Protein kinase inhibitors

Abstract

In one aspect, the invention provides compounds of Formula I or pharmaceutically acceptable salts thereof. In another aspect, the invention provides methods for treatment of diseases or disorders mediated by a protein kinase, comprising administering a therapeutically effective amount of a compound of this invention.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 Y is O or NR 9 ; 
 R 1  is cycloalkyl or heterocycloalkyl; 
 R 2  is H, alkyl, or cycloalkyl; 
 each of R 3  and R 4  is independently H, alkyl, cycloalkyl, aryl, or heteroaryl; or R 3  and R 4 , together with the carbon atom to which they are attached, form a cycloalkyl; 
 each of R 5  and R 6  is independently H, alkyl, cycloalkyl, aryl, or heteroaryl; 
 R 7  is H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; or 
 R 8  is alkyl; 
 R 9  is H or alkyl; or 
 R 2  and R 9 , together with the atoms to which they are attached, optionally form a 5- to 8-membered monocyclic ring containing additional 0 to 2 hetero atoms each independently selected from O, N, and S, wherein said monocyclic ring is optionally substituted with 0 to 4 groups each independently being alkyl, halo, alkoxy, or hydroxy; and 
 q is 0 or 1. 
 
       
     
     
         2 . The compound of  claim 1 , wherein R 2  is alkyl. 
     
     
         3 . The compound of  claim 2 , wherein R 2  is methyl. 
     
     
         4 . The compound of  claim 1 , wherein Y is O. 
     
     
         5 . The compound of  claim 1 , wherein each of R 3  and R 4  is independently H or alkyl. 
     
     
         6 . The compound of  claim 5 , wherein each of R 3  and R 4  is independently H, methyl, or ethyl. 
     
     
         7 . The compound of  claim 1 , wherein R 7  is alkyl or cycloalkyl. 
     
     
         8 . The compound of  claim 7 , wherein R 7  is cycloalkyl. 
     
     
         9 . The compound of  claim 8 , wherein R 7  is cyclopentyl. 
     
     
         10 . The compound of  claim 1 , wherein R 8  is optionally substituted alkyl. 
     
     
         11 . The compound of  claim 10 , wherein R 8  is methyl, ethyl, or methoxymethyl, hydroxymethyl, or hydroxyethyl. 
     
     
         12 . The compound of  claim 1 , wherein R 1  is optionally substituted C 3-7  cycloalkyl or optionally substituted C 3-7  heterocycloalkyl. 
     
     
         13 . The compound of  claim 12 , wherein R 1  is optionally substituted cyclohexyl or optionally substituted piperidinyl. 
     
     
         14 . The compound of  claim 13 , wherein R 1  is cyclohexyl or piperidinyl, and is optionally substituted with alkyl or cyanoalkyl. 
     
     
         15 . The compound of  claim 14 , wherein R 1  is cyclohexyl, 4-piperidinyl, N-methylpiperidin-4-yl, or N-cyanomethylpiperidin-4-yl. 
     
     
         16 . The compound of  claim 1 , wherein q is 1. 
     
     
         17 . The compound of  claim 16 , wherein each of R 5  and R 6  is independently H or alkyl. 
     
     
         18 . The compound of  claim 17 , wherein each of R 5  and R 6  is H. 
     
     
         19 . The compound of  claim 16 , wherein R 1  is cyclohexyl or piperidinyl, and is optionally substituted with alkyl or cyanoalkyl. 
     
     
         20 . The compound of  claim 19 , wherein R 1  is cyclohexyl. 
     
     
         21 . The compound of  claim 19 , wherein R 1  is 4-piperidinyl optionally substituted with alkyl or cyanoalkyl. 
     
     
         22 . The compound of  claim 21 , wherein R 1  is 4-piperidinyl, N-methylpiperidin-4-yl, or N-cyanomethylpiperidin-4-yl. 
     
     
         23 . The compound of  claim 1 , wherein the compound is represented by Formula Ia. 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 23 , wherein the compound is
 2-(1-cyclohexylethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;   9-cyclopentyl-5,7,7-trimethyl-2-(1-(piperidin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;   9-cyclopentyl-5,7,7-trimethyl-2-(1-(1-methylpiperidin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;   2-(4-(1-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)ethyl)piperidin-1-yl)acetonitrile;   
     
     
         25 . The compound of  claim 1 , wherein R 1  is cyclohexyl or piperidinyl, and is optionally substituted with alkyl, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, heterocyclyl, aminoalkylcarbonyl, hydroxyalkylcarbonyl, or alkylsulfonyl. 
     
     
         26 . The compound of  claim 1 , wherein q is 0. 
     
     
         27 . The compound of  claim 26 , wherein each of R 3  and R 4  is independently H or alkyl. 
     
     
         28 . The compound of  claim 27 , wherein each of R 3  and R 4  is independently H, methyl, or ethyl. 
     
