Hydroxylated and methoxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors

Abstract

The present invention provides compounds, including resolved enantiomers, resolved diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula I:Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       and tautomers, resolved enantiomers, resolved diastereomers, solvates, metabolites, and salts thereof, wherein:
 R 1  is H, Me, Et, vinyl, CF 3 , CHF 2  or CH 2 F; 
 R 2  is H or Me; 
 R 5  is H, Me, Et, or CF 3 ; 
 A is 
 
       
         
           
           
               
               
           
         
         G is phenyl optionally substituted by one to four R 9  groups or a 5-6 membered heteroaryl optionally substituted by a halogen; 
         R 6  and R 7  are independently H, OCH 3 , (C 3 -C 6  cycloalkyl)-(CH 2 ), (C 3 -C 6  cycloalkyl)-(CH 2 CH 2 ), V—(CH 2 ) 0-1  wherein V is a 5-6 membered heteroaryl, W—(CH 2 ) 1-2  wherein W is phenyl optionally substituted with F, Cl, Br, I, OMe, CF 3  or Me, C 3 -C 6 -cycloalkyl optionally substituted with C 1 -C 3  alkyl or O(C 1 -C 3  alkyl), hydroxy-(C 3 -C 6 -cycloalkyl), fluoro-(C 3 -C 6 -cycloalkyl), CH(CH 3 )CH(OH)phenyl, 4-6 membered heterocycle optionally substituted with F, OH, C 1 -C 3  alkyl, cyclopropylmethyl or C(═O)(C 1 -C 3  alkyl), or C 1 -C 6 -alkyl optionally substituted with one or more groups independently selected from OH, oxo, O(C 1 -C 6 -alkyl), CN, F, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl, 
         or R 6  and R 7  together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF 3 , CH 2 CF 3 , CH 2 CH 2 OH, O(C 1 -C 3  alkyl), C(═O)CH 3 , NH 2 , NHMe, N(Me) 2 , S(O) 2 CH 3 , cyclopropylmethyl and C 1 -C 3  alkyl; 
         R a  and R b  are H, 
         or R a  is H, and R b  and R 6  together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; 
         R c  and R d  are H or Me, 
         or R c  and R d  together with the atom to which they are attached form a cyclopropyl ring; 
         R 8  is H, Me, F or OH, 
         or R 8  and R 6  together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; 
         each R 9  is independently halogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, O—(C 1 -C 6 -alkyl), CF 3 , OCF 3 , S(C 1 -C 6 -alkyl), CN, OCH 2 -phenyl, CH 2 O-phenyl, NH 2 , NH—(C 1 -C 6 -alkyl), N—(C 1 -C 6 -alkyl) 2 , piperidine, pyrrolidine, CH 2 F, CHF 2 , OCH 2 F, OCHF 2 , OH, SO 2 (C 1 -C 6 -alkyl), C(O)NH 2 , C(O)NH(C 1 -C 6 -alkyl), and C(O)N(C 1 -C 6 -alkyl) 2 ; 
         R 10  is H or Me; and 
         m, n and p are independently 0 or 1. 
       
     
     
         2 - 76 . (canceled) 
     
     
         77 . A pharmaceutical composition comprising a compound as claimed in  claim 1 . 
     
     
         78 . A method of treating an AKT-mediated disease or disorder in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound as claimed in  claim 1 . 
     
     
         79 . The method of claim  76 , wherein said disease or disorder is an inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological, or dermatological disease or disease, 
     
     
         80 . A method of inhibiting the production of AKT protein kinase in a mammal, which comprises administering to said mammal an effective amount of a compound as claimed in  claim 1 . 
     
     
         81 . A method of inhibiting the activity of AKT protein kinase in a mammal, which comprises contacting said kinase with a compound as claimed in  claim 1 . 
     
     
         82 . A kit for treating an AKT protein kinase-mediated condition, wherein said kit comprises: a) a first pharmaceutical composition comprising a compound as claimed in  claim 1 ;
 and b) optionally instructions for use.   
     
