ISOINDOLINE, AZAISOINDOLINE, DIHYDROINDENONE AND DIHYDROAZAINDENONE INHIBITORS OF MNK1 AND MNK2The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds A1, A2, A3, A4, A5, W1, Y, R1, R2, R3, R4, R5, R6a, R6b, R7, R8, R8a, R8b, R9, R9a, R9b, and R10 and subscript "n" are as defined in the specification. The inventive Formula I compounds are inhibitors of Mnk and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.A compound according to Formula (I): a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof wherein:A1 and A2 independently are -N- or -CR6a;A3 is -N- or -CR7;A4 is -N- or -CR6b;A5 is - R8 or -CR8aR8b;W1 is O, S, H, NO(R9) or CR9aR9b;Y is -0-, -S-, -C(O)-, -NR10, -S=0, -S(0)2- -CH2- or -CH(OH); n is 1, 2 or 3;R1 and R2 independently are -H, -NHR10, NHR10-alkylene, (Ci-C8)alkyl,(C2-C8)alkenyl, (C2-C8)alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene, or heteroarylalkylene, such that at least one of R1 or R2 is not -H; orR1 and R2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;R3 , R4 , R5 and R6b independently are -H, -OH, -CN, -SR10, halogen, -S(0)2(Ci-C8) alkyl, -C(0)NHR10, -C(O)NR10R10, -NHR10, -NR10R10, NHR10-alkylene, NR10R10-alkylene, (C C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (Ci-C8)haloalkyl, -0(Ci-C8)alkyl, -0(Ci-C8)haloalkyl, -0(Ci-C8)alkyleneNHR , -0(Ci-C8)alkyleneNRiUR , cycloalkyl, heterocyclyl, heteroaryl, aryl, aiylalkylene, cycloalkylalkylene, heterocyclylalkylene, heteroaryl alkylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, or heterocyclyl aminyl; orR4 and R5 together with the respective carbon atoms to which they are attached form a fused aryl, cycloalkyl, heterocyclyl or heteroaryl ring;R6a is -H, -OH, halogen, -CN, acetyl, -(Ci-C8)alkyl, -S(Ci-C8)alkyl, -(C2-C8)alkenyl, -(C2-C8)alkynyl, -0(Ci-C8)alkyl, -(Ci-C8)haloalkyl, - HR10, - R10R10, HR10-alkylene,R10R10-alkylene or -0(Ci-C8)haloalkyl;R7 is -H, -OH, -SH, -CN, -S(0)2R10, halogen, -S(Ci-C8)alkyl, -NHR10, -NR10R10, (Ci- C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (Ci-C8)haloalkyl, -0(Ci-C8)haloalkyl, -0(Ci-C8)alkyl, -0(Ci-C8)alkyleneNHR10, -O(Ci-C8)alkyleneNR10R10, -(Ci-C8)alkyleneNHR10, -(CC8)alkyleneNR10R10, -S(Ci-C8)alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;R8 is -H, -OH, acetyl, -(Ci-C8)alkyl, -C(0)alkyl, -C(0)cycloalkyl, -C(0)0-(Ci-C8)alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;R8a and R8b independently are -H, -OH, acetyl, -(Ci-C8)alkyl, -0(Ci-C8)alkyl,-C(0)alkyl, -C(0)cycloalkyl, -C(0)0-(Ci-C8)alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;R9, R9a and R9b are independently -H, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene, or heteroarylalkylene; orR9a and R9b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;R10 is -H, -OH, -C(0)0(Ci-C8)alkyl, -C(0)( Ci-C8)alkyl, -C(0)-NH2, -C(0)-NH(Ci- C8)alkyl, NH2-C(0)-alkylene , -S(Ci-C8)alkyl, acetyl, -(Ci-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, -0(Ci-C8)alkyl, (Ci-C8) haloalkyl, alkylcarbonylaminyl, alkylaminyl, -C(0)alkyl, -C(0)cycloalkyl, -C(0)0-(Ci-C8)alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl; wherein any alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene,cycloalkylalkylene, heterocyclylalkylene, heteroarylalkylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, or heterocyclylaminyl is optionally substituted with 1, 2, or 3 groups selected from -OH, -CN, -SH , -S(0) H2, -S(0) H2, halogen, - H2, - H(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2,-C(0) H2, -COOH, -COOMe, acetyl, -(Ci-C8)alkyl, -0(Ci- C8)alkyl (C2-C8)alkenyl, (C2-C8)alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, H2-C(0)-alkylene , H2-C(0)-alkylene, - H(Me)-C(0)-alkylene, -CH2-C(0)-lower alkyl, -C(0)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, -CH2-C(0)-cycloalkyl, -C(0)-cycloalkyl, -CH2- C(0)-aryl, -CH2-aryl, -C(0)-aryl, -CH2-C(0)-heterocycloalkyl, -C(0)-heterocycloalkyl, heterocyclylaminyl or heterocyclyl.
MNK1 및 MNK2의 이소인돌린, 아자이소인돌린, 디히드로인데논 및 디히드로아자인데논 억제제본 발명은 화학식 I에 따른 화합물, 또는 그의 입체이성질체, 호변이성질체 또는 제약상 허용되는 염의 합성, 제약상 허용되는 제제 및 용도를 제공한다. 화학식 I의 화합물에 대하여, A1, A2, A3, A4, A5, W1, Y, R1, R2, R3, R4, R5, R6a, R6b, R7, R8, R8a, R8b, R9, R9a, R9b, 및 R10 및 아래첨자 "n"은 명세서에 정의된 바와 같다. 본 발명의 화학식 I의 화합물은 Mnk의 억제제이고, 비제한적으로 염증 및 다양한 암의 치료를 포함하는 임의의 수의 치료 적용에서 유용성을 갖는다.화학식 I에 따른 화합물, 그의 입체이성질체, 호변이성질체 또는 제약상 허용되는 염.