Substituted pyrido[2,3-c]pyridazin-4(1H)-ones as tumor necrosis factor alpha and phosphodiesterase 4 inhibitors

摘要

The present invention pertains to field of medical technology, specifically relates to a pyridino-oxopyridazine derivative of formula (I), its pharmaceutically acceptable salts, its stereoisomers or its solvates, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R7′, R8′, R9′, L and ring A are defined as the description; the present invention further relates to methods for preparing the compounds, a pharmaceutical composition comprising the compound, and use of the compound and the pharmaceutical composition in manufacture of a medicament for treatment and/or prophylaxis of an inflammatory disease, symptom and condition characterized in undesired inflammatory immunoreaction or associated with undesired inflammatory immunoreaction, as well as all diseases induced by oversecretion of TNF-α and PDE-4 or associated with oversecretion of TNF-α and PDE-4.;

主权项

1. A compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Formula (I) is: wherein R1 is hydrogen, C1-8 alkyl optionally substituted with 1-3 substituents, C1-8 alkoxy optionally substituted with 1-3 substituents, C3-8 cycloalkyl optionally substituted with 1-3 substituents, C2-8 alkenyl optionally substituted with 1-3 substituents, C3-8 alkynyl optionally substituted with 1-3 substituents, —C(O)—Ra, —S(O)q—Ra, C6-14 aryl each optionally substituted with 1-3 substituents, 5-15-membered heteroaryl optionally substituted with 1-3 substituents, or 3-15-membered heterocyclyl-C1-8 alkyl optionally substituted with 1-3 substituents; R2 is hydrogen, C1-8 alkyl optionally substituted with 1-3 substituents, or C3-8 cycloalkyl optionally substituted with 1-3 substituents; each of R3, R4, R5 and R6 independently is hydrogen, halogen, C1-8 alkyl optionally substituted with 1-3 substituents, C1-8 alkoxy optionally substituted with 1-3 substituents, —C(O)—Ra, —S(O)q—Ra, nitro, cyano, or —NRaRa′; R7 is phenyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, or thiadiazolyl, each optionally substituted with 1-3 substituents; pyridyl, pyrimidyl, indolyl, quinolyl, or imidazolyl or a nitrogen oxide thereof, each optionally substituted with 1-3 substituents; hydrogen; C1-8 alkyl optionally substituted with 1-3 substituents; or C3-8 cycloalkyl optionally substituted with 1-3 substituents; R7′ is absent, or is phenyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, or thiadiazolyl, each optionally substituted with 1-3 substituents; pyridyl, pyrimidyl, indolyl, quinolyl, or imidazolyl or a nitrogen oxide thereof, each optionally substituted with 1-3 substituents; hydrogen; C1-8 alkyl optionally substituted with 1-3 substituents; or C3-8 cycloalkyl optionally substituted with 1-3 substituents; R8 is hydrogen, halogen, nitro, cyano, ═N—O—C1-8 alkyl, —O—N═C1-8 alkyl, —CH(N═NOH)—C1-8 alkyl, C1-8 alkyl each optionally substituted with 1-3 substituents, C3-8 cycloalkyl optionally substituted with 1-3 substituents, C1-8 alkoxy optionally substituted with 1-3 substituents, C6-14 aryl optionally substituted with 1-3 substituents, 5-15-membered heteroaryl optionally substituted with 1-3 substituents, 3-15-membered heterocyclylC1-8 alkyl optionally substituted with 1-3 substituents, —NRaRa′, —C(O)—Ra, —C(O)NRaRa′, —NRaC(O)Ra′, —S(O)q—Ra, —S(O)q—NRaRa′, —NRa—S(O)q—Ra′, or —C(O)ORa; R8′ is absent, or is hydrogen, halogen, nitro, cyano, ═N—O—C1-8 alkyl, —O—N═C1-8 alkyl, —CH(N═NOH)—C1-8 alkyl, C1-8 alkyl optionally substituted with 1-3 substituents, C3-8 cycloalkyl optionally substituted with 1-3 substituents, C1-8 alkoxy optionally substituted with 1-3 substituents, C6-14 aryl optionally substituted with 1-3 substituents, 5-15-membered heteroaryl optionally substituted with 1-3 substituents, 3-15-membered heterocyclylC1-8 alkyl optionally substituted with 1-3 substituents, —NRaRa′, —C(O)—Ra, —C(O)NRaRa′, —NRaC(O)Ra′, —S(O)q—Ra, —S(O)q—NRaRa′, —NRa—S(O)q—Ra′, or —C(O)ORa; R9 is hydrogen, hydroxy, halogen, C1-8 alkyl optionally substituted with 1-3 substituents, or —NRbRb′; R9′ is absent, or is hydrogen, hydroxy, halogen, C1-8 alkyl optionally substituted with 1-3 substituents, or —NRbRb′; ring A is phenyl, 5-8-membered heteroaryl containing 1-4 heteroatoms selected from N, S and O, or 8-14-membered bicyclic heterocyclyl group containing 1-4 heteroatoms selected from N, S and O; L is q is 0, 1 or 2; n is 1, 2, 3 or 4; and Ra and Ra′ are independently selected from hydrogen, C1-8 alkyl optionally substituted with 1-3 substituents, C3-8 cycloalkyl optionally substituted with 1-3 substituents, C3-8 cycloalkyl C1-8 alkyl optionally substituted with 1-3 substituents, C6-14 aryl optionally substituted with 1-3 substituents, or 3-15-membered heterocyclyl group, optionally substituted with 1-3 substituents; wherein the substituent of the substituted C1-8 alkyl, substituted C1-8 alkoxy, substituted C2-8 alkenyl, substituted C3-8 alkynyl, substituted C3-8 cycloalkyl, substituted C3-8 cycloalkyl C1-8 alkyl, substituted C6-14 aryl, substituted 5-15-membered heteroaryl, substituted 3-15-membered heterocyclyl group, substituted 3-15-membered heterocyclylC1-8 alkyl, substituted phenyl, pyridyl, pyrimidyl, indolyl, quinolyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl refers to one or more groups independently selected from hydroxy, carboxy, nitro, cyano, halogen, C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, halogenated C1-8 alkyl, halogenated C1-8 alkoxy, —NRbRb′, —C(O)—Rb, —C(O)NRbRb′, —NRbC(O)Rb′, ═N—O—C1-8 alkyl, —O—N═C1-8 alkyl, —S(O)q—Rb, —S(O)q—NRbRb′, —NRb—S(O)q—Rb′, or —C(O)ORb, wherein each of Rb and Rb′ independently is hydrogen, C1-8 alkyl, C3-8 cycloalkyl or C6-14 aryl.