WO2023016296A1 - Heterocyclic compound and preparation method therefor and use thereof - Google Patents

Heterocyclic compound and preparation method therefor and use thereof Download PDF

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Publication number
WO2023016296A1
WO2023016296A1 PCT/CN2022/109584 CN2022109584W WO2023016296A1 WO 2023016296 A1 WO2023016296 A1 WO 2023016296A1 CN 2022109584 W CN2022109584 W CN 2022109584W WO 2023016296 A1 WO2023016296 A1 WO 2023016296A1
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Prior art keywords
compound
alkyl
pharmaceutically acceptable
acceptable salt
cycloalkyl
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PCT/CN2022/109584
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French (fr)
Chinese (zh)
Inventor
刘金明
刘谦
段霜霜
景连栋
杨志
吴勇勇
田强
宋宏梅
葛均友
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN202280042003.4A priority Critical patent/CN117561260A/en
Publication of WO2023016296A1 publication Critical patent/WO2023016296A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a compound with Axl and/or Mer inhibitory activity and its preparation and application.
  • RTKs Receptor Tyrosine Kinases
  • the TAM family belongs to the receptor tyrosine kinase subfamily, and its members include Tyro-3, Axl and Mer, among which Axl and Mer regulate various cellular functions in signal transduction pathways.
  • Axl Ufo, Ark or Tyro7
  • Axl was discovered by Bryan et al. in the DNA of human chronic myeloid leukemia in 1991.
  • Axl not only has a similar gene structure to Tyro3, but also has a similar tyrosine kinase domain amino acid sequence to Mer, and they They also share a common Growth Arrest Specific 6 (Gas6) ligand.
  • Axl is activated in a number of different ways: (1) homodimerization through ligand binding; (2) homodimerization independent of ligand binding, that is, overexpression of Axl self-dimerization; (3) heterodimerization of Axl receptor with two other TAM receptors; (4) heterodimerization of Axl receptor with non-TAM receptors; (5) two different Cellular extracellular domain binding activation.
  • binding to ligand is the main way of Axl activation. After Gas6 binds to the extracellular domain of Axl, Axl dimerizes, resulting in the phosphorylation of three phosphorylation sites (Y779, Y821, and Y866) in the intracellular domain of Axl.
  • phosphorylation sites can bind to phosphatidylinositol 3-kinase subunit (PI3K), phospholipase C (PLC) and growth factor receptor binding protein 2 (Grb2), activate RAS/ERK, PI3K/Akt and many other Related signaling pathways promote cell inflammation, cell survival, migration, invasion and metastasis and other physiological effects.
  • PI3K phosphatidylinositol 3-kinase subunit
  • PLC phospholipase C
  • Grb2 growth factor receptor binding protein 2
  • Axl In addition to high expression of Axl in various cells and tissues of the human body, high expression of Axl has been found in various malignant tumors such as lung cancer, breast cancer, colon cancer, gastric cancer, liver cancer and ovarian cancer. Abnormal expression of Axl can antagonize tumor cell apoptosis, promote tumor cell invasion and metastasis, promote tumor angiogenesis, promote tumor occurrence and development, and is closely related to tumor occurrence, recurrence and poor prognosis. Studies in recent years have shown that the high expression of Axl may mediate the acquired drug resistance of EGFR. Clinical studies have shown that about 20% of EGFR drug-resistant patients have high expression of Axl.
  • Axl inhibitors and EGFR inhibitors can effectively overcome and improve the problem of EGFR inhibitor resistance, and clinical combination therapy is also underway.
  • Axl is highly expressed in the tumor microenvironment (such as macrophages, dendritic cells, etc.), and can cooperate with tumor cells and other stromal cells to promote tumor progression. Abnormal activation caused by overexpression of Axl interacts with other targets. There is also a close relationship between drug resistance and chemotherapeutic drug resistance.
  • MerTK signaling plays a role in diverse physiological processes, such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeletal reorganization, and phagocytosis, and regulates many physiological processes, including cell survival, migration, differentiation, and phagocytosis of apoptotic cells
  • Mer-mediated signaling pathways mainly include: (1) AKT signaling pathway: Mer receptors bind to Gas6 to activate PI3K phosphorylation, and with the participation of phosphatidylinositol-dependent protein kinase, the activated AKT further Affects the activation status of downstream factors, participates in the regulation of cell apoptosis, and also has a certain regulatory effect on cell proliferation and migration; (2) MAPK signaling pathway: the combination of Gas6 and Mer makes MAPK (mainly extracellular regulatory protein kinase and p38 subfamily) Phosphorylated and activated MAPK transduces signals into the nucleus, affects cell proliferation and invasion by activating nuclear transcription
  • STAT Signal transducer and activator of transcription
  • a first aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a pharmaceutically acceptable salt thereof, metabolites or prodrugs,
  • R 1 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 6 ;
  • RA is independently selected from H and C 1 -C 6 alkyl
  • p is selected from 1 and 2;
  • Each occurrence of R 2 is independently selected from H, -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 - C 8 cycloalkyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 8 cycloalkyl are optionally substituted by one or more R 8 ;
  • Each occurrence of R 8 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
  • n is selected from 0, 1, 2, 3 and 4;
  • R 3 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclic group, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 9 ;
  • Each occurrence of R 9 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
  • R 4 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R 10 ;
  • Each occurrence of R 10 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 haloalkoxy and 3-8 membered heterocyclic groups;
  • X is selected from CH and N;
  • R 5 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, halogen, -CN, -CONR 5a R 5b and C 1 -C 6 haloalkyl; and
  • R 5a and R 5b are each independently selected from H and C 1 -C 6 alkyl.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph , solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
  • the present invention provides a kit comprising:
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof , metabolites or prodrugs, or the pharmaceutical composition of the present invention, or the kit of the present invention, which is used for the prevention or treatment of Axl and/or Mer-related diseases (especially tumor diseases).
  • the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof , metabolites or prodrugs or the pharmaceutical composition of the present invention or the kit of the present invention in the preparation of medicines for the prevention or treatment of Axl and/or Mer-related diseases (especially tumor diseases).
  • the present invention provides a method for preventing or treating diseases related to Axl and/or Mer (especially tumor diseases), which comprises administering a preventive or therapeutically effective amount of the compound of the present invention or Pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, or pharmaceutical combinations of the present invention thing, or the kit of the present invention.
  • the present invention provides a method for preparing the compound of the present invention, which comprises the steps shown in Scheme 1 below:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and m are as defined above.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon group.
  • C 1 -C 6 alkyl refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which are optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen.
  • cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g. monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic rings, including spiro, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo [3.2.1] octyl or bicyclo[5.2.0] nonyl, decalinyl, etc.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, cyclo
  • the cycloalkyl group has 3 to 15, eg, 3 to 10, 3 to 8, or 3 to 6 carbon atoms.
  • C 3 -C 8 cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring ( For example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) optionally substituted by one or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl base.
  • alkoxy means an "alkyl” group, as defined above, attached to the parent molecular moiety through an oxygen atom, for example, C 1 -C 6 alkoxy, C 1 -C 3 alkoxy base.
  • Representative examples of C 1 -C 6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, Oxy, hexyloxy, etc., said alkoxy may be optionally substituted by one or more (such as 1 to 3) same or different substituents.
  • halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • haloalkyl refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms.
  • C 1 -C 6 haloalkyl refers to a haloalkyl group having 1 to 6 carbon atoms, including but not limited to -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 Cl, etc.
  • the haloalkyl groups herein are optionally substituted with one or more (such as 1 to 3) substituents described herein.
  • haloalkoxy means a "haloalkyl” as defined above attached to the parent molecular moiety through an oxygen atom, eg, C 1 -C 6 haloalkoxy.
  • Heterocyclyl includes saturated and partially unsaturated non-aromatic heterocyclic rings.
  • a saturated heterocyclic group may be called a heterocycloalkyl group, such as a 3-8 membered heterocycloalkyl group, a 3-6 membered heterocycloalkyl group, a 5-6 membered heterocycloalkyl group, and the like.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, an amalgamated ring system, a bridged ring system or a spiro ring system.
  • a 3-8 membered heterocyclic group is a group having 3-8 carbon atoms and heteroatoms in the ring, for example, it has 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7 or 5 to 6 carbon atoms and heteroatoms (respectively referred to as 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7 and 5 to 6 heterocyclic groups), for example But not limited to oxiranyl, aziridinyl, azetidinyl, azepanyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl , tetrahydropyranyl, aza base, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl), etc.; and their ring derivatives or be
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system. Common aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.
  • C6 - C10 aryl refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkyl, etc.).
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, having, for example, 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially with 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, additionally, in each case may be benzofused of.
  • heteroatom selected from N, O and S
  • 5-10 membered heteroaryl means a monocyclic, bicyclic or tricyclic aromatic ring system having 5-10 ring atoms, and containing at least one which may be the same or different A heteroatom (the heteroatom is eg N, O or S).
  • heteroaryl groups examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, Triazolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.
  • Heteroaryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, C 1 -C 6 alkyl, etc.).
  • Alkenyl groups can be straight or branched chain alkenyl groups and contain 2 to 15 carbon atoms.
  • C 2 -C 6 alkenyl herein is an alkenyl group containing 2 to 6 carbon atoms.
  • Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl.
  • Alkenyl groups can be unsubstituted or substituted with one or more same or different substituents.
  • alkynyl refers to a hydrocarbon group having at least one C ⁇ C triple bond.
  • the alkynyl group can be straight or branched and contains 2 to 15 carbon atoms.
  • C 2 -C 6 alkynyl herein is an alkynyl group containing 2 to 6 carbon atoms.
  • Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like.
  • Alkynyl groups can be unsubstituted or substituted with one or more same or different substituents.
  • substituted means that one or more (eg, 1, 2, 3, 4 or 5) hydrogens on the indicated atom are replaced by a selection from the indicated group, provided that no more than the indicated The atoms are at their normal valences under the circumstances and the substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituents can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Substituents of choice are either substituted or unsubstituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected substituents Substituted or not.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other components making up the formulation and/or with the mammal being treated therewith.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts.
  • stereoisomer means having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.) that has a perpendicular plane of asymmetry, Stable isomers that can thus rotate plane-polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may give rise to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can be present as single stereoisomers, racemates, enantiomers and mixtures of diastereomers form exists.
  • these compounds can be prepared in the form of racemates. However, such compounds can be prepared or isolated as pure stereoisomers, i.e., single enantiomers or diastereomers, or enriched in single stereoisomers (purity ⁇ 98%, ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%, ⁇ 85%, or ⁇ 80%).
  • stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral centers, or by separation or resolution following the preparation of mixtures of enantiomeric products obtained, for example, after conversion into a mixture of diastereoisomers followed by separation or recrystallization, chromatographic treatment, use of chiral resolving agents, or direct separation of the enantiomers on a chiral chromatography column.
  • Starting compounds with specific stereochemistry can be obtained commercially, or can be prepared according to the methods described below and then resolved by methods well known in the art.
  • the term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other.
  • racemic mixture or “racemate” refers to a mixture containing equal parts of a single enantiomer (ie, an equimolar mixture of the two R and S enantiomers).
  • non-racemic mixture refers to a mixture containing unequal parts of the individual enantiomers. Unless otherwise indicated, all stereoisomeric forms of the compounds of the invention are within the scope of the invention.
  • tautomer refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers include, but are not limited to, interconversions via migration of a proton, such as keto-enol isomerization, imine-enamine isomerization , amide-iminoalcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • polymorph refers to a solid crystalline form of a compound or complex. Polymorphs of molecules can be obtained by those skilled in the art by a number of known methods. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, fast evaporation, fast cooling, slow cooling, vapor phase diffusion, and sublimation.
  • polymorphs can be detected, classified and identified using well-known techniques including, but not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD) , single crystal X-ray diffraction (SCXRD), solid-state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy and scanning electron microscopy (SEM), etc.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • XRPD X-ray powder diffraction
  • SCXRD single crystal X-ray diffraction
  • NMR nuclear magnetic resonance
  • IR infrared spectroscopy
  • Raman spectroscopy Raman spectroscopy
  • SEM scanning electron microscopy
  • solvate refers to a substance formed by combining a compound of the present invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include, but are not limited to, hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetonates, and the like.
  • nitrogen oxide refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or a nitrogen-containing (aromatic) heterocyclic compound.
  • nitrogen oxide refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or a nitrogen-containing (aromatic) heterocyclic compound.
  • the 1-position nitrogen atom in the nucleus of the compound of formula I can form the corresponding nitrogen oxide.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. 2 H, 3 H, deuterium D, tritium T); isotopes of carbon (e.g.
  • chlorine isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N
  • isotopes of oxygen such as 15 O, 17 O and 18 O
  • sulfur isotopes eg 35 S
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention which themselves may have little or no pharmacological activity, when administered to the body or
  • prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention which themselves may have little or no pharmacological activity, when administered to the body or
  • the above can be converted into compounds of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the term "independently" means that at least two groups (or ring systems) present in the structure with the same or similar value range may have the same or different meanings under specific circumstances.
  • the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl, then when the substituent X is hydrogen, the substituent Y can be either hydrogen or halogen, Hydroxyl, cyano, alkyl or aryl; similarly; when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protecting groups, these references are incorporated herein by reference.
  • Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • One object of the present invention is to provide a compound of formula I or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compounds, metabolites or prodrugs,
  • R 1 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 6 ;
  • RA is independently selected from H and C 1 -C 6 alkyl
  • p is selected from 1 and 2;
  • Each occurrence of R 2 is independently selected from H, -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 - C 8 cycloalkyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 8 cycloalkyl are optionally substituted by one or more R 8 ;
  • Each occurrence of R 8 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
  • n is selected from 0, 1, 2, 3 and 4;
  • R 3 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclic group, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 9 ;
  • Each occurrence of R 9 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
  • R 4 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R 10 ;
  • Each occurrence of R 10 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 haloalkoxy and 3-8 membered heterocyclic groups;
  • X is selected from CH and N;
  • R 5 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, halogen, -CN, -CONR 5a R 5b and C 1 -C 6 haloalkyl; and
  • R 5a and R 5b are each independently selected from H and C 1 -C 6 alkyl.
  • R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R 6 .
  • each occurrence of R 6 is independently selected from halogen, -CN, -OH, -S(O) pRA , C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl, said C 3 -C 8 cycloalkyl or C 6 -C 10 aryl is optionally substituted by one or more R 7 .
  • R A is C 1 -C 6 alkyl.
  • p is 2.
  • R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 - C Cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R 6 ;
  • Each occurrence of R 6 is independently selected from halogen, -CN, -OH, -S(O) p R A , C 3 -C 8 cycloalkyl and C 6 -C 10 aryl, said C 3 -C 8 cycloalkyl or C 6 -C 10 aryl is optionally substituted by one or more R 7 ;
  • RA is C 1 -C 6 alkyl
  • R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-6 membered oxygen-containing heterocycloalkyl
  • R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, said C 1 - C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted with one or more groups each independently selected from the following groups: -F, -CN, -OH, -S(O) 2 CH 3 , Tetrahydropyranyl, and fluorophenyl.
  • R 1 is selected from C 1 -C 6 alkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, and said C 1 -C 6 alkyl is optionally replaced by 1 , 2 or 3 -F substitutions.
  • R is selected from CF 3 CH 2 -, CH 3 -,
  • R is selected from CF 3 CH 2 -, CH 3 -,
  • each occurrence of R 2 is independently selected from H and halogen.
  • each occurrence of R is independently selected from H and F.
  • R is H.
  • m is 1.
  • R 3 is selected from C 6 -C 10 aryl and 5-10 membered heteroaryl, and the C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally replaced by one or multiple R 9 substitutions.
  • each occurrence of R 9 is independently selected from halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • each occurrence of R9 is independently selected from halogen.
  • each occurrence of R 9 is independently selected from halogen and C 1 -C 6 haloalkyl.
  • each occurrence of R 9 is independently selected from F, Cl, -CF 3 and -CH 3 .
  • each occurrence of R9 is independently selected from F and Cl.
  • R 3 is selected from C 6 -C 10 aryl and 5-10 membered heteroaryl, and the C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally replaced by one or a plurality of groups each independently selected from the following: halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R is selected from phenyl and 5-6 membered heteroaryl, and said phenyl or 5-6 membered heteroaryl is optionally selected from one or more of each independently selected from The group substitution of: halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R is selected from phenyl and 5-6 membered nitrogen-containing heteroaryl, the phenyl or 5-6 membered nitrogen-containing heteroaryl optionally replaced by one or more independently is substituted with a group selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R 3 is selected from phenyl and pyridyl, said phenyl or pyridyl is optionally substituted with one or more groups each independently selected from: halogen, C 1 - C 6 alkyl and C 1 -C 6 haloalkyl.
  • R is selected from phenyl and pyridyl, said phenyl or pyridyl is optionally substituted with one or more groups each independently selected from: F, Cl, - CF3 and -CH3 .
  • R is selected from phenyl and pyridyl, optionally substituted with F or Cl.
  • R is selected from:
  • R is selected from:
  • R 4 is selected from C 1 -C 6 alkyl groups optionally replaced by one or more C 1 -C 6 alkoxy groups or 3-8 membered Heterocyclyl substitution.
  • R 4 is selected from C 1 -C 6 alkyl optionally replaced by C 1 -C 6 alkoxy or 5-6 membered oxa Cycloalkyl substitution.
  • R 4 is selected from C 1 -C 6 alkyl optionally replaced by C 1 -C 6 alkoxy, tetrahydrofuranyl or tetrahydropyranyl base substitution.
  • R 4 is selected from C 1 -C 6 alkyl optionally substituted with methoxy, tetrahydrofuranyl or tetrahydropyranyl .
  • R is selected from isopropyl, 2-methylpropyl, methoxyethyl,
  • R 5 is selected from H, C 1 -C 6 alkyl and halogen.
  • R 5 is H.
  • the present invention covers compounds of formula I obtained by any combination of the above-mentioned preferred groups.
  • the compound of the invention is a compound of formula I-1:
  • R 1 , R 2 , R 3 , R 4 , R 5 and m are as defined above.
  • the compound of the present invention is a compound of formula I-1-1:
  • R 1 , R 2 , R 4 , R 5 , R 9 and m are as defined above;
  • q is selected from 0, 1, 2, 3, 4 and 5; preferably, q is 1.
  • the compound of the present invention is a compound of formula I-1-1a:
  • R 1 , R 4 , R 9 and q are as defined above.
  • the compound of the present invention is a compound of formula I-1-2:
  • R 1 , R 2 , R 4 , R 5 , R 9 and m are as defined above;
  • q is selected from 0, 1, 2, 3, 4 and 5; preferably, q is 1.
  • the compound of the present invention is a compound of formula I-1-2a:
  • R 1 , R 4 , R 9 and q are as defined above.
  • the present invention covers compounds of formulas I-1, I-1-1, I-1-1a, 1-1-2, 1-1-2a obtained by any combination of the above preferred groups.
  • R 1 is selected from C 1 -C 6 alkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, and the C 1 -C 6 alkyl is optionally substituted by 1, 2 or 3 -F;
  • R 4 is selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkoxy, tetrahydrofuranyl or tetrahydropyranyl;
  • R is independently selected from halogen
  • the compound of the invention is a compound of formula I-2:
  • R 1 , R 2 , R 3 , R 4 , R 5 and m are as defined above.
  • the compound of the present invention is a compound of formula I-2-1:
  • R 1 , R 2 , R 4 , R 5 , R 9 and m are as defined above;
  • q is selected from 0, 1, 2, 3, 4 and 5; preferably, q is 1.
  • the compound of the present invention is a compound of formula I-2-1a:
  • R 1 , R 4 , R 9 and q are as defined above.
  • the compound of the present invention is a compound of formula I-2-2:
  • R 1 , R 2 , R 4 , R 5 , R 9 and m are as defined above;
  • q is selected from 0, 1, 2, 3, 4 and 5; preferably, q is 1.
  • the compound of the present invention is a compound of formula I-2-2a:
  • R 1 , R 4 , R 9 and q are as defined above.
  • the present invention covers compounds of formulas I-2, I-2-1, I-2-1a, 1-2-2, 1-2-2a obtained by any combination of the above preferred groups.
  • R 1 is selected from C 1 -C 6 alkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, and the C 1 -C 6 alkyl is optionally substituted by 1, 2 or 3 -F;
  • R 4 is selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkoxy, tetrahydrofuryl or tetrahydropyranyl;
  • R is independently selected from halogen
  • the compound of the present invention is selected from:
  • Another object of the present invention is to provide a method for preparing the compound of the present invention, which includes the steps shown in the following reaction scheme 1:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and m are as defined above.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base.
  • the organic base or inorganic base can be selected from diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate and cesium carbonate, preferably diisopropylethylamine.
  • the reaction is preferably carried out in the presence of a suitable condensing agent which may be selected from DCC, EDCI, HOBt, BOP, PyBOP, HATU, HBTU, preferably HATU.
  • a suitable condensing agent which may be selected from DCC, EDCI, HOBt, BOP, PyBOP, HATU, HBTU, preferably HATU.
  • the reaction is carried out in a suitable organic solvent.
  • the organic solvent may be selected from dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 20-80°C.
  • the reaction is carried out for a suitable time, eg 2-24 hours.
  • the present invention provides a synthetic method for intermediates I-A and I-B, wherein intermediate I-A can be synthesized by the method shown in the following reaction scheme 2:
  • LG represents a leaving group, which includes, but is not limited to, a halogen atom, methanesulfonyloxy, triflate, etc.;
  • R 1 , R 2 , X and m are as defined above for the compound of formula I.
  • Step 1 Reaction of Compound IAI with R 1 -LG to give Compound IA-II
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base.
  • the organic base or inorganic base can be selected from diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate.
  • the reaction is carried out in a suitable organic solvent.
  • the organic solvent may be selected from dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 80-90°C.
  • the reaction is carried out for a suitable time, eg 2-24 hours.
  • Step 2 Reaction of compound I-A-II with p-aminophenylboronate to obtain compound I-A
  • the reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is preferably a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine palladium , palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the base is preferably an inorganic base, such as potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium carbonate.
  • the reaction is carried out in a suitable solvent.
  • the solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably 1 , A mixed solvent of 4-dioxane and water.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 60-100°C.
  • the reaction is carried out for a suitable time, eg 2-8 hours.
  • intermediate I-A can also be synthesized by the method shown in Scheme 3 below:
  • R 1 , R 2 , X and m are as defined above for the compound of formula I.
  • Step 1 Reaction of Compound IA-III with R 1 OH to give Compound IA-IV
  • the reaction is preferably carried out in the presence of a phosphine catalyst and an azodicarboxylate.
  • the phosphine catalyst is preferably a phosphine ligand catalyst, such as triphenylphosphine, tributylphosphine, trihexylphosphine, tris(2-methylphenyl)phosphine, preferably triphenylphosphine.
  • the azodicarboxylates are such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, bis(4-chlorobenzyl) azodicarboxylate, Diethyl azodicarboxylate is preferred.
  • the reaction is carried out in a suitable solvent.
  • the solvent may be selected from tetrahydrofuran, diethyl ether, toluene, N,N-dimethylformamide and any combination thereof, preferably tetrahydrofuran.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 25-70°C.
  • the reaction is carried out for a suitable time, eg 8-16 hours.
  • Step 2 Substitution reaction of compound I-A-IV with ammonia water to obtain compound I-A-II
  • the reaction is carried out in a suitable organic solvent.
  • the organic solvent may be selected from dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane and any combination thereof, preferably 1,4-dioxane.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 80-90°C.
  • the reaction is carried out under suitable conditions.
  • the conditions are preferably microwave heating.
  • the reaction is carried out for a suitable time, eg 2-24 hours.
  • Step 3 Reaction of compound I-A-II with p-aminophenyl borate to obtain compound I-A
  • the reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is preferably a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine palladium , palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the base is preferably an inorganic base, such as potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium carbonate.
  • the reaction is carried out in a suitable solvent.
  • the solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably 1 , A mixed solvent of 4-dioxane and water.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 60-100°C.
  • the reaction is carried out for a suitable time, eg 2-8 hours.
  • Step 1 react compound I-B-I with a chlorinating reagent to obtain compound I-B-II
  • the reaction is carried out in the presence of a suitable solvent.
  • the solvent may be selected from dichloromethane, 1,2-dichloroethane, chloroform and any combination thereof, preferably dichloromethane.
  • the reaction is carried out in the presence of a chlorinating reagent.
  • the chlorination reagent is preferably oxalyl chloride, thionyl chloride, preferably oxalyl chloride.
  • the reaction is preferably carried out in the presence of a catalyst.
  • the catalyst is preferably N,N-dimethylformamide.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 0-25°C.
  • the reaction is carried out for a suitable time, eg 2-8 hours.
  • Step 2 react compound I-B-II with ethyl diazoacetate to obtain compound I-B-III
  • the reaction is preferably carried out in the presence of an inert gas.
  • the inert gas may be selected from nitrogen, argon, preferably nitrogen.
  • the reaction is carried out in a suitable solvent.
  • the solvent may be selected from dichloromethane, 1,2-dichloroethane, chloroform and any combination thereof, preferably dichloromethane.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 0-25°C.
  • the reaction is carried out for a suitable time, eg 4-16 hours.
  • Step 3 Compound I-B-III is reduced to obtain Compound I-B-IV
  • the reaction is carried out in the presence of a reducing agent.
  • the reducing agent is preferably tributylphosphine.
  • the reaction is carried out in a suitable solvent.
  • the solvent may be selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether and any combination thereof, preferably isopropyl ether.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 0-25°C.
  • the reaction is carried out for a suitable time, eg 2-8 hours.
  • Step 4 Reaction of compound I-B-IV with di-tert-butyl dicarbonate to obtain compound I-B-V
  • the reaction is carried out in a suitable solvent.
  • the solvent may be selected from dichloromethane, chloroform, tetrahydrofuran, diethyl ether and any combination thereof, preferably tetrahydrofuran.
  • the reaction is preferably carried out in the presence of a base.
  • the base is preferably an organic base, such as triethylamine, diisopropylethylamine, preferably triethylamine.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 0-25°C.
  • the reaction is carried out for a suitable time, eg 4-16 hours.
  • Step 5 Compound I-B-V undergoes a ring closure reaction and removes the protecting group Boc to obtain compound I-B-VI
  • the reaction is carried out in a suitable solvent.
  • the solvent may be selected from tetrahydrofuran, toluene and any combination thereof, preferably tetrahydrofuran.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 0-90°C.
  • the reaction is carried out in the presence of a suitable acid.
  • the acid is preferably a solution of hydrochloric acid, such as dioxane hydrochloride, ethyl acetate hydrochloride, preferably dioxane hydrochloride.
  • Step 6 Reaction of compound IB-VI with R 4 -LG to obtain compound IB-VII
  • LG represents a leaving group
  • the leaving group includes but not limited to halogen atom, methanesulfonyloxy group, trifluoromethanesulfonate, etc.;
  • the reaction is carried out in a suitable solvent.
  • the organic solvent may be selected from dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide and any combination thereof, preferably N,N-dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base.
  • the organic base or inorganic base can be selected from diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 80-90°C.
  • the reaction is carried out for a suitable time, eg 2-24 hours.
  • Step 7 Compound I-B-VII is subjected to ester group hydrolysis to obtain compound I-B
  • the reaction is carried out in a mixed solvent of methanol/tetrahydrofuran/water at an appropriate ratio.
  • the reaction is preferably carried out in the presence of a suitable inorganic base.
  • the inorganic base may be selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, preferably sodium hydroxide.
  • intermediate I-B can also be synthesized by the method shown in Scheme 5 below:
  • Step 1 Reaction of compound I-B-I with N,N'-carbonyldiimidazole to obtain compound I-B-VIII
  • the reaction is carried out in a suitable solvent.
  • the solvent may be selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether and any combination thereof, preferably tetrahydrofuran.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 0-25°C.
  • the reaction is carried out for a suitable period of time, for example 6-16 hours.
  • Step 2 Compound I-B-VIII reacts with monoethyl malonate potassium salt to obtain compound I-B-IX
  • the reaction is carried out in a suitable solvent.
  • the solvent may be selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether and any combination thereof, preferably tetrahydrofuran.
  • the reaction is preferably carried out in the presence of a base.
  • the base is preferably an organic base, such as triethylamine, diisopropylethylamine, preferably triethylamine.
  • the reaction is carried out over a suitable catalyst.
  • the catalyst is preferably magnesium chloride.
  • the reaction is carried out at a suitable temperature.
  • the temperature is preferably 0-25°C.
  • the reaction is carried out for a suitable time, eg 4-24 hours.
  • Step 3 Reaction of compound I-B-IX with p-toluenesulfonyl azide to obtain compound I-B-III
  • the reaction is carried out in a suitable solvent.
  • the solvent may be selected from tetrahydrofuran, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably acetonitrile.
  • the reaction is preferably carried out in the presence of a base.
  • the base is preferably an organic base, such as triethylamine, diisopropylethylamine, preferably triethylamine.
  • the reaction is carried out at a suitable temperature, preferably 0-10°C.
  • the reaction is carried out for a suitable time, eg 1-4 hours.
  • Step 4 to step 8 are the same as step 3 to step 7 in reaction scheme 3.
  • the term "suitable" means that the choice of specific compounds or conditions will depend on the particular synthetic procedure being performed and the nature of the molecule or molecules to be transformed, but is within the purview of those skilled in the art .
  • the steps of all processes/methods described herein are performed under conditions sufficient to provide the products shown.
  • reaction conditions including, for example, the reaction solvent, reaction time, reaction temperature, and whether the reaction should be carried out under anhydrous or inert atmosphere, etc.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph , solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide a kit comprising:
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent, and which is suitable for contacting humans and/or other subjects within the scope of reasonable medical judgment. Animal tissues without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • compositions of the invention may act systemically and/or locally.
  • they can be administered by suitable routes, for example by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes or administered as an inhaler.
  • the pharmaceutical composition of the present invention can be administered in an appropriate dosage form.
  • the dosage forms include but are not limited to tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , injectable solutions, elixirs, syrups, etc.
  • the pharmaceutical composition of the present invention can also be administered in the form of sterile injection, including sterile injectable water or oil suspension, or sterile injectable water or oil solution.
  • the pharmaceutical composition of the present invention may contain 0.01 mg to 1000 mg of the compound of the present invention.
  • the present invention provides a method for preparing the pharmaceutical composition or pharmaceutical preparation of the present invention, the method comprising the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer , polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs in combination with one or more pharmaceutically acceptable carriers.
  • composition of the present invention may optionally be administered in combination with other agents which have at least some effect in the treatment of various diseases.
  • the invention provides combined formulations of a compound of the invention and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.
  • Another object of the present invention is to provide the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound , metabolites or prodrugs, or the pharmaceutical composition of the present invention, or the kit of the present invention, which is used for the prevention or treatment of Axl and/or Mer-related diseases (especially tumor diseases).
  • Another object of the present invention is to provide the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound , metabolites or prodrugs or the pharmaceutical composition of the present invention or the kit of the present invention in the preparation of medicines for the prevention or treatment of Axl and/or Mer-related diseases (especially tumor diseases).
  • Another object of the present invention is to provide a method for preventing or treating diseases related to Axl and/or Mer (especially tumor diseases), which includes administering a preventive or therapeutically effective amount of the compound of the present invention or Pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, or pharmaceutical combinations of the present invention thing, or the kit of the present invention.
  • an effective amount refers to an amount sufficient to achieve a desired prophylactic or therapeutic effect, eg, an amount that achieves alleviation of one or more symptoms associated with the disease being treated.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • an effective dosage is about 0.001 mg/kg body weight/day to about 10000 mg/kg body weight/day.
  • the effective dose is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • About 0.01 to 1000 mg/kg of the subject's body weight, usually 0.1 to 500 mg/kg of the subject's body weight may be administered every day, every two days or every three days.
  • Exemplary treatment regimens are one or more daily or one or more weekly or one or more monthly administrations.
  • the formulation will be administered in multiples, with intervals between single doses being daily, weekly, monthly or yearly.
  • the formulation may be administered as a sustained release formulation, in which case less frequent dosing will be required. Dosage and frequency vary according to the half-life of the formulation in the subject. It can also differ depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered chronically at relatively infrequent intervals. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or stopped, and preferably until the individual exhibits partial or complete amelioration of disease symptoms, after which time the patient may be given prevention program.
  • the amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
  • treating aims at alleviating or eliminating the disease state or disorder addressed. If a subject receives a therapeutic amount of a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof according to the methods described herein, the subject exhibits one or more of the signs and symptoms Observable and/or detectable reduction or improvement, the subject is successfully "treated”. It should also be understood that reference to treatment of a disease state or disorder includes not only complete treatment, but also incomplete treatment while achieving some biologically or medically relevant result.
  • Treatment means any administration of a compound of the invention, including:
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • prevention used in the present invention includes suppression and delay of the onset of a disease, and includes not only prevention before the development of the disease, but also prevention of recurrence of the disease after treatment.
  • the structures of the compounds described in the following Examples were confirmed by 1 H-NMR or MS.
  • the 1 H-NMR measuring instrument used a Bruker 400MHz nuclear magnetic resonance instrument, the measuring solvent was DMSO-d 6 , the internal standard substance was TMS, and all ⁇ values were expressed in ppm.
  • the mass spectrometer (MS) was measured by an Agilent (ESI) mass spectrometer, model Agilent 6120B.
  • the monitoring of reaction adopts thin-layer chromatography (TLC) or LC-MS
  • the developer system that uses comprises: dichloromethane and methanol system, normal hexane and ethyl acetate system, and sherwood oil and ethyl acetate system, the volume of solvent
  • the ratio is adjusted according to the polarity of the compound or by adding triethylamine or the like.
  • Column chromatography generally uses 200-300 mesh silica gel as the carrier.
  • the eluent system includes: dichloromethane and methanol system, and petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of triethylamine.
  • Instrument model Agilent 1260, chromatographic column: Waters SunFire Prep C18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); chromatographic column temperature: 25°C; flow rate: 20.0mL/min; detection wavelength: 214nm; elution gradient: (0min: 10 %A, 90%B; 16.0min: 90%A, 10%B); mobile phase A: 100% acetonitrile; mobile phase B: 100% water, 0.05% formic acid.
  • reaction temperature in the examples is room temperature (20° C. to 30° C.).
  • the reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd., etc.
  • Step 4 (E)-2-(tert-butoxycarbonyl-hydrazone)-4-(4-fluorophenyl)-3-oxobutanoic acid ethyl ester (T3-5)
  • Step 5 Ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (T3-6)
  • Step 6 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridazine-3-carboxy Ethyl acetate (T3-7)
  • Step 7 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridazine-3-carboxy Acid (T3)
  • Step 1 Ethyl 5-(4-fluorophenyl)-1-isobutyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T4-1)
  • Step 2 5-(4-fluorophenyl)-1-isobutyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T4)
  • Step 1 Ethyl 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T5-1)
  • Step 2 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T5)
  • Step 4 Ethyl 4-(5-fluoropyridin-2-yl)-2-hydrazone-3-oxobutanoate (T6-5)
  • Step 5 Ethyl 2-(tert-butoxycarbonyl-hydrazone)-(4-(5-fluoropyridin-2-yl)-3-oxobutanoate (T6-6)
  • Step 6 Ethyl 5-(5-fluoropyridin-2-yl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (T6-7)
  • Step 7 Ethyl 5-(5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T6-8)
  • Step 8 5-(5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T6)
  • Step 1 Ethyl 5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (T7-1)
  • Step 2 5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T7)
  • Step 1 Ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridazine-3-carboxylate (T8- 1)
  • Step 2 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridazine-3-carboxylic acid (T8)
  • Step 4 (E)-2-(tert-butoxycarbonyl-hydrazone)-(4-(4-chlorophenyl)-3-oxobutanoic acid ethyl ester (T9-5)
  • Step 5 Ethyl 5-(4-chlorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (T9-6)
  • Step 6 Ethyl 5-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T9-7)
  • Step 7 5-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T9)
  • Step 3 Ethyl 4-(5-chloropyridin-2-yl)-2-diazo-3-oxobutanoate (T10-4)
  • Step 4 Ethyl 4-(5-chloropyridin-2-yl)-2-hydrazone-3-oxobutanoate (T10-5)
  • Step 5 2-(tert-butoxycarbonyl-hydrazone)-(4-(5-chloropyridin-2-yl)-3-oxobutanoic acid ethyl ester (T10-6)
  • Step 6 Ethyl 5-(5-chloropyridin-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (T10-7)
  • Step 7 Ethyl 5-(5-chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T10-8)
  • Step 8 5-(5-Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T10)
  • Example 8 N-(4-(4-amino-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4 -Fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 8)
  • Example 28 N-(4-(4-amino-7-(1,1,1-trifluoropropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzene Base)-5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 28)
  • Example 36 N-(4-(4-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl )-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 36)
  • Example 37 N-(4-(4-Amino-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl) -5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 37)
  • Example 54 N-(4-(4-Amino-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 54)
  • T2 45mg, 129 ⁇ mol
  • T10 40mg, 129 ⁇ mol
  • N,N-dimethylformamide 4mL
  • 2-(7-azobenzotriazole)-N,N , N', N'-tetramethylurea hexafluorophosphate 99 mg, 258 ⁇ mol
  • N, N-diisopropylethylamine 42 mg, 327 ⁇ mol
  • Example 60 N-(4-(4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) -5-(5-Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 60)
  • Example 61 N-(4-(4-amino-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(5 -Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 61)
  • Example 62 N-(4-(4-Amino-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(5-chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 62)
  • Example 64 N-(4-(4-Amino-7-(2-fluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(5- Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 64)
  • Example 65 N-(4-(4-Amino-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl) Phenyl)-5-(5-chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 65)
  • Test Example 1 Compounds are tested for Axl, Mer and Tyro3 kinase activity
  • HTRF kit HTRF KinEASE TM -TK (Cisbio)
  • TK-substrate-biotin/ATP mixed working solution Pre-incubate the enzyme with different concentrations of test compounds at 25°C for a certain period of time, then add 5 ⁇ TK-substrate-biotin/ATP mixed working solution, react at 25°C for a period of time, and finally add 2 ⁇ Streptavidin-XL665 and The mixed working solution of TK Antibody-Cryptate was incubated at 25°C for a period of time, and the fluorescence signal ratio (Ratio) was detected by a microplate reader.
  • Percent inhibition rate (1-(compound Ratio of different concentrations-blank control Ratio)/(negative control Ratio-blank control Ratio)) ⁇ 100%;
  • the half maximal inhibitory concentration (IC 50 ) or range of the compound is calculated according to the following formula:
  • IC 50 X ⁇ (1-percent inhibition rate (%))/percent inhibition rate (%), wherein: X is the test concentration of the compound when the inhibition rate is between 30-80%.
  • the compound of the present invention shows strong inhibitory activity on Axl and Mer.
  • Test example 2 Compound inhibits the proliferation activity of Ba/F3-TEL-Axl cells
  • Kit name/manufacturer Luminescent Cell Viability Assay, Promega
  • the Ba/F3-TEL-Axl cells were cultured in a monolayer in vitro, the culture condition was 10% FBS+1% P/S RPMI-1640 medium, and cultured in an incubator containing 5% CO 2 air at 37°C.
  • Spread cells in 96-well plate, 2000 cells/well, then add pre-diluted compound, add DMSO to negative control group, add culture medium to blank control group, and incubate at 37°C for 72 hours in an incubator with 5% CO2 air.
  • Add the detection reagent CellTiter-Glo to each well, and read the relative chemiluminescence unit value (RLU) in the chemiluminescence detection mode of the microplate reader.
  • RLU relative chemiluminescence unit value
  • Percent inhibition rate (1-(chemiluminescent signal value of test compound-chemiluminescent signal value of blank control)/(chemiluminescent signal value of negative control-chemiluminescent signal value of blank control)) ⁇ 100%, using Graphpad 7.0
  • the curve was fitted according to the four-parameter model, and the half-maximal inhibitory concentration (IC 50 ) of the compound was calculated.
  • the growth inhibitory activity of the compounds on Ba/F3-TEL-Axl cells was determined according to the above method, and the results are shown in Table 2.
  • the compound of the present invention has strong proliferation inhibitory activity on Ba/F3-TEL-Axl cells.
  • Test Example 3 Inhibitory test of compounds on the proliferation activity of HCC827erlotinib R cells
  • HCC827erlotinib R (erlotinib-resistant HCC827 cells)
  • Kit name/manufacturer Luminescent Cell Viability Assay, Promega
  • HCC827 erlotinib R cells were cultured in a monolayer in vitro, the culture condition was RPMI1640+10% FBS medium+200nM erlotinib, and cultured in an incubator at 37°C with 5% CO 2 air. Cells were plated in 96-well plates, 4000 cells/well, and then pre-diluted compounds were added. The negative control group was added with DMSO, and the blank control group was added with culture medium. The culture medium used for plating did not contain erlotinib.
  • the detection reagent CellTiter-Glo was added to each well, and the relative chemiluminescence unit value (RLU) was read in the chemiluminescence detection mode of a microplate reader.
  • Percent inhibition rate (1-(chemiluminescent signal value of test compound-chemiluminescent signal value of blank control)/(chemiluminescent signal value of negative control-chemiluminescent signal value of blank control)) ⁇ 100%, using Graphpad 7.0
  • the curve was fitted according to the four-parameter model, and the half-maximal inhibitory concentration (IC 50 ) of the compound was calculated.
  • the proliferation inhibitory activity of the compound on HCC827 erlotinib R cells was determined according to the above method, and the results are shown in Table 3.
  • the compound of the present invention has strong proliferation inhibitory activity on erlotinib-resistant HCC827 cells.
  • Test Example 4 CYP enzyme (cytochrome P450) inhibition test
  • Test group Add different concentrations of test compounds to the microwell plate. Luciferin-ME (100 ⁇ M), K 3 PO 4 (100 mM) and CYP1A2 (0.01 pmol/ ⁇ L) were added to each well, and pre-incubated at room temperature for 10 min. Then add NADPH regeneration system and react at room temperature for 30min. Finally, an equal volume of detection buffer was added and incubated at room temperature for 20 min. Chemiluminescent detection is then performed.
  • Negative control group the experimental method is the same as that of the test group, but no compound to be tested is added.
  • Blank control group The experimental method is the same as that of the test group, but the test compound is not added, and CYP1A2 is replaced by CYP1A2 Membrance (0.01pmol/ ⁇ L).
  • Test group Add different concentrations of test compounds to the microwell plate. Luciferin-ME EGE (3 ⁇ M), K 3 PO 4 (100 mM) and CYP2D6 (5 nM) were added to each well, and pre-incubated at room temperature for 10 min. Then add NADPH regeneration system and react at 37°C for 30min. Finally, an equal volume of detection buffer was added and incubated at room temperature for 20 min. Chemiluminescent detection is then performed.
  • Negative control group the experimental method is the same as that of the test group, but no compound to be tested is added.
