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KR-102961668-B1 - Thienopyridinyl and thiazolopyridinyl compounds useful as IRAK4 inhibitors

KR102961668B1KR 102961668 B1KR102961668 B1KR 102961668B1KR-102961668-B1

Abstract

A compound of the following chemical formula (I), or its salt or precursor drug is disclosed: Herein: X is CR4 or N; R1 , R2 , R3 , R4 , and n are defined herein. Methods of using these compounds as modifiers of IRAK4, and pharmaceutical compositions comprising these compounds are also disclosed. These compounds are useful for treating, preventing, or delaying inflammatory and autoimmune diseases, or for treating cancer.

Inventors

  • 아흐마드, 살림
  • 리, 링
  • 우, 홍
  • 하이네스, 존

Assignees

  • 브리스톨-마이어스 스큅 컴퍼니

Dates

Publication Date
20260508
Application Date
20200722
Priority Date
20190723

Claims (10)

  1. Compound of chemical formula (I) or its salt: Here: X is CR 4 or N and; R 1 is: (i) -C(O)NHR 1a or -C(O)NH(CH 2 ) 1-3 R 1b or; or (ii) pyrazolil, imidazolyl, isoxazolil, or triazolil, each substituted with 0 or 1 R 1c ; R 1a is: (i) hydrogen, or a C3-6 alkyl substituted with 1 to 4 substituents independently selected from F, -CN, -OH, C1-2 alkoxy, C1-2 fluoroalkoxy, -NR yR y , -NR x C(O)( C1-3 alkyl), -C(O)NR yR y , -S(O) 2 ( C1-3 alkyl), and -NR x S(O) 2 ( C1-3 alkyl); or (ii) a cyclic group selected from C3-6 cycloalkyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, pyridinyl, imidazolyl, and triazolyl, wherein the cyclic group is -OH, -C(O)( C1-3 alkyl), -C(O)(C1-3 fluoroalkyl), -C(O)O( C1-3 alkyl), -OC(O)CH3, -NH2 , -NHC( O ) CH3 , -NHC(O) OCH3 , -S(O) 2 ( C1-3 alkyl), -S(O) 2 ( C1-3 fluoroalkyl), -C(O)( C3-6 cycloalkyl), -C(O)(morpholinyl), -CH2 (pyridinyl), -S (O) Substituted with 0 or 1 substituent selected from 2 (pyridinyl), morpholinyl, and triazolyl; R 1b is C 3-6 cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, deoxydothiomorpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, or pyridinyl, each of which is substituted with 0 to 3 substituents independently selected from F, -OH, -CH 3 , -CF 3 , and -CH 2 OH; R1c is a C1-6 alkyl substituted with 0 to 4 substituents independently selected from F, Cl, -OH, -CN, or F, -CN, -OH , C1-2 alkoxy, C3-6 cycloalkyl, -NR yR y, -NR x C(O)( C1-3 alkyl), -C(O)NR yR y , -S(O) 2 ( C1-3 alkyl), and -NR x S(O) 2 (C1-3 alkyl ); R 2 is: (i) a C 1-6 alkyl substituted with 0 to 4 substituents independently selected from F, Cl, -OH, and -CN; or (ii) a cyclic group selected from C3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, wherein the cyclic group is substituted with 0 to 3 substituents independently selected from F, -OH, -CN, C1-2 alkyl, C1-2 fluoroalkyl, and C1-2 hydroxyalkyl; R3 is R3a or -NHR3a and; R3a is pyrazolyl, thiazolyl, phenyl, pyridinyl, pyridinonyl, pyridazinyl, pyrrolo[2,3-b]pyridinyl, or imidazolo[1,2-a]pyridinyl, each of which is substituted with 0 to 1 substituent selected from F, Cl, -CN, C1-2 alkyl, C1-2 fluoroalkyl, C1-2 hydroxyalkyl, C1-2 alkoxy, -NR x R x , -S(O) 2 ( C1-3 alkyl), and pyrazolyl; Each R₄ is independently hydrogen, F, Cl, -CH₃ , or -CF₃ ; Each R x is independently hydrogen or -CH3 and; Each R y is independently hydrogen or C 1-4 alkyl.
