SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE

摘要

The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof useful in preventing, treating or lessening the severity of a protein kinase-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of protein kinase-mediated disease.

主权项

1. A compound having Formula (I):or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
Z is C7-C12 spiro bicycloalkyl, C7-C12 fused bicycloalkyl, 7-12 membered spiro heterobicyclyl or 7-12 membered fused heterobicycloalkyl, wherein Z is optionally substituted by 1, 2, 3, 4 or 5 R2 groups; Z1 is H, C1-C12 alkyl, C3-C12 cycloalkyl or 3-12 membered heterocyclyl, wherein Z1 is optionally substituted by 1, 2, 3, 4 or 5 R3 groups; A is pyrazolyl or imidazolyl, wherein A is optionally substituted by 1, 2, 3, 4 or 5 R4 groups; R1 is H, F, Cl, Br, I, NO2, N3, CN, C1-C12 alkyl, C1-C12 haloalkyl, C1-C12 alkoxyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl, 5-12 membered heteroaryl, —(CR6R7)n—ORc, —(CR6R7)n—NRaRb, —C(═O)R5, —OC(═O)R5, —O(CR6R7)n—R5, —N(Rc)C(═O)R5, —(CR6R7)nC(═O)ORc, —(CR6R7)nC(═O)NRaRb, —C(═NRc)NRaRb, —N(Rc)C(═O)NRaRb, —N(Rc)S(═O)mR5 or —S(═O)2NRaRb, wherein R1 is optionally substituted by 1, 2, 3, 4 or 5 R8 groups; each R2 is independently H, F, Cl, Br, I, NO2, N3, CN, OH, NH2, —C(═O)CH2CN, C1-C12 alkyl, C1-C12 haloalkyl, C1-C12 alkoxy, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, —(CR6R7)n—ORc, —(CR6R7)n—NRaRb, —C(═O)R5, —S(═O)2R5, —OC(═O)R5, —O(CR6R7)n—R5, —O(CR6R7)n—ORc, —N(Rc)C(═O)R5, —(CR6R7)nC(═O)ORc, —(CR6R7)nC(═O)NRaRb, —C(═NRc)NRaRb, —N(Rc)C(═O)NRaRb, —N(Rc)S(═O)mR5 or —S(═O)2NRaRb, or two adjacent R2 taken together with the atoms to which they are attached form a C3-C12 cycloalkyl or 3-12 membered heterocycloalkyl group, wherein each of the above substituents is optionally independently substituted by 1, 2, 3, 4 or 5 R8 groups; each R3 and R4 is independently H, F, Cl, Br, I, NO2, N3, CN, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, —(C1-C4 alkylene)-(C3-C12 cycloalkyl), C6-C12 aryl, 3-12 membered heterocyclyl, —(C1-C4 alkylene)-(3-12 membered heterocyclyl), 5-12 membered heteroaryl, —(CR6R7)n—ORc, —(CR6R7)n—NRaRb, —C(═O)R5, —OC(═O)R5, —O(CR6R7)n—R5, —N(Rc)C(═O)R5, —(CR6R7)nC(═O)ORc, —(CR6R7)nC(═O)NRaRb, —C(═NRc)NRaRb, —N(Rc)C(═O)NRaRb, —N(Rc)S(═O)mR5 or —S(═O)2NRaRb, wherein each R3 and R4 is optionally independently substituted by 1, 2, 3, 4 or 5 R8 groups; each R5 is independently H, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, wherein each R5 is optionally independently substituted by 1, 2, 3, 4 or 5 R8 groups; each R6 and R7 is independently H, F, Cl, Br, I, NO2, N3, CN, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, or R6 and R7 taken together with the carbon atom to which they are attached form a C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl group, wherein each of the above substituents is optionally independently substituted by 1, 2, 3, 4 or 5 R8 groups; each R8 is independently F, Cl, Br, I, CN, NO2, N3, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, NH2, —NH(C1-C12 alkyl), —NH(CH2)n—(C3-C12 cycloalkyl), —NH(CH2)n—(C6-C12 aryl), —NH(CH2)n-(3-12 membered heterocyclyl), —NH(CH2)n-(5-12 membered heteroaryl), —N(C1-C12 alkyl)2, —N[(CH2)n—(C3-C12 cycloalkyl)]2, —N[(CH2)n—(C6-C12 aryl)]2, —N[(CH2)n-(3-12 membered heterocyclyl)]2, —N[(CH2)n—(5-12 membered heteroaryl)]2, OH, —O(C1-C12 alkyl), —O(CH2)n—(C3-C12cycloalkyl), —O(CH2)n—(C6-C12 aryl), —O(CH2)n-(3-12 membered heterocyclyl) or —O(CH2)n-(5-12 membered heteroaryl); each Ra, Rb and Rc is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, —(C1-C4 alkylene)-(C3-C6 cycloalkyl), 3-6 membered heterocyclyl, —(C1-C4 alkylene)-(3-6 membered heterocyclyl), C6-C10 aryl, —(C1-C4 alkylene)-(C6-C10 aryl), 5-10 membered heteroaryl or —(C1-C4 alkylene)-(5-10 membered heteroaryl), or Ra and Rb taken together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl group, wherein each of the above substituents is optionally independently substituted by 1, 2, 3 or 4 substitutents independently selected from F, Cl, Br, CN, N3, OH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 alkylamino; each m is independently 1 or 2; and each n is independently 0, 1, 2, 3 or 4.