  • Blank control group the experimental method is the same as that of the test group, but no test compound is added, and CYP2D6 Membrance (5nM) is used instead of CYP2D6.
  • Test group Add different concentrations of test compounds to the microwell plate. Luciferin-IPA (3 ⁇ M), K 3 PO 4 (100 mM) and CYP3A4 (2 nM) were added to each well, and pre-incubated at room temperature for 10 min. Then add NADPH regeneration system and react at room temperature for 30min. Finally, an equal volume of detection buffer was added and incubated at room temperature for 20 min. Chemiluminescent detection is then performed.
  • Negative control group the experimental method is the same as that of the test group, but no compound to be tested is added.
  • Blank control group the experimental method is the same as that of the test group, but no test compound is added, and CYP3A4 Membrance (2nM) is used instead of CYP3A4.
  • Percent inhibition rate (%) (1-(chemiluminescence signal value of test compound-chemiluminescence signal value of blank control)/(chemiluminescence signal value of negative control-chemiluminescence signal value of blank control)) ⁇ 100% ;
  • IC 50 X ⁇ (1-percent inhibition rate (%))/percent inhibition rate (%), wherein: X is the test concentration of the compound.
  • the compound of the present invention has no obvious inhibitory effect on the three major CYP subtypes, indicating that its potential drug interaction is relatively low.
  • Kit Predictor TM hERG Fluorescence Polarization Assay, (ThermoFisher),
  • the kit contains:
  • Test group Add different concentrations of compounds to be tested into microwell plates containing hERG cell membranes, and then add Tracer, a tracer with high hERG affinity, to each well. After incubating the microwell plates at room temperature for 2 hours, use multiple Functional microplate reader detects the change of fluorescence polarization (Excitation: 540nm; Emission: 590nm) value.
  • Positive control group 30 ⁇ M positive control compound E4031 was used instead of the test compound, and the experimental method was the same as that of the test group.
  • Blank control group hERG buffer was used instead of the compound to be tested, and hERG cell membrane was not added, and the experimental method was the same as that of the test group.
  • Percent inhibition rate (1-(fluorescence polarization value of the compound to be tested-fluorescence polarization value of the positive control group)/(fluorescence polarization value of the blank control group-fluorescence polarization value of the positive control group))*100%
  • the half inhibitory concentration (IC 50 ) or range of the compound against hERG is estimated according to the following formula:
  • IC 50 X ⁇ (1-percent inhibition rate (%))/percent inhibition rate (%), wherein: X is the test concentration of the compound when the inhibition rate is between 30-80%.
  • test results show that most of the compounds of the present invention have low affinity with hERG, and the IC 50 of the competition with the affinity tracer Tracer is all >10 ⁇ M. It was demonstrated that the vast majority of compounds of the present invention have a low risk of cardiotoxicity associated with hERG ion channels.
  • Prototype remaining rate (%) 100 ⁇ (A incubation sample /A 0h )
  • a incubation sample the peak area ratio of the compound and the internal standard after incubation for the corresponding time
  • a 0h the peak area ratio of the compound and the internal standard when unreacted.
  • the residual rate of the original form of the compound after being incubated in human and rat liver microsomes for 15 min was determined according to the above method, as shown in Table 6.
  • Most of the compounds of the present invention have stable metabolism in human liver microsomes, relatively stable metabolism in rat liver microsomes, and the overall metabolic stability is good.
  • Test Example 7 Compound pharmacokinetics test in SD rats
  • the compound of the present invention was administered to male SD rats by intragastric administration (PO), and the pharmacokinetic characteristics were investigated.

Abstract

The present invention relates to a heterocyclic compound and a preparation method therefor and a use thereof. Specifically, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, polymorph, a solvate, an N-oxide, an isotopically labeled compound, a metabolite, or a prodrug, a pharmaceutical composition and kit containing the compound, a preparation method for the compound, and a use of the compound in the preparation of a drug for preventing or treating Axl and/or Mer-related diseases (especially tumor diseases).

Description

一类杂环化合物及其制备方法和用途A class of heterocyclic compounds and their preparation methods and uses 技术领域technical field
本发明属于医药领域，具体涉及一种具有Axl和/或Mer抑制活性的化合物及其制备和用途。The invention belongs to the field of medicine, and specifically relates to a compound with Axl and/or Mer inhibitory activity and its preparation and application.
背景技术Background technique
目前人类已发现58个受体酪氨酸激酶(Receptor Tyrosine Kinases，RTKs)，它们是细胞表面的跨膜受体，主要由胞外域、跨膜域和胞内域组成，其中胞内域具有激酶活性。RTKs与配体结合后进行二聚化、自磷酸化，从而自身活化，继而激活胞内的下游信号级联，调控细胞的有丝分裂发生、细胞周期、细胞粘附、迁移和血管生成等功能。At present, 58 receptor tyrosine kinases (Receptor Tyrosine Kinases, RTKs) have been discovered in humans. They are transmembrane receptors on the cell surface, mainly composed of extracellular domain, transmembrane domain and intracellular domain, and the intracellular domain has a kinase active. RTKs undergo dimerization and autophosphorylation after binding to ligands, thereby activating themselves, and then activating intracellular downstream signaling cascades to regulate cell mitosis, cell cycle, cell adhesion, migration, and angiogenesis.
TAM家族属于受体酪氨酸激酶亚家族，成员包括Tyro-3、Axl和Mer，其中Axl和Mer在信号转导通路中调节多种细胞功能。Axl(Ufo，Ark或Tyro7)于1991年由Bryan等在人类慢性髓细胞白血病的DNA中发现，Axl不仅与Tyro3具有相似的基因结构，与Mer具有相似的酪氨酸激酶域氨基酸序列，而且它们还拥有共同的生长停滞特异性蛋白6(Growth Arrest Specific 6，Gas6)配体。The TAM family belongs to the receptor tyrosine kinase subfamily, and its members include Tyro-3, Axl and Mer, among which Axl and Mer regulate various cellular functions in signal transduction pathways. Axl (Ufo, Ark or Tyro7) was discovered by Bryan et al. in the DNA of human chronic myeloid leukemia in 1991. Axl not only has a similar gene structure to Tyro3, but also has a similar tyrosine kinase domain amino acid sequence to Mer, and they They also share a common Growth Arrest Specific 6 (Gas6) ligand.
Axl的活化有多种不同的方式：(1)通过配体结合而产生的同源二聚化；(2)不依赖于配体结合而产生的同源二聚化，即Axl的过度表达而发生的自二聚化；(3)Axl受体与其他2个TAM受体的异源二聚化；(4)Axl受体与非TAM受体的异型二聚化；(5)两个不同细胞的细胞外域结合激活。其中与配体结合是主要的Axl活化方式，Gas6与Axl的胞外域结合后，Axl发生二聚化，从而导致Axl的胞内域中3个磷酸化位点(Y779、Y821、Y866)发生磷酸化，这些磷酸化位点可与磷脂酰肌醇3激酶亚基(PI3K)、磷脂酶C(PLC)和生长因子受体结合蛋白2(Grb2)结合，激活RAS/ERK、PI3K/Akt等多条相关信号通路，促进细胞炎症，细胞的生存、迁移、侵袭和转移等生理学效应。Axl is activated in a number of different ways: (1) homodimerization through ligand binding; (2) homodimerization independent of ligand binding, that is, overexpression of Axl self-dimerization; (3) heterodimerization of Axl receptor with two other TAM receptors; (4) heterodimerization of Axl receptor with non-TAM receptors; (5) two different Cellular extracellular domain binding activation. Among them, binding to ligand is the main way of Axl activation. After Gas6 binds to the extracellular domain of Axl, Axl dimerizes, resulting in the phosphorylation of three phosphorylation sites (Y779, Y821, and Y866) in the intracellular domain of Axl. These phosphorylation sites can bind to phosphatidylinositol 3-kinase subunit (PI3K), phospholipase C (PLC) and growth factor receptor binding protein 2 (Grb2), activate RAS/ERK, PI3K/Akt and many other Related signaling pathways promote cell inflammation, cell survival, migration, invasion and metastasis and other physiological effects.
Axl除了在人体多种细胞和组织中高表达外，在肺癌、乳腺癌、结肠癌、胃癌、肝癌和卵巢癌等多种恶性肿瘤中均有发现Axl的高表达。Axl异常表达能够拮抗肿瘤细胞的凋亡，促进肿瘤细胞的侵袭和转移，促进肿瘤血管新生，推动肿瘤的发生和发展，与肿瘤的发生、复发和不良预后密切相关。近年来研究显示，Axl的高表达可能介导EGFR的获得性耐药，临床研究表明约20％的EGFR耐药病人中存在Axl的高表达。临床前研究发现Axl抑制剂与EGFR抑制剂的联合用药可以有效克服和改善EGFR抑制剂耐药的问题，临床上的联合用药也正在开展。此外Axl在肿瘤微环境(如巨噬细胞、树突状细胞等)中高表达，可以通过与肿瘤细胞以及其他基质细胞交互作用，协同促进肿瘤的进展，Axl过度表达导致的异常激活，与其他靶向药物的耐药以及化疗药物的耐药也存在密切关系。In addition to high expression of Axl in various cells and tissues of the human body, high expression of Axl has been found in various malignant tumors such as lung cancer, breast cancer, colon cancer, gastric cancer, liver cancer and ovarian cancer. Abnormal expression of Axl can antagonize tumor cell apoptosis, promote tumor cell invasion and metastasis, promote tumor angiogenesis, promote tumor occurrence and development, and is closely related to tumor occurrence, recurrence and poor prognosis. Studies in recent years have shown that the high expression of Axl may mediate the acquired drug resistance of EGFR. Clinical studies have shown that about 20% of EGFR drug-resistant patients have high expression of Axl. Preclinical studies have found that the combination of Axl inhibitors and EGFR inhibitors can effectively overcome and improve the problem of EGFR inhibitor resistance, and clinical combination therapy is also underway. In addition, Axl is highly expressed in the tumor microenvironment (such as macrophages, dendritic cells, etc.), and can cooperate with tumor cells and other stromal cells to promote tumor progression. Abnormal activation caused by overexpression of Axl interacts with other targets. There is also a close relationship between drug resistance and chemotherapeutic drug resistance.
MerTK信号传导在多种生理过程中起作用，例如凋亡细胞的巨噬细胞清除，血小板聚集，细胞骨架重组和吞噬，并调节许多生理过程，包括细胞存活，迁移，分化和凋亡细胞的吞噬作用，Mer介导的信号传导通路主要包括：(1)AKT信号通路：Mer受体与Gas6结合后使PI3K磷酸化激活，在磷酯酰肌醇依赖性蛋白激酶的参与下，活化的AKT进一步影响下游因子的活化状态，参与调节细胞凋亡，对细胞的增殖和迁移也有一定调节作用；(2)MAPK信号通路：Gas6与Mer结合使MAPK(主要为细胞外调节蛋白激酶和p38亚族)磷酸化，激活的MAPK将信号转导入细胞核,通过激活核转录因子影响细胞增殖和侵袭，同时也参与细胞凋亡进程。(3)信号转导子和转录激活子(STAT)信号通路：Mer信号通路激活后，STAT5、STAT6被磷酸化后形成二聚体，进入细胞核结合靶基因调控区域，使细胞因子信号抑制物的表达增加，起抑制炎症反应的作用，并与肿瘤细胞增殖密切相关。MerTK signaling plays a role in diverse physiological processes, such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeletal reorganization, and phagocytosis, and regulates many physiological processes, including cell survival, migration, differentiation, and phagocytosis of apoptotic cells Mer-mediated signaling pathways mainly include: (1) AKT signaling pathway: Mer receptors bind to Gas6 to activate PI3K phosphorylation, and with the participation of phosphatidylinositol-dependent protein kinase, the activated AKT further Affects the activation status of downstream factors, participates in the regulation of cell apoptosis, and also has a certain regulatory effect on cell proliferation and migration; (2) MAPK signaling pathway: the combination of Gas6 and Mer makes MAPK (mainly extracellular regulatory protein kinase and p38 subfamily) Phosphorylated and activated MAPK transduces signals into the nucleus, affects cell proliferation and invasion by activating nuclear transcription factors, and also participates in the process of cell apoptosis. (3) Signal transducer and activator of transcription (STAT) signaling pathway: After the Mer signaling pathway is activated, STAT5 and STAT6 are phosphorylated to form a dimer, enter the nucleus and bind to the target gene regulatory region, so that the cytokine signal inhibitor The expression increases, plays a role in inhibiting inflammatory response, and is closely related to tumor cell proliferation.
在人类癌症治疗上仍有大量未得到满足的临床需求，基于Axl和/或Mer抑制剂在临床前显示出的确切抗肿瘤效果以及大量正在开展的临床研究现状，Axl和/或Mer抑制剂的开发已成为抗肿瘤药物研究的热点方向。综上所述，本领域亟待开发新型的Axl和/或Mer小分子抑制剂。There are still a large number of unmet clinical needs in the treatment of human cancer. Based on the definite anti-tumor effect of Axl and/or Mer inhibitors in preclinical and the status of a large number of ongoing clinical studies, the potential of Axl and/or Mer inhibitors Development has become a hot spot in the research of anticancer drugs. In summary, there is an urgent need to develop new small molecule inhibitors of Axl and/or Mer in this field.
发明概述Summary of the invention
本发明的第一方面涉及式I的化合物或其药学上可接受的盐、立体异构体、互变异构体、多 晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，A first aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a pharmaceutically acceptable salt thereof, metabolites or prodrugs,
Figure PCTCN2022109584-appb-000001
Figure PCTCN2022109584-appb-000001
其中，in,
R 1选自H、C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基和5-10元杂芳基，所述C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 6取代； R 1 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 6 ;
R 6在每次出现时各自独立地选自卤素、-CN、-OH、-NH 2、-NO 2、-S(O) pR A、-COR A、＝O、C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基、3-8元杂环基、C 2-C 6烯基、C 2-C 6炔基、C 6-C 10芳基和5-10元杂芳基，所述C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基、3-8元杂环基、C 2-C 6烯基、C 2-C 6炔基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 7取代； Each occurrence of R 6 is independently selected from halogen, -CN, -OH, -NH 2 , -NO 2 , -S(O) pRA , -CORA , =O, C 1 -C 6 alkane C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, 3-8 membered heterocyclyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl and 5-10 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, 3-8 membered heterocyclic group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 7 ;
R 7在每次出现时各自独立地选自卤素、-CN、-OH、-NH 2、-NO 2、-S(O) pR A、-COR A和＝O； Each occurrence of R 7 is independently selected from halogen , -CN, -OH, -NH 2 , -NO 2 , -S(O) pRA , -COR A and =O;
R A独立地选自H和C 1-C 6烷基； RA is independently selected from H and C 1 -C 6 alkyl;
p选自1和2；p is selected from 1 and 2;
R 2在每次出现时各自独立地选自H、-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷基、C 1-C 6烷氧基和C 3-C 8环烷基，所述C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 8环烷基任选地被一个或多个R 8取代； Each occurrence of R 2 is independently selected from H, -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 - C 8 cycloalkyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 8 cycloalkyl are optionally substituted by one or more R 8 ;
R 8在每次出现时各自独立地选自-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基； Each occurrence of R 8 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
m选自0、1、2、3和4；m is selected from 0, 1, 2, 3 and 4;
R 3选自H、C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基和5-10元杂芳基，所述C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 9取代； R 3 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclic group, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 9 ;
R 9在每次出现时各自独立地选自-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基； Each occurrence of R 9 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
R 4选自H、C 1-C 6烷基、C 3-C 8环烷基和3-8元杂环基，所述C 1-C 6烷基、C 3-C 8环烷基或3-8元杂环基任选地被一个或多个R 10取代； R 4 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R 10 ;
R 10在每次出现时各自独立地选自-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基和3-8元杂环基； Each occurrence of R 10 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 haloalkoxy and 3-8 membered heterocyclic groups;
X选自CH和N；X is selected from CH and N;
R 5选自H、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基、3-8元杂环基、卤素、-CN、-CONR 5aR 5b和C 1-C 6卤代烷基；且 R 5 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, halogen, -CN, -CONR 5a R 5b and C 1 -C 6 haloalkyl; and
R 5a和R 5b各自独立地选自H和C 1-C 6烷基。 R 5a and R 5b are each independently selected from H and C 1 -C 6 alkyl.
另一方面，本发明提供了一种药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及一种或多种药学可接受的载体。In another aspect, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph , solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
另一方面，本发明提供了一种药盒，其包含：In another aspect, the present invention provides a kit comprising:
a)本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者本发明的药物组合物；和a) Compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof , or a pharmaceutical composition of the present invention; and
b)任选存在的包装和/或说明书。b) Optional packaging and/or instructions.
另一方面，本发明提供了本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒，其用于预防或治疗与Axl和/或Mer相关的疾病(特别是肿瘤疾病)。In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof , metabolites or prodrugs, or the pharmaceutical composition of the present invention, or the kit of the present invention, which is used for the prevention or treatment of Axl and/or Mer-related diseases (especially tumor diseases).
另一方面，本发明提供了本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的 药物组合物或者本发明的药盒在制备用于预防或治疗与Axl和/或Mer相关的疾病(特别是肿瘤疾病)的药物中的用途。In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof , metabolites or prodrugs or the pharmaceutical composition of the present invention or the kit of the present invention in the preparation of medicines for the prevention or treatment of Axl and/or Mer-related diseases (especially tumor diseases).
另一方面，本发明提供了预防或治疗与Axl和/或Mer相关的疾病(特别是肿瘤疾病)的方法，其包括向有此需要的个体给药预防或治疗有效量的本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒。In another aspect, the present invention provides a method for preventing or treating diseases related to Axl and/or Mer (especially tumor diseases), which comprises administering a preventive or therapeutically effective amount of the compound of the present invention or Pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, or pharmaceutical combinations of the present invention thing, or the kit of the present invention.
另一方面，本发明提供了制备本发明的化合物的方法，其包括以下反应路线1所示的步骤：In another aspect, the present invention provides a method for preparing the compound of the present invention, which comprises the steps shown in Scheme 1 below:
反应路线1Reaction scheme 1
Figure PCTCN2022109584-appb-000002
Figure PCTCN2022109584-appb-000002
其中，R 1、R 2、R 3、R 4、R 5、X和m如上文中所定义。 Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , X and m are as defined above.
发明详述Detailed description of the invention
在进一步描述本发明之前，应当理解，本发明不限于文中所述的具体实施方案。还应理解，文中所使用的术语仅用于描述而非限制具体实施方案。Before the present invention is further described, it is to be understood that this invention is not limited to the particular embodiments described herein. It is also to be understood that the terminology used herein is for the purpose of description and not limitation of particular embodiments.
定义definition
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless defined otherwise hereinafter, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including those variations of the techniques or substitutions of equivalent techniques that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
如本文中所使用，术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。As used herein, the terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended, and do not Other unlisted elements or method steps are excluded.
如本文中所使用，术语“烷基”定义为直链或支链的饱和脂肪族烃基。例如，如本文中所使用，术语“C 1-C 6烷基”指具有1至6个碳原子的直链或支链的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被一或多个(诸如1至3个)适合的取代基如卤素取代。 As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon group. For example, as used herein, the term "C 1 -C 6 alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which are optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen.
如本文中所使用，术语“环烷基”指饱和或部分不饱和的非芳族单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统，诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被一个或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个，例如3至10个碳原子、3至8个碳原子或3至6个碳原子。例如，如本文中所使用，术语“C 3-C 8环烷基”指具有3至8个成环碳原子的饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基、环己基、环庚基)，其任选地被一或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。 As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g. monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic rings, including spiro, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo [3.2.1] octyl or bicyclo[5.2.0] nonyl, decalinyl, etc.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15, eg, 3 to 10, 3 to 8, or 3 to 6 carbon atoms. For example, as used herein, the term "C 3 -C 8 cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring ( For example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) optionally substituted by one or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl base.
如本文中所使用，术语“烷氧基”意指通过氧原子连接至母体分子部分的如上文所定义的“烷基”，例如C 1-C 6烷氧基、C 1-C 3烷氧基。C 1-C 6烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基等，所述烷氧基可以任选地被一或多个(诸如1至3个)相同或不同的取代基取代。 As used herein, the term "alkoxy" means an "alkyl" group, as defined above, attached to the parent molecular moiety through an oxygen atom, for example, C 1 -C 6 alkoxy, C 1 -C 3 alkoxy base. Representative examples of C 1 -C 6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, Oxy, hexyloxy, etc., said alkoxy may be optionally substituted by one or more (such as 1 to 3) same or different substituents.
如本文中所使用，术语“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。As used herein, the term "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
如本文中所使用，术语“卤代烷基”是指被一或多个(诸如1至3个)相同或不同的卤素原子取代的烷基。例如，本文中所使用的术语“C 1-C 6卤代烷基”是指具有1至6个碳原子的卤代烷基，包括但不限于-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3、-CH 2Cl等。本文中的卤代烷基任选地被一或多个(诸如1至3个)本文所描述的取代基取代。 As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms. For example, the term "C 1 -C 6 haloalkyl" as used herein refers to a haloalkyl group having 1 to 6 carbon atoms, including but not limited to -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , -CH 2 CH 2 CF 3 , -CH 2 Cl, etc. The haloalkyl groups herein are optionally substituted with one or more (such as 1 to 3) substituents described herein.
如本文中所使用，术语“卤代烷氧基”是指通过氧原子连接至母体分子部分的如上文所定义的“卤代烷基”，例如C 1-C 6卤代烷氧基。 As used herein, the term "haloalkoxy" means a "haloalkyl" as defined above attached to the parent molecular moiety through an oxygen atom, eg, C 1 -C 6 haloalkoxy.
如本文中所使用，术语“杂环基”指单环或多环基团，其在环中例如具有2、3、4、5、6、7、8、9个碳原子和一个或多个(例如1个、2个、3个或4个)选自O、S、S(＝O)、S(＝O) 2、N和NR(R表示氢原子或取代基，例如但不限于烷基或环烷基)的基团。杂环基包括饱和及部分不饱和的非芳香 杂环。饱和杂环基可称为杂环烷基，例如3-8元杂环烷基、3-6元杂环烷基、5-6元杂环烷基等。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、并环体系、桥环体系或螺环体系。特别地，3-8元杂环基为在环中具有3-8个碳原子及杂原子的基团，例如，其具有4至8、4至7、4至6、5至8、5至7或者5至6个碳原子及杂原子(分别称作4至8元、4至7元、4至6元、5至8元、5至7元以及5至6元杂环基)，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁基、氮杂环庚基、氧杂环丁基、四氢呋喃基、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、四氢吡喃基、氮杂
Figure PCTCN2022109584-appb-000003
基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基、三噻烷基(trithianyl)等；以及它们的并环衍生物或苯并衍生物或杂芳基并衍生物或螺环衍生物等。 As used herein, the term "heterocyclyl" refers to a monocyclic or polycyclic group having, for example, 2, 3, 4, 5, 6, 7, 8, 9 carbon atoms and one or more (eg 1, 2, 3 or 4) selected from O, S, S(=O), S(=O) 2 , N and NR (R represents a hydrogen atom or a substituent such as but not limited to an alkane group or cycloalkyl) group. Heterocyclyl includes saturated and partially unsaturated non-aromatic heterocyclic rings. A saturated heterocyclic group may be called a heterocycloalkyl group, such as a 3-8 membered heterocycloalkyl group, a 3-6 membered heterocycloalkyl group, a 5-6 membered heterocycloalkyl group, and the like. Unless otherwise specified in this specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, an amalgamated ring system, a bridged ring system or a spiro ring system. In particular, a 3-8 membered heterocyclic group is a group having 3-8 carbon atoms and heteroatoms in the ring, for example, it has 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7 or 5 to 6 carbon atoms and heteroatoms (respectively referred to as 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7 and 5 to 6 heterocyclic groups), for example But not limited to oxiranyl, aziridinyl, azetidinyl, azepanyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl , tetrahydropyranyl, aza
Figure PCTCN2022109584-appb-000003
base, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl), etc.; and their ring derivatives or benzo derivatives or hetero Aryl derivatives or spiro derivatives, etc.
如本文中所使用，术语“芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。常见的芳基包括(但不限于)苯基、萘基、蒽基、菲基、苊基、薁基、芴基、茚基、芘基等。例如，术语“C 6-C 10芳基”指含有6至10个碳原子的芳族基团，诸如苯基或萘基。芳基任选地被一或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-C 6烷基等)取代。 As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. Common aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like. For example, the term " C6 - C10 aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. Aryl is optionally substituted with one or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkyl, etc.).
如本文中所使用，术语“杂芳基”指含有至少一个选自N、O和S的杂原子的单环、双环或三环芳族环系，其具有例如5、6、8、9、10、11、12、13或14个环原子，特别是具有1或2或3或4或5或6或9或10个碳原子，并且，另外在每一种情况下可为苯并稠合的。例如，如本文中所使用，术语“5-10元杂芳基”意指具有5-10个环原子的单环、双环或三环芳族环系统，并且其中包含至少一个可以相同或不同的杂原子(所述杂原子是例如N、O或S)。5-10元杂芳基的实例包括但不限于噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等，以及它们的苯并衍生物；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物。杂芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、C 1-C 6烷基等)取代。 As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, having, for example, 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially with 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, additionally, in each case may be benzofused of. For example, as used herein, the term "5-10 membered heteroaryl" means a monocyclic, bicyclic or tricyclic aromatic ring system having 5-10 ring atoms, and containing at least one which may be the same or different A heteroatom (the heteroatom is eg N, O or S). Examples of 5-10 membered heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, Triazolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives. Heteroaryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, C 1 -C 6 alkyl, etc.).
如本文中所使用，术语“烯基”是指含有至少一个C＝C双键的烃基。烯基可以是直链或支链烯基，并且含有2至15个碳原子。例如本文中“C 2-C  6烯基”为含有2至6个碳原子的烯基。烯基的非限制性例子包括乙烯基、丙烯基、正丁烯基、3-甲基丁-2-烯基、正戊烯基、辛烯基和癸烯基。烯基可以是未取代的，也可以被一或多个相同或不同的取代基取代。 As used herein, the term "alkenyl" refers to a hydrocarbon group containing at least one C=C double bond. Alkenyl groups can be straight or branched chain alkenyl groups and contain 2 to 15 carbon atoms. For example, "C 2 -C 6 alkenyl" herein is an alkenyl group containing 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. Alkenyl groups can be unsubstituted or substituted with one or more same or different substituents.
如本文中所使用，术语“炔基”是指具有至少一个C≡C三键的烃基。炔基可以是直链或支链炔基，并且含有2至15个碳原子。例如本文中“C 2-C 6炔基”为含有2至6个碳原子的炔基。炔基的非限制性实例包括但不限于乙炔基、2-丙炔基、2-丁炔基和1,3-丁二炔基等。炔基可以是未取代的，也可以被一或多个相同或不同的取代基取代。 As used herein, the term "alkynyl" refers to a hydrocarbon group having at least one C≡C triple bond. The alkynyl group can be straight or branched and contains 2 to 15 carbon atoms. For example, "C 2 -C 6 alkynyl" herein is an alkynyl group containing 2 to 6 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Alkynyl groups can be unsubstituted or substituted with one or more same or different substituents.
术语“取代”指所指定的原子上的一个或多个(例如1个、2个、3个、4个或5个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。The term "substituted" means that one or more (eg, 1, 2, 3, 4 or 5) hydrogens on the indicated atom are replaced by a selection from the indicated group, provided that no more than the indicated The atoms are at their normal valences under the circumstances and the substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
如果取代基被描述为“任选地被….取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的取代基替代或未替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的取代基替代或未替代。If a substituent is described as being "optionally substituted by", the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Substituents of choice are either substituted or unsubstituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected substituents Substituted or not.
如果取代基被描述为“独立地选自”一组基团，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。If substituents are described as being "independently selected from" a group, each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
如本文中所使用，术语“一或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个、6个、7个、8个、9个或10个。As used herein, the term "one or more" means 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。As used herein, unless otherwise indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。When a bond for a substituent is shown as being through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring-forming atom in such a substitutable ring.
本发明所用术语“药学上可接受的”是指物质或组合物必须与构成制剂的其他组分和/或用其治疗的哺乳动物在化学和/或毒理学上相容。The term "pharmaceutically acceptable" as used herein means that the substance or composition must be chemically and/or toxicologically compatible with the other components making up the formulation and/or with the mammal being treated therewith.
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。适合的酸加成盐由形成药学上可接受盐的酸来形成。适合的碱加成盐由形成药学上可接受盐的碱来形成。适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. For a review of suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
术语“立体异构体”(或称“旋光异构体”)是指由于具有至少一个手性因素(包括手性中心、手性轴、手性面等)而导致具有垂直的不对称平面，从而能够使平面偏振光旋转的稳定异构体。由于本 发明的化合物存在可能导致立体异构的不对称中心以及其他化学结构，因此本发明也包括这些立体异构体及其混合物。由于本发明的化合物(或其药学上可接受的盐)包括不对称碳原子，因而能够以单一立体异构体形式、外消旋物、对映异构体和非对映异构体的混合物形式存在。通常，这些化合物能够以外消旋物的形式制备。然而，如果需要的话，可以将这类化合物制备或分离后得到纯的立体异构体，即单一对映异构体或非对映异构体，或者单一立体异构体富集化(纯度≥98％、≥95％、≥93％、≥90％、≥88％、≥85％或≥80％)的混合物。如下文中所述，化合物的单一立体异构体是由含有所需手性中心的旋光起始原料合成制备得到的，或者是通过制备得到对映异构体产物的混合物之后再分离或拆分制备得到的，例如转化为非对映异构体的混合物之后再进行分离或重结晶、色谱处理、使用手性拆分试剂，或者在手性色谱柱上将对映异构体进行直接分离。具有特定立体化学的起始化合物既可以商购得到，也可以按照下文中描述的方法制备再通过本领域熟知的方法拆分得到。术语“对映异构体”是指彼此具有不能重叠的镜像的一对立体异构体。术语“非对映异构体”或“非对映体”是指彼此不构成镜像的旋光异构体。术语“外消旋混合物”或“外消旋物”是指含有等份的单一对映异构体的混合物(即两种R和S对映体的等摩尔量混合物)。术语“非外消旋混合物”是指含有不等份的单一对映异构体的混合物。除非另外指出，本发明的化合物的所有立体异构体形式都在本发明的范围之内。The term "stereoisomer" (or "optical isomer") means having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.) that has a perpendicular plane of asymmetry, Stable isomers that can thus rotate plane-polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may give rise to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) include asymmetric carbon atoms, they can be present as single stereoisomers, racemates, enantiomers and mixtures of diastereomers form exists. Generally, these compounds can be prepared in the form of racemates. However, such compounds can be prepared or isolated as pure stereoisomers, i.e., single enantiomers or diastereomers, or enriched in single stereoisomers (purity ≥ 98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85%, or ≥80%). As described hereinafter, individual stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral centers, or by separation or resolution following the preparation of mixtures of enantiomeric products obtained, for example, after conversion into a mixture of diastereoisomers followed by separation or recrystallization, chromatographic treatment, use of chiral resolving agents, or direct separation of the enantiomers on a chiral chromatography column. Starting compounds with specific stereochemistry can be obtained commercially, or can be prepared according to the methods described below and then resolved by methods well known in the art. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereoisomer" or "diastereomer" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (ie, an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of the individual enantiomers. Unless otherwise indicated, all stereoisomeric forms of the compounds of the invention are within the scope of the invention.
术语“互变异构体”(或称“互变异构形式”)是指具有不同能量的，可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(或称质子转移互变异构体)包括(但不限于)通过质子迁移来进行的互相转化，如酮-烯醇异构化、亚胺-烯胺异构化、酰胺-亚胺醇异构化等。除非另外指出，本发明的化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or prototropic tautomers) include, but are not limited to, interconversions via migration of a proton, such as keto-enol isomerization, imine-enamine isomerization , amide-iminoalcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
术语“多晶型物”(或称“多晶型形式”)是指化合物或复合物的固体晶体形式。本领域技术人员可通过许多已知的方法获得分子的多晶型物。这些方法包括(但不限于)熔融重结晶、熔融冷却、溶剂重结晶、去溶剂化、快速蒸发、快速冷却、慢速冷却、汽相扩散和升华。另外，可用熟知的技术检测、分类和鉴定多晶型物，这些技术包括(但不限于)差示扫描量热法(DSC)、热重分析法(TGA)、X射线粉末衍射法(XRPD)、单晶X射线衍射法(SCXRD)、固态核磁共振(NMR)、红外光谱法(IR)、拉曼光谱法和扫描电镜术(SEM)等。The term "polymorph" (or "polymorphic form") refers to a solid crystalline form of a compound or complex. Polymorphs of molecules can be obtained by those skilled in the art by a number of known methods. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, fast evaporation, fast cooling, slow cooling, vapor phase diffusion, and sublimation. In addition, polymorphs can be detected, classified and identified using well-known techniques including, but not limited to, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD) , single crystal X-ray diffraction (SCXRD), solid-state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy and scanning electron microscopy (SEM), etc.
术语“溶剂合物”是指由本发明的化合物(或其药学上可接受的盐)与至少一种溶剂分子通过非共价分子间作用力结合而形成的物质。常见的溶剂合物包括(但不限于)水合物(包括半水合物、一水合物、二水合物、三水合物等)、乙醇合物、丙酮合物等。The term "solvate" refers to a substance formed by combining a compound of the present invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include, but are not limited to, hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetonates, and the like.
术语“氮氧化物”是指叔胺类或含氮(芳)杂环类化合物结构中的氮原子经氧化而形成的化合物。例如，式I化合物母核中的1位氮原子可以形成相应的氮氧化物。The term "nitrogen oxide" refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or a nitrogen-containing (aromatic) heterocyclic compound. For example, the 1-position nitrogen atom in the nucleus of the compound of formula I can form the corresponding nitrogen oxide.
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括但不限于氢的同位素(例如 2H、 3H、氘D、氚T)；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 37Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；及硫的同位素(例如 35S)。 The present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. 2 H, 3 H, deuterium D, tritium T); isotopes of carbon (e.g. 11 C, 13 C, and 14 C); chlorine isotopes of fluorine (such as 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (such as 13 N and 15 N); isotopes of oxygen (such as 15 O, 17 O and 18 O); and sulfur isotopes (eg 35 S).
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。Also included within the scope of the present invention are metabolites of the compounds of the present invention, ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物，当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention which themselves may have little or no pharmacological activity, when administered to the body or The above can be converted into compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association). The prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
术语“各自独立地”是指结构中存在的取值范围相同或相近的至少两个基团(或环系)可以在特定情形下具有相同或不同的含义。例如，取代基X和取代基Y各自独立地为氢、卤素、羟基、氰基、烷基或芳基，则当取代基X为氢时，取代基Y既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基；同理；当取代基Y为氢时，取代基X既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基。The term "independently" means that at least two groups (or ring systems) present in the structure with the same or similar value range may have the same or different meanings under specific circumstances. For example, the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl, then when the substituent X is hydrogen, the substituent Y can be either hydrogen or halogen, Hydroxyl, cyano, alkyl or aryl; similarly; when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，可以在适当的后续阶段移除保护基。The invention also encompasses compounds of the invention which contain protecting groups. During any of the preparations of the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming chemically protected forms of the compounds of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protecting groups, these references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
本发明所用术语“约”在用于修饰某一数值或数值范围时，是指包括该数值或数值范围以及该数值或数值范围的本领域技术人员可接受的误差范围，例如该误差范围为±10％、±5％、±4％、±3％、±2％、±1％、±0.5％等。When the term "about" used in the present invention is used to modify a certain numerical value or numerical range, it means including the numerical value or numerical range and the error range acceptable to those skilled in the art of the numerical value or numerical range, for example, the error range is ± 10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, etc.
化合物compound
本发明的一个目的在于提供一种式I的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，One object of the present invention is to provide a compound of formula I or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compounds, metabolites or prodrugs,
Figure PCTCN2022109584-appb-000004
Figure PCTCN2022109584-appb-000004
其中，in,
R 1选自H、C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基和5-10元杂芳基，所述C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 6取代； R 1 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 6 ;
R 6在每次出现时各自独立地选自卤素、-CN、-OH、-NH 2、-NO 2、-S(O) pR A、-COR A、＝O、C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基、3-8元杂环基、C 2-C 6烯基、C 2-C 6炔基、C 6-C 10芳基和5-10元杂芳基，所述C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基、3-8元杂环基、C 2-C 6烯基、C 2-C 6炔基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 7取代； Each occurrence of R 6 is independently selected from halogen, -CN, -OH, -NH 2 , -NO 2 , -S(O) pRA , -CORA , =O, C 1 -C 6 alkane C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, 3-8 membered heterocyclyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl and 5-10 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, 3-8 membered heterocyclic group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 7 ;
R 7在每次出现时各自独立地选自卤素、-CN、-OH、-NH 2、-NO 2、-S(O) pR A、-COR A和＝O； Each occurrence of R 7 is independently selected from halogen , -CN, -OH, -NH 2 , -NO 2 , -S(O) pRA , -COR A and =O;
R A独立地选自H和C 1-C 6烷基； RA is independently selected from H and C 1 -C 6 alkyl;
p选自1和2；p is selected from 1 and 2;
R 2在每次出现时各自独立地选自H、-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷基、C 1-C 6烷氧基和C 3-C 8环烷基，所述C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 8环烷基任选地被一个或多个R 8取代； Each occurrence of R 2 is independently selected from H, -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 - C 8 cycloalkyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 8 cycloalkyl are optionally substituted by one or more R 8 ;
R 8在每次出现时各自独立地选自-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基； Each occurrence of R 8 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
m选自0、1、2、3和4；m is selected from 0, 1, 2, 3 and 4;
R 3选自H、C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基和5-10元杂芳基，所述C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 9取代； R 3 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclic group, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 9 ;
R 9在每次出现时各自独立地选自-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基； Each occurrence of R 9 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
R 4选自H、C 1-C 6烷基、C 3-C 8环烷基和3-8元杂环基，所述C 1-C 6烷基、C 3-C 8环烷基或3-8元杂环基任选地被一个或多个R 10取代； R 4 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R 10 ;
R 10在每次出现时各自独立地选自-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基和3-8元杂环基； Each occurrence of R 10 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 haloalkoxy and 3-8 membered heterocyclic groups;
X选自CH和N；X is selected from CH and N;
R 5选自H、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基、3-8元杂环基、卤素、-CN、-CONR 5aR 5b和C 1-C 6卤代烷基；且 R 5 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, halogen, -CN, -CONR 5a R 5b and C 1 -C 6 haloalkyl; and
R 5a和R 5b各自独立地选自H和C 1-C 6烷基。 R 5a and R 5b are each independently selected from H and C 1 -C 6 alkyl.
根据本发明的一些实施方案，R 1选自C 1-C 6烷基、C 3-C 8环烷基和3-8元杂环基，所述C 1-C 6 烷基、C 3-C 8环烷基或3-8元杂环基任选地被一个或多个R 6取代。 According to some embodiments of the present invention, R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 - C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R 6 .
根据本发明的一些实施方案，R 6在每次出现时各自独立地选自卤素、-CN、-OH、-S(O) pR A、C 3-C 8环烷基和C 6-C 10芳基，所述C 3-C 8环烷基或C 6-C 10芳基任选地被一个或多个R 7取代。 According to some embodiments of the present invention, each occurrence of R 6 is independently selected from halogen, -CN, -OH, -S(O) pRA , C 3 -C 8 cycloalkyl, and C 6 -C 10 aryl, said C 3 -C 8 cycloalkyl or C 6 -C 10 aryl is optionally substituted by one or more R 7 .
根据本发明的一些实施方案，R 7在每次出现时各自独立地选自卤素和＝O。 According to some embodiments of the invention, each occurrence of R7 is independently selected from halogen and =0.
根据本发明的一些实施方案，R A为C 1-C 6烷基。 According to some embodiments of the invention, R A is C 1 -C 6 alkyl.
根据本发明的一些实施方案，p为2。According to some embodiments of the invention, p is 2.
根据本发明的一些实施方案，R 1选自C 1-C 6烷基、C 3-C 8环烷基和3-8元杂环基，所述C 1-C 6烷基、C 3-C 8环烷基或3-8元杂环基任选地被一个或多个R 6取代； According to some embodiments of the present invention, R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 - C Cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R 6 ;
R 6在每次出现时各自独立地选自卤素、-CN、-OH、-S(O) pR A、C 3-C 8环烷基和C 6-C 10芳基，所述C 3-C 8环烷基或C 6-C 10芳基任选地被一个或多个R 7取代； Each occurrence of R 6 is independently selected from halogen, -CN, -OH, -S(O) p R A , C 3 -C 8 cycloalkyl and C 6 -C 10 aryl, said C 3 -C 8 cycloalkyl or C 6 -C 10 aryl is optionally substituted by one or more R 7 ;
R 7在每次出现时各自独立地选自卤素和＝O； Each occurrence of R is independently selected from halogen and =0;
R A为C 1-C 6烷基；且 RA is C 1 -C 6 alkyl; and
p为2。p is 2.
在本发明的一些实施方案中，R 1选自C 1-C 6烷基、C 3-C 6环烷基和3-6元杂环烷基，所述C 1-C 6烷基、C 3-C 6环烷基或3-6元杂环烷基任选地被一个或多个各自独立地选自以下的基团取代：卤素、-CN、-OH、-S(O) 2(C 1-C 6烷基)、任选地被卤素或＝O取代的C 3-C 6环烷基、以及任选地被卤素取代的苯基。 In some embodiments of the present invention, R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-6 membered heterocycloalkyl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted by one or more groups independently selected from the following groups: halogen, -CN, -OH, -S(O) 2 ( C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl optionally substituted by halogen or =O, and phenyl optionally substituted by halogen.
在本发明的一些实施方案中，R 1选自C 1-C 6烷基、C 3-C 6环烷基和3-6元含氧杂环烷基，所述C 1-C 6烷基、C 3-C 6环烷基或3-6元含氧杂环烷基任选地被一个或多个各自独立地选自以下的基团取代：卤素、-CN、-OH、-S(O) 2(C 1-C 6烷基)、任选地被卤素或＝O取代的C 3-C 6环烷基、以及任选地被卤素取代的苯基。 In some embodiments of the present invention, R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-6 membered oxygen-containing heterocycloalkyl, the C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl or 3-6 membered oxygen-containing heterocycloalkyl are optionally substituted by one or more groups independently selected from the following groups: halogen, -CN, -OH, -S( O) 2 (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl optionally substituted by halogen or =O, and phenyl optionally substituted by halogen.
