WO2019182960A1 - Shp2 inhibitors and uses thereof - Google Patents

Shp2 inhibitors and uses thereof Download PDF

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Publication number
WO2019182960A1
WO2019182960A1 PCT/US2019/022717 US2019022717W WO2019182960A1 WO 2019182960 A1 WO2019182960 A1 WO 2019182960A1 US 2019022717 W US2019022717 W US 2019022717W WO 2019182960 A1 WO2019182960 A1 WO 2019182960A1
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Prior art keywords
oxo
amino
compound
ring
thio
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English (en)
French (fr)
Inventor
Yinong Xie
Lee E. BABISS
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Synblia Therapeutics Inc
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Synblia Therapeutics Inc
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Priority to CA3097709A priority Critical patent/CA3097709A1/en
Priority to RU2020133727A priority patent/RU2020133727A/ru
Priority to EP19771115.3A priority patent/EP3768664B1/en
Priority to KR1020207030224A priority patent/KR102724968B1/ko
Priority to JP2020550667A priority patent/JP7265275B2/ja
Priority to AU2019239658A priority patent/AU2019239658A1/en
Priority to CN201980031603.9A priority patent/CN112368272B/zh
Publication of WO2019182960A1 publication Critical patent/WO2019182960A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure relates to inhibitors of protein tyrosine phosphatase SHP2 (Src Homolgy-2 phosphatase) and their use in treating SHP2 mediated disorders. More specifically, this disclosure is directed to compounds that inhibit SHP2 and compositions comprising these compounds, methods of treating diseases associated with the aberrant activity of SHP2, and methods of synthesizing these compounds.
  • Tyrosyl phosphorylation regulates human cellular processes from cell differentiation to growth and apoptosis etc. Tyrosyl phosphorylation is regulated by protein-tyrosine kinases (PTK) and protein-tyrosine phosphatases (PTP). The imbalance of regulation governed by PTK and PTP activity leads to various diseases.
  • PTK protein-tyrosine kinases
  • PTP protein-tyrosine phosphatases
  • SHP2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the Protein-tyrosine phosphatase non-receptor type 11 (PTPN11) gene. It contains two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain, and a C-terminal tail. The protein exists in an inactive, auto-inhibited basal conformation that blocks the active site. This self-inhibition state is stabilized by a binding network involving residues from both the N-SH2 and catalytic domains. Stimulation by, for example, cytokines or growth factors results in enzymatic activation of SHP2 and makes the active site available for dephosphorylation of PTPN11 substrates.
  • PTP protein tyrosine phosphatase
  • PTPN11 Protein-tyrosine phosphatase non-receptor type 11
  • SHP2 is widely expressed in most tissues and contributes to various cellular functions including proliferation, differentiation, cell cycle maintenance and migration. It is involved in signaling through the Ras-mitogen-activated protein kinase, the JAK-STAT, EGFR, or the phosphoinositol 3-kinase-AKT pathways.
  • PTPN11/SHP2 may be implicated in immune evasion during tumorigenesis, and hence a SHP2 inhibitor could stimulate the immune response in cancer patients.
  • SHP2 plays an important role in JAK/STAT3 pathway, with clear correlation between its phosphatase activity and systemic autoimmunity, thus a SHP2 inhibitor could be used to treat autoimmune diseases such as Lupus and Rheumatoid Arthritis.
  • SHP2 represents a highly attractive target for the development of novel therapies for the treatment of various diseases associated with the aberrant activity of SHP2.
  • Ring A is an optionally substituted aryl, heteroaryl, or bicyclic ring system
  • Ring B is an optionally substituted heterocyclic ring system, including non-aromatic ring system and heteroaryl, comprising a mono-cyclic ring, a bicyclic ring system, a tricyclic ring system, or a tetracyclic ring system, wherein the heterocyclic ring system contains at least 2 ring nitrogen atoms
  • R A is H or Ci- 6 hydrocarbyl.
  • Some embodiments include a method of treating diseases, disorders, or conditions associated with the aberrant activity of SHP2, such as but not limited to, cancer, and autoimmune disorders, comprising administering a therapeutically effective amount of a compound described herein, or any optionally substituted compound represented in Table I below, or a pharmaceutically acceptable salt thereof (referred to collectively herein as a "subject compound”), to a patient in need thereof.
  • Some embodiments include use of a compound described herein, such as a compound of Formula 1, a subject compound described herein in the manufacture of a medicament for the treatment of cancer, autoimmune diseases, inflammatory diseases, autoinflammatory conditions, and other SHP2 mediated disorders in a mammal.
  • a compound described herein such as a compound of Formula 1
  • a subject compound described herein in the manufacture of a medicament for the treatment of cancer, autoimmune diseases, inflammatory diseases, autoinflammatory conditions, and other SHP2 mediated disorders in a mammal.
  • Some embodiments include a pharmaceutical composition comprising a therapeutically effective amount of a subject compound described herein, or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable vehicle, diluent, or carrier.
  • Some embodiments include a process for making a pharmaceutical composition comprising combining a subject compound described herein and at least one pharmaceutically acceptable carrier.
  • Some embodiments include a medicament comprising a composition comprising a therapeutically effective amount of a subject compound. Some embodiments include a kit comprising a medicament of above and a label indicating that the medicament is for treating a disease, disorders, or condition associated with the aberrant activity of SHP2.
  • any reference to a compound herein by structure, name, or any other means includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts, or HCI, H2SO4, HCO2H, and CF3CO2H salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • pharmaceutically acceptable salts such as sodium, potassium, and ammonium salts, or HCI, H2SO4, HCO2H, and CF3CO2H salts
  • prodrugs such as ester prodrugs
  • alternate solid forms such as polymorphs, solvates, hydrates, etc.
  • tautomers or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • stereochemistry is not indicated, a name or structural depiction includes any stereoisomer or any mixture of stereoisomers.
  • a compound or chemical structural feature such as aryl when referred to as being “optionally substituted,” it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is "substituted,” meaning that the feature has one or more substituents.
  • substituted is broad, and includes a moiety that occupies a position normally occupied by one or more hydrogen atoms attached to a parent compound or structural feature.
  • a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g.
  • a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight of 15 g/mol to 200 g/mol.
  • a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, P, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, S, P, Si, F, Cl, Br, or I atom.
  • substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, al kylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihal
  • molecular weight is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.
  • treating includes the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.
  • a hydrogen atom in any position of a compound of Formula 1 may be replaced by a deuterium.
  • a compound of Formula 1 contains a deuterium atom or multiple deuterium atoms.