여기서A1 및 A2는 독립적으로 -N- 또는 -CR6a이고;A3은 -N- 또는 -CR7이고;A4는 -N- 또는 -CR6b이고;A5는 -NR8 또는 -CR8aR8b이고;W1은 O, S, NH, NO(R9) 또는 CR9aR9b이고;Y는 -O-, -S-, -C(O)-, -NR10, -S=O, -S(O)2-, -CH2- 또는 -CH(OH)이고;n은 1, 2 또는 3이고;R1 및 R2는 독립적으로 -H, -NHR10, NHR10-알킬렌, (C1-C8)알킬, (C2-C8)알케닐, (C2-C8)알키닐, 시클로알킬, 헤테로시클릴, 헤테로아릴, 아릴, 아릴알킬렌, 시클로알킬알킬렌, 헤테로시클릴알킬렌, 또는 헤테로아릴알킬렌이며, R1 또는 R2 중 적어도 1개는 -H가 아니거나; 또는R1 및 R2는 이들이 부착되어 있는 탄소 원자와 함께, 시클로알킬 또는 헤테로시클릴 고리를 형성하고;R3, R4, R5 및 R6b는 독립적으로 -H, -OH, -CN, -SR10, 할로겐, -S(O)2(C1-C8) 알킬, -C(O)NHR10, -C(O)NR10R10, -NHR10, -NR10R10, NHR10-알킬렌, NR10R10-알킬렌, (C1-C8)알킬, (C2-C8)알케닐, (C2-C8)알키닐, (C1-C8)할로알킬, -O(C1-C8)알킬, -O(C1-C8)할로알킬, -O(C1-C8)알킬렌NHR10, -O(C1-C8)알킬렌NR10R10, 시클로알킬, 헤테로시클릴, 헤테로아릴, 아릴, 아릴알킬렌, 시클로알킬알킬렌, 헤테로시클릴알킬렌, 헤테로아릴알킬렌, 알킬아미닐, 알킬카르보닐아미닐, 시클로알킬카르보닐아미닐, 시클로알킬아미닐, 또는 헤테로시클릴아미닐이거나; 또는R4 및 R5는 이들이 부착되어 있는 각각의 탄소 원자와 함께, 융합된 아릴, 시클로알킬, 헤테로시클릴 또는 헤테로아릴 고리를 형성하고;R6a는 -H, -OH, 할로겐, -CN, 아세틸, -(C1-C8)알킬, -S(C1-C8)알킬, -(C2-C8)알케닐, -(C2-C8)알키닐, -O(C1-C8)알킬, -(C1-C8)할로알킬, -NHR10, -NR10R10, NHR10-알킬렌, NR10R10-알킬렌 또는 -O(C1-C8)할로알킬이고;R7은 -H, -OH, -SH, -CN, -S(O)2R10, 할로겐, -S(C1-C8)알킬, -NHR10, -NR10R10, (C1-C8)알킬, (C2-C8)알케닐, (C2-C8)알키닐, (C1-C8)할로알킬, -O(C1-C8)할로알킬, -O(C1-C8)알킬, -O(C1-C8)알킬렌NHR10, -O(C1-C8)알킬렌NR10R10, -(C1-C8)알킬렌NHR10, -(C1-C8)알킬렌NR10R10, -S(C1-C8)알킬, 시클로알킬, 헤테로시클릴, 헤테로아릴 또는 아릴이고;R8은 -H, -OH, 아세틸, -(C1-C8)알킬, -C(O)알킬, -C(O)시클로알킬, -C(O)O-(C1-C8)알킬, 시클로알킬, 아릴, 헤테로아릴 또는 헤테로시클릴이고;R8a 및 R8b는 독립적으로 -H, -OH, 아세틸, -(C1-C8)알킬, -O(C1-C8)알킬, -C(O)알킬, -C(O)시클로알킬, -C(O)O-(C1-C8)알킬, 시클로알킬, 아릴, 헤테로아릴 또는 헤테로시클릴이고;R9, R9a 및 R9b는 독립적으로 -H, (C1-C8)알킬, (C2-C8)알케닐, (C2-C8)알키닐, 시클로알킬, 헤테로시클릴, 헤테로아릴, 아릴, 아릴알킬렌, 시클로알킬알킬렌, 헤테로시클릴알킬렌, 또는 헤테로아릴알킬렌이거나; 또는R9a 및 R9b는 이들이 부착되어 있는 탄소 원자와 함께, 시클로알킬 또는 헤테로시클릴 고리를 형성하고;R10은 -H, -OH, -C(O)O(C1-C8)알킬, -C(O)(C1-C8)알킬, -C(O)-NH2, -C(O)-NH(C1-C8)알킬, NH2-C(O)-알킬렌, -S(C1-C8)알킬, 아세틸, -(C1-C8)알킬, (C2-C8)알케닐, (C2-C8)알키닐, -O(C1-C8)알킬, (C1-C8) 할로알킬, 알킬카르보닐아미닐, 알킬아미닐, -C(O)알킬, -C(O)시클로알킬, -C(O)O-(C1-C8)알킬, 아릴, 헤테로아릴, 헤테로시클릴 또는 시클로알킬이고;여기서 임의의 알킬, 시클로알킬, 헤테로시클릴, 헤테로아릴, 아릴, 아릴알킬렌, 시클로알킬알킬렌, 헤테로시클릴알킬렌, 헤테로아릴알킬렌, 알킬아미닐, 알킬카르보닐아미닐, 시클로알킬카르보닐아미닐, 시클로알킬아미닐, 또는 헤테로시클릴아미닐은 -OH, -CN, -SH, -S(O)NH2, -S(O)NH2, 할로겐, -NH2, -NH(C1-C4)알킬, -N[(C1-C4)알킬]2, -C(O)NH2, -COOH, -COOMe, 아세틸, -(C1-C8)알킬, -O(C1-C8)알킬 (C2-C8)알케닐, (C2-C8)알키닐, 할로알킬, 티오알킬, 시아노메틸렌, 알킬아미닐, NH2-C(O)-알킬렌, NH2-C(O)-알킬렌, -NH(Me)-C(O)-알킬렌, -CH2-C(O)-저급 알킬, -C(O)-저급 알킬, 알킬카르보닐아미닐, 시클로알킬, 시클로알킬알킬렌, 시클로알킬알케닐렌, 시클로알킬카르보닐아미닐, 시클로알킬아미닐, -CH2-C(O)-시클로알킬, -C(O)-시클로알킬, -CH2-C(O)-아릴, -CH2-아릴, -C(O)-아릴, -CH2-C(O)-헤테로시클로알킬, -C(O)-헤테로시클로알킬, 헤테로시클릴아미닐 또는 헤테로시클릴로부터 선택된 1, 2, 또는 3개의 기로 임의로 치환된다.