3-(2-AMINOPYRIMIDIN-4-YL)-5-(3-HYDROXYPROPYNYL)-1H-PYRROLO[2,3-C]PYRIDINE DERIVATIVES AS NIK INHIBITORS FOR THE TREATMENT OF CANCER

摘要

The present invention relates to compounds of formula (I) which are inhibitors of NF-KB-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.;

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; C1-6alkyl substituted with one or more fluoro substituents; and C1-6alkyl substituted with one substituent selected from the group of —NR1aR1b; —OH and —OC1-4alkyl; R2 is selected from the group of hydrogen; C1-6alkyl; C1-6alkyl substituted with one or more fluoro substituents; C1-6alkyl substituted with one substituent selected from the group of —NR2aR2b, —OH, C3-6cycloalkyl, Het1, Het2 and phenyl; —C(═O)—NR2cR2d; C3-6cycloalkyl; Het1; Het2; and phenyl; wherein the phenyl groups are optionally substituted with one or two substituents independently selected from the group of halogen, cyano, C1-4alkoxy, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyloxy substituted with one or more fluoro substituents; R1a, R1b, R2a, R2b, R2c and R2d are each independently selected from hydrogen and C1-4alkyl; Het1 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 C1-4alkyl; Het2 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 or a Het3 group; wherein Het3 is a heterocyclyl selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; or Het3 is 2-oxo-3-pyrrolidinyl optionally substituted with one C1-4alkyl; R3 is selected from the group of hydrogen; halo; C3-6cycloalkyl; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and C1-4alkyloxy substituted with one or more fluoro substituents; R4 is selected from the group of hydrogen; halogen; C1-4alkyl; C1-4alkyl substituted with one or more fluoro substituents; and cyano; 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, C3-6cycloalkyl, and Het4; C3-6cycloalkyl; and —C(═O)—NR5cR5d; wherein R5a and R5b are each independently selected from the group of hydrogen and C1-4alkyl; and R5c and R5d are each independently selected from the group of hydrogen; C1-6alkyl optionally substituted with Het5; and C2-6alkyl substituted with one substituent selected from —NR5xR5y, —OH and —OC1-4alkyl; Het4 is a heterocyclyl selected from the group of piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; Het5 is a heterocyclyl selected from the group of piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one C1-4alkyl; R5x and R5y are each independently selected from the group of hydrogen and C1-4alkyl; or R5c and R5d together with the nitrogen atom to which they are attached form a Het6 group; wherein Het6 is a heterocyclyl selected from the group of piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl and morpholinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl; —OC1-4alkyl; 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; C1-6alkyl substituted with one NH2; —C1-6alkyloxyC1-4alkyl; —C1-6alkyl-C(═O)—NR6aR6b; —OC1-6alkyl; —OC1-6alkyl substituted with one or more fluoro substituents; —OC1-6alkyl substituted with one Het7 substituent; —OC2-6alkyl substituted with one substituent selected from the group of —NR6cR6d, —OH, and —OC1-4alkyl; and —C(═O)—NR6aR6b; wherein 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; R6x is hydrogen or C1-4alkyl and R6y is C1-4alkyl; and Het7 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 C1-4alkyl; R7 is selected from the group of hydrogen, C1-4alkyl, cyano, —OC1-4alkyl, —NHC1-4alkyl, —NH—C(═O)—C1-4alkyl and —C(═O)—NR7aR7b; wherein R7a and R7b are each independently selected from hydrogen and C1-4alkyl; R8 is selected from the group of hydrogen; —C(═O)—NR8gR8h; Het8; C1-6alkyl optionally substituted with Het9; —C(═O)—Het12; C3-6cycloalkyl optionally substituted with one —OC1-4alkyl; C1-6alkyl substituted with one cyano; —CH2—C(═O)NR8aR8b; and C2-6alkyl substituted with one or more substituents independently selected from the group of (i) fluoro, (ii) —NR8aR8b, (iii) —NR8cC(═O)R8d, (iv) —NR8cC(═O)NR8aR8b, (v) —NR8cC(═O)OR8e, (vi) —NR8cS(═O)2NR8aR8b, (vii) —NR8cS(═O)2R8d, (viii) —OR8f, (ix) —OC(═O)NR8aR8b, (x) —C(═O)NR8aR8b, (xi) —SR8e, (xii) —S(O)2R8d, and (xiii) —S(O)2NR8aR8b; wherein R8a, R8b, R8c and R8f are each independently selected from the group of hydrogen; C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; 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, Het10 and Het11; and C3-6cycloalkyl; R8e is selected from the group of C1-6alkyl, which may be optionally substituted with one substituent selected from Het10 and Het11; C3-6cycloalkyl; and C2-6alkyl substituted with one substituent selected from —NR8xR8y, —OH, and —OC1-4alkyl; wherein R8x and R8y are each independently selected from hydrogen and C1-4alkyl; R8g and R8h are each independently selected from the group of hydrogen, C1-4alkyl and C2-4alkyl substituted with one —OC1-4alkyl; and Het8 is a heterocyclyl, bound through any available carbon atom, selected from the group of piperidinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl and oxetanyl, each of which may be optionally substituted with one substituent selected from halo, —C(═O)—C1-4alkyl, C1-4alkyl, C3-6cycloalkyl, C1-4alkyl substituted with one C3-6cycloalkyl, C1-4alkyl substituted with one or more fluoro substituents, and C1-4alkyl substituted with one —OC1-4alkyl; Het9 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 substituent selected from halo, C1-4alkyl, C1-4alkyl substituted with one or more fluoro substituents, and —OC1-4alkyl; or Het9 is a heteroaryl selected from the group of oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl, each of which may be optionally substituted with one C1-4alkyl; or Het9 is selected from the group of Het10 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 C1-4alkyl; Het11 is selected from the group of Het12 is a heterocyclyl selected from the group of 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 1-azetidinyl, each of which may be optionally substituted with one substituent selected from C1-4alkyl and —OC1-4alkyl; R9 is hydrogen or C1-4alkyl; or a pharmaceutically acceptable salt or a solvate thereof.