  2. In paragraph 1, R 1a a: (i) hydrogen, or a C3-5 alkyl substituted with 1 to 4 substituents independently selected from F, -CN, -OH, C1-2 alkoxy, C1-2 fluoroalkoxy, and -S(O) 2 ( C1-2 alkyl); or (ii) a cyclic group selected from C3-6 cycloalkyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and pyridinyl, each of which is substituted with 0 or 1 substituent selected from -OH, -C(O)( C1-2 alkyl), -C(O)O( C1-3 alkyl), -OC(O) CH3 , -NH2 , -NHC(O) CH3 , -NHC(O) OCH3 , -S(O) 2 ( C1-2 alkyl), -S(O) 2 ( C1-3 fluoroalkyl), -C(O)( C3-6 cycloalkyl), -C(O)(morpholinyl), -CH2 (pyridinyl), -S(O) 2 (pyridinyl), morpholinyl, and triazolyl; R 1b is C 3-6 cycloalkyl, pyrrolidinyl, piperidinyl, deoxydothiomorpholinyl, triazolyl, or pyridinyl, each of which is substituted with 0 to 3 substituents independently selected from F, -OH, -CH 3 , and -CH 2 OH; R 1c is a C 1-6 alkyl substituted with 0 to 4 substituents independently selected from F, Cl, -OH, -CN, or F, -CN, -OH, C 1-2 alkoxy, C 3-6 cycloalkyl, -NR y R y , -NR x C(O)(C 1-2 alkyl), and -C(O)NR y R y ; R 2 a: (i) a C 1-4 alkyl group substituted with 0 to 2 substituents independently selected from F, -OH, and -CN; or (ii) a cyclic group selected from C3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, wherein the cyclic group is substituted with 0 to 2 substituents independently selected from F, -OH, -CN, C1-2 alkyl, C1-2 fluoroalkyl, and C1-2 hydroxyalkyl; R 3a is pyrazolyl, thiazolyl, phenyl, pyridinyl, pyridinonyl, pyridazinyl, pyrrolo[2,3-b]pyridinyl, or imidazolo[1,2-a]pyridinyl, each of which is substituted with 0 to 1 substituent selected from F, Cl, -CN, C1-2 alkyl, -CF3 , C1-2 hydroxyalkyl, C1-2 alkoxy, -NH2 , -S(O) 2 ( C1-2 alkyl), and pyrazolyl. Compound or its salt.
  3. In paragraph 1, R 1 is: (i) -C(O)NHR 1a or -C(O)NH(CH 2 ) 1-3 R 1b or; or ( ii ) a triazolyl substituted with -CH2CH2CH ( CH3 ) 2 , -CH2CH2CH2OH , -CH2CH2C ( CH3 ) 2OH , or -CH2 (cyclopropyl); R 1a a: (i) -CH 2 CH 2 CN, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH 2 CH(CH 3 )OH, -CH 2 CH 2 S(O) 2 CH 3 , -CH 2 CH 2 NHS(O) 2 CH 3 , -CH 2 CHFC(CH 3 ) 2 OH, or -CH 2 CH 2 CH 2 NHS(O) 2 CH 3 ; or (ii) cyclobutyl, cyclohexyl, or piperidinyl, each substituted with -OH, -NH₂ , -C(O) CH₃ , -OC(O) CH₃ , -NHC(O) CH₃ , or -NHC(O) OCH₃ ; R 1b is cyclopropyl, cyclobutyl, pyrrolidinyl, piperidinyl, deoxydothiomorpholinyl, triazolyl, or pyridinyl, each of which is substituted with 0 to 3 substituents independently selected from F, -OH, and -CH 2 OH; R2 is -CH2CH3 , -CH ( CH3 ) 2 , -CH( CH3 ) CH2OH , cyclopropyl, cyclopentyl, oxetanil, tetrahydropyranil, or difluoroethylpyrazolyl; R 3a is pyrazolyl, thiazolyl, phenyl, pyridinyl, pyridinonyl, pyridazinyl, pyrrolo[2,3-b]pyridinyl, or imidazolo[1,2-a]pyridinyl, each of which is substituted with 0 to 1 substituent selected from F, -CN , -CH3, -OCH3 , -NH2 , -S(O) 2CH3 , and pyrazolyl Compound or its salt.
  4. In claim 1, a compound having the structure of the following chemical formula (Ia) or a salt thereof: .
  5. In claim 1, a compound having the structure of the following chemical formula (Ib) or a salt thereof: .
