PYRROLO-, PYRAZOLO-, IMIDAZO-PYRIMIDINE AND PYRIDINE COMPOUNDS THAT INHIBIT 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, A6, A7, W1, R1, R2, R3, R4, R5a, R5b, R6, R7, R7a, R7b, R8, R8a, R8b, R9, R9a, R9b and R10 and subscripts "m" and "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):I a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof wherein: A1 and A2 independently are -N- or -CR5a; A3 is -N- or -CR6; A4 is -N- or -CR5b; A5 is - R7 or -CR7aR7b;A6 and A7 are independently -N- or -CR8a when represents a bond, otherwise A6 and A7 are independently -NR8 or -CR8aR8b;W1 is O, S, NH, NO(R9) or CR9aR9b; m and n independently are 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; orR1 and R2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;R3 and R4 independently are -H, -OH, -CN, -SR10, S(0)2(Ci-C8) alkyl,-C(0)NHR10, -C(O)NR10R10, -NHR10, -NR10R10, NHR10-alkylene, NR10R10-alkylene, (d- 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;R5a 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;R5b and R6 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, -(Ci- C8)alkyleneNR10R10, -S(Ci-C8)alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl;R7 is -H, -OH, acetyl, -(Ci-C8)alkyl, -C(0)alkyl, -C(0)cycloalkyl, -C(0)0-(Ci-C8)alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;R7a and R713 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;R8 is -H, -OH, acetyl, (Ci-C8)alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;R8a and R8b independently are -H, -OH, -CN, acetyl, -SH, -S(0)2R10, halogen, -S(C C8)alkyl, -NHR10, -NR10R10, (Ci-C8)alkyl, (Ci-C8)haloalkyl, -0(Ci-C8)alkyl, -0(Ci- C8)alkylNHR10, -O(Ci-C8)alkylNR10R10, -(Ci-C8)alkylNHR10, -(Ci-C8)alkylNR10R10, cycloalkyl, heterocyclyl, heteroaryl or aryl;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(O)- aryl, -CH2-C(0)-heterocycloalkyl, -C(0)-heterocycloalkyl, heterocyclylaminyl or heterocyclyl; and— represents the option of having a double bond.
MNK1 및 MNK2를 억제하는 피롤로-, 피라졸로-, 이미다조-피리미딘 및 피리딘 화합물본 발명은 화학식 (I)에 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, A6, A7, W1, R1, R2, R3, R4, R5a, R5b, R6, R7, R7a, R7b, R8, R8a, R8b, R9, R9a, R9b 및 R10 및 아래첨자 "m" 및 "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, 및 그의 입체이성질체, 호변이성질체 또는 제약상 허용되는 염. 여기서 A1 및 A2는 독립적으로 -N- 또는 -CR5a이고; A3은 -N- 또는 -CR6이고; A4는 -N- 또는 -CR5b이고; A5는 -NR7 또는 -CR7aR7b이고; A6 및 A7은 가 결합을 나타내는 경우, 독립적으로 -N- 또는 -CR8a이거나; 다르게는 A6 및 A7은 독립적으로 -NR8 또는 -CR8aR8b이고; W1은 O, S, NH, NO(R9) 또는 CR9aR9b이고; m 및 n은 독립적으로 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 헤테로아릴알킬렌이거나; 또는R1 및 R2는 이들이 부착되어 있는 탄소 원자와 함께, 시클로알킬 또는 헤테로시클릴 고리를 형성하고; R3 및 R4는 독립적으로 -H, -OH, -CN, -SR10, 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 헤테로시클릴아미닐이고; R5a는 -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; R5b 및 R6은 -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;R7은 -H, -OH, 아세틸, -(C1-C8)알킬, -C(O)알킬, -C(O)시클로알킬, -C(O)O-(C1-C8)알킬, 시클로알킬, 아릴, 헤테로아릴 또는 헤테로시클릴이고; R7a 및 R7b는 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;R8은 -H, -OH, 아세틸, (C1-C8)알킬, 시클로알킬, 헤테로시클릴, 헤테로아릴 또는 아릴이고; R8a 및 R8b는 독립적으로 -H, -OH, -CN, 아세틸, -SH, -S(O)2R10, 할로겐, -S(C1-C8)알킬, -NHR10, -NR10R10, (C1-C8)알킬, (C1-C8)할로알킬, -O(C1-C8)알킬, -O(C1-C8)알킬NHR10, -O(C1-C8)알킬NR10R10, -(C1-C8)알킬NHR10, -(C1-C8)알킬NR10R10, 시클로알킬, 헤테로시클릴, 헤테로아릴 또는 아릴이고;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 시클로알킬이며; 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 치환되고;은 이중 결합을 갖는 옵션을 나타낸다.