US 12,492,186 B2Granted

Bicyclic heterocyclic compounds useful as IRAK4 inhibitors

AssigneeBristol-Myers Squibb Company

InventorsSaleem Ahmad, Kandhasamy Sarkunam, Ling Li, Lidet A. Negash, John Hynes

Life of this patent

Estimating the term…

Abstract

Disclosed are compounds of Formula (I) or a salt or prodrug thereof, wherein: X is CR4a or N; Y is CR4b or N; Z is CR4d or N; provided that zero or 1 of X, Y, and Z is N; and R1, R2, R3, R4a, R4b, R4c, and R4d are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.

Claims6

Dependent claims

A compound of Formula (I)

or a salt or prodrug thereof, wherein:
X is CR4a;
Y is CR4b or N;
Z is CR4a or N;
provided that zero or 1 of Y and Z is N;
R1 is:
(i) —C(O)NHR1a;
or
(ii) pyrazolyl, imidazolyl, isoxazolyl, or triazolyl, each substituted with zero or 1 R1b;
R1a is:
(i) hydrogen or C3-6 alkyl substituted with 1 to 4 substituents independently selected from F, —CN, —OH, C1-2 alkoxy, C1-2 fluoroalkoxy, —NRaRa, —NRaC(O)(C1-3 alkyl), —C(O)NRaRa, —S(O)2(C1-3 alkyl), and —NRaS(O)2(C1-3 alkyl);
(ii) —(CRyRy)0-3Rx, —(CRaRa)1-2C(O)Rx, or —CRy(CH2CH2OH)Rx;
or
(iii) a cyclic group selected from C3-6 cycloalkyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, pyridinyl, imidazolyl, and triazolyl, each substituted with zero or one substituent selected from —OH, —C(O)(C1-3 alkyl), —C(O)(C1-3 fluoroalkyl), —C(O)O(C1-3 alkyl), —NRaRa, —NRaC(O)(C1-3 alkyl), —NRaC(O)O(C1-3 alkyl), —S(O)2(C1-3 alkyl), —S(O)2(C1-3 fluoroalkyl), —C(O)(C3-6 cycloalkyl), —C(O)(morpholinyl), —CH2(pyridinyl), —S(O)2(pyridinyl), morpholinyl, and triazolyl;
R1b is:
(i) F, Cl, —OH, —CN, or C1-6 alkyl substituted with zero to 4 substituents independently selected from F, —CN, —OH, C1-2 alkoxy, C3-6 cycloalkyl, —NRaRa, —NRaC(O)(C1-3 alkyl), —C(O)NRaRa, —S(O)2(C1-3 alkyl), and —NRaS(O)2(C1-3 alkyl);
or
(ii) C3-6 cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidinonyl, morpholinyl, pyrrolidinyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, or pyrimidinyl, each substituted with zero to 4 substituents independently selected F, —CN, —OH, —NRyRy, C1-3 alkyl, C1-3 fluoroalkyl, —CH(phenyl)2, —O(C1-3 alkyl), —C(O)(C1-3 alkyl), —C(O)(C1-3 deuteroalkyl), —C(O)(C3-6 cycloalkyl), —C(O)O(C1-4 alkyl), —C(O)NRyRy, —C(O)(phenyl), —C(O)(pyridinyl), —C(O)CH2(C3-6 cycloalkyl), —NHC(O)CH3, —NHC(O)OCH3, —NHC(O)OC(CH3)3, —S(O)2(C1-3 alkyl), and —OS(O)2(C1-3 alkyl);
Rx is C3-6 cycloalkyl, oxetanyl, isoxazolyl, oxazolyl, imidazolyl, morpholinyl, oxadiazolyl, piperidinonyl, dioxidotetrahydrothiophenyl, dioxidotetrahydrothiopyranyl, dioxoimidazolidinyl, dioxidothiomorpholinyl, pyrrolidinyl, tetrazolyl, triazolyl, thiazolyl, triazolyl, pyridinyl, or phenyl, each substituted with zero to 3 substituents independently selected from F, —OH, —CH3, —CH2OH, —NH2, —C(O)CH3, and —C(O)(cyclopropyl);
each Ry is independently hydrogen or —CH3;
each Ra is independently hydrogen or C1-4 alkyl;
R2 is —CH3, —CH2CH3, —CH(CH2)2, —CH2CHF2, —CH2CH(CH3)OH, —CH2CH2C(CH3)2OH,
R3 is phenyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridinonyl, or pyrimidinyl, each substituted with zero to 3 substituents selected from F, Cl, —OH, —CN, C1-2 alkyl, —CF3, and —CH2OH;
and
each of R4a, R4b, R4c, and R4d is independently hydrogen or —CH3.