     
         83 . A method of preparing a compound as claimed in  claim 1 , said method comprising: reacting a compound having the formula: 
       
         
           
           
               
               
           
         
       
       with a compound having the formula 
       
         
           
           
               
               
           
         
       
     
     
         84 . A method of treating cancer in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a compound selected from the group consisting of:
 (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one or a salt thereof;   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)propan-1-one or a salt thereof;   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one or a salt thereof;   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-pyrrolidin-3-ylamino)propan-1-one or a salt thereof;   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((S)-pyrrolidin-3-ylamino)propan-1-one or a salt thereof;   (S)-3-(1-acetylpiperidin-4-ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one or a salt thereof; and   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one or a salt thereof.   
     
     
         85 . The method of  claim 84 , comprising administering to the mammal an effective amount of (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one or a salt thereof. 
     
     
         86 . A method of treating an inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological, or dermatological disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound of Formula (I), a tautomer thereof, a resolved enantiomer thereof, a resolved diastereomer thereof, or a salt thereof; wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, Me, Et, vinyl, CF 3 , CHF 2  or CH 2 F; 
 R 2  is H or Me; 
 R 5  is H, Me, Et, or CF 3 ; 
 A is 
 
       
         
           
           
               
               
           
         
         G is phenyl optionally substituted by one to four R 9  groups or a 5-6 membered heteroaryl optionally substituted by a halogen; 
         R 6  and R 7  are independently H, OCH 3 , (C 3 -C 6  cycloalkyl)-(CH 2 ), (C 3 -C 6  cycloalkyl)-(CH 2 CH 2 ), V—(CH 2 ) 0-1  wherein V is a 5-6 membered heteroaryl, W—(CH 2 ) 1-2  wherein W is phenyl optionally substituted with F, Cl, Br, I, OMe, CF 3  or Me, C 3 -C 6 -cycloalkyl optionally substituted with C 1 -C 3  alkyl or O(C 1 -C 3  alkyl), hydroxy-(C 3 -C 6 -cycloalkyl), fluoro-(C 3 -C 6 -cycloalkyl), CH(CH 3 )CH(OH)phenyl, 4-6 membered heterocycle optionally substituted with F, OH, C 1 -C 3  alkyl, cyclopropylmethyl or C(═O)(C 1 -C 3  alkyl), or C 1 -C 6 -alkyl optionally substituted with one or more groups independently selected from OH, oxo, O(C 1 -C 6 -alkyl), CN, F, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl, 
         or R 6  and R 7  together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF 3 , CH 2 CF 3 , CH 2 CH 2 OH, O(C 1 -C 3  alkyl), C(═O)CH 3 , NH 2 , NHMe, N(Me) 2 , S(O) 2 CH 3 , cyclopropylmethyl and C 1 -C 3  alkyl; 
         R a  and R b  are H, 
         or R a  is H, and R b  and R 6  together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; 
         R c  and R d  are H or Me, 
         or R c  and R d  together with the atom to which they are attached form a cyclopropyl ring; 
         R 8  is H, Me, F or OH, 
         or R 8  and R 6  together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; 
         each R 9  is independently halogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, O—(C 1 -C 6 -alkyl), CF 3 , OCF 3 , S(C 1 -C 6 -alkyl), CN, OCH 2 -phenyl, CH 2 O-phenyl, NH 2 , NH—(C 1 -C 6 -alkyl), N—(C 1 -C 6 -alkyl) 2 , piperidine, pyrrolidine, CH 2 F, CHF 2 , OCH 2 F, OCHF 2 , OH, SO 2 (C 1 -C 6 -alkyl), C(O)NH 2 , C(O)NH(C 1 -C 6 -alkyl), and C(O)N(C 1 -C 6 -alkyl) 2 ; 
         R 10  is H or Me; and 
         m, n and p are independently 0 or 1. 
       
     
     
         87 . The method of  claim 86 , wherein:
 R 1  is Me;   A is   
       
         
           
           
               
               
           
         
       
       and
 R 2 , R 5 , R 8 , R c , and R d  are H. 
 
