Macrocyclic salt-inducible kinase inhibitorsThe present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of SIK kinase, more in particular SIK1, SIK2 and/or SIK3 and/or mutants thereof, for use in the diagnosis, prevention and/or treatment of SIK-kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.The compound of formula i or its stereoisomer, tautomer, racemic modification, metabolite, prodrug, salt, hydrate, n-oxide form or solvate, for diagnosis, prevents and/or treats sik-kinase-associated conditions,whereina 1and a 2be selected from c and n; wherein work as a 1when being c, then a 2n; and wherein work as a 2when being c, then a 1n; r 1and r 41each independently selected from-h ,-halogen ,-oh ,-c 1-6alkyl ,-o-c 1-6alkyl ,-s-c 1-6alkyl ,-nr 9r 10,-(c=o)-r 4,-(c=s)-r 4,-so 2-r 4,-cn ,-nr 9-so 2-r 4,-c 3-6cycloalkyl ,-ar 7with-het 1; wherein said-c 1-6alkyl optionally each and being selected from-halogen ,-oh ,-nr by 1 to 3 independently 11r 12,-o-c 1-6alkyl and-s-c 1-6the substituent group of alkyl replaces; r 2be selected from-h ,-halogen ,-oh ,-c 1-6alkyl ,-o-c 1-6alkyl ,-s-c 1-6alkyl ,-(c=o)-c 1-6alkyl ,-(c=s)-c 1-6alkyl ,-(c=o)-o-c 1-6alkyl ,-(c=s)-o-c 1-6alkyl ,-(c=o)-nr 27r 28,-(c=s)-nr 27r 28,-c 3-6cycloalkyl ,-het 3,-ar 2,-(c=o)-het 3,-(c=s)-het 3,-(c=o)-ar 2,-(c=s)-ar 2,-(c=o)-c 3-6cycloalkyl ,-(c=s)-c 3-6cycloalkyl and-so 2-c 1-6alkyl; wherein said-c 1-6alkyl optionally each and being selected from-halogen ,-oh ,-o-c by 1 to 3 independently 1-6alkyl ,-s-c 1-6alkyl ,-het 3,-ar 2with-nr 13r 14substituent group replace; r 3be selected from-h ,-halogen ,-oh ,-c 1-6alkyl ,-o-c 1-6alkyl ,-s-c 1-6alkyl ,-(c=o)-c 1-6alkyl ,-(c=s)-c 1-6alkyl ,-(c=o)-o-c 1-6alkyl ,-(c=s)-o-c 1-6alkyl ,-(c=o)-nr 29r 30,-(c=s)-nr 29r 30,-c 3-6cycloalkyl ,-het 2,-ar 3,-(c=o)-het 2,-(c=s)-het 2,-(c=o)-ar 3,-(c=s)-ar 3,-(c=o)-c 3-6cycloalkyl ,-(c=s)-c 3-6cycloalkyl and-so 2-c 1-6alkyl; wherein said-c 1-6alkyl optionally each and being selected from-halogen ,-oh ,-o-c by 1 to 3 independently 1-6alkyl ,-s-c 1-6alkyl ,-c 3-6cycloalkyl ,-het 2,-ar 3with-nr 15r 16substituent group replace; r 4independently selected from-halogen ,-oh ,-c 1-6alkyl ,-o-c 1-6alkyl ,-s-c 1-6alkyl ,-nr 17r 18,-c 3-6cycloalkyl ,-ar 8with-het 4; r 5and r 7each independently selected from-h ,-oh ,-halogen ,-c 1-6alkyl ,-o-c 1-6alkyl ,-s-c 1-6alkyl ,-het 9,-ar 1,-c 3-6cycloalkyl ,-so 2-ar 1,-so 2,-so 2-c 1-6alkyl ,-(c=o) ,-(c=o)-c 1-6alkyl ,-(c=s) ,-(c=s)-c 1-6alkyl ,-o-(c=o)-c 1-6alkyl ,-o-(c=s)-c 1-6alkyl ,-(c=o)-o-c 1-6alkyl and-(c=s)-o-c 1-6alkyl; wherein said-c 1-6alkyl optionally each and being selected from-halogen ,-oh ,-o-c by 1 to 3 independently 1-6alkyl ,-s-c 1-6alkyl ,-c 3-6cycloalkyl ,-ar 1,-het 9with-nr 23r 24substituent group replace; r 6be selected from-c 1-6alkyl ,-so 2,-so 2-c 1-6alkyl ,-so 2-c 3-6cycloalkyl ,-(c=o) ,-(c=o)-c 1-6alkyl ,-(c=o)-c 2-6thiazolinyl ,-(c=o)-o-c 1-6alkyl ,-(c=o)-het 6,-(c=o)-ar 6,-(c=o)-c 3-6cycloalkyl ,-(c=o)-nr 31r 32,-(c=o)-nr 31-(c=o)-r 32,-(c=s) ,-(c=s)-c 1-6alkyl ,-(c=s)-c 2-6thiazolinyl ,-(c=s)-o-c 1-6alkyl ,-(c=s)-het 6,-(c=s)-ar 6,-(c=s)-c 3-6cycloalkyl ,-(c=s)-nr 31r 32,-(c=s)-nr 31-(c=s)-r 32,-het 6,-ar 6with-c 3-6cycloalkyl; wherein said-c 1-6alkyl optionally each and be selected from=o ,-halogen ,-oh ,-o-c by 1 to 3 independently 1-6alkyl ,-s-c 1-6alkyl ,-c 3-6cycloalkyl ,-het 6,-ar 6,-nr 25r 26,-(c=o)-nr 25r 26,-nr 33(c=o)-nr 25r 26,-(c=s)-nr 25r 26with-nr 33(c=s)-nr 25r 26substituent group replace; and wherein said-c 3-6cycloalkyl optionally each and be selected from-c by 1 to 3 independently 1-6alkyl ,=o ,-halogen ,-oh ,-o-c 1-6alkyl ,-s-c 1-6alkyl ,-het 12,-ar 11with-nr 53r 54,-(c=o)-nr 53r 54,-nr 55(c=o)-nr 53r 54,-(c=s)-nr 53r 54with-nr 55(c=s)-nr 53r 54substituent group replace; r 8be selected from-nr 34-(c=o)-r 35,-nr 34-(c=s)-r 35,-nr 36-(c=o)-nr 34r 35,-nr 36-(c=s)-nr 34r 35,-nr 34-(so 2)-r 35,-nr 34-(c=o)-o-r 35,-nr 34-(c=s)-o-r 35,-o-(c=o)-nr 34r 35with-o-(c=s)-nr 34r 35; r 9, r 10, r 11, r 12, r 13, r 14, r 15, r 16, r 17, r 18, r 19, r 20, r 21, r 22, r 23, r 24, r 25, r 26, r 27, r 28, r 29, r 30, r 31, r 32, r 33, r 34, r 35, r 36, r 37, r 38, r 39, r 40, r 44, r 45, r 46, r 47, r 48, r 49, r 50, r 53, r 54and r 55each independently selected from-h ,-halogen ,=o ,-oh ,-c 1-6alkyl ,-o-c 1-6alkyl ,-s-c 1-6alkyl ,-c 3-6cycloalkyl ,-ar 5with-het 7; wherein said-c 1-6alkyl optionally each and being selected from-halogen ,-oh ,-o-c by 1 to 3 independently 1-6alkyl ,-s-c 1-6alkyl ,-c 3-6cycloalkyl ,-het 7,-ar 5with-nr 51r 52substituent group replace; r 51and r 52each independently selected from-h ,-halogen ,-oh ,-c 1-6alkyl ,-o-c 1-6alkyl ,-s-c 1-6alkyl ,-c 3-6cycloalkyl ,-ar 10with-het 10; r 42be selected from-h ,-oh ,-halogen ,-c 1-6alkyl ,-o-c 1-6alkyl ,-s-c 1-6alkyl ,-nr 46r 47,-c 3-6cycloalkyl ,-ar 9with-het 8; r 43be selected from-h ,-c 1-6alkyl and-c 3-6cycloalkyl; wherein said-c 1-6alkyl optionally each and being selected from-halogen ,-oh ,-o-c by 1 to 3 independently 1-6alkyl ,-s-c 1-6alkyl ,-het 5,-c 3-6cycloalkyl-ar 4with-nr 44r 45substituent group replace; a is selected from-(ch 2) n-y-(ch 2) m-,-(c=o)-,-(c=s)-,-(c=n)-r 49-,-(so 2)-,-so 2-nr 5-,-(c=o)-nr 5-,-(c=s)-nr 5-,-nr 5-(c=o)-nr 7-,-nr 5-(c=s)-nr 7-,-nr 6-,-nr 5-(c=o)-o-,-nr 5-(c=s)-o-and-chr 8-; x 1be selected fr...