22 more elements

A compound or a salt thereof, wherein said compound is:

(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (1);
(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(pyridin-4-yl) quinoline-3-carboxamide (2);
(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(pyridin-3-yl) quinoline-3-carboxamide (3);
(R)-6-(5-cyanopyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino) quinoline-3-carboxamide (4);
(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(pyrimidin-5-yl) quinoline-3-carboxamide (5);
(R)-6-(3-cyanophenyl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino) quinoline-3-carboxamide (6);
(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(thiazol-5-yl) quinoline-3-carboxamide (7);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(tetrahydro-2H-pyran-3-yl) quinoline-3-carboxamide (8);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl) quinoline-3-carboxamide (9);
N-(2-ethoxyethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (10);
N-((1R,4R)-4-hydroxycyclohexyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (11);
N-(1-cyclopropyl-3-hydroxypropyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (12);
(R)—N-(4-hydroxybutan-2-yl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (13);
4-(isopropylamino)-N-(oxazol-5-ylmethyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (14);
N-isopentyl-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (15);
4-(isopropylamino)-N-((3-methylisoxazol-5-yl)methyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (16);
N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (17);
4-(isopropylamino)-N-(2-methoxyethyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (18);
N-(3-hydroxy-2,2-dimethylpropyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (19);
N-((3-(hydroxymethyl) oxetan-3-yl)methyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (20);
N-((1-(hydroxymethyl)cyclopropyl)methyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (21);
N-((4H-1,2,4-triazol-3-yl)methyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (22);
N-((1R,4R)-4-aminocyclohexyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (23);
N-((1R,4R)-4-acetamidocyclohexyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (24);
methyl ((1r,4r)-4-(4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamido)cyclohexyl) carbamate (25);
methyl ((1S,3S)-3-(4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamido) cyclopentyl) carbamate (26);
(R)-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (27);
(R)-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(thiazol-5-yl) quinoline-3-carboxamide (28);
4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (29);
N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-hydroxypropyl)amino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (30);
(R)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(thiazol-5-yl) quinoline-3-carboxamide (31);
N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((2-hydroxypropyl)amino)-6-(thiazol-5-yl) quinoline-3-carboxamide (32);
(R)-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (33);
(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (34);
(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)-6-(thiazol-5-yl) quinoline-3-carboxamide (35);
N-(3-hydroxybutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (36);
4-(ethylamino)-N-(3-hydroxy-3-methylbutyl)-6-(thiazol-5-yl) quinoline-3-carboxamide (37);
4-(ethylamino)-N-(3-hydroxy-3-methylbutyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (38);
N-((1s,3s)-3-hydroxycyclobutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (39);
N-(3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (40);
N-(3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)-6-(thiazol-5-yl) quinoline-3-carboxamide (41);
N-(2-(3,3-difluoro-1-hydroxycyclobutyl)ethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (42);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(3,3,3-trifluoropropyl) quinoline-3-carboxamide (43);
