WO2023143147A1 - Composés de pyridazopyridone, composition pharmaceutique de ceux-ci et leur utilisation - Google Patents

Composés de pyridazopyridone, composition pharmaceutique de ceux-ci et leur utilisation Download PDF

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WO2023143147A1
WO2023143147A1 PCT/CN2023/072192 CN2023072192W WO2023143147A1 WO 2023143147 A1 WO2023143147 A1 WO 2023143147A1 CN 2023072192 W CN2023072192 W CN 2023072192W WO 2023143147 A1 WO2023143147 A1 WO 2023143147A1
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alkyl
optionally substituted
substituted
unsubstituted
group
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PCT/CN2023/072192
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English (en)
Chinese (zh)
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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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Priority claimed from CN202210622064.XA external-priority patent/CN116554166A/zh
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Publication of WO2023143147A1 publication Critical patent/WO2023143147A1/fr

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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
    • A61K31/50—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine 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

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a pyridazinopyridone compound, a pharmaceutical composition and application thereof.
  • 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 compound capable of inhibiting 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,
  • 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 , 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 above 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 or 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 and 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 heterocycle Aphenyl, optionally substituted C3-C8 carbocyclic 5-6 membered heteroaryl or optionally substituted 4-8 membered heterocyclic 5-6 membered heteroaryl; more preferably, the A ring is selected from: Optionally substituted phenyl, optionally substituted
  • the A ring is selected from:
  • R d1 , R d2 and 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 Metaheteroaryl;
  • R d4 are independently selected from: halogen, optionally substituted C1-C6 alkyl or
  • q 0, 1, 2 or 3;
  • R d5 is selected from: hydrogen, optionally substituted C6-C10 membered aryl or optionally substituted 5-16 membered heteroaryl;
  • Z is selected from: O or NR N ;
  • RN is selected from: H or optionally substituted C1-C6 alkyl;
  • 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, -NH(R'substituted or Unsubstituted C1-C6 alkyl), -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , -CH 2 -NH(R'substituted or unsubstituted C1-C6 alkyl), -CH 2 -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , and -CH 2 -(4-8 membered heterocyclic group), wherein R' is selected from the following
  • R d5a and R d5b are independently selected from: H or substituted or unsubstituted C1-C3 alkyl, or R d5a , R d5b and their connected N atoms form a substituted or unsubstituted 4-8 membered heterocycle Base; 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;
  • the R2 is selected from
  • R 2' is selected from: cyano, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 haloalkyl-S-; preferably, R 2 ' Selected from: cyano, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkyl-S-, C1-C3 haloalkyl- S-, C1-C3 alkylhydroxy, C1-C3 alkoxy C1-C3 alkyl, C1-C3 alkoxy C1-C3 alkoxy; more preferably, R 2' is selected from: methyl, ethyl , monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio,
  • 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 the following groups substituted or unsubstituted by R: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, nitrogen Heterocyclohexyl, oxetanyl, oxolyl, oxetyl; preferably, Selected from the following groups substituted or unsubstituted by R: wherein R is as defined above.
  • ring B is selected from the following group of substituted or unsubstituted groups: C3-C6 carbocyclyl or optionally substituted 4-6 membered heterocyclic group, preferably, ring B is selected from substituted or unsubstituted Substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxolyl , Oxycyclohexyl; Wherein, the substitution refers to being substituted by one or more groups selected from the following group: halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6
  • R is selected from:
  • ring A, R 1 , R 2 , R, ring B and R 2' are the groups corresponding to the specific compounds in the examples.
  • the compound is selected from the following group:
  • the compound is the compound shown in the examples.
  • the present invention provides a compound represented by formula II, or a salt, solvate, polymorph or deuterated compound thereof,
  • 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;
  • Each R is independently selected from: H, halogen, cyano, amino, hydroxyl, oxo
  • 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 third aspect of the present invention provides the compound described in the first aspect, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, The use of the solvate, polymorph or deuterium, or the pharmaceutical composition as described in the second 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, endometrium Tumor, stomach 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 and colorectal cancers.
  • 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
  • carbon Carbon atoms in the cyclic group can be optionally oxidized.
  • Examples of carbocyclyl 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 ,6,7,8,9,10-
  • cycloalkyl refers to the above-mentioned fully saturated carbocyclic (group), typical cycloalkyl groups include but not limited to cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.
  • 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”.
  • middle Indicates the attachment position of the group R.
  • 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.
  • alkoxyalkoxy refers to an alkoxy group substituted with an alkoxy group, and examples include OCH 2 OCH 3 , OCH 2 CH 2 OCH 3 , OCH 2 CH 2 OCH 2 CH 3 and the like.
  • Alkoxyalkyl means an alkyl group substituted with an alkoxy group, and examples include CH2OCH3 , CH2CH2OCH3 , CH2CH2OCH2CH3 , and the like .
  • 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 sorafen
  • 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 a mixture of these, 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
  • 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 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.
  • the term “indefinite combination” means in the form of separate entities At least one compound described herein and at least one co-agent are administered to the patient simultaneously, co-administered, or sequentially at variable intervals. 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 II can be prepared by the following method:
  • Compound a and b react to generate compound c in the presence of a base, and the base is selected from: sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, hydroxide Potassium, n-butyllithium, 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]undec-7-ene, or combinations thereof;
  • R 2 is as defined above.
  • the compound of formula I can be prepared by the following method:
  • the aromatic nucleophilic substitution reaction between compound h and compound i generates compound I
  • the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, and sodium hydroxide , potassium hydroxide, 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]undec-7-ene, or a combination thereof; or compound h and compound i takes place Buchwald-Hartwig reaction generates compound I;
  • R 1 , R 2 , and ring A are as above.
  • 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); liquid mass spectrometry (LCMS) is recorded by Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD -M20A, CBM-20A, LCMS-2020 type mass spectrometer records; preparative HPLC separation using Gilson-281 type liquid chromatograph.
  • LCMS liquid mass spectrometry
  • 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) The hydrochloride of embodiment 1 17.65
  • 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