在本发明的一些实施方案中，R 1选自C 1-C 6烷基、C 3-C 6环烷基、氧杂环丁基、四氢呋喃基和四氢吡喃基，所述C 1-C 6烷基或C 3-C 6环烷基任选地被一个或多个各自独立地选自以下的基团取代：卤素、-CN、-OH、-S(O) 2(C 1-C 6烷基)、任选地被卤素或＝O取代的C 3-C 6环烷基、以及任选地被卤素取代的苯基。 In some embodiments of the present invention, R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, said C 1 - C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted by one or more groups independently selected from the group consisting of halogen, -CN, -OH, -S(O) 2 (C 1 - C 6 alkyl), C 3 -C 6 cycloalkyl optionally substituted by halogen or =O, and phenyl optionally substituted by halogen.
在本发明的一些实施方案中，R 1选自C 1-C 6烷基、C 3-C 6环烷基、氧杂环丁基、四氢呋喃基和四氢吡喃基，所述C 1-C 6烷基或C 3-C 6环烷基任选地被一个或多个各自独立地选自以下的基团取代：-F、-CN、-OH、-S(O) 2CH 3、四氢吡喃基、以及氟代苯基。 In some embodiments of the present invention, R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, said C 1 - C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted with one or more groups each independently selected from the following groups: -F, -CN, -OH, -S(O) 2 CH 3 , Tetrahydropyranyl, and fluorophenyl.
在本发明的一些实施方案中，R 1选自C 1-C 6烷基、氧杂环丁基、四氢呋喃基和四氢吡喃基，所述C 1-C 6烷基任选地被1、2或3个-F取代。 In some embodiments of the present invention, R 1 is selected from C 1 -C 6 alkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, and said C 1 -C 6 alkyl is optionally replaced by 1 , 2 or 3 -F substitutions.
在本发明的一些实施方案中，R 1选自
Figure PCTCN2022109584-appb-000005
Figure PCTCN2022109584-appb-000006
CF 3CH 2-、CH 3-、
Figure PCTCN2022109584-appb-000007
In some embodiments of the invention, R is selected from
Figure PCTCN2022109584-appb-000005
Figure PCTCN2022109584-appb-000006
CF 3 CH 2 -, CH 3 -,
Figure PCTCN2022109584-appb-000007
其中波浪线
Figure PCTCN2022109584-appb-000008
表示该基团与分子其余部分的连接点。 where tilde
Figure PCTCN2022109584-appb-000008
Indicates the point of attachment of the group to the rest of the molecule.
在本发明的一些实施方案中，R 1选自
Figure PCTCN2022109584-appb-000009
CF 3CH 2-、CH 3-、
Figure PCTCN2022109584-appb-000010
Figure PCTCN2022109584-appb-000011
In some embodiments of the invention, R is selected from
Figure PCTCN2022109584-appb-000009
CF 3 CH 2 -, CH 3 -,
Figure PCTCN2022109584-appb-000010
Figure PCTCN2022109584-appb-000011
其中波浪线
Figure PCTCN2022109584-appb-000012
表示该基团与分子其余部分的连接点。 where tilde
Figure PCTCN2022109584-appb-000012
Indicates the point of attachment of the group to the rest of the molecule.
根据本发明的一些实施方案，R 2在每次出现时各自独立地选自H和卤素。 According to some embodiments of the invention, each occurrence of R 2 is independently selected from H and halogen.
在本发明的一些实施方案中，R 2在每次出现时各自独立地选自H和F。 In some embodiments of the invention, each occurrence of R is independently selected from H and F.
在本发明的一些实施方案中，R 2为H。 In some embodiments of the invention, R is H.
根据本发明的一些实施方案，m为1。According to some embodiments of the invention, m is 1.
根据本发明的一些实施方案，R 3选自C 6-C 10芳基和5-10元杂芳基，所述C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 9取代。 According to some embodiments of the present invention, R 3 is selected from C 6 -C 10 aryl and 5-10 membered heteroaryl, and the C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally replaced by one or multiple R 9 substitutions.
根据本发明的一些实施方案，R 9在每次出现时各自独立地选自卤素、C 1-C 6烷基和C 1-C 6卤代烷基。 According to some embodiments of the present invention, each occurrence of R 9 is independently selected from halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
根据本发明的一些实施方案，R 9在每次出现时各自独立地选自卤素。 According to some embodiments of the invention, each occurrence of R9 is independently selected from halogen.
根据本发明的一些实施方案，R 9在每次出现时各自独立地选自卤素和C 1-C 6卤代烷基。 According to some embodiments of the present invention, each occurrence of R 9 is independently selected from halogen and C 1 -C 6 haloalkyl.
根据本发明的一些实施方案，R 9在每次出现时各自独立地选自F、Cl、-CF 3和-CH 3。 According to some embodiments of the invention, each occurrence of R 9 is independently selected from F, Cl, -CF 3 and -CH 3 .
根据本发明的一些实施方案，R 9在每次出现时各自独立地选自F和Cl。 According to some embodiments of the invention, each occurrence of R9 is independently selected from F and Cl.
根据本发明的一些实施方案，R 3选自C 6-C 10芳基和5-10元杂芳基，所述C 6-C 10芳基或5-10元杂芳基任选地被一个或多个各自独立地选自以下的基团取代：卤素、C 1-C 6烷基和C 1-C 6卤代烷基。 According to some embodiments of the present invention, R 3 is selected from C 6 -C 10 aryl and 5-10 membered heteroaryl, and the C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally replaced by one or a plurality of groups each independently selected from the following: halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
在本发明的一些实施方案中，R 3选自苯基和5-6元杂芳基，所述苯基或5-6元杂芳基任选地被一个或多个各自独立地选自以下的基团取代：卤素、C 1-C 6烷基和C 1-C 6卤代烷基。 In some embodiments of the present invention, R is selected from phenyl and 5-6 membered heteroaryl, and said phenyl or 5-6 membered heteroaryl is optionally selected from one or more of each independently selected from The group substitution of: halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
在本发明的一些实施方案中，R 3选自苯基和5-6元含氮杂芳基，所述苯基或5-6元含氮杂芳基任选地被一个或多个各自独立地选自以下的基团取代：卤素、C 1-C 6烷基和C 1-C 6卤代烷基。 In some embodiments of the present invention, R is selected from phenyl and 5-6 membered nitrogen-containing heteroaryl, the phenyl or 5-6 membered nitrogen-containing heteroaryl optionally replaced by one or more independently is substituted with a group selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
在本发明的一些实施方案中，R 3选自苯基和吡啶基，所述苯基或吡啶基任选地被一个或多个各自独立地选自以下的基团取代：卤素、C 1-C 6烷基和C 1-C 6卤代烷基。 In some embodiments of the present invention, R 3 is selected from phenyl and pyridyl, said phenyl or pyridyl is optionally substituted with one or more groups each independently selected from: halogen, C 1 - C 6 alkyl and C 1 -C 6 haloalkyl.
在本发明的一些实施方案中，R 3选自苯基和吡啶基，所述苯基或吡啶基任选地被一个或多个各自独立地选自以下的基团取代：F、Cl、-CF 3和-CH 3。 In some embodiments of the present invention, R is selected from phenyl and pyridyl, said phenyl or pyridyl is optionally substituted with one or more groups each independently selected from: F, Cl, - CF3 and -CH3 .
在本发明的一些实施方案中，R 3选自苯基和吡啶基，所述苯基或吡啶基任选地被F或Cl取代。 In some embodiments of the invention, R is selected from phenyl and pyridyl, optionally substituted with F or Cl.
在本发明的一些实施方案中，R 3选自：
Figure PCTCN2022109584-appb-000013
In some embodiments of the invention, R is selected from:
Figure PCTCN2022109584-appb-000013
Figure PCTCN2022109584-appb-000014
Figure PCTCN2022109584-appb-000014
其中波浪线
Figure PCTCN2022109584-appb-000015
表示该基团与分子其余部分的连接点。 where tilde
Figure PCTCN2022109584-appb-000015
Indicates the point of attachment of the group to the rest of the molecule.
在本发明的一些实施方案中，R 3选自：
Figure PCTCN2022109584-appb-000016
In some embodiments of the invention, R is selected from:
Figure PCTCN2022109584-appb-000016
其中波浪线
Figure PCTCN2022109584-appb-000017
表示该基团与分子其余部分的连接点。 where tilde
Figure PCTCN2022109584-appb-000017
Indicates the point of attachment of the group to the rest of the molecule.
根据本发明的一些实施方案，R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被一个或多个C 1-C 6烷氧基或3-8元杂环基取代。 According to some embodiments of the present invention, R 4 is selected from C 1 -C 6 alkyl groups optionally replaced by one or more C 1 -C 6 alkoxy groups or 3-8 membered Heterocyclyl substitution.
在本发明的一些实施方案中，R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被C 1-C 6烷氧基或5-6元含氧杂环烷基取代。 In some embodiments of the present invention, R 4 is selected from C 1 -C 6 alkyl optionally replaced by C 1 -C 6 alkoxy or 5-6 membered oxa Cycloalkyl substitution.
在本发明的一些实施方案中，R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被C 1-C 6烷氧基、四氢呋喃基或四氢吡喃基取代。 In some embodiments of the present invention, R 4 is selected from C 1 -C 6 alkyl optionally replaced by C 1 -C 6 alkoxy, tetrahydrofuranyl or tetrahydropyranyl base substitution.
在本发明的一些实施方案中，R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被甲氧基、四氢呋喃基或四氢吡喃基取代。 In some embodiments of the present invention, R 4 is selected from C 1 -C 6 alkyl optionally substituted with methoxy, tetrahydrofuranyl or tetrahydropyranyl .
在本发明的一些实施方案中，R 4选自异丙基、2-甲基丙基、甲氧基乙基、
Figure PCTCN2022109584-appb-000018
In some embodiments of the invention, R is selected from isopropyl, 2-methylpropyl, methoxyethyl,
Figure PCTCN2022109584-appb-000018
其中波浪线
Figure PCTCN2022109584-appb-000019
表示该基团与分子其余部分的连接点。 where tilde
Figure PCTCN2022109584-appb-000019
Indicates the point of attachment of the group to the rest of the molecule.
根据本发明的一些实施方案，R 5选自H、C 1-C 6烷基和卤素。 According to some embodiments of the present invention, R 5 is selected from H, C 1 -C 6 alkyl and halogen.
在本发明的一些实施方案中，R 5为H。 In some embodiments of the invention, R 5 is H.
本发明涵盖对上述优选基团进行任意组合所得的式I的化合物。The present invention covers compounds of formula I obtained by any combination of the above-mentioned preferred groups.
根据本发明的一些实施方案，本发明的化合物为式I-1的化合物：According to some embodiments of the invention, the compound of the invention is a compound of formula I-1:
Figure PCTCN2022109584-appb-000020
Figure PCTCN2022109584-appb-000020
其中，in,
R 1、R 2、R 3、R 4、R 5和m如上文中所定义。 R 1 , R 2 , R 3 , R 4 , R 5 and m are as defined above.
根据本发明的一些实施方案，本发明的化合物为式I-1-1的化合物：According to some embodiments of the present invention, the compound of the present invention is a compound of formula I-1-1:
Figure PCTCN2022109584-appb-000021
Figure PCTCN2022109584-appb-000021
其中，in,
R 1、R 2、R 4、R 5、R 9和m如上文中所定义；且 R 1 , R 2 , R 4 , R 5 , R 9 and m are as defined above; and
q选自0、1、2、3、4和5；优选地，q为1。q is selected from 0, 1, 2, 3, 4 and 5; preferably, q is 1.
根据本发明的一些实施方案，本发明的化合物为式I-1-1a的化合物：According to some embodiments of the present invention, the compound of the present invention is a compound of formula I-1-1a:
Figure PCTCN2022109584-appb-000022
Figure PCTCN2022109584-appb-000022
其中，in,
R 1、R 4、R 9和q如上文中所定义。 R 1 , R 4 , R 9 and q are as defined above.
根据本发明的一些实施方案，本发明的化合物为式I-1-2的化合物：According to some embodiments of the present invention, the compound of the present invention is a compound of formula I-1-2:
Figure PCTCN2022109584-appb-000023
Figure PCTCN2022109584-appb-000023
其中，in,
R 1、R 2、R 4、R 5、R 9和m如上文中所定义；且 R 1 , R 2 , R 4 , R 5 , R 9 and m are as defined above; and
q选自0、1、2、3、4和5；优选地，q为1。q is selected from 0, 1, 2, 3, 4 and 5; preferably, q is 1.
根据本发明的一些实施方案，本发明的化合物为式I-1-2a的化合物：According to some embodiments of the present invention, the compound of the present invention is a compound of formula I-1-2a:
Figure PCTCN2022109584-appb-000024
Figure PCTCN2022109584-appb-000024
其中，in,
R 1、R 4、R 9和q如上文中所定义。 R 1 , R 4 , R 9 and q are as defined above.
本发明涵盖对上述优选基团进行任意组合所得的式I-1、I-1-1、I-1-1a、1-1-2、1-1-2a的化合物。The present invention covers compounds of formulas I-1, I-1-1, I-1-1a, 1-1-2, 1-1-2a obtained by any combination of the above preferred groups.
例如，根据本发明的一些实施方案，在式I-1-1a或I-1-2a中，For example, according to some embodiments of the present invention, in formula I-1-1a or I-1-2a,
R 1选自C 1-C 6烷基、氧杂环丁基、四氢呋喃基和四氢吡喃基，所述C 1-C 6烷基任选地被1、2或3个-F取代； R 1 is selected from C 1 -C 6 alkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, and the C 1 -C 6 alkyl is optionally substituted by 1, 2 or 3 -F;
R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被C 1-C 6烷氧基、四氢呋喃基或四氢吡喃基取代； R 4 is selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkoxy, tetrahydrofuranyl or tetrahydropyranyl;
R 9在每次出现时各自独立地选自卤素；且 Each occurrence of R is independently selected from halogen; and
q为1。q is 1.
根据本发明的一些实施方案，本发明的化合物为式I-2的化合物：According to some embodiments of the invention, the compound of the invention is a compound of formula I-2:
Figure PCTCN2022109584-appb-000025
Figure PCTCN2022109584-appb-000025
其中，in,
R 1、R 2、R 3、R 4、R 5和m如上文中所定义。 R 1 , R 2 , R 3 , R 4 , R 5 and m are as defined above.
根据本发明的一些实施方案，本发明的化合物为式I-2-1的化合物：According to some embodiments of the present invention, the compound of the present invention is a compound of formula I-2-1:
Figure PCTCN2022109584-appb-000026
Figure PCTCN2022109584-appb-000026
其中，in,
R 1、R 2、R 4、R 5、R 9和m如上文中所定义；且 R 1 , R 2 , R 4 , R 5 , R 9 and m are as defined above; and
q选自0、1、2、3、4和5；优选地，q为1。q is selected from 0, 1, 2, 3, 4 and 5; preferably, q is 1.
根据本发明的一些实施方案，本发明的化合物为式I-2-1a的化合物：According to some embodiments of the present invention, the compound of the present invention is a compound of formula I-2-1a:
Figure PCTCN2022109584-appb-000027
Figure PCTCN2022109584-appb-000027
其中，in,
R 1、R 4、R 9和q如上文中所定义。 R 1 , R 4 , R 9 and q are as defined above.
根据本发明的一些实施方案，本发明的化合物为式I-2-2的化合物：According to some embodiments of the present invention, the compound of the present invention is a compound of formula I-2-2:
Figure PCTCN2022109584-appb-000028
Figure PCTCN2022109584-appb-000028
其中，in,
R 1、R 2、R 4、R 5、R 9和m如上文中所定义；且 R 1 , R 2 , R 4 , R 5 , R 9 and m are as defined above; and
q选自0、1、2、3、4和5；优选地，q为1。q is selected from 0, 1, 2, 3, 4 and 5; preferably, q is 1.
根据本发明的一些实施方案，本发明的化合物为式I-2-2a的化合物：According to some embodiments of the present invention, the compound of the present invention is a compound of formula I-2-2a:
Figure PCTCN2022109584-appb-000029
Figure PCTCN2022109584-appb-000029
其中，in,
R 1、R 4、R 9和q如上文中所定义。 R 1 , R 4 , R 9 and q are as defined above.
本发明涵盖对上述优选基团进行任意组合所得的式I-2、I-2-1、I-2-1a、1-2-2、1-2-2a的化合物。The present invention covers compounds of formulas I-2, I-2-1, I-2-1a, 1-2-2, 1-2-2a obtained by any combination of the above preferred groups.
例如，根据本发明的一些实施方案，在式I-2-1a或I-2-2a中，For example, according to some embodiments of the present invention, in formula I-2-1a or I-2-2a,
R 1选自C 1-C 6烷基、氧杂环丁基、四氢呋喃基和四氢吡喃基，所述C 1-C 6烷基任选地被1、2或3个-F取代； R 1 is selected from C 1 -C 6 alkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, and the C 1 -C 6 alkyl is optionally substituted by 1, 2 or 3 -F;
R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被C 1-C 6烷氧基、四氢呋喃基或四氢吡喃基取代； R 4 is selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkoxy, tetrahydrofuryl or tetrahydropyranyl;
R 9在每次出现时各自独立地选自卤素；且 Each occurrence of R is independently selected from halogen; and
q为1。q is 1.
根据本发明的一些实施方案，本发明的化合物选自：According to some embodiments of the present invention, the compound of the present invention is selected from:
Figure PCTCN2022109584-appb-000030
Figure PCTCN2022109584-appb-000030
Figure PCTCN2022109584-appb-000031
Figure PCTCN2022109584-appb-000031
Figure PCTCN2022109584-appb-000032
Figure PCTCN2022109584-appb-000032
Figure PCTCN2022109584-appb-000033
Figure PCTCN2022109584-appb-000033
制备方法Preparation
本发明的另一目的在于提供制备本发明的化合物的方法，其包括以下反应路线1所示的步骤：Another object of the present invention is to provide a method for preparing the compound of the present invention, which includes the steps shown in the following reaction scheme 1:
反应路线1Reaction scheme 1
Figure PCTCN2022109584-appb-000034
Figure PCTCN2022109584-appb-000034
其中，in,
R 1、R 2、R 3、R 4、R 5、X和m如上文中所定义。 R 1 , R 2 , R 3 , R 4 , R 5 , X and m are as defined above.
该反应优选在适合的有机碱或无机碱的存在下进行。所述有机碱或无机碱可选自二异丙基乙胺、三乙胺、碳酸钠、碳酸钾和碳酸铯，优选二异丙基乙胺。The reaction is preferably carried out in the presence of a suitable organic or inorganic base. The organic base or inorganic base can be selected from diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate and cesium carbonate, preferably diisopropylethylamine.
该反应优选在合适的缩合剂的存在下进行，所述缩合剂可选自DCC、EDCI、HOBt、BOP、PyBOP、HATU、HBTU，优选HATU。The reaction is preferably carried out in the presence of a suitable condensing agent which may be selected from DCC, EDCI, HOBt, BOP, PyBOP, HATU, HBTU, preferably HATU.
该反应在适合的有机溶剂中进行。所述有机溶剂可选自二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜及其任意组合，优选N,N-二甲基甲酰胺。The reaction is carried out in a suitable organic solvent. The organic solvent may be selected from dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide and any combination thereof, preferably N,N-dimethylformamide.
该反应在适合的温度下进行。所述温度优选为20-80℃。The reaction is carried out at a suitable temperature. The temperature is preferably 20-80°C.
该反应进行合适的时间，例如2-24小时。The reaction is carried out for a suitable time, eg 2-24 hours.
另一方面，本发明提供了中间体I-A和I-B的合成方法，其中中间体I-A可通过以下反应路线2所示的方法合成：On the other hand, the present invention provides a synthetic method for intermediates I-A and I-B, wherein intermediate I-A can be synthesized by the method shown in the following reaction scheme 2:
反应路线2Reaction Scheme 2
Figure PCTCN2022109584-appb-000035
Figure PCTCN2022109584-appb-000035
其中，in,
LG表示离去基团，所述离去基团包括但不限于卤素原子、甲磺酰基氧基、三氟甲磺酸酯等；且LG represents a leaving group, which includes, but is not limited to, a halogen atom, methanesulfonyloxy, triflate, etc.; and
R 1、R 2、X和m如上文中对式I的化合物所定义。 R 1 , R 2 , X and m are as defined above for the compound of formula I.
步骤一：使化合物I-A-I与R 1-LG反应以得到化合物I-A-II Step 1: Reaction of Compound IAI with R 1 -LG to give Compound IA-II
该反应优选在适合的有机碱或无机碱的存在下进行。所述有机碱或无机碱可选自二异丙基乙胺、三乙胺、碳酸钠、碳酸钾和碳酸铯，优选碳酸铯。The reaction is preferably carried out in the presence of a suitable organic or inorganic base. The organic base or inorganic base can be selected from diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate.
该反应在适合的有机溶剂中进行。所述有机溶剂可选自二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜及其任意组合，优选N,N-二甲基甲酰胺。The reaction is carried out in a suitable organic solvent. The organic solvent may be selected from dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide and any combination thereof, preferably N,N-dimethylformamide.
该反应在适合的温度下进行。所述温度优选为80-90℃。The reaction is carried out at a suitable temperature. The temperature is preferably 80-90°C.
该反应进行合适的时间，例如2-24小时。The reaction is carried out for a suitable time, eg 2-24 hours.
步骤二：使化合物I-A-II与对氨基苯基硼酸酯反应以得到化合物I-AStep 2: Reaction of compound I-A-II with p-aminophenylboronate to obtain compound I-A
该反应优选在金属催化剂和碱的存在下进行。所述金属催化剂优选为钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、三苯基膦钯、醋酸钯，优选[1,1'-双(二苯基 膦基)二茂铁]二氯化钯。所述碱优选为无机碱，例如磷酸钾、碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钠。The reaction is preferably carried out in the presence of a metal catalyst and a base. The metal catalyst is preferably a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine palladium , palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. The base is preferably an inorganic base, such as potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium carbonate.
该反应在适合的溶剂中进行。所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的混合溶剂。The reaction is carried out in a suitable solvent. The solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably 1 , A mixed solvent of 4-dioxane and water.
该反应在适合的温度下进行。所述温度优选为60-100℃。The reaction is carried out at a suitable temperature. The temperature is preferably 60-100°C.
该反应进行合适的时间，例如2-8小时。The reaction is carried out for a suitable time, eg 2-8 hours.
或者，中间体I-A也可通过以下反应路线3所示的方法合成：Alternatively, intermediate I-A can also be synthesized by the method shown in Scheme 3 below:
反应路线3Reaction scheme 3
Figure PCTCN2022109584-appb-000036
Figure PCTCN2022109584-appb-000036
其中，in,
R 1、R 2、X和m如如上文中对式I的化合物所定义。 R 1 , R 2 , X and m are as defined above for the compound of formula I.
步骤一：使化合物I-A-III与R 1OH反应以得到化合物I-A-IV Step 1: Reaction of Compound IA-III with R 1 OH to give Compound IA-IV
该反应优选在膦催化剂和偶氮二甲酸酯的存在下进行。所述膦催化剂优选为膦配体催化剂，例如三苯基膦、三丁基膦、三已基膦、三(2-甲基苯基)膦，优选三苯基膦。所述偶氮二甲酸酯例如偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、偶氮二甲酸二叔丁酯、双(4-氯苄基)偶氮二甲酸酯，优选偶氮二甲酸二乙酯。The reaction is preferably carried out in the presence of a phosphine catalyst and an azodicarboxylate. The phosphine catalyst is preferably a phosphine ligand catalyst, such as triphenylphosphine, tributylphosphine, trihexylphosphine, tris(2-methylphenyl)phosphine, preferably triphenylphosphine. The azodicarboxylates are such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, bis(4-chlorobenzyl) azodicarboxylate, Diethyl azodicarboxylate is preferred.
该反应在适合的溶剂中进行。所述溶剂可选自四氢呋喃、乙醚、甲苯、N,N-二甲基甲酰胺及其任意组合，优选四氢呋喃。The reaction is carried out in a suitable solvent. The solvent may be selected from tetrahydrofuran, diethyl ether, toluene, N,N-dimethylformamide and any combination thereof, preferably tetrahydrofuran.
该反应在适合的温度下进行。所述温度优选为25-70℃。The reaction is carried out at a suitable temperature. The temperature is preferably 25-70°C.
该反应进行合适的时间，例如8-16小时。The reaction is carried out for a suitable time, eg 8-16 hours.
步骤二：使化合物I-A-IV与氨水发生取代反应以得到化合物I-A-IIStep 2: Substitution reaction of compound I-A-IV with ammonia water to obtain compound I-A-II
该反应在合适的有机溶剂中进行。所述有机溶剂可选自二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜、1,4-二氧六环及其任意组合，优选1,4-二氧六环。The reaction is carried out in a suitable organic solvent. The organic solvent may be selected from dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane and any combination thereof, preferably 1,4-dioxane.
该反应在适合的温度下进行。所述温度优选为80-90℃。The reaction is carried out at a suitable temperature. The temperature is preferably 80-90°C.
该反应在合适的条件下进行。所述条件优选为微波加热。The reaction is carried out under suitable conditions. The conditions are preferably microwave heating.
该反应进行合适的时间，例如2-24小时。The reaction is carried out for a suitable time, eg 2-24 hours.
步骤三：使化合物I-A-II与对氨基苯基硼酸酯反应以得到化合物I-AStep 3: Reaction of compound I-A-II with p-aminophenyl borate to obtain compound I-A
该反应优选在金属催化剂和碱的存在下进行。所述金属催化剂优选为钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、三苯基膦钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述碱优选为无机碱，例如磷酸钾、碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钠。The reaction is preferably carried out in the presence of a metal catalyst and a base. The metal catalyst is preferably a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine palladium , palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride. The base is preferably an inorganic base, such as potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium carbonate.
该反应在适合的溶剂中进行。所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的混合溶剂。The reaction is carried out in a suitable solvent. The solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably 1 , A mixed solvent of 4-dioxane and water.
该反应在适合的温度下进行。所述温度优选为60-100℃。The reaction is carried out at a suitable temperature. The temperature is preferably 60-100°C.
该反应进行合适的时间，例如2-8小时。The reaction is carried out for a suitable time, eg 2-8 hours.
中间体I-B可通过以下反应路线4所示的方法合成：Intermediate I-B can be synthesized by the method shown in Scheme 4 below:
反应路线4Reaction scheme 4
Figure PCTCN2022109584-appb-000037
Figure PCTCN2022109584-appb-000037
步骤一：使化合物I-B-I与氯化试剂反应以得到化合物I-B-IIStep 1: react compound I-B-I with a chlorinating reagent to obtain compound I-B-II
该反应在适合的溶剂存在下进行。所述溶剂可选自二氯甲烷、1,2-二氯乙烷、氯仿及其任意组合， 优选二氯甲烷。The reaction is carried out in the presence of a suitable solvent. The solvent may be selected from dichloromethane, 1,2-dichloroethane, chloroform and any combination thereof, preferably dichloromethane.
该反应在氯化试剂的存在下进行。所述氯化试剂优选为草酰氯、氯化亚砜，优选草酰氯。The reaction is carried out in the presence of a chlorinating reagent. The chlorination reagent is preferably oxalyl chloride, thionyl chloride, preferably oxalyl chloride.
该反应优选在催化剂的存在下进行。所述催化剂优选为N,N-二甲基甲酰胺。The reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably N,N-dimethylformamide.
该反应在适合的温度下进行。所述温度优选为0-25℃。The reaction is carried out at a suitable temperature. The temperature is preferably 0-25°C.
该反应进行合适的时间，例如2-8小时。The reaction is carried out for a suitable time, eg 2-8 hours.
步骤二：使化合物I-B-II和重氮乙酸乙酯反应以得到化合物I-B-IIIStep 2: react compound I-B-II with ethyl diazoacetate to obtain compound I-B-III
该反应优选在惰性气体的存在下进行。所述惰性气体可选自氮气、氩气，优选氮气。The reaction is preferably carried out in the presence of an inert gas. The inert gas may be selected from nitrogen, argon, preferably nitrogen.
该反应在适合的溶剂中进行。所述溶剂可选自二氯甲烷、1,2-二氯乙烷、氯仿及其任意组合，优选二氯甲烷。The reaction is carried out in a suitable solvent. The solvent may be selected from dichloromethane, 1,2-dichloroethane, chloroform and any combination thereof, preferably dichloromethane.
该反应在适合的温度下进行。所述温度优选为0-25℃。The reaction is carried out at a suitable temperature. The temperature is preferably 0-25°C.
该反应进行合适的时间，例如4-16小时。The reaction is carried out for a suitable time, eg 4-16 hours.
步骤三：将化合物I-B-III还原以得到化合物I-B-IVStep 3: Compound I-B-III is reduced to obtain Compound I-B-IV
该反应在还原剂的存在下进行。所述还原剂优选为三丁基膦。The reaction is carried out in the presence of a reducing agent. The reducing agent is preferably tributylphosphine.
该反应在适合的溶剂中进行。所述溶剂可选自四氢呋喃、乙醚、甲基叔丁基醚、异丙醚及其任意组合，优选异丙醚。The reaction is carried out in a suitable solvent. The solvent may be selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether and any combination thereof, preferably isopropyl ether.
该反应在适合的温度下进行。所述温度优选为0-25℃。The reaction is carried out at a suitable temperature. The temperature is preferably 0-25°C.
该反应进行合适的时间，例如2-8小时。The reaction is carried out for a suitable time, eg 2-8 hours.
步骤四：使化合物I-B-IV与二碳酸二叔丁酯反应以得到化合物I-B-VStep 4: Reaction of compound I-B-IV with di-tert-butyl dicarbonate to obtain compound I-B-V
该反应在适合的溶剂中进行。所述溶剂可选自二氯甲烷、氯仿、四氢呋喃、乙醚及其任意组合，优选四氢呋喃。The reaction is carried out in a suitable solvent. The solvent may be selected from dichloromethane, chloroform, tetrahydrofuran, diethyl ether and any combination thereof, preferably tetrahydrofuran.
该反应优选在碱的存在下进行。所述碱优选为有机碱，例如三乙胺、二异丙基乙基胺，优选三乙胺。This reaction is preferably carried out in the presence of a base. The base is preferably an organic base, such as triethylamine, diisopropylethylamine, preferably triethylamine.
该反应在适合的温度下进行。所述温度优选为0-25℃。The reaction is carried out at a suitable temperature. The temperature is preferably 0-25°C.
该反应进行合适的时间，例如4-16小时。The reaction is carried out for a suitable time, eg 4-16 hours.
步骤五：使化合物I-B-V通过闭环反应和脱除保护基Boc以得到化合物I-B-VIStep 5: Compound I-B-V undergoes a ring closure reaction and removes the protecting group Boc to obtain compound I-B-VI
该反应在合适的溶剂中进行。所述溶剂可选自四氢呋喃、甲苯及其任意组合，优选四氢呋喃。The reaction is carried out in a suitable solvent. The solvent may be selected from tetrahydrofuran, toluene and any combination thereof, preferably tetrahydrofuran.
该反应在合适的温度下进行。所述温度优选为0-90℃。The reaction is carried out at a suitable temperature. The temperature is preferably 0-90°C.
该反应在合适的酸的存在下进行。所述酸优选为盐酸的溶液，例如盐酸二氧六环、盐酸乙酸乙酯，优选盐酸二氧六环。The reaction is carried out in the presence of a suitable acid. The acid is preferably a solution of hydrochloric acid, such as dioxane hydrochloride, ethyl acetate hydrochloride, preferably dioxane hydrochloride.
步骤六：使化合物I-B-VI与R 4-LG反应以得到化合物I-B-VII Step 6: Reaction of compound IB-VI with R 4 -LG to obtain compound IB-VII
其中LG表示离去基团，所述离去基团包括但不限于卤素原子、甲磺酰基氧基、三氟甲磺酸酯等；Where LG represents a leaving group, the leaving group includes but not limited to halogen atom, methanesulfonyloxy group, trifluoromethanesulfonate, etc.;
该反应在合适的溶剂中进行。所述有机溶剂可选自二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜及其任意组合，优选N,N-二甲基甲酰胺。The reaction is carried out in a suitable solvent. The organic solvent may be selected from dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide and any combination thereof, preferably N,N-dimethylformamide.
该反应优选在适合的有机碱或无机碱的存在下进行。所述有机碱或无机碱可选自二异丙基乙胺、三乙胺、碳酸钠、碳酸钾和碳酸铯，优选碳酸铯。The reaction is preferably carried out in the presence of a suitable organic or inorganic base. The organic base or inorganic base can be selected from diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate.
该反应在适合的温度下进行。所述温度优选为80-90℃。The reaction is carried out at a suitable temperature. The temperature is preferably 80-90°C.
该反应进行合适的时间，例如2-24小时。The reaction is carried out for a suitable time, eg 2-24 hours.
步骤七：使化合物I-B-VII经酯基水解以得到化合物I-BStep 7: Compound I-B-VII is subjected to ester group hydrolysis to obtain compound I-B
该反应在合适比例的甲醇/四氢呋喃/水的混合溶剂中进行。优选的溶剂比例为甲醇/四氢呋喃/水＝1/1/1。The reaction is carried out in a mixed solvent of methanol/tetrahydrofuran/water at an appropriate ratio. The preferred solvent ratio is methanol/tetrahydrofuran/water=1/1/1.
该反应优选在适合的无机碱的存在下进行。所述无机碱可选自氢氧化钠、氢氧化锂、氢氧化钾，优选氢氧化钠。The reaction is preferably carried out in the presence of a suitable inorganic base. The inorganic base may be selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, preferably sodium hydroxide.
或者，中间体I-B也可通过以下反应路线5所示的方法合成：Alternatively, intermediate I-B can also be synthesized by the method shown in Scheme 5 below:
反应路线5Reaction scheme 5
Figure PCTCN2022109584-appb-000038
Figure PCTCN2022109584-appb-000038
步骤一：化合物I-B-I与N,N’-羰基二咪唑反应以得到化合物I-B-VIIIStep 1: Reaction of compound I-B-I with N,N'-carbonyldiimidazole to obtain compound I-B-VIII
该反应在适合的溶剂中进行。所述溶剂可选自四氢呋喃、乙醚、甲基叔丁基醚及其任意组合，优选四氢呋喃。The reaction is carried out in a suitable solvent. The solvent may be selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether and any combination thereof, preferably tetrahydrofuran.
该反应在适合的温度下进行。所述温度优选为0-25℃。The reaction is carried out at a suitable temperature. The temperature is preferably 0-25°C.
该反应进行合适的时间，例如6-16小时。The reaction is carried out for a suitable period of time, for example 6-16 hours.
步骤二：化合物I-B-VIII与丙二酸单乙酯钾盐反应以得到化合物I-B-IXStep 2: Compound I-B-VIII reacts with monoethyl malonate potassium salt to obtain compound I-B-IX
该反应在适合的溶剂中进行。所述溶剂可选自四氢呋喃、乙醚、甲基叔丁基醚及其任意组合，优选四氢呋喃。The reaction is carried out in a suitable solvent. The solvent may be selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether and any combination thereof, preferably tetrahydrofuran.
该反应优选在碱的存在下进行。所述碱优选为有机碱，例如三乙胺、二异丙基乙基胺，优选三乙胺。This reaction is preferably carried out in the presence of a base. The base is preferably an organic base, such as triethylamine, diisopropylethylamine, preferably triethylamine.
该反应在合适的催化剂下进行。所述催化剂优选为氯化镁。The reaction is carried out over a suitable catalyst. The catalyst is preferably magnesium chloride.
该反应在适合的温度下进行。所述温度优选为0-25℃。The reaction is carried out at a suitable temperature. The temperature is preferably 0-25°C.
该反应进行合适的时间，例如4-24小时。The reaction is carried out for a suitable time, eg 4-24 hours.
步骤三：使化合物I-B-IX与对甲苯磺酰叠氮反应以得到化合物I-B-IIIStep 3: Reaction of compound I-B-IX with p-toluenesulfonyl azide to obtain compound I-B-III
该反应在适合的溶剂中进行。所述溶剂可选自四氢呋喃、乙醚、乙腈、二甲基亚砜、N,N-二甲基甲酰胺及其任意组合，优选乙腈。The reaction is carried out in a suitable solvent. The solvent may be selected from tetrahydrofuran, diethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide and any combination thereof, preferably acetonitrile.
该反应优选在碱存在下进行。所述碱优选为有机碱，例如三乙胺、二异丙基乙基胺，优选三乙胺。The reaction is preferably carried out in the presence of a base. The base is preferably an organic base, such as triethylamine, diisopropylethylamine, preferably triethylamine.
该反应在适合的温度下进行，所述温度优选为0-10℃。The reaction is carried out at a suitable temperature, preferably 0-10°C.
该反应进行合适的时间，例如1-4小时。The reaction is carried out for a suitable time, eg 1-4 hours.
步骤四至步骤八同反应路线3中的步骤三到步骤七。Step 4 to step 8 are the same as step 3 to step 7 in reaction scheme 3.
本文所用的术语“适合的”意指对具体化合物或条件的选择会取决于所要进行的特定合成操作以及所要转化的一个或多个分子的特性，但该选择在本领域技术人员的能力范围内。本文所述的所有工艺/方法的步骤均在足以提供所示产物的条件下进行。本领域技术人员会理解，可以改变所有反应条件(包括例如反应溶剂、反应时间、反应温度以及反应是否应在无水或惰性气氛下进行，等等)以优化期望的产物的收率，且这些变化在本领域技术人员的能力范围内。As used herein, the term "suitable" means that the choice of specific compounds or conditions will depend on the particular synthetic procedure being performed and the nature of the molecule or molecules to be transformed, but is within the purview of those skilled in the art . The steps of all processes/methods described herein are performed under conditions sufficient to provide the products shown. Those skilled in the art will appreciate that all reaction conditions (including, for example, the reaction solvent, reaction time, reaction temperature, and whether the reaction should be carried out under anhydrous or inert atmosphere, etc.) can be changed to optimize the yield of the desired product, and these Variations are within the purview of those skilled in the art.
药物组合物和药盒Pharmaceutical compositions and kits
本发明的另一目的在于提供一种药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及一种或多种药学可接受的载体。Another object of the present invention is to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph , solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
本发明的另一目的在于提供一种药盒，其包含：Another object of the present invention is to provide a kit comprising:
a)本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者本发明的药物组合物；和a) Compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof , or a pharmaceutical composition of the present invention; and
b)任选存在的包装和/或说明书。b) Optional packaging and/or instructions.
本发明中“药学可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应 或与合理的益处/风险比相应的其它问题或并发症。"Pharmaceutically acceptable carrier" in the present invention refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent, and which is suitable for contacting humans and/or other subjects within the scope of reasonable medical judgment. Animal tissues without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂给药。The pharmaceutical compositions of the invention may act systemically and/or locally. For this purpose, they can be administered by suitable routes, for example by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes or administered as an inhaler.
对于这些给药途径，可以适合的剂型给药本发明的药物组合物。所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂等。For these routes of administration, the pharmaceutical composition of the present invention can be administered in an appropriate dosage form. The dosage forms include but are not limited to tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , injectable solutions, elixirs, syrups, etc.
本发明的药物组合物还可以无菌注射剂的形式给药，包括无菌注射水或油混悬剂、或者无菌注射水或油溶液剂。The pharmaceutical composition of the present invention can also be administered in the form of sterile injection, including sterile injectable water or oil suspension, or sterile injectable water or oil solution.
本发明的药物组合物可以包含0.01mg至1000mg的本发明的化合物。The pharmaceutical composition of the present invention may contain 0.01 mg to 1000 mg of the compound of the present invention.
在一些实施方案中，本发明提供制备本发明的药物组合物或药物制剂的方法，所述方法包括将本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药与一种或多种药学上可接受的载体组合。In some embodiments, the present invention provides a method for preparing the pharmaceutical composition or pharmaceutical preparation of the present invention, the method comprising the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer , polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs in combination with one or more pharmaceutically acceptable carriers.
本发明的药物组合物可以任选地与在治疗各种疾病中至少有一定效果的其它药剂联合给药。在一些实施方案中，本发明提供同时、分开或依次用于治疗的本发明化合物与额外治疗剂的组合制剂。The pharmaceutical composition of the present invention may optionally be administered in combination with other agents which have at least some effect in the treatment of various diseases. In some embodiments, the invention provides combined formulations of a compound of the invention and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.
治疗方法和用途Treatments and uses
本发明的另一目的在于提供本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒，其用于预防或治疗与Axl和/或Mer相关的疾病(特别是肿瘤疾病)。Another object of the present invention is to provide the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound , metabolites or prodrugs, or the pharmaceutical composition of the present invention, or the kit of the present invention, which is used for the prevention or treatment of Axl and/or Mer-related diseases (especially tumor diseases).
本发明的另一目的在于提供本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物或者本发明的药盒在制备用于预防或治疗与Axl和/或Mer相关的疾病(特别是肿瘤疾病)的药物中的用途。Another object of the present invention is to provide the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound , metabolites or prodrugs or the pharmaceutical composition of the present invention or the kit of the present invention in the preparation of medicines for the prevention or treatment of Axl and/or Mer-related diseases (especially tumor diseases).
本发明的另一目的在于提供预防或治疗与Axl和/或Mer相关的疾病(特别是肿瘤疾病)的方法，其包括向有此需要的个体给药预防或治疗有效量的本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者本发明的药物组合物，或者本发明的药盒。Another object of the present invention is to provide a method for preventing or treating diseases related to Axl and/or Mer (especially tumor diseases), which includes administering a preventive or therapeutically effective amount of the compound of the present invention or Pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, or pharmaceutical combinations of the present invention thing, or the kit of the present invention.
如本文中所使用的术语“有效量”是指足以实现所需预防或治疗效果的量，例如，实现减轻与待治疗疾病相关的一或多种症状的量。The term "effective amount" as used herein refers to an amount sufficient to achieve a desired prophylactic or therapeutic effect, eg, an amount that achieves alleviation of one or more symptoms associated with the disease being treated.
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量为约0.001mg/千克体重/天至约10000mg/千克体重/天。在合适的情况下，有效剂量为约0.01mg/千克体重/天至约1000mg/千克体重/天。可以每天、每两天或每三天给药约0.01至1000mg/kg受试者体重，通常0.1至500mg/kg受试者体重。示例性的治疗方案为每天一次或多次或每周一次或多次或每月一次或多次给药。通常多次给予所述制剂，单次剂量之间的间隔可以是每天、每周、每月或每年。或者，可以缓释制剂的形式给予所述制剂，在这种情况下，需要较低的给药频率。剂量和频率根据制剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中，以相对低频率的间隔长期给予相对低的剂量。在治疗性应用中，有时需要以相对短的间隔给予相对高的剂量，直至疾病的进展被延缓或停止，并优选地直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。The amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician. In general, an effective dosage is about 0.001 mg/kg body weight/day to about 10000 mg/kg body weight/day. In suitable cases, the effective dose is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day. About 0.01 to 1000 mg/kg of the subject's body weight, usually 0.1 to 500 mg/kg of the subject's body weight may be administered every day, every two days or every three days. Exemplary treatment regimens are one or more daily or one or more weekly or one or more monthly administrations. Typically the formulation will be administered in multiples, with intervals between single doses being daily, weekly, monthly or yearly. Alternatively, the formulation may be administered as a sustained release formulation, in which case less frequent dosing will be required. Dosage and frequency vary according to the half-life of the formulation in the subject. It can also differ depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered chronically at relatively infrequent intervals. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or stopped, and preferably until the individual exhibits partial or complete amelioration of disease symptoms, after which time the patient may be given prevention program.