거대고리 염-유도성 키나아제 억제제본 발명은 거대고리 화합물 및, SIK-키나아제 관련 질병의 진단, 예방 및/또는 치료에 사용하기 위한, 키나아제 억제제, 특히 SIK 키나아제의 억제제, 더욱 특히 SIK1, SIK2 및/또는 SIK3 및/또는 이들의 변이체들로서 작용하는 상기 화합물을 함유하는 조성물에 관한 것이다. 더욱이, 본 발명은 상기 화합물을 예를 들면, 약제 또는 진단제로서 사용하는 방법을 제공한다.SIK-키나아제 관련 질병의 진단, 예방 및/또는 치료에 사용하기 위한, 하기 화학식 I의 화합물, 또는 그의 입체이성체, 호변체, 라세믹, 대사물, 프로드럭 또는 프리드럭, 염, 수화물, N-산화물 형태 또는 용매화합물,(화학식 I)[이미지](화학식 I에서,A1 및 A2는 C 및 N에서 선택되며; 즉 A1이 C이면, A2는 N이며; 및 A2가 C이면, A1이 N이며;R1 및 R41은 각각 -H, -할로, -OH, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -NR9R10, -(C=O)-R4, -(C=S)-R4, -SO2-R4,-CN, -NR9-SO2-R4, -C3-6시클로알킬, -Ar7 및 -Het1로부터 독립적으로 선택되며; 상기 -C1-6알킬은 각각 -할로, -OH, -NR11R12, -O-C1-6알킬, 및 -S-C1-6알킬로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며;R2는 -H, -할로, -OH, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -(C=O)-C1-6알킬, -(C=S)-C1-6알킬, -(C=O)-O-C1-6알킬, -(C=S)-O-C1-6알킬, -(C=O)-NR27R28, -(C=S)-NR27R28, -C3-6시클로알킬, -Het3, -Ar2, -(C=O)-Het3, -(C=S)-Het3, -(C=O)-Ar2, -(C=S)-Ar2, -(C=O)-C3-6시클로알킬, -(C=S)-C3-6시클로알킬, 및 -SO2-C1-6알킬로부터 선택되며; 상기 -C1-6알킬은 각각 -할로, -OH, -O-C1-6알킬, -S-C1-6알킬, -Het3, -Ar2, 및 -NR13R14로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며;R3은 -H, -할로, -OH, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -(C=O)-C1-6알킬, -(C=S)-C1-6알킬, -(C=O)-O-C1-6알킬, -(C=S)-O-C1-6알킬, -(C=O)-NR29R30, -(C=S)-NR29R30, -C3-6시클로알킬 -Het2, -Ar3, -(C=O)-Het2, -(C=S)-Het2, -(C=O)-Ar3, -(C=S)-Ar3, -(C=O)-C3-6시클로알킬, -(C=S)-C3-6시클로알킬 및 -SO2-C1-6알킬로부터 선택되며; 상기 -C1-6알킬은 각각 -할로, -OH, -O-C1-6알킬, -S-C1-6알킬, -C3-6시클로알킬, -Het2, -Ar3, 및 -NR15R16으로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며;R4는 -할로, -OH, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -NR17R18, -C3-6시클로알킬, -Ar8 및-Het4로부터 독립적으로 선택되며;R5 및R7은 각각 -H, -OH, -할로, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -Het9, -Ar1, -C3-6시클로알킬, -SO2-Ar1, -SO2, -SO2-C1-6알킬, -(C=O), -(C=O)-C1-6알킬, -(C=S), -(C=S)-C1-6알킬, -O-(C=O)-C1-6알킬, -O-(C=S)-C1-6알킬, -(C=O)-O-C1-6알킬, 및 -(C=S)-O-C1-6알킬로부터 독립적으로 선택되며; 상기 -C1-6알킬은 각각 -할로, -OH, -O-C1-6알킬, -S-C1-6알킬, -C3-6시클로알킬, -Ar1, -Het9, 및 -NR23R24로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며; R6은 -C1-6알킬, -SO2, -SO2-C1-6알킬, -SO2-C3-6시클로알킬, -(C=O), -(C=O)-C1-6알킬, -(C=O)-C2-6알케닐, -(C=O)-O-C1-6알킬, -(C=O)-Het6, -(C=O)-Ar6, -(C=O)-C3-6시클로알킬, -(C=O)-NR31R32, -(C=O)-NR31-(C=O)-R32, -(C=S), -(C=S)-C1-6알킬, -(C=S)-C2-6알케닐, -(C=S)-O-C1-6알킬, -(C=S)-Het6, -(C=S)-Ar6, -(C=S)-C3-6시클로알킬, -(C=S)-NR31R32, -(C=S)-NR31-(C=S)-R32, -Het6, -Ar6, 및 -C3-6시클로알킬로부터 선택되며; 상기 -C1-6알킬은 각각 =O, -할로, -OH, -O-C1-6알킬, -S-C1-6알킬, -C3-6시클로알킬, -Het6, -Ar6, -NR25R26, -(C=O)-NR25R26, -NR33(C=O)-NR25R26, -(C=S)-NR25R26, 및 -NR33(C=S)-NR25R26으로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며; 및 상기 -C3-6시클로알킬은 각각 -C1-6알킬, =O, -할로, -OH, -O-C1-6알킬, -S-C1-6알킬, -Het12, -Ar11, 및 -NR53R54, -(C=O)-NR53R54, -NR55(C=O)-NR53R54, -(C=S)-NR53R54, 및 -NR55(C=S)-NR53R54로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며;R8은 -NR34-(C=O)-R35, -NR34-(C=S)-R35, -NR36-(C=O)-NR34R35, -NR36-(C=S)-NR34R35, -NR34-(SO2)-R35, -NR34-(C=O)-O-R35, -NR34-(C=S)-O-R35, -O-(C=O)-NR34R35, 및 -O-(C=S)-NR34R35로부터 선택되며;R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R44, R45, R46, R47, R48, R49, R50, R53, R54 및R55는 각각 -H, -할로, =O, -OH, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -C3-6시클로알킬, -Ar5 및-Het7로부터 독립적으로 선택되며; 상기 -C1-6알킬은 각각 -할로, -OH, -O-C1-6알킬, -S-C1-6알킬, -C3-6시클로알킬, -Het7, -Ar5 및-NR51R52로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며;R51 및 R52는 각각 -H, -할로, -OH, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -C3-6시클로알킬, -Ar10 및-Het10으로부터 독립적으로 선택되며;R42는 -H, -OH, -할로, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -NR46R47, -C3-6시클로알킬, -Ar9 및 -Het8로부터 선택되며;R43은 -H -C1-6알킬, 및 -C3-6시클로알킬로부터 선택되며; 상기 -C1-6알킬은 각각 -할로, -OH, -O-C1-6알킬, -S-C1-6알킬, -Het5, -C3-6시클로알킬 -Ar4, 및 -NR44R45로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며;A는 -(CH2)n-Y-(CH2)m-, -(C=O)-, -(C=S)-, -(C=N)-R49-, -(SO2)-, -SO2-NR5-, -(C=O)-NR5-, -(C=S)-NR5-, -NR5-(C=O)-NR7-, -NR5-(C=S)-NR7-, -NR6,-, -NR5-(C=O)-O-, -NR5-(C=S)-O-, 및 -CHR8-로부터 선택되며;X1은 -C1-6알킬-, -O-C1-6알킬-, -S-C1-6알킬-, -(C=O)-, -NR3-(C=O)-, -C1-6알킬-NR3-, -NR3-, -(C=O)-, -NR3-(C=O)-NR48-, -NR3-C1-6알킬-, -NR3-SO2-, -NR3-(C=O)-C1-6알킬-, -(C=O)-NR3-C1-6알킬-, -O-C1-6알킬-O-C1-6알킬- 및 -C1-6알킬-NR3-C1-6알킬-로부터 선택되며; 상기 -C1-6알킬-은 각각 -할로, -OH, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -페닐, 및 -NR37R38로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며;X2는 -C1-6알킬-, -O-C1-6알킬-, -S-C1-6알킬-, -(C=O)-, -NR2-(C=O)-, -C1-6알킬-NR2-, -NR2-, -(C=O)-, -NR2-(C=O)-NR50-, -NR2-C1-6알킬-, -NR2-SO2-, -NR2-(C=O)-C1-6알킬-, -(C=O)-NR2-C1-6알킬-, -O-C1-6알킬-O-C1-6알킬- 및 -C1-6알킬-NR2-C1-6알킬-로부터 선택되며; 상기 -C1-6알킬-은 각각 -할로, -OH, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, -페닐 및 -NR39R40으로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며;Y는 직접 결합, -CHR42-, -O-, -S-, 및 -NR43-으로부터 선택되며;Ar1,Ar2,Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10 및 Ar11은 각각 독립적으로 O, N 및 S로부터 선택되는 1 또는 2개의 헤테로원자들을 선택적으로 포함하는 5- 내지 10-원자 방향족 헤테로사이클이며; 상기 Ar1,Ar2,Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, 및 Ar10은 각각 -할로, -OH, -C1-6알킬, -O-C1-6알킬, -S-C1-6알킬, 및 -NR19R20으로부터 선택되는 1 내지 3개의 치환체들에 의해 선택적으로 및 독립적으로 치환되며; 상기 -C1-6알킬은 각각 1 내지 3개의 -할로에 의해 선택적으로 및 독립적으로 치환되며;Het1, Het2, Het3,Het4, Het5,Het6, Het7, Het8, Het9, Het10, 및 Het12는 각각 독립적으로 O, N 및 S로부터 선택되는 1 내지 3개의 헤테로원자들을 갖는 4- 내지 10-원자 헤테로사이클이며, 상기 Het1, Het2, Het3,Het4, Het5,Het6, Het7, Het8, Het9, Het10, 및 Het12는 각각 -할로, -OH, -C1-6알킬, -OC1-6알킬, -SC1-6알킬, =O, -(C=O)-C1-6알킬, 및 ...