  • Ring A is: optionally substituted phenyl, optionally substituted naphthalen-l-yl, optionally substituted pyridin-3-yl, optionally substituted pyridin-4-yl, optionally substituted 2-oxo-l,2-dihydropyridin-4-yl, optionally substituted lH-indol-4- yl, optionally substituted 2-oxoindolin-4-yl, optionally substituted indolin-4-yl, optionally substituted 3-(2-oxo-2,5-dihydro-lH-pyrrole-3-carboxamido)phenyl, optionally substituted 3-(4-oxo-4H- pyrido[l,2-a]pyrimidine-3-carboxamido)phenyl, optionally substituted 3-(4-oxo-4H-pyrazino[l,2- a]pyrimidine-3-carboxamido)phenyl, optionally substituted 3-(4-oxo-4H
  • Ring A is unsubstituted.
  • Ring A has a Cl substituent.
  • Ring A has two Cl substituents.
  • Ring A has two Cl substituents at 2- and 3-positions; for example, Ring A is 2,3-dichlorophenyl.
  • Ring A has a CF3 substituent.
  • Ring A has a CF3 substituent at 2-position.
  • Ring A has an N FI2 substituent.
  • Ring A has an N FI2 substituent and a Cl substituent.
  • Ring A has an NFI2 substituent and a Cl substituent with Cl at 2-position and N FI2 at 5-position. In some embodiments, Ring A has an NH2 substituent and a Cl substituent with Cl at 2-position and N H2 at 3-position.
  • Ring A has an NH2 substituent and a Cl substituent with Cl at 3-position and N H2 at 2-position.
  • Ring A has an -OCH 3 substituent.
  • Ring A has an -OCH 3 substituent and a Cl substituent.
  • Ring A has an -OCH 3 substituent and a Cl substituent with Cl at 2- position and -OCH 3 at 3-position.
  • Ring A has an F substituent.
  • Ring A has two F substituents.
  • Ring A has two F substituents at same position.
  • Ring A has two F substituents at 2- and 3-positions.
  • Ring A has an F substituent and a Cl substituent.
  • Ring A has an F substituent and a Cl substituent with Cl at 2-position and F at 3-position.
  • Ring A has an acetyl substituent.
  • Ring A has a CH 3 substituent.
  • Ring A has two CH 3 substituents that are at same position.
  • Ring A has a CH 3 substituent and a Cl substituent.
  • Ring A has a CH3 substituent and a Cl substituent with Cl at 2-position and CH3 at 4-position.
  • Ring A has a CH3 substituent and a Cl substituent with Cl at 2-position and CH3 at 3-position.
  • Ring A has a CH 3 substituent and two F substituents.
  • Ring A has a CH 3 substituent and two F substituents with two F at same position.
  • Ring A has an OFI substituent.
  • Ring A has an OFI substituent and a Cl substituent. In some embodiments, Ring A has multiple substituents with any combination of the above substituents.
  • Ring B is: optionally substituted 6-oxo-5- (piperidin-l-yl)-l,6-dihydropyrazin-2-yl, optionally substituted 6-oxo-5-(pyrrolidin-l-yl)-l,6- dihydropyrazin-2-yl, optionally substituted 5-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-6-oxo-l,6- dihydropyrazin-2-yl, optionally substituted 5-(3,6-diazabicyclo[3.2.0] heptan-6-yl)-6-oxo-l,6- dihydropyrazin-2-yl, optionally substituted 6-oxo-5-(2-oxa-8-azaspiro[4.5]decan-8-yl)-l,6- dihydropyrazin-2-yl, optionally substituted 6-oxo-5-(piperidin-4-ylamino
  • Ring B is unsubstituted.
  • Ring B has a -CH 3 substituent.
  • Ring B has a -CH 2 NH 2 substituent.
  • Ring B has a -NH 2 substituent.
  • Ring B has a -CH 2 CH 2 NH 2 substituent.
  • Ring B has a l-aminopropan-2-yl substituent.
  • Ring B has a -CN substituent.
  • Ring B has an -F substituent.
  • Ring B has a -Cl substituent.
  • Ring B has a -CH2F substituent.
  • Ring B has an -OFI substituent.
  • Ring B has an -OCFI 3 substituent.
  • Ring B has multiple substituents with any combination of the above substituents.
  • X is S, O, NR A , CFIR A , SO, SO 2 , CO, or a bond.
  • X is S. In some embodiments, X is a bond. In some embodiments, X is O. In some embodiments, X is N H. In some embodiments, X is— CH(CH 3 ). In some embodiments, X is CH 2 .
  • R A is FI or C 1-6 hydrocarbyl. In some embodiments, R A is FI. In some embodiments, R A is CFI3.
  • Ring A could be any core structure in any of these depicted possibilities, wherein these core structures are optionally substituted.
  • Ring B could be any core structure in any of these depicted possibilities, wherein these core structures are optionally substituted.
  • Some embodiments include one of the compounds in Table 1, wherein any of the compounds in Table 1 below may be optionally substituted.
  • Table 1
  • a pharmaceutical composition comprising a compound of Formula 1 may be adapted for oral, or parental, such as intravenous, intramuscular, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder.
  • the dosage of a compound of Formula 1 may vary depending on the route of administration, body weight, age, the type and condition of the disease being treated.
  • a pharmaceutical composition provided herein may optionally comprise two or more compounds of the Formula 1 without an additional therapeutic agent, or may comprise an additional therapeutic agent (i.e., a therapeutic agent other than a compound provided herein).
  • the subject compounds can be administered simultaneously, sequentially, or separately in combination with at least one other therapeutic agent.
  • the other therapeutic agent can be a small molecule, an antibody-drug conjugate, or a biologic.
  • Therapeutic agents suitable for combination with a subject compound include, but are not limited to antibiotics, antiemetic agents, antidepressants, and antifungal agents, anti-inflammatory agents, antiviral agents, and anticancer agents that are known in the art.
  • the other therapeutic agents are chemotherapy agents, for example, mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel; or tyrosine kinase inhibitors, for example Erlotinib; ALK inhibitors such as Crizotinib; BRAF inhibitors such as Vemurafanib; MEK inhibitors such as trametinib; or other anticancer agents, i.e. cisplatin, flutamide, gemcitabine, CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors.
  • mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel
  • tyrosine kinase inhibitors for example Erlotinib
  • ALK inhibitors such as Crizotinib
  • BRAF inhibitors such as Vemurafanib
  • MEK inhibitors such as trametinib
  • other anticancer agents i.e. cisplatin, flut
  • the pharmaceutical composition may be used for the treatment of cancer, autoimmune diseases, inflammatory diseases, autoinflammatory conditions, and other SHP2 mediated disorders in patients.