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。The amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
本发明所用的术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物、其旋光异构体或其药学上可接受的盐或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。The term "treating" as used herein aims at alleviating or eliminating the disease state or disorder addressed. If a subject receives a therapeutic amount of a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof according to the methods described herein, the subject exhibits one or more of the signs and symptoms Observable and/or detectable reduction or improvement, the subject is successfully "treated". It should also be understood that reference to treatment of a disease state or disorder includes not only complete treatment, but also incomplete treatment while achieving some biologically or medically relevant result.
“治疗”表示本发明化合物的任何给药，包括："Treatment" means any administration of a compound of the invention, including:
(1)在正在经历或显示疾病病理学或症状学的动物中抑制疾病(也就是阻止病理学和/或症状学的进一步发展)；或者or
(2)在正在经历或显示疾病病理学或症状学的动物中改善疾病(也就是逆转病理学和/或症状学)。(2) Amelioration of disease (ie, reversal of pathology and/or symptomology) in an animal experiencing or exhibiting disease pathology or symptomology.
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。"Individual" as used herein includes a human or non-human animal. Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
本发明所用的术语“预防”包括抑制和延迟疾病的发作，并且不仅包括在发展疾病之前的预防，还包括在治疗后预防疾病的复发。The term "prevention" used in the present invention includes suppression and delay of the onset of a disease, and includes not only prevention before the development of the disease, but also prevention of recurrence of the disease after treatment.
实施例Example
为了使本发明的目的和技术方案更加清楚，以下结合实施例对本发明的实施方案进行详细描述。但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，均按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。In order to make the purpose and technical solution of the present invention clearer, the embodiments of the present invention will be described in detail below in conjunction with examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Those who do not indicate specific conditions in the examples are carried out according to conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.
在本申请中，当化学名称和结构式不一致时，应当以结构式所示为准，除非根据上下文可以推断化学名称而非结构式是正确的。In this application, when the chemical name and the structural formula are inconsistent, the structural formula shall prevail, unless the chemical name rather than the structural formula can be inferred from the context to be correct.
在常规的合成法以及实施例和中间体合成例中，各缩写的含义如下表所示。In conventional synthesis methods, examples and intermediate synthesis examples, the meanings of each abbreviation are shown in the table below.
Figure PCTCN2022109584-appb-000039
Figure PCTCN2022109584-appb-000039
以下实施例中记载的化合物的结构通过 1H-NMR或MS来确证。 1H-NMR的测定仪器使用Bruker 400MHz核磁共振仪，测定溶剂为DMSO-d 6，内标物质为TMS，全部δ值用ppm值表示。质谱(MS)的测定仪器使用Agilent(ESI)质谱仪，型号为Agilent 6120B。 The structures of the compounds described in the following Examples were confirmed by 1 H-NMR or MS. The 1 H-NMR measuring instrument used a Bruker 400MHz nuclear magnetic resonance instrument, the measuring solvent was DMSO-d 6 , the internal standard substance was TMS, and all δ values were expressed in ppm. The mass spectrometer (MS) was measured by an Agilent (ESI) mass spectrometer, model Agilent 6120B.
薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm)，薄层层析分离纯化采用的是GF 254(0.4～0.5mm)。Aluminum plate (20×20cm) produced by Merck was used for thin-layer chromatography silica gel plate (TLC), and GF 254 (0.4-0.5mm) was used for separation and purification of thin-layer chromatography.
反应的监测采用薄层色谱法(TLC)或LC-MS，使用的展开剂体系包括：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系、以及石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节或者加入三乙胺等进行调节。The monitoring of reaction adopts thin-layer chromatography (TLC) or LC-MS, and the developer system that uses comprises: dichloromethane and methanol system, normal hexane and ethyl acetate system, and sherwood oil and ethyl acetate system, the volume of solvent The ratio is adjusted according to the polarity of the compound or by adding triethylamine or the like.
柱层析一般使用200～300目硅胶为载体。洗脱剂的体系包括：二氯甲烷和甲醇体系、以及石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进 行调节。Column chromatography generally uses 200-300 mesh silica gel as the carrier. The eluent system includes: dichloromethane and methanol system, and petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of triethylamine.
制备高效液相色谱仪，仪器型号：Agilent 1260，色谱柱：Waters XBridge Prep C 18OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：20.0mL/min；检测波长：214nm；洗脱梯度：(0min：10％A，90％B；16.0min：90％A，10％B)；流动相A：100％乙腈；流动相B：0.05％碳酸氢铵水溶液。 Preparative high-performance liquid chromatography, instrument model: Agilent 1260, chromatographic column: Waters XBridge Prep C 18 OBD (19mm×150mm×5.0μm); chromatographic column temperature: 25°C; flow rate: 20.0mL/min; detection wavelength: 214nm; Elution gradient: (0min: 10%A, 90%B; 16.0min: 90%A, 10%B); mobile phase A: 100% acetonitrile; mobile phase B: 0.05% aqueous ammonium bicarbonate.
仪器型号：Agilent 1260，色谱柱：Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：20.0mL/min；检测波长：214nm；洗脱梯度：(0min：10％A，90％B；16.0min：90％A，10％B)；流动相A：100％乙腈；流动相B：100％水，0.05％甲酸。Instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C18 OBD (19mm×150mm×5.0μm); chromatographic column temperature: 25°C; flow rate: 20.0mL/min; detection wavelength: 214nm; elution gradient: (0min: 10 %A, 90%B; 16.0min: 90%A, 10%B); mobile phase A: 100% acetonitrile; mobile phase B: 100% water, 0.05% formic acid.
除非特别指出，实施例的反应温度为室温(20℃～30℃)。Unless otherwise specified, the reaction temperature in the examples is room temperature (20° C. to 30° C.).
本发明所使用的试剂购自Acros Organics、Aldrich Chemical Company、上海特伯化学科技有限公司等。The reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd., etc.
中间体制备例：Intermediate preparation example:
中间体制备例1：3-(4-氨基苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(T1)Intermediate Preparation 1: 3-(4-aminophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (T1)
Figure PCTCN2022109584-appb-000040
Figure PCTCN2022109584-appb-000040
步骤一：3-溴-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(T1-2)Step 1: 3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (T1-2)
将化合物T1-1(1g，4.67mmol)溶解在N,N-二甲基甲酰胺(10mL)中，然后冰浴下加入NaH(537.09mg，14.02mmol)，0℃反应0.5小时后,滴加碘甲烷(729.51mg，5.14mmol)，0℃反应1h后，加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩后得标题化合物T1-2(600mg)。Dissolve compound T1-1 (1g, 4.67mmol) in N,N-dimethylformamide (10mL), then add NaH (537.09mg, 14.02mmol) under ice-cooling, react at 0°C for 0.5 hours, dropwise Iodomethane (729.51mg, 5.14mmol), reacted at 0°C for 1h, added water, extracted with ethyl acetate, dried the organic phase with anhydrous sodium sulfate, concentrated to give the title compound T1-2 (600mg).
MS m/z(ESI):228.1[M+H] +. MS m/z(ESI):228.1[M+H] + .
步骤二：3-(4-氨基苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基胺(T1)Step 2: 3-(4-aminophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (T1)
将化合物T1-2(600mg，1.32mmol)溶解在1,4-二氧六环/水(10ml/2ml)中，然后加入4-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)苯胺(576.42mg,2.63mmol)、碳酸钠(278.86mg,2.63mmol)、Pd(dppf)Cl 2(214.86mg,263μmol)，用氮气置换三次后，于90℃反应16小时。向反应液中加入硫酸钠固体后用硅藻土过滤，将滤液浓缩，将浓缩后的粗品用硅胶柱分离(二氯甲烷/甲醇＝50/1)得标题化合物T1(490mg)。 Compound T1-2 (600mg, 1.32mmol) was dissolved in 1,4-dioxane/water (10ml/2ml), then 4-(4,4,5,5-tetramethyl-1,3 ,2-Dioxybenzaldehyde-2-yl)aniline (576.42mg, 2.63mmol), sodium carbonate (278.86mg, 2.63mmol), Pd(dppf)Cl 2 (214.86mg, 263μmol), after three times of replacement with nitrogen, React at 90°C for 16 hours. After adding solid sodium sulfate to the reaction solution, it was filtered with celite, the filtrate was concentrated, and the concentrated crude product was separated on a silica gel column (dichloromethane/methanol=50/1) to obtain the title compound T1 (490 mg).
MS m/z(ESI):241.1[M+H] +. MS m/z(ESI):241.1[M+H] + .
中间体制备例2：5-(4-氨基苯基)-7-(氧杂环丁-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(T2)Intermediate Preparation 2: 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (T2)
Figure PCTCN2022109584-appb-000041
Figure PCTCN2022109584-appb-000041
步骤一：5-溴-4-氯-7-(氧杂环丁-3-基)-7H-吡咯并[2,3-d]嘧啶(T2-2)Step 1: 5-bromo-4-chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (T2-2)
将化合物T2-1(600mg,2.53mmol)、3-氧杂环丁醇(574mg,7.59mmol)、三苯基膦(1.38g,5.16mmol)溶于1,4-二氧六环(4mL)中，室温下加入偶氮二甲酸二乙酯(917mg,5.16mmol)，向反应容器中充入氮气，于85℃微波反应1小时。反应完毕，将反应液浓缩，加入水，用乙酸乙酯萃取，合并有机相，分别用水和饱和食盐水洗，用无水硫酸钠干燥，经硅胶柱层析(石油醚/乙酸乙酯＝2/1)分离得标题化合物T2-2(350mg)。Compound T2-1 (600mg, 2.53mmol), 3-oxetanol (574mg, 7.59mmol), triphenylphosphine (1.38g, 5.16mmol) were dissolved in 1,4-dioxane (4mL) Diethyl azodicarboxylate (917mg, 5.16mmol) was added at room temperature, nitrogen gas was filled into the reaction vessel, and microwave reaction was carried out at 85°C for 1 hour. After the reaction was complete, the reaction solution was concentrated, added water, extracted with ethyl acetate, combined the organic phases, washed with water and saturated brine respectively, dried with anhydrous sodium sulfate, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate=2/ 1) The title compound T2-2 (350 mg) was isolated.
MS m/z(ESI):289.1[M+H] +. MS m/z(ESI):289.1[M+H] + .
步骤二：5-溴-7-(氧杂环丁-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(T2-3)Step 2: 5-Bromo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (T2-3)
将化合物T2-2(250mg,0.81mmol)溶于氨水(2mL)和1,4-二氧六环(1mL)的混合溶剂中，于90℃微波反应1.5小时。反应完毕，浓缩，用乙酸乙酯打浆，抽滤，得标题化合物T2-3(195mg)。Compound T2-2 (250mg, 0.81mmol) was dissolved in a mixed solvent of ammonia (2mL) and 1,4-dioxane (1mL), and reacted by microwave at 90°C for 1.5 hours. After the reaction was completed, it was concentrated, slurried with ethyl acetate, and filtered with suction to obtain the title compound T2-3 (195 mg).
MS m/z(ESI):270.1[M+H] +. MS m/z(ESI):270.1[M+H] + .
步骤三：5-(4-氨基苯基)-7-(氧杂环丁-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(T2)Step 3: 5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (T2)
将化合物T2-3(160mg,0.56mmol)、4-氨基苯硼酸频哪醇酯(126mg,0.56mmol)、PdCl 2(dppf)(42 mg,0.06mmol)和碳酸铯(372mg,1.12mmol)溶于1,4-二氧六环(10mL)和水(2mL)中，在氮气保护下加热至90℃反应12小时。反应完毕，冷却至室温，向反应液中加入水，用乙酸乙酯萃取，合并有机相，分别用水和饱和食盐水洗，用无水硫酸钠干燥，经硅胶柱层析(二氯甲烷/甲醇＝20/1)分离得标题化合物T2(102mg)。 Compound T2-3 (160mg, 0.56mmol), 4-aminophenylboronic acid pinacol ester (126mg, 0.56mmol), PdCl 2 (dppf) (42 mg, 0.06mmol) and cesium carbonate (372mg, 1.12mmol) were dissolved In 1,4-dioxane (10 mL) and water (2 mL), heated to 90° C. for 12 hours under nitrogen protection. After the reaction was completed, cool to room temperature, add water to the reaction solution, extract with ethyl acetate, combine the organic phases, wash with water and saturated brine respectively, dry with anhydrous sodium sulfate, and perform silica gel column chromatography (dichloromethane/methanol = 20/1) the title compound T2 (102 mg) was isolated.
MS m/z(ESI):282.2[M+H] +. MS m/z(ESI):282.2[M+H] + .
中间体制备例3：5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢哒嗪-3-羧酸(T3)Intermediate Preparation Example 3: 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridazine- 3-Carboxylic acid (T3)
Figure PCTCN2022109584-appb-000042
Figure PCTCN2022109584-appb-000042
步骤一：2-(4-氟苯基)乙酰氯(T3-2)Step 1: 2-(4-fluorophenyl)acetyl chloride (T3-2)
将化合物T3-1(20.0g，127.8mmol)溶解在二氯甲烷(200mL)中，向体系中加入催化量的N,N-二甲基甲酰胺(0.1mL)，然后缓慢加入草酰氯(33.1g，255.6mmol)，于25℃反应2小时。直接浓缩反应体系得标题化合物T3-2(22.0g)。Compound T3-1 (20.0g, 127.8mmol) was dissolved in dichloromethane (200mL), a catalytic amount of N,N-dimethylformamide (0.1mL) was added to the system, and then oxalyl chloride (33.1 g, 255.6 mmol), reacted at 25°C for 2 hours. The reaction system was directly concentrated to obtain the title compound T3-2 (22.0 g).
MS m/z(ESI):173.3[M+H] +. MS m/z(ESI):173.3[M+H] + .
步骤二：2-重氮-4-(4-氟苯基)-3-氧代丁酸乙酯(T3-3)Step 2: Ethyl 2-diazo-4-(4-fluorophenyl)-3-oxobutanoate (T3-3)
将化合物T3-2(22g，121mmol)溶于二氯甲烷(200mL)中，在氮气保护、冰水浴下加入重氮乙酸乙酯(29g，242mmol)，于25℃反应8小时。加水淬灭，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，将浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)得标题化合物T3-3(10.4g)。Compound T3-2 (22g, 121mmol) was dissolved in dichloromethane (200mL), ethyl diazoacetate (29g, 242mmol) was added under nitrogen protection and ice-water bath, and reacted at 25°C for 8 hours. Quenched with water, extracted with ethyl acetate, dried the organic phase with anhydrous sodium sulfate, and concentrated the residue by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound T3-3 ( 10.4g).
MS m/z(ESI):251.2[M+H] +. MS m/z(ESI):251.2[M+H] + .
步骤三：(E)-4-(4-氟苯基)-2-腙-3-氧代丁酸乙酯(T3-4)Step 3: (E)-4-(4-fluorophenyl)-2-hydrazone-3-oxobutanoic acid ethyl ester (T3-4)
将化合物T3-3(10.4g，36.99mmol)溶于异丙醚(100mL)中，冰水浴下加入三丁基膦(8.4g，40.69mmol)，于25℃反应2小时。加水淬灭，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，浓缩后得标题粗产品化合物T3-4(9.0g)。Compound T3-3 (10.4g, 36.99mmol) was dissolved in isopropyl ether (100mL), tributylphosphine (8.4g, 40.69mmol) was added under an ice-water bath, and reacted at 25°C for 2 hours. Add water to quench, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain the title crude product compound T3-4 (9.0 g).
MS m/z(ESI):251.3[M-H] +. MS m/z(ESI):251.3[MH] + .
步骤四：(E)-2-(叔丁氧羰基-腙)-4-(4-氟苯基)-3-氧代丁酸乙酯(T3-5)Step 4: (E)-2-(tert-butoxycarbonyl-hydrazone)-4-(4-fluorophenyl)-3-oxobutanoic acid ethyl ester (T3-5)
将化合物T3-4(9.0g，31.40mmol)溶于四氢呋喃(100mL)中，分别加入二碳酸二叔丁酯(7.69g，34.54mmol)、三乙胺(9.73g，94.2mmol)、4-二甲氨基吡啶(40mg，0.31mmol)，于25℃反应8小时。将反应体系直接抽滤即得标题化合物T3-5(5.0g)。Compound T3-4 (9.0g, 31.40mmol) was dissolved in tetrahydrofuran (100mL), and di-tert-butyl dicarbonate (7.69g, 34.54mmol), triethylamine (9.73g, 94.2mmol), 4-dicarbonate were added Aminopyridine (40mg, 0.31mmol), react at 25°C for 8 hours. The reaction system was directly filtered with suction to obtain the title compound T3-5 (5.0 g).
MS m/z(ESI):351.1[M-H] +. MS m/z(ESI):351.1[MH] + .
步骤五：5-(4-氟苯基)-4-氧代-1,4-二氢哒嗪-3-羧酸乙酯(T3-6)Step 5: Ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (T3-6)
将化合物T3-5(5.0g，13.72mmol)溶于四氢呋喃(50mL)中，加热回流，滴加1-叔丁氧基-N,N,N',N'-四甲基-甲二胺(4.88g，27.45mmol)，于70℃反应2小时。反应完毕后降至室温，滴加盐酸二氧六环(10mL，4M)，搅拌30分钟，直接进行抽滤得标题化合物T3-6(4.0g)。Compound T3-5 (5.0 g, 13.72 mmol) was dissolved in tetrahydrofuran (50 mL), heated to reflux, and 1-tert-butoxy-N, N, N', N'-tetramethyl-methanediamine ( 4.88g, 27.45mmol), reacted at 70°C for 2 hours. After the reaction was completed, it was lowered to room temperature, dioxane hydrochloride (10 mL, 4M) was added dropwise, stirred for 30 minutes, and directly subjected to suction filtration to obtain the title compound T3-6 (4.0 g).
MS m/z(ESI):263.1[M+H] +. MS m/z(ESI):263.1[M+H] + .
步骤六：5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢哒嗪-3-羧酸乙酯(T3-7)Step 6: 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridazine-3-carboxy Ethyl acetate (T3-7)
将化合物T3-6(770mg，2.08mmol)溶解在N,N-二甲基甲酰胺(10mL)中，然后加入碳酸钾(1.17g，8.3mmol)、4-(溴甲基)四氢吡喃(455mg，2.49mmol)，于80℃反应8小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩，将浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)得标题化合物T3-7(700mg)。Compound T3-6 (770mg, 2.08mmol) was dissolved in N,N-dimethylformamide (10mL), then potassium carbonate (1.17g, 8.3mmol), 4-(bromomethyl)tetrahydropyran were added (455mg, 2.49mmol), react at 80°C for 8 hours. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and use silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound T3-7 ( 700mg).
MS m/z(ESI):361.2[M+H] +. MS m/z(ESI):361.2[M+H] + .
步骤七：5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢哒嗪-3-羧酸(T3)Step 7: 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridazine-3-carboxy Acid (T3)
将化合物T3-7(700mg，2.3mmol)溶解在甲醇(5mL)、四氢呋喃(5mL)、水(5mL)中，然后加入氢氧化钠(500mg，12.49mmol)，于25℃反应2小时。浓缩溶剂，滴加1N盐酸调至酸性，直接抽滤得标题化合物T3(600mg)。Compound T3-7 (700mg, 2.3mmol) was dissolved in methanol (5mL), tetrahydrofuran (5mL), water (5mL), and sodium hydroxide (500mg, 12.49mmol) was added to react at 25°C for 2 hours. The solvent was concentrated, 1N hydrochloric acid was added dropwise to make it acidic, and the title compound T3 (600 mg) was obtained by suction filtration.
MS m/z(ESI):333.1[M+H] +. MS m/z(ESI):333.1[M+H] + .
中间体制备例4：5-(4-氟苯基)-1-异丁基-4-氧代-1,4-二氢哒嗪-3-羧酸(T4)Intermediate Preparation 4: 5-(4-fluorophenyl)-1-isobutyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T4)
Figure PCTCN2022109584-appb-000043
Figure PCTCN2022109584-appb-000043
步骤一：5-(4-氟苯基)-1-异丁基-4-氧代-1,4-二氢哒嗪-3-羧酸乙酯(T4-1)Step 1: Ethyl 5-(4-fluorophenyl)-1-isobutyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T4-1)
将化合物T3-6(500mg，1.22mmol)加入到N,N-二甲基甲酰胺(10mL)中，然后加入碳酸钾(516mg，3.66mmol)、1-碘-2-甲基丙烷(241mg，1.3mmol)，于70℃反应8小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩，将浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)得标题化合物T4-1(260mg)。Compound T3-6 (500mg, 1.22mmol) was added to N,N-dimethylformamide (10mL), then potassium carbonate (516mg, 3.66mmol), 1-iodo-2-methylpropane (241mg, 1.3mmol), and reacted at 70°C for 8 hours. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and use silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound T4-1 ( 260mg).
MS m/z(ESI):319.1[M+H] +. MS m/z(ESI):319.1[M+H] + .
步骤二：5-(4-氟苯基)-1-异丁基-4-氧代-1,4-二氢哒嗪-3-羧酸(T4)Step 2: 5-(4-fluorophenyl)-1-isobutyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T4)
将化合物T4-1(222mg，0.691mmol)加入到甲醇(5mL)、四氢呋喃(5mL)、水(5mL)的混合液中，然后加入氢氧化锂(33.4mg，1.38mmol)，于25℃反应2小时。浓缩溶剂，滴加1N盐酸调至酸性，直接过滤得标题化合物T4(200mg)。Compound T4-1 (222mg, 0.691mmol) was added to a mixture of methanol (5mL), tetrahydrofuran (5mL), and water (5mL), and then lithium hydroxide (33.4mg, 1.38mmol) was added to react at 25°C for 2 Hour. The solvent was concentrated, 1N hydrochloric acid was added dropwise to make it acidic, and the title compound T4 (200 mg) was obtained by direct filtration.
MS m/z(ESI):291.1[M+H] +. MS m/z(ESI):291.1[M+H] + .
中间体制备例5：5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸(T5)Intermediate Preparation 5: 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T5)
Figure PCTCN2022109584-appb-000044
Figure PCTCN2022109584-appb-000044
步骤一：5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸乙酯(T5-1)Step 1: Ethyl 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T5-1)
将化合物T3-6(920mg,1.97mmol)溶解在N,N-二甲基甲酰胺(10mL)中，然后加入碳酸钾(1.11g,7.88mmol)、2-碘丙烷(410mg,2.37mmol)，于70℃反应8小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩，将浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)得标题化合物T5-1(550mg)。Compound T3-6 (920mg, 1.97mmol) was dissolved in N,N-dimethylformamide (10mL), then potassium carbonate (1.11g, 7.88mmol), 2-iodopropane (410mg, 2.37mmol) were added, React at 70°C for 8 hours. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and use silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound T5-1 ( 550mg).
MS m/z(ESI):305.1[M+H] +. MS m/z(ESI):305.1[M+H] + .
步骤二：5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸(T5)Step 2: 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T5)
将化合物T5-1(550mg,1.91mmol)溶解在甲醇(5mL)、四氢呋喃(5mL)、水(5mL)中，然后加入氢氧化钠(300mg,7.71mmol)，于25℃反应2小时。浓缩溶剂，滴加1N盐酸调至酸性，直接抽滤得标题化合物T5(350mg)。Compound T5-1 (550mg, 1.91mmol) was dissolved in methanol (5mL), tetrahydrofuran (5mL), water (5mL), then sodium hydroxide (300mg, 7.71mmol) was added, and reacted at 25°C for 2 hours. The solvent was concentrated, 1N hydrochloric acid was added dropwise to make it acidic, and the title compound T5 (350 mg) was obtained by suction filtration directly.
MS m/z(ESI):277.1[M+H] +. MS m/z(ESI):277.1[M+H] + .
中间体制备例6：5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸(T6)Intermediate Preparation 6: 5-(5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T6)
Figure PCTCN2022109584-appb-000045
Figure PCTCN2022109584-appb-000045
步骤一：2-(5-氟吡啶-2-基)-1-(1H-咪唑-1-基)乙烷-1-酮(T6-2)Step 1: 2-(5-fluoropyridin-2-yl)-1-(1H-imidazol-1-yl)ethan-1-one (T6-2)
将化合物T6-1(3.00g,15.74mmol)溶于THF(10mL)中，然后加入N,N-羰基二咪唑(2.70g,18.60mmol)，于25℃反应1小时，反应不处理直接用在下一步。Compound T6-1 (3.00g, 15.74mmol) was dissolved in THF (10mL), then N,N-carbonyldiimidazole (2.70g, 18.60mmol) was added, and reacted at 25°C for 1 hour, and the reaction was directly used in the following step.
步骤二：4-(5-氟吡啶-2-基)-3-氧代丁酸甲酯(T6-3)Step 2: Methyl 4-(5-fluoropyridin-2-yl)-3-oxobutanoate (T6-3)
将丙二酸单乙酯钾盐(8.14g,47.37mmol)、氯化镁(4.56g,47.37mmol)和三乙胺(6.46g,63.16mmol)溶解在四氢呋喃(100mL)和N,N-二甲基甲酰胺(30mL)中，然后在冰浴下持续搅拌1小时，升至室温， 持续搅拌一小时，再降至零度后，缓慢加入T6-2，在室温下持续搅拌16小时，加水洗涤，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T6-3(3.00g)。Dissolve monoethyl malonate potassium salt (8.14 g, 47.37 mmol), magnesium chloride (4.56 g, 47.37 mmol) and triethylamine (6.46 g, 63.16 mmol) in tetrahydrofuran (100 mL) and N,N-dimethyl Formamide (30mL), then kept stirring for 1 hour under ice bath, rose to room temperature, kept stirring for one hour, and then lowered to zero, slowly added T6-2, kept stirring at room temperature for 16 hours, washed with water, washed with After extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography (petroleum ether/ethyl acetate=20/1-5/1) to obtain the title compound T6-3 (3.00 g).
MS m/z(ESI):228.1[M+H] +. MS m/z(ESI):228.1[M+H] + .
步骤三：4-(5-氟吡啶-2-基)-2-重氮-3-氧代丁酸乙酯(T6-4)Step 3: Ethyl 4-(5-fluoropyridin-2-yl)-2-diazo-3-oxobutanoate (T6-4)
将T6-3(3.00g,12.65mmol)溶解在乙腈(30mL)中，然后在冰浴下加入三乙胺(3.08g,37.96mmol)、对甲苯磺酰叠氮(3.16g,12.02mmol)，持续搅拌2小时。加水洗涤，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T6-4(3.00g)。Dissolve T6-3 (3.00g, 12.65mmol) in acetonitrile (30mL), then add triethylamine (3.08g, 37.96mmol), p-toluenesulfonyl azide (3.16g, 12.02mmol) under ice-cooling, Stirring was continued for 2 hours. Wash with water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate and use silica gel column chromatography (petroleum ether/ethyl acetate=20/1-5/1) to obtain the title compound T6-4 (3.00 g).
MS m/z(ESI):268.1[M+H] +. MS m/z(ESI):268.1[M+H] + .
步骤四：4-(5-氟吡啶-2-基)-2-腙-3-氧代丁酸乙酯(T6-5)Step 4: Ethyl 4-(5-fluoropyridin-2-yl)-2-hydrazone-3-oxobutanoate (T6-5)
将化合物T6-4(3.00g,11.34mmol)溶解在异丙醚(30mL)中，然后加入三丁基膦(2.81g,13.61mmol)，于室温下持续搅拌2小时，加水洗涤，用乙酸乙酯萃取，将有机相无水硫酸钠干燥，旋干得标题化合物T6-5(2.50g)。Compound T6-4 (3.00g, 11.34mmol) was dissolved in isopropyl ether (30mL), then tributylphosphine (2.81g, 13.61mmol) was added, stirring was continued at room temperature for 2 hours, washed with water, washed with ethyl acetate After ester extraction, the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the title compound T6-5 (2.50 g).
MS m/z(ESI):270.1[M+H] +. MS m/z(ESI):270.1[M+H] + .
步骤五：2-(叔丁氧羰基-腙)-(4-(5-氟吡啶-2-基)-3-氧代丁酸乙酯(T6-6)Step 5: Ethyl 2-(tert-butoxycarbonyl-hydrazone)-(4-(5-fluoropyridin-2-yl)-3-oxobutanoate (T6-6)
将化合物T6-5(2.34g,9.06mmol)溶解在四氢呋喃(10mL)中，然后加入二碳酸二叔丁酯(2.12g,9.51mmol)、三乙胺(2.81g,27.17mmol)、4-二甲氨基吡啶(112mg,900μmol)，于室温下持续搅拌16小时，加水洗涤，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T6-6(2.50g)。Compound T6-5 (2.34g, 9.06mmol) was dissolved in tetrahydrofuran (10mL), then di-tert-butyl dicarbonate (2.12g, 9.51mmol), triethylamine (2.81g, 27.17mmol), 4-di Aminopyridine (112 mg, 900 μmol) was continuously stirred at room temperature for 16 hours, washed with water, extracted with ethyl acetate, dried with anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate =20/1-5/1) to obtain the title compound T6-6 (2.50 g).
MS m/z(ESI):370.1[M+H] +. MS m/z(ESI):370.1[M+H] + .
步骤六：5-(5-氟吡啶-2-基)-4-氧代-1,4-二氢哒嗪-3-羧酸乙酯(T6-7)Step 6: Ethyl 5-(5-fluoropyridin-2-yl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (T6-7)
将化合物T6-6(2.10g,5.65mmol)溶解在四氢呋喃(20mL)中，然后加入叔丁氧基双(二甲胺基)甲烷(1.97g,11.29mmol)，于70℃下持续搅拌1小时，加水洗涤，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T6-7(1g)。Compound T6-6 (2.10g, 5.65mmol) was dissolved in tetrahydrofuran (20mL), then tert-butoxybis(dimethylamino)methane (1.97g, 11.29mmol) was added, and stirring was continued at 70°C for 1 hour , washed with water, extracted with ethyl acetate, dried the organic phase with anhydrous sodium sulfate, concentrated and then used silica gel column chromatography (petroleum ether/ethyl acetate=20/1-5/1) to obtain the title compound T6-7 ( 1g).
MS m/z(ESI):280.1[M+H] +. MS m/z(ESI):280.1[M+H] + .
步骤七：5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸乙酯(T6-8)Step 7: Ethyl 5-(5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T6-8)
将化合物T6-7(900mg,3.25mmol)溶解在N,N-二甲基甲酰胺(5mL)中，然后加入碘代异丙烷(552mg,3.25mmol)、碳酸钾(1.35g,9.74mmol)，于70℃下持续搅拌1小时，加水洗涤，用乙酸乙酯萃取，将有机相无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T6-8(700mg)。Compound T6-7 (900mg, 3.25mmol) was dissolved in N,N-dimethylformamide (5mL), then iodoisopropane (552mg, 3.25mmol), potassium carbonate (1.35g, 9.74mmol) were added, Stir continuously at 70°C for 1 hour, wash with water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography (petroleum ether/ethyl acetate=20/1-5/1) The title compound T6-8 (700 mg) was obtained.
MS m/z(ESI):322.1[M+H] +. MS m/z(ESI):322.1[M+H] + .
步骤八：5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸(T6)Step 8: 5-(5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T6)
将化合物T6-8(660mg,1.95mmol)溶解在四氢呋喃(5mL)和水(1mL)的混合溶剂中，然后加入氢氧化锂(141mg,5.84mmol)，于25℃下持续搅拌1小时，用1N盐酸调节PH＝5，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，旋干得标题化合物T6(500mg)。Compound T6-8 (660mg, 1.95mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (1mL), then lithium hydroxide (141mg, 5.84mmol) was added, stirring was continued at 25°C for 1 hour, and 1N Adjust the pH to 5 with hydrochloric acid, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and spin dry to obtain the title compound T6 (500 mg).
MS m/z(ESI):294.1[M+H] +. MS m/z(ESI):294.1[M+H] + .
中间体制备例7：5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-羧酸(T7)Intermediate Preparation 7: 5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T7)
Figure PCTCN2022109584-appb-000046
Figure PCTCN2022109584-appb-000046
步骤一：5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-羧酸乙酯(T7-1)Step 1: Ethyl 5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (T7-1)
将化合物T3-6(1.0g,2.14mmol)溶解在N,N-二甲基甲酰胺(10mL)中，然后加入碳酸钾(1.21g,8.57mmol)、1-甲氧基-2-甲基磺酰乙烷(370mg,2.57mmol)，于70℃反应8小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩，将浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)得标题化合物T7-1(600mg)。Compound T3-6 (1.0g, 2.14mmol) was dissolved in N,N-dimethylformamide (10mL), then potassium carbonate (1.21g, 8.57mmol), 1-methoxy-2-methyl Sulfonyl ethane (370mg, 2.57mmol) was reacted at 70°C for 8 hours. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and use silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound T7-1 ( 600mg).
MS m/z(ESI):321.2[M+H] +. MS m/z(ESI):321.2[M+H] + .
步骤二：5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-羧酸(T7)Step 2: 5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T7)
将化合物T7-1(600mg,1.84mmol)溶解在甲醇(5mL)、四氢呋喃(5mL)、水(5mL)中，然后加入氢氧化钠(300mg,7.34mmol)，于25℃反应2小时。浓缩溶剂，滴加1N盐酸调至酸性，直接抽滤得标题化合物T7(470mg)。Compound T7-1 (600mg, 1.84mmol) was dissolved in methanol (5mL), tetrahydrofuran (5mL), water (5mL), then sodium hydroxide (300mg, 7.34mmol) was added, and reacted at 25°C for 2 hours. The solvent was concentrated, 1N hydrochloric acid was added dropwise to make it acidic, and the title compound T7 (470 mg) was obtained by suction filtration directly.
MS m/z(ESI):293.2[M+H] +. MS m/z(ESI):293.2[M+H] + .
中间体制备例8：5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢哒嗪-3-羧酸(T8)Intermediate Preparation 8: 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridazine-3-carboxylic acid (T8 )
Figure PCTCN2022109584-appb-000047
Figure PCTCN2022109584-appb-000047
步骤一：5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢哒嗪-3-羧酸乙酯(T8-1)Step 1: Ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridazine-3-carboxylate (T8- 1)
将化合物T3-6(500mg,1.22mmol)分散到N,N-二甲基甲酰胺(10mL)中，然后加入碳酸钾(516mg,3.66mmol)、四氢呋喃-3-基甲基甲磺酸酯(222mg,1.3mmol)，于70℃反应8小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩，将浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)得标题化合物T8-1(260mg)。Compound T3-6 (500mg, 1.22mmol) was dispersed into N,N-dimethylformamide (10mL), then potassium carbonate (516mg, 3.66mmol), tetrahydrofuran-3-ylmethyl methanesulfonate ( 222mg, 1.3mmol), react at 70°C for 8 hours. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and use silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain the title compound T8-1 ( 260mg).
MS m/z(ESI):347.2[M+H] +. MS m/z(ESI):347.2[M+H] + .
步骤二：5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢哒嗪-3-羧酸(T8)Step 2: 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridazine-3-carboxylic acid (T8)
将化合物T8-1(230mg,0.69mmol)加入到甲醇(5mL)、四氢呋喃(5mL)、水(5mL)的混合液中，然后加入氢氧化锂(33.4mg，1.38mmol)，于25℃反应2小时。浓缩溶剂，滴加1N盐酸调至pH＝3-4，直接过滤得标题化合物T8(198mg)。Compound T8-1 (230mg, 0.69mmol) was added to a mixture of methanol (5mL), tetrahydrofuran (5mL), and water (5mL), then lithium hydroxide (33.4mg, 1.38mmol) was added, and reacted at 25°C for 2 Hour. The solvent was concentrated, 1N hydrochloric acid was added dropwise to adjust the pH to 3-4, and the title compound T8 (198 mg) was obtained by direct filtration.
MS m/z(ESI):319.1[M+H] +. MS m/z(ESI):319.1[M+H] + .
中间体制备例9：5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸(T9)Intermediate Preparation 9: 5-(4-Chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T9)
Figure PCTCN2022109584-appb-000048
Figure PCTCN2022109584-appb-000048
步骤一：2-(4-氯苯基)乙酰氯(T9-2)Step 1: 2-(4-chlorophenyl)acetyl chloride (T9-2)
将化合物T9-1(11.22g,64.48mmol)溶解在二氯甲烷(100mL)与催化量的N,N-二甲基甲酰胺(0.1mL)中，然后缓慢滴加草酰氯(16.7g,128.96mmol)，于25℃反应2小时。直接浓缩反应体系得标题化合物T9-2(12.19g)。Compound T9-1 (11.22g, 64.48mmol) was dissolved in dichloromethane (100mL) and a catalytic amount of N,N-dimethylformamide (0.1mL), and then oxalyl chloride (16.7g, 128.96 mmol), reacted at 25°C for 2 hours. The reaction system was directly concentrated to obtain the title compound T9-2 (12.19 g).
MS m/z(ESI):185.3[M+H] +. MS m/z(ESI):185.3[M+H] + .
步骤二：2-重氮-4-(4-氯苯基)-3-氧代丁酸乙酯(T9-3)Step 2: Ethyl 2-diazo-4-(4-chlorophenyl)-3-oxobutanoate (T9-3)
将化合物T9-2(10g,51.84mmol)溶于乙酸乙酯(100mL)中，于氮气保护、冰水浴下加入重氮乙酸乙酯(12.07g,103.68mmol)，于25℃反应16小时。加水淬灭，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)得标题化合物T9-3(10.8g)。Compound T9-2 (10 g, 51.84 mmol) was dissolved in ethyl acetate (100 mL), and ethyl diazoacetate (12.07 g, 103.68 mmol) was added under nitrogen protection under an ice-water bath, and reacted at 25°C for 16 hours. Quenched with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound T9- 3 (10.8g).
MS m/z(ESI):267.2[M+H] +. MS m/z(ESI):267.2[M+H] + .
步骤三：(E)-4-(4-氯苯基)-2-腙-3-氧代丁酸乙酯(T9-4)Step 3: (E)-4-(4-chlorophenyl)-2-hydrazone-3-oxobutanoic acid ethyl ester (T9-4)
将化合物T9-3(10.8g,28.35mmol)溶于异丙醚(100mL)中，冰水浴下加入三丁基膦(6.44g,31.18mmol)，于25℃反应2小时。加水淬灭，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)得标题化合物T9-4(5.6g)。Compound T9-3 (10.8g, 28.35mmol) was dissolved in isopropyl ether (100mL), tributylphosphine (6.44g, 31.18mmol) was added under an ice-water bath, and reacted at 25°C for 2 hours. Quenched with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the title compound T9- 4 (5.6g).
MS m/z(ESI):269.2[M+H] +. MS m/z(ESI):269.2[M+H] + .
步骤四：(E)-2-(叔丁氧羰基-腙)-(4-(4-氯苯基)-3-氧代丁酸乙酯(T9-5)Step 4: (E)-2-(tert-butoxycarbonyl-hydrazone)-(4-(4-chlorophenyl)-3-oxobutanoic acid ethyl ester (T9-5)
将化合物T9-4(5.6g,16.67mmol)溶于四氢呋喃(60mL)中，分别加入二碳酸二叔丁酯(4.08g,18.34mmol)、三乙胺(5.16g,50.02mmol)、4-二甲氨基吡啶(20.8mg,166.7μmol)，于25℃反应16小时。反应体系直接浓缩即得标题化合物T9-5(6.0g)。Compound T9-4 (5.6g, 16.67mmol) was dissolved in tetrahydrofuran (60mL), and di-tert-butyl dicarbonate (4.08g, 18.34mmol), triethylamine (5.16g, 50.02mmol), 4-di Aminopyridine (20.8 mg, 166.7 μmol) was reacted at 25°C for 16 hours. The reaction system was directly concentrated to obtain the title compound T9-5 (6.0 g).
MS m/z(ESI):369.1[M+H] +. MS m/z(ESI):369.1[M+H] + .
步骤五：5-(4-氯苯基)-4-氧代-1,4-二氢哒嗪-3-羧酸乙酯(T9-6)Step 5: Ethyl 5-(4-chlorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate (T9-6)
将化合物T9-5(5.0g,13.72mmol)溶于四氢呋喃(50mL)中，加热回流后，滴加1-叔丁氧基- N,N,N',N'-四甲基-甲二胺(3.38g,18.98mmol)，于70℃反应2小时。反应完毕降至室温，滴加盐酸1,4-二氧六环(15mL,4M)，搅拌30分钟，直接进行抽滤得标题化合物T9-6(2.8g)。Compound T9-5 (5.0g, 13.72mmol) was dissolved in tetrahydrofuran (50mL), and after heating to reflux, 1-tert-butoxy-N,N,N',N'-tetramethyl-methylenediamine was added dropwise (3.38g, 18.98mmol), react at 70°C for 2 hours. After the reaction was completed and cooled down to room temperature, 1,4-dioxane hydrochloride (15 mL, 4M) was added dropwise, stirred for 30 minutes, and directly subjected to suction filtration to obtain the title compound T9-6 (2.8 g).
MS m/z(ESI):279.3[M+H] +. MS m/z(ESI):279.3[M+H] + .
步骤六：5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸乙酯(T9-7)Step 6: Ethyl 5-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T9-7)
将化合物T9-6(1.01g,3.05mmol)溶解在N,N-二甲基甲酰胺(20mL)中，然后加入碳酸钾(1.29g,9.14mmol)、2-碘丙烷(634.07mg,3.66mmol)，于70℃反应16小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩，将浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)得标题化合物T9-7(970mg)。Compound T9-6 (1.01g, 3.05mmol) was dissolved in N,N-dimethylformamide (20mL), then potassium carbonate (1.29g, 9.14mmol), 2-iodopropane (634.07mg, 3.66mmol) were added ), reacted at 70°C for 16 hours. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and use silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain the title compound T9-7 ( 970mg).
MS m/z(ESI):321.3[M+H] +. MS m/z(ESI):321.3[M+H] + .
步骤七：5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸(T9)Step 7: 5-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T9)
将化合物T9-7(900mg,2.67mmol)溶解在甲醇(5mL)、四氢呋喃(5mL)、水(5mL)中，然后加入氢氧化钠(326mg,8mmol)，于25℃反应2小时。浓缩溶剂，滴加1N盐酸调至PH＝3，直接抽滤得标题化合物T9(490mg)。Compound T9-7 (900mg, 2.67mmol) was dissolved in methanol (5mL), tetrahydrofuran (5mL), water (5mL), then sodium hydroxide (326mg, 8mmol) was added, and reacted at 25°C for 2 hours. The solvent was concentrated, 1N hydrochloric acid was added dropwise to adjust the pH to 3, and the title compound T9 (490 mg) was obtained by direct suction filtration.
