SUBSTITUTED IMIDAZO[1,2-a]PYRIDINE COMPOUNDS AS TROPOMYOSIN RECEPTOR KINASE A (TrkA) INHIBITORS

摘要

The present application relates to a series of substituted imidazo[1,2-a]pyridine compounds of formula (I),;;pharmaceutically acceptable salts, pharmaceutically acceptable solvates or stereoisomers thereof, their use as tropomyosin receptor kinase (Trk) family protein kinase inhibitors, method of making and pharmaceutical compositions comprising such compounds.

主权项

1. A compound having the formula (I), or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof or stereoisomers thereof, wherein,
R1 is —Xa—Ra;R2 is —Xb—Rb;Xa is a 3-7 membered heterocyclyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, thiomorpholinyl, 1,1-dioxo-thiomorphonyl and morpholinyl, any of which is optionally substituted with 1-3 times with R3;R3, in each occurrence is selected independently from halogen, hydroxy, —(C1-C6)alkyl, —(C1-C6)alkoxy and halo(C1-C6)alkoxy;Ra is a phenyl ring optionally substituted 1-3 times with R4;R4, in each occurrence is selected independently from halogen, —(C1-C6)alkyl and —O—R5;Alternatively, two R4, on adjacent carbon atoms, together with the carbon atoms to which they are attached may form a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl ring;R5 is selected from —(C1-C6)alkyl, halo(C1-C6)alkyl and 5-6 membered heterocyclyl;Xb is selected from —CO—, —CONR6—, —NR6CO—, —C(═N—OR6)—, —CONR6—SO2—, —CONR6—SO2—NR6—, and —R6N—CO—NR6;Rb is selected from
(i) alkyl, optionally substituted with 1-3 substituents selected independently from halogen, —(C1-C6)alkoxy, hydroxyl and —CO—(CR7R8)p—OR9;(ii) aryl, heteroaryl or cycloalkyl, any of which is optionally substituted with 1-3 substituents selected independently from halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, —(C1-C6)alkoxy, hydroxyl, —(C1-C6)alkyl and —R10;(iii) heterocyclyl, optionally substituted with 1-3 substituents selected independently from halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, —(C1-C6)alkoxy, hydroxyl, —(C1-C6)alkyl, and N(Ri)2, wherein Ri, in each occurrence, independently selected from hydrogen, —(C1-C6)alkyl or —(C3-C6)alkyl;Alternatively, R6 and Rb together with Nitrogen atom to which they are attached, may form a 3-10 membered heterocyclic ring optionally substituted 1-3 times with R11;R6, in each occurrence, is independently selected from hydrogen, —(C1-C6)alkyl and —(C1-C6)alkyl-(C3-C6)cycloalkyl;R7, R8 or R9, in each occurrence, is independently selected from hydrogen and —(C1-C6)alkyl;R10 is a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl, any of which is optionally substituted with 1-2 substituents selected independently from —(C1-C6)alkyl, halogen, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, —(C1-C6)alkoxy and hydroxyl;R11 is selected from halogen, hydroxyl, alkyl and NH2; andp is 0, 1, 2 or 3.