Indazole compounds useful as ketohexokinase inhibitors

摘要

The present invention is directed to substituted indazole compounds of formula (I);pharmaceutical compositions of these compounds and methods of use thereof. The compounds of the present invention are ketohexokinase (KHK) inhibitors, useful for treating or ameliorating a KHK mediated metabolic disorders and/or diseases such as obesity, Type II diabetes mellitus and Metabolic Syndrome X.

主权项

1. A compound of formula (I) wherein a is an integer from 0 to 1; X is selected from the group consisting of —O— and —S—; R1 is selected from the group consisting of C1-4alkyl and halogenated C1-4alkyl; b is an integer from 0 to 2; R2 is selected from the group consisting of halogen, hydroxy, cyano, nitro, NRARB, C1-4alkyl, —O—C1-4alkyl, —S—C1-4alkyl and halogenated C1-4alkyl; wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-4alkyl; R3 is selected from the group containing of hydrogen, halogen, hydroxy, —O—C1-4alkyl and NRCRD; wherein RC and RD are each independently selected from the group consisting of hydrogen and C1-4alkyl; Y is CH and Z is CH; Q is selected from the group consisting of -(L1)c-(Ring A), -(L1)c-(Ring B)-(Ring C) and -(Ring B)-L1-(Ring C); c is an integer from 0 to 1; L1 is selected from the group consisting of —CH2—, —CH(OH)—, —CH2CH2—, —CH2CH2CH2—, —CH═CH—, —CH═CH—CH2—, —O—, —O—CH2—, —C(O)—, —C(O)—C(O)—, —C(O)—CH2—, —C(O)—N(R4)—, —N(R4)—, —N(R4)—CH2—, —N(R4)—CH2CH2—, —N(R4)—(CO)—, —N(R4)—C(O)—CH2—, —N(R4)—C(O)—CH2—CH2— and —N(R4)—C(O)—N(R5)—; wherein R4 and R5 are each independently selected from the group consisting of hydrogen and C1-2alkyl; (Ring A) is selected from the group consisting of phenyl and 4 to 10 membered, nitrogen containing ring structure; wherein (Ring A) is optionally substituted with a substituent selected from the group consisting of halogen, C1-4alkyl, cyano, NRERF, —C(═NH)—NRERF, —C(O)—CH2—NRERF, —C(O)—CH2CH2—NRERF and phenyl; wherein RE and RF are each independently selected from the group consisting of hydrogen and C1-4alkyl; (Ring B) is selected from the group consisting of phenyl and 4 to 10 membered, nitrogen containing ring structure; (Ring C) is selected from the group consisting of 4 to 10 membered, nitrogen containing ring structure; wherein (Ring C) is optionally substituted with one to two substituents independently selected from the group consisting C1-4alkyl; or a pharmaceutically acceptable salt thereof.