MS m/z(ESI):293.3[M+H] +. MS m/z(ESI):293.3[M+H] + .
中间体制备例10：5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸(T10)Intermediate Preparation 10: 5-(5-Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T10)
Figure PCTCN2022109584-appb-000049
Figure PCTCN2022109584-appb-000049
步骤一：2-(5-氯吡啶-2-基)-1-(1H-咪唑-1-基)乙烷-1-酮(T10-2)Step 1: 2-(5-Chloropyridin-2-yl)-1-(1H-imidazol-1-yl)ethan-1-one (T10-2)
将化合物T10-1(3.00g,14.60mmol)溶于四氢呋喃(10mL)中，然后加入N,N-羰基二咪唑(2.70g,18.60mmol)，于25℃反应1小时，反应不处理直接用在下一步。Compound T10-1 (3.00g, 14.60mmol) was dissolved in tetrahydrofuran (10mL), then N,N-carbonyldiimidazole (2.70g, 18.60mmol) was added and reacted at 25°C for 1 hour. The reaction was directly used in the following step.
步骤二：4-(5-氯吡啶-2-基)-3-氧代丁酸甲酯(T10-3)Step 2: Methyl 4-(5-chloropyridin-2-yl)-3-oxobutanoate (T10-3)
将丙二酸单乙酯钾盐(8.14g,47.37mmol)、氯化镁(4.56g,47.37mmol)和三乙胺(6.46g,63.16mmol)溶解在四氢呋喃(100mL)/N,N-二甲基甲酰胺(30mL)中，然后在冰浴下持续搅拌一小时，升至室温，持续搅拌一小时，再降至零度后，缓慢加入T10-2，在室温下持续搅拌16小时，加水洗涤，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T10-3(3.00g)。Dissolve monoethyl malonate potassium salt (8.14 g, 47.37 mmol), magnesium chloride (4.56 g, 47.37 mmol) and triethylamine (6.46 g, 63.16 mmol) in tetrahydrofuran (100 mL)/N,N-dimethyl formamide (30mL), then kept stirring for one hour under ice bath, raised to room temperature, kept stirring for one hour, and then lowered to zero, slowly added T10-2, kept stirring at room temperature for 16 hours, washed with water, washed with After extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and then subjected to silica gel column chromatography (petroleum ether/ethyl acetate=20/1-5/1) to obtain the title compound T10-3 (3.00 g).
MS m/z(ESI):228.1[M+H] +. MS m/z(ESI):228.1[M+H] + .
步骤三：4-(5-氯吡啶-2-基)-2-重氮-3-氧代丁酸乙酯(T10-4)Step 3: Ethyl 4-(5-chloropyridin-2-yl)-2-diazo-3-oxobutanoate (T10-4)
将T10-3(3.00g,14.20mmol)溶解在乙腈(30mL)中，然后在冰浴下加入三乙胺(3.08g,37.96mmol)、对甲苯磺酰叠氮(3.16g,12.02mmol)，持续搅拌2小时。加水洗涤，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T10-4(3.00g)。Dissolve T10-3 (3.00g, 14.20mmol) in acetonitrile (30mL), then add triethylamine (3.08g, 37.96mmol) and p-toluenesulfonyl azide (3.16g, 12.02mmol) under ice-cooling, Stirring was continued for 2 hours. Wash with water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate and use silica gel column chromatography (petroleum ether/ethyl acetate=20/1-5/1) to obtain the title compound T10-4 (3.00 g).
MS m/z(ESI):268.1[M+H] +. MS m/z(ESI):268.1[M+H] + .
步骤四：4-(5-氯吡啶-2-基)-2-腙-3-氧代丁酸乙酯(T10-5)Step 4: Ethyl 4-(5-chloropyridin-2-yl)-2-hydrazone-3-oxobutanoate (T10-5)
将化合物T10-4(3.00g,11.95mmol)溶解在异丙醚(30mL)中，然后加入三丁基膦(2.81g,13.61mmol)，于室温下持续搅拌2小时，加水洗涤，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，旋干得标题化合物T10-5(2.50g)。Compound T10-4 (3.00g, 11.95mmol) was dissolved in isopropyl ether (30mL), then tributylphosphine (2.81g, 13.61mmol) was added, stirring was continued at room temperature for 2 hours, washed with water, washed with ethyl acetate After ester extraction, the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the title compound T10-5 (2.50 g).
MS m/z(ESI):270.1[M+H] +. MS m/z(ESI):270.1[M+H] + .
步骤五：2-(叔丁氧羰基-腙)-(4-(5-氯吡啶-2-基)-3-氧代丁酸乙酯(T10-6)Step 5: 2-(tert-butoxycarbonyl-hydrazone)-(4-(5-chloropyridin-2-yl)-3-oxobutanoic acid ethyl ester (T10-6)
将化合物T10-5(2.34g,9.24mmol)溶解在四氢呋喃(10mL)中，然后加入二碳酸二叔丁酯(2.12g,9.51mmol)、三乙胺(2.81g,27.17mmol)、4-二甲氨基吡啶(112mg,900μmol)，于室温下持续搅拌16小时，加水洗涤，用乙酸乙酯萃取，将有机相无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T10-6(2.50g)。Compound T10-5 (2.34g, 9.24mmol) was dissolved in tetrahydrofuran (10mL), then di-tert-butyl dicarbonate (2.12g, 9.51mmol), triethylamine (2.81g, 27.17mmol), 4-di Aminopyridine (112mg, 900μmol) was continuously stirred at room temperature for 16 hours, washed with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 20/1-5/1) to obtain the title compound T10-6 (2.50 g).
MS m/z(ESI):370.1[M+H] +. MS m/z(ESI):370.1[M+H] + .
步骤六：5-(5-氯吡啶-2-基)-4-氧代-1,4-二氢吡啶-3-羧酸乙酯(T10-7)Step 6: Ethyl 5-(5-chloropyridin-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (T10-7)
将化合物T10-6(2.10g,5.94mmol)溶解在四氢呋喃(20mL)中，然后加入叔丁氧基双(二甲胺基)甲烷(1.97g,11.29mmol)，于70℃下持续搅拌1小时，加水洗涤，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T10-7(1g)。Compound T10-6 (2.10g, 5.94mmol) was dissolved in tetrahydrofuran (20mL), then tert-butoxybis(dimethylamino)methane (1.97g, 11.29mmol) was added, and stirring was continued at 70°C for 1 hour , washed with water, extracted with ethyl acetate, dried the organic phase with anhydrous sodium sulfate, concentrated and then used silica gel column chromatography (petroleum ether/ethyl acetate=20/1-5/1) to obtain the title compound T10-7 ( 1g).
MS m/z(ESI):280.1[M+H] +. MS m/z(ESI):280.1[M+H] + .
步骤七：5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸乙酯(T10-8)Step 7: Ethyl 5-(5-chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylate (T10-8)
将化合物T10-7(900mg,3.42mmol)溶解在N,N-二甲基甲酰胺(5mL)中，然后加入碘代异丙烷(552mg,3.25mmol)、碳酸钾(1.35g,9.74mmol)，于70℃下持续搅拌1小时，加水洗涤，用乙酸乙酯萃取，将有机相无水硫酸钠干燥、浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝20/1-5/1)得标题化合物T10-8(700mg)。Compound T10-7 (900mg, 3.42mmol) was dissolved in N,N-dimethylformamide (5mL), then iodoisopropane (552mg, 3.25mmol), potassium carbonate (1.35g, 9.74mmol) were added, Stir continuously at 70°C for 1 hour, wash with water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography (petroleum ether/ethyl acetate=20/1-5/1) The title compound T10-8 (700 mg) was obtained.
MS m/z(ESI):322.1[M+H] +. MS m/z(ESI):322.1[M+H] + .
步骤八：5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-羧酸(T10)Step 8: 5-(5-Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (T10)
将化合物T10-8(660mg,2.16mmol)溶解在四氢呋喃(5mL)和水(1mL)的混合溶剂中，然后加入氢氧化锂(141mg,5.84mmol)，于室温下持续搅拌1小时，用1N盐酸调节PH＝5，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，旋干得标题化合物T10(500mg)。Compound T10-8 (660mg, 2.16mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (1mL), then lithium hydroxide (141mg, 5.84mmol) was added, and stirring was continued at room temperature for 1 hour. Adjust the pH to 5, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and spin dry to obtain the title compound T10 (500 mg).
MS m/z(ESI):294.1[M+H] +. MS m/z(ESI):294.1[M+H] + .
制备例：Preparation example:
实施例1：N-(4-(4-氨基-1-(氮杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢哒嗪-3-甲酰胺(化合物1)Example 1: N-(4-(4-amino-1-(azetidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridazine-3-carboxamide (compound 1 )
Figure PCTCN2022109584-appb-000050
Figure PCTCN2022109584-appb-000050
将化合物3-(4-氨基苯基)-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(40mg,0.12mmol)、T3(43mg,0.12mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(69mg,0.18mmol)、N,N-二异丙基乙胺(47mg,0.36mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆得标题化合物1(44mg)。Compound 3-(4-aminophenyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40mg, 0.12mmol), T3 (43mg, 0.12mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (69mg, 0.18mmol), N,N -Diisopropylethylamine (47mg, 0.36mmol) was added to N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was slurried with methanol to obtain the title compound 1 (44 mg).
MS m/z(ESI):597.2[M+H] +. MS m/z(ESI):597.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.39(s,1H),8.96(s,1H),8.29(s,1H),8.01-7.92(m,4H),7.77(d,J＝8.4Hz,2H),7.43-7.34(m,2H),6.11-6.00(m,1H),5.13(t,J＝6.4Hz,2H),5.03(t,J＝7.2Hz,2H),4.25(d,J＝7.2Hz,2H),3.90(dd,J＝11.2,2.8Hz,2H),3.31(d,J＝11.2Hz,2H),2.26(d,J＝3.6Hz,1H),1.56(d,J＝11.2Hz,2H),1.38(qd,J＝12.0,4.0Hz,2H). 1 H NMR(400MHz,DMSO)δ12.39(s,1H),8.96(s,1H),8.29(s,1H),8.01-7.92(m,4H),7.77(d,J＝8.4Hz,2H ), 7.43-7.34(m, 2H), 6.11-6.00(m, 1H), 5.13(t, J=6.4Hz, 2H), 5.03(t, J=7.2Hz, 2H), 4.25(d, J= 7.2Hz, 2H), 3.90(dd, J=11.2, 2.8Hz, 2H), 3.31(d, J=11.2Hz, 2H), 2.26(d, J=3.6Hz, 1H), 1.56(d, J= 11.2Hz, 2H), 1.38(qd, J=12.0, 4.0Hz, 2H).
实施例2：N-(4-(4-氨基-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丁基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物2)Example 2: N-(4-(4-amino-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-fluorophenyl)-1-isobutyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 2)
Figure PCTCN2022109584-appb-000051
Figure PCTCN2022109584-appb-000051
将化合物T4(45mg,0.15mmol)和3-(4-氨基苯基)-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(50mg,0.18mmol)加入到N,N-二甲基甲酰胺(4mL)中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(89mg,0.23mmol)、N,N-二异丙基乙胺(60mg,0.46mmol)，于20℃反应2小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物2(66mg)。Compound T4 (45mg, 0.15mmol) and 3-(4-aminophenyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl Amine (50 mg, 0.18 mmol) was added to N,N-dimethylformamide (4 mL), followed by 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (89mg, 0.23mmol) and N,N-diisopropylethylamine (60mg, 0.46mmol) were reacted at 20°C for 2 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 2 (66 mg).
MS m/z(ESI):555.2[M+H] +. MS m/z(ESI):555.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.35(s,1H),8.92(s,1H),8.25(s,1H),7.99-7.83(m,4H),7.77(d,J＝8.0Hz,2H),7.37-7.32(m,2H),6.04-6.01(m,1H),5.13-5.09(m,2H),5.02-4.98(m,2H),4.15(d,J＝8.0 Hz,2H),2.35-2.14(m,1H),2.33-2.21(m,1H),0.98(t,J＝8.0Hz,6H). 1 H NMR(400MHz,DMSO)δ12.35(s,1H),8.92(s,1H),8.25(s,1H),7.99-7.83(m,4H),7.77(d,J＝8.0Hz,2H ),7.37-7.32(m,2H),6.04-6.01(m,1H),5.13-5.09(m,2H),5.02-4.98(m,2H),4.15(d,J＝8.0 Hz,2H), 2.35-2.14(m,1H),2.33-2.21(m,1H),0.98(t,J＝8.0Hz,6H).
实施例3：N-(4-(4-氨基-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物3)Example 3: N-(4-(4-amino-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 3)
Figure PCTCN2022109584-appb-000052
Figure PCTCN2022109584-appb-000052
将化合物3-(4-氨基苯基)-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(60mg,0.19mmol)、T5(43mg,0.12mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(111mg,0.29mmol)、N,N-二异丙基乙胺(76mg,0.54mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆得标题化合物3(36mg)。Compound 3-(4-aminophenyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (60mg, 0.19mmol), T5 (43mg, 0.12mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (111mg, 0.29mmol), N,N -Diisopropylethylamine (76mg, 0.54mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was slurried with methanol to obtain the title compound 3 (36 mg).
MS m/z(ESI):541.1[M+H] +. MS m/z(ESI):541.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.44(s,1H),8.92(s,1H),8.28(s,1H),8.02-7.93(m,4H),7.76(d,J＝8.4Hz,2H),7.36(t,J＝8.8Hz,2H),6.10-6.01(m,1H),5.14(t,J＝6.4Hz,2H),5.03(t,J＝7.2Hz,2H),4.82-4.74(m,1H),1.55(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ12.44(s,1H),8.92(s,1H),8.28(s,1H),8.02-7.93(m,4H),7.76(d,J＝8.4Hz,2H ), 7.36(t, J=8.8Hz, 2H), 6.10-6.01(m, 1H), 5.14(t, J=6.4Hz, 2H), 5.03(t, J=7.2Hz, 2H), 4.82-4.74 (m,1H),1.55(d,J=6.4Hz,6H).
实施例4：N-(4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物4)Example 4: N-(4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl) -1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 4)
Figure PCTCN2022109584-appb-000053
Figure PCTCN2022109584-appb-000053
将化合物T1(78mg,0.29mmol)、T5(85mg,0.29mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(170mg,0.44mmol)、N,N-二异丙基乙胺(115mg,0.88mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物4(43mg)。Compound T1 (78mg, 0.29mmol), T5 (85mg, 0.29mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (170mg, 0.44mmol), N,N-diisopropylethylamine (115mg, 0.88mmol) were added to N,N-dimethylformamide (5mL), and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 4 (43 mg).
MS m/z(ESI):499.1[M+H] +. MS m/z(ESI):499.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.39(s,1H),8.92(s,1H),8.28(s,1H),8.00-7.95(m,2H),7.92(d,J＝8.4Hz,2H),7.70(d,J＝8.4Hz,2H),7.40-7.32(m,2H),4.76(hept,J＝6.4Hz,1H),3.98(s,3H),1.55(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ12.39(s,1H),8.92(s,1H),8.28(s,1H),8.00-7.95(m,2H),7.92(d,J＝8.4Hz,2H ), 7.70(d, J=8.4Hz, 2H), 7.40-7.32(m, 2H), 4.76(hept, J=6.4Hz, 1H), 3.98(s, 3H), 1.55(d, J=6.4Hz ,6H).
实施例5：N-(4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物5)Example 5: N-(4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl) -1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 5)
Figure PCTCN2022109584-appb-000054
Figure PCTCN2022109584-appb-000054
将化合物T1(72mg,0.27mmol)、T7(83mg,0.27mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(160mg,0.40mmol)、N,N-二异丙基乙胺(106mg,0.81mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物5(37mg)。Compound T1 (72mg, 0.27mmol), T7 (83mg, 0.27mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (160mg, 0.40mmol), N,N-diisopropylethylamine (106mg, 0.81mmol) were added into N,N-dimethylformamide (5mL), and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 5 (37 mg).
MS m/z(ESI):515.2[M+H] +. MS m/z(ESI):515.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.29(s,1H),8.87(s,1H),8.30(s,1H),7.99-7.89(m,4H),7.70(d,J＝8.4Hz,2H),7.42-7.33(m,2H),4.58-4.47(m,2H),3.99(s,3H),3.85(t,J＝5.2Hz,2H),3.33(s,3H). 1 H NMR (400MHz,DMSO)δ12.29(s,1H),8.87(s,1H),8.30(s,1H),7.99-7.89(m,4H),7.70(d,J＝8.4Hz,2H ),7.42-7.33(m,2H),4.58-4.47(m,2H),3.99(s,3H),3.85(t,J=5.2Hz,2H),3.33(s,3H).
实施例6：N-(4-(4-氨基-1-(四氢呋喃-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物6)Example 6: N-(4-(4-amino-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4 -Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 6)
Figure PCTCN2022109584-appb-000055
Figure PCTCN2022109584-appb-000055
将化合物3-(4-氨基苯基)-1-(四氢呋喃-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(75mg,0.23mmol)、T5(66mg,0.23mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(132mg,0.34mmol)、N,N-二异丙基乙胺(90mg,0.68mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物6(30mg)。Compound 3-(4-aminophenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (75mg, 0.23mmol), T5 (66mg , 0.23mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (132mg, 0.34mmol), N,N-diiso Propylethylamine (90mg, 0.68mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 6 (30 mg).
MS m/z(ESI):555.2[M+H] +. MS m/z(ESI):555.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.42(s,1H),8.92(s,1H),8.28(s,1H),8.00-7.96(m,2H),7.93(d,J＝8.4Hz,2H),7.71(d,J＝8.4Hz,2H),7.35(dd,J＝12.4,5.6Hz,2H),5.56-5.50(m,1H),4.81-4.72(m,1H),4.18-4.08(m,2H),3.96(ddd,J＝21.6,12.0,5.6Hz,2H),2.44(q,J＝6.8Hz,2H),1.55(d,J＝6.8Hz,6H). 1 H NMR(400MHz,DMSO)δ12.42(s,1H),8.92(s,1H),8.28(s,1H),8.00-7.96(m,2H),7.93(d,J＝8.4Hz,2H ), 7.71(d, J=8.4Hz, 2H), 7.35(dd, J=12.4, 5.6Hz, 2H), 5.56-5.50(m, 1H), 4.81-4.72(m, 1H), 4.18-4.08( m, 2H), 3.96(ddd, J=21.6, 12.0, 5.6Hz, 2H), 2.44(q, J=6.8Hz, 2H), 1.55(d, J=6.8Hz, 6H).
实施例7：N-(4-(4-氨基-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物7)Example 7: N-(4-(4-amino-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 7)
Figure PCTCN2022109584-appb-000056
Figure PCTCN2022109584-appb-000056
将化合物3-(4-氨基苯基)-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(75mg,0.24mmol)、T7(74mg,0.24mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(140mg,0.36mmol)、N,N-二异丙基乙胺(95mg,0.72mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物7(44mg)。The compound 3-(4-aminophenyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (75mg, 0.24mmol), T7 (74mg, 0.24mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (140mg, 0.36mmol), N,N -Diisopropylethylamine (95mg, 0.72mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 7 (44 mg).
MS m/z(ESI):557.15[M+H] +. MS m/z(ESI):557.15[M+H] + .
1H NMR(400MHz,DMSO)δ12.33(s,1H),8.88(s,1H),8.28(s,1H),7.98-7.93(m,4H),7.77(d,J＝8.4Hz,2H),7.41-7.35(m,2H),6.10-6.00(m,1H),5.17-5.11(m,2H),5.03(t,J＝7.2Hz,2H),4.53(t,J＝5.2Hz,2H),3.85(t,J＝5.2Hz,2H),3.33(s,3H). 1 H NMR(400MHz,DMSO)δ12.33(s,1H),8.88(s,1H),8.28(s,1H),7.98-7.93(m,4H),7.77(d,J＝8.4Hz,2H ),7.41-7.35(m,2H),6.10-6.00(m,1H),5.17-5.11(m,2H),5.03(t,J＝7.2Hz,2H),4.53(t,J＝5.2Hz, 2H), 3.85(t, J=5.2Hz, 2H), 3.33(s, 3H).
实施例8：N-(4-(4-氨基-1-(四氢呋喃-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物8)Example 8: N-(4-(4-amino-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4 -Fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 8)
Figure PCTCN2022109584-appb-000057
Figure PCTCN2022109584-appb-000057
将化合物3-(4-氨基苯基)-1-(四氢呋喃-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(89mg,0.27mmol)、T7(83mg,0.27mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(157mg,0.41mmol)、N,N-二异丙基乙胺(107mg,0.81mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物8(60mg)。Compound 3-(4-aminophenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (89mg, 0.27mmol), T7 (83mg , 0.27mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (157mg, 0.41mmol), N,N-diiso Propylethylamine (107mg, 0.81mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 8 (60 mg).
MS m/z(ESI):571.1[M+H] +. MS m/z(ESI):571.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.32(s,1H),8.87(s,1H),8.28(s,1H),7.99-7.86(m,4H),7.71(d,J＝8.8Hz,2H),7.37(t,J＝8.8Hz,2H),5.59-5.47(m,1H),4.52(t,J＝4.8Hz,2H),4.19-4.03(m,2H),3.95 (ddd,J＝21.6,12.0,5.6Hz,2H),3.85(t,J＝5.2Hz,2H),3.33(d,J＝4.8Hz,3H),2.44(q,J＝6.8Hz,2H). 1 H NMR (400MHz,DMSO)δ12.32(s,1H),8.87(s,1H),8.28(s,1H),7.99-7.86(m,4H),7.71(d,J＝8.8Hz,2H ), 7.37(t, J=8.8Hz, 2H), 5.59-5.47(m, 1H), 4.52(t, J=4.8Hz, 2H), 4.19-4.03(m, 2H), 3.95 (ddd, J= 21.6, 12.0, 5.6Hz, 2H), 3.85(t, J=5.2Hz, 2H), 3.33(d, J=4.8Hz, 3H), 2.44(q, J=6.8Hz, 2H).
实施例9：N-(4-(4-氨基-1-异丁基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物9)Example 9: N-(4-(4-amino-1-isobutyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl )-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 9)
Figure PCTCN2022109584-appb-000058
Figure PCTCN2022109584-appb-000058
将化合物3-(4-氨基苯基)-1-异丁基-1H-吡唑并[3,4-d]嘧啶-4-基胺(80mg,0.26mmol)、T5(74mg,0.26mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(148mg,0.38mmol)、N,N-二异丙基乙胺(100mg,0.77mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物9(55mg)。Compound 3-(4-aminophenyl)-1-isobutyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (80mg, 0.26mmol), T5 (74mg, 0.26mmol) , 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (148mg, 0.38mmol), N,N-diisopropylethylamine (100mg, 0.77mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 9 (55 mg).
MS m/z(ESI):541.1[M+H] +. MS m/z(ESI):541.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.41(s,1H),8.92(s,1H),8.27(s,1H),8.01-7.95(m,2H),7.93(d,J＝8.4Hz,2H),7.71(d,J＝8.4Hz,2H),7.36(t,J＝8.8Hz,2H),4.82-4.74(m,1H),4.19(d,J＝7.2Hz,2H),2.30(dt,J＝13.6,6.8Hz,1H),1.55(d,J＝6.8Hz,6H),0.92(d,J＝6.8Hz,6H). 1 H NMR(400MHz,DMSO)δ12.41(s,1H),8.92(s,1H),8.27(s,1H),8.01-7.95(m,2H),7.93(d,J＝8.4Hz,2H ), 7.71(d, J=8.4Hz, 2H), 7.36(t, J=8.8Hz, 2H), 4.82-4.74(m, 1H), 4.19(d, J=7.2Hz, 2H), 2.30(dt ,J=13.6,6.8Hz,1H),1.55(d,J=6.8Hz,6H),0.92(d,J=6.8Hz,6H).
实施例10：N-(4-(4-氨基-1-异丁基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物10)Example 10: N-(4-(4-amino-1-isobutyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl )-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 10)
Figure PCTCN2022109584-appb-000059
Figure PCTCN2022109584-appb-000059
将化合物3-(4-氨基苯基)-1-异丁基-1H-吡唑并[3,4-d]嘧啶-4-基胺(80mg,0.26mmol)、T7(78mg,0.26mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(148mg,0.38mmol)、N,N-二异丙基乙胺(100mg,0.77mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物10(70mg)。Compound 3-(4-aminophenyl)-1-isobutyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (80mg, 0.26mmol), T7 (78mg, 0.26mmol) , 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (148mg, 0.38mmol), N,N-diisopropylethylamine (100mg, 0.77mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 10 (70 mg).
MS m/z(ESI):557.2[M+H] +. MS m/z(ESI):557.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.30(s,1H),8.87(s,1H),8.27(s,1H),7.97-7.90(m,4H),7.71(d,J＝8.4Hz,2H),7.40-7.34(m,2H),4.52(t,J＝4.8Hz,2H),4.19(d,J＝7.2Hz,2H),3.85(t,J＝4.8Hz,2H),3.33-3.30(m,3H),2.36-2.24(m,1H),0.92(d,J＝6.8Hz,6H). 1 H NMR(400MHz,DMSO)δ12.30(s,1H),8.87(s,1H),8.27(s,1H),7.97-7.90(m,4H),7.71(d,J＝8.4Hz,2H ),7.40-7.34(m,2H),4.52(t,J=4.8Hz,2H),4.19(d,J=7.2Hz,2H),3.85(t,J=4.8Hz,2H),3.33-3.30 (m,3H),2.36-2.24(m,1H),0.92(d,J=6.8Hz,6H).
实施例11：N-(4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丁基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物11)Example 11: N-(4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl) -1-isobutyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 11)
Figure PCTCN2022109584-appb-000060
Figure PCTCN2022109584-appb-000060
将化合物T4(45mg,0.15mmol)和T1(45mg,0.18mmol)加入到N,N-二甲基甲酰胺(4mL)中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(89mg,0.23mmol)、N,N-二异丙基乙胺(60mg,0.46mmol)，于20℃反应2小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物11(10mg)。Compound T4 (45mg, 0.15mmol) and T1 (45mg, 0.18mmol) were added to N,N-dimethylformamide (4mL), and then 2-(7-azobenzotriazole)-N , N,N',N'-tetramethyluronium hexafluorophosphate (89mg, 0.23mmol), N,N-diisopropylethylamine (60mg, 0.46mmol), react at 20°C for 2 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 11 (10 mg).
MS m/z(ESI):513.2[M+H] +. MS m/z(ESI):513.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.33(s,1H),8.94(s,1H),8.29(s,1H),8.07-7.86(m,4H),7.71(d,J＝8.0Hz,2H),7.37(s,2H),4.16(s,2H),3.98(s,3H),2.30(s,1H),0.99(d,J＝4.0Hz,6H). 1 H NMR(400MHz,DMSO)δ12.33(s,1H),8.94(s,1H),8.29(s,1H),8.07-7.86(m,4H),7.71(d,J＝8.0Hz,2H ),7.37(s,2H),4.16(s,2H),3.98(s,3H),2.30(s,1H),0.99(d,J=4.0Hz,6H).
实施例12：N-(-(4-氨基-1-(四氢呋喃-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丁 基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物12)Example 12: N-(-(4-amino-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4- Fluorophenyl)-1-isobutyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 12)
Figure PCTCN2022109584-appb-000061
Figure PCTCN2022109584-appb-000061
将化合物T4(60mg,0.21mmol)和化合物3-(4-氨基苯基)-1-(四氢呋喃-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(74mg,0.25mmol)加入到N,N-二甲基甲酰胺(4mL)中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(119mg,0.31mmol)、N,N-二异丙基乙胺(80mg,0.61mmol)，于20℃反应2小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物12(25mg)。Compound T4 (60mg, 0.21mmol) and compound 3-(4-aminophenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine ( 74mg, 0.25mmol) was added to N,N-dimethylformamide (4mL), and then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (119mg, 0.31mmol) and N,N-diisopropylethylamine (80mg, 0.61mmol) were reacted at 20°C for 2 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 12 (25 mg).
MS m/z(ESI):569.2[M+H] +. MS m/z(ESI):569.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.37(s,1H),8.95(s,1H),8.29(s,1H),7.97-7.97(m,4H),7.71(d,J＝8.0Hz,2H),7.48-7.26(m,2H),5.55-5.52(m,1H),4.27-4.04(m,4H),4.04-3.85(m,2H),2.47-2.41(m,2H),2.30-2.29(m,1H),1.37(t,J＝8.0Hz,1H),0.99-0.95(m,7H). 1 H NMR(400MHz,DMSO)δ12.37(s,1H),8.95(s,1H),8.29(s,1H),7.97-7.97(m,4H),7.71(d,J＝8.0Hz,2H ),7.48-7.26(m,2H),5.55-5.52(m,1H),4.27-4.04(m,4H),4.04-3.85(m,2H),2.47-2.41(m,2H),2.30-2.29 (m,1H),1.37(t,J=8.0Hz,1H),0.99-0.95(m,7H).
实施例13：N-(4-(4-氨基-1-异丁基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丁基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物13)Example 13: N-(4-(4-amino-1-isobutyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl )-1-isobutyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 13)
Figure PCTCN2022109584-appb-000062
Figure PCTCN2022109584-appb-000062
将化合物T4(60mg,0.21mmol)和化合物3-(4-氨基苯基)-1-异丁基-1H-吡唑并[3,4-d]嘧啶-4-基胺(74mg,0.25mmol)加入到N,N-二甲基甲酰胺(4mL)中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(119mg,0.31mmol)、N,N-二异丙基乙胺(80mg,0.61mmol)，于20℃反应2小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物13(28mg)。Compound T4 (60mg, 0.21mmol) and compound 3-(4-aminophenyl)-1-isobutyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (74mg, 0.25mmol ) into N,N-dimethylformamide (4mL), then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphoric acid Ester (119mg, 0.31mmol), N,N-diisopropylethylamine (80mg, 0.61mmol), react at 20°C for 2 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 13 (28 mg).
MS m/z(ESI):555.2[M+H] +. MS m/z(ESI):555.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.35(s,1H),8.95(s,1H),8.27(s,1H),8.04-7.84(m,4H),7.71(d,J＝8.0Hz,2H),7.39-7.35(m,2H),4.20-4.16(m,4H),2.31(s,2H),0.99(d,J＝8.0Hz,6H),0.92(d,J＝8.0Hz,6H). 1 H NMR (400MHz,DMSO)δ12.35(s,1H),8.95(s,1H),8.27(s,1H),8.04-7.84(m,4H),7.71(d,J＝8.0Hz,2H ),7.39-7.35(m,2H),4.20-4.16(m,4H),2.31(s,2H),0.99(d,J＝8.0Hz,6H),0.92(d,J＝8.0Hz,6H) .
实施例14：N-(4-(4-氨基-1-(四氢呋喃-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢哒嗪-3-甲酰胺(化合物14)Example 14: N-(4-(4-amino-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4 -Fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridazine-3-carboxamide (compound 14)
Figure PCTCN2022109584-appb-000063
Figure PCTCN2022109584-appb-000063
将化合物T8(67mg,0.21mmol)和化合物3-(4-氨基苯基)-1-(四氢呋喃-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(74mg,0.25mmol)加入到N,N-二甲基甲酰胺(4mL)中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(119mg,0.31mmol)、N,N-二异丙基乙胺(80mg,0.61mmol)，于20℃反应2小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物14(25mg)。Compound T8 (67mg, 0.21mmol) and compound 3-(4-aminophenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine ( 74mg, 0.25mmol) was added to N,N-dimethylformamide (4mL), and then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (119mg, 0.31mmol) and N,N-diisopropylethylamine (80mg, 0.61mmol) were reacted at 20°C for 2 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 14 (25 mg).
MS m/z(ESI):597.2[M+H] +. MS m/z(ESI):597.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.31(s,1H),8.96(s,1H),8.25(s,1H),7.96-7.88(m,4H),7.68(d,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,2H),5.53-5.47(m,1H),4.33(d,J＝8.0Hz,2H),4.13-4.06(m,2H),3.97-3.74(m,4H),3.70-3.56(m,2H),2.91-2.84(m,1H),2.44-2.39(m,2H),2.05-1.97(m,2H). 1 H NMR(400MHz,DMSO)δ12.31(s,1H),8.96(s,1H),8.25(s,1H),7.96-7.88(m,4H),7.68(d,J＝8.0Hz,2H ),7.34(t,J=8.0Hz,2H),5.53-5.47(m,1H),4.33(d,J=8.0Hz,2H),4.13-4.06(m,2H),3.97-3.74(m, 4H),3.70-3.56(m,2H),2.91-2.84(m,1H),2.44-2.39(m,2H),2.05-1.97(m,2H).
实施例15：N-(4-(4-氨基-1-异丁基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢哒嗪-3-甲酰胺(化合物15)Example 15: N-(4-(4-amino-1-isobutyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl )-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridazine-3-carboxamide (compound 15)
Figure PCTCN2022109584-appb-000064
Figure PCTCN2022109584-appb-000064
将化合物T8(60mg,0.21mmol)和化合物3-(4-氨基苯基)-1-异丁基-1H-吡唑并[3,4-d]嘧啶-4-基胺(74mg,0.25mmol)加入到N,N-二甲基甲酰胺(4mL)中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(119mg,0.31mmol)、N,N-二异丙基乙胺(80mg,0.61mmol)，于20℃反应2小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物15(27mg)。Compound T8 (60mg, 0.21mmol) and compound 3-(4-aminophenyl)-1-isobutyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (74mg, 0.25mmol ) into N,N-dimethylformamide (4mL), then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphoric acid Ester (119mg, 0.31mmol), N,N-diisopropylethylamine (80mg, 0.61mmol), react at 20°C for 2 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 15 (27 mg).
MS m/z(ESI):583.3[M+H] +. MS m/z(ESI):583.3[M+H] + .
1H NMR(400MHz,DMSO)δ12.36(s,1H),9.02(s,1H),8.30(s,1H),8.03-7.99(m,2H),7.95(d,J＝8.0Hz,2H),7.74(t,J＝8.0Hz,2H),4.39(d,J＝8.0Hz,2H),4.22(d,J＝8.0Hz,2H),3.91-3.81(m,2H),3.76-3.62(m,2H),2.97-2.90(m,1H),2.39-2.29(m,1H),2.11-2.03(m,1H),1.82-1.74(m,1H),0.95(d,J＝8.0Hz,6H). 1 H NMR (400MHz,DMSO)δ12.36(s,1H),9.02(s,1H),8.30(s,1H),8.03-7.99(m,2H),7.95(d,J＝8.0Hz,2H ), 7.74(t, J=8.0Hz, 2H), 4.39(d, J=8.0Hz, 2H), 4.22(d, J=8.0Hz, 2H), 3.91-3.81(m, 2H), 3.76-3.62 (m,2H),2.97-2.90(m,1H),2.39-2.29(m,1H),2.11-2.03(m,1H),1.82-1.74(m,1H),0.95(d,J＝8.0Hz ,6H).
实施例16：N-(4-(4-氨基-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢哒嗪-3-甲酰胺(化合物16)Example 16: N-(4-(4-Amino-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridazine-3-carboxamide (compound 16)
Figure PCTCN2022109584-appb-000065
Figure PCTCN2022109584-appb-000065
将化合物T8(61mg,0.21mmol)和化合物3-(4-氨基苯基)-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(74mg,0.25mmol)加入到N,N-二甲基甲酰胺(4mL)中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(119mg,0.31mmol)、N,N-二异丙基乙胺(80mg,0.61mmol)，于20℃反应2小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物16(23mg)。Compound T8 (61mg, 0.21mmol) and compound 3-(4-aminophenyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4- Baseamine (74mg, 0.25mmol) was added to N,N-dimethylformamide (4mL), and then 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (119mg, 0.31mmol) and N,N-diisopropylethylamine (80mg, 0.61mmol) were reacted at 20°C for 2 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 16 (23 mg).
MS m/z(ESI):583.1[M+H] +. MS m/z(ESI):583.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.31(s,1H),8.96(s,1H),8.24(s,1H),7.95-7.90(m,4H),7.74-7.71(m,2H),7.33(t,J＝8.0Hz,2H),6.04-5.97(m,1H),5.11-5.08(m,2H),4.98(t,J＝8.0Hz,2H),4.32(d,J＝8.0Hz,2H),3.84-3.77(m,2H),3.69-3.63(m,1H),3.59-3.55(m,1H),2.90-2.83(m,1H),2.02-1.96(m,1H),1.75-1.66(m,1H). 1 H NMR (400MHz,DMSO)δ12.31(s,1H),8.96(s,1H),8.24(s,1H),7.95-7.90(m,4H),7.74-7.71(m,2H),7.33 (t,J=8.0Hz,2H),6.04-5.97(m,1H),5.11-5.08(m,2H),4.98(t,J=8.0Hz,2H),4.32(d,J=8.0Hz, 2H),3.84-3.77(m,2H),3.69-3.63(m,1H),3.59-3.55(m,1H),2.90-2.83(m,1H),2.02-1.96(m,1H),1.75- 1.66(m,1H).
实施例17：N-(4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-(四氢呋喃-3-基甲基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物17)Example 17: N-(4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl) -1-(tetrahydrofuran-3-ylmethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 17)
Figure PCTCN2022109584-appb-000066
Figure PCTCN2022109584-appb-000066
将化合物T8(46mg,0.15mmol)和化合物T1(45mg,0.18mmol)加入到N,N-二甲基甲酰胺(4mL)中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(119mg,0.31mmol)、N,N-二异丙基乙胺(80mg,0.61mmol)，于20℃反应2小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物17(20mg)。Compound T8 (46mg, 0.15mmol) and compound T1 (45mg, 0.18mmol) were added to N,N-dimethylformamide (4mL), and then 2-(7-azobenzotriazole)- N,N,N',N'-Tetramethyluronium hexafluorophosphate (119mg, 0.31mmol), N,N-diisopropylethylamine (80mg, 0.61mmol) were reacted at 20°C for 2 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 17 (20 mg).
MS m/z(ESI):513.2[M+H] +. MS m/z(ESI):513.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.34(s,1H),9.01(s,1H),8.32(s,1H),8.02-7.94(m,4H),7.73(d,J＝8.0Hz,2H),7.40(t,J＝8.0Hz,2H),4.39-4.38(m,2H),4.01(s,3H),3.91-3.80(m,2H),3.76-3.62(m,2H),2.97-2.90(m,1H),2.11-2.03(m,1H),1.82-1.73(m,1H) 1 H NMR(400MHz,DMSO)δ12.34(s,1H),9.01(s,1H),8.32(s,1H),8.02-7.94(m,4H),7.73(d,J＝8.0Hz,2H ),7.40(t,J＝8.0Hz,2H),4.39-4.38(m,2H),4.01(s,3H),3.91-3.80(m,2H),3.76-3.62(m,2H),2.97- 2.90(m,1H),2.11-2.03(m,1H),1.82-1.73(m,1H)
实施例18：N-(4-(4-氨基-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物18)Example 18: N-(4-(4-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl )-5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 18)
Figure PCTCN2022109584-appb-000067
Figure PCTCN2022109584-appb-000067
将化合物3-(4-氨基苯基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(40mg,0.12mmol)、T7(36mg,0.12mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(67mg,0.15mmol)、N,N-二异丙基乙胺(46mg,0.35mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物18(28mg)。Compound 3-(4-aminophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40mg, 0.12 mmol), T7 (36mg, 0.12mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (67mg, 0.15mmol), N,N-Diisopropylethylamine (46mg, 0.35mmol) was added into N,N-dimethylformamide (5mL), and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 18 (28 mg).
MS m/z(ESI):585.2[M+H] +. MS m/z(ESI):585.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.31(s,1H),8.87(s,1H),8.28(s,1H),7.99-7.90(m,5H),7.71(d,J＝8.4Hz,2H),7.37(t,J＝8.8Hz,2H),5.02-4.93(m,1H),4.52(t,J＝4.8Hz,2H),4.04(d,J＝8.0Hz,2H),3.85(t,J＝4.8Hz,2H),3.58(t,J＝11.6Hz,2H),3.33(s,3H),2.25(qd,J＝12.4,4.4Hz,2H),1.92(d,J＝10.4Hz,2H). 1 H NMR(400MHz,DMSO)δ12.31(s,1H),8.87(s,1H),8.28(s,1H),7.99-7.90(m,5H),7.71(d,J＝8.4Hz,2H ), 7.37(t, J=8.8Hz, 2H), 5.02-4.93(m, 1H), 4.52(t, J=4.8Hz, 2H), 4.04(d, J=8.0Hz, 2H), 3.85(t ,J=4.8Hz,2H),3.58(t,J=11.6Hz,2H),3.33(s,3H),2.25(qd,J=12.4,4.4Hz,2H),1.92(d,J=10.4Hz ,2H).
实施例19：N-(4-(4-氨基-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物19)Example 19: N-(4-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 19)
Figure PCTCN2022109584-appb-000068
Figure PCTCN2022109584-appb-000068
将化合物3-(4-氨基苯基)-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(37mg,0.12mmol)、T7(36mg,0.12mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(67mg,0.15mmol)、N,N-二异丙基乙胺(46mg,0.35mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物19(18mg)。The compound 3-(4-aminophenyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (37mg, 0.12mmol), T7 (36mg, 0.12mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (67mg, 0.15mmol), N,N -Diisopropylethylamine (46mg, 0.35mmol) was added to N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 19 (18 mg).
MS m/z(ESI):564.2[M+H] +. MS m/z(ESI):564.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.23(s,1H),8.87(s,1H),8.21(s,1H),7.95(dd,J＝8.4,5.6Hz,2H),7.87(d,J＝8.4Hz,2H),7.51(d,J＝8.4Hz,2H),7.38(t,J＝8.8Hz,3H),6.60(s,1H),6.46(s,1H),6.32(s,1H),4.68(dd,J＝15.6,12.4Hz,2H),4.52(t,J＝4.8Hz,2H),3.85(t,J＝5.2Hz,2H),3.33(s,3H). 1 H NMR (400MHz,DMSO)δ12.23(s,1H),8.87(s,1H),8.21(s,1H),7.95(dd,J=8.4,5.6Hz,2H),7.87(d,J =8.4Hz, 2H), 7.51(d, J=8.4Hz, 2H), 7.38(t, J=8.8Hz, 3H), 6.60(s, 1H), 6.46(s, 1H), 6.32(s, 1H ), 4.68(dd, J=15.6, 12.4Hz, 2H), 4.52(t, J=4.8Hz, 2H), 3.85(t, J=5.2Hz, 2H), 3.33(s, 3H).