     
         29 . The compound of  claim 28 , wherein R 3  is ethyl and R 4  is H. 
     
     
         30 . The compound of  claim 26 , wherein R 2  is alkyl. 
     
     
         31 . The compound of  claim 30 , wherein R 2  is methyl. 
     
     
         32 . The compound of  claim 26 , wherein R 7  is optionally substituted cycloalkyl. 
     
     
         33 . The compound of  claim 32 , wherein R 7  is optionally substituted cyclopentyl. 
     
     
         34 . The compound of  claim 26 , wherein R 1  is cyclohexyl or piperidinyl, and is optionally substituted with alkyl, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, heterocyclyl, aminoalkylcarbonyl, hydroxyalkylcarbonyl, or alkylsulfonyl. 
     
     
         35 . The compound of  claim 34 , wherein R 1  is cyclohexyl. 
     
     
         36 . The compound of  claim 34 , wherein R 1  is 4-piperidinyl optionally substituted at the ring nitrogen atom with alkyl, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, heterocyclyl, aminoalkylcarbonyl, hydroxyalkylcarbonyl, or alkylsulfonyl. 
     
     
         37 . The compound of  claim 36 , wherein R 1  is 4-piperidinyl, 1-methylpiperidin-4-yl, 1-cyanomethylpiperidin-4-yl, 1-(2-hydroxyethyl)piperidin-4-yl, 1-(tert-butoxycarbonyl)piperidin-4-yl, 1-(aminocarbonylmethyl)piperidin-4-yl, 1-(methylcarbonyl)piperidin-4-yl, 1-(aminomethylcarbonyl)piperidin-4-yl, 1-(dimethylaminomethylcarbonyl)piperidin-4-yl, 1-(hydroxymethylcarbonyl)piperidin-4-yl, 1-((2-hydroxyprop-2-yl)carbonyl)piperidin-4-yl, or 1-(1-(methylsulfonyl)piperidin-4-yl. 
     
     
         38 . The compound of  claim 26 , wherein the compound is represented by Formula Ib. 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 1 , wherein the compound is
 2-(1-cyclohexylethylamino)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one;   8-cyclopentyl-7-ethyl-5-methyl-2-(1-(piperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one;   8-cyclopentyl-7-ethyl-5-methyl-2-(1-(1-methylpiperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one   2-(4-(1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)ethyl)piperidin-1-yl)acetonitrile   8-cyclopentyl-7-ethyl-2-(1-(1-(2-hydroxyethyl)piperidin-4-yl)ethylamino)-5-methyl-7,8-dihydropteridin-6(5H)-one   8-cyclopentyl-7-ethyl-5-methyl-2-(1-(1′-methyl-1,4′-bipiperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one   2-(4-(1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)ethyl)piperidin-1-yl)acetonitrile;   tert-butyl 4-(1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)ethyl)piperidine-1-carboxylate;   8-cyclopentyl-7-ethyl-5-methyl-2-(1-(1-(prop-2-ynyl)piperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one;   2-(4-(1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)ethyl)piperidin-1-yl)acetamide;   2-(1-(1-acetylpiperidin-4-yl)ethylamino)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one;   2-(1-(1-(2-aminoacetyl)piperidin-4-yl)ethylamino)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one;   8-cyclopentyl-2-(1-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)ethylamino)-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one   8-cyclopentyl-7-ethyl-2-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)ethylamino)-5-methyl-7,8-dihydropteridin-6(5H)-one;   8-cyclopentyl-7-ethyl-2-(1-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)ethylamino)-5-methyl-7,8-dihydropteridin-6(5H)-one   8-cyclopentyl-7-ethyl-5-methyl-2-(1-(1-(methylsulfonyl)piperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one.   
     
     
         40 . The compound of  claim 1 , wherein Y is NR 9 . 
     
     
         41 . The compound of  claim 40 , wherein R 2  and R 9 , together with the atoms to which they are attached, form a 5- to 8-membered monocyclic ring containing additional 0-2 hetero atoms each independently selected from O, N, and S, and the monocyclic ring is optionally substituted with 0 to 4 groups each independently being a halo or alkyl. 
     
     
         42 . The compound of  claim 41 , wherein q is 0. 
     
     
         43 . The compound of  claim 41 , wherein each of R 3  and R 4  is independently H or alkyl. 
     
     
         44 . The compound of  claim 43 , wherein each of R 3  and R 4  is independently H, methyl, or ethyl. 
     
     
         45 . The compound of  claim 44 , wherein R 3  is ethyl and R 4  is H. 
     
     
         46 . The compound of  claim 41 , wherein R 7  is optionally substituted cycloalkyl. 
     
     
         47 . The compound of  claim 46 , wherein R 7  is optionally substituted cyclopentyl. 
     
     
         48 . The compound of  claim 41 , wherein R 8  is optionally substituted alkyl. 
     
     
         49 . The compound of  claim 48 , wherein R 8  is methyl. 
     