La présente invention concerne des composés de pyridazopyridone, une composition pharmaceutique de ceux-ci, et leur utilisation. Spécifiquement, les composés ont des structures telles que représentées dans la formule (I). Les composés peuvent interférer avec l'interaction entre la protéine SOS1 et la protéine RAS, et sont ainsi destinés à être utilisés pour préparer des médicaments pour le traitement de maladies telles que des tumeurs à mutation RAS.
PCT/CN2023/072192 2022-01-28 2023-01-13 Composés de pyridazopyridone, composition pharmaceutique de ceux-ci et leur utilisation WO2023143147A1 (fr)

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WO2010025201A1 (fr) * 2008-08-29 2010-03-04 Amgen Inc. Composés pyridazino-pyridinone utilisés pour le traitement de maladies médiées par une protéine kinase
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
CN110563722A (zh) * 2018-06-06 2019-12-13 上海青煜医药科技有限公司 吡啶或哒嗪并环化合物及其应用
CN111372932A (zh) * 2017-12-21 2020-07-03 勃林格殷格翰国际有限公司 作为sos1抑制剂的新颖苄氨基取代吡啶并嘧啶酮及衍生物
WO2021127429A1 (fr) * 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
CN113200981A (zh) * 2021-02-10 2021-08-03 杭州英创医药科技有限公司 作为sos1抑制剂的杂环化合物

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WO2010025201A1 (fr) * 2008-08-29 2010-03-04 Amgen Inc. Composés pyridazino-pyridinone utilisés pour le traitement de maladies médiées par une protéine kinase
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
CN111372932A (zh) * 2017-12-21 2020-07-03 勃林格殷格翰国际有限公司 作为sos1抑制剂的新颖苄氨基取代吡啶并嘧啶酮及衍生物
CN110563722A (zh) * 2018-06-06 2019-12-13 上海青煜医药科技有限公司 吡啶或哒嗪并环化合物及其应用
WO2021127429A1 (fr) * 2019-12-20 2021-06-24 Mirati Therapeutics, Inc. Inhibiteurs de sos1
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