Compounds for the treatment of kinase-dependent disorders
Inventors
Bannen, Lynne Canne • Bui, Minna • Jiang, Faming • Wang, Yong • Xu, Wei
Assignees
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Publication Number
US-11708367-B2
Publication Date
2023-07-25
Expiration Date
Abstract
Disclosed herein are compounds of Formula (I′). Compounds of Formula (I′) inhibit, regulate and/or modulate kinase receptor, particularly Axl and Mer signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.
Core Innovation
The invention relates to cyclopropane-1,1-dicarboxamide compounds of Formula I, or pharmaceutically acceptable salts thereof. The compounds include a ring A framework in which substituents are defined using Markush-structure variables such as Y, R18, R19, R13, R12, R14, R15, Ra, and X. Y is selected from O, S, SO, SO2, NH, and N(C1-6 alkyl), and X is N or CH.
The ring A substituent options include groups for R18 and R19 that are individually selected from H, halo, (C1-6) alkyl, (C1-6) haloalkyl, (C1-6) haloalkoxy, (C6-10) aryl, (C3-10) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, 5-14 membered heteroaryl, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, NHRa, NRaRa, and NRaC(O)Ra, with optional substitution patterns defined for these groups. R18 and R19 are further defined as either independently substituted members of those groups or taken together with the atoms to which they are attached to form a fused C3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring.
The scaffold additionally defines substituent sets for R13, R12, R14, R15, and Ra, together with integer subscripts n, m, and p. The described example structures show variations in these substituent selections, including fluorophenyl N-substituent, oxy-linked substituted pyrido[3,2-d]pyrimidine or fused naphthyridine core, and aryl-linked and oxy-heteroaryl linked cyclopropane-1,1-dicarboxamide members.
Claims Coverage
Independent claims cover Formula I cyclopropane-1,1-dicarboxamide compounds, and pharmaceutically acceptable salts thereof. The inventive features center on the Markush structural restrictions for Y, ring A, X, R18, R19, R13, R12, R14, R15, Ra, and the integer subscripts n, m, and p, with one portion of the claims also reciting process claims for making a compound of Formula I via reactions between specified formula intermediates.
Formula I cyclopropane-1,1-dicarboxamide compounds and salts
A compound of Formula I, or a pharmaceutically acceptable salt thereof, having Y selected from O, S, SO, SO2, NH, and N(C1-6 alkyl), with X defined as N or CH.
Ring A substituent framework with R18 and R19 fusion constraint
Ring A is defined so that R18 and R19 are each independently selected from H, halo, (C1-6) alkyl, (C1-6) haloalkyl, (C1-6) haloalkoxy, (C6-10) aryl, (C3-10) cycloalkyl, 4-14 membered heterocycloalkyl, phenyl, 5-14 membered heteroaryl, CN, NO2, ORa, SRa, C(O)Ra, C(O)NRaRa, C(O)ORa, NHRa, NRaRa, and NRaC(O)Ra, or R18 and R19 taken together with the atoms to which they are attached form a fused C3-7 cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring.
Additional substituent and integer-subscript definitions
R10 and R11 are H; R13 is selected from H, halo, OH, CN, optionally substituted (C1-6) alkyl, (C1-6) alkoxy, (C1-6) haloalkoxy, NH2, NH(C1-6)alkyl, N(C1-6 alkyl)2, and (C3-6) cycloalkyl; R14 is selected from H, halo, and (C1-6) alkyl; R15 is H; R12 is selected from H and halo; Ra is selected from H, (C1-6) alkyl, (C3-10) cycloalkyl, 4-14 membered heterocycloalkyl, and (4-14 membered heterocycloalkyl)-(C1-4) alkylene-, with optional substitution by (C1-6) alkyl, (C1-6) alkoxy, and C(O)O(C1-4) alkyl; n is 1, 2, 3, or 4; m is 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, or 4.
The claim coverage is grounded in a single Formula I cyclopropane-1,1-dicarboxamide scaffold, with scope defined by Markush variable selections for Y and ring A, including independent or fused-ring R18/R19 definitions, and by defined choices for X and the substituents R13, R12, R14, R15, Ra, and the integer subscripts n, m, and p.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating kinase-mediated diseases or conditions mediated by protein kinase modulation using TAM receptor tyrosine kinase inhibition, regulation, or modulation, including Axl and Mer.
Radiometric kinase assay for targets including AXL, KDR, Mer, and Met.
Cellular autophosphorylation ELISAs for AXL, Met, KDR, and Mer.
Combination therapy with immunotherapy, including immune checkpoint inhibitor synergy involving PD-1/PD-L1/PD-L2 and CTLA-4 pathways.
Pharmaceutical composition use of the disclosed compounds, including pharmaceutically acceptable salts.
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