     
         50 . The compound of  claim 41 , wherein R 1  is cyclohexyl or piperidinyl, each optionally substituted. 
     
     
         51 . The compound of  claim 50 , wherein the compound is represented by Formula Ic. 
       
         
           
           
               
               
           
         
       
     
     
         52 . The compound of  claim 1 , wherein the compound is
 (S)-2-(1-cyclohexylethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;   (R,S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(piperidin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;   (R,S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(1-methylpiperidin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;   (R,S)-2-(4-(1-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)ethyl)piperidin-1-yl)acetonitrile;   (R)-2-((S)-1-cyclohexylethylamino)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one;   tert-butyl 4-((R,S)-1-((R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)ethyl)piperidine-1-carboxylate;   (R,S)-8-cyclopentyl-7-ethyl-5-methyl-2-((S)-1-(piperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one;   2-(4-((R,S)-1-((R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)ethyl)piperidin-1-yl)acetonitrile;   (R)-8-cyclopentyl-7-ethyl-5-methyl-2-((R,S)-1-(1-(prop-2-ynyl)piperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one;   2-(4-((R,S)-1-((R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)ethyl)piperidin-1-yl)acetamide;   (R)-2-((R,S)-1-(1-acetylpiperidin-4-yl)ethylamino)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one;   (R)-8-cyclopentyl-7-ethyl-5-methyl-2-((S)-1-(1-(1′-methyl-1,4′-bipiperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one;   (R)-2-((R,S)-1-(1-(2-aminoacetyl)piperidin-4-yl)ethylamino)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one;   (R)-8-cyclopentyl-2-((R,S)-1-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)ethylamino)-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one;   (R)-8-cyclopentyl-7-ethyl-2-((R,S)-1-(1-(2-hydroxyacetyl)piperidin-4-yl)ethylamino)-5-methyl-7,8-dihydropteridin-6(5H)-one;   (R)-8-cyclopentyl-7-ethyl-5-methyl-2-((R,S)-1-(1-(methylsulfonyl)piperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one;   (R)-8-cyclopentyl-7-ethyl-2-((R)-1-(1-(2-hydroxyethyl)piperidin-4-yl)ethylamino)-5-methyl-7,8-dihydropteridin-6(5H)-one;   (R)-8-cyclopentyl-7-ethyl-2-((S)-1-(1-(2-hydroxyethyl)piperidin-4-yl)ethylamino)-5-methyl-7,8-dihydropteridin-6(5H)-one;   (R)-8-cyclopentyl-7-ethyl-5-methyl-2-((R)-1-(1-methylpiperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one;   (R)-8-cyclopentyl-7-ethyl-5-methyl-2-((S)-1-(1-methylpiperidin-4-yl)ethylamino)-7,8-dihydropteridin-6(5H)-one; or   (R)-8-cyclopentyl-7-ethyl-2-((R,S)-1-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)ethylamino)-5-methyl-7,8-dihydropteridin-6(5H)-one.   
     
     
         53 . A pharmaceutical composition comprising a compound of any of  claims 1 - 52  and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
     
     
         54 . A method of inhibiting protein kinase in a patient comprising administering to said patient in need thereof a pharmaceutically effective amount of a compound of any of  claims 1 - 52  or a composition of  claim 53 . 
     
     
         55 . The method of  claim 54 , wherein the protein kinase is a PLK. 
     
     
         56 . The method of  claim 55 , wherein said protein kinase is PLK1. 
     
     
         57 . A method of inhibiting protein kinase in a biological sample comprising contacting said biological sample with a pharmaceutically effective amount of a compound of any of  claims 1 - 52  or a composition of  claim 53 . 
     
     
         58 . The method of  claim 57 , wherein the protein kinase is a PLK. 
     
     
         59 . The method of  claim 58 , wherein the protein kinase is PLK1. 
     
     
         60 . A method of treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of any of  claims 1 - 52  or a composition of  claim 53 . 
     
     
         61 . The method of  claim 60 , further comprising administering to the patient a chemotherapeutic agent, an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, an immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorder, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorder, an agent for treating diabetes, and an agent for treating immunodeficiency disorder. 
     
     
         62 . A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, colon cancer, breast cancer, gastric cancer, ovarian cancer, cervical cancer, lung cancer, central nervous system cancer, renal cancer, prostate cancer, bladder cancer, or pancreatic cancer, in a patient, comprising administering to the patient in need thereof a pharmaceutically effective amount of a compound of any of  claims 1 - 52  or a composition of  claim 53 . 
     
     
         63 . A method of treating cancer in a patient, comprising administering to the patient in need thereof a pharmaceutically effective amount of a compound of any of  claims 1 - 52  or a composition of  claim 53 . 
     
     
         64 . The method of  claim 63 , wherein the method comprises disrupting mitosis of the cancer cells by inhibiting PLK with the compound of any of  claims 1 - 52  or the composition of  claim 53 .