     
     
         88 . The method of  claim 86 , wherein G is phenyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, Me, ethyl, isopropyl, CN, CF 3 , OCF 3 , SMe, OMe and OCH 2 Ph. 
     
     
         89 . The method of  claim 86 , wherein G is 4-chlorophenyl, 2,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-bromophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-thiomethylphenyl, or 4-methylphenyl. 
     
     
         90 . The method of  claim 86 , wherein R 6  and R 7  are independently selected from H, OCH 3 , (C 3 -C 6  cycloalkyl)-(CH 2 ), (C 3 -C 6  cycloalkyl)-(CH 2 CH 2 ), V—(CH 2 ) 0-1  wherein V is a 5-6 membered heteroaryl having from one to two ring heteroatoms independently selected from N, O and S, W—(CH 2 ) 1-2  wherein W is phenyl optionally substituted with F, Cl or Me, C 3 -C 6 -cycloalkyl optionally substituted with OCH 3 , hydroxy-(C 3 -C 6 -cycloalkyl), fluoro-(C 3 -C 6 -cycloalkyl), CH(CH 3 )CH(OH)phenyl, 5-6 membered heterocycle optionally substituted with CH 3  or C(═O)CH 3 , or C 1 -C 6 -alkyl optionally substituted with one or more groups independently selected from OH, oxo, O(C 1 -C 6 -alkyl), CN, F, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, and tetrahydropyranyl. 
     
     
         91 . The method of  claim 86 , wherein R 6  and R 7  are independently selected from H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, 3-pentyl, OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 OMe, CH 2 CH 2 CF 3 , CH 2 CH(CH 3 )OH, CH 2 CH(CF 3 )OH, CH 2 CF 3 , CH 2 CH 2 F, CH 2 C(═O)NH 2 , CH 2 C(═O)NH(CH 3 ), CH 2 C(═O)N(CH 3 ) 2 , CH 2 C(═O)NH(iPr), CH 2 CH 2 C(═O)NH 2 , CH 2 -cyclopropyl, CH 2 -cyclopentyl, CH 2 -tBu (neopentyl), cyclopropyl, cyclopentyl, cyclohexyl, 4-methoxycyclohexyl, 4,4-dimethylcyclohexyl, 3,3-dimethylcyclohexyl, CH 2 -(pyrid-3-yl), 4-hydroxycyclohex-1-yl, CH(CH 3 )CH(OH)phenyl, CH(phenyl)CH 2 OH, CH(tetrahydropyranyl)CH 2 OH, CH 2 CH 2 CH 2 (imidazolyl), CH 2 CH 2 (morpholinyl), CH 2 (tetrahydropyranyl), CH 2 CH 2 (tetrahydropyranyl), pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, 
       
         
           
           
               
               
           
         
       
     
     
         92 . The method of  claim 86 , wherein R 6  and R 7  together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF 3 , CH 2 CF 3 , CH 2 CH 2 OH, OCH 3 , C(═O)CH 3 , NH 2 , NHMe, N(Me) 2 , S(O) 2 CH 3 , and (C 1 -C 3 )alkyl. 
     
     
         93 . The method of  claim 86 , wherein A is: 
       
         
           
           
               
               
           
         
       
     
     
         94 . The method of  claim 86 , wherein the compound of Formula (I) is
 (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one or a salt thereof;   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(methyl(tetrahydro-2H-pyran-Response to Notice to File Missing Parts 4-yl)amino)propan-1-one or a salt thereof;   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(3-hydroxyazetidin-1-yl)propan-1-one or a salt thereof;   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-pyrrolidin-3-ylamino)propan-1-one or a salt thereof;   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((S)-pyrrolidin-3-ylamino)propan-1-one or a salt thereof;   (S)-3-(1-acetylpiperidin-4-ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one or a salt thereof; or   (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one or a salt thereof.   
     
     
         95 . The method of  claim 86 , wherein the compound of Formula (I) is (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one or a salt thereof.