CDK Inhibitors And Their Use As Pharmaceuticals

Abstract

The disclosure is directed to compounds of Formula IPharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.

1 - 54 . (canceled) 
     
     
         55 . A method of treating an auto-immune disease, neurodegeneration, an inflammatory disease or a viral infection in a patient in need thereof, comprising administering to said patient a compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate or N-oxide thereof, wherein
 ring A is a 5-7-membered heteroaryl; 
 V═CL 1 R 1  or N 
 n is 1 or 2 or 3; 
 m is 1 or 2; 
 o is 1, 2, 3, 4, or 5; 
 each L 1  is independently a bond, O, NR or C 1 -C 6  alkylene, wherein R is H or C 1 -C 6 alkyl; 
 each R 1  is independently H, D, halogen, —OH, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —SR a , —NR c R d , —NR a R c , —C(O)R b , —OC(O)R b , —C(O)OR b , —C(O)NR c R d , —S(O)R b , —S(O) 2 NR c R d , —S(O)(═NR b )R b , —SF 5 , —P(O)R b R b , —P(O)(OR b )(OR b ), —B(OR c )(OR d ) or —S(O) 2 R b ; 
 each R 2  is independently H, D, halogen, C 1 -C 8  alkoxide C 1 -C 8  alkyl, haloalkyl, or CN and 
 each R 3  is independently H, D, halogen, oxo, —OH, —CN, —NO 2 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, C 0 -C 1 alk-aryl, C 0 -C 1 alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —OR a , —OR b , —SR b , —NR c R d , —NR a R c , —C(O)R b , —OC(O)R b , —C(O)OR b , —C(O)NR c R d , —S(O)R b , —S(O) 2 NR c R d , —S(O)(═NR b )R b , —SF 5 , —P(O)R b R b , —P(O)(OR b )(OR b ), —B(OR d )(OR c ) or —S(O) 2 R b ; 
 each R a  is independently H, D, —C(O)R b , —C(O)OR c , —C(O)NR c R d , —C(═NR b )NR b R c , —C(═NOR b )NR b R c , —C(═NCN)NR b R c , —P(OR c ) 2 , —P(O)R c R b , —P(O)OR c OR b , —S(O)R b , —S(O)NR c R d , —S(O) 2 R b , —S(O) 2 NR c R d , SiR b   3 , —C 1 -C 10 alkyl, —C 2 -C 10  alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; 
 each R b , is independently H, D, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; 
 each R c  or R d  is independently H, D, —C 1 -C 10  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; 
 or R c  and R d , together with the atom to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group; 
 each R 4  is independently H, D, halogen, C 1 -C 8  alkoxide or C 1 -C 8  alkyl, haloalkyl or CN. 
 
     
     
         56 . The method of  claim 55 , wherein ring A is a 5-membered heteroaryl having at least one N atom. 
     
     
         57 . The method of  claim 55 , wherein ring A is a 6-membered heteroaryl having at least one N atom. 
     
     
         58 . The method of  claim 55 , wherein n, m and o are each 1. 
     
     
         59 . The method of  claim 55 , wherein each R 2  is independently H, halogen or C 1-6  alkyl. 
     
     
         60 . The method of  claim 55 , wherein each R 3  is independently H, oxo bound to a nitrogen atom, C 1-6  alkyl or C 3-10  cycloalkyl. 
     
     
         61 . The method of  claim 55 , wherein each R 1  is independently 6-membered heterocyclalkyl or 7-membered heterocyclalkyl. 
     
     
         62 . The method of  claim 55 , wherein R 4  is H or C 1-6  alkyl. 
     
     
         63 . The method of  claim 55 , wherein the compound is in the form of a pharmaceutically acceptable salt. 
     
     
         64 . The method of  claim 55 , wherein the compound is a compound of formula II, formula III, formula IV, formula V, formula VI or formula VII: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 each X is independently N, N-oxide or CR 3  and at least one X is N or N-oxide; and 
 each Y is independently N or CR 3  and at least one Y is N. 
 
     
     
         65 . The method of  claim 55 , wherein the compound is a compound of formula VIII, formula IX, formula X, formula XI, formula XII, or formula XIII: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 each X is independently N, N-oxide or CR 3  and at least one X is N or N-oxide; and 
 Y is N or CHR 3 . 
 
     
     
         66 . The method of  claim 55 , wherein the compound is a compound of formula XV, formula XVI, formula XVII, formula XVIII, formula XIX, formula XX, formula XXI, formula XXII, formula XXIII, formula XXIV, formula XXV, formula XXVI, or formula XXVII: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         67 . The method of  claim 55 , wherein the compound is a compound of formula XXIX, formula XXX, formula XXXI, or formula XXXII: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 W is CH or N; 
 U is C(R 10 ) 2 , NR 10 , or O; 
 R 10  is H, fluoro, C 1-6 alkyl, or C 1-6 alkoxide; and 
 each g, h, j and k is independently 0, 1, 2 or 3. 
 