  6. (R)-7-(cyclopropylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-2-phenylthiazolo[5,4-b]pyridine-6-carboxamide (1); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-7-(isopropylamino)-2-phenylthiazolo[5,4-b]pyridine-6-carboxamide (2); (R)-7-(cyclopentylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-2-phenylthiazolo[5,4-b]pyridine-6-carboxamide (3); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-2-phenyl-7-((tetrahydro-2H-pyran-4-yl)amino)thiazolo[5,4-b]pyridine-6-carboxamide (4); (R)-7-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-2-phenylthiazolo[5,4-b]pyridine-6-carboxamide (5); N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-7-(((R)-1-hydroxypropane-2-yl)amino)-2-phenylthiazolo[5,4-b]pyridine-6-carboxamide (6); (R)-N-(3-hydroxy-3-methylbutyl)-7-((1-hydroxypropane-2-yl)amino)-2-phenylthiazolo[5,4-b]pyridine-6-carboxamide (7); (R)-7-((1-hydroxypropane-2-yl)amino)-N-(3-morpholinopropyl)-2-phenylthiazolo[5,4-b]pyridine-6-carboxamide (8); (R)-N-(2-cyanoethyl)-7-((1-hydroxypropane-2-yl)amino)-2-phenylthiazolo[5,4-b]pyridine-6-carboxamide (9); (R)-7-((1-hydroxypropane-2-yl)amino)-N-(2-(methylsulfonyl)ethyl)-2-phenylthiazolo[5,4-b]pyridine-6-carboxamide (10); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-7-(isopropylamino)-2-(pyridine-3-yl)thiazolo[5,4-b]pyridine-6-carboxamide (11); N-(3-hydroxy-3-methylbutyl)-2-(pyridine-3-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)thiazolo[5,4-b]pyridine-6-carboxamide (12); N-(2-(4-hydroxypiperidin-1-yl)ethyl)-2-(pyridin-3-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)thiazolo[5,4-b]pyridin-6-carboxamide (13); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-2-(pyridin-3-yl)-7-((tetrahydro-2H-pyran-4-yl)amino)thiazolo[5,4-b]pyridin-6-carboxamide (14); (R)-2-((4-(1H-pyrazol-1-yl)phenyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-7-(isopropylamino)thiazolo[5,4-b]pyridin-6-carboxamide (15); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-7-(isopropylamino)-2-(pyridin-3-ylamino)thiazolo[5,4-b]pyridin-6-carboxamide (16); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-7-(isopropylamino)-2-((4-(methylsulfonyl)phenyl)amino)thiazolo[5,4-b]pyridin-6-carboxamide (17); 7-(isopropylamino)-2-(pyridin-3-yl)-N-(3,3,3-trifluoropropyl)thiazolo[5,4-b]pyridin-6-carboxamide (18); N-(2-cyclopropylethyl)-7-(isopropylamino)-2-(pyridin-3-yl)thiazolo[5,4-b]pyridin-6-carboxamide (19); (1r,4r)-4-(7-(isopropylamino)-2-(pyridin-3-yl)thiazolo[5,4-b]pyridin-6-carboxamido)cyclohexyl acetate (20); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridin-5-carboxamide (21); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(pyridin-3-yl)thieno[2,3-b]pyridin-5-carboxamide (22); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(pyridin-4-yl)thieno[2,3-b]pyridin-5-carboxamide (23); (R)-2-(3-cyanophenyl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)thieno[2,3-b]pyridin-5-carboxamide (24); (R)-2-(6-cyanopyridine-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)thieno[2,3-b]pyridine-5-carboxamide (25); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-2-(imidazo[1,2-a]pyridine-6-yl)-4-(isopropylamino)thieno[2,3-b]pyridine-5-carboxamide (26); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (27); (R)-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)thieno[2,3-b]pyridin-5-carboxamide (28); N-isopentyl-4-(isopropylamino)-2-(pyridin-4-yl)thieno[2,3-b]pyridin-5-carboxamide (29); N-isopentyl-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridin-5-carboxamide (30); N-isopentyl-4-(isopropylamino)-2-(pyridin-3-yl)thieno[2,3-b]pyridin-5-carboxamide (31); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(pyridazine-4-yl)thieno[2,3-b]pyridin-5-carboxamide (32); N-isopentyl-4-(isopropylamino)-2-(pyridazine-4-yl)thieno[2,3-b]pyridin-5-carboxamide (33); 4-(isopropylamino)-N-(2-methoxyethyl)-2-(thiazole-5-yl)thieno[2,3-b]pyridin-5-carboxamide (34); 4-(isopropylamino)-N-((3-methylisoxazole-5-yl)methyl)-2-(thiazole-5-yl)thieno[2,3-b]pyridin-5-carboxamide (35); N-((1r,4r)-4-hydroxycyclohexyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (36); N-(2-(1-(hydroxymethyl)cyclopropyl)ethyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (37); N-((1r,4r)-4-aminocyclohexyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (38); N-(1-cyclopropyl-3-hydroxypropyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (39); (R)-N-(4-hydroxybutane-2-yl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (40); 4-(isopropylamino)-N-(oxazole-4-ylmethyl)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (41); N-((1H-1,2,4-triazole-5-yl)methyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (42); N-(2-ethoxyethyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (43); N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (44); N-((1r,4r)-4-acetamicyclohexyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (45); N-(3-hydroxy-2,2-dimethylpropyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (46); N-((3-(hydroxymethyl)oxetane-3-yl)methyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (47); (R)-4-((1-(2,2-difluoroethyl)-1H-pyrazole-4-yl)amino)-N-(4-hydroxybutane-2-yl)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (48); 4-((1-(2,2-difluoroethyl)-1H-pyrazole-4-yl)amino)-N-((1s,4s)-4-hydroxycyclohexyl)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (49); methyl ((1r,4r)-4-(4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamido)cyclohexyl)carbamide (50); 4-((1-(2,2-difluoroethyl)-1H-pyrazole-4-yl)amino)-N-(2-methoxyethyl)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (51); (R)-4-((1-(2,2-difluoroethyl)-1H-pyrazole-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (52); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetane-3-ylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (53); N-((1s,4s)-4-hydroxycyclohexyl)-4-(oxetane-3-ylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (54); N-((1H-1,2,4-triazole-5-yl)methyl)-4-(oxetane-3-ylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (55); (R)-2-(2-aminothiazole-5-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)thieno[2,3-b]pyridine-5-carboxamide (56); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(2-methylthiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (57); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(2-methoxythiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (58); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(6-oxo-1,6-dihydropyridine-3-yl)thieno[2,3-b]pyridine-5-carboxamide (59); N-(3-hydroxybutyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (60); N-(3-hydroxycyclobutyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (61); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-2-(thiazole-4-yl)thieno[2,3-b]pyridine-5-carboxamide (62); N-(2-(3,3-difluoro-1-hydroxycyclobutyl)ethyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (63); (R)-2-(6-cyanopyridine-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)thieno[2,3-b]pyridine-5-carboxamide (64); (R)-2-(5-cyanopyridine-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)thieno[2,3-b]pyridine-5-carboxamide (65); N-(1-acetylpiperidine-4-yl)-4-(isopropylamino)-2-(6-oxo-1,6-dihydropyridine-3-yl)thieno[2,3-b]pyridine-5-carboxamide (66); 4-(isopropylamino)-N-(3-(methylsulfonamido)propyl)-2-(6-oxo-1,6-dihydropyridine-3-yl)thieno[2,3-b]pyridine-5-carboxamide (67); N-(2-(1,1-deoxydothiomorpholino)ethyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (68); N-((1,1-deoxydotetrahydrothiophene-3-yl)methyl)-4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridine-5-carboxamide (69); 4-(isopropylamino)-2-(6-oxo-1,6-dihydropyridine-3-yl)-N-(2-(pyrrolidin-3-yl)ethyl)thieno[2,3-b]pyridine-5-carboxamide (70); 4-(isopropylamino)-2-(6-oxo-1,6-dihydropyridine-3-yl)-N-(2-(pyridine-4-yl)ethyl)thieno[2,3-b]pyridine-5-carboxamide (71); 4-(isopropylamino)-2-(6-oxo-1,6-dihydropyridine-3-yl)-N-(2-(pyridine-3-yl)ethyl)thieno[2,3-b]pyridine-5-carboxamide (72); N-(2-(1,1-deoxydothiomorpholino)ethyl)-4-(isopropylamino)-2-(6-oxo-1,6-dihydropyridine-3-yl)thieno[2,3-b]pyridine-5-carboxamide (73); 4-(1-(4-(isopropylamino)-2-(pyridine-3-yl)thieno[2,3-b]pyridine-5-yl)-1H-1,2,3-triazole-4-yl)-2-methylbutan-2-ol (74); 4-(1-(4-(isopropylamino)-2-(pyridin-4-yl)thieno[2,3-b]pyridin-5-yl)-1H-1,2,3-triazole-4-yl)-2-methylbutan-2-ol (75); 5-(4-isopentyl-1H-1,2,3-triazole-1-yl)-N-isopropyl-2-(pyridin-4-yl)thieno[2,3-b]pyridin-4-amine (76); 5-(5-isopentyl-1H-1,2,4-triazole-3-yl)-N-isopropyl-2-(thiazole-5-yl)thieno[2,3-b]pyridin-4-amine (77); Compounds selected from 5-(1-(cyclopropylmethyl)-1H-1,2,3-triazole-4-yl)-N-isopropyl-2-(thiazole-5-yl)thieno[2,3-b]pyridin-4-amine (78); 3-(4-(4-(isopropylamino)-2-(thiazole-5-yl)thieno[2,3-b]pyridin-5-yl)-1H-1,2,3-triazole-1-yl)propan-1-ol (79); and 5-(5-(1-(3-hydroxypropyl)-1H-1,2,3-triazole-4-yl)-4-(isopropylamino)thieno[2,3-b]pyridin-2-yl)pyridin-2(1H)-one (80) or salts thereof.
  7. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or diluent for use in the treatment of inflammatory diseases, autoimmune diseases or cancer.
  8. A pharmaceutical composition according to claim 7, wherein the disease is selected from Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease, Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, cryopyrin-associated periodic syndrome, TNF receptor-associated periodic syndrome, familial Mediterranean fever, adult-onset Still's disease, systemic onset juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis.
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  10. delete

