PTPN11 inhibitors
Inventors
Jones, Philip • Czako, Barbara • Carroll, Christopher L. • MANDAL, Pijus • Cross, Jason
Assignees
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Publication Number
US-11104675-B2
Publication Date
2021-08-31
Expiration Date
Abstract
The present invention relates to compounds which are 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 relates to compounds represented by Formula I, or salts thereof, defined by subscript a, subscript b, linkage options Y1 and Y2, and enumerated selections for variable groups R1 through R21. The compounds are constrained by allowable ring-forming and bridge-forming relationships and by optional substitution patterns for aryl, heteroaryl, heterocyclyl, and cycloalkyl moieties.
Y1 is a direct bond or CR17R18, and Y2 is selected from C1-4 alkyl, amino, C1-4 alkylC(O)O—, C1-4 alkylamino, and C1-4 aminoalkyl. R1 is selected from C6-10 aryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, and a 5-10 membered heteroaryl group having 1 to 4 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S, and the aryl or heteroaryl of R1 is optionally substituted with halo, hydroxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 aminoalkyl, and additional ring-forming possibilities tied to selected groups.
The structural definition further includes ring-forming and bridge-forming relationships involving R6 and R7, selected pairs among R2, R3, R4, R5, R7, R8, R9, R10, and R11, and additional constrained selections for R13 through R21. The disclosure also defines pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier, and therapeutic methods for inhibiting PTPN11 (SHP2) protein tyrosine phosphatase functions and treating PTPN11-mediated diseases, including Noonan Syndrome, LEOPARD Syndrome, and cancers.
Claims Coverage
The consolidated claim coverage includes one independent compound claim for Formula I compounds, together with dependent claims refining substituent choices, a pharmaceutical composition claim, and a treatment claim for PTPN11-mediated disease. The inventive features center on the extensive structural constraints of Formula I and the therapeutic linkage to PTPN11 (SHP2) inhibition and related uses.
Formula I compound and salts
A compound represented by Formula I or a salt thereof, wherein subscript a is 0 or 1, subscript b is 0 or 1, Y1 is a direct bond or CR17R18, Y2 is selected from C1-4 alkyl, amino, C1-4 alkylC(O)O—, C1-4 alkylamino and C1-4 aminoalkyl, and the remaining substituent groups are constrained as defined.
R1 aryl or heteroaryl selection with optional substitution
R1 is selected from C6-10 aryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, and a 5-10 membered heteroaryl group having 1 to 4 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S; said aryl or heteroaryl of R1 is optionally substituted with halo, hydroxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 aminoalkyl, and additional ring-forming possibilities tied to selected groups.
Ring-forming and bridge-forming constraints
R6 and R7 together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring having 0 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O)m, and selected pairs among R2, R3, R4, R5, R7, R8, R9, R10, and R11 can form a 5 to 6 membered ring or a direct bond or carbon bridge.
Pharmaceutical composition comprising Formula I compound
A pharmaceutical composition comprising a compound represented by Formula I or a salt thereof, and a pharmaceutically acceptable carrier.
Treatment of PTPN11-mediated disease
A method of treating a PTPN11-mediated disease comprising administering to a patient in need a therapeutically effective amount of a compound of Formula I, including Noonan syndrome, LEOPARD syndrome, and cancers such as breast cancer, colon cancer, and leukemia.
Claim coverage is anchored in the Formula I compound framework with extensive enumerated and relational constraints across substituent variables and ring or bridge-forming options. The consolidated claims also include a pharmaceutical composition and methods of treatment for PTPN11-mediated diseases and selected cancers by administering therapeutically effective amounts of the Formula I compounds.
Stated Advantages
Provides pharmaceutical compositions comprising a compound of the disclosure and a pharmaceutically acceptable carrier.
Enables inhibiting PTPN11 (SHP2) protein tyrosine phosphatase functions.
Treats PTPN11-mediated diseases including Noonan Syndrome and LEOPARD Syndrome.
Treats cancers, including breast cancer, colon cancer, and leukemia.
Documented Applications
Treating PTPN11-mediated diseases including Noonan Syndrome and LEOPARD Syndrome.
Treating cancers, including breast cancer, colon cancer, and leukemia.
Pharmaceutical composition use comprising the compound and a pharmaceutically acceptable carrier.
In vitro enzymatic fluorogenic assay evaluation of PTPN11 inhibition.
Cell-based assessment of target engagement by measuring ERK phosphorylation.
Functional cell growth evaluation using a colony formation assay.
In vivo anti-tumor efficacy assessment in NSG xenografts.
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