WO2023116763A1 - Composé pyridazine, composition pharmaceutique et leur utilisation - Google Patents

Composé pyridazine, composition pharmaceutique et leur utilisation Download PDF

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WO2023116763A1
WO2023116763A1 PCT/CN2022/140697 CN2022140697W WO2023116763A1 WO 2023116763 A1 WO2023116763 A1 WO 2023116763A1 CN 2022140697 W CN2022140697 W CN 2022140697W WO 2023116763 A1 WO2023116763 A1 WO 2023116763A1
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optionally substituted
alkyl
substituted
compound
group
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PCT/CN2022/140697
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陈旭星
陈艳红
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上海优理惠生医药有限公司
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Publication of WO2023116763A1 publication Critical patent/WO2023116763A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a pyridazine compound, its pharmaceutical composition and application.
  • Rat sarcoma protein is an important signal transduction regulator in the human body, regulating important physiological processes including cell proliferation, differentiation, migration and survival.
  • RAS belongs to guanosine triphosphate hydrolase (GTPase), and regulates the downstream RAF/MEK/ Several important signaling pathways such as ERK and PI3K/AKT.
  • GTPase guanosine triphosphate hydrolase
  • This cycle includes two processes, in which the negative regulation catalyzes the hydrolysis of RAS-GTP to RAS-GDP through GTPase-activating protein (GAP), and the positive regulation guanylate exchange factor (GEF) catalyzes the dissociation of RAS from GDP, followed by RAS Will bind to the high concentration of GTP in the cell.
  • GAP GTPase-activating protein
  • GEF positive regulation guanylate exchange factor
  • the RAS protein family includes KRAS (kirsten rat sarcoma viral oncogene), NRAS (neuroblastoma RAS viral oncogene) and HRAS (Harvey murine sarcoma viral oncogene), among which the tumors caused by KRAS mutations are the most common.
  • KRAS mutation causes the protein to remain in the RAS-GTP state, continuously activating downstream signaling pathways, and SOS1 plays an important role in this cancer-causing physiological process. Knockdown of SOS1 effectively reduced the growth rate of KRAS mutant tumors and did not affect the growth of KRAS wild-type cell lines.
  • Small-molecule inhibitors bind to the catalytic pocket of SOS1, affect the binding of SOS1 and RAS protein, and can effectively inhibit the phosphorylation level of downstream RAS signaling pathways such as ERK (extracellular regulated protein kinases), thereby inhibiting tumor growth.
  • ERK extracellular regulated protein kinases
  • the purpose of the present invention is to provide a new pyridazine compound and a pharmaceutical composition containing it, which can effectively inhibit the interaction between SOS1 and RAS mutein.
  • the first aspect of the present invention provides a compound represented by formula I, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, Solvates, polymorphs, deuterated compounds or combinations thereof,
  • X 1 is selected from: CH, oxygen atom, sulfur atom, nitrogen atom or -NH; Preferably, X 1 is CH;
  • X 2 is selected from: sulfur atom, oxygen atom, nitrogen atom, -NR x - or -CR x ,; wherein, R x is selected from: H, optionally substituted C1-C3 alkyl; preferably, X 2 is sulfur Atom; wherein, the substitution refers to being substituted by one or more R;
  • R is selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, cyano, wherein, R 1a and R 1b are each independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl or optionally substituted 4-8 membered heterocyclic group; wherein, The substitution refers to being substituted by one or more R;
  • R 2 is selected from: optionally substituted C1-C6 alkyl, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclic group; wherein, the substitution refers to being replaced by one or more R replaces;
  • Ring A is selected from: optionally substituted C6-C16 aryl, optionally substituted 5-16 membered heteroaryl, optionally substituted C3-C16 carbocyclic and C6-C10 aryl, optionally substituted 4-16 Member heterocycle and C6-C10 aryl, optionally substituted C3-C16 carbocycle and 5-16 member heteroaryl or optionally substituted 4-16 member heterocycle and 5-16 member heteroaryl; wherein, The above substitution refers to being substituted by one or more R;
  • Each R is independently selected from: H, halogen, cyano, amino, hydroxyl, oxo
  • the R 1 is selected from: H, halogen, optionally substituted C1-C3 alkyl or optionally substituted C3-C8 carbocyclyl, preferably, R 1 is selected from: H, halogen or methyl; wherein, the substitution refers to substitution by one or more R, and the definition of R is as above.