  • patient herein means a mammal (e.g., a human or an animal). In some embodiments, the patient has cancer.
  • the pharmaceutical composition described herein can be prepared by combining a compound of Formula 1 with at least one pharmaceutical acceptable inert ingredient, such as a carrier, excipient, filler, lubricant, flavoring agent, buffer, etc., selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • a pharmaceutical acceptable inert ingredient such as a carrier, excipient, filler, lubricant, flavoring agent, buffer, etc.
  • the relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.
  • Some embodiments include a method of treating a SHP2 mediated disease or disorder comprising administering a therapeutically effective amount of a compound of Formula 1, or any compound described herein, or a pharmaceutically acceptable salt thereof ("subject compound”), or a pharmaceutical composition comprising a subject compound to a patient in need thereof.
  • a "therapeutically effective amount” herein refers to an amount of a subject compound, or a pharmaceutical composition containing a subject compound, sufficient to be effective in inhibiting SH P2 and thus providing a benefit in the treatment of cancer, autoimmune diseases, inflammatory diseases, autoinflammatory conditions, and other SH P2 mediated disorders in patients, such as to delay or minimize symptoms associated with cancer, autoimmune, inflammatory diseases, and autoinflammatory conditions, or to ameliorate a disease or infection or cause thereof, or to prevent the further development of a disorder, or reducing the severity of symptoms that are otherwise expected to develop without treatment.
  • Formula 1-1 Formula 1 -2 Scheme 1 illustrates a method for preparing compounds of Formula 1.
  • L is S, O, N or a bond
  • Ri is H, C1-C6 alkyl, NH2, or CN
  • R 2 is aryl, heterocycloalkyl or heteroaryl
  • R3 is C1-C6 alkyl, ORi
  • R5 is alkyl, H
  • R6 is alkyl, H
  • R5 and R6 together with the atom or atoms to which they are attached, can combine to form a monocyclic or polycyclic C3-C12 cycloalkyl or heterocycle.
  • Compound int-1 is treated with aryl or alkyl boronic acids or esters or salts (where L is a bond) under suitable metal catalysts (such Pd2(dba)3, or the like), suitable ligands (such as dppf, or the like), suitable bases (such as Cs 2 C0 3 , or the like), suitable solvents (such as DMF, or the like) to provide a product of int-2.
  • suitable metal catalysts such Pd2(dba)3, or the like
  • suitable ligands such as dppf, or the like
  • suitable bases such as Cs 2 C0 3 , or the like
  • suitable solvents such as DMF, or the like
  • compound int-1 was reacted with corresponding phenols, thiophenols, thioalcohols or amines under suitable metal catalysts (such as Cul, Pd2(dba) 3 ), suitable ligands (such as TMEDA, XPFIOS, Xantphos, or the like), suitable salts or bases (such as Cs 2 C0 3 , K 3 P0 4 or the like), suitable solvents (such as DMF, dioxane or the like) to provide a product of int-2.
  • suitable metal catalysts such as Cul, Pd2(dba) 3
  • suitable ligands such as TMEDA, XPFIOS, Xantphos, or the like
  • suitable salts or bases such as Cs 2 C0 3 , K 3 P0 4 or the like
  • suitable solvents such as DMF, dioxane or the like
  • Scheme 2 illustrates a method for preparing compounds of Formula 1-3.
  • Compound lnt-1 was first halogenated to provide intermediate lnt-2.
  • the activated chlorine in lnt-2 was displaced by an amine to afford lnt-4.
  • lnt-6 was regioselectively hydrolyzed to provide lnt-3, and then followed by substitutions and couplings to offer target compounds.
  • the compounds of Formula 1-3 can be synthesized using an alternative way, as illustrated in Scheme 3.
  • the order of reaction steps may alter. Coupling reactions may occur before the amine displacement.
  • Scheme 4 illustrates a method for preparing compounds of Formula I-4.
  • Int-l was reacted with an aryl amine or phenol in the presence of a suitable metal catalyst (such as Cul, or the like), a suitable ligand (such as TMEDA, TMFID, or the like), a suitable salt (such as K3PO4, or the like) and a suitable solvent (such as dioxane or the like).
  • a suitable metal catalyst such as Cul, or the like
  • a suitable ligand such as TMEDA, TMFID, or the like
  • a suitable salt such as K3PO4, or the like
  • a suitable solvent such as dioxane or the like.
  • the reaction proceeds at a temperature ranged 80 °C to 140 °C, with the reaction time from 1 - 24 hours lnt-2 reacted with an amine in the presence of a suitable coupling reagent (such as BOP-CI, or the like), a suitable base (such DIEPA, DBU, or the like), and a suitable solvent (such as DMF, TH F or the like).
  • a suitable coupling reagent such as BOP-CI, or the like
  • a suitable base such DIEPA, DBU, or the like
  • a suitable solvent such as DMF, TH F or the like
  • the order of reactions can be modified to change the overall synthesis to allow for variations at different positions of the molecule at different stages of the preparation.
  • compound of Formula lnt-1 is activated and reacted with an amine to provide lnt-2 first, and then followed with the coupling reaction, to provide compound of Formula 1-4.
  • Scheme 6 illustrates a method for preparing compounds of Formula I-5.
