Bicyclic oxa-lactam kinase inhibitors

摘要

Provided are bicyclic oxa-lactam compounds of formula I:;
and pharmaceutically acceptable salts thereof which are inhibitors of JAK/Syk kinase. The present disclosure is also directed to intermediates used in making such compounds, methods for their preparation, pharmaceutical compositions thereof, methods for inhibiting JAK/Syk kinase activity, and methods for treating conditions mediated at least in part by JAK/Syk kinase activity.

主权项

1. A compound of Formula (I):or a tautomer or a pharmaceutically acceptable salt thereof, wherein
G1 is N and G2 is N; L1 is selected from the group consisting of a bond, NH, O, and S; Z1 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with 1 to 5 R1; t is 1; R1 is independently selected from the group consisting of halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)nSR1a, (CH2)nOR1a, O(CH2)jOR1a, (CH2)nNR1bR1c, (CH2)nCOR1e, (CH2)nCONR1bR1c, (CH2)nNR1bCOR1e, (CH2)nCONR1b(OR1a), (CH2)nCO2R1a, O(CH2)nCO2R1a, (CH2)nNR1bCO2R1a, (CH)nSO2NR1bR1c, (CH2)nNR1bSO2R1e, (CH2)nSOR1e, (CH2)nSO2R1e, oxo, (CH2)nCN, N3, NO2, and -L2-W, where n is 0, 1, 2, 3, 4, 5, or 6 and j is 1, 2, 3, 4, 5, or 6; L2 is selected from the group consisting of —O(CH2)b—, —SO—, —SO2—, —CO—, —NR1d—, —CONR1d(CH2)b—, —NR1dCO—, —NR1dSO2—, —SO2NR1d—, a bond, and —(CH2)e— where b is 0, 1, 2, 3, 4, or 5 and e is 1, 2, 3, 4, or 5; W is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl each optionally substituted with 1 to 3 R2; R2 is independently selected from the group consisting of halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)mSR2a, (CH2)mOR2a, O(CH2)kOR2a, (CH2)mNR2bR2c, (CH2)mCOR2e, (CH2)mCONR2bR2c, (CH2)mNR2bCOR2e, (CH2)mCONR2b(OR2a), (CH2)mCO2R2a, O(CH2)mCO2R2a, (CH2)mNR2bCO2R2a, (CH)mSO2NR2bR2c, (CH2)mNR2bSO2R2e, (CH2)mSOR2e, (CH2)mSO2R2e, oxo, (CH2)mCN, N3, and NO2, where m is 0, 1, 2, 3, 4, 5, or 6 and k is 1, 2, 3, 4, 5, or 6; R1a, R1b, R1c, R1d, R2a, R2b, and R2c are independently selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl; R1e and R2e are independently selected from the group consisting of C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl; Y1 isor (CH2)v(Y2), wherein
v is 0, 1, 2, or 3; Y2 is selected from the group consisting of CH2CH3, (CH2)3NH2, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 3 R10; R4 is selected from the group consisting of H, halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)pSR4a, (CH2)pSOR4a, (CH2)pSO2R4a, (CH2)pOR4a, (CH2)pNR4bR4c, (CH2)fCONR4bR4c, (CH2)pNR4bCOR4d, (CH2)fCO2R4a, (CH2)pNR4bCO2R4a, (CH2)fcycloalkyl, (CH2)p(O)cycloalkyl, (CH2)p(S)cycloalkyl, (CH)pSO2NR4bR4c, (CH2)pNHcycloalkyl, (CH2)fCN, (CH2)f(aryl), (CH2)f(heteroaryl), (CH2)f(aryl)(heteroaryl), (CH2)f(heterocyclyl), (CH2)p(O)(CH2)f(aryl), (CH2)p(O)(CH2)f(heteroaryl), (CH2)p(O)(CH2)fC3-8cycloalkyl, and (CH2)p(O)(CH2)f(heterocyclyl), where the aryl, heteroaryl, cycloalkyl, and heterocyclyl are each optionally substituted with 1 to 3 R11a, f is 0, 1, 2, 3, 4, 5, or 6, and p is 1, 2, 3, 4, 5, or 6; or R4 and R5 together form ═O or a 3 to 8 membered carbocyclic or heterocyclic ring optionally substituted with 1 to 3 R11a; R5 is selected from the group consisting of H and C1-8alkyl; or R5 is joined to the adjacent nitrogen atom to form a 4 to 6 membered heterocyclic ring optionally substituted with 1 to 3 R11a; R6 is selected from the group consisting of H, C1-8alkyl, OH, O(C1-8alkyl), CO2R6a, CO(NR6aR6b), and C3-8cycloalkyl; or R6 together with R7 and the atoms to which they are attached to form a heterocyclyl ring optionally substituted with 1 to 3 R11b; R7 is selected from the group consisting of H, C1-8alkyl, and cycloalkyl; R8 is selected from the group consisting of H, C1-8alkyl, (CH2)uNR8bR8c, (CH2)gCONR8bR8c, (CH2)gCO(CH2)uNR8bR8c, (CH2)gCO2R8a, (CH2)uOR8a, CH(C1-8alkyl)OR8a, (CH2)gcycloalkyl, (CH2)gheterocyclyl, (CH2)garyl, (CH2)gheteroaryl, and (CH2)u(O)(aryl), where the aryl, cycloalkyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R11c, g is 0, 1, 2, 3, 4, 5, or 6 and u is 1, 2, 3, 4, 5, or 6; or R8 together with R9 and the atoms to which they are attached to form ═O, ═S, or a cycloalkyl or heterocyclyl ring optionally substituted with R11c; R9 is H or C1-8alkyl; R10 is independently selected from the group consisting of halo, C1-8alkyl, C2-8alkenyl, haloC1-8alkyl, (CH2)qSR10a, (CH2)qOR10a, (CH2)qNR10bR10c, (CH2)qCOR10d, (CH2)qCONR10bR10c, (CH2)qNR10bCOR10d, (CH2)qCONR10b(OR10a), (CH2)qCO2R10a, O(CH2)qCO2R10a, (CH2)qNR10bCO2R10a, (CH)qSO2NR10bR10c, (CH2)qNR10bSO2R10d, (CH2)qSOR10d, (CH2)qSO2R10d, oxo, (CH2)qCN, N3, N═CH2, NO2, C(O)heterocyclyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, where the aryl, cycloalkyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 to 3 R11d and q is 0, 1, 2, 3, 4, 5, or 6; R11a, R11b, R11c, and R11d are independently selected from the group consisting of halo, C1-8alkyl, haloC1-8alkyl, OH, C1-8alkoxy, haloC1-8alkoxy, C(O)C1-8alkyl, CO2C1-8alkyl, and SO2C1-8alkyl; R4a, R4b, R4c, R6a, R6b, R8a, R8b, R8c, R10a, R10b, and R10c are independently selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl; R4d and R10d are independently selected from the group consisting of C1-8alkyl, C2-8alkenyl, and haloC1-8alkyl; and
the wavy line indicates the point of attachment to the rest of the molecule.