     
     
         68 . The method of  claim 55 , wherein the compound is a compound of formula XXXV, formula XXXVI, formula XXXVII, formula XXXVIII, formula XXXIX, formula XL, formula XLI, formula XLII, formula XLIII, or formula XLIV: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 W is CH or N; 
 U is C(R 10 ) 2 , NR 10  or O; 
 R 10  is H, fluoro, C 1-4 alkyl or C 1-4 alkoxide; and 
 each g, h, j and k is independently 0, 1, 2 or 3. 
 
     
     
         69 . The method of  claim 55 , wherein the compound is a compound of formula XLV, formula XLVI, formula XLVII, formula XLVIII, formula XLIX or formula L: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 W is CH or N; 
 U is C(R 10 ) 2 , NR 10  or O; 
 R 10  is H, fluoro, C 1-4 alkyl or C 1-4 alkoxide. 
 
     
     
         70 . The method of  claim 55 , wherein the compound is a compound of formula LI, formula LII, formula LIII, or formula LIV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 W is CH or N; 
 U is C(R 10 ) 2 , NR 10  or O; 
 R 10  is H, fluoro, C 1-4 alkyl or C 1-4 alkoxide. 
 
     
     
         71 . The method of  claim 55 , wherein the compound is a compound of formula LVII, formula LVIII, formula LIX, or formula LX: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein
 R 10  is H, C 1-6 alkyl, or C 1-6 alkoxide. 
 
     
     
         72 . The method of  claim 55 , wherein the compound is a compound of formula LXIII, formula LXIV, formula LXV, formula LXVI, formula LXVII or formula LXVIII: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein R 10  is H, C 1-4 alkyl or C 1-4 alkoxide. 
     
     
         73 . The method of  claim 55 , wherein the compound is:
 4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;   N-(5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;   N-(5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;   4-(3-Cyclobutyl-2,6-dimethylthieno[2,3-d]imidazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;   4-(3-Cyclobutyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;   5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;   4-(3-Cyclobutyl-2,6-dimethylthieno[2,3-d]imidazol-5-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;   4-(3-Cyclopentyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;   N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   2-[2-[2-[[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol;   2-[2-[2-[[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol;   N-[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;   4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(1-ethylpiperidin-4-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   2-[2-[2-[[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol;   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;   N-[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   2-[2-[2-[[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol;   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;   2-[2-[2-[[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol;   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;   2-[2-[2-[[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol;   4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;   N-(5-(2,6-Diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoropyrimidin-2-amine;   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine;   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine;   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinopyridin-2-yl)pyrimidin-2-amine;   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methoxypiperidin-1-yl)pyridin-2-yl]pyrimidin-2-amine;   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinopyridin-2-yl)pyrimidin-2-amine;   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-morpholin-4-ylpyridin-2-yl)pyrimidin-2-amine;   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine;   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine;   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(7-Cyclopentyl-3-methylthieno[2,3-c]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;   4-(4-Cyclopentyl-7-methylthieno[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;   N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(4-oxido-7-propan-2-ylthieno[3,2-b]pyridin-4-ium-2-yl)pyrimidin-2-amine;   2-[5-Fluoro-2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethyl-7-propan-2-ylthieno[3,2-c]pyridin-4-one;   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro [3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   6-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine;   (4-Ethylpiperazin-1-yl)-[6-[[5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone;   4-(2,6-Dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(2-((5-(6-Ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;   2-(2-((5-(4-Ethylpiperazine-1-carbonyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methylthieno[3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   6-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one;   2-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one;   or a pharmaceutically acceptable salt thereof.   
     
