Substituted heterocyclic inhibitors of PTPN11
Inventors
Jones, Philip • Cross, Jason • Burke, Jason • McAfoos, Timothy • Kang, Zhijun
Assignees
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Publication Number
US-10954243-B2
Publication Date
2021-03-23
Expiration Date
Abstract
The present invention relates to compounds which may be useful as inhibitors of PTPN11 for the treatment or prevention of cancer and other PTP-mediated diseases. Disclosed herein are new compounds and compounds based on pyrazolopyrazines and their application as pharmaceuticals for the treatment of disease.
Core Innovation
The invention provides compounds of structural Formula I, including salts and tautomers thereof, with defined values of a and b and with substituent variables R1a, R1b, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R13, R15, and R16 together with optional ring-forming and substituent options. The structure includes a defined aromatic or heteroaryl substituent selection for R1a and an R1b selection, with broad structural variability constrained by the claim’s ring and substitution rules.
The core structural concept restricts R1a to halo, phenyl, or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms, where the phenyl or heteroaryl is optionally substituted by 1 to 5 R12 groups selected from a large set of functional groups and substituent types. The invention further constrains multiple other substituent positions to defined sets of hydrogen, alkyl, cycloalkyl, cyano, alkoxy, amino, hydroxy, halo, and alkylamino. In addition, R6 and R7 together form a 3- to 7-membered ring containing 1 to 3 heteroatoms or groups selected from N, C(O), O, and S(O)m, with optional R17 and R18 substitution.
The invention also includes flexibility in additional ring formation, specifying that any two groups of R2, R3, R4, R5, R8, R9, R10 and R11 can form a 5- to 6-membered ring optionally containing a N, O or S heteroatom, and that any two groups of R2, R4, R8, and R10 can form a direct bond or a 1 or 2 atom carbon bridge. The invention further constrains R13, R15, and R16 to hydrogen, C1-4 alkyl, C3-8 cycloalkyl, and 3- to 6-membered heterocyclyl, optionally substituted with hydroxy, cyano and halo, while each R17 and R18 is independently selected from amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4 alkyl, and C1-4 alkoxy.
Claims Coverage
The independent claim coverage centers on a structurally defined Formula I compound, including salt or tautomer forms, with tightly delimited substituent sets and explicit ring-forming constraints. The inventive features are primarily the Formula I substituent framework, the allowed ring and bridge relationships, and the defined substituent sets for R13, R15, R16, R17, and R18.
Compound of structural Formula I with defined substituent and ring-formation variables
A compound of structural Formula I, or a salt or tautomer thereof, wherein a is 0 or 1 and b is 0 or 1, with R1a selected from halo, phenyl, or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms, and R1b selected from halogen and C1-6 alkyl, while R2, R3, R10, and R11; R4, R5, R8, and R9; and R6 and R7 are constrained by specified group sets and optional substitutions by R17 and R18, and wherein ring formation options apply to selected R2/R3/R4/R5/R8/R9/R10/R11 groups as further limited.
Optional substitution and heterocyclyl substitutions restricted for R13, R15, R16, R17, and R18
R13, R15, and R16 are independently selected from hydrogen, C1-4 alkyl, C3-8 cycloalkyl, and 3- to 6-membered heterocyclyl optionally substituted by one or more substituents selected from hydroxy, cyano and halo, and each R17 and R18 is independently selected from amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4 alkyl, and C1-4 alkoxy.
The claim coverage centers on a structurally defined Formula I compound, including salt or tautomer forms, with explicit heteroaryl selection for R1a, alkyl or halogen selection for R1b, ring construction from R6 and R7, and additional 5- to 6-membered ring or bridge formation rules among the specified R-position groups.
Stated Advantages
Reported PTPN11 inhibitor biological activity using enzymatic DiFMUP fluorogenic assay and downstream pERK AlphaScreen in KYSE-520 cells, supported by IC50 values.
Reported effects in a colony formation assay, with selumetinib used as a reference low control.
Documented Applications
Use of compounds as PTPN11 inhibitors.
Treatment of Noonan syndrome.
Treatment of Leopard syndrome.
Treatment of cancer, including breast cancer, colon cancer, leukemia, and melanoma.
Cognition enhancement.
Treatment of a PTPN11-mediated disease by administering a therapeutically effective amount of the compound to a patient in need.
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