Back to results
US 2023/0416256 A1Published application
SMALL MOLECULE INHIBITORS OF NF-kB INDUCING KINASE
AssigneeJanssen Pharamceutica NV
InventorsWilliam M. Jones, Alec D. Lebsack, Ronald L. Wolin, Alexander R. Rovira
Life of this patent
Estimating the term…
Abstract
This invention relates to compounds of Formula I that inhibit NIK and pharmaceutical compositions comprising such compounds and methods of using the same. These compounds and pharmaceutical compositions are useful for preventing or treating diseases such as cancer (such as B-cell malignancies including leukemias, lymphomas and myeloma), inflammatory disorders, autoimmune disorders, immunodermatologic disorders such as palmoplantar pustulosis and hidradenitis suppurativa, and metabolic disorders such as obesity and diabetes.
Claims31
A compound of Formula I or a pharmaceutically acceptable salt thereof,
- wherein
- C1 is —C(OH)—,
- R1 is C1-C3 alkyl;
- R2 is a 5 or 6 membered substituted or unsubstituted heteroaryl;
- or R1 and R2 can be taken together with the carbon atom to which they are attached to form a substituted or unsubstituted heterocycle;
- R3a, R3b and R3c are independently H or C1-C3 alkyl;
- is a substituted or unsubstituted heteroaryl,
- X, Y and Z are independently selected from O, S, N, N—R4 or C—R5;
- W is N or C;
- R4 is H or —C1-C3 alkyl;
- and
- R5 is H, halo, CN, —C1-C3 alkyl or CH2OH;
- Het C is selected from the group consisting of
- R6a, R6b, R6c is independently H, halo, —C1-C3 alkyl, —C1-C3 haloalkyl, —CN, —CO2H, —OC1-C3 alkyl, —SO2CH3 or —NH2;
- R7 is H, D, halo or —C1-C3 alkyl;
- R8a, R8b, and R8c is independently H, D, halo or —C1-C3 alkyl;
- R9, R10a and R10b is independently H or NH2;
- T is N or C—R8c;
- and
- U is N or CH.
17 more elements
(canceled)
(canceled)
(canceled)
(canceled)
11-12. (canceled)
17-19. (canceled)
21-23. (canceled)
(canceled)
A compound selected from
- (S)-7-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;
- (R)-7-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;
- (R)-3-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-5-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (R)-7-(3-(2-(7H-Pyrrolo[2,3-d]pyrimidin-5-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;
- (S)-7-(3-(2-(7H-Pyrrolo[2,3-d]pyrimidin-5-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;
- (R)-3-Hydroxy-1-methyl-3-(3-(2-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)pyrrolidin-2-one;
- (R)-3-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (R)-7-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(4-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (S)-7-(3-(4-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-7H-pyrrolo[1,2-a]imidazol-7-ol;
- (S)-7-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-7H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-3-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-2,3-dihydrofuro[3,2-b]pyridin-3-ol;
- (R)-3-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-2,3-dihydrofuro[3,2-b]pyridin-3-ol;
- (S)-7-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl-2-ci)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(2-(7H-Pyrrolo[2,3-d]pyrimidin-5-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (S)-7-(3-(2-(7H-Pyrrolo[2,3-d]pyrimidin-5-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;
- (S)-7-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;
- (R)-7-(3-(2-(5-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(2-(5-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-3-(4-(3-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-yl)phenyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile;
- (R)-7-(3-(2-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(2-(5-(Methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(2-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(5-(1H-Pyrrolo[2,3-b]pyridin-3-yl)furan-3-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (S)-4-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-5,6-dihydro-4H-cyclopenta[d]thiazol-4-ol;
- (R)-4-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-5,6-dihydro-4H-cyclopenta[d]thiazol-4-ol;
- (R)-7-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-7H-cyclopenta[b]pyridin-7-ol;
- (R)-7-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol.
- (S)-8-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-ol;
- (R)-8-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-ol;
- (R)-3-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (R)-7-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (S)-7-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-3-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-(2,2,2-trifluoroethyl)pyrrolidin-2-one;
- (R)-3-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylazetidin-2-one;
- (R)-3-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (S)-3-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (R)-3-Hydroxy-3-(3-(2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-1-methylpyrrolidin-2-one;
- (R)-3-Hydroxy-3-(3-(5-(hydroxymethyl)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-1-methylpyrrolidin-2-one;
- (R)-3-(4-(3-(3-Hydroxy-1-methyl-2-oxopyrrolidin-3-yl)phenyl)thiazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid;
- (S)-3-(3-(2-(7H-Pyrrolo[2,3-d]pyrimidin-5-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (R)-3-(3-(2-(7H-Pyrrolo[2,3-d]pyrimidin-5-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (R)-3-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylpiperidin-2-one;
- (R)-3-(3-(4-(2-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (R)-3-(3-(2-(2-Fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (S)-4-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)phenyl)-5,6-dihydro-4H-cyclopenta[d]thiazol-4-ol;
- (R)-4-(3-(4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl)phenyl)-5,6-dihydro-4H-cyclopenta[d]thiazol-4-ol;
- (R)-1-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-1-(pyridin-2-yl)ethan-1-ol;
- (R)-7-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl-6-d)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl-2-d)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- and pharmaceutically acceptable salts thereof.
51 more elements
A compound as claimed in claim 0, wherein said compound is selected from
- (R)-4-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-5,6-dihydro-4H-cyclopenta[d]thiazol-4-ol;
- (R)-3-(3-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-5-yl)phenyl)-3-hydroxy-1-methylpyrrolidin-2-one;
- (R)-3-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-2,3-dihydrofuro[3,2-b]pyridin-3-ol;
- (R)-7-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-7-(3-(4-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-2-yl)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-7-ol;
- (S)-7-(3-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol;
- (S)-7-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-7H-pyrrolo[1,2-a]imidazol-7-ol;
- (R)-3-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-methylazetidin-2-one;
- (R)-3-(3-(2-(5H-Pyrrolo[2,3-b]pyrazin-7-yl)thiazol-4-yl)phenyl)-3-hydroxy-1-Methylpiperidin-2-one;
- and pharmaceutically acceptable salts thereof.
7 more elements
28-38. (canceled)
(canceled)
A method as claimed in claim 0 wherein the disease, disorder or medical condition is selected from the group consisting of cancer, inflammatory disorders, autoimmune disorders, immunodermatologic disorders and metabolic disorders.
A method as claimed in claim 0 wherein the disease, disorder or medical condition is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Graft-Versus-Host Disease, transplant rejection, Sjogren's Syndrome, pemphigus vulgaris, palmoplantar pustulosis, hidradenitis suppurativa, obesity and diabetes.
46-48. (canceled)
Dependencies are inferred from the claim text.