4-(isopropylamino)-N-(2-morpholinoethyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (44);
N-(3,3-difluoropropyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (45);
N-((1R,3R)-3-acetamidocyclobutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (46);
methyl ((1R,3R)-3-(4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamido) cyclobutyl) carbamate (47);
4-(isopropylamino)-N-(3-(methylamino)-3-oxopropyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (48);
N-(3-(dimethylamino)-3-oxopropyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (49);
4-(isopropylamino)-N-(3-oxo-3-(pyrrolidin-1-yl) propyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (50);
N-(2-cyclopropylethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (51);
4-((3,3-difluorocyclobutyl)amino)-N-(3-hydroxy-3-methylbutyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (52);
4-((3,3-difluorocyclobutyl)amino)-N-(3-hydroxybutyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (53-54);
4-((3,3-difluorocyclobutyl)amino)-6-(1H-pyrazol-4-yl)-N-(3,3,3-trifluoropropyl) quinoline-3-carboxamide (55);
N-(2-cyclopropylethyl)-4-((3,3-difluorocyclobutyl)amino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (56);
N-((1R,3R)-3-acetamidocyclobutyl)-4-((3,3-difluorocyclobutyl)amino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (57);
methyl ((1R,3R)-3-(4-((3,3-difluorocyclobutyl)amino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamido)cyclobutyl) carbamate (58);
N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-methyl-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (59);
N-((1R,3R)-3-hydroxycyclobutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (60);
N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-methyl-6-(thiazol-5-yl) quinoline-3-carboxamide (61);
4-((2,2-difluoroethyl)amino)-N-(3-hydroxy-3-methylbutyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (62);
4-((2,2-difluoroethyl)amino)-N-(2-morpholinoethyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (63);
4-((2,2-difluoroethyl)amino)-N-(3-hydroxybutyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (64-65);
4-((2,2-difluoroethyl)amino)-N-(3-(methylamino)-3-oxopropyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (66);
4-((2,2-difluoroethyl)amino)-N-(3,3-difluoropropyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (67);
4-((2,2-difluoroethyl)amino)-6-(1H-pyrazol-4-yl)-N-(3,3,3-trifluoropropyl) quinoline-3-carboxamide (68);
6-(6-cyanopyridin-3-yl)-N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino) quinoline-3-carboxamide (69);
6-(6-fluoropyridin-3-yl)-N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino) quinoline-3-carboxamide (70);
6-(6-fluoro-5-methylpyridin-3-yl)-N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino) quinoline-3-carboxamide (71);
6-(5-fluoropyridin-3-yl)-N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino) quinoline-3-carboxamide (72);
6-(2,6-difluoropyridin-3-yl)-N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino) quinoline-3-carboxamide (73);
N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(6-oxo-1,6-dihydropyridin-3-yl) quinoline-3-carboxamide (74);
N-(2-cyclopropylethyl)-4-((2,2-difluoroethyl)amino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (75);
N-(1-(4-fluorobenzyl) piperidin-4-yl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (76);
N-(1-acetylpiperidin-4-yl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (77);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(1-(pyridin-4-ylmethyl) piperidin-4-yl) quinoline-3-carboxamide (78);
4-(isopropylamino)-N-(1-(methylsulfonyl) piperidin-4-yl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (79);
ethyl 4-(4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamido) piperidine-1-carboxylate (80);
N-(1-(cyclopropanecarbonyl) piperidin-4-yl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (81);