实施例20：N-(4-(4-氨基-7-(2,2,2-三氟-1-甲基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物20)Example 20: N-(4-(4-amino-7-(2,2,2-trifluoro-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl )phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 20)
Figure PCTCN2022109584-appb-000069
Figure PCTCN2022109584-appb-000069
称取化合物5-(4-氨基苯基)-7-(1,1,1-三氟丙烷-2-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(64mg,180μmol)、T5(55mg,180μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(138mg,360μmol)、N,N-二异丙基乙胺(23mg,80μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物20(15mg)。Weigh compound 5-(4-aminophenyl)-7-(1,1,1-trifluoropropane-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (64mg , 180μmol), T5 (55mg, 180μmol) were dissolved in N,N-dimethylformamide (2mL), added 2-(7-azabenzotriazole)-N,N,N',N' -Tetramethylurea hexafluorophosphate (138 mg, 360 μmol), N,N-diisopropylethylamine (23 mg, 80 μmol), stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 20 (15 mg).
MS m/z(ESI):580.1[M+H] +. MS m/z(ESI):580.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.35(s,1H),8.93(s,1H),8.23(s,1H),7.98(dd,J＝8.8,5.6Hz,2H),7.88(d,J＝8.4Hz,2H),7.61(s,1H),7.54(d,J＝8.4Hz,2H),7.37(t,J＝8.8Hz,2H),5.70(d,J＝7.2Hz,1H),4.82-4.72(m,1H),3.33(s,3H),1.78(d,J＝7.2Hz,3H),1.55(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ12.35(s,1H),8.93(s,1H),8.23(s,1H),7.98(dd,J＝8.8,5.6Hz,2H),7.88(d,J =8.4Hz, 2H), 7.61(s, 1H), 7.54(d, J=8.4Hz, 2H), 7.37(t, J=8.8Hz, 2H), 5.70(d, J=7.2Hz, 1H), 4.82-4.72(m,1H),3.33(s,3H),1.78(d,J=7.2Hz,3H),1.55(d,J=6.4Hz,6H).
实施例21：N-(4-(4-氨基-1-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物21)Example 21: N-(4-(4-amino-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl) Phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 21)
Figure PCTCN2022109584-appb-000070
Figure PCTCN2022109584-appb-000070
称取化合物3-(4-氨基苯基)-1-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(58mg,172μmol)、T5(50mg,172μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99mg,257μmol)、N,N-二异丙基乙胺(45mg,343μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物21(24mg)。Weigh compound 3-(4-aminophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine ( 58mg, 172μmol), T5 (50mg, 172μmol) were dissolved in N,N-dimethylformamide (2mL), added 2-(7-azabenzotriazole)-N,N,N',N '-Tetramethylurea hexafluorophosphate (99mg, 257μmol), N,N-diisopropylethylamine (45mg, 343μmol), stirred at 25°C for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 21 (24 mg).
MS m/z(ESI):581.1[M+H] +. MS m/z(ESI):581.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.43(s,1H),8.94(s,1H),8.34(s,1H),8.01-7.93(m,4H),7.72(d,J＝8.4Hz,2H),7.37(t,J＝8.8Hz,2H),5.79-5.69(m,1H),4.82-4.72(m,1H),1.82(d,J＝7.2Hz,3H),1.55(d,J＝6.4Hz,6H). 1 H NMR(400MHz,DMSO)δ12.43(s,1H),8.94(s,1H),8.34(s,1H),8.01-7.93(m,4H),7.72(d,J＝8.4Hz,2H ), 7.37(t, J=8.8Hz, 2H), 5.79-5.69(m, 1H), 4.82-4.72(m, 1H), 1.82(d, J=7.2Hz, 3H), 1.55(d, J= 6.4Hz,6H).
实施例22：N-[4-[4-氨基-7-(2-氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基]苯基]-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物22)Example 22: N-[4-[4-amino-7-(2-fluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]-5-(4- Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 22)
Figure PCTCN2022109584-appb-000071
Figure PCTCN2022109584-appb-000071
称取化合物5-(4-氨基苯基)-7-(2-氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(84mg,295μmol)、T5(69mg,236μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(134mg,353μmol)、N,N-二异丙基乙胺(38mg,295μmol)，于25℃搅拌2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水水洗，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆得标题化合物22(20mg)。Weigh the compound 5-(4-aminophenyl)-7-(2-fluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (84mg, 295μmol), T5 (69mg, 236μmol) was dissolved in N,N-dimethylformamide (2mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added Ester (134 mg, 353 μmol), N,N-diisopropylethylamine (38 mg, 295 μmol), stirred at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was slurried with methanol to obtain the title compound 22 (20 mg).
MS m/z(ESI):530.2[M+H] +. MS m/z(ESI):530.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.32(s,1H),8.93(s,1H),8.19(s,1H),7.99-7.96(m,2H),7.86(d,J＝8.0Hz,2H),7.50(d,J＝8.0Hz,2H),7.40-7.34(m,3H),4.90-4.88(m,1H),4.80-4.73(m,2H),4.55(t,J＝4.8Hz,1H),4.49(t,J＝4.8Hz,1H),1.55(d,J＝8.0Hz,6H). 1 H NMR (400MHz,DMSO)δ12.32(s,1H),8.93(s,1H),8.19(s,1H),7.99-7.96(m,2H),7.86(d,J＝8.0Hz,2H ),7.50(d,J=8.0Hz,2H),7.40-7.34(m,3H),4.90-4.88(m,1H),4.80-4.73(m,2H),4.55(t,J=4.8Hz, 1H), 4.49(t, J=4.8Hz, 1H), 1.55(d, J=8.0Hz, 6H).
实施例23：N-(4-(4-氨基-7-(2,2-二氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物23)Example 23: N-(4-(4-amino-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5- (4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 23)
Figure PCTCN2022109584-appb-000072
Figure PCTCN2022109584-appb-000072
将化合物5-(4-氨基苯基)-7-(2,2-二氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(130mg,0.35mmol)、T5(102mg,0.12mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(67mg,0.15mmol)、N,N-二异丙基乙胺(46mg,0.35mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物23(40mg)。Compound 5-(4-aminophenyl)-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (130mg, 0.35mmol), T5 (102mg, 0.12mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (67mg, 0.15mmol), N,N- Diisopropylethylamine (46mg, 0.35mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 23 (40 mg).
MS m/z(ESI):548.2[M+H] +. MS m/z(ESI):548.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.34(s,1H),8.93(s,1H),8.21(s,1H),7.98(dd,J＝8.8,5.6Hz,2H),7.87(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,2H),7.37(dd,J＝11.6,6.4Hz,3H),4.81-4.62(m,3H),1.55(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ12.34(s,1H),8.93(s,1H),8.21(s,1H),7.98(dd,J=8.8,5.6Hz,2H),7.87(d,J =8.4Hz, 2H), 7.50(d, J=8.4Hz, 2H), 7.37(dd, J=11.6, 6.4Hz, 3H), 4.81-4.62(m, 3H), 1.55(d, J=6.4Hz ,6H).
实施例24：N-(4-(4-氨基-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物24)Example 24: N-(4-(4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) -5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 24)
Figure PCTCN2022109584-appb-000073
Figure PCTCN2022109584-appb-000073
将化合物5-(4-氨基苯基)-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(13mg,0.038mmol)、T7(12mg,0.038mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(23mg,0.058mmol)、N,N-二异丙基乙胺(15mg,0.12mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆分离得标题化合物24(13mg)。Compound 5-(4-aminophenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (13mg, 0.038mmol ), T7 (12mg, 0.038mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23mg, 0.058mmol), N , N-Diisopropylethylamine (15mg, 0.12mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by methanol beating to obtain the title compound 24 (13 mg).
MS m/z(ESI):584.2[M+H] +. MS m/z(ESI):584.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.24(s,1H),8.87(s,1H),8.17(s,1H),7.97-7.92(m,2H),7.85(d,J＝8.4Hz,2H),7.54-7.49(m,3H),7.41-7.35(m,2H),4.87(tt,J＝12.0,4.0Hz,1H),4.52(t,J＝4.8Hz,2H),4.03(dd,J＝11.2,4.0Hz,2H),3.84(t,J＝4.8Hz,2H),3.60-3.51(m,2H),3.32(s,3H),2.15(qd,J＝12.4,3.6Hz,2H),1.96-1.86(m,2H). 1 H NMR(400MHz,DMSO)δ12.24(s,1H),8.87(s,1H),8.17(s,1H),7.97-7.92(m,2H),7.85(d,J＝8.4Hz,2H ),7.54-7.49(m,3H),7.41-7.35(m,2H),4.87(tt,J=12.0,4.0Hz,1H),4.52(t,J=4.8Hz,2H),4.03(dd, J＝11.2, 4.0Hz, 2H), 3.84(t, J＝4.8Hz, 2H), 3.60-3.51(m, 2H), 3.32(s, 3H), 2.15(qd, J＝12.4, 3.6Hz, 2H ),1.96-1.86(m,2H).
实施例25：N-(4-(4-氨基-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物25)Example 25: N-(4-(4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) -5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 25)
Figure PCTCN2022109584-appb-000074
Figure PCTCN2022109584-appb-000074
称取化合物5-(4-氨基苯基)-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(6mg,19μmol)、T5(6mg,19μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(15mg,39μmol)、N,N-二异丙基乙胺(6mg,48μmol)，在25℃下搅拌10分钟。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物25(5mg)。Weigh compound 5-(4-aminophenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (6mg, 19μmol ), T5 (6 mg, 19 μmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (15 mg, 39 μmol) and N,N-diisopropylethylamine (6 mg, 48 μmol) were stirred at 25° C. for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 25 (5 mg).
MS m/z(ESI):568.2[M+H] +. MS m/z(ESI):568.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.31(s,1H),8.90(s,1H),8.14(s,1H),7.97-7.93(m,2H),7.83(d,J＝8.4Hz,2H),7.50(d,J＝4.8Hz,2H),7.47(s,1H),7.34(t,J＝8.8Hz,2H),4.75-4.72(m,1H),4.00(d,J＝8Hz,2H),3.53(t,J＝12Hz,2H),3.30(m,1H),2.12(m,1H),1.87(d,J＝12Hz,2H),1.52(d,J＝8Hz,6H). 1 H NMR(400MHz,DMSO)δ12.31(s,1H),8.90(s,1H),8.14(s,1H),7.97-7.93(m,2H),7.83(d,J＝8.4Hz,2H ),7.50(d,J=4.8Hz,2H),7.47(s,1H),7.34(t,J=8.8Hz,2H),4.75-4.72(m,1H),4.00(d,J=8Hz, 2H), 3.53(t, J=12Hz, 2H), 3.30(m, 1H), 2.12(m, 1H), 1.87(d, J=12Hz, 2H), 1.52(d, J=8Hz, 6H).
实施例26：N-[4-[4-氨基-1-(2-氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基]苯基]-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物26)Example 26: N-[4-[4-amino-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-5-(4 -Fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 26)
Figure PCTCN2022109584-appb-000075
Figure PCTCN2022109584-appb-000075
称取化合物3-(4-氨基苯基)-1-(2-氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(100mg,349μmol)、T5(81mg,279μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(159mg,419μmol)、N,N-二异丙基乙胺(90mg,697μmol)，于25℃搅拌2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相。用饱和食盐水水洗，用无水硫酸钠干燥，浓缩，粗品经制备HPLC分离得标题化合物26(86mg)。Weigh the compound 3-(4-aminophenyl)-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (100mg, 349μmol), T5 (81mg ,279μmol) was dissolved in N,N-dimethylformamide (4mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluoro Phosphate ester (159 mg, 419 μmol), N,N-diisopropylethylamine (90 mg, 697 μmol), stirred at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phases were combined. Washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by preparative HPLC to obtain the title compound 26 (86 mg).
MS m/z(ESI):531.2[M+H] +. MS m/z(ESI):531.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.39(s,1H),8.93(s,1H),8.29(s,1H),7.99-7.96(m,2H),7.95-7.92(m,2H),7.72(d,J＝8.0Hz,2H),7.40-7.34(m,2H),4.97(t,J＝4.8Hz,1H),4.86(t,J＝4.8Hz,1H),4.80-7.75(m,1H),4.72(t,J＝4.8Hz,1H),4.65(t,J＝4.8Hz,1H),1.55(d,J＝8.0Hz,6H). 1 H NMR (400MHz,DMSO)δ12.39(s,1H),8.93(s,1H),8.29(s,1H),7.99-7.96(m,2H),7.95-7.92(m,2H),7.72 (d, J=8.0Hz, 2H), 7.40-7.34(m, 2H), 4.97(t, J=4.8Hz, 1H), 4.86(t, J=4.8Hz, 1H), 4.80-7.75(m, 1H), 4.72(t, J=4.8Hz, 1H), 4.65(t, J=4.8Hz, 1H), 1.55(d, J=8.0Hz, 6H).
实施例27：N-[4-[4-氨基-1-(2-氟乙基)吡唑并[3,4-d]嘧啶-3-基]苯基]-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物27)Example 27: N-[4-[4-amino-1-(2-fluoroethyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-5-(4-fluorobenzene Base)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 27)
Figure PCTCN2022109584-appb-000076
Figure PCTCN2022109584-appb-000076
称取化合物3-(4-氨基苯基)-1-(2-氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(100mg,349μmol)、T7(86mg,279μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入N,N-二异丙基乙胺(90mg,697μmol)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(134mg,353μmol)，于25℃搅拌2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相。用饱和食盐水水洗，用无水硫酸钠干燥，浓缩，粗品经柱层析分离得标题化合物27(38mg)。Weigh compound 3-(4-aminophenyl)-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (100mg, 349μmol), T7 (86mg ,279μmol) was dissolved in N,N-dimethylformamide (4mL), N,N-diisopropylethylamine (90mg, 697μmol), 2-(7-azabenzotriazole)- N,N,N',N'-Tetramethylurea hexafluorophosphate (134 mg, 353 μmol), stirred at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phases were combined. Washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to obtain the title compound 27 (38 mg).
MS m/z(ESI):547.1[M+H] +. MS m/z(ESI):547.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.30(s,1H),8.88(s,1H),8.29(s,1H),7.97-7.92(m,4H),7.72(d,J＝8.0Hz,2H),7.40-7.36(m,2H),4.97(t,J＝4.8Hz,1H),4.86(t,J＝4.8Hz,1H),4.72(t,J＝4.8Hz,1H),4.65(t,J＝4.8Hz,1H),4.52(t,J＝4.8Hz,2H),3.84(t,J＝4.8Hz,2H),3.32(s,3H). 1 H NMR (400MHz,DMSO)δ12.30(s,1H),8.88(s,1H),8.29(s,1H),7.97-7.92(m,4H),7.72(d,J＝8.0Hz,2H ), 7.40-7.36(m, 2H), 4.97(t, J=4.8Hz, 1H), 4.86(t, J=4.8Hz, 1H), 4.72(t, J=4.8Hz, 1H), 4.65(t ,J=4.8Hz,1H),4.52(t,J=4.8Hz,2H),3.84(t,J=4.8Hz,2H),3.32(s,3H).
实施例28：N-(4-(4-氨基-7-(1,1,1-三氟丙烷-2-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物28)Example 28: N-(4-(4-amino-7-(1,1,1-trifluoropropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzene Base)-5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 28)
Figure PCTCN2022109584-appb-000077
Figure PCTCN2022109584-appb-000077
称取化合物5-(4-氨基苯基)-7-(1,1,1-三氟丙烷-2-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(52mg,162μmol)、T5(50mg,162μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(93mg,243μmol)、N,N-二异丙基乙胺(42mg,325μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物28(6mg)。Weigh compound 5-(4-aminophenyl)-7-(1,1,1-trifluoropropane-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (52mg , 162μmol), T5 (50mg, 162μmol) were dissolved in N,N-dimethylformamide (2mL), added 2-(7-azabenzotriazole)-N,N,N',N' -Tetramethylurea hexafluorophosphate (93 mg, 243 μmol), N,N-diisopropylethylamine (42 mg, 325 μmol), stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 28 (6 mg).
MS m/z(ESI):596.1[M+H] +. MS m/z(ESI):596.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.25(s,1H),8.88(s,1H),8.23(s,1H),7.95(dd,J＝8.8,5.6Hz,2H),7.87(d,J＝8.4Hz,2H),7.61(s,1H),7.53(d,J＝8.4Hz,2H),7.38(t,J＝8.8Hz,2H),4.52(t,J＝4.8Hz,2H),3.84(t,J＝4.8Hz,2H),3.32(s,3H),1.78(d,J＝7.2Hz,3H). 1 H NMR (400MHz,DMSO)δ12.25(s,1H),8.88(s,1H),8.23(s,1H),7.95(dd,J=8.8,5.6Hz,2H),7.87(d,J =8.4Hz, 2H), 7.61(s, 1H), 7.53(d, J=8.4Hz, 2H), 7.38(t, J=8.8Hz, 2H), 4.52(t, J=4.8Hz, 2H), 3.84(t, J=4.8Hz, 2H), 3.32(s, 3H), 1.78(d, J=7.2Hz, 3H).
实施例29：N-(4-(4-氨基-1-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物29)Example 29: N-(4-(4-amino-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl) Phenyl)-5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 29)
Figure PCTCN2022109584-appb-000078
Figure PCTCN2022109584-appb-000078
称取化合物3-(4-氨基苯基)-1-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(69mg,195μmol)、T5(60mg,195μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(112mg,292μmol)、N,N-二异丙基乙胺(51mg,390μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物29(34mg)。Weigh compound 3-(4-aminophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine ( 69mg, 195μmol), T5 (60mg, 195μmol) were dissolved in N,N-dimethylformamide (2mL), added 2-(7-azabenzotriazole)-N,N,N',N '-Tetramethylurea hexafluorophosphate (112mg, 292μmol), N,N-diisopropylethylamine (51mg, 390μmol), stirred at 25°C for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 29 (34 mg).
MS m/z(ESI):597.1[M+H] +. MS m/z(ESI):597.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.33(s,1H),8.89(s,1H),8.34(s,1H),7.94(d,J＝8.4Hz,4H),7.72(d,J＝8.4Hz,2H),7.38(t,J＝8.8Hz,2H),4.52(t,J＝4.8Hz,2H),3.85(d,J＝5.2Hz,2H),3.32(s,3H),1.81(d,J＝7.2Hz,3H). 1 H NMR(400MHz,DMSO)δ12.33(s,1H),8.89(s,1H),8.34(s,1H),7.94(d,J=8.4Hz,4H),7.72(d,J=8.4 Hz, 2H), 7.38(t, J=8.8Hz, 2H), 4.52(t, J=4.8Hz, 2H), 3.85(d, J=5.2Hz, 2H), 3.32(s, 3H), 1.81( d,J=7.2Hz,3H).
实施例30：N-(4-(4-氨基-7-(氧杂环丁-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-异 丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物30)Example 30: N-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5- (4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 30)
Figure PCTCN2022109584-appb-000079
Figure PCTCN2022109584-appb-000079
称取化合物3-(4-氨基苯基)-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(68mg,230μmol)、T5(67mg,230μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(175mg,459μmol)、N,N-二异丙基乙胺(59mg,459μmol)，在25℃下搅拌10分钟。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物30(33mg)。Weigh the compound 3-(4-aminophenyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (68mg, 230μmol), T5 (67 mg, 230 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (175 mg, 459 μmol) and N,N-diisopropylethylamine (59 mg, 459 μmol) were stirred at 25° C. for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 30 (33 mg).
MS m/z(ESI):540.2[M+H] +. MS m/z(ESI):540.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.32(s,1H),8.91(s,1H),8.15(s,1H),8.00-7.90(m,2H),7.85(d,J＝8.0Hz,2H),7.76(s,1H),7.52(d,J＝4.0Hz,2H),7.34(t,J＝4.0Hz,2H),5.90-5.86(m,1H),5.04-4.96(m,4H),4.76-4.72(m,1H),1.52(d,J＝8.0Hz,6H). 1 H NMR(400MHz,DMSO)δ12.32(s,1H),8.91(s,1H),8.15(s,1H),8.00-7.90(m,2H),7.85(d,J＝8.0Hz,2H ),7.76(s,1H),7.52(d,J=4.0Hz,2H),7.34(t,J=4.0Hz,2H),5.90-5.86(m,1H),5.04-4.96(m,4H) ,4.76-4.72(m,1H),1.52(d,J＝8.0Hz,6H).
实施例31：N-(4-(4-氨基-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物31)Example 31: N-(4-(4-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl )-5-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 31)
Figure PCTCN2022109584-appb-000080
Figure PCTCN2022109584-appb-000080
将化合物3-(4-氨基苯基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(153mg,0.44mmol)、T9(111mg,0.34mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(198mg,0.51mmol)、N,N-二异丙基乙胺(135mg,1.02mmol)加入N,N-二甲基甲酰胺(10mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物31(100mg)。Compound 3-(4-aminophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (153mg, 0.44 mmol), T9 (111mg, 0.34mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (198mg, 0.51mmol), N,N-Diisopropylethylamine (135mg, 1.02mmol) was added into N,N-dimethylformamide (10mL), and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 31 (100 mg).
MS m/z(ESI):585.2[M+H] +. MS m/z(ESI):585.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.34(s,1H),8.97(s,1H),8.28(s,1H),7.98(d,J＝8.8Hz,2H),7.93(d,J＝8.8Hz,2H),7.71(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),5.02-4.93(m,1H),4.82-4.72(m,1H),4.04(d,J＝7.2Hz,2H),3.58(t,J＝11.2Hz,2H),2.24(td,J＝12.0,7.6Hz,2H),1.92(d,J＝10.4Hz,2H),1.55(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ12.34(s, 1H), 8.97(s, 1H), 8.28(s, 1H), 7.98(d, J=8.8Hz, 2H), 7.93(d, J=8.8 Hz, 2H), 7.71(d, J=8.4Hz, 2H), 7.60(d, J=8.4Hz, 2H), 5.02-4.93(m, 1H), 4.82-4.72(m, 1H), 4.04(d ,J=7.2Hz,2H),3.58(t,J=11.2Hz,2H),2.24(td,J=12.0,7.6Hz,2H),1.92(d,J=10.4Hz,2H),1.55(d ,J＝6.4Hz,6H).
实施例32：N-(4-(4-氨基-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物32)Example 32: N-(4-(4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) -5-(4-Chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 32)
Figure PCTCN2022109584-appb-000081
Figure PCTCN2022109584-appb-000081
将化合物5-(4-氨基苯基)-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(64mg,0.21mmol)、T9(54mg,0.17mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(120mg,0.31mmol)、N,N-二异丙基乙胺(82mg，0.62mmol)加入N,N-二甲基甲酰胺(5m)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物32(41mg)。Compound 5-(4-aminophenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (64mg, 0.21mmol ), T9 (54mg, 0.17mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120mg, 0.31mmol), N , N-diisopropylethylamine (82mg, 0.62mmol) was added into N,N-dimethylformamide (5m) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 32 (41 mg).
MS m/z(ESI):584.2[M+H] +. MS m/z(ESI):584.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.26(s,1H),8.96(s,1H),8.17(s,1H),7.97(d,J＝8.8Hz,2H),7.85(d,J＝8.4Hz,2H),7.60(d,J＝8.8Hz,2H),7.55-7.49(m,3H),4.86(dd,J＝13.6,10.0Hz,1H),4.76(dt,J＝13.2,6.4Hz,1H),4.03(dd,J＝11.2,3.6Hz,2H),3.56(t,J＝11.2Hz,2H),2.14(td,J＝12.4,8.0Hz,2H),1.90(d,J＝12.4Hz,2H),1.54(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ12.26(s, 1H), 8.96(s, 1H), 8.17(s, 1H), 7.97(d, J=8.8Hz, 2H), 7.85(d, J=8.4 Hz, 2H), 7.60(d, J=8.8Hz, 2H), 7.55-7.49(m, 3H), 4.86(dd, J=13.6, 10.0Hz, 1H), 4.76(dt, J=13.2, 6.4Hz ,1H),4.03(dd,J=11.2,3.6Hz,2H),3.56(t,J=11.2Hz,2H),2.14(td,J=12.4,8.0Hz,2H),1.90(d,J= 12.4Hz, 2H), 1.54(d, J=6.4Hz, 6H).
实施例33：N-(4-(4-氨基-7-(2,2-二氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物33)Example 33: N-(4-(4-amino-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5- (4-Chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 33)
Figure PCTCN2022109584-appb-000082
Figure PCTCN2022109584-appb-000082
将化合物5-(4-氨基苯基)-7-(2,2-二氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(160mg,0.62mmol)、T9(120mg,0.48mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(278mg,0.72mmol)、N,N-二异丙基乙胺(190mg,1.43mmol)加入N,N-二甲基甲酰胺(10mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物33(78mg)。Compound 5-(4-aminophenyl)-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (160mg, 0.62mmol), T9 (120mg, 0.48mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (278mg, 0.72mmol), N,N- Diisopropylethylamine (190mg, 1.43mmol) was added into N,N-dimethylformamide (10mL) and reacted at 25°C for 4 hours. Water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 33 (78 mg).
MS m/z(ESI):564.2[M+H] +. MS m/z(ESI):564.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.27(s,1H),8.96(s,1H),8.21(s,1H),7.98(d,J＝8.8Hz,2H),7.87(d,J＝8.4Hz,2H),7.60(d,J＝8.8Hz,2H),7.51(d,J＝8.4Hz,2H),7.39(s,1H),6.61(s,1H),6.47(t,J＝3.6Hz,1H),6.33(s,1H),4.82-4.62(m,3H),1.55(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ12.27(s, 1H), 8.96(s, 1H), 8.21(s, 1H), 7.98(d, J=8.8Hz, 2H), 7.87(d, J=8.4 Hz, 2H), 7.60(d, J=8.8Hz, 2H), 7.51(d, J=8.4Hz, 2H), 7.39(s, 1H), 6.61(s, 1H), 6.47(t, J=3.6 Hz,1H),6.33(s,1H),4.82-4.62(m,3H),1.55(d,J＝6.4Hz,6H).
实施例34：N-(4-(4-氨基-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物34)Example 34: N-(4-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 34)
Figure PCTCN2022109584-appb-000083
Figure PCTCN2022109584-appb-000083
称取化合物3-(4-氨基苯基)-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(70mg,229μmol)、T5(67mg,229μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(174mg,458μmol)、N,N-二异丙基乙胺(59mg,458μmol)，在25℃下搅拌10分钟。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物34(5mg)。Weigh the compound 3-(4-aminophenyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (70mg, 229μmol), T5 (67 mg, 229 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (174 mg, 458 μmol) and N,N-diisopropylethylamine (59 mg, 458 μmol) were stirred at 25° C. for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 34 (5 mg).
MS m/z(ESI):549.2[M+H] +. MS m/z(ESI):549.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.38(s,1H),8.91(s,1H),8.29(s,1H),7.97-7.90(m,4H),7.69(d,J＝8.0Hz,2H),7.34(t,J＝12.0Hz,2H),6.63-6.36(m,1H),4.85-4.76(m,2H),4.75-4.71(m,1H),1.52(d,J＝4.0Hz,6H). 1 H NMR(400MHz,DMSO)δ12.38(s,1H),8.91(s,1H),8.29(s,1H),7.97-7.90(m,4H),7.69(d,J＝8.0Hz,2H ),7.34(t,J=12.0Hz,2H),6.63-6.36(m,1H),4.85-4.76(m,2H),4.75-4.71(m,1H),1.52(d,J=4.0Hz, 6H).
实施例35：N-(4-(4-氨基-7-(2,2,2-三氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物35)Example 35: N-(4-(4-amino-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 35)
Figure PCTCN2022109584-appb-000084
Figure PCTCN2022109584-appb-000084
称取化合物5-(4-氨基苯基)-7-(2,2,2-三氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(90mg,293μmol)、T5(81mg,293μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(167mg,439μmol)、N,N-二异丙基乙胺(76mg,586μmol)，在25℃下搅拌10分钟。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物35(9.4mg)。Weigh compound 5-(4-aminophenyl)-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (90mg, 293μmol) , T5 (81mg, 293μmol) was dissolved in N,N-dimethylformamide (2mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl urea hexafluorophosphate (167 mg, 439 μmol), N,N-diisopropylethylamine (76 mg, 586 μmol), and stirred at 25° C. for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 35 (9.4 mg) .
MS m/z(ESI):566.2[M+H] +. MS m/z(ESI):566.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.31(s,1H),8.90(s,1H),8.21(s,1H),7.97-7.93(m,2H),7.85(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.38(s,1H),7.34(t,J＝8.0Hz,2H),5.10(q,J＝8.0Hz,2H),4.75-4.72(m,1H),1.52(d,J＝8.0Hz,6H). 1 H NMR(400MHz,DMSO)δ12.31(s,1H),8.90(s,1H),8.21(s,1H),7.97-7.93(m,2H),7.85(d,J＝8.0Hz,2H ), 7.48(d, J=8.0Hz, 2H), 7.38(s, 1H), 7.34(t, J=8.0Hz, 2H), 5.10(q, J=8.0Hz, 2H), 4.75-4.72(m ,1H),1.52(d,J=8.0Hz,6H).
实施例36：N-(4-(4-氨基-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物36)Example 36: N-(4-(4-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl )-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 36)
Figure PCTCN2022109584-appb-000085
Figure PCTCN2022109584-appb-000085
称取化合物3-(4-氨基苯基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(100mg,323μmol)、T5(89mg,323μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(184mg,485μmol)、N,N-二异丙基乙胺(84mg,646μmol)，在25℃下搅拌10分钟。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物36(5mg)。Weigh compound 3-(4-aminophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (100mg, 323μmol), T5 (89mg, 323μmol) were dissolved in N,N-dimethylformamide (2mL), added 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (184 mg, 485 μmol), N,N-diisopropylethylamine (84 mg, 646 μmol), stirred at 25° C. for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 36 (5 mg).
MS m/z(ESI):569.2[M+H] +. MS m/z(ESI):569.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.38(s,1H),8.91(s,1H),8.25(s,1H),7.96(q,J＝4.0Hz,2H),7.90(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,2H),7.34(t,J＝4.0Hz,2H),4.76-4.72(m,1H),4.01(d,J＝8.0Hz,2H),3.55(t,J＝8.0Hz,2H),3.34(br,1H),2.23-2.19(m,2H),1.89(d,J＝8.0Hz,2H),1.52(d,J＝8.0Hz,6H). 1 H NMR (400MHz,DMSO)δ12.38(s,1H),8.91(s,1H),8.25(s,1H),7.96(q,J=4.0Hz,2H),7.90(d,J=8.0 Hz, 2H), 7.68(d, J=8.0Hz, 2H), 7.34(t, J=4.0Hz, 2H), 4.76-4.72(m, 1H), 4.01(d, J=8.0Hz, 2H), 3.55(t, J=8.0Hz, 2H), 3.34(br, 1H), 2.23-2.19(m, 2H), 1.89(d, J=8.0Hz, 2H), 1.52(d, J=8.0Hz, 6H ).
实施例37：N-(4-(4-氨基-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物37)Example 37: N-(4-(4-Amino-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl) -5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 37)
Figure PCTCN2022109584-appb-000086
Figure PCTCN2022109584-appb-000086
称取化合物3-(4-氨基苯基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(89mg,276μmol)、T5(80mg,276μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(157mg,414μmol)、N,N-二异丙基乙胺(71mg,551μmol)，在25℃下搅拌10分钟。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物37(70mg)。Weigh compound 3-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (89mg, 276μmol ), T5 (80mg, 276μmol) were dissolved in N,N-dimethylformamide (2mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (157 mg, 414 μmol) and N,N-diisopropylethylamine (71 mg, 551 μmol) were stirred at 25° C. for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 37 (70 mg).
MS m/z(ESI):567.2[M+H] +. MS m/z(ESI):567.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.39(s,1H),8.91(s,1H),8.32(s,1H),7.97-7.94(m,2H),7.92(d,J＝8.0Hz,2H),7.70(d,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,2H),5.27(q,J＝8.0Hz,2H),4.77-4.71(m,1H),1.52(d,J＝8.0Hz,6H). 1 H NMR(400MHz,DMSO)δ12.39(s,1H),8.91(s,1H),8.32(s,1H),7.97-7.94(m,2H),7.92(d,J＝8.0Hz,2H ), 7.70(d, J=8.0Hz, 2H), 7.34(t, J=8.0Hz, 2H), 5.27(q, J=8.0Hz, 2H), 4.77-4.71(m, 1H), 1.52(d ,J＝8.0Hz,6H).
实施例38：N-[4-[4-氨基-7-(氧杂环丁-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基]苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物38)Example 38: N-[4-[4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]-5- (5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 38)
Figure PCTCN2022109584-appb-000087
Figure PCTCN2022109584-appb-000087
将化合物T2(53mg,178μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(52mg,178μmol)、N,N-二异丙基乙胺(46mg,355μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(101mg,267μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物38(38mg)。Compound T2 (53 mg, 178 μmol) was dissolved in N,N-dimethylformamide (4 mL), T6 (52 mg, 178 μmol), N,N-diisopropylethylamine (46 mg, 355 μmol), 2- (7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (101 mg, 267 μmol) was reacted at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 38 (38 mg).
MS m/z(ESI):541.2[M+H] +. MS m/z(ESI):541.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.0(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(s,1H),8.18(s,1H),7.94-7.87(m,3H),7.79(s,1H),7.56(d,J＝8.0Hz,2H),5.93-5.89(m,1H),5.08-5.01(m,4H),4.99-4.88(m,1H),1.28(d,J＝7.2Hz,6H). 1 H NMR (400MHz,DMSO)δ12.0(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(s,1H),8.18(s,1H),7.94-7.87 (m,3H),7.79(s,1H),7.56(d,J＝8.0Hz,2H),5.93-5.89(m,1H),5.08-5.01(m,4H),4.99-4.88(m,1H ),1.28(d,J＝7.2Hz,6H).
实施例39：N-[4-[4-氨基-7-(2,2-二氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基]苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物39)Example 39: N-[4-[4-amino-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]-5- (5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 39)
Figure PCTCN2022109584-appb-000088
Figure PCTCN2022109584-appb-000088
将化合物5-(4-氨基苯基)-7-(2,2-二氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(54mg,178μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(52mg,178μmol)、N,N-二异丙基乙胺(46mg,355μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(101mg,267μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物39(28mg)。The compound 5-(4-aminophenyl)-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (54 mg, 178 μmol) was dissolved in N , in N-dimethylformamide (4mL), add T6 (52mg, 178μmol), N,N-diisopropylethylamine (46mg, 355μmol), 2-(7-azobenzotriazole) -N,N,N',N'-Tetramethylurea hexafluorophosphate (101 mg, 267 μmol), react at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 39 (28 mg).
MS m/z(ESI):549.2[M+H] +. MS m/z(ESI):549.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.98(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J＝3.2Hz,1H),8.21(s,1H),7.94-7.87(m,3H),7.52(d,J＝8.0Hz,2H),7.39(s,1H),6.60-6.30(m,1H),4.93-4.88(m,4H),4.72-4.64(m,1H),1.53(d,J＝7.2Hz,6H). 1 H NMR (400MHz,DMSO)δ11.98(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J=3.2Hz,1H),8.21(s,1H ),7.94-7.87(m,3H),7.52(d,J＝8.0Hz,2H),7.39(s,1H),6.60-6.30(m,1H),4.93-4.88(m,4H),4.72- 4.64(m,1H),1.53(d,J=7.2Hz,6H).
实施例40：N-[4-[4-氨基-7-(2-氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基]苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物40)Example 40: N-[4-[4-amino-7-(2-fluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]-5-(5- Fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 40)
Figure PCTCN2022109584-appb-000089
Figure PCTCN2022109584-appb-000089
将化合物5-(4-氨基苯基)-7-(2-氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(150mg,276μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(81mg,276μmol)、N,N-二异丙基乙胺(71mg,553μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(210mg,553μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物40(30mg)。The compound 5-(4-aminophenyl)-7-(2-fluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (150 mg, 276 μmol) was dissolved in N,N- In dimethylformamide (4mL), add T6 (81mg, 276μmol), N,N-diisopropylethylamine (71mg, 553μmol), 2-(7-azobenzotriazole)-N, N,N',N'-Tetramethyluronium hexafluorophosphate (210 mg, 553 μmol) was reacted at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 40 (30 mg).
MS m/z(ESI):531.2[M+H] +. MS m/z(ESI):531.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.98(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J＝3.2Hz,1H),8.19(s,1H),7.94-7.87(m,3H),7.52(d,J＝8.0Hz,2H),7.41(s,1H),4.90-4.88(m,4H),4.78-4.76(m,1H),4.57-4.55(m,1H),4.50-4.48(m,1H),1.53(d,J＝7.2Hz,6H). 1 H NMR(400MHz,DMSO)δ11.98(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J=3.2Hz,1H),8.19(s,1H) ),7.94-7.87(m,3H),7.52(d,J＝8.0Hz,2H),7.41(s,1H),4.90-4.88(m,4H),4.78-4.76(m,1H),4.57- 4.55(m,1H),4.50-4.48(m,1H),1.53(d,J=7.2Hz,6H).
实施例41：N-[4-(4-氨基-7-四氢吡喃-4-基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物41)Example 41: N-[4-(4-amino-7-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]-5-(5 -Fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 41)
Figure PCTCN2022109584-appb-000090
Figure PCTCN2022109584-appb-000090
将化合物5-(4-氨基苯基)-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(58mg,178μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(52mg,178μmol)、N,N-二异丙基乙胺(46mg,356μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(101mg,267μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物41(28mg)。Compound 5-(4-aminophenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (58mg, 178μmol) Dissolve in N,N-dimethylformamide (4mL), add T6 (52mg, 178μmol), N,N-diisopropylethylamine (46mg, 356μmol), 2-(7-azobenzotri Azolazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (101mg, 267μmol), react at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 41 (28 mg).
MS m/z(ESI):569.2[M+H] +. MS m/z(ESI):569.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.98(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J＝3.2Hz,1H),8.17(s,1H),7.94-7.87(m,3H),7.54-7.50(m,3H),4.91-4.86(m,2H),4.05-4.01(m,2H),3.59-3.54(m,2H),2.17-2.12(m,2H),1.91-1.89(m,2H),1.53(d,J＝7.2Hz,6H). 1 H NMR(400MHz,DMSO)δ11.98(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J=3.2Hz,1H),8.17(s,1H) ),7.94-7.87(m,3H),7.54-7.50(m,3H),4.91-4.86(m,2H),4.05-4.01(m,2H),3.59-3.54(m,2H),2.17-2.12 (m,2H),1.91-1.89(m,2H),1.53(d,J=7.2Hz,6H).
实施例42：N-[4-[4-氨基-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基]苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物42)Example 42: N-[4-[4-Amino-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl] -5-(5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 42)
Figure PCTCN2022109584-appb-000091
Figure PCTCN2022109584-appb-000091
将化合物3-(4-氨基苯基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(58mg,178μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(52mg,178μmol)、N,N-二异丙基乙胺(46mg,356μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(101mg,267μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物42(8mg)。Compound 3-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (58mg, 178μmol) Dissolve in N,N-dimethylformamide (4mL), add T6 (52mg, 178μmol), N,N-diisopropylethylamine (46mg, 356μmol), 2-(7-azobenzotri Azolazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (101mg, 267μmol), react at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 42 (8 mg).
MS m/z(ESI):568.2[M+H] +. MS m/z(ESI):568.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.05(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J＝3.2Hz,1H),8.36(s,1H),7.96-7.89(m,3H),7.75-7.73(m,2H),5.34-5.27(m,2H),4.93-4.88(m,1H),1.53(d,J＝7.2Hz,6H). 1 H NMR (400MHz,DMSO)δ12.05(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J=3.2Hz,1H),8.36(s,1H ),7.96-7.89(m,3H),7.75-7.73(m,2H),5.34-5.27(m,2H),4.93-4.88(m,1H),1.53(d,J=7.2Hz,6H).
实施例43：N-[4-(4-氨基-1-四氢吡喃-4-基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物43)Example 43: N-[4-(4-Amino-1-tetrahydropyran-4-yl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-5-( 5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 43)
Figure PCTCN2022109584-appb-000092
Figure PCTCN2022109584-appb-000092
将化合物3-(4-氨基苯基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(58mg,178μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(52mg,178μmol)、N,N-二异丙基乙胺(46mg,356μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(101mg,267μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物43(27mg)。Compound 3-(4-aminophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (58mg, 178μmol ) was dissolved in N,N-dimethylformamide (4mL), T6 (52mg, 178μmol), N,N-diisopropylethylamine (46mg, 356μmol), 2-(7-azobenzo Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (101mg, 267μmol), react at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 43 (27 mg).
MS m/z(ESI):570.2[M+H] +. MS m/z(ESI):570.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.05(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J＝3.2Hz,1H),8.28(s,1H),7.96-7.89(m,3H),7.75-7.73(m,2H),5.00-4.88(m,2H),4.06-4.02(m,2H),3.61-3.55(m,2H),2.27-2.23(m,2H),1.93-1.91(m,2H),1.53(d,J＝7.2Hz,6H). 1 H NMR (400MHz,DMSO)δ12.05(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J=3.2Hz,1H),8.28(s,1H ),7.96-7.89(m,3H),7.75-7.73(m,2H),5.00-4.88(m,2H),4.06-4.02(m,2H),3.61-3.55(m,2H),2.27-2.23 (m,2H),1.93-1.91(m,2H),1.53(d,J=7.2Hz,6H).
实施例44：N-[4-[4-氨基-1-(2-氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基]苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物44)Example 44: N-[4-[4-amino-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-5-(5 -Fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 44)
Figure PCTCN2022109584-appb-000093
Figure PCTCN2022109584-appb-000093
将化合物3-(4-氨基苯基)-1-(2-氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(51mg,178μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(52mg,178μmol)、N,N-二异丙基乙胺(46mg,356μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(101mg,267μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物44(26mg)。The compound 3-(4-aminophenyl)-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (51 mg, 178 μmol) was dissolved in N,N - In dimethylformamide (4mL), add T6 (52mg, 178μmol), N,N-diisopropylethylamine (46mg, 356μmol), 2-(7-azobenzotriazole)-N , N,N',N'-tetramethyluronium hexafluorophosphate (101mg, 267μmol), reacted at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 44 (26 mg).
MS m/z(ESI):532.2[M+H] +. MS m/z(ESI):532.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.04(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J＝3.2Hz,1H),8.29(s,1H),7.96-7.89(m,3H),7.75-7.72(m,2H),5.00-4.88(m,3H),4.73-4.64(m,2H),1.53(d,J＝7.2 Hz,6H). 1 H NMR (400MHz,DMSO)δ12.04(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J=3.2Hz,1H),8.29(s,1H) ),7.96-7.89(m,3H),7.75-7.72(m,2H),5.00-4.88(m,3H),4.73-4.64(m,2H),1.53(d,J＝7.2 Hz,6H).