     
         74 . The method of  claim 55 , wherein the compound is:
 N-[5-[[4-(2,2-Difluoroethyl)piperazin-1-yl]methyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl) pyrimidin-2-amine;   1-[[6-[[5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d] imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methyl]-N,N-dimethylpyrrolidine-3-carboxamide;   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-pyridin-2-ylpyrimidin-2-amine;   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl) pyridin-2-yl]pyrimidin-2-amine;   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(4-ethyl-6,6-difluoro-1,4-diazepan-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-[2,2,3,3,5,5,6,6-octadeuterio-4-(trideuteriomethyl)piperazin-1-yl]pyridin-2-yl]pyrimidin-2-amine;   N-[5-(5,5-Difluoro-7-methyl-2,7-diazaspiro[3.4]octan-2-yl)pyridin-2-yl]-4-(2,6-dimethyl-3-propan-2-ylthieno[2,3-d] imidazol-5-yl)-5-fluoropyrimidin-2-amine;   (6-Dthyl-2,6-diazaspiro[3.3]heptan-2-yl)-[6-[[5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d] imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone;   N-[5-[3-(Dimethylamino) azetidin-1-yl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;   N-[5-[3-(Dimethylamino) pyrrolidin-1-yl]pyridin-2-yl]-4-(2,6-dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-amine;   N-[5-(6-ethyl-3,6-Diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;   1-[6-[[4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-yl] amino]pyridin-3-yl]-4-methylpiperazin-2-one;   2-(5-Fluoro-2-((5-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-((3aS,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;   2-(2-((5-(5-Ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno [3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(1-(methyl-d3)piperidin-4-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(2-((5-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3-methyl-5-(methyl-d3)thieno[3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;   2-(2-((5-(1-Ethylpiperidin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(2-45-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-45-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((6-(1-methylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino) pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;   2-(5-Fluoro-2-((5-(1-isopropylpyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;   7-Isopropyl-5-methyl-2-(2-((5-(1-methylpiperidin-4-yl) pyridine-2-yl)amino) pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one;   7-Isopropyl-5-methyl-2-(5-methyl-2-45-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thieno [3,2-c]pyridin-4(5H)-one;   4-(6-((5-Fluoro-4-(7-isopropyl-3,5-dimethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-2-yl)pyrimidin-2-yl)amino) pyridin-3-yl)-1-methylpiperidine 1-oxide;   5-Fluoro-4-(3-isopropyl-2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;   N-(5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine;   4-(3-Cyclopropyl-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;   2-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)-1,1,1-trifluoropropan-2-ol;   1-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c] pyrazol-3-yl)ethan-1-one;   1-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c] pyrazol-3-yl)ethan-1-ol;   N-(5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(3-(2-methoxypropan-2-yl)-2,6-dimethyl-2H-thieno[3,2-c] pyrazol-5-yl)pyrimidin-2-amine;   4-(1,6-dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl) pyridin-2-yl]-5-fluoropyrimidin-2-amine;   N-(5-Fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine;   5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-amine;   tert-Butyl 3-(2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5-methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyridazin-7-yl)azetidine-1-carboxylate;   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-methylthieno[2,3-d]pyridazin-4(5H)-one;   5-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3-isopropyl-N,N,6-trimethyl-3H-thieno[2,3-d]imidazol-2-amine;   N-(5-(2-Ethyl-2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[6-(4-ethylpiperazin-1-yl) pyridin-2-yl]-5-fluoropyrimidin-2-amine;   5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(1-methylpyrrolidin-3-yl)oxypyridin-2-yl]pyrimidin-2-amine;   5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylmorpholin-2-yl)pyridin-2-yl)pyrimidin-2-amine;   N-[5-[1-(4-Ethylpiperazin-1-yl)ethyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl) pyrimidin-2-amine;   3-[6-[[5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-1,4-dimethylpiperazin-2-one;   ((8aS)-6-(6-((5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl) pyrimidin-2-yl)amino)pyridin-3-yl)-2-methylhexahydropyrrolo [1,2-a]pyrazin-3(4H)-one;   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[4-(4-ethylpiperazin-1-yl) pyridin-2-yl]-5-fluoropyrimidin-2-amine;   4-(3-Isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-4-yl) pyridin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;   N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-[7-propan-2-yl-3-(trifluoromethyl) thieno[3,2-b]pyridin-2-yl]pyrimidin-2-amine;   2-(2-((5-(4-Ethylpiperazin-1-yl) pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropylthieno[3,2-b]pyridine-3-carbonitrile;   5-Fluoro-N-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]-4-(3-methyl-7-propan-2-ylthieno[3,2-c]pyridin-2-yl) pyrimidin-2-amine;   N-[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;   5-Fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl) pyrimidin-2-amine (isomer 1);   5-Fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine (isomer 2);   4-(3-Isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-methoxy-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;   N-(5-(1-Ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl) pyrimidin-2-amine;   N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl) pyridin-2-yl)-5-fluoro-4-(3-isopropyl-3H-thieno[2,3-d] imidazol-5-yl)pyrimidin-2-amine;   5-Chloro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-3-yl)pyridin-2-yl)pyrimidin-2-amine;   2-(5-Fluoro-2-45-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methylthieno[3,2-c]pyridine 5-oxide;   or a pharmaceutically acceptable salt thereof.   
     
     
         75 . The method of  claim 55 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         76 . The method of  claim 55 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         77 . The method of  claim 55 , wherein the neurodegeneration is associated with Parkinson's disease, Alzheimer's disease or ischaemia. 
     
     
         78 . The method of  claim 55 , wherein the compound is administered as the pharmaceutically acceptable salt. 
     
     
         79 . The method of  claim 55 , wherein the patient is administered a pharmaceutically acceptable composition comprising the compound of Formula (I). 
     
     
         80 . The method of  claim 55 , wherein the administration is oral administration. 
     
     
         81 . The method of  claim 55 , further comprising administering an additional therapeutic agent to the patient; wherein the additional therapeutic agent is a PRMTS inhibitor, a HER2 kinase inhibitor, an aromatase inhibitor, an estrogen receptor antagonist or an alkylating agent. 
     
     
         82 . The method of  claim 81 , wherein the aromatase inhibitor is letrozole; the estrogen receptor antagonist is fulvestrant; or the alkylating agent is temozolomide.