  • Step 1 preparation of tert-butyl ((l-(4,5-dichloro-l-methyl-6-oxo-l,6-dihydropyrimidin-2-yl)-4- methylpiperidin-4-yl)methyl)carbamate (3)
  • Step 2 preparation of tert-butyl ((l-(5-chloro-4-cyano-l-methyl-6-oxo-l,6-dihydropyrimidin-2-yl)-4- methylpiperidin-4-yl)methyl)carbamate (4)
  • Step 3 preparation of tert-butyl ((l-(4-cyano-5-(2,3-dichlorophenyl)-l-methyl-6-oxo-l,6- dihydropyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (6)
  • Step 4 preparation of 2-(4-(aminomethyl)-4-methylpiperidin-l-yl)-5-(2,3-dichlorophenyl)-l-methyl- 6-oxo-l,6-dihydropyrimidine-4-carbonitrile
  • Step 2 preparation of 3-(benzyloxy)-5-bromo-2-chloropyrazine (4)
  • Step 4 preparation of tert-butyl ((l-(3-(benzyloxy)-5-(2,3-dichlorophenyl)pyrazin-2-yl)-4- methylpiperidin-4-yl)methyl)carbamate (8)
  • Step 5 preparation of 3-(4-(aminomethyl)-4-methylpiperidin-l-yl)-6-(2,3-dichlorophenyl)- pyrazin-2(lH)-one
  • Step 1 preparation of 3-(benzyloxy)-2-chloro-5-((2,3-dichlorophenyl)thio)pyrazine (3)
  • Step 2 preparation of 3-chloro-6-((2,3-dichlorophenyl)thio)pyrazin-2(lH)-one (4)
  • Step 3 preparation of 3-chloro-6-((2,3-dichlorophenyl)thio)-l-methylpyrazin-2(lH)-one (5)
  • Step 4 preparation of tert-butyl ((l-(5-((2,3-dichlorophenyl)thio)-4-methyl-3-oxo-3,4- dihydropyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (7)
  • Step 3 preparation of 3-(4-(aminomethyl)-4-methyl piperidin-l-yl)-6-((2,3-dichlorophenyl)thio)-l- methylpyrazin-2(lH)-one
  • Step 1 prepa ration of 2, 4, 6-trichloropyrimidine-5-ca rba ldehyde (2) A mixture of compound 1 (25.6 g, 1.0 eq) with POCI 3 (100 mL) and DMF (30 mL) was heated at 120 °C for 15 h, and then DMF was evaporated. Ice water was added to the residue and the solid formed was collected and dried to give compound 2 (9.2 g, 21%).
  • Step 2 preparation of 4, 6-dichloro-lFI-pyrazolo [3, 4-d] pyrimidine (3)
  • Step 4 preparation of 6-chloro-3-iodo-4-methoxy-lH-pyrazolo [3, 4-d] pyrimidine (5)
  • Step 5 preparation of 6-chloro-3-iodo-4-methoxy-l-((2-(trimethylsilyl) ethoxy) methyl)-lH-pyrazolo [3, 4-d] pyrimidine (6)
  • Step 6 preparation of tert-butyl ((l-(3-iodo-4-methoxy-l-((2-(trimethylsilyl) ethoxy) methyl)-lH- pyrazolo [3, 4-d] pyrimidin-6-yl)-4-methylpiperidin-4-yl) methyl) carbamate (8)
  • Step 7 preparation of tert-butyl ((l-(3-((2,3-dichlorophenyl)amino)-4-methoxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[3,4-d] pyrimidin-6-yl)-4-methylpiperidin-4- yl)methyl)carbamate (10)
  • Step 8 preparation of 6-(4-(aminomethyl)-4-methylpiperidin-l-yl)-3-((2, 3-dichlorophenyl) amino)-l, 5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one
  • Step 3 preparation of tert-butyl ((l-(3-((2,3-dichlorophenyl)thio)-lH-pyrazolo[3,4-d] pyrimidin-6-yl)- 4-methylpiperidin-4-yl)methyl)carbamate (6)
  • compound 4 145mg, 1.0 eq
  • DIEA DIEA
  • compound 5 300 mg, 3.0 eq
  • the reaction was quenched by water and worked up under standard operation to give compound 6 as a yellow oil (110 mg, 48%).
  • Step 4 preparation of (l-(3-((2,3-dichlorophenyl)thio)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-4- methylpiperidin-4-yl)methanamine
  • Step 3 preparation of 6-amino-5-((2,3-dichlorophenyl)thio)-3-methylpyrimidine-2,4(lH,3H)-dione (5)
  • compound 3 500 mg, 1.0 eq
  • compound 4 813 mg, 2.0 eq
  • K3PO4 1445 mg, 3.0 eq
  • TMEDA 105 mg, 0.4 eq
  • Cul 86 mg, 0.2 eq
  • Step 4 preparation of tert-butyl 5-(4-amino-5-((2,3-dichlorophenyl)thio)-l-methyl-6-oxo-l,6- dihydropyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (7)
  • Step 5 preparation of 6-amino-5-((2,3-dichlorophenyl)thio)-2-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)- yl)-3-methylpyrimidin-4(3H)-one
  • Step 1 preparation of tert-butyl ((l-(3-(benzyloxy)-5-((2-chloro-3-(4-hydroxy-l,5,5-trimethyl-2- oxo-2,5-dihydro-lH-pyrrole-3-carboxamido)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4- yl)methyl)carbamate (3)
  • Step 2 preparation of N-(3-((5-(4-(aminomethyl)-4-methylpiperidin-l-yl)-6-oxo-l,6-dihydropyrazin- 2-yl)thio)-2-chlorophenyl)-4-hydroxy-l,5,5-trimethyl-2-oxo-2,5-dihydro-lH-pyrrole-3-carboxamide
  • BCIB 1.9 mL, 1.0 mol/L in DCM, 10.0 eq
  • Step 4 Preparation of tert-butyl (3-(4-(2,3-dichlorophenyl)-2-oxopyridin-l(2H)- yl)cyclohexyl)carbamate (7)
  • Step 5 Synthesis of l-(3-aminocyclohexyl)-4-(2,3-dichlorophenyl)pyridin-2(lH)-one
  • Full length SHP2 enzyme (diluted to 0.1 nM in reaction buffer) were co-incubated with 1 uM IRS-1 peptide and 0.01 nM to 10 mM compounds of the disclosure for 60 min.
  • the surrogate substrate DiFM UP (5 pL, 100 mM) was added, and incubated at rt for 60 min.
  • the reaction was then quenched by the addition of 5 pL of a 40 mM solution of bpV(Phen).
  • the fluorescence signal was monitored using a microplate reader (Envision, Perkin-Elmer) using excitation and emission wavelengths of 360 nm and 450 nm, respectively.
  • the inhibitor dose-response curves were analyzed using normalized IC50 regression curve fitting with control-based normalization.
  • the inhibitory activity results of the compounds of the disclosure is shown in Table 2.
  • IC50 +++: ⁇ 50 nM; ++: ⁇ 100 nM; +: ⁇ 1 mM;
  • IC50 +++: ⁇ 0.1 mM; ++: ⁇ 0.5 mM; +: ⁇ 1 mM;
  • the compounds described herein is very potent and selective, with enzymatic IC50 less than 10 nM.
  • the compounds tested also displayed superior anti-tumor activities in the in vivo animal models. I n some embodiments, the dose amount per day falls within the range of 3-100 mg/kg to achieve the tumor regression or >80% tumor growth inhibition.

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Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020156243A1 (zh) * 2019-01-31 2020-08-06 贝达药业股份有限公司 Shp2抑制剂及其应用
US10851110B2 (en) 2016-05-31 2020-12-01 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of PTPN11
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
US10954243B2 (en) 2018-05-02 2021-03-23 Navire Pharma, Inc. Substituted heterocyclic inhibitors of PTPN11
WO2021073439A1 (zh) * 2019-10-14 2021-04-22 杭州雷索药业有限公司 用于抑制shp2活性的吡嗪衍生物
US11001561B2 (en) 2019-04-08 2021-05-11 Merck Patent Gmbh Pyrimidinone derivatives as SHP2 antagonists
WO2021092115A1 (en) 2019-11-08 2021-05-14 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2021143680A1 (zh) * 2020-01-16 2021-07-22 浙江海正药业股份有限公司 杂芳基类衍生物及其制备方法和用途
WO2021147879A1 (zh) * 2020-01-21 2021-07-29 贝达药业股份有限公司 Shp2抑制剂及其应用
US11104675B2 (en) 2018-08-10 2021-08-31 Navire Pharma, Inc. PTPN11 inhibitors
US11179397B2 (en) 2018-10-03 2021-11-23 Gilead Sciences, Inc. Imidazopyrimidine derivatives
WO2021257736A1 (en) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Methods for delaying, preventing, and treating acquired resistance to ras inhibitors
WO2021259077A1 (zh) * 2020-06-22 2021-12-30 四川科伦博泰生物医药股份有限公司 取代吡嗪类化合物，包含其的药物组合物及其用途
WO2022060583A1 (en) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
WO2022060836A1 (en) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Indole derivatives as ras inhibitors in the treatment of cancer
US11466016B2 (en) 2018-03-02 2022-10-11 Otsuka Pharmaceutical Co., Ltd. Pharmaceutical compounds
US11466017B2 (en) 2011-03-10 2022-10-11 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of PTPN11
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
CN115353509A (zh) * 2018-10-10 2022-11-18 江苏豪森药业集团有限公司 含氮杂芳类衍生物调节剂、其制备方法和应用
WO2022259157A1 (en) 2021-06-09 2022-12-15 Novartis Ag A triple pharmaceutical combination comprising dabrafenib, trametinib and a shp2 inhibitor
WO2022269525A1 (en) 2021-06-23 2022-12-29 Novartis Ag Pharmaceutical combinations comprising a kras g12c inhibitor and uses thereof for the treatment of cancers
WO2023031781A1 (en) 2021-09-01 2023-03-09 Novartis Ag Pharmaceutical combinations comprising a tead inhibitor and uses thereof for the treatment of cancers
WO2023060253A1 (en) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Ras inhibitors
US11634417B2 (en) 2019-04-02 2023-04-25 Array Biopharma Inc. Protein tyrosine phosphatase inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
US11827644B2 (en) 2019-03-04 2023-11-28 Suzhou Genhouse Pharmaceutical Co., Ltd Pyrazine derivative and application thereof in inhibiting SHP2
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
CN117683033A (zh) * 2019-12-19 2024-03-12 首药控股(北京)股份有限公司 取代的炔基杂环化合物
JP2024516317A (ja) * 2021-05-12 2024-04-12 薬雅科技（上海）有限公司 Ｓｈｐ２リン酸化酵素阻害剤の調製と応用
US12037345B2 (en) 2018-07-24 2024-07-16 Taiho Pharmaceutical Co., Ltd. Heterobicyclic compounds for inhibiting the activity of SHP2
JP2024527535A (ja) * 2021-07-09 2024-07-25 カナプ セラピューティクス インコーポレイテッド Ｓｈｐ２阻害剤及びその使用
US12071415B2 (en) 2018-10-16 2024-08-27 Georgia State University Research Foundation, Inc. Carbon monoxide prodrugs for the treatment of medical disorders
US12097203B2 (en) 2021-05-05 2024-09-24 Huyabio International, Llc Combination therapies comprising SHP2 inhibitors and PD-1 inhibitors
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024211663A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024211712A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024216048A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof
WO2024216016A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of a ras inhibitor
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
US12187721B2 (en) 2018-10-17 2025-01-07 Array Biopharma Inc. Protein tyrosine phosphatase inhibitors
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
US12390469B2 (en) 2021-05-05 2025-08-19 Huyabio International, Llc SHP2 inhibitor monotherapy and uses thereof
US12458640B2 (en) 2019-08-20 2025-11-04 Otsuka Pharmaceutical Co., Ltd. Pyrazolo[3,4-b]pyrazine SHP2 phosphatase inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
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WO2026050446A1 (en) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Ras inhibitors
WO2026072904A2 (en) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions and methods for treating lung cancer

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102598895B1 (ko) 2016-07-12 2023-11-07 레볼루션 메디슨즈, 인크. 다른자리 입체성 shp2 억제제로서의 2,5-이치환 3-메틸 피라진 및 2,5,6-3치환 3-메틸 피라진
US11529347B2 (en) 2016-09-22 2022-12-20 Relay Therapeutics, Inc. SHP2 phosphatase inhibitors and methods of use thereof
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MX2019008696A (es) 2017-01-23 2019-09-13 Revolution Medicines Inc Compuestos de piridina como inhibidores de shp2 alostericos.
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WO2018218133A1 (en) 2017-05-26 2018-11-29 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine derivatives as shp2 phosphatase inhibitors
EP3687997A1 (en) 2017-09-29 2020-08-05 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine derivatives as shp2 phosphatase inhibitors
MX2020003579A (es) * 2017-10-12 2020-07-22 Revolution Medicines Inc Compuestos de piridina, pirazina, y triazina como inhibidores de shp2 alostericos.