  • the A ring is selected from: optionally substituted C6-C10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C8 carbocyclic and C6-C10 aryl Base, optionally substituted 4-8 membered heterocycle and C6-C10 aryl, optionally substituted C3-C8 carbocycle and 5-10 membered heteroaryl or optionally substituted 4-8 membered heterocycle and 5- 10-membered heteroaryl; preferably ring A is optionally substituted phenyl, 5-6-membered heteroaryl, optionally substituted C3-C8 carbocyclophenyl, optionally substituted 4-8-membered heterocyclic Phenyl, optionally substituted C3-C8 carbocyclic and 5-6 membered heteroaryl or optionally substituted 4-8 membered heterocyclic and 5-6 membered heteroaryl; more preferably, ring A is selected from: any Optionally substituted phenyl, optionally substituted 5-10
  • the A ring is wherein, q is 0, 1, 2, 3 or 4, and each R d is independently selected from: H, halogen, amino, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1-C6 alkylsulfone, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl Or an optionally substituted 5-16 membered heteroaryl group, or any adjacent 2 R d and the carbon atom connected to it form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbon ring group;
  • substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo R'substituted or unsubstituted C1-C6 alkyl, R'substituted or unsubstituted C1-C6 alkoxy, R'substituted or unsubstituted C1-C6 alkylsulfone, R'substituted or unsubstituted C3 -C16 carbocyclyl, R'substituted or unsubstituted 4-16 membered heterocyclic group, -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , -CH 2 -N(R'substituted or unsubstituted Substituted C1-C6 alkyl) 2 , and -CH 2 -(4-8 membered heterocyclic group), wherein,
  • the A ring is selected from:
  • R d1 , R d2 , R d3 are independently selected from: H, halogen, amino, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally Substituted C1-C6 alkylsulfone group, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl group or optionally substituted 5-16 Member heteroaryl;
  • R d4 are independently selected from: halogen, optionally substituted C1-C6 alkyl and q is 0, 1, 2 or 3;
  • R d5 is selected from: hydrogen, optionally substituted C6-C10 membered aromatic group or optionally substituted 5-16 membered heteroaromatic ring group;
  • Z is selected from: O or NR N ;
  • R N is selected from: H or optionally substituted C1-C6 alky
  • substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl sulfone, C3-C16 carbocyclyl, 4-16 membered heterocyclic group, -N(R' substituted or Unsubstituted C1-C6 alkyl) 2 , -CH 2 -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , and -CH 2 -(4-8 membered heterocyclic group), where R' One or more groups selected from the group consisting of H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy;
  • ring A is wherein, R d5a and R d5b are independently selected from: H or substituted or unsubstituted C1-C3 alkyl, or R d5a , R d5b and connected N atoms form a 4-8 membered heterocyclic group; R d5c is selected from : H, halogen or substituted or unsubstituted C1-C3 alkyl;
  • substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy;
  • R 2 is Wherein, X 3 is selected from: CR 2' or N;
  • R2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 2' is selected from: methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, Difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl;
  • Ring B is selected from: optionally substituted C3-C16 carbocyclic group or optionally substituted 4-16 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R; the definition of R is as above;
  • ring B is selected from: optionally substituted C3-C11 carbocyclyl or optionally substituted 4-11 membered heterocyclic group, more preferably, ring B is selected from: optionally substituted C5- C11 carbocyclyl or optionally substituted 5-11 membered heterocyclic group, more preferably, ring B is selected from: optionally substituted C5-C8 carbocyclic group or optionally substituted 5-8 membered heterocyclic group, more preferably
  • ring B is an optionally substituted 6-membered heterocyclic group, such as, optionally substituted tetrahydropyranyl Optionally substituted piperidinyl
  • the substitution refers to substitution by one or more R; the definition of R is as above.