4-(isopropylamino)-N-(1-(morpholine-4-carbonyl) piperidin-4-yl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (82);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(1-(3,3,3-trifluoropropanoyl) piperidin-4-yl) quinoline-3-carboxamide (83);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(1-(pyridin-3-ylsulfonyl) piperidin-4-yl) quinoline-3-carboxamide (84);
N-(2-(1-acetylpyrrolidin-2-yl)ethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (85);
4-(isopropylamino)-N-(2-(2-oxopiperidin-1-yl)ethyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (86);
N-((1,1-dioxidotetrahydrothiophen-3-yl)methyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (87);
4-(isopropylamino)-N-(2-(methylsulfonyl)ethyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (88);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(1-((3,3,3-trifluoropropyl) sulfonyl) piperidin-4-yl) quinoline-3-carboxamide (89);
4-(isopropylamino)-N-(2-morpholino-2-oxoethyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (90);
4-(isopropylamino)-N-(2-methyl-1-morpholino-1-oxopropan-2-yl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (91);
4-(isopropylamino)-N-(1-(methylsulfonyl) azetidin-3-yl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (92);
N-(2-(1-(cyclopropanecarbonyl) pyrrolidin-2-yl)ethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (93);
N-(2-(1,1-dioxidothiomorpholino)ethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (94);
4-(isopropylamino)-N-(3-(methylsulfonamido) propyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (95);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(2-(pyrrolidin-2-yl)ethyl) quinoline-3-carboxamide (96);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(2-(pyrrolidin-3-yl)ethyl) quinoline-3-carboxamide (97);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(2-(pyridin-3-yl)ethyl) quinoline-3-carboxamide (98);
4-((3-hydroxy-3-methylbutyl)amino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (99);
4-(isopropylamino)-N-(6-morpholinopyridin-3-yl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (100);
N-((1R,4R)-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (101);
N-(2-(1H-imidazol-4-yl)ethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (102);
N-(3-(1H-imidazol-1-yl) propyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (103);
N-(2-(1H-1,2,4-triazol-5-yl)ethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (104);
4-(isopropylamino)-N-((4-methyl-2,5-dioxoimidazolidin-4-yl)methyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (105);
N-(2-(1,2,4-oxadiazol-5-yl)ethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (106);
N-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (107);
4-(methylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (108);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(2-(pyridin-4-yl)ethyl) quinoline-3-carboxamide (109);
N-(2-(1H-tetrazol-5-yl)ethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (110);
4-(methylamino)-6-(thiazol-5-yl) quinoline-3-carboxamide (111);
N-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (112);
N-(3-(2-aminothiazol-4-yl) propyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (113);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(3-(pyridin-4-yl) propyl) quinoline-3-carboxamide (114);
4-(cyclopropylamino)-6-(1H-pyrazol-4-yl)-N-(2-(pyridin-3-yl)ethyl) quinoline-3-carboxamide (115);
4-(cyclopropylamino)-N-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (116);
4-(cyclopropylamino)-N-(2-(1,1-dioxidothiomorpholino)ethyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (117);
4-(cyclopropylamino)-6-(1H-pyrazol-4-yl)-N-(3-(pyridin-4-yl) propyl) quinoline-3-carboxamide (118);
N-(2-(1,1-dioxidothiomorpholino)ethyl)-4-((1-methylcyclopropyl)amino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (119);
4-(cyclopropylamino)-N-(2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (120);
(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-methylcyclopropyl)amino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (121);