Description

Thienopyridinyl and thiazolopyridinyl compounds useful as IRAK4 inhibitors Cross-reference This application claims priority to U.S. provisional application serial number 62/877,334 filed on July 23, 2019, the entirety of which is incorporated herein. Technology field The present invention relates to thienopyridinyl and thiazolopyridinyl compounds that are generally useful as kinase inhibitors, including the modulation of IRAK-4. Thienopyridinyl and thiazolopyridinyl compounds, compositions comprising these compounds, and methods of using the same are provided herein. The present invention further relates to a pharmaceutical composition containing at least one compound according to the present invention that is useful for treating conditions associated with kinase modulation, and a method for inhibiting the activity of kinases, including IRAK-4, in mammals. Members of the Toll/IL-1 receptor family are important regulators of inflammation and host resistance. The Toll-like receptor (TLR) family recognizes molecular patterns derived from infectious organisms, including bacteria, fungi, parasites, and viruses (reviewed in [Kawai, T. et al., Nature Immunol., 11:373-384 (2010)]). Ligand binding to the receptor induces dimerization and the recruitment of adapter molecules to conserved cytoplasmic motifs within the receptor, referred to as the Toll/IL-1 receptor (TIR) domain. With the exception of TLR3, all TLRs recruit the adapter molecule MyD88. The IL-1 receptor family also contains cytoplasmic TIR motifs and recruits MyD88 upon ligand binding (reviewed in [Sims, J.E. et al., Nature Rev. Immunol., 10:89-102 (2010)]). Members of the IRAK family of serine/threonine kinases are recruited to receptors through interactions with MyD88. The family consists of four members. Some evidence indicates that IRAK4 plays a critical and non-redundant role in initiating signaling via MyD88-dependent TLRs and members of the IL-1R family. Structural data confirmed that IRAK4 directly interacts with MyD88 and subsequently recruits IRAK1 or IRAK2 to the receptor complex, thereby facilitating downstream signaling (Lin, S. et al., Nature, 465:885-890 (2010)). IRAK4 directly phosphorylates IRAK1, facilitating downstream signaling to the E3 ubiquitin ligase TRAF6, which induces the activation of the serine/threonine kinase TAK1 and subsequent activation of the NFκB pathway and the MAPK cascade (Flannery, S. et al., Biochem. Pharmacol., 80:1981-1991 (2010)). A subset of human patients lacking IRAK4 expression has been identified (Picard, C. et al., Science, 299:2076-2079 (2003)). Cells from these patients do not respond to all TLR agonists except TLR3, as well as members of the IL-1 family, including IL-1β and IL-18 (Ku, C. et al., J. Exp. Med., 204:2407-2422 (2007)). Deletion of IRAK4 in mice results in severe blockade of all TLR-dependent responses except IL-1, IL-18, and TLR3 (Suzuki, N. et al., Nature, 416:750-754 (2002)). In contrast, deletion of IRAK1 (Thomas, J.A. et al., J. Immunol., 163:978-984 (1999); Swantek, J.L. et al., J. Immunol., 164:4301-4306 (2000)) or IRAK2 (Wan, Y. et al., J. Biol. Chem., 284:10367-10375 (2009)) results in partial loss of signal transduction. Furthermore, IRAK4 is the only member of the IRAK family whose kinase activity is considered necessary for the initiation of signal transduction. Substitution of wild-type IRAK4 with a kinase-inactive mutant (KDKI) in the mouse genome impairs signaling through all MyD88-dependent receptors, including all TLRs except IL-1, IL-18, and TLR3 (Koziczak-Holbro, M. et al., J. Biol. Chem., 282:13552-13560 (2007); Kawagoe, T. et al., J. Exp. Med., 204:1013-1024 (2007); and Fraczek, J. et al., J. Biol. Chem., 283:31697-31705 (2008)). Compared to wild-type animals, IRAK4 KDKI mice were very [unclear] in mouse models of multiple sclerosis (Staschke, K.A. et al., J. Immunol., 183:568-577 (2009)), rheumatoid arthritis (Koziczak-Holbro, M. et al., Arthritis Rheum., 60:1661-1671 (2009)), atherosclerosis (Kim, T.W. et al., J. Immunol., 186:2871-2880 (2011) and Rekhter, M. et al., Biochem. Biophys. Res. Comm., 367:642-648 (2008)), and myocardial infarction (Maekawa, Y. et al., Circulation, 120:1401-1414 (2009)). It indicates reduced disease severity. As described, IRAK4 inhibitors will block all MyD88-dependent signaling. MyD88-dependent TLRs are known to contribute to the pathogenesis of multiple sclerosis, rheumatoid arthritis, cardiovascular disease, metabolic syndrome, sepsis, systemic lupus erythematosus, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, autoimmune uveitis, asthma, allergies, type I diabetes, and allograft rejection (Keogh, B. et al., Trends Pharmacol. Sci., 32:435-442 (2011); Mann, D.L., Circ. Res., 108:1133-1145 (2011); Horton, C.G. et al., Mediators Inflamm., Article ID 498980 (2010), doi:10.1155/2010/498980; Goldstein, D.R. et al., J. Heart Lung Transplant., 24:1721-1729 (2005); and Cario, E., Inflamm. Bowel Dis., 16:1583-1597 (2