  • ring B is selected from: optionally substituted 4-6 membered monocyclic heterocyclic group or optionally substituted 7-11 membered spiro heterocyclic group or optionally substituted 7-11 membered bridged heterocyclic group group, wherein the substitution refers to being substituted by one or more groups selected from the following group: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkane Base, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH 2 ) 1-2 C3-C6 cycloalkyl, (CH 2 ) 1-2 4-6 membered heterocyclyl , C(O)C1-C6 alkyl, C(O)C1-C6 alkoxy, C(O)C3-C6 cycloalkyl, C(O)4-6 membered heterocyclyl, CONH(C
  • R is selected from:
  • X 1 , X 2 , R 1 , R 2 , ring A, ring B and R 2' are groups corresponding to specific compounds in the examples.
  • the compound is selected from the following group:
  • the present invention provides a compound represented by formula II, or a salt, solvate, polymorph or deuterated product thereof,
  • a pharmaceutical composition wherein the pharmaceutical composition comprises:
  • a therapeutically effective amount selected from the compound described in the first aspect, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, One or more of solvates, polymorphs and deuterated compounds as active ingredients; and
  • the fourth aspect of the present invention provides the compound described in the first aspect, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, Use of the solvate, polymorph or deuterated product or the pharmaceutical composition described in the third aspect in the preparation of a medicament for preventing or treating cancer mediated by RAS mutation.
  • the cancer is selected from: lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovium Sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer, especially selected from non-small cell lung cancer, pancreatic cancer, and colorectal cancer.
  • the term “comprises” or “includes (comprising)” can be open, semi-closed and closed. In other words, the term also includes “consisting essentially of”, or “consisting of”.
  • reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein.
  • the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the abbreviated notation does not include carbons that may be present in substituents of the stated group.
  • halogen means fluorine, chlorine, bromine or iodine.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below substituted with a hydroxyl group (-OH).
  • Niro means -NO2 .
  • Amino refers to -NH2 .
  • Substituted amino means an amino group substituted by one or two alkyl, alkylcarbonyl, arylalkyl, heteroarylalkyl groups as defined below, for example, monoalkylamino, dialkylamino, Alkylamido, arylalkylamino, heteroarylalkylamino.
  • Carboxy means -COOH.
  • alkyl refers to a fully saturated straight-chain or branched hydrocarbon chain group, Consists solely of carbon and hydrogen atoms, has for example 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is connected to the rest of the molecule by 1 or more single bonds, Examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2- Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, etc.
  • alkyl refers to a fully saturated straight-chain or branched hydrocarbon chain group, Consists solely of carbon and hydrogen atoms, has for example 1 to 12 (preferably 1 to 8, more preferably 1 to 6)
  • alkenyl as a group or part of another group, means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 2, more preferably 2 to 6) carbon atoms and is connected to the rest of the molecule by 1 or more single bonds, such as but not limited to vinyl, propenyl, alkenyl Propyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
  • alkynyl herein, as a group or part of another group, means consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10 2, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by 1 or more single bonds, straight or branched hydrocarbon chain groups, such as but not limited to ethynyl, 1-propyne base, 1-butynyl, heptynyl, octynyl, etc.
  • the term "carbocycle (group)” means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed only of carbon atoms and hydrogen atoms, which may include A fused, bridged or spiro ring system having 3 to 16 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and It is a saturated or unsaturated ring (ie cycloalkyl, cycloalkenyl, etc.) and can be connected to the rest of the molecule by 1 or more single bonds via any suitable carbon atom.
  • a fused, bridged or spiro ring system having 3 to 16 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and It is a saturated or unsaturated ring (ie cycloalkyl, cycloalkenyl, etc.) and can be connected to the
  • carbocyclyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-indanyl, octahydro-4, 7-methylene-1H-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclo Hexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5 ,6,7,8,9
  • cycloalkyl refers to the above-mentioned fully saturated carbocycle (group), preferably C3-C6 cycloalkyl.
  • Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
  • cycloalkenyl refers to a partially unsaturated carbocyclic (group)
  • typical cycloalkenyl groups include but not limited to cyclobutenyl, cyclopentenyl alkenyl, cyclohexenyl, etc.
  • heterocycle (group) means 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Composed of stable 3- to 20-membered non-aromatic cyclic groups.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon, or sulfur atoms of can be optionally oxidized; the nitrogen atoms can be optionally quaternized; and the heterocyclyl can be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and via 1 or more single bonds.
  • one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • heterocyclyl is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octanyl , 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo [2.2.1] Heptane-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuryl, oxazinyl, dioxolyl, tetrahydroisoquinyl Linyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinozinyl, thiazolidinyl, isothiazo
  • aryl as a group or part of another group, means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • aryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system and can also be fused to a carbocyclyl or heterocyclyl as defined above, provided that the aryl is via The atoms in the aromatic ring are connected to the rest of the molecule by 1 or more single bonds.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazin-3(4H)-on-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group, means having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 carbon atoms selected from the group consisting of nitrogen A 5- to 16-membered conjugated ring system group of heteroatoms of oxygen and sulfur.
  • heteroaryl may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and may also be fused to a carbocyclyl or heterocyclyl as defined above, provided that the heteroaryl An aryl group is attached to the rest of the molecule by one or more single bonds through atoms on the heteroaromatic ring.
  • a nitrogen, carbon or sulfur atom in a heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 heteroatoms selected from A stable 5- to 10-membered aromatic group of heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridine Base, phena
  • heteroarylalkyl refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.
  • absent means that the two sides of the group defined above are directly connected by a chemical bond.
  • B is absent in A-B-C
  • A-C means "A-C”.
  • substituents When an atom or group is substituted by multiple substituents, the substituents may be the same or different.
  • the terms “moiety”, “structural moiety”, “chemical moiety”, “group”, “chemical group” refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules. In the present invention, “optionally substituted” and “substituted or unsubstituted” have the same meaning and can be used interchangeably.
  • (C1-C4 alkyl) 2 amino represents 2 C1-C4 alkyl substituted amines, such as wait.
  • Multiple in the present invention means 2, 3 or 4.
  • C(O)OC1-C6 alkyl namely Represents a C1-C6 alkyl substituted ester group, such as
  • N(C1-C6 alkyl) 2 or called (C1-C6 alkyl) 2 amino, represents that two hydrogens on NH 2 are replaced by 2 C1-C6 alkyl groups, for example, it can be wait.
  • Intermediates refer to semi-finished products, which are products formed in the process of producing the required products.
  • inventors can proceed with the production of products from intermediates as starting materials. Therefore, screening suitable intermediates can optimize the process route, thereby achieving the purpose of increasing yield, saving time and cost.
  • the intermediate refers to the following compounds
  • R 1 , X 1 , and X 2 are as above.
  • the intermediate is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the preparation method of the intermediate comprises steps:
  • compound a-1 is reacted with a cyanide reagent (such as cuprous cyanide) to obtain compound a-2;
  • a cyanide reagent such as cuprous cyanide
  • compound a-2 is reacted with hydrazine or a salt thereof (such as hydrazine hydrochloride) to obtain compound a-3;
  • compound a-3 is reacted in the presence of nitrite (tert-butyl nitrite) and cuprous chloride to obtain compound a.
  • a solvent such as acetonitrile
  • reaction time and reaction temperature can be selected according to the specific reactants.
  • compound of the present invention or “active ingredient” refers to the compound shown in formula I, and also includes its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer isomers, cis-trans isomers, solvates, polymorphs, deuteriums, or combinations thereof.
  • Stepoisomer refers to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures.
  • the present invention will encompass each stereoisomer and mixtures thereof.
  • the compounds of the present invention are intended to include both E- and Z-geometric isomers.