4-((1-methylcyclopropyl)amino)-6-(1H-pyrazol-4-yl)-N-(2-(pyridin-3-yl)ethyl) quinoline-3-carboxamide (122);
N-((1,1-dioxidotetrahydrothiophen-3-yl)methyl)-4-((1-methylcyclopropyl)amino)-6-(1H-pyrazol-4-yl) quinoline-3-carboxamide (123);
3-(5-isobutyl-1H-1,2,4-triazol-3-yl)-N-isopropyl-6-(1H-pyrazol-4-yl) quinolin-4-amine (124);
N-isopropyl-3-(5-propyl-1H-1,2,4-triazol-3-yl)-6-(1H-pyrazol-4-yl) quinolin-4-amine (125);
3-(5-isopentyl-1H-1,2,4-triazol-3-yl)-N-isopropyl-6-(1H-pyrazol-4-yl) quinolin-4-amine (126);
1-(4-(5-(4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinolin-3-yl) isoxazol-3-yl) piperidin-1-yl) ethan-1-one (127);
N-isopropyl-3-(3-(piperidin-2-yl) isoxazol-5-yl)-6-(1H-pyrazol-4-yl) quinolin-4-amine (128);
3-(1-isopentyl-1H-1,2,3-triazol-4-yl)-N-isopropyl-6-(1H-pyrazol-4-yl) quinolin-4-amine (129);
3-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-N-isopropyl-6-(1H-pyrazol-4-yl) quinolin-4-amine (130);
3-(4-(4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinolin-3-yl)-1H-1,2,3-triazol-1-yl) propan-1-ol (131);
1-(3-(4-(4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinolin-3-yl)-1H-1,2,3-triazol-1-yl) azetidin-1-yl) ethan-1-one (132);
N-isopropyl-3-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-6-(1H-pyrazol-4-yl) quinolin-4-amine (133);
3-(1-(1-(2,2-difluoroethyl) azetidin-3-yl)-1H-1,2,3-triazol-4-yl)-N-isopropyl-6-(1H-pyrazol-4-yl) quinolin-4-amine (134);
1-(4-(4-(4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinolin-3-yl)-1H-1,2,3-triazol-1-yl) piperidin-1-yl) ethan-1-one (135);
3-(4-(4-(isopropylamino)-6-(1H-pyrazol-4-yl) quinolin-3-yl)-1H-1,2,3-triazol-1-yl)-1-methylpyrrolidin-2-one (136);
N-isopropyl-3-(1-(2-(methylsulfonyl)ethyl)-1H-1,2,3-triazol-4-yl)-6-(1H-pyrazol-4-yl) quinolin-4-amine (137);
N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxamide (138);
N-isopentyl-4-(isopropylamino)-6-(1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxamide (139);
N-(3-hydroxybutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxamide (140);
(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxamide (141);
4-(isopropylamino)-6-(1H-pyrazol-4-yl)-N-(3,3,3-trifluoropropyl)-1,5-naphthyridine-3-carboxamide (142);
N-((1R,3R)-3-hydroxycyclobutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxamide (143);
4-(isopropylamino)-N-(2-morpholinoethyl)-6-(1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxamide (144);
N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(pyridin-4-yl)-1,5-naphthyridine-3-carboxamide (145);
N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(pyridin-3-yl)-1,5-naphthyridine-3-carboxamide (146);
N-(2-cyclopropylethyl)-6-((5-fluoropyridin-3-yl)amino)-4-(isopropylamino)-1,5-naphthyridine-3-carboxamide (147);
N-(2-cyclopropylethyl)-4-(isopropylamino)-6-(thiazol-5-yl)-1,5-naphthyridine-3-carboxamide (148);
N-(2-cyclopropylethyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxamide (149);
N-(3-amino-3-methylbutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxamide (150);
6-(5-cyanopyridin-3-yl)-N-(2-cyclopropylethyl)-4-(isopropylamino)-1,5-naphthyridine-3-carboxamide (151);
N-((1R,4R)-4-acetamidocyclohexyl)-6-(2-cyanopyridin-4-yl)-4-(isopropylamino)-1,5-naphthyridine-3-carboxamide (152);
N-((1R,4R)-4-acetamidocyclohexyl)-4-(isopropylamino)-6-(pyridin-3-yl)-1,5-naphthyridine-3-carboxamide (153);
N-((1R,4R)-4-acetamidocyclohexyl)-6-(5-cyanopyridin-3-yl)-4-(isopropylamino)-1,5-naphthyridine-3-carboxamide (154);
N-((1R,4R)-4-acetamidocyclohexyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxamide (155);
N-((1R,4R)-4-acetamidocyclohexyl)-4-(isopropylamino)-6-(thiazol-5-yl)-1,5-naphthyridine-3-carboxamide (156);
6-(2-cyanopyridin-4-yl)-N-(2-cyclopropylethyl)-4-(isopropylamino)-1,5-naphthyridine-3-carboxamide (157);
or
(R)—N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-6-(1H-pyrazol-4-yl)-1,8-naphthyridine-3-carboxamide (161).

