IMIDAZOPYRIDINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE

摘要

The invention provides compounds of Formulas Ia-Ib, stereoisomers or pharmaceutically acceptable salts thereof, wherein A, X, Ra, R1, R2, R4, R5 and R16 are defined herein, a pharmaceutical composition that includes a compound of Formulas Ia-Ib and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of using the compound or composition in therapy.;

主权项

1. A compound of Formulas Ia-Ib: or a salt thereof, wherein: A is CR3 or N; X is CR15 or N; one R1 is —CN and the other R1 is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, 3-6 membered heterocyclyl, —CF3, —OR6, —SR6, —OCF3, —CN, —NO2, —C(O)R6, —C(O)OR6, —C(O)NR6R7, —S(O)1-2R6, —S(O)1-2NR6R7, —NR6S(O)1-2R7, —NR6SO2NR6R7, —NR6C(O)R7, —NR6C(O)OR7, —NR6C(O)NR6R7, —OC(O)NR6R7or —NR6R7, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl and heterocyclyl are independently optionally substituted by R0; R2 and R3 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, —(C0-C3 alkyl)CN, —(C0-C3 alkyl)OR8, —(C0-C3 alkyl)SR8, —(C0-C3 alkyl)NR8R9, —(C0-C3 alkyl)CF3, —O(C0-C3 alkyl)CF3, —(C0-C3 alkyl)NO2, —(C0-C3 alkyl)C(O)R8, —(C0-C3 alkyl)C(O)OR8, —(C0-C3 alkyl)C(O)NR8R9, —(C0-C3 alkyl)NR8C(O)R9, —(C0-C3 alkyl)S(O)1-2R8, —(C0-C3 alkyl)NR8S(O)1-2R9, —(C0-C3 alkyl)S(O)1-2NR8R9, —(C0-C3 alkyl)(C3-C6 cycloalkyl), —(C0-C3 alkyl(3-6-membered heterocyclyl), —(C0-C3 alkyl)(5-6-membered heteroaryl) or —(C0-C3 alkyl)phenyl, wherein R2 and R3 are independently optionally substituted by R0; R4 is hydrogen, halogen, —NR6—, —NR6R7, —NR6C(O)—, —NR6C(O)O—, —NR6C(O)NR7—, —NR6S(O)1-2— or —NR6S(O)1-2NR7—; R5 is absent, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, 3-7-membered heterocyclyl or 5-10-membered heteroaryl, wherein R5 is optionally substituted by R10; R6 and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein said alkyl, alkenyl, alkynyl and cycloalkyl are independently optionally substituted by halogen, C1-C6 alkyl, oxo, —CN, —OR11 or —NR11R12; or R6 and R7 are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR11, —NR11R12 or C1-C6 alkyl optionally substituted by halogen or oxo; R8 and R9 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, 3-6-membered heterocyclyl or 5-6-membered heteroaryl, wherein said alkyl, alkyenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl are independently optionally substituted by R10; or R8 and R9 are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR11, —NR11R12 or C1-C6 alkyl optionally substituted by halogen or oxo; R10 is independently hydrogen, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, —(C0-C3 alkyl)CN, —(C0-C3 alkyl)OR11, —(C0-C3 alkyl)SR11, —(C0-C3 alkyl)NR11R12, —(C0-C3 alkyl)CF3, —(C0-C3 alkyl)NO2, —C═NH(OR11), —(C0-C3 alkyl)C(O)R11, —(C0-C3 alkyl)C(O)OR11, —(C0-C3 alkyl)C(O)NR11R12, —(C0-C3 alkyl)NR11C(O)NR11R12, —(C0-C3 alkyl)OC(O)NR11R12, —(C0-C3 alkyl)NR11C(O)R12, —(C0-C3 alkyl)NR11C(O)OR12, —(C0-C3 alkyl)S(O)1-2R11, —(C0-C3 alkyl)NR11S(O)1-2R12, —(C0-C3 alkyl)S(O)1-2NR11R12, —(C0-C3 alkyl)(C3-C6 cycloalkyl), —(C0-C3 alkyl)(3-6-membered heterocyclyl), —(C0-C3 alkyl)C(O)(3-6-membered heterocyclyl), —(C0-C3 alkyl)(5-6-membered heteroaryl) or —(C0-C3 alkyl)phenyl, wherein R10 is independently optionally substituted by halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, oxo, —CF3, —OCF3, —(C0-C3 alkyl)OR13, —(C0-C3 alkyl)NR13R14, —(C0-C3 alkyl)C(O)R13 or —(C0-C3 alkyl)S(O)1-2R13; R11 and R12 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C3 alkyl(C3-C6 cycloalkyl), —(C0-C3 alkyl)(3-6-membered heterocyclyl), or —(C0-C3 alkyl)phenyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and phenyl are independently optionally substituted by halogen, oxo, —OR13, —NR13R14, C1-C3 alkyl, —(C0-C3 alkyl(C3-C6 cycloalkyl), —(C0-C3 alkyl)phenyl, —(C0-C3 alkyl)(3-6-membered heterocyclyl) or —(C0-C3 alkyl)(5-6-membered heteroaryl); or R11 and R12 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR3, —NR13R14 or C1-C6 alkyl; R13 and R14 are independently hydrogen, C1-C6 alkyl, OH or O(C1-C6 alkyl), wherein said alky is optionally substituted by halogen, —NH2, —N(CH3)2 or oxo; or R13 and R14 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —NH2, —N(CH3)2 or C1-C3 alkyl; R15 is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C3 alkyl)CN, —(C0-C3 alkyl)OR18, —(C0-C3 alkyl)SR18, —(C0-C3 alkyl)NR18R19, —(C0-C3 alkyl)CF3, —O(C0-C3 alkyl)CF3, —(C0-C3 alkyl)NO2, —(C0-C3 alkyl)C(O)R18, —(C0-C3 alkyl)C(O)OR18, —(C0-C3 alkyl)C(O)NR18R19, —(C0-C3 alkyl)NR18C(O)R19, —(C0-C3 alkyl)S(O)1-2R18, —(C0-C3 alkyl)NR18S(O)12R19, —(C0-C3 alkyl)S(O)1-2NR18R19, —(C0-C3 alkyl)(C3-C6 cycloalkyl), —(C0-C3 alkyl)(3-6-membered heterocyclyl), —(C0-C3 alkyl)(5-6-membered heteroaryl) or —(C0-C3 alkyl)phenyl, wherein R15 is optionally substituted by R0; R16 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C3 alkyl)CN, —(C1-C3 alkyl)OR18, —(C1-C3 alkyl)SR18, —(C1-C3 alkyl)NR18R19, —(C1-C3 alkyl)CF3, —O(C1-C3 alkyl)CF3, —(C2-C3 alkyl)NO2, —(C0-C3 alkyl)C(O)R18, —(C0-C3 alkyl)C(O)OR18, —(C0-C3 alkyl)C(O)NR18R19, —(C0-C3 alkyl)NR18C(O)R19, —(C0-C3 alkyl)S(O)1-2R18, —(C0-C3 alkyl)NR11S(O)1-2R9, —(C0-C3 alkyl)S(O)1-2NR18R19, —(C0-C3 alkyl(C3-C6 cycloalkyl), —(C0-C3 alkyl)(3-6-membered heterocyclyl), —(C0-C3 alkyl)(5-6-membered heteroaryl) or —(C0-C3 alkyl)phenyl, wherein R16 is optionally substituted by R10; R18 and R19 are independently hydrogen or C1-C6 alkyl optionally substituted by halogen, oxo, CN or —NR20R21; or R18 and R19 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, C1-C3 alkyl, CN or —NR20R21; R20 and R21 are independently hydrogen or C1-C6 alkyl; Ra is hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, —(C0-C3 alkyl)CN, —(C0-C3 alkyl)OR22, —(C0-C3 alkyl)SR22, —(C0-C3 alkyl)NR22R23, —(C0-C3 alkyl)CF3, —O(C0-C3alkyl)CF3, —(C0-C3 alkyl)NO2, —(C0-C3 alkyl)C(O)R22, —(C0-C3 alkyl)C(O)OR22, —(C0-C3 alkyl)C(O)NR22R23, —(C0-C3 alkyl)NR22C(O)R23, —(C0-C3 alkyl)S(O)12R22, —(C0-C3 alkyl)NRS(O)1-2R23, —(C0-C3 alkyl)S(O)1-2NR22R23, —(C0-C3 alkyl)(C3-C6 cycloalkyl), —(C0-C3 alkyl)(3-6-membered heterocyclyl), —(C0-C3 alkyl)(5-6-membered heteroaryl) or —(C0-C3 alkyl)phenyl, wherein R1 is optionally substituted by R0; R22 and R23 are independently hydrogen or C1-C6 alkyl optionally substituted by halogen, oxo, CN, —OR24 or —NR24R25; or R22 and R23 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, C1-C3 alkyl, CN, —OR2 or —NR24R25; and R24 and R25 are independently hydrogen or C1-C6 alkyl optionally substituted by halogen or oxo.