BR112020009757A2 (pt) 2017-12-15 2020-11-03 Revolution Medicines, Inc. compostos policíclicos como inibidores alostéricos de shp2
WO2019183364A1 (en) 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors and methods of use thereof
SG11202009245TA (en) 2018-03-21 2020-10-29 Relay Therapeutics Inc Shp2 phosphatase inhibitors and methods of use thereof
AU2020354475A1 (en) 2019-09-24 2022-05-05 Relay Therapeutics, Inc. SHP2 phosphatase inhibitors and methods of making and using the same
CN114829362A (zh) * 2019-12-10 2022-07-29 成都倍特药业股份有限公司 一种可用作shp2抑制剂的含氮杂原子的六元并五元芳环衍生物
CN115028649B (zh) * 2021-03-05 2026-03-17 四川科伦博泰生物医药股份有限公司 三并环类化合物，包含其的药物组合物及其用途
CN113248449B (zh) * 2021-05-06 2022-09-23 中国药科大学 一种含甲脒的芳基螺环类化合物及其制备方法与应用
CN115340559A (zh) * 2021-05-12 2022-11-15 药雅科技(上海)有限公司 Shp2磷酸酶杂环类抑制剂的制备及其应用
CN115340561A (zh) * 2021-05-14 2022-11-15 药雅科技(上海)有限公司 Shp2磷酸酶稠环类抑制剂的制备及其应用
CN115340545A (zh) * 2021-05-14 2022-11-15 浙江海正药业股份有限公司 双环杂芳基类衍生物及其制备方法和用途
EP4573095A1 (en) 2022-08-17 2025-06-25 Treeline Biosciences, Inc. Pyridopyrimidine kras inhibitors
CN121568944A (zh) * 2023-07-11 2026-02-24 勤浩医药(苏州)股份有限公司 用作shp2抑制剂的杂环化合物、包含其的药物组合物及其制备方法和用途
TW202528315A (zh) 2023-09-21 2025-07-16 美商樹線生物科學公司 螺環二氫哌喃并吡啶ＫＲａｓ抑制劑
WO2025081291A1 (en) * 2023-10-16 2025-04-24 Canwell Biotech Limited Benzo [c] [1, 2] oxaborol-1 (3h) -ol derivatives as shp2 inhibitors, compositions and methods thereof
WO2025245127A1 (en) 2024-05-21 2025-11-27 Treeline Biosciences, Inc. Spirocyclic dihydropyranopyrimidine kras inhibitors

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050182072A1 (en) * 2004-01-14 2005-08-18 Amgen Inc. Substituted heterocyclic compounds and methods of use
WO2006060318A2 (en) * 2004-11-30 2006-06-08 Amgen Inc. Quinolines and quinazoline analogs and their use as medicaments for treating cancer
WO2007149448A2 (en) * 2006-06-21 2007-12-27 E. I. Du Pont De Nemours And Company Pyrazinones as cellular proliferation inhibitors
WO2008107398A2 (en) * 2007-03-02 2008-09-12 Basf Se Pyrazine compounds
WO2011022440A2 (en) * 2009-08-17 2011-02-24 Memorial Sloan-Kettering Cancer Center Heat shock protein binding compounds, compositions, and methods for making and using same
WO2015036560A1 (de) * 2013-09-16 2015-03-19 Bayer Pharma Aktiengesellschaft Heterocyclisch substituierte trifluormethylpyrimidinone und ihre verwendung
WO2015168466A1 (en) * 2014-05-01 2015-11-05 Quanticel Pharmaceuticals, Inc. Inhibitors of lysine specific demethylase-1
WO2015175707A1 (en) * 2014-05-13 2015-11-19 Memorial Sloan Kettering Cancer Center Hsp70 modulators and methods for making and using the same
WO2016203404A1 (en) * 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2016203405A1 (en) 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2017156397A1 (en) * 2016-03-11 2017-09-14 Board Of Regents, The University Of Texas Sysytem Heterocyclic inhibitors of ptpn11
WO2018013597A1 (en) * 2016-07-12 2018-01-18 Revolution Medicines, Inc. 2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric shp2 inhibitors
WO2018031658A1 (en) * 2016-08-10 2018-02-15 Celgene Corporation Treatment of relapsed and/or refractory solid tumors and non-hodgkin's lymphomas

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10238477A1 (de) * 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Purinderivate, deren Herstellung und deren Verwendung als Arzneimittel
WO2004096806A1 (ja) * 2003-04-30 2004-11-11 Sumitomo Pharmaceuticals Co. Ltd. 縮合イミダゾール誘導体
US20070219178A1 (en) * 2003-12-04 2007-09-20 Eisai Co., Ltd. Preventive or therapeutic agents for multiple sclerosis
US8350043B2 (en) * 2005-06-07 2013-01-08 Pharmacopeia, Inc. Azinone and diazinone V3 inhibitors for depression and stress disorders
WO2009049098A2 (en) 2007-10-09 2009-04-16 Indiana University Research & Technology Corporation Materials and methods for regulating the activity of phosphatases
CN102080087B (zh) 2010-12-08 2012-05-30 厦门大学 蛋白酪氨酸磷酸酶shp2的核酸适体及其制备方法
AU2014256984B2 (en) 2013-04-26 2019-02-14 Indiana University Research & Technology Corporation Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
EP3016652A4 (en) 2013-07-03 2017-03-08 Indiana University Research and Technology Corporation Shp2 inhibitors and methods of treating autoimmune and/or glomerulonephritis-associated diseases using shp2 inhibitors
JP6523303B2 (ja) 2014-01-17 2019-05-29 ノバルティス アーゲー Ｓｈｐ２の活性を阻害するための１−ピリダジン／トリアジン−３−イル−ピペラジン／ピペリジン／ピロリジン誘導体およびその組成物
CN105899493B (zh) 2014-01-17 2019-03-29 诺华股份有限公司 用于抑制shp2活性的1-(三嗪-3-基/哒嗪-3-基)-哌(-嗪)啶衍生物及其组合物
JO3517B1 (ar) 2014-01-17 2020-07-05 Novartis Ag ان-ازاسبيرو الكان حلقي كبديل مركبات اريل-ان مغايرة وتركيبات لتثبيط نشاط shp2
RS60658B1 (sr) * 2014-06-27 2020-09-30 Celgene Quanticel Research Inc Inhibitori lizin specifične demetilaze-1
WO2016196569A1 (en) 2015-06-01 2016-12-08 Indiana University Research & Technology Corporation Small molecule inhibitors of protein tyrosine phosphatases and uses thereof
CN112625028B (zh) 2015-06-19 2024-10-29 诺华股份有限公司 用于抑制shp2活性的化合物和组合物
US9932288B2 (en) 2015-12-09 2018-04-03 West Virginia University Chemical compound for inhibition of SHP2 function and for use as an anti-cancer agent
CN107286150B (zh) 2016-04-11 2020-07-07 中国科学院上海有机化学研究所 N-杂环类化合物、其中间体、制备方法、药物组合物和应用
EA202092441A1 (ru) 2016-06-07 2021-05-21 Джакобио Фармасьютикалс Ко., Лтд. Новые гетероциклические производные, применимые в качестве ингибиторов shp2
MX383856B (es) * 2016-06-14 2025-03-14 Novartis Ag Compuestos y composiciones para inhibir la actividad de shp2.
US11529347B2 (en) 2016-09-22 2022-12-20 Relay Therapeutics, Inc. SHP2 phosphatase inhibitors and methods of use thereof
TW202500565A (zh) 2016-10-24 2025-01-01 美商傳達治療有限公司 Shp2磷酸酶抑制劑及其使用方法
US20190343836A1 (en) 2017-01-10 2019-11-14 Novartis Ag Pharmaceutical combination comprising an alk inhibitor and a shp2 inhibitor
MX2019008696A (es) 2017-01-23 2019-09-13 Revolution Medicines Inc Compuestos de piridina como inhibidores de shp2 alostericos.
CN108341791B (zh) 2017-01-23 2020-09-29 中国科学院上海药物研究所 苯并噻二唑类化合物、其制备方法及用途
MX2019008695A (es) 2017-01-23 2019-09-11 Revolution Medicines Inc Compuestos biciclicos como inhibidores alostericos de shp2.
EP3589647A1 (en) 2017-02-28 2020-01-08 Novartis AG Shp inhibitor compositions and uses for chimeric antigen receptor therapy
KR20240026521A (ko) 2017-03-23 2024-02-28 자코바이오 파마슈티칼스 컴퍼니 리미티드 Shp2 억제제로서 유용한 신규한 헤테로환형 유도체
WO2018218133A1 (en) 2017-05-26 2018-11-29 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine derivatives as shp2 phosphatase inhibitors
CA3074690A1 (en) 2017-09-07 2019-03-14 Revolution Medicines, Inc. Shp2 inhibitor compositions and methods for treating cancer
EP3687997A1 (en) 2017-09-29 2020-08-05 Relay Therapeutics, Inc. Pyrazolo[3,4-b]pyrazine derivatives as shp2 phosphatase inhibitors
MX2020003579A (es) 2017-10-12 2020-07-22 Revolution Medicines Inc Compuestos de piridina, pirazina, y triazina como inhibidores de shp2 alostericos.
CN108113984B (zh) 2017-12-20 2021-05-07 中国科学院成都生物研究所 Shp2抑制剂在制备抗肿瘤的药物中的用途
WO2019165073A1 (en) * 2018-02-21 2019-08-29 Relay Therapeutics, Inc. Shp2 phosphatase inhibitors and methods of use thereof
CN108578395B (zh) 2018-06-21 2019-10-25 厦门大学 苯丙烯酸类化合物在制备Shp2特异性抑制剂中的用途及其制药用途
CN109646441A (zh) 2019-01-25 2019-04-19 上海交通大学医学院附属仁济医院 Shp-2抑制剂在制备靶向前神经元型胶质瘤的药物中的应用

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050182072A1 (en) * 2004-01-14 2005-08-18 Amgen Inc. Substituted heterocyclic compounds and methods of use
WO2006060318A2 (en) * 2004-11-30 2006-06-08 Amgen Inc. Quinolines and quinazoline analogs and their use as medicaments for treating cancer
WO2007149448A2 (en) * 2006-06-21 2007-12-27 E. I. Du Pont De Nemours And Company Pyrazinones as cellular proliferation inhibitors
WO2008107398A2 (en) * 2007-03-02 2008-09-12 Basf Se Pyrazine compounds
WO2011022440A2 (en) * 2009-08-17 2011-02-24 Memorial Sloan-Kettering Cancer Center Heat shock protein binding compounds, compositions, and methods for making and using same
WO2015036560A1 (de) * 2013-09-16 2015-03-19 Bayer Pharma Aktiengesellschaft Heterocyclisch substituierte trifluormethylpyrimidinone und ihre verwendung
WO2015168466A1 (en) * 2014-05-01 2015-11-05 Quanticel Pharmaceuticals, Inc. Inhibitors of lysine specific demethylase-1
WO2015175707A1 (en) * 2014-05-13 2015-11-19 Memorial Sloan Kettering Cancer Center Hsp70 modulators and methods for making and using the same
WO2016203404A1 (en) * 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2016203405A1 (en) 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2017156397A1 (en) * 2016-03-11 2017-09-14 Board Of Regents, The University Of Texas Sysytem Heterocyclic inhibitors of ptpn11
WO2018013597A1 (en) * 2016-07-12 2018-01-18 Revolution Medicines, Inc. 2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric shp2 inhibitors
WO2018031658A1 (en) * 2016-08-10 2018-02-15 Celgene Corporation Treatment of relapsed and/or refractory solid tumors and non-hodgkin's lymphomas

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
PHILIP J. KOCIENSKI: "Protecting Groups", 1994, GEORG THIEME VERLAG
See also references of EP3768664A4
SNELL B.K.: "Pyrimidines . Part II. The Photo-Fries Rearrangement of 2-Dialkyl- amino-4-pyrimidinyl Esters of Alkyl and Arylsulphonic Acids", JOURNAL OF THE CHEMICAL SOCIETY C: ORGANIC, 1968, pages 2367 - 2370, XP055638701 *
THEODORA W. GREENEPETER G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY INTERSCIENCE

Cited By (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11466017B2 (en) 2011-03-10 2022-10-11 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of PTPN11
US10851110B2 (en) 2016-05-31 2020-12-01 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of PTPN11
US11840536B2 (en) 2016-05-31 2023-12-12 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of PTPN11
US11466016B2 (en) 2018-03-02 2022-10-11 Otsuka Pharmaceutical Co., Ltd. Pharmaceutical compounds
US10954243B2 (en) 2018-05-02 2021-03-23 Navire Pharma, Inc. Substituted heterocyclic inhibitors of PTPN11
EP3787627A4 (en) * 2018-05-02 2021-12-01 Navire Pharma, Inc. SUBSTITUTED HETEROCYCLIC INHIBITORS FOR PTPN11
US11932643B2 (en) 2018-05-02 2024-03-19 Navire Pharma, Inc. Substituted heterocyclic inhibitors of PTPN11
US12037345B2 (en) 2018-07-24 2024-07-16 Taiho Pharmaceutical Co., Ltd. Heterobicyclic compounds for inhibiting the activity of SHP2
US11945815B2 (en) 2018-08-10 2024-04-02 Navire Pharma, Inc. PTPN11 inhibitors
US11104675B2 (en) 2018-08-10 2021-08-31 Navire Pharma, Inc. PTPN11 inhibitors
US11034705B2 (en) 2018-09-18 2021-06-15 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US12264167B2 (en) 2018-09-18 2025-04-01 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphate inhibitors
US11518772B2 (en) 2018-09-18 2022-12-06 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
US11459340B2 (en) 2018-09-18 2022-10-04 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
US11179397B2 (en) 2018-10-03 2021-11-23 Gilead Sciences, Inc. Imidazopyrimidine derivatives