154 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/632,811Filed 5 Aug 2020 · us provisional application
Priority: 6 Aug 2019
Published: US 2022/0281844 A18 Sep 2022
Granted: 9 Dec 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
C07D 213/04
Having three double bonds between ring members or between ring members and non-ring members: having no bond between the ring nitrogen atom and a…
C07D 213/22
Containing only hydrogen and carbon atoms in addition to the ring nitrogen atom: containing two or more pyridine rings directly linked together,…
C07D 213/38
Radicals substituted by singly-bound nitrogen atoms: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom

Family

Application62/883,264Us provisional application · filed 6 Aug 2019
US 2022/0281844 A1Pre-grant publication · published 8 Sep 2022
US 12,492,186 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of Formula (I)

or a salt or prodrug thereof, wherein:
X is CR4a;
Y is CR4b or N;
Z is CR4a or N;
provided that zero or 1 of Y and Z is N;
R1 is:
(i) —C(O)NHR1a;
or
(ii) pyrazolyl, imidazolyl, isoxazolyl, or triazolyl, each substituted with zero or 1 R1b;
R1a is:
(i) hydrogen or C3-6 alkyl substituted with 1 to 4 substituents independently selected from F, —CN, —OH, C1-2 alkoxy, C1-2 fluoroalkoxy, —NRaRa, —NRaC(O)(C1-3 alkyl), —C(O)NRaRa, —S(O)2(C1-3 alkyl), and —NRaS(O)2(C1-3 alkyl);
(ii) —(CRyRy)0-3Rx, —(CRaRa)1-2C(O)Rx, or —CRy(CH2CH2OH)Rx;
or
(iii) a cyclic group selected from C3-6 cycloalkyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrazolyl, pyridinyl, imidazolyl, and triazolyl, each substituted with zero or one substituent selected from —OH, —C(O)(C1-3 alkyl), —C(O)(C1-3 fluoroalkyl), —C(O)O(C1-3 alkyl), —NRaRa, —NRaC(O)(C1-3 alkyl), —NRaC(O)O(C1-3 alkyl), —S(O)2(C1-3 alkyl), —S(O)2(C1-3 fluoroalkyl), —C(O)(C3-6 cycloalkyl), —C(O)(morpholinyl), —CH2(pyridinyl), —S(O)2(pyridinyl), morpholinyl, and triazolyl;
R1b is:
(i) F, Cl, —OH, —CN, or C1-6 alkyl substituted with zero to 4 substituents independently selected from F, —CN, —OH, C1-2 alkoxy, C3-6 cycloalkyl, —NRaRa, —NRaC(O)(C1-3 alkyl), —C(O)NRaRa, —S(O)2(C1-3 alkyl), and —NRaS(O)2(C1-3 alkyl);
or
(ii) C3-6 cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidinonyl, morpholinyl, pyrrolidinyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, or pyrimidinyl, each substituted with zero to 4 substituents independently selected F, —CN, —OH, —NRyRy, C1-3 alkyl, C1-3 fluoroalkyl, —CH(phenyl)2, —O(C1-3 alkyl), —C(O)(C1-3 alkyl), —C(O)(C1-3 deuteroalkyl), —C(O)(C3-6 cycloalkyl), —C(O)O(C1-4 alkyl), —C(O)NRyRy, —C(O)(phenyl), —C(O)(pyridinyl), —C(O)CH2(C3-6 cycloalkyl), —NHC(O)CH3, —NHC(O)OCH3, —NHC(O)OC(CH3)3, —S(O)2(C1-3 alkyl), and —OS(O)2(C1-3 alkyl);
Rx is C3-6 cycloalkyl, oxetanyl, isoxazolyl, oxazolyl, imidazolyl, morpholinyl, oxadiazolyl, piperidinonyl, dioxidotetrahydrothiophenyl, dioxidotetrahydrothiopyranyl, dioxoimidazolidinyl, dioxidothiomorpholinyl, pyrrolidinyl, tetrazolyl, triazolyl, thiazolyl, triazolyl, pyridinyl, or phenyl, each substituted with zero to 3 substituents independently selected from F, —OH, —CH3, —CH2OH, —NH2, —C(O)CH3, and —C(O)(cyclopropyl);
each Ry is independently hydrogen or —CH3;
each Ra is independently hydrogen or C1-4 alkyl;
R2 is —CH3, —CH2CH3, —CH(CH2)2, —CH2CHF2, —CH2CH(CH3)OH, —CH2CH2C(CH3)2OH,
R3 is phenyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridinonyl, or pyrimidinyl, each substituted with zero to 3 substituents selected from F, Cl, —OH, —CN, C1-2 alkyl, —CF3, and —CH2OH;
and
each of R4a, R4b, R4c, and R4d is independently hydrogen or —CH3.

22 more elements

Facts

Application

17/632,811Filed 5 Aug 2020 · us provisional application

Priority

6 Aug 2019

Published

US 2022/0281844 A18 Sep 2022

Granted

9 Dec 2025

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
C07D 213/04
Having three double bonds between ring members or between ring members and non-ring members: having no bond between the ring nitrogen atom and a…
C07D 213/22
Containing only hydrogen and carbon atoms in addition to the ring nitrogen atom: containing two or more pyridine rings directly linked together,…
C07D 213/38
Radicals substituted by singly-bound nitrogen atoms: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom