Triazolopyridine Derivatives As Modulators of TNF Activity

摘要

A series of substituted [1,2,4]triazolo[4,3-a]pyridine derivatives, being potent modulators of human TNF activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

主权项

1. A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof: wherein
E represents a covalent bond; or E represents —O—, —S—, —S(O)—, —S(O)2— or —N(R5)—; or E represents an optionally substituted straight or branched C1-4 alkylene chain;Y represents C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;R1, R2, R3 and R4 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —ORa, —SRa, —SORa, —SO2Ra, —SF5, —NRbRc, —NRcCORd, —NRcCO2Rd, —NHCONRbRc, —NRcSO2Re, —N(SO2Re)2, —NHSO2NRbRc, —CORd, —CO2Rd, —CONRbRc, —CON(ORa)Rb, —SO2NRbRc or —SO(NRb)Rd; or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkenyl, C4-9 heterobicycloalkyl, heteroaryl, heteroaryl(C1-6)alkyl, (C3-7)heterocycloalkyl(C1-6)alkyl-aryl-, heteroaryl(C3-7)heterocycloalkyl-, (C3-7)cycloalkyl-heteroaryl-, (C3-7)cycloalkyl(C1-6)alkyl-heteroaryl-, (C4-7)cycloalkenyl-heteroaryl-, (C4-9)bicycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(C1-6)alkyl-heteroaryl-, (C3-7)heterocycloalkenyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents;R5 represents hydrogen or C1-6 alkyl;Ra represents C1-6 alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;Rb and Rc independently represent hydrogen or trifluoromethyl; or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; orRb and Rc, when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents;Rd represents hydrogen; or C1-6 alkyl, C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; andRe represents C1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.