Indoline compounds as granzyme B inhibitors

摘要

Granzyme B inhibitor compounds, compositions that include the compounds, and methods for using the compounds. The compounds of the invention have advantageous water solubility and effectively inhibit Granzyme B.

主权项

1. A compound having Formula (I): its stereoisomers and pharmaceutically acceptable salts thereof, wherein: R1a is a heteroaryl group selected from
(a) 1,2,3-triazolyl optionally substituted with C1-C2 alkyl,(b) 1,2,3,4-tetrazolyl, and(c) 1,2,3-thiadiazolyl; R1b and R1c are independently selected from hydrogen, methyl, and halogen; R2a and R2b are independently selected from hydrogen and methyl, or R2a and R2b taken together are oxo; n is 1 or 2; R3 is selected from hydrogen and C1-C4 alkyl optionally substituted with a carboxylic acid or a carboxylate group or an amine group; Z is an acyl group selected from the group
(a) (b) wherein o is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid;
(c) wherein p is 1 or 2, and R5a is C4-acyl substituted with a carboxylic acid; and
(d) wherein Y is heteroaryl;
whereinR4 is selected from
(i) C1-C12 alkyl,(ii) C1-C6 heteroalkyl optionally substituted with C1-C6 alkyl,(iii) C3-C6 cycloalkyl,(iv) C6-C10 aryl,(v) heterocyclyl,(vi) C3-C10 heteroaryl,(vii) aralkyl, and(viii) heteroalkylaryl;R5 is —C(═O)—R10, wherein R10 is selected from
(i) C1-C12 alkyl optionally substituted with C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid,(ii) C1-C10 heteroalkyl optionally substituted with C1-C6 alkyl or carboxylic acid,(iii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid,(iv) C6-C10 aryl optionally substituted with C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C10 heteroaryl, amino, or carboxylic acid,(v) heterocyclyl,(vi) C3-C10 heteroaryl,(vii) aralkyl, and(viii) heteroalkylaryl; and R6, R7, R8, and R9 are independently selected from
(a) hydrogen,(b) halogen,(c) C1-C6 alkyl,(d) —XR11, wherein X is selected from O, C(═O), S, S═O, or S(═O)2,(e) —C(═O)N(R12)(R13),(f) —N(R11)(R12)(R13),(g) —N—C(═O)—R11, and(h) —N—C(═O)O—R11,wherein R11, R12, and R13 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C6-C10 aryl, aralkyl, and C3-C10 heteroaryl.