  • Tautomer refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be within the scope of the invention.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, Propionate, Caproate, Caprylate, Caprate, Undecylenate, Glycolate, Gluconate, Lactate, Sebacate, Hexanoate glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine,
  • the functional groups of intermediate compounds may need to be protected by appropriate protecting groups.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • compositions and methods of administration are provided.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • the compound of general formula (I) can be used in combination with other known drugs for treating or improving similar diseases.
  • the administration method and dose of the original drug can be kept unchanged, and the compound of formula I can be administered simultaneously or subsequently.
  • the pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used.
  • Drug combinations also include administration of a compound of formula I and one or more other known drugs for overlapping periods of time.
  • the dosage of the compound of formula I or known drugs may be lower than that of their single administration.
  • Drugs or active ingredients that can be combined with the compound described in general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, etc.), PD-L1 inhibitors ( Such as durvalumab, atezolizumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, etc.), CD20 antibodies (such as rituximab, ibrutinib, etc.), KRAS inhibitors ( Such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), EGFR inhibitors (such as afatinib, gefitinib , erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as soraf
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively nontoxic, i.e., the substance can be administered to an individual without causing adverse biological effects. React or interact in an undesirable manner with any component contained in the composition.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the "tumor” mentioned in the present invention includes but not limited to lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, Endometrioma, stomach cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer and other diseases.
  • the terms “prophylactic”, “prevention” and “prevention” include reducing the likelihood of a disease or condition occurring or worsening in a patient.
  • treatment and other similar synonyms include the following meanings:
  • a therapeutically effective amount refers to at least one agent or compound which, when administered, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated amount. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system.
  • a therapeutically “effective amount” is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to methods capable of delivering a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, as described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
  • the terms “pharmaceutical combination”, “drug combination”, “combination”, “administration of other treatments”, “administration of other therapeutic agents” and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, It includes both fixed and non-fixed combinations of active ingredients.
  • the term “fixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one co-agent in the form of a single entity or single dosage form.
  • variable combination refers to simultaneous, concomitant or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent as separate entities to a patient. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • the functional groups of intermediate compounds may need to be protected by appropriate protecting groups.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, allyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyl, allyloxycarbonyl , p-toluenesulfonyl, pivaloyl, trifluoroacetyl, etc.
  • Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C).
  • the reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.
  • the compound of formula I can be prepared by the following method:
  • Compound a and b-1 undergo Friedel-Crafts acylation in the presence of a Lewis acid to generate compound c, and the Lewis acid is selected from: aluminum trichloride, tin dichloride, zinc chloride, boron trifluoride , titanium tetrachloride, titanium tetraisopropyloxide, etc.; or compound a reacts with compound b-2 in the presence of a strong base to generate compound c, and the strong base is from the following group: n-butyllithium, diisopropyl Lithium amide, tert-butyllithium, sec-butyllithium, lithium hexamethyldisilazide, or combinations thereof;
  • the aromatic nucleophilic substitution reaction between compound c and compound d generates compound I
  • the reducing agent is selected from the group consisting of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, hydrogen Potassium oxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, potassium carbonate, cesium carbonate, sodium carbonate , sodium phosphate, potassium phosphate, triethylamine, diisopropylethylamine, 1.8-diazabicyclo[5.4.0]undecane-7-ene, or a combination thereof; or compound c and compound d occur Buchwald-Hartwig reaction generates compound I;
  • the compound of the application can effectively inhibit the binding of SOS1 and RAS protein
  • the compound of the present application has better pharmacokinetics and pharmacodynamics.
  • 1 H NMR is recorded by a BRUKER AVANCE NEO 400MHz nuclear magnetic resonance instrument, and the chemical shift is expressed in ⁇ (ppm); -M20A, CBM-20A, LCMS-2020 type mass spectrometer records; preparative HPLC separation using Gilson-281 type liquid chromatograph.
  • Embodiment 1415,17 synthetic compound 14,15 and 17 are identical to Embodiment 14,15,17 synthetic compound 14,15 and 17
  • Embodiment 30 synthetic compound 30
  • KRAS (G12C) mutant protein was purchased from Pujian Biotechnology Co., Ltd.
  • SOS1 protein was purchased from Cytoskeleton Co., Ltd.
  • labeled antibodies Mab Anti 6HIS-XL665 and Mab Anti GST-Eu cryptate were purchased from Cisbio;
  • the stock solution concentration of the compound is 1000 ⁇ mol/L starting, 5-fold dilution, set 8 gradient concentrations, use 1-fold concentration buffer solution to dilute each gradient of the compound to be tested into 2% DMSO working solution, add 5 ⁇ L/well to the corresponding well , each concentration is set to duplicate hole detection.
  • the IC 50 of the compound was calculated with Graphpad software. The results are shown in Table 1.
  • test compound IC 50 (nM) Example 1 389.4 Example 2 62.78 Example 3 340.90 Example 4 125.70 Example 5 123.30 Example 6 340.40 Example 7 25.85 Example 8 50.89 Example 9 18.96
  • Example 10 81.84 Example 11 73.93 Example 12 152.9 Example 13 38.62 Example 14 572.60 Example 15 75.60 Example 16 105.80 Example 18 113.20 Example 19 102.60 Example 20 44.04 Example 21 36.21 Example 22 45.17 Example 23 224.1 Example 24 69.57 Example 25 89.75 Example 26 242.2 Example 27 92.95 Example 28 111.7 Example 29 239.8 Example 30 99.27 Example 31 387.8 Example 32 193.7 Example 33 221.5 Example 35 130.7 Example 36 44.88 Example 37 195.0 Example 38 31.59
  • the present invention illustrates the pyridazine compounds, pharmaceutical compositions containing them and their applications through the above examples, but the present invention is not limited to the above examples, that is, it does not mean that the present invention must rely on the above implementation example can be implemented.
  • Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

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Abstract

L'invention concerne un composé pyridazine, et une composition pharmaceutique et leur utilisation. Spécifiquement, le composé a une structure telle que représentée dans la formule (I), peut interférer avec l'interaction entre une protéine SOS1 et une protéine RAS, et est censé être utilisé dans la préparation d'un médicament pour le traitement de maladies telles que des tumeurs avec des mutations RAS.
PCT/CN2022/140697 2021-12-23 2022-12-21 Composé pyridazine, composition pharmaceutique et leur utilisation WO2023116763A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102711475A (zh) * 2009-09-18 2012-10-03 吴章桂 新颖化合物及其用于抑制蛋白激酶的治疗用途
CN110366550A (zh) * 2016-12-22 2019-10-22 美国安进公司 作为用于治疗肺癌、胰腺癌或结直肠癌的KRAS G12C抑制剂的苯并异噻唑、异噻唑并[3,4-b]吡啶、喹唑啉、酞嗪、吡啶并[2,3-d]哒嗪和吡啶并[2,3-d]嘧啶衍生物
WO2021113436A1 (fr) * 2019-12-04 2021-06-10 Arcus Biosciences, Inc. Inhibiteurs de hif-2 alpha
WO2021127429A1 (fr) * 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
CN114516883A (zh) * 2020-11-20 2022-05-20 苏州优理生物医药科技有限公司 一种噻吩并嘧啶类化合物、其药物组合物及应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102711475A (zh) * 2009-09-18 2012-10-03 吴章桂 新颖化合物及其用于抑制蛋白激酶的治疗用途
CN110366550A (zh) * 2016-12-22 2019-10-22 美国安进公司 作为用于治疗肺癌、胰腺癌或结直肠癌的KRAS G12C抑制剂的苯并异噻唑、异噻唑并[3,4-b]吡啶、喹唑啉、酞嗪、吡啶并[2,3-d]哒嗪和吡啶并[2,3-d]嘧啶衍生物
WO2021113436A1 (fr) * 2019-12-04 2021-06-10 Arcus Biosciences, Inc. Inhibiteurs de hif-2 alpha
WO2021127429A1 (fr) * 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
CN114516883A (zh) * 2020-11-20 2022-05-20 苏州优理生物医药科技有限公司 一种噻吩并嘧啶类化合物、其药物组合物及应用

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