Substituted heterocyclic inhibitors of PTPN11
Inventors
Jones, Philip • Cross, Jason • Burke, Jason • McAfoos, Timothy • Kang, Zhijun
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11932643-B2
Publication Date
2024-03-19
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 relates to compounds of structural Formula I, including a salt or tautomer thereof, defined by parameters a and b and by substituent selections for R1a, R1b, R2 through R11, R13, R15, R16, R17, R18, and R19 through R21. The defined chemical classes include halo, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and additional functional group selections, together with constraints on ring size, heteroatom content, and bridging or ring-closure relationships among substituents.
R6 and R7 together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring that contains 1 to 3 heteroatoms or groups selected from N, C(O), O, and S(O)m. 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 any two groups of R2, R4, R8, and R10 can form a direct bond or a 1 or 2 atom carbon bridge.
Representative compounds include pyrazolopyrazine and pyrazolo[3,4-b]pyrazine derivatives and pharmaceutically acceptable salts, with formula variants illustrating aryl and heteroaryl substitution patterns and additional scaffold variants. The disclosure states that the compounds inhibit PTPN11 activity and are used to treat or prevent PTPN11-mediated diseases, including cancers such as leukemia, melanoma, breast, lung, and colon.
Claims Coverage
The consolidated claim coverage centers on one independent compound claim to structural Formula I or a salt or tautomer thereof, with multiple inventive features expressed through variable definitions and ring-formation constraints. Additional dependent coverage refines substituent identity, bridging, and ring content, and one dependent claim provides a treatment method for PTPN11-mediated disease.
Structural formula I compound definition
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 defined substituent classes for R1a, R1b, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R13, R15, R16, R17, R18, R19, R20, and R21.
Aryl and heteroaryl selection for R1a
R1a is selected from halo, C6-10 aryl, C3-8 cycloalkyl, C3-8 cycloalkenyl, and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S, with optional R12 substitution.
Functional group selection for R1b
R1b is selected from cyano, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 dihydroxyalkyl, —CF2OH, —CHFOH, —NH—NHR19, —NH—OR19, —O—NR20R19, —NHR19, —OR19, —NHC(O)R19, —NHC(O)NHR19, —NHS(O)2NHR19, —NHS(O)2R19, —C(O)OR19, —C(O)NR19R20, cycloalkyl, and heteroaryl or heterocyclyl options with defined heteroatom ring-vertex constraints.
Ring formation constraints using R6 and R7
R6 and R7 together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring containing 1 to 3 heteroatoms or groups independently selected from N, C(O), O, and S(O)m, where m is 0, 1, or 2, and the ring is optionally substituted.
Additional ring closure and bridging constraints
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 any two groups of R2, R4, R8, and R10 can form a direct bond or a 1 or 2 atom carbon bridge.
Treatment method for PTPN11-mediated disease
A method for treating a PTPN11-mediated disease, comprising administering a therapeutically effective amount of the compound recited in claim 1 to a patient who needs it.
Overall, the independent claim establishes the core inventive concept as a structural Formula I pyrazolopyrazine-based compound with extensive, explicitly defined substituent and ring-formation constraints. The dependent coverage further specifies substituent identities, bridging and ring closure, and includes a method for treating PTPN11-mediated disease.
Stated Advantages
Inhibits PTPN11 activity.
Treats or prevents PTPN11-mediated diseases.
Therapeutically useful for cancer, including leukemia, melanoma, breast, lung, and colon.
Provides PTPN11 inhibitor biological activity data including IC50 values in an enzymatic DiFMUP assay and pERK inhibition testing.
Provides detailed synthesis characterization data, including MS, NMR, and yields, for a series of pyrazolo[3,4-b]pyrazine derivatives.
Documented Applications
Treating or preventing PTPN11-mediated diseases, including cancer types such as leukemia, melanoma, breast, lung, and colon.
Administering a compound of structural Formula I, or a salt or tautomer thereof, for treating a PTPN11-mediated disease in a patient in need thereof.
PTPN11 inhibition testing, including an enzymatic DiFMUP assay and pERK inhibition testing using an AlphaScreen pERK (SureFire) format, with colony formation assay described.
Interested in licensing this patent?