexyl-acetyl)piperazin-1-yl]-pyridin-2-ylamino}-7-cyclope- ntyl-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-ylami- no}-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. 10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3 wherein R.sup.3 is H, methyl, ethyl, propyl, isopropyl, CH.sub.2OH, or CH.sub.2CH.sub.2OH. 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 R.sup.8 is methyl, ethyl, propyl, butyl, oxo, or two R.sup.8 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 ##STR00258## 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 R.sup.3 is H, methyl, ethyl, propyl, or isopropyl, or CH.sub.2OH, or CH.sub.2CH.sub.2OH; or a pharmaceutically acceptable salt thereof.