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US 2020/0048262 A1Published application
Pyrrolopyrimidine itk inhibitors
AssigneeAclaris Therapeutics, Inc.
InventorsEric Jon JACOBSEN, David Randolph ANDERSON, James Robert BLINN, Susan Landis HOCKERMAN, Richard HEIER, Paramita MUKHERJEE
Life of this patent
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Abstract
Disclosed herein are arylpyridinone compounds and compositions useful in the treatment of ITK mediated diseases, such as inflammation, having the structures of Formulas (I)-(IV): wherein the R groups, m, n, and X are as defined in the detailed description. Methods of inhibition of ITK activity in a human or animal subject are also provided.
Claims19
A compound of Formula (I):
- wherein:
- X is N or CR3;
- n is 0, 1 or 2;
- m is 0, 1, or 2;
- R1 is selected from COOR6, C1-C5 alkyl-COOR6, bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are optionally substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR6, or C1-C5-alkyl-COOR6;
- R2 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, CN, OH, C1-C5 alkoxy, and halogen where two R2 groups on the same carbon may be joined with or without a heteroatom to make a spirocyclic ring system;
- R3 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl;
- R4 is selected from H, C1-C6 alkyl;
- R5 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkyl NH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy or C1-C6 alkyl-heterocyclyl;
- R6 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, C1-C5 alkyl-C1-C5 alkoxy, C1-C5 alkyl-OH, C1-C5 alkyl-NH2, C1-C5 alkyl-NH—C1-C5 alkyl, and C1-C5 alkyl-N—(C1-C5 alkyl)(C1-C5 alkyl);
- and a derivative thereof.
8 more elements
A compound of Formula (II):
- wherein:
- X is N or CR23;
- n is 0, 1 or 2;
- m is 0, 1, or 2;
- R21 is selected from COOR26, C1-C5 alkyl-COOR26, bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are optionally substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR26, or C1-C5-alkyl-COOR26;
- R22 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, CN, OH, C1-C5 alkoxy, halogen and where two R2 groups on the same carbon may be joined with or without a heteroatom to make a spirocyclic ring system;
- R23 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl;
- R24 is selected from H, C1-C6 alkyl;
- R25 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkyl NH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy or C1-C6 alkyl-heterocyclyl;
- R26 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, C1-C5 alkyl-C1-C5 alkoxy, C1-C5 alkyl-OH, C1-C5 alkyl-NH2, C1-C5 alkyl-NH—C1-C5 alkyl, and C1-C5 alkyl-N—(C1-C5 alkyl)(C1-C5 alkyl);
- and a derivative thereof.
8 more elements
A compound of Formula (III):
- wherein:
- X is CR33 or N;
- n is 1 or 2;
- m is 0, 1 or 2 when n is 1, m is 1 when n is 2;
- R31 is selected from COOR36, C1-C5 alkyl-COOR36, bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are optionally substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR36, or C1-C5-alkyl-COOR36;
- R32 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cyclcoalkyl;
- R33 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl;
- R34 is selected from H, C1-C6 alkyl;
- R35 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkyl NH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy;
- R36 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, C1-C5 alkyl-C1-C5 alkoxy, C1-C5 alkyl-OH, C1-C5 alkyl-NH2, C1-C5 alkyl-NH—C1-C5 alkyl, and C1-C5 alkyl-N—(C1-C5 alkyl)(C1-C5 alkyl);
- and a derivative thereof.
8 more elements
A compound of Formula (IV):
- wherein:
- X is CR43 or N;
- n is 1 or 2;
- m is 0, 1 or 2 when n is 1, m is 1 when n is 2;
- R41 is selected from COOR46, C1-C5 alkyl-COOR46, bicycloalkyl, C1-C5-alkyl-heterocyclyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, C3-C6 cycloalkyl, C(O)C1-C5 alkyl, C(O)C3-C6 cycloalkyl, C(O)C3-C6 heterocyclyl, where cycloalkyl, bicycloalkyl, heterocyclyl, and alkyl are optionally substituted with one or more groups selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkyl-C1-C5 alkoxy, CN, halogen, COOR46, or C1-C5-alkyl-COOR46;
- R42 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cyclcoalkyl;
- R43 is selected from H, CN, C1-C6 alkyl, C3-C6 cycloalkyl;
- R44 is selected from H, C1-C6 alkyl;
- R45 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6-alkyl-NH2, C1-C6 alkyl NH(C1-C6 alkyl), C1-C6 alkyl-N(C1-C6 alkyl)(C1-C6 alkyl), C1-C5 alkyl-C1-C5 alkoxy;
- R46 is selected from H, C1-C5 alkyl, C3-C6 cycloalkyl, C1-C5-alkyl-C3-C6-cyclcoalkyl, C1-C5 alkyl-C1-C5 alkoxy, C1-C5 alkyl-OH, C1-C5 alkyl-NH2, C1-C5 alkyl-NH—C1-C5 alkyl, and C1-C5 alkyl-N—(C1-C5 alkyl)(C1-C5 alkyl);
- and a derivative thereof.
8 more elements
A pharmaceutical composition comprising:
- one or more compounds selected from the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and derivatives thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
A method of inhibiting ITK or JAK3 activity in a population of cells, said method comprising:
- administering, to a population of cells, one or more compounds selected from the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and derivatives thereof in an amount effective to inhibit ITK or JAK3 activity in the population of cells.
A method of treating an ITK-mediated or JAK3 mediated disorder in a subject in need thereof, comprising:
- administering to the subject one or more compounds selected from the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and derivatives thereof in an amount effective to treat the ITK-mediated or JAK3 mediated disorder.
Use of a compound selected from the compounds of Formula (I), Formula (II), Formula (III), Formula (IV), and derivatives thereof for the manufacture of a medicant to treat an ITK-mediated or JAK3 mediated disease.
Dependencies are inferred from the claim text.