发明名称 NEW 1-(4-PYRIMIDINYL)-1H-PYRROLO[3,2-c]PYRIDINE DERIVATIVES AS NIK INHIBITORS
摘要 The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.
申请公布号 US2016257679(A1) 申请公布日期 2016.09.08
申请号 US201415024603 申请日期 2014.09.25
申请人 JANSSEN PHARMACEUTICA NV 发明人 HYND George;TISSELLI Patrizia;CLARK David Edward;KULAGOWSKI Janusz Jozef;MACLEOD Calum;MANN Samuel Edward;PANCHAL Terry Aaron;PRICE Stephen Colin;MONTANA John Gary
分类号 C07D471/04 主分类号 C07D471/04
代理机构 代理人
主权项 1. A compound of Formula (I): or a tautomer or a stereoisomeric form thereof, wherein R1 is selected from the group of hydrogen; C1-6alkyl; and C1-6alkyl substituted with one or more fluoro substituents; R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C3-6cycloalkyl; and Het1; Het1 is a heteroaryl selected from the group of thienyl, thiazolyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one or two substituents independently selected from halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents; or R1 and R2 together with the carbon atom to which they are attached form a C3-6cycloalkyl; R3 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; and C1-6alkyl substituted with one or more substituents independently selected from fluoro, —OH, C1-4alkoxy and NR3aR3b; R3a and R3b are each independently selected from the group of hydrogen and C1-4alkyl; R4 is selected from the group of hydrogen; halogen; C1-4alkyl; and C1-4alkyl substituted with one or more fluoro substituents; R5 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; cyano; C1-6alkyl substituted with one substituent selected from the group of —NR5aR5b, —OH, —OC1-4alkyl, and Het2; and —C(═O)—NR5cR5d; R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; R5c and R5d are each independently selected from the group of hydrogen; C1-6alkyl optionally substituted with Het3; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl; R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl; Het2 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl and C1-4alkyl substituted with one or more fluoro substituents; Het3 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl and C1-4alkyl substituted with one or more fluoro substituents; or R5c and R5d together with the nitrogen atom to which they are attached form a Het4 group; wherein Het4 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OH; R6 is selected from the group of hydrogen; halogen; cyano; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one —OH; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl substituted with one Het5 substituent; —OC2-6alkyl substituted with one substituent selected from the group of —NR6cR6d, —OH, and —OC1-4alkyl; and —C(═O)—NR6aR6b; R6a, R6c and R6d are each independently selected from hydrogen and C1-4alkyl; and R6b is selected from hydrogen, C1-4alkyl, C2-4alkyloxyC1-4alkyl and C2-4alkylNR6xR6y; or R6a and R6b, together with the nitrogen atom to which they are attached form a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl and azetidinyl, each of which may be optionally substituted with one C1-4alkyl or C1-4alkyl substituted with one or more fluoro substituents; R6x is hydrogen or C1-4alkyl and R6y is C1-4alkyl; Het5 is a heterocyclyl selected from the group of piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl and C1-4alkyl substituted with one or more fluoro substituents; R7 is selected from the group of hydrogen, cyano, —OC1-4alkyl, —NHC1-4alkyl and —NHC(O)C1-4alkyl; R8 is selected from the group of hydrogen, Het6, fluoro, cyano, —NR8aR8b, —NR8cC(═O)R8d, —NR8cC(═O)NR8aR8b, —NR8cC(═O)OR8e, —NR8cS(═O)2NR8aR8b, —NR8cS(═O)2R8d, —OR8f, —OC(═O)NR8aR8b, —C(═O)NR8aR8b, —S(O)2R8d, —S(O)2NR8aR8b, C1-6alkyl, and C2-6alkenyl; wherein C1-6alkyl and C2-6alkenyl are optionally substituted with one or more substituents each independently selected from the group of fluoro, cyano, —NR8aR8b, —NR8cC(═O)R8d, —NR8cC(═O)NR8aR8b, —NR8cC(═O)OR8e, —NR8cS(═O)2NR8aR8b, —NR8cS(═O)2R8d, —OR8f, —OC(═O)NR8aR8b, —C(═O)NR8aR8b, —S(O)2R8d, —S(O)2NR8aR8b, and Het7; R8a, R8b, R8e and R8f are each independently selected from the group of hydrogen; C1-6alkyl, which may be optionally substituted with one substituent selected from Het8; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl; R8d is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from —NR8xR8y, —OH, —OC1-4alkyl and Het8; and C3-6cycloalkyl; R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from Het8; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl; R8x and R8y are each independently selected from hydrogen and C1-4alkyl; Het6 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, benzyl, C1-4alkyl, —OC1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one —OC1-4alkyl, and C1-4alkyl substituted with one or more fluoro substituents; Het7 is a heterocyclyl selected from the group of morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl, —OC1-4alkyl, C1-4alkyl substituted with one —OC1-4alkyl, and C1-4alkyl substituted with one or more fluoro substituents; Het8 is a heterocyclyl selected from the group of piperazinyl, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one or two substituents independently selected from fluoro, C1-4alkyl and C1-4alkyl substituted with one or more fluoro substituents; and R9 is hydrogen or C1-4alkyl; or a pharmaceutically acceptable addition salt or a solvate thereof.
地址 Beerse BE