NOVEL DIHYDROPYRIMIDINOISOQUINOLINONES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS (GPR84 ANTAGONISTS)

摘要

A compound according to Formula (Ia),;;wherein Cy, L1, G, and R1 are as described herein. The present invention relates to novel compounds according to Formula (I) that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions, and methods for the production of these novel compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis), lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of the invention.

主权项

1. A compound according to Formula Ia: wherein Cy is whereinX is O or S;Y is —CH2—, or S;Z is —CH2—;each of the subscript n, m, or p is independently selected from 0, and 1; and A is phenyl, or 5-6-membered heteroaryl comprising one or two N-atoms; optionally substituted with one or more independently selected R5 groups;any one of Cy1 and Cy2 is optionally substituted by one or more independently selected C1-4 alkyl groups; R1 is H, Me, or halo; L1 is absent or is —O—, —S—, or —NR4a—; G is
R2,—W-L2-R2, or—W-L3-R3 W is C1-4 alkylene, C2-4 alkenylene having one double bond, or C2-4 alkynylene having one triple bond; L2 is absent or is —O—; R2 is
H,C1-8 alkyl optionally substituted with one to three groups independently selected from
OH,halo,CN,C1-6 alkoxy,C3-7 cycloalkyl,4-6 membered heterocycloalkyl (comprising one to three heteroatoms independently selected from S, and O),5-6 membered heteroaryl (comprising one to three heteroatoms independently selected from N, S, and O), andphenyl,C4-7 cycloalkenyl comprising one double bond,5-7 membered heterocycloalkenyl comprising one double bond, and one to three heteroatoms independently selected from O, and S,C3-7 cycloalkyl (optionally substituted with one or more independently selected R6 groups),4-10 membered heterocycloalkyl comprising one to two heteroatoms independently selected from S, and O, (optionally substituted with one to three independently selected R6 groups),5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O (optionally substituted with one to three independently selected R7 groups), orC6-10 aryl (optionally substituted with one or more independently selected R7 groups); L3 is —NR4b—; R3 is
C1-4 alkyl substituted with C6-10 aryl (optionally substituted with one or more independently selected R8 groups), or 5-10 membered heteroaryl (optionally substituted with one or more independently selected R8 groups) comprising one to three heteroatoms independently selected from N, S, and O,5-10 membered heteroaryl comprising one to three heteroatoms independently selected from N, S, and O, (optionally substituted with one or more independently selected R8 groups), orC6-10 aryl (optionally substituted with one or more independently selected R8 groups); Each R4a and R4b is independently selected from H, C1-4 alkyl, and C3-7 cycloalkyl; R5 is halo, C1-4 alkyl or C1-4 alkoxy; R6 is oxo or R7; R7 is
OH,halo,—NO2,C1-6 alkyl (optionally substituted with one to three groups independently selected from halo, and OH),C1-6 alkoxy (optionally substituted with one to three groups independently selected from halo, and OH),C3-7 cycloalkyl,—C(═O)OR9,—C(═O)NR10R11,—NHC(═O)—C1-4 alkyl,—CN,phenyl,—O-phenyl,4-7 membered heterocycloalkyl comprising one to three heteroatoms independently selected from N, O, and S, or5-6 membered heteroaryl comprising one to three heteroatoms independently selected from N, O, and S; (optionally substituted with one or more independently selected C1-4 alkyl, C1-4 alkoxy, CN, halo, and —C(═O)OR12); R8 is C1-4 alkyl, or halo; each of R9, R10, R11 and R12, is independently selected from H and C1-4 alkyl, or a pharmaceutically acceptable salt, or a solvate, or a solvate of the pharmaceutically acceptable salts.