CN115353509B (zh) * 2018-10-10 2024-04-12 江苏豪森药业集团有限公司 含氮杂芳类衍生物调节剂、其制备方法和应用
CN115353509A (zh) * 2018-10-10 2022-11-18 江苏豪森药业集团有限公司 含氮杂芳类衍生物调节剂、其制备方法和应用
US12071415B2 (en) 2018-10-16 2024-08-27 Georgia State University Research Foundation, Inc. Carbon monoxide prodrugs for the treatment of medical disorders
US12187721B2 (en) 2018-10-17 2025-01-07 Array Biopharma Inc. Protein tyrosine phosphatase inhibitors
WO2020156243A1 (zh) * 2019-01-31 2020-08-06 贝达药业股份有限公司 Shp2抑制剂及其应用
US11827644B2 (en) 2019-03-04 2023-11-28 Suzhou Genhouse Pharmaceutical Co., Ltd Pyrazine derivative and application thereof in inhibiting SHP2
US11884664B2 (en) 2019-04-02 2024-01-30 Array Biopharma Inc. Protein tyrosine phosphatase inhibitors
US11634417B2 (en) 2019-04-02 2023-04-25 Array Biopharma Inc. Protein tyrosine phosphatase inhibitors
US11001561B2 (en) 2019-04-08 2021-05-11 Merck Patent Gmbh Pyrimidinone derivatives as SHP2 antagonists
US11702392B2 (en) 2019-04-08 2023-07-18 Merck Patent Gmbh Pyrimidinone derivatives as SHP2 antagonists
US12458640B2 (en) 2019-08-20 2025-11-04 Otsuka Pharmaceutical Co., Ltd. Pyrazolo[3,4-b]pyrazine SHP2 phosphatase inhibitors
WO2021073439A1 (zh) * 2019-10-14 2021-04-22 杭州雷索药业有限公司 用于抑制shp2活性的吡嗪衍生物
CN112724145A (zh) * 2019-10-14 2021-04-30 杭州雷索药业有限公司 用于抑制shp2活性的吡嗪衍生物
US11168102B1 (en) 2019-11-08 2021-11-09 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2021092115A1 (en) 2019-11-08 2021-05-14 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
US12258366B2 (en) 2019-11-08 2025-03-25 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
EP4620531A2 (en) 2019-11-08 2025-09-24 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
CN117683033A (zh) * 2019-12-19 2024-03-12 首药控股(北京)股份有限公司 取代的炔基杂环化合物
WO2021143680A1 (zh) * 2020-01-16 2021-07-22 浙江海正药业股份有限公司 杂芳基类衍生物及其制备方法和用途
JP2023510929A (ja) * 2020-01-16 2023-03-15 浙江海正薬業股▲ふん▼有限公司 ヘテロアリール誘導体、その製造方法およびその使用
CN114867720B (zh) * 2020-01-16 2024-10-22 浙江海正药业股份有限公司 杂芳基类衍生物及其制备方法和用途
CN114867720A (zh) * 2020-01-16 2022-08-05 浙江海正药业股份有限公司 杂芳基类衍生物及其制备方法和用途
US20230348467A1 (en) * 2020-01-16 2023-11-02 Zhejiang Hisun Pharmaceutical Co., Ltd. Heteroaryl Derivative, Preparation Method Therefor, And Use Thereof
JP7392164B2 (ja) 2020-01-16 2023-12-05 浙江海正薬業股▲ふん▼有限公司 ヘテロアリール誘導体、その製造方法およびその使用
WO2021147879A1 (zh) * 2020-01-21 2021-07-29 贝达药业股份有限公司 Shp2抑制剂及其应用
WO2021257736A1 (en) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Methods for delaying, preventing, and treating acquired resistance to ras inhibitors
JP2023530838A (ja) * 2020-06-22 2023-07-20 スーチュアン・コールン－バイオテック・バイオファーマシューティカル・カンパニー・リミテッド 置換されたピラジン化合物、当該化合物を含む医薬組成物、及びその使用
WO2021259077A1 (zh) * 2020-06-22 2021-12-30 四川科伦博泰生物医药股份有限公司 取代吡嗪类化合物，包含其的药物组合物及其用途
CN115667239A (zh) * 2020-06-22 2023-01-31 四川科伦博泰生物医药股份有限公司 取代吡嗪类化合物，包含其的药物组合物及其用途
WO2022060583A1 (en) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
WO2022060836A1 (en) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Indole derivatives as ras inhibitors in the treatment of cancer
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
US12097203B2 (en) 2021-05-05 2024-09-24 Huyabio International, Llc Combination therapies comprising SHP2 inhibitors and PD-1 inhibitors
US12390469B2 (en) 2021-05-05 2025-08-19 Huyabio International, Llc SHP2 inhibitor monotherapy and uses thereof
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
JP2024516317A (ja) * 2021-05-12 2024-04-12 薬雅科技（上海）有限公司 Ｓｈｐ２リン酸化酵素阻害剤の調製と応用
WO2022259157A1 (en) 2021-06-09 2022-12-15 Novartis Ag A triple pharmaceutical combination comprising dabrafenib, trametinib and a shp2 inhibitor
WO2022269525A1 (en) 2021-06-23 2022-12-29 Novartis Ag Pharmaceutical combinations comprising a kras g12c inhibitor and uses thereof for the treatment of cancers
EP4368625A4 (en) * 2021-07-09 2025-07-23 Kanaph Therapeutics Inc SHP2 INHIBITOR AND ITS USE
JP7843785B2 (ja) 2021-07-09 2026-04-10 カナプ セラピューティクス インコーポレイテッド Ｓｈｐ２阻害剤及びその使用
JP2024527535A (ja) * 2021-07-09 2024-07-25 カナプ セラピューティクス インコーポレイテッド Ｓｈｐ２阻害剤及びその使用
WO2023031781A1 (en) 2021-09-01 2023-03-09 Novartis Ag Pharmaceutical combinations comprising a tead inhibitor and uses thereof for the treatment of cancers
WO2023060253A1 (en) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Ras inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024211712A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024211663A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024216016A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of a ras inhibitor
WO2024216048A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025080946A2 (en) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Ras inhibitors
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015790A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015825A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Use of ras inhibitor for treating pancreatic cancer
WO2026015796A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026050446A1 (en) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Ras inhibitors
WO2026072904A2 (en) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions and methods for treating lung cancer

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US10561655B2 (en) 2020-02-18
KR20200144102A (ko) 2020-12-28
CA3097709A1 (en) 2019-09-26
US20190290649A1 (en) 2019-09-26
EP3768664A1 (en) 2021-01-27

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