Pyrimidine compounds useful in the treatment of diseases mediated by IKKE and/or TBK1 mechanisms

摘要

Compounds of the general formula (I) and salts thereof are useful in the treatment of diseases associated with aberrant activity of the protein kinases IKKε and/or TBK-1 in which one of V and W is N, and the other of V and W is C—H; and R1, R2, R3 and R4 are as defined in the specification. The invention also provides uses of the compounds and compositions containing them.;

主权项

1. A compound of the general formula I:in which:
one of V and W is N, and the other of V and W is C—H; R1 represents an aliphatic heterocyclyl group having 4, 5, 6, 7, 8 or 9 ring atoms, bonded to the pyridyl group shown in formula I through a ring nitrogen atom, and optionally substituted by one or more substituents selected from halogen; OH; ═O; NO2; CN; NRaRb; (CHRa)xCORc; O.CO.Rc; CO2Ra; CONHRd; (CHRa)xNRa.CORc; NRaCO2Rb; C(═NH)NH2; SO2Rc; NRaSO2Rc; CH(CF3)NH2; and C1-4alkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, C2-4alkenyl and C2-4alkynyl groups, each optionally substituted by one or more substituents independently selected from halogen atoms, OH, S-alkyl, CONHRa and NRaRb groups; or R1 represents a NRa—(CHRa)x—C3-6cycloalkyl group or a NRa—(CHRa)x—C3-6heterocycloalkyl group, said heterocycloalkyl group containing one heteroatom, wherein the heteroatom is oxygen or nitrogen, and said cycloalkyl or heterocycloalkyl being optionally substituted by one or more substituents selected from halogen; OH; ═O; NO2; CN; NRaRb; (CHRa)xCORc; O.CO.Rc; CO2Ra; CONHRd; (CHRa)xNRa.CORc; NRaCO2Rb; C(═NH)NH2; SO2Rc; NRaSO2Rc; CH(CF3)NH2; and C1-4alkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, C2-4alkenyl and C2-4alkynyl groups, each optionally substituted by one or more substituents independently selected from halogen atoms, OH, S-alkyl, CONHRa and NRaRb groups; or R1 represents NRa—C1-6alkyl optionally substituted by one or more substituents independently selected from halogen; OH; ═O; NO2; CN; NRaRb; (CHRa)xCORc; O.CO.Rc; CO2Ra; CONHRd; (CHRa)xNRa.CORc; NRaCO2Rb; C(═NH)NH2; SO2Rc; NRaSO2Rc; CH(CF3)NH2; and C1-4alkyl, C1-4alkoxy, C1-4alkoxyC1-4 alkyl, C2-4alkenyl and C2-4alkynyl groups, each optionally substituted by one or more substituents independently selected from halogen atoms, OH, S-alkyl, CONHRa and a NRaRb group; x is 0, 1 or 2; R2 represents wherein A is a phenyl or 5 to 10 membered heteroaryl ring containing 1, 2 or 3 heteroatoms; n is 0, 1, 2 or 3; each Z is a group independently selected from —(CHRa)p—, —(CHRa)p—O—(CHRa)r—, —(CHRa)p—NRa—(CHRa)r—, —C(═O)—, C(═O)NRa— and —NRaC(═O)(CHRa)p—, in which p is 0, 1 or 2; and r is 0, 1, 2 or 3; and each R5 is a group independently selected from:
H, halogen, ORb, or NRaRb;a 4 to 8 membered heterocyclyl ring containing 1, 2, or 3 heteroatoms, optionally substituted by one or more substituents independently selected from halogen atoms, OH, ═O, NRaRb, O—C1-4alkyl and C1-4alkyl groups, optionally substituted with one or more halogen atoms, O—C1-4alkyl, OH and NRaRb;C1-4alkyl, C3-7cycloalkyl, C1-4alkoxy, C1-4alkoxyC1-4alkyl, C2-4alkenyl or C2-4alkynyl groups, each optionally substituted by one or more substituents independently selected from halogen, O—C1-4alkyl, OH and NRaRb;NO2; CN; O.CO.Rc; NRa.CORc; NRaCO2Rb; C(═NH)NH2; SO2Rc; NRaSO2Rc; and CH(CF3)NH2; or two Z—R5 groups on adjacent ring atoms together with the two adjacent ring atoms form a 5-7 membered fused ring composed of the two adjacent ring atoms and —(CHRa)r—(CHR5)—(CHRa)r—, wherein the —CHR5— moiety can be replaced with —O— or —NR5— and each r is independently 0, 1, 2, 3 or 4; or a 5-7 membered fused ring composed of the two adjacent ring atoms and —NRa.CO.(CH2)q—, wherein one —CH2— moiety can be replaced with —O— or —NRa—; and each Ra independently represents a hydrogen atom or a C1-4alkyl group; each Rb independently represents a hydrogen atom; a C1-4alkyl group optionally substituted by one or more groups selected from OH, O—C1-4alkyl, halogen, SO2Rc, CONHRc, NRa.CORc, CORc, N(Ra)2 and phenyl; or a C3-8cycloalkyl group in which a CH2 moiety may be replaced by an oxygen atom or an NRa group; Rc represents a hydrogen atom; a —NRaRb group; a C3-8cycloalkyl group, in which CH2 moiety may optionally be replaced by an oxygen atom or an NRb group; or a C1-4alkyl group optionally substituted by a OH, O—C1-4alkyl or a NRaRb group; Rd represents a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms, optionally substituted with one or more C1-4alkyl groups; q represents 1, 2 or 3; R3 represents a hydrogen atom, a C1-4alkyl group or a halogen atom; and R4 represents a hydrogen atom, a C1-4alkyl group or a halogen atom;or a salt thereof.