实施例45：N-[4-[4-氨基-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基]苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物45)Example 45: N-[4-[4-Amino-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-5 -(5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 45)
Figure PCTCN2022109584-appb-000094
Figure PCTCN2022109584-appb-000094
将化合物3-(4-氨基苯基)-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(53mg,177.78μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(52mg,178μmol)、N,N-二异丙基乙胺(46mg,356μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(101mg,267μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物45(28mg)。Compound 3-(4-aminophenyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (53 mg, 177.78 μmol) was dissolved In N,N-dimethylformamide (4mL), add T6 (52mg, 178μmol), N,N-diisopropylethylamine (46mg, 356μmol), 2-(7-azobenzotriazole Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (101mg, 267μmol), react at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 45 (28 mg).
MS m/z(ESI):542.2[M+H] +. MS m/z(ESI):542.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.08(s,1H),9.34(s,1H),8.86-8.83(m,1H),8.76(d,J＝3.2Hz,1H),8.29(s,1H),7.98-7.89(m,3H),7.79-7.77(m,2H),6.10-6.02(m,1H),5.16-5.12(m,2H),5.03-5.01(m,2H),4.94-4.87(m,1H),1.53(d,J＝7.2Hz,6H). 1 H NMR(400MHz,DMSO)δ12.08(s,1H),9.34(s,1H),8.86-8.83(m,1H),8.76(d,J=3.2Hz,1H),8.29(s,1H) ),7.98-7.89(m,3H),7.79-7.77(m,2H),6.10-6.02(m,1H),5.16-5.12(m,2H),5.03-5.01(m,2H),4.94-4.87 (m,1H),1.53(d,J=7.2Hz,6H).
实施例46：N-[4-[4-氨基-7-(2,2,2-三氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基]苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物46)Example 46: N-[4-[4-amino-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]- 5-(5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 46)
Figure PCTCN2022109584-appb-000095
Figure PCTCN2022109584-appb-000095
将化合物5-(4-氨基苯基)-7-(2,2,2-三氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(170mg,276μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(81mg,276μmol)、N,N-二异丙基乙胺(71mg,553μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(210mg,553μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物46(29mg)。Compound 5-(4-aminophenyl)-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (170mg, 276μmol) was dissolved In N,N-dimethylformamide (4mL), add T6 (81mg, 276μmol), N,N-diisopropylethylamine (71mg, 553μmol), 2-(7-azobenzotriazol Azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (210mg, 553μmol), react at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 46 (29 mg).
MS m/z(ESI):567.2[M+H] +. MS m/z(ESI):567.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.98(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J＝3.2Hz,1H),8.29(s,1H),7.98-7.87(m,3H),7.53-7.51(m,2H),7.41(s,1H),5.16-5.09(m,2H),4.92-4.86(m,1H),1.53(d,J＝7.2Hz,6H). 1 H NMR(400MHz,DMSO)δ11.98(s,1H),9.33(s,1H),8.86-8.83(m,1H),8.76(d,J=3.2Hz,1H),8.29(s,1H ),7.98-7.87(m,3H),7.53-7.51(m,2H),7.41(s,1H),5.16-5.09(m,2H),4.92-4.86(m,1H),1.53(d,J =7.2Hz,6H).
实施例47：N-[4-[4-氨基-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基]苯基]-5-(5-氟吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物47)Example 47: N-[4-[4-amino-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-5 -(5-fluoropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 47)
Figure PCTCN2022109584-appb-000096
Figure PCTCN2022109584-appb-000096
将化合物3-(4-氨基苯基)-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(54mg,178μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入T6(52mg,178μmol)、N,N-二异丙基乙胺(46mg,356μmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(101mg,267μmol)，于25℃下反应2小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物47(27mg)。The compound 3-(4-aminophenyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (54 mg, 178 μmol) was dissolved in In N,N-dimethylformamide (4mL), add T6 (52mg, 178μmol), N,N-diisopropylethylamine (46mg, 356μmol), 2-(7-azobenzotriazole )-N,N,N',N'-tetramethyluronium hexafluorophosphate (101mg, 267μmol), react at 25°C for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 47 (27 mg).
MS m/z(ESI):550.2[M+H] +. MS m/z(ESI):550.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.05(s,1H),9.37(s,1H),8.86-8.83(m,1H),8.76(d,J＝3.2Hz,1H),8.32(s,1H),7.98-7.89(m,3H),7.74-7.72(m,2H),6.66-6.38(m,1H),4.93-4.80(m,3H),1.53(d,J＝7.2 Hz,6H). 1 H NMR (400MHz,DMSO)δ12.05(s,1H),9.37(s,1H),8.86-8.83(m,1H),8.76(d,J=3.2Hz,1H),8.32(s,1H ),7.98-7.89(m,3H),7.74-7.72(m,2H),6.66-6.38(m,1H),4.93-4.80(m,3H),1.53(d,J＝7.2 Hz,6H).
实施例48：N-(4-(4-氨基-7-(2,2,2-三氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物48)Example 48: N-(4-(4-amino-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 5-(4-Chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 48)
Figure PCTCN2022109584-appb-000097
Figure PCTCN2022109584-appb-000097
将化合物5-(4-氨基苯基)-7-(2,2,2-三氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(90mg,0.29mmol)、T9(71mg,0.23mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(386mg,1.00mmol)、N,N-二异丙基乙胺(116mg,0.88mmol)加入N,N-二甲基甲酰胺(10mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆抽滤得标题化合物48(25mg)。Compound 5-(4-aminophenyl)-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (90mg, 0.29mmol) , T9 (71mg, 0.23mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (386mg, 1.00mmol), N, N-Diisopropylethylamine (116mg, 0.88mmol) was added into N,N-dimethylformamide (10mL) and reacted at 25°C for 4 hours. Add water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate and concentrate, and filter the concentrated residue through methanol to obtain the title compound 48 (25 mg).
MS m/z(ESI):582.2[M+H] +. MS m/z(ESI):582.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.28(s,1H),8.95(d,J＝5.2Hz,1H),8.23(s,1H),7.97(d,J＝8.8Hz,2H),7.87(d,J＝8.4Hz,2H),7.60(d,J＝8.8Hz,2H),7.51(d,J＝8.4Hz,2H),7.40(s,1H),5.13(q,J＝9.2Hz,2H),4.81-4.70(m,1H),1.54(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ12.28(s, 1H), 8.95(d, J=5.2Hz, 1H), 8.23(s, 1H), 7.97(d, J=8.8Hz, 2H), 7.87( d,J=8.4Hz,2H),7.60(d,J=8.8Hz,2H),7.51(d,J=8.4Hz,2H),7.40(s,1H),5.13(q,J=9.2Hz, 2H), 4.81-4.70(m, 1H), 1.54(d, J＝6.4Hz, 6H).
实施例49：N-(4-(4-氨基-7-(2-氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物49)Example 49: N-(4-(4-amino-7-(2-fluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4- Chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 49)
Figure PCTCN2022109584-appb-000098
Figure PCTCN2022109584-appb-000098
将化合物5-(4-氨基苯基)-7-(2-氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(135mg,0.50mmol)、T9(120mg,0.40mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(289mg,0.75mmol)、N,N-二异丙基乙胺(197mg,1.49mmol)加入N,N-二甲基甲酰胺(10mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物滴加盐酸1,4-二氧六环成盐后经制备HPLC分离得标题化合物49(1.73mg)。The compound 5-(4-aminophenyl)-7-(2-fluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (135mg, 0.50mmol), T9 (120mg, 0.40mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (289mg, 0.75mmol), N,N-diisopropyl Ethylamine (197mg, 1.49mmol) was added into N,N-dimethylformamide (10mL) and reacted at 25°C for 4 hours. Add water, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate and concentrate, add 1,4-dioxane hydrochloride dropwise to the concentrated residue to form a salt, and then separate by preparative HPLC to obtain the title compound 49 (1.73 mg).
MS m/z(ESI):546.1[M+H] +. MS m/z(ESI):546.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.26(s,1H),8.96(s,1H),8.19(s,1H),7.97(d,J＝8.4Hz,2H),7.86(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,2H),7.41(s,1H),4.89(s,1H),4.77(s,2H),4.52(d,J＝27.2Hz,2H),1.54(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ12.26(s, 1H), 8.96(s, 1H), 8.19(s, 1H), 7.97(d, J=8.4Hz, 2H), 7.86(d, J=8.4 Hz,2H),7.60(d,J=8.4Hz,2H),7.50(d,J=8.4Hz,2H),7.41(s,1H),4.89(s,1H),4.77(s,2H), 4.52(d, J=27.2Hz, 2H), 1.54(d, J=6.4Hz, 6H).
实施例50：N-(4-(4-氨基-7-(氧杂环丁-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物50)Example 50: N-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5- (4-Chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 50)
Figure PCTCN2022109584-appb-000099
Figure PCTCN2022109584-appb-000099
将化合物T2(125mg,0.40mmol)、T9(96mg,0.32mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(232mg,0.60mmol)、N,N-二异丙基乙胺(158mg,1.20mmol)加入N,N-二甲基甲酰胺(10mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆抽滤得标题化合物50(109mg)。Compound T2 (125mg, 0.40mmol), T9 (96mg, 0.32mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (232mg, 0.60mmol), N,N-diisopropylethylamine (158mg, 1.20mmol) were added to N,N-dimethylformamide (10mL), and reacted at 25°C for 4 hours. Add water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate and concentrate, and filter the concentrated residue through methanol to obtain the title compound 50 (109 mg).
MS m/z(ESI):556.1[M+H] +. MS m/z(ESI):556.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.21(s,1H),8.89(s,1H),8.10(s,1H),7.90(d,J＝8.8Hz,2H),7.80 (d,J＝8.8Hz,2H),7.72(s,1H),7.52(d,J＝8.8Hz,2H),7.48(d,J＝8.4Hz,2H),5.83(dd,J＝14.4,7.2Hz,1H),4.96(dt,J＝14.4,7.2Hz,4H),4.73-4.65(m,1H),1.47(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ12.21(s,1H),8.89(s,1H),8.10(s,1H),7.90(d,J=8.8Hz,2H),7.80 (d,J=8.8 Hz, 2H), 7.72(s, 1H), 7.52(d, J=8.8Hz, 2H), 7.48(d, J=8.4Hz, 2H), 5.83(dd, J=14.4, 7.2Hz, 1H), 4.96(dt,J=14.4,7.2Hz,4H),4.73-4.65(m,1H),1.47(d,J=6.4Hz,6H).
实施例51：N-(4-(4-氨基-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物51)Example 51: N-(4-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-Chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 51)
Figure PCTCN2022109584-appb-000100
Figure PCTCN2022109584-appb-000100
将化合物3-(4-氨基苯基)-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(112mg,0.39mmol)、T9(93mg,0.31mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(224mg,0.58mmol)、N,N-二异丙基乙胺(153mg,1.16mmol)加入N,N-二甲基甲酰胺(10mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥并浓缩，将浓缩后的残留物经甲醇打浆抽滤得标题化合物51(100mg)。The compound 3-(4-aminophenyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (112mg, 0.39mmol), T9 (93mg, 0.31mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (224mg, 0.58mmol), N,N -Diisopropylethylamine (153mg, 1.16mmol) was added into N,N-dimethylformamide (10mL) and reacted at 25°C for 4 hours. Add water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate and concentrate, and filter the concentrated residue through methanol to obtain the title compound 51 (100 mg).
MS m/z(ESI):565.1[M+H] +. MS m/z(ESI):565.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.36(s,1H),8.99(s,1H),8.34(s,1H),7.98(dd,J＝14.4,8.8Hz,4H),7.74(d,J＝8.4Hz,2H),7.62(d,J＝8.4Hz,2H),6.68(s,1H),6.54(t,J＝3.6Hz,1H),6.41(t,J＝3.6Hz,1H),4.91-4.75(m,3H),1.56(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ12.36(s,1H),8.99(s,1H),8.34(s,1H),7.98(dd,J=14.4,8.8Hz,4H),7.74(d,J =8.4Hz, 2H), 7.62(d, J=8.4Hz, 2H), 6.68(s, 1H), 6.54(t, J=3.6Hz, 1H), 6.41(t, J=3.6Hz, 1H), 4.91-4.75(m,3H),1.56(d,J＝6.4Hz,6H).
实施例52：N-(4-(4-氨基-1-(2-氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物52)Example 52: N-(4-(4-Amino-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4 -Chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 52)
Figure PCTCN2022109584-appb-000101
Figure PCTCN2022109584-appb-000101
将化合物3-(4-氨基苯基)-1-(2-氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(54mg,0.20mmol)、T9(60mg,0.20mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(115mg,0.30mmol)、N,N-二异丙基乙胺(78mg,0.60mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，浓缩后经甲醇打浆纯化抽滤得标题化合物52(47mg)。Compound 3-(4-aminophenyl)-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (54mg, 0.20mmol), T9 (60mg , 0.20mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115mg, 0.30mmol), N,N-diiso Propylethylamine (78mg, 0.60mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Add water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, concentrate, purify by beating with methanol and filter with suction to obtain the title compound 52 (47 mg).
MS m/z(ESI):547.1[M+H] +. MS m/z(ESI):547.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.34(s,1H),8.96(s,1H),8.29(s,1H),7.96(dd,J＝16.4,8.4Hz,4H),7.72(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),4.98(t,J＝4.8Hz,1H),4.86(t,J＝4.8Hz,1H),4.75(ddd,J＝16.8,11.6,5.6Hz,2H),4.65(t,J＝4.8Hz,1H),1.55(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ12.34(s,1H),8.96(s,1H),8.29(s,1H),7.96(dd,J=16.4,8.4Hz,4H),7.72(d,J =8.4Hz, 2H), 7.60(d, J=8.4Hz, 2H), 4.98(t, J=4.8Hz, 1H), 4.86(t, J=4.8Hz, 1H), 4.75(ddd, J=16.8 ,11.6,5.6Hz,2H),4.65(t,J=4.8Hz,1H),1.55(d,J=6.4Hz,6H).
实施例53：N-(4-(4-氨基-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物53)Example 53: N-(4-(4-Amino-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl) -5-(4-Chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 53)
Figure PCTCN2022109584-appb-000102
Figure PCTCN2022109584-appb-000102
将化合物3-(4-氨基苯基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(55mg,0.17mmol)、T9(53mg,0.18mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(102mg,0.26mmol)、N,N-二异丙基乙胺(69mg,0.52mmol)加入N,N-二甲基甲酰胺(5mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，浓缩后经甲醇打浆纯化抽滤得标题化合物53(31mg)。Compound 3-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (55mg, 0.17mmol ), T9 (53mg, 0.18mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (102mg, 0.26mmol), N , N-Diisopropylethylamine (69mg, 0.52mmol) was added into N,N-dimethylformamide (5mL) and reacted at 25°C for 4 hours. Add water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, concentrate, purify by beating with methanol and filter with suction to obtain the title compound 53 (31 mg).
MS m/z(ESI):583.1[M+H] +. MS m/z(ESI):583.1[M+H] + .
1H NMR(400MHz,DMSO)δ12.35(s,1H),8.96(s,1H),8.35(s,1H),7.96(dd,J＝12.0,8.4Hz,4H), 7.73(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),5.38-5.18(m,2H),4.82-4.71(m,1H),1.55(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ12.35(s,1H),8.96(s,1H),8.35(s,1H),7.96(dd,J=12.0,8.4Hz,4H), 7.73(d,J =8.4Hz, 2H), 7.60(d, J=8.4Hz, 2H), 5.38-5.18(m, 2H), 4.82-4.71(m, 1H), 1.55(d, J=6.4Hz, 6H).
实施例54：N-(4-(4-氨基-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氯苯基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物54)Example 54: N-(4-(4-Amino-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(4-chlorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 54)
Figure PCTCN2022109584-appb-000103
Figure PCTCN2022109584-appb-000103
将化合物3-(4-氨基苯基)-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(176mg,0.62mmol)、T9(150mg,0.50mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(362mg,0.94mmol)、N,N-二异丙基乙胺(246mg,1.87mmol)加入N,N-二甲基甲酰胺(10mL)中，于25℃反应4小时。加水，用乙酸乙酯萃取，将有机相用无水硫酸钠干燥，浓缩后经甲醇打浆纯化抽滤得标题化合物54(130mg)。The compound 3-(4-aminophenyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (176mg, 0.62mmol), T9 (150mg, 0.50mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (362mg, 0.94mmol), N,N -Diisopropylethylamine (246mg, 1.87mmol) was added into N,N-dimethylformamide (10mL) and reacted at 25°C for 4 hours. Add water, extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, concentrate, purify by beating with methanol and filter with suction to obtain the title compound 54 (130 mg).
MS m/z(ESI):557.2[M+H] +. MS m/z(ESI):557.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.37(s,1H),8.97(s,1H),8.29(s,1H),7.97(dd,J＝10.8,8.4Hz,4H),7.77(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),5.14(t,J＝6.4Hz,2H),5.03(t,J＝7.2Hz,2H),4.83-4.74(m,1H),3.20(d,J＝5.2Hz,1H),1.55(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ12.37(s,1H),8.97(s,1H),8.29(s,1H),7.97(dd,J=10.8,8.4Hz,4H),7.77(d,J =8.4Hz, 2H), 7.60(d, J=8.4Hz, 2H), 5.14(t, J=6.4Hz, 2H), 5.03(t, J=7.2Hz, 2H), 4.83-4.74(m, 1H ), 3.20(d, J=5.2Hz, 1H), 1.55(d, J=6.4Hz, 6H).
实施例55：N-(4-(4-氨基-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物55)Example 55: N-(4-(4-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl )-5-(5-chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 55)
Figure PCTCN2022109584-appb-000104
Figure PCTCN2022109584-appb-000104
称取化合物3-(4-氨基苯基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(50mg,129μmol)、T10(40mg,129μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99mg,258μmol)、N,N-二异丙基乙胺(33mg,258μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物55(21mg)。Weigh compound 3-(4-aminophenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (50mg, 129μmol), T10 (40mg, 129μmol) were dissolved in N,N-dimethylformamide (2mL), added 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (99 mg, 258 μmol), N,N-diisopropylethylamine (33 mg, 258 μmol), stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 55 (21 mg).
MS m/z(ESI):587.2[M+H] +. MS m/z(ESI):587.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.98(s,1H),9.37(s,1H),8.81(d,J＝8.8Hz,1H),8.79(d,J＝2.4Hz,1H),8.28(s,1H),8.12(dd,J＝8.8,2.4Hz,1H),7.94(d,J＝8.4Hz,2H),7.72(d,J＝8.8Hz,2H),4.97(s,1H),4.94-4.82(m,1H),4.04(d,J＝7.2Hz,2H),3.58(t,J＝11.2Hz,2H),2.25(td,J＝12.4,8.0Hz,2H),1.92(d,J＝10.4Hz,2H),1.53(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ11.98(s, 1H), 9.37(s, 1H), 8.81(d, J=8.8Hz, 1H), 8.79(d, J=2.4Hz, 1H), 8.28( s,1H),8.12(dd,J=8.8,2.4Hz,1H),7.94(d,J=8.4Hz,2H),7.72(d,J=8.8Hz,2H),4.97(s,1H), 4.94-4.82(m, 1H), 4.04(d, J=7.2Hz, 2H), 3.58(t, J=11.2Hz, 2H), 2.25(td, J=12.4, 8.0Hz, 2H), 1.92(d ,J=10.4Hz,2H),1.53(d,J=6.4Hz,6H).
实施例56：N-(4-(4-氨基-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物56)Example 56: N-(4-(4-Amino-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl) -5-(5-Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 56)
Figure PCTCN2022109584-appb-000105
Figure PCTCN2022109584-appb-000105
称取化合物3-(4-氨基苯基)-1-(2,2,2-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(50mg,129μmol)、T10(40mg,129μmol)溶解在N,N-二甲基甲酰胺(2mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99mg,258μmol)、N,N-二异丙基乙胺(33mg,258μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩， 将浓缩后的残留物经制备HPLC分离得标题化合物56(22mg)。Weigh compound 3-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (50mg, 129μmol ), T10 (40mg, 129μmol) were dissolved in N,N-dimethylformamide (2mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (99 mg, 258 μmol) and N,N-diisopropylethylamine (33 mg, 258 μmol) were stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 56 (22 mg).
MS m/z(ESI):584.2[M+H] +. MS m/z(ESI):584.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.98(s,1H),9.37(s,1H),8.81(d,J＝8.8Hz,1H),8.79(d,J＝2.4Hz,1H),8.35(s,1H),8.12(dd,J＝8.8,2.4Hz,1H),7.95(d,J＝8.4Hz,2H),7.73(d,J＝8.8Hz,2H),5.31(q,J＝9.2Hz,2H),4.94-4.83(m,1H),1.53(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ11.98(s, 1H), 9.37(s, 1H), 8.81(d, J=8.8Hz, 1H), 8.79(d, J=2.4Hz, 1H), 8.35( s,1H),8.12(dd,J=8.8,2.4Hz,1H),7.95(d,J=8.4Hz,2H),7.73(d,J=8.8Hz,2H),5.31(q,J=9.2 Hz,2H),4.94-4.83(m,1H),1.53(d,J＝6.4Hz,6H).
实施例57：N-(4-(4-氨基-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物57)Example 57: N-(4-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(5-chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 57)
Figure PCTCN2022109584-appb-000106
Figure PCTCN2022109584-appb-000106
称取化合物3-(4-氨基苯基)-1-(2,2-二氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(50mg,163μmol)、T10(50mg,163μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(94mg,245μmol)、N,N-二异丙基乙胺(42mg,327μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物57(29mg)。Weigh the compound 3-(4-aminophenyl)-1-(2,2-difluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (50mg, 163μmol), T10 (50 mg, 163 μmol) was dissolved in N,N-dimethylformamide (4 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (94 mg, 245 μmol) and N,N-diisopropylethylamine (42 mg, 327 μmol) were stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 57 (29 mg).
MS m/z(ESI):566.2[M+H] +. MS m/z(ESI):566.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.97(s,1H),9.37(s,1H),8.81(d,J＝8.8Hz,1H),8.79(d,J＝2.4Hz,1H),8.32(s,1H),8.12(dd,J＝8.4,2.4Hz,1H),7.94(d,J＝8.8Hz,2H),7.73(d,J＝8.8Hz,2H),6.71-6.33(m,1H),4.88(s,1H),4.88-4.78(m,2H),1.53(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ11.97(s, 1H), 9.37(s, 1H), 8.81(d, J=8.8Hz, 1H), 8.79(d, J=2.4Hz, 1H), 8.32( s,1H),8.12(dd,J=8.4,2.4Hz,1H),7.94(d,J=8.8Hz,2H),7.73(d,J=8.8Hz,2H),6.71-6.33(m,1H ),4.88(s,1H),4.88-4.78(m,2H),1.53(d,J＝6.4Hz,6H).
实施例58：N-(4-(4-氨基-7-(2,2-二氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物58)Example 58: N-(4-(4-Amino-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5- (5-Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 58)
Figure PCTCN2022109584-appb-000107
Figure PCTCN2022109584-appb-000107
称取化合物5-(4-氨基苯基)-7-(2,2-二氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(47mg,129μmol)、T10(40mg,129μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99mg,258μmol)、N,N-二异丙基乙胺(42mg,327μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物58(33mg)。Weigh compound 5-(4-aminophenyl)-7-(2,2-difluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (47mg, 129μmol), T10 (40mg, 129μmol) was dissolved in N,N-dimethylformamide (4mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea was added Hexafluorophosphate (99 mg, 258 μmol) and N,N-diisopropylethylamine (42 mg, 327 μmol) were stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 58 (33 mg).
MS m/z(ESI):565.2[M+H] +. MS m/z(ESI):565.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.91(s,1H),9.37(s,1H),8.81(d,J＝8.8Hz,1H),8.79(d,J＝2.4Hz,1H),8.21(s,1H),8.12(dd,J＝8.8,2.4Hz,1H),7.88(d,J＝8.4Hz,2H),7.51(d,J＝8.4Hz,2H),7.39(s,1H),4.94-4.85(m,1H),4.68(dd,J＝15.2,12.0Hz,2H),1.53(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ11.91(s, 1H), 9.37(s, 1H), 8.81(d, J=8.8Hz, 1H), 8.79(d, J=2.4Hz, 1H), 8.21( s,1H),8.12(dd,J=8.8,2.4Hz,1H),7.88(d,J=8.4Hz,2H),7.51(d,J=8.4Hz,2H),7.39(s,1H), 4.94-4.85(m,1H),4.68(dd,J=15.2,12.0Hz,2H),1.53(d,J=6.4Hz,6H).
实施例59：N-(4-(4-氨基-7-(氧杂环丁-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物59)Example 59: N-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5- (5-Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 59)
Figure PCTCN2022109584-appb-000108
Figure PCTCN2022109584-appb-000108
称取化合物T2(45mg,129μmol)、T10(40mg,129μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99mg,258μmol)、N,N-二异丙基乙胺(42 mg,327μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物59(30mg)。Weigh compound T2 (45mg, 129μmol), T10 (40mg, 129μmol) and dissolve in N,N-dimethylformamide (4mL), add 2-(7-azobenzotriazole)-N,N , N', N'-tetramethylurea hexafluorophosphate (99 mg, 258 μmol), N, N-diisopropylethylamine (42 mg, 327 μmol), stirred at 25°C for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 59 (30 mg).
MS m/z(ESI):558.2[M+H] +. MS m/z(ESI):558.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.92(s,1H),9.37(s,1H),8.81(d,J＝8.8Hz,1H),8.79(d,J＝2.4Hz,1H),8.18(s,1H),8.12(dd,J＝8.4,2.4Hz,1H),7.88(d,J＝8.4Hz,2H),7.79(s,1H),7.56(d,J＝8.4Hz,2H),5.91(dd,J＝14.4,7.2Hz,1H),5.04(dt,J＝14.4,6.8Hz,4H),4.95-4.85(m,1H),1.53(d,J＝6.8Hz,6H). 1 H NMR (400MHz, DMSO) δ11.92(s, 1H), 9.37(s, 1H), 8.81(d, J=8.8Hz, 1H), 8.79(d, J=2.4Hz, 1H), 8.18( s,1H),8.12(dd,J=8.4,2.4Hz,1H),7.88(d,J=8.4Hz,2H),7.79(s,1H),7.56(d,J=8.4Hz,2H), 5.91(dd, J=14.4, 7.2Hz, 1H), 5.04(dt, J=14.4, 6.8Hz, 4H), 4.95-4.85(m, 1H), 1.53(d, J=6.8Hz, 6H).
实施例60：N-(4-(4-氨基-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物60)Example 60: N-(4-(4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) -5-(5-Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 60)
Figure PCTCN2022109584-appb-000109
Figure PCTCN2022109584-appb-000109
称取化合物5-(4-氨基苯基)-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(50mg,129μmol)、T10(40mg,129μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99mg,258μmol)、N,N-二异丙基乙胺(42mg,327μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物60(5mg)。Weigh compound 5-(4-aminophenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (50mg, 129μmol ), T10 (40mg, 129μmol) were dissolved in N,N-dimethylformamide (4mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate (99 mg, 258 μmol) and N,N-diisopropylethylamine (42 mg, 327 μmol) were stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 60 (5 mg).
MS m/z(ESI):586.2[M+H] +. MS m/z(ESI):586.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.92(s,1H),9.38(s,1H),8.82(s,1H),8.79(s,1H),8.30(s,1H),8.13(dd,J＝8.4,2.4Hz,1H),7.88(d,J＝8.4Hz,2H),7.70(s,1H),7.54(d,J＝8.4Hz,2H),4.92-4.89(m,1H),4.05(d,J＝7.2Hz,2H),3.59(d,J＝11.2Hz,2H),2.18(d,J＝8.0Hz,2H),1.92(d,J＝9.2Hz,2H),1.54(d,J＝6.4Hz,6H). 1 H NMR (400MHz,DMSO)δ11.92(s,1H),9.38(s,1H),8.82(s,1H),8.79(s,1H),8.30(s,1H),8.13(dd,J =8.4,2.4Hz,1H),7.88(d,J=8.4Hz,2H),7.70(s,1H),7.54(d,J=8.4Hz,2H),4.92-4.89(m,1H),4.05 (d, J=7.2Hz, 2H), 3.59(d, J=11.2Hz, 2H), 2.18(d, J=8.0Hz, 2H), 1.92(d, J=9.2Hz, 2H), 1.54(d ,J＝6.4Hz,6H).
实施例61：N-(4-(4-氨基-1-(2-氟乙基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物61)Example 61: N-(4-(4-amino-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(5 -Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 61)
Figure PCTCN2022109584-appb-000110
Figure PCTCN2022109584-appb-000110
称取化合物3-(4-氨基苯基)-1-(2-氟乙基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(46mg,161μmol)、T10(50mg,161μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(94mg,245μmol)、N,N-二异丙基乙胺(42mg,327μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物61(30mg)。Weigh compound 3-(4-aminophenyl)-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (46mg, 161μmol), T10 (50mg ,161μmol) was dissolved in N,N-dimethylformamide (4mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluoro Phosphate ester (94mg, 245μmol), N,N-diisopropylethylamine (42mg, 327μmol), stirred at 25°C for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 61 (30 mg).
MS m/z(ESI):548.2[M+H] +. MS m/z(ESI):548.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.97(s,1H),9.37(s,1H),8.81(d,J＝8.8Hz,1H),8.79(d,J＝2.4Hz,1H),8.29(s,1H),8.12(dd,J＝8.8,2.4Hz,1H),7.94(d,J＝8.4Hz,2H),7.73(d,J＝8.4Hz,2H),4.98(t,J＝4.8Hz,3H),4.69(d,J＝26.8Hz,2H),1.53(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ11.97(s, 1H), 9.37(s, 1H), 8.81(d, J=8.8Hz, 1H), 8.79(d, J=2.4Hz, 1H), 8.29( s,1H),8.12(dd,J=8.8,2.4Hz,1H),7.94(d,J=8.4Hz,2H),7.73(d,J=8.4Hz,2H),4.98(t,J=4.8 Hz,3H),4.69(d,J=26.8Hz,2H),1.53(d,J=6.4Hz,6H).
实施例62：N-(4-(4-氨基-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物62)Example 62: N-(4-(4-Amino-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5 -(5-chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 62)
Figure PCTCN2022109584-appb-000111
Figure PCTCN2022109584-appb-000111
称取化合物3-(4-氨基苯基)-1-(氧杂环丁-3-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(45mg,129μmol)、T10(40mg,129μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99mg,258μmol)、N,N-二异丙基乙胺(33mg,258μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物62(18mg)。Weigh compound 3-(4-aminophenyl)-1-(oxetan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (45mg, 129μmol), T10 (40 mg, 129 μmol) was dissolved in N,N-dimethylformamide (4 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (99 mg, 258 μmol) and N,N-diisopropylethylamine (33 mg, 258 μmol) were stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 62 (18 mg).
MS m/z(ESI):558.2[M+H] +. MS m/z(ESI):558.2[M+H] + .
1H NMR(400MHz,DMSO)δ12.00(s,1H),9.38(s,1H),8.82(d,J＝8.8Hz,1H),8.79(d,J＝2.4Hz,1H),8.29(s,1H),8.12(dd,J＝8.8,2.4Hz,1H),7.96(d,J＝8.4Hz,2H),7.78(d,J＝8.4Hz,2H),6.06(t,J＝7.2Hz,1H),5.14(t,J＝6.4Hz,2H),5.03(t,J＝7.2Hz,2H),4.95-4.85(m,1H),1.53(s,6H). 1 H NMR (400MHz, DMSO) δ12.00(s, 1H), 9.38(s, 1H), 8.82(d, J=8.8Hz, 1H), 8.79(d, J=2.4Hz, 1H), 8.29( s,1H),8.12(dd,J=8.8,2.4Hz,1H),7.96(d,J=8.4Hz,2H),7.78(d,J=8.4Hz,2H),6.06(t,J=7.2 Hz,1H),5.14(t,J=6.4Hz,2H),5.03(t,J=7.2Hz,2H),4.95-4.85(m,1H),1.53(s,6H).
实施例63：N-(4-(4-氨基-7-(2,2,2-三氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物63)Example 63: N-(4-(4-Amino-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 5-(5-Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 63)
Figure PCTCN2022109584-appb-000112
Figure PCTCN2022109584-appb-000112
称取化合物5-(4-氨基苯基)-7-(2,2,2-三氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(50mg,129μmol)、T10(40mg,129μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99mg,258μmol)、N,N-二异丙基乙胺(33mg,258μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物63(11mg)。Weigh compound 5-(4-aminophenyl)-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (50mg, 129μmol) , T10 (40mg, 129μmol) was dissolved in N,N-dimethylformamide (4mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (99 mg, 258 μmol), N,N-diisopropylethylamine (33 mg, 258 μmol), stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 63 (11 mg).
MS m/z(ESI):583.2[M+H] +. MS m/z(ESI):583.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.91(s,1H),9.37(s,1H),8.81(d,J＝8.8Hz,1H),8.79(d,J＝2.4Hz,1H),8.24(s,1H),8.12(dd,J＝8.8,2.4Hz,1H),7.88(d,J＝8.8Hz,2H),7.52(d,J＝8.8Hz,2H),7.41(s,1H),5.13(q,J＝9.2Hz,2H),4.93-4.84(m,1H),1.53(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ11.91(s, 1H), 9.37(s, 1H), 8.81(d, J=8.8Hz, 1H), 8.79(d, J=2.4Hz, 1H), 8.24( s,1H),8.12(dd,J=8.8,2.4Hz,1H),7.88(d,J=8.8Hz,2H),7.52(d,J=8.8Hz,2H),7.41(s,1H), 5.13(q, J=9.2Hz, 2H), 4.93-4.84(m, 1H), 1.53(d, J=6.4Hz, 6H).
实施例64：N-(4-(4-氨基-7-(2-氟乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物64)Example 64: N-(4-(4-Amino-7-(2-fluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(5- Chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (compound 64)
Figure PCTCN2022109584-appb-000113
Figure PCTCN2022109584-appb-000113
称取化合物5-(4-氨基苯基)-7-(2-氟乙基)-7H-吡咯并[2,3-d]嘧啶-4-基胺(46mg,161μmol)、T10(50mg,161μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(94mg,245μmol)、N,N-二异丙基乙胺(42mg,323μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物64(11mg)。Weigh the compound 5-(4-aminophenyl)-7-(2-fluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (46mg, 161μmol), T10 (50mg, 161μmol) was dissolved in N,N-dimethylformamide (4mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added Ester (94mg, 245μmol), N,N-diisopropylethylamine (42mg, 323μmol), stirred at 25°C for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 64 (11 mg).
MS m/z(ESI):547.2[M+H] +. MS m/z(ESI):547.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.91(s,1H),9.37(s,1H),8.81(d,J＝12.4Hz,2H),8.19(s,1H),8.11(s,1H),7.86(s,2H),7.53(s,2H),7.42(s,1H),4.90(s,2H),4.78(s,1H),4.50(s,3H),1.53(s,7H). 1 H NMR (400MHz,DMSO)δ11.91(s,1H),9.37(s,1H),8.81(d,J=12.4Hz,2H),8.19(s,1H),8.11(s,1H), 7.86(s,2H),7.53(s,2H),7.42(s,1H),4.90(s,2H),4.78(s,1H),4.50(s,3H),1.53(s,7H).
实施例65：N-(4-(4-氨基-1-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(5-氯吡啶-2-基)-1-异丙基-4-氧代-1,4-二氢哒嗪-3-甲酰胺(化合物65)Example 65: N-(4-(4-Amino-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl) Phenyl)-5-(5-chloropyridin-2-yl)-1-isopropyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (Compound 65)
Figure PCTCN2022109584-appb-000114
Figure PCTCN2022109584-appb-000114
称取化合物3-(4-氨基苯基)-1-(1,1,1-三氟丙烷-2-基)-1H-吡唑并[3,4-d]嘧啶-4-基胺(52mg,129μmol)、T10(40mg,129μmol)溶解在N,N-二甲基甲酰胺(4mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(99mg,258μmol)、N,N-二异丙基乙胺(33mg,258μmol)，在25℃下搅拌5小时。向反应液中加入水，用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，用无水硫酸钠干燥并浓缩，将浓缩后的残留物经制备HPLC分离得标题化合物65(77mg)。Weigh compound 3-(4-aminophenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine ( 52mg, 129μmol), T10 (40mg, 129μmol) were dissolved in N,N-dimethylformamide (4mL), added 2-(7-azobenzotriazole)-N,N,N',N '-Tetramethylurea hexafluorophosphate (99 mg, 258 μmol), N,N-diisopropylethylamine (33 mg, 258 μmol), stirred at 25° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the concentrated residue was separated by preparative HPLC to obtain the title compound 65 (77 mg).
MS m/z(ESI):598.2[M+H] +. MS m/z(ESI):598.2[M+H] + .
1H NMR(400MHz,DMSO)δ11.93(s,1H),9.37(s,1H),8.81(d,J＝8.8Hz,1H),8.79(d,J＝2.4Hz,1H),8.23(s,1H),8.12(dd,J＝8.4,2.4Hz,1H),7.88(d,J＝8.8Hz,2H),7.61(s,1H),7.54(d,J＝8.4Hz,2H),5.76-5.65(m,1H),4.91(dd,J＝13.2,6.8Hz,1H),1.78(d,J＝7.2Hz,3H),1.53(d,J＝6.4Hz,6H). 1 H NMR (400MHz, DMSO) δ11.93(s, 1H), 9.37(s, 1H), 8.81(d, J=8.8Hz, 1H), 8.79(d, J=2.4Hz, 1H), 8.23( s,1H),8.12(dd,J=8.4,2.4Hz,1H),7.88(d,J=8.8Hz,2H),7.61(s,1H),7.54(d,J=8.4Hz,2H), 5.76-5.65(m,1H),4.91(dd,J=13.2,6.8Hz,1H),1.78(d,J=7.2Hz,3H),1.53(d,J=6.4Hz,6H).
生物学评价：Biological Evaluation:
试验例1：化合物对Axl、Mer和Tyro3激酶活性测试Test Example 1: Compounds are tested for Axl, Mer and Tyro3 kinase activity
1.试验系统：1. Test system:
激酶：Axl(Carna)；激酶：Mer(Carna)；激酶：Tyro3(Carna)Kinase: Axl(Carna); Kinase: Mer(Carna); Kinase: Tyro3(Carna)
HTRF试剂盒：HTRF KinEASE TM-TK(Cisbio) HTRF kit: HTRF KinEASE TM -TK (Cisbio)
2.试验参数：2. Test parameters:
Figure PCTCN2022109584-appb-000115
Figure PCTCN2022109584-appb-000115
3.实验方法：3. Experimental method:
将酶分别与不同浓度的测试化合物在25℃下预孵育一定时间，然后加入5×TK-substrate-biotin/ATP混合工作液，在25℃下分别反应一段时间，最后加入2×Streptavidin-XL665与TK Antibody-Cryptate的混合工作液，在25℃下孵育一段时间后，通过酶标仪检测荧光信号比值(Ratio)。Pre-incubate the enzyme with different concentrations of test compounds at 25°C for a certain period of time, then add 5×TK-substrate-biotin/ATP mixed working solution, react at 25°C for a period of time, and finally add 2×Streptavidin-XL665 and The mixed working solution of TK Antibody-Cryptate was incubated at 25°C for a period of time, and the fluorescence signal ratio (Ratio) was detected by a microplate reader.
4.数据处理：4. Data processing:
以溶剂组(DMSO)为阴性对照、反应缓冲液组为空白对照，按照下式计算不同浓度化合物的百分比抑制率：With the solvent group (DMSO) as the negative control and the reaction buffer group as the blank control, the percentage inhibition rates of different concentrations of compounds were calculated according to the following formula:
百分比抑制率＝(1-(不同浓度化合物Ratio-空白对照Ratio)/(阴性对照Ratio-空白对照Ratio))×100％；Percent inhibition rate=(1-(compound Ratio of different concentrations-blank control Ratio)/(negative control Ratio-blank control Ratio))×100%;
当百分比抑制率介于30-80％时，按照下述公式计算化合物的半数抑制浓度(IC 50)或范围： When the percentage inhibition rate is between 30-80%, the half maximal inhibitory concentration (IC 50 ) or range of the compound is calculated according to the following formula:
IC 50＝X×(1-百分比抑制率(％))/百分比抑制率(％)，其中：X为抑制率介于30-80％时化合物的测试浓度。 IC 50 =X×(1-percent inhibition rate (%))/percent inhibition rate (%), wherein: X is the test concentration of the compound when the inhibition rate is between 30-80%.
5.试验结果：5. Test results:
按照上述方法测定化合物对Axl/Mer/Tyro3的抑制作用，结果如表1-1、1-2、1-3中所示。The inhibitory effect of the compounds on Axl/Mer/Tyro3 was determined according to the above method, and the results are shown in Tables 1-1, 1-2, and 1-3.
表1-1.本发明的化合物对Axl的抑制活性Table 1-1. Compounds of the present invention have inhibitory activity on Axl
化合物编号Compound number Axl IC 50(nM) Axl IC 50 (nM)
11 2.42.4
22 3.33.3
33 2.62.6
44 6.16.1
55 1.61.6
66 1.31.3
77 1.91.9
88 0.40.4
99 3.73.7
1010 2.12.1
1111 3.63.6
1212 4.04.0
1313 18.718.7
1414 0.20.2
1515 4.04.0
1616 0.20.2
1717 1.51.5
1818 2.32.3
1919 5.85.8
2020 1.61.6
21twenty one 12.912.9
22twenty two 4.24.2
23twenty three 0.30.3
24twenty four 4.34.3
2525 1.31.3
2626 1.81.8
2727 0.20.2
2828 12.412.4
2929 3.23.2
3030 3.23.2
3131 2.32.3
3232 2.92.9
3333 4.24.2
3434 2.12.1
3535 11.811.8
3636 9.09.0
3737 1.81.8
3838 9.79.7
3939 0.70.7
4040 0.50.5
4141 4.84.8
4242 10.910.9
4343 7.47.4
4444 11.511.5
4545 71.871.8
4646 14.414.4
4747 8.38.3
4848 19.119.1
4949 3.03.0
5050 21.421.4
5151 34.534.5
5252 27.327.3
5353 30.530.5
5454 19.819.8
5555 10.010.0
5656 46.246.2
5757 14.414.4
5858 4.84.8
5959 7.97.9
6060 1.81.8
6161 4.84.8
6262 36.936.9
6363 6.86.8
6464 3.43.4
6565 5.75.7
表1-2.本发明的化合物对Mer的抑制活性Table 1-2. The inhibitory activity of the compounds of the present invention on Mer
化合物编号Compound number Mer IC 50(nM) Mer IC 50 (nM)
11 9.39.3
77 65.165.1
1818 13.813.8
1919 7.37.3
23twenty three 2.52.5
2525 4.64.6
2626 3.53.5
2727 6.26.2
2828 6.16.1
2929 18.818.8
3939 8.78.7
4040 4.04.0
4646 29.529.5
5858 6.26.2
6363 20.820.8
表1-3.本发明的化合物对Tyro3的抑制活性Table 1-3. The inhibitory activity of the compound of the present invention to Tyro3
化合物编号Compound number Tyro3IC 50(nM) Tyro3IC 50 (nM)
11 138.7138.7
1616 86.786.7
1717 104.0104.0
2828 170.6170.6
2929 244.1244.1
6363 140.8140.8
结论：in conclusion:
本发明的化合物对Axl和Mer表现出较强的抑制活性。The compound of the present invention shows strong inhibitory activity on Axl and Mer.
试验例2：化合物对Ba/F3-TEL-Axl细胞的增殖活性抑制试验Test example 2: Compound inhibits the proliferation activity of Ba/F3-TEL-Axl cells
1.试验系统：1. Test system:
细胞名称/制造商：Ba/F3-TEL-Axl/合肥普瑞昇Cell name/manufacturer: Ba/F3-TEL-Axl/Hefei Presun
试剂盒名称/制造商：
Figure PCTCN2022109584-appb-000116
Luminescent Cell Viability Assay,Promega Kit name/manufacturer:
Figure PCTCN2022109584-appb-000116
Luminescent Cell Viability Assay, Promega
2.试验参数：2. Test parameters:
细胞数量：2000细胞/孔Cell number: 2000 cells/well
培养基：RPMI-1640+10％FBS+1％P/SMedium: RPMI-1640+10%FBS+1%P/S
DMSO含量：0.1％DMSO content: 0.1%
化合物孵育条件：37℃，5％CO 2 Compound incubation conditions: 37 °C, 5% CO2
孵育时间：72hIncubation time: 72h
检测温度：RTDetection temperature: RT
检测仪器：Molecular DevicesTesting instrument: Molecular Devices
3.试验步骤：3. Test steps:
将Ba/F3-TEL-Axl细胞体外单层培养，培养条件为10％FBS+1％P/S的RPMI-1640培养基，于37℃、含5％CO 2空气的培养箱中培养。在96孔板中铺入细胞，2000个/孔，然后加入预先稀释的化合物，阴性对照组加DMSO，空白对照组加培养基，于37℃、5％CO 2空气的培养箱孵育72h 后，向每孔中加入检测试剂CellTiter-Glo，在酶标仪化学发光检测模式下读取相对化学发光单位值(RLU)。 The Ba/F3-TEL-Axl cells were cultured in a monolayer in vitro, the culture condition was 10% FBS+1% P/S RPMI-1640 medium, and cultured in an incubator containing 5% CO 2 air at 37°C. Spread cells in 96-well plate, 2000 cells/well, then add pre-diluted compound, add DMSO to negative control group, add culture medium to blank control group, and incubate at 37°C for 72 hours in an incubator with 5% CO2 air. Add the detection reagent CellTiter-Glo to each well, and read the relative chemiluminescence unit value (RLU) in the chemiluminescence detection mode of the microplate reader.
4.数据处理：4. Data processing:
按照下述公式计算不同浓度化合物的百分比抑制率：Calculate the percentage inhibition rate of different concentrations of compounds according to the following formula:
百分比抑制率＝(1-(测试化合物的化学发光信号值-空白对照的化学发光信号值)/(阴性对照的化学发光信号值-空白对照的化学发光信号值))×100％，采用Graphpad 7.0按照四参数模型拟合曲线，计算化合物的半数抑制浓度(IC 50)。 Percent inhibition rate=(1-(chemiluminescent signal value of test compound-chemiluminescent signal value of blank control)/(chemiluminescent signal value of negative control-chemiluminescent signal value of blank control))×100%, using Graphpad 7.0 The curve was fitted according to the four-parameter model, and the half-maximal inhibitory concentration (IC 50 ) of the compound was calculated.
5.试验结果：5. Test results:
按照上述方法测定化合物对Ba/F3-TEL-Axl细胞的增殖抑制活性，结果如表2中所示。The growth inhibitory activity of the compounds on Ba/F3-TEL-Axl cells was determined according to the above method, and the results are shown in Table 2.
表2.化合物对Ba/F3-TEL-Axl细胞增殖活性抑制结果Table 2. Compounds inhibit the proliferation of Ba/F3-TEL-Axl cells
化合物编号Compound number Ba/F3-TEL-Axl,IC 50(nM) Ba/F3-TEL-Axl, IC 50 (nM)
44 9.69.6
55 34.334.3
77 29.729.7
88 33.633.6
99 8.38.3
1616 6.16.1
1717 5.95.9
23twenty three 0.90.9
2929 1.01.0
3030 2.72.7
3131 4.34.3
3232 2.32.3
3333 2.12.1
3434 3.43.4
3535 1.41.4
3636 2.62.6
3737 6.66.6
3838 14.314.3
3939 3.23.2
4040 5.45.4
4141 3.53.5
4242 33.233.2
4343 12.312.3
4444 16.616.6
4545 44.744.7
4646 9.79.7
4747 24.724.7
4848 4.04.0
4949 3.63.6
5050 4.84.8
5151 7.07.0
5858 9.89.8
结论：in conclusion:
本发明的化合物对Ba/F3-TEL-Axl细胞具有较强的增殖抑制活性。The compound of the present invention has strong proliferation inhibitory activity on Ba/F3-TEL-Axl cells.
试验例3：化合物对HCC827erlotinib R细胞的增殖活性抑制试验Test Example 3: Inhibitory test of compounds on the proliferation activity of HCC827erlotinib R cells
1.试验系统：1. Test system:
细胞名称：HCC827erlotinib R(厄洛替尼耐药的HCC827细胞)Cell name: HCC827erlotinib R (erlotinib-resistant HCC827 cells)
试剂盒名称/制造商：
Figure PCTCN2022109584-appb-000117
Luminescent Cell Viability Assay,Promega Kit name/manufacturer:
Figure PCTCN2022109584-appb-000117
Luminescent Cell Viability Assay, Promega
2.试验参数：2. Test parameters:
细胞数量：4000细胞/孔Cell number: 4000 cells/well
培养基：RPMI1640+10％FBSMedium: RPMI1640+10%FBS
DMSO含量：0.5％DMSO content: 0.5%
化合物孵育条件：37℃，5％CO 2 Compound incubation conditions: 37 °C, 5% CO2
孵育时间：72hIncubation time: 72h
检测温度：RTDetection temperature: RT
检测仪器：Thermo VarioskanDetection instrument: Thermo Varioskan
3.试验步骤：3. Test steps:
将HCC827 erlotinib R细胞体外单层培养，培养条件为RPMI1640+10％FBS培养基+200nM厄洛替尼，于37℃、含5％CO 2空气的培养箱中培养。在96孔板中铺入细胞，4000个/孔，然后加入预先稀释的化合物，阴性对照组加DMSO，空白对照组加培养基，铺板所用培养基不含厄洛替尼，于37℃、5％CO 2空气的培养箱孵育72h后，向每孔中加入检测试剂CellTiter-Glo，在酶标仪化学发光检测模式下读取相对化学发光单位值(RLU)。 HCC827 erlotinib R cells were cultured in a monolayer in vitro, the culture condition was RPMI1640+10% FBS medium+200nM erlotinib, and cultured in an incubator at 37°C with 5% CO 2 air. Cells were plated in 96-well plates, 4000 cells/well, and then pre-diluted compounds were added. The negative control group was added with DMSO, and the blank control group was added with culture medium. The culture medium used for plating did not contain erlotinib. After incubating in an incubator with % CO 2 air for 72 hours, the detection reagent CellTiter-Glo was added to each well, and the relative chemiluminescence unit value (RLU) was read in the chemiluminescence detection mode of a microplate reader.
4.数据处理：4. Data processing:
按照下述公式计算不同浓度化合物的百分比抑制率：Calculate the percentage inhibition rate of different concentrations of compounds according to the following formula:
百分比抑制率＝(1-(测试化合物的化学发光信号值-空白对照的化学发光信号值)/(阴性对照的化学发光信号值-空白对照的化学发光信号值))×100％，采用Graphpad 7.0按照四参数模型拟合曲线，计算化合物的半数抑制浓度(IC 50)。 Percent inhibition rate=(1-(chemiluminescent signal value of test compound-chemiluminescent signal value of blank control)/(chemiluminescent signal value of negative control-chemiluminescent signal value of blank control))×100%, using Graphpad 7.0 The curve was fitted according to the four-parameter model, and the half-maximal inhibitory concentration (IC 50 ) of the compound was calculated.
5.试验结果：5. Test results:
按照上述方法测定化合物对HCC827 erlotinib R细胞的增殖抑制活性，结果如表3中所示。The proliferation inhibitory activity of the compound on HCC827 erlotinib R cells was determined according to the above method, and the results are shown in Table 3.
表3.化合物对HCC827 erlotinib R细胞增殖抑制活性结果Table 3. The results of the compound's inhibitory activity on the proliferation of HCC827 erlotinib R cells
化合物编号Compound number HCC827 erlotinib R,IC 50(μM) HCC827 erlotinib R, IC 50 (μM)
1919 0.110.11
21twenty one 0.050.05
23twenty three 0.580.58
2525 0.370.37
3131 0.360.36
3232 0.160.16
3434 0.600.60
3838 0.720.72
3939 0.300.30
4040 0.240.24
4141 0.400.40
4646 0.710.71
4848 0.120.12
5050 0.150.15
5151 0.200.20
结论：in conclusion:
本发明的化合物对厄洛替尼耐药的HCC827细胞具有较强的增殖抑制活性。The compound of the present invention has strong proliferation inhibitory activity on erlotinib-resistant HCC827 cells.
试验例4：CYP酶(细胞色素P450)抑制试验Test Example 4: CYP enzyme (cytochrome P450) inhibition test
1、试验系统：1. Test system:
P450-Glo TM CYP1A2筛选系统(Promega)； P450-Glo ™ CYP1A2 Screening System (Promega);
P450-Glo TM CYP2D6筛选系统(Promega)； P450-Glo ™ CYP2D6 Screening System (Promega);
P450-Glo TM CYP3A4筛选系统(Promega)。 P450-Glo ™ CYP3A4 Screening System (Promega).
2、测试仪器：2. Test equipment:
BMG PHERAstar FS Luminescent。BMG PHERAstar FS Luminescent.
3、试验方法：3. Test method:
分别按照试剂盒说明书进行试验，步骤如下：The test was carried out according to the instructions of the kit respectively, and the steps were as follows:
3.1.对CYP1A2的抑制：3.1. Inhibition of CYP1A2:
测试组：将不同浓度的待测化合物加入到微孔板中。向每孔中加入Luciferin-ME(100μM)、K 3PO 4(100mM)和CYP1A2(0.01pmol/μL)，在室温下预孵育10min。随后加入NADPH再生系统，在室温下反应30min。最后加入等体积的检测缓冲液，在室温下孵育20min。然后进行化学发光检测。 Test group: Add different concentrations of test compounds to the microwell plate. Luciferin-ME (100 μM), K 3 PO 4 (100 mM) and CYP1A2 (0.01 pmol/μL) were added to each well, and pre-incubated at room temperature for 10 min. Then add NADPH regeneration system and react at room temperature for 30min. Finally, an equal volume of detection buffer was added and incubated at room temperature for 20 min. Chemiluminescent detection is then performed.
阴性对照组：实验方法同测试组，但不加待测化合物。Negative control group: the experimental method is the same as that of the test group, but no compound to be tested is added.
空白对照组：实验方法同测试组，但不加待测化合物，并且用CYP1A2 Membrance(0.01pmol/μL)代替CYP1A2。Blank control group: The experimental method is the same as that of the test group, but the test compound is not added, and CYP1A2 is replaced by CYP1A2 Membrance (0.01pmol/μL).
3.2.对CYP2D6的抑制：3.2. Inhibition of CYP2D6:
测试组：将不同浓度的待测化合物加入到微孔板中。向每孔中加入Luciferin-ME EGE(3μM)、K 3PO 4(100mM)和CYP2D6(5nM)，在室温下预孵育10min。随后加入NADPH再生系统，在37℃下反应30min。最后加入等体积的检测缓冲液，在室温下孵育20min。然后进行化学发光检测。 Test group: Add different concentrations of test compounds to the microwell plate. Luciferin-ME EGE (3 μM), K 3 PO 4 (100 mM) and CYP2D6 (5 nM) were added to each well, and pre-incubated at room temperature for 10 min. Then add NADPH regeneration system and react at 37°C for 30min. Finally, an equal volume of detection buffer was added and incubated at room temperature for 20 min. Chemiluminescent detection is then performed.
阴性对照组：实验方法同测试组，但不加待测化合物。Negative control group: the experimental method is the same as that of the test group, but no compound to be tested is added.
空白对照组：实验方法同测试组，但不加待测化合物，并且用CYP2D6 Membrance(5nM)代替CYP2D6。Blank control group: the experimental method is the same as that of the test group, but no test compound is added, and CYP2D6 Membrance (5nM) is used instead of CYP2D6.
3.3.对CYP3A4的抑制：3.3. Inhibition of CYP3A4:
测试组：将不同浓度的待测化合物加入到微孔板中。向每孔中加入Luciferin-IPA(3μM)、K 3PO 4(100mM)和CYP3A4(2nM)，在室温下预孵育10min。随后加入NADPH再生系统，在室温下反应30min。最后加入等体积的检测缓冲液，在室温下孵育20min。然后进行化学发光检测。 Test group: Add different concentrations of test compounds to the microwell plate. Luciferin-IPA (3 μM), K 3 PO 4 (100 mM) and CYP3A4 (2 nM) were added to each well, and pre-incubated at room temperature for 10 min. Then add NADPH regeneration system and react at room temperature for 30min. Finally, an equal volume of detection buffer was added and incubated at room temperature for 20 min. Chemiluminescent detection is then performed.
阴性对照组：实验方法同测试组，但不加待测化合物。Negative control group: the experimental method is the same as that of the test group, but no compound to be tested is added.
空白对照组：实验方法同测试组，但不加待测化合物，并且用CYP3A4 Membrance(2nM)代替CYP3A4。Blank control group: the experimental method is the same as that of the test group, but no test compound is added, and CYP3A4 Membrance (2nM) is used instead of CYP3A4.
4、数据处理：4. Data processing:
百分比抑制率(％)＝(1-(待测化合物的化学发光信号值-空白对照的化学发光信号值)/(阴性对照的化学发光信号值-空白对照的化学发光信号值))×100％；Percent inhibition rate (%)=(1-(chemiluminescence signal value of test compound-chemiluminescence signal value of blank control)/(chemiluminescence signal value of negative control-chemiluminescence signal value of blank control))×100% ;
根据不同浓度化合物对CYP酶的抑制率，估算化合物的半数抑制浓度(IC 50)或范围： According to the inhibitory rate of different concentrations of compounds on CYP enzymes, estimate the half inhibitory concentration (IC 50 ) or range of the compound:
IC 50＝X×(1-百分比抑制率(％))/百分比抑制率(％)，其中：X为化合物的测试浓度。 IC 50 =X×(1-percent inhibition rate (%))/percent inhibition rate (%), wherein: X is the test concentration of the compound.
5、实验结果：5. Experimental results:
按照上述方法测定本发明化合物对三种CYPs的抑制，结果如下表4中所示。The inhibition of the compounds of the present invention on three CYPs was determined according to the above method, and the results are shown in Table 4 below.
表4.CYPs抑制试验结果Table 4. Results of CYPs inhibition test
Figure PCTCN2022109584-appb-000118
Figure PCTCN2022109584-appb-000118
Figure PCTCN2022109584-appb-000119
Figure PCTCN2022109584-appb-000119
结论：in conclusion:
本发明的化合物对3种主要CYP亚型均无明显抑制作用，表明其潜在的药物相互作用可能性相对较低。The compound of the present invention has no obvious inhibitory effect on the three major CYP subtypes, indicating that its potential drug interaction is relatively low.
试验例5.生化hERG抑制试验Test Example 5. Biochemical hERG Inhibition Test
1.试验系统：1. Test system:
试剂盒：Predictor TM hERG Fluorescence Polarization Assay,(ThermoFisher)， Kit: Predictor TM hERG Fluorescence Polarization Assay, (ThermoFisher),
试剂盒中含有：The kit contains:
阳性对照化合物hERG钾通道阻断剂E4031；Positive control compound hERG potassium channel blocker E4031;
hERG细胞膜；hERG cell membrane;
亲和性示踪剂Tracer；Affinity tracer Tracer;
hERG缓冲液。hERG buffer.
2.试验参数：2. Test parameters:
hERG浓度：1×hERG concentration: 1×
Tracer浓度：1nMTracer concentration: 1nM
孵育时间：2hIncubation time: 2h
BMG PHERAstar FS FPBMG PHERAstar FS FP
3.试验方法：3. Test method:
按照试剂盒说明书进行试验，步骤如下：Carry out the test according to the kit instructions, the steps are as follows:
测试组：将不同浓度的待测化合物加入到含有hERG细胞膜的微孔板中，每孔中再加入具有高hERG亲和性示踪剂Tracer，将微孔板在室温孵育2小时后，使用多功能酶标仪检测荧光 偏振(Excitation：540nm；Emission：590nm)值的变化。Test group: Add different concentrations of compounds to be tested into microwell plates containing hERG cell membranes, and then add Tracer, a tracer with high hERG affinity, to each well. After incubating the microwell plates at room temperature for 2 hours, use multiple Functional microplate reader detects the change of fluorescence polarization (Excitation: 540nm; Emission: 590nm) value.
阳性对照组：用30μM阳性对照化合物E4031代替待测化合物，实验方法与测试组相同。Positive control group: 30 μM positive control compound E4031 was used instead of the test compound, and the experimental method was the same as that of the test group.
空白对照组：用hERG缓冲液代替待测化合物，并且不加hERG细胞膜，实验方法与测试组相同。Blank control group: hERG buffer was used instead of the compound to be tested, and hERG cell membrane was not added, and the experimental method was the same as that of the test group.
4.数据处理：4. Data processing:
根据下述公式，计算本发明的化合物在不同浓度下对hERG的百分比抑制率。According to the following formula, the percentage inhibition rate of the compound of the present invention on hERG at different concentrations was calculated.
百分比抑制率＝(1-(待测化合物的荧光偏振值-阳性对照组的荧光偏振值)/(空白对照组的的荧光偏振值-阳性对照组的荧光偏振值))*100％Percent inhibition rate=(1-(fluorescence polarization value of the compound to be tested-fluorescence polarization value of the positive control group)/(fluorescence polarization value of the blank control group-fluorescence polarization value of the positive control group))*100%
当百分比抑制率介于30-80％之间时，根据下述公式，估算化合物对hERG的半数抑制浓度(IC 50)或范围： When the percentage inhibition rate is between 30-80%, the half inhibitory concentration (IC 50 ) or range of the compound against hERG is estimated according to the following formula:
IC 50＝X×(1-百分比抑制率(％))/百分比抑制率(％)，其中：X为抑制率介于30-80％时化合物的测试浓度。 IC 50 =X×(1-percent inhibition rate (%))/percent inhibition rate (%), wherein: X is the test concentration of the compound when the inhibition rate is between 30-80%.
5.实验结果：5. Experimental results:
采用上述方法测定化合物对hERG的抑制，结果如下表5中所示。The above method was used to determine the inhibition of the compounds on hERG, and the results are shown in Table 5 below.
表5.hERG抑制试验结果Table 5. hERG inhibition test results
实施例编号Example number IC 50(μM) IC50 (μM)
44 >10>10
55 >10>10
77 >10>10
88 >10>10
99 10.410.4
1010 >10>10
1919 10.010.0
21twenty one >10>10
22twenty two 9.29.2
23twenty three >10>10
2525 >10>10
3131 >10>10
3434 >10>10
3535 >10>10
3737 >10>10
3838 >10>10
4040 >10>10
4141 >10>10
4343 >10>10
4444 >10>10
4646 >10>10
4747 >10>10
5555 >10>10
5858 >10>10
5959 >10>10
6060 9.89.8
6363 >10>10
6565 >10>10
测试结果表明，本发明绝大多数化合物与hERG亲和性低，与亲和性示踪剂Tracer竞争的 IC 50均＞10μM。证明本发明的绝大多数化合物hERG离子通道相关的心脏毒性风险较低。 The test results show that most of the compounds of the present invention have low affinity with hERG, and the IC 50 of the competition with the affinity tracer Tracer is all >10 μM. It was demonstrated that the vast majority of compounds of the present invention have a low risk of cardiotoxicity associated with hERG ion channels.
试验例6：化合物肝微粒体代谢稳定性测试Test Example 6: Metabolic Stability Test of Compound Liver Microsomes
1.材料与方法1. Materials and methods
1.1主要试验材料1.1 Main test materials
睾酮          Dr.Ehrenstorfer，德国Testosterone Dr. Ehrenstorfer, Germany
混合人肝微粒体       Xenotech或BioIVT，美国Pooled human liver microsomes Xenotech or BioIVT, USA
混合雄性SD大鼠肝微粒体     BioIVT，美国Mixed male SD rat liver microsomes BioIVT, USA
1.2肝微粒体孵育体系1.2 Liver microsome incubation system
将阳性化合物睾酮或待测物(肝微粒体溶液，50μl)与PBS(25μl)混合，预孵(37℃)5min后，加入NADPH(25μl)，使阳性化合物或待测物终浓度为1μM，人和大鼠肝微粒体蛋白终浓度为0.5mg/ml，将待测物组和阳性化合物组孵育0、15min。反应相应时间后加入300μl含内标的冰乙腈终止反应，涡旋，存于-80℃待测。所有孵育样本均为双样本。Mix the positive compound testosterone or the test substance (liver microsomal solution, 50 μl) with PBS (25 μl), pre-incubate (37°C) for 5 minutes, add NADPH (25 μl), so that the final concentration of the positive compound or test substance is 1 μM, The final concentration of human and rat liver microsomal protein was 0.5 mg/ml, and the test substance group and positive compound group were incubated for 0 and 15 minutes. After the corresponding reaction time, 300 μl of glacial acetonitrile containing internal standard was added to terminate the reaction, vortexed, and stored at -80°C for testing. All incubation samples were double samples.
1.3样品预处理1.3 Sample pretreatment
将待测物涡流1min，离心10min(4℃，4000rpm)。取上清液160μl，向其中加入160μl的50％乙腈-水，混匀后，进行LC-MS/MS分析。Vortex the sample for 1 min and centrifuge for 10 min (4°C, 4000 rpm). Take 160 μl of the supernatant, add 160 μl of 50% acetonitrile-water to it, mix well, and perform LC-MS/MS analysis.
2.数据处理2. Data processing
使用Excel软件，计算孵育体系中原形药物的剩余率(％)：Use Excel software to calculate the remaining rate (%) of the prototype drug in the incubation system:
原形剩余率(％)＝100×(A 孵育样品/A 0h) Prototype remaining rate (%)=100×(A incubation sample /A 0h )
注：A 孵育样品：孵育相应时间后化合物与内标峰面积比；A 0h：未反应时化合物与内标峰面积比。 Note: A incubation sample : the peak area ratio of the compound and the internal standard after incubation for the corresponding time; A 0h : the peak area ratio of the compound and the internal standard when unreacted.
3.结果与结论3. Results and conclusions
按照上述方法测定化合物在人和大鼠肝微粒体中孵育15min后的原形剩余率如表6所示。The residual rate of the original form of the compound after being incubated in human and rat liver microsomes for 15 min was determined according to the above method, as shown in Table 6.
表6.本发明的化合物在人和大鼠肝微粒体中孵育15min后的原形剩余率Table 6. The residual rate of the prototype of the compound of the present invention after being incubated in human and rat liver microsomes for 15min
Figure PCTCN2022109584-appb-000120
Figure PCTCN2022109584-appb-000120
结论：in conclusion:
本发明的大部分化合物在人肝微粒体中代谢稳定，在大鼠肝微粒体中代谢也较为稳定，总体代谢稳定性良好。Most of the compounds of the present invention have stable metabolism in human liver microsomes, relatively stable metabolism in rat liver microsomes, and the overall metabolic stability is good.
试验例7：化合物在SD大鼠体内药代动力学试验测试Test Example 7: Compound pharmacokinetics test in SD rats
通过灌胃(PO)向雄性SD大鼠给予本发明的化合物，考察药代动力学特点。The compound of the present invention was administered to male SD rats by intragastric administration (PO), and the pharmacokinetic characteristics were investigated.
将本发明的化合物进行PO给药，给药剂量如表7所示。在PO给药前(0h)以及给药后0.25、0.5、1、2、4、6、8、24h采集血样，经尾静脉取血0.3ml，置于K 2-EDTA抗凝试管中，在4000rpm下离心5min(4℃)，分离血浆，-80℃保存待测。血浆样品经沉淀蛋白处理后进行LC-MS/MS分析。应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见表7。 The compounds of the present invention were administered PO, and the doses are shown in Table 7. Blood samples were collected before PO administration (0h) and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24h after administration, and 0.3ml of blood was collected through the tail vein, placed in a K 2 -EDTA anticoagulant test tube, and placed in a K 2 -EDTA anticoagulation test tube. Centrifuge at 4000rpm for 5min (4°C) to separate the plasma and store it at -80°C for testing. Plasma samples were processed by precipitating protein for LC-MS/MS analysis. The non-compartmental model was used to calculate the pharmacokinetic parameters using WinNonlin 6.3 software, and the results are shown in Table 7.
表7：本发明化合物在大鼠体内的药代动力学参数Table 7: Pharmacokinetic parameters of the compounds of the present invention in rats
Figure PCTCN2022109584-appb-000121
Figure PCTCN2022109584-appb-000121
a溶媒为：0.5％MC；b溶媒为：10％DMSO:10％Solutol(聚乙二醇-15羟基硬脂酸酯):80％生理盐水的混合物(pH＝2)；c溶媒为：10％DMSO:20％Solutol(聚乙二醇-15羟基硬脂酸酯):70％超纯水。a vehicle is: 0.5% MC; b vehicle is: 10% DMSO: 10% Solutol (polyethylene glycol-15 hydroxystearate): the mixture of 80% normal saline (pH=2); c vehicle is: 10 %DMSO: 20% Solutol (polyethylene glycol-15 hydroxystearate): 70% ultrapure water.
结论：in conclusion:
本发明的化合物23、40和63通过PO给药后在大鼠体内暴露量高。Compounds 23, 40 and 63 of the present invention showed high exposure in rats after PO administration.
本说明书中公开的所有技术特征，或公开的所有方法或过程中的步骤，除了互相排斥的技术特征和/或步骤以外，均可以以任何方式组合。All technical features disclosed in this specification, or steps in all disclosed methods or processes, except for mutually exclusive technical features and/or steps, may be combined in any manner.

Claims (21)

  1. 式I的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof,
    Figure PCTCN2022109584-appb-100001
    Figure PCTCN2022109584-appb-100001
    其中，in,
    R 1选自H、C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基和5-10元杂芳基，所述C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 6取代； R 1 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 6 ;
    R 6在每次出现时各自独立地选自卤素、-CN、-OH、-NH 2、-NO 2、-S(O) pR A、-COR A、＝O、C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基、3-8元杂环基、C 2-C 6烯基、C 2-C 6炔基、C 6-C 10芳基和5-10元杂芳基，所述C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基、3-8元杂环基、C 2-C 6烯基、C 2-C 6炔基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 7取代； Each occurrence of R 6 is independently selected from halogen, -CN, -OH, -NH 2 , -NO 2 , -S(O) pRA , -CORA , =O, C 1 -C 6 alkane C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, 3-8 membered heterocyclyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl and 5-10 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, 3-8 membered heterocyclic group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 7 ;
    R 7在每次出现时各自独立地选自卤素、-CN、-OH、-NH 2、-NO 2、-S(O) pR A、-COR A和＝O； Each occurrence of R 7 is independently selected from halogen , -CN, -OH, -NH 2 , -NO 2 , -S(O) pRA , -COR A and =O;
    R A独立地选自H和C 1-C 6烷基； RA is independently selected from H and C 1 -C 6 alkyl;
    p选自1和2；p is selected from 1 and 2;
    R 2在每次出现时各自独立地选自H、-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷基、C 1-C 6烷氧基和C 3-C 8环烷基，所述C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 8环烷基任选地被一个或多个R 8取代； Each occurrence of R 2 is independently selected from H, -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and C 3 - C 8 cycloalkyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 8 cycloalkyl are optionally substituted by one or more R 8 ;
    R 8在每次出现时各自独立地选自-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基； Each occurrence of R 8 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
    m选自0、1、2、3和4；m is selected from 0, 1, 2, 3 and 4;
    R 3选自H、C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基和5-10元杂芳基，所述C 1-C 6烷基、C 3-C 8环烷基、3-8元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 9取代； R 3 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclic group, C 6 -C 10 aryl and 5-10 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl are optionally substituted by one or more R 9 ;
    R 9在每次出现时各自独立地选自-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基； Each occurrence of R 9 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 haloalkoxy;
    R 4选自H、C 1-C 6烷基、C 3-C 8环烷基和3-8元杂环基，所述C 1-C 6烷基、C 3-C 8环烷基或3-8元杂环基任选地被一个或多个R 10取代； R 4 is selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 3-8 membered heterocyclyl is optionally substituted by one or more R 10 ;
    R 10在每次出现时各自独立地选自-OH、卤素、-CN、-NH 2、-NO 2、C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基和3-8元杂环基； Each occurrence of R 10 is independently selected from -OH, halogen, -CN, -NH 2 , -NO 2 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 haloalkoxy and 3-8 membered heterocyclic groups;
    X选自CH和N；X is selected from CH and N;
    R 5选自H、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基、3-8元杂环基、卤素、-CN、-CONR 5aR 5b和C 1-C 6卤代烷基；且 R 5 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, halogen, -CN, -CONR 5a R 5b and C 1 -C 6 haloalkyl; and
    R 5a和R 5b各自独立地选自H和C 1-C 6烷基。 R 5a and R 5b are each independently selected from H and C 1 -C 6 alkyl.
  2. 权利要求1的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, in,
    R 1选自C 1-C 6烷基、C 3-C 8环烷基和3-8元杂环基，所述C 1-C 6烷基、C 3-C 8环烷基或3-8元杂环基任选地被一个或多个R 6取代； R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and 3-8 membered heterocyclyl, the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 3- 8-membered heterocyclyl is optionally substituted by one or more R 6 ;
    R 6在每次出现时各自独立地选自卤素、-CN、-OH、-S(O) pR A、C 3-C 8环烷基和C 6-C 10芳基，所述C 3-C 8环烷基或C 6-C 10芳基任选地被一个或多个R 7取代； Each occurrence of R 6 is independently selected from halogen, -CN, -OH, -S(O) p R A , C 3 -C 8 cycloalkyl and C 6 -C 10 aryl, said C 3 -C 8 cycloalkyl or C 6 -C 10 aryl is optionally substituted by one or more R 7 ;
    R 7在每次出现时各自独立地选自卤素和＝O； Each occurrence of R is independently selected from halogen and =O;
    R A为C 1-C 6烷基；且 RA is C 1 -C 6 alkyl; and
    p为2。p is 2.
  3. 权利要求2的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，The compound of claim 2 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, in,
    R 1选自C 1-C 6烷基、C 3-C 6环烷基和3-6元含氧杂环烷基，所述C 1-C 6烷基、C 3-C 6环烷基或3-6元含氧杂环烷基任选地被一个或多个各自独立地选自以下的基团取代：卤素、-CN、-OH、-S(O) 2(C 1-C 6烷基)、任选地被卤素或＝O取代的C 3-C 6环烷基、以及任选地被卤素取代的苯基； R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-6 membered oxygen-containing heterocycloalkyl, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl Or a 3-6 membered oxygen-containing heterocycloalkyl group is optionally substituted by one or more groups independently selected from the following groups: halogen, -CN, -OH, -S(O) 2 (C 1 -C 6 Alkyl), C 3 -C 6 cycloalkyl optionally substituted by halogen or =O, and phenyl optionally substituted by halogen;
    优选地，R 1选自C 1-C 6烷基、C 3-C 6环烷基、氧杂环丁基、四氢呋喃基和四氢吡喃基，所述C 1-C 6烷基或C 3-C 6环烷基任选地被一个或多个各自独立地选自以下的基团取代：卤素、-CN、-OH、-S(O) 2(C 1-C 6烷基)、任选地被卤素或＝O取代的C 3-C 6环烷基、以及任选地被卤素取代的苯基， Preferably, R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of halogen, -CN, -OH, -S(O) 2 (C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl optionally substituted by halogen or =O, and phenyl optionally substituted by halogen,
    更优选地，R 1选自C 1-C 6烷基、C 3-C 6环烷基、氧杂环丁基、四氢呋喃基和四氢吡喃基，所述C 1-C 6烷基或C 3-C 6环烷基任选地被一个或多个各自独立地选自以下的基团取代：-F、-CN、-OH、-S(O) 2CH 3、四氢吡喃基、以及氟代苯基； More preferably, R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, the C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl is optionally substituted with one or more groups each independently selected from: -F, -CN, -OH, -S(O) 2 CH 3 , tetrahydropyranyl , and fluorophenyl;
    更优选地，R 1选自C 1-C 6烷基、氧杂环丁基、四氢呋喃基和四氢吡喃基，所述C 1-C 6烷基任选地被1、2或3个-F取代； More preferably, R 1 is selected from C 1 -C 6 alkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, said C 1 -C 6 alkyl is optionally replaced by 1, 2 or 3 -F replace;
    更优选地，R 1选自
    Figure PCTCN2022109584-appb-100002
    CF 3CH 2-、CH 3-、
    Figure PCTCN2022109584-appb-100003
    More preferably, R 1 is selected from
    Figure PCTCN2022109584-appb-100002
    CF 3 CH 2 -, CH 3 -,
    Figure PCTCN2022109584-appb-100003
    更优选地，R 1选自
    Figure PCTCN2022109584-appb-100004
    CF 3CH 2-、CH 3-、
    Figure PCTCN2022109584-appb-100005
    More preferably, R 1 is selected from
    Figure PCTCN2022109584-appb-100004
    CF 3 CH 2 -, CH 3 -,
    Figure PCTCN2022109584-appb-100005
    其中波浪线
    Figure PCTCN2022109584-appb-100006
    表示该基团与分子其余部分的连接点。     where tilde
    Figure PCTCN2022109584-appb-100006
    Indicates the point of attachment of the group to the rest of the molecule.
  4. 权利要求1-3中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, or a pharmaceutically acceptable salt thereof, metabolites or prodrugs, where,
    R 2在每次出现时各自独立地选自H和卤素； Each occurrence of R is independently selected from H and halogen;
    优选地，R 2在每次出现时各自独立地选自H和F； Preferably, each occurrence of R is independently selected from H and F;
    更优选地，R 2为H。 More preferably, R2 is H.
  5. 权利要求1-4中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, or a pharmaceutically acceptable salt thereof, metabolites or prodrugs, where,
    m为1。m is 1.
  6. 权利要求1-5中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, or a pharmaceutically acceptable salt thereof, metabolites or prodrugs, where,
    R 3选自C 6-C 10芳基和5-10元杂芳基，所述C 6-C 10芳基或5-10元杂芳基任选地被一个或多个各自独立地选自以下的基团取代：卤素、C 1-C 6烷基和C 1-C 6卤代烷基； R 3 is selected from C 6 -C 10 aryl and 5-10 membered heteroaryl, and the C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally selected from one or more of The following group substitutions: halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl;
    优选地，R 3选自苯基和5-6元含氮杂芳基，所述苯基或5-6元含氮杂芳基任选地被一个或多个各自独立地选自以下的基团取代：卤素、C 1-C 6烷基和C 1-C 6卤代烷基； Preferably, R 3 is selected from phenyl and 5-6 membered nitrogen-containing heteroaryl, and said phenyl or 5-6 membered nitrogen-containing heteroaryl is optionally replaced by one or more groups each independently selected from Group substitution: halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl;
    更优选地，R 3选自苯基和吡啶基，所述苯基或吡啶基任选地被一个或多个各自独立地选自以下的基团取代：卤素、C 1-C 6烷基和C 1-C 6卤代烷基； More preferably, R is selected from phenyl and pyridyl optionally substituted by one or more groups each independently selected from halogen, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl;
    更优选地，R 3选自苯基和吡啶基，所述苯基或吡啶基任选地被一个或多个各自独立地选自以下的基团取代：F、Cl、-CF 3和-CH 3； More preferably, R is selected from phenyl and pyridyl optionally substituted with one or more groups each independently selected from: F, Cl, -CF and -CH 3 ;
    更优选地，R 3选自苯基和吡啶基，所述苯基或吡啶基任选地被F或Cl取代； More preferably, R is selected from phenyl and pyridyl, optionally substituted by F or Cl;
    更优选地，R 3选自：
    Figure PCTCN2022109584-appb-100007
    More preferably, R is selected from:
    Figure PCTCN2022109584-appb-100007
    更优选地，R 3选自：
    Figure PCTCN2022109584-appb-100008
    More preferably, R is selected from:
    Figure PCTCN2022109584-appb-100008
    其中波浪线
    Figure PCTCN2022109584-appb-100009
    表示该基团与分子其余部分的连接点。     where tilde
    Figure PCTCN2022109584-appb-100009
    Indicates the point of attachment of the group to the rest of the molecule.
  7. 权利要求1-6中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, or a pharmaceutically acceptable salt thereof, metabolites or prodrugs, where,
    R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被一个或多个C 1-C 6烷氧基或3-8元杂环基取代； R 4 is selected from C 1 -C 6 alkyl groups, the C 1 -C 6 alkyl groups are optionally substituted by one or more C 1 -C 6 alkoxy groups or 3-8 membered heterocyclic groups;
    优选地，R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被C 1-C 6烷氧基或5-6元含氧杂环烷基取代； Preferably, R 4 is selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkoxy or 5-6 membered oxygen-containing heterocycloalkyl;
    更优选地，R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被C 1-C 6烷氧基、四氢呋喃基或四氢吡喃基取代； More preferably, R 4 is selected from C 1 -C 6 alkyl optionally substituted by C 1 -C 6 alkoxy, tetrahydrofuranyl or tetrahydropyranyl;
    更优选地，R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被甲氧基、四氢呋喃基或四氢吡喃基取代； More preferably, R 4 is selected from C 1 -C 6 alkyl optionally substituted by methoxy, tetrahydrofuranyl or tetrahydropyranyl ;
    更优选地，R 4选自异丙基、2-甲基丙基、甲氧基乙基、
    Figure PCTCN2022109584-appb-100010
    More preferably, R is selected from isopropyl, 2-methylpropyl, methoxyethyl,
    Figure PCTCN2022109584-appb-100010
    其中波浪线
    Figure PCTCN2022109584-appb-100011
    表示该基团与分子其余部分的连接点。     where tilde
    Figure PCTCN2022109584-appb-100011
    Indicates the point of attachment of the group to the rest of the molecule.
  8. 权利要求1-7中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, or a pharmaceutically acceptable salt thereof, metabolites or prodrugs, where,
    R 5选自H、C 1-C 6烷基和卤素； R 5 is selected from H, C 1 -C 6 alkyl and halogen;
    优选地，R 5为H。 Preferably, R 5 is H.
  9. 权利要求1-8中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物为式I-1的化合物：The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, or a pharmaceutically acceptable salt thereof, Metabolite or prodrug, wherein said compound is the compound of formula I-1:
    Figure PCTCN2022109584-appb-100012
    Figure PCTCN2022109584-appb-100012
  10. 权利要求9的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物为式I-1-1的化合物：The compound of claim 9 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, Wherein said compound is the compound of formula I-1-1:
    Figure PCTCN2022109584-appb-100013
    Figure PCTCN2022109584-appb-100013
    其中，in,
    q选自0、1、2、3、4和5；q is selected from 0, 1, 2, 3, 4 and 5;
    优选地，q为1。Preferably, q is 1.
  11. 权利要求9的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物为式I-1-2的化合物：The compound of claim 9 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, Wherein said compound is the compound of formula I-1-2:
    Figure PCTCN2022109584-appb-100014
    Figure PCTCN2022109584-appb-100014
    其中，in,
    q选自0、1、2、3和4；q is selected from 0, 1, 2, 3 and 4;
    优选地，q为1。Preferably, q is 1.
  12. 权利要求1-8中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物为式I-2的化合物：The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, or a pharmaceutically acceptable salt thereof, Metabolites or prodrugs, wherein the compound is a compound of formula I-2:
    Figure PCTCN2022109584-appb-100015
    Figure PCTCN2022109584-appb-100015
  13. 权利要求12的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物为式I-2-1的化合物：The compound of claim 12 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, Wherein said compound is the compound of formula I-2-1:
    Figure PCTCN2022109584-appb-100016
    Figure PCTCN2022109584-appb-100016
    其中，in,
    q选自0、1、2、3、4和5；q is selected from 0, 1, 2, 3, 4 and 5;
    优选地，q为1。Preferably, q is 1.
  14. 权利要求13的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物为式I-2-1a的化合物：The compound of claim 13 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, Wherein said compound is the compound of formula I-2-1a:
    Figure PCTCN2022109584-appb-100017
    Figure PCTCN2022109584-appb-100017
  15. 权利要求14的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，The compound of claim 14 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, in,
    R 1选自C 1-C 6烷基、氧杂环丁基、四氢呋喃基和四氢吡喃基，所述C 1-C 6烷基任选地被1、2或3个-F取代； R 1 is selected from C 1 -C 6 alkyl, oxetanyl, tetrahydrofuryl and tetrahydropyranyl, and the C 1 -C 6 alkyl is optionally substituted by 1, 2 or 3 -F;
    R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选地被C 1-C 6烷氧基、四氢呋喃基或四氢吡喃基取代； R 4 is selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl is optionally substituted by C 1 -C 6 alkoxy, tetrahydrofuryl or tetrahydropyranyl;
    R 9为卤素；且 R9 is halogen; and
    q为1。q is 1.
  16. 权利要求12的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物为式I-2-2的化合物：The compound of claim 12 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, Wherein said compound is the compound of formula I-2-2:
    Figure PCTCN2022109584-appb-100018
    Figure PCTCN2022109584-appb-100018
    其中，in,
    q选自0、1、2、3和4；q is selected from 0, 1, 2, 3 and 4;
    优选地，q为1。Preferably, q is 1.
  17. 权利要求1-8中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, or a pharmaceutically acceptable salt thereof, Metabolites or prodrugs, wherein the compound is selected from:
    Figure PCTCN2022109584-appb-100019
    Figure PCTCN2022109584-appb-100019
    Figure PCTCN2022109584-appb-100020
    Figure PCTCN2022109584-appb-100020
    Figure PCTCN2022109584-appb-100021
    Figure PCTCN2022109584-appb-100021
    Figure PCTCN2022109584-appb-100022
    Figure PCTCN2022109584-appb-100022
  18. 药物组合物，其包含预防或治疗有效量的权利要求1-17中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及一种或多种药学可接受的载体。A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of any one of claims 1-17 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate Substances, N-oxides, isotope-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.
  19. 药盒，其包含：A kit containing:
    a)权利要求1-17中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者权利要求18所述的药物组合物；和a) The compound according to any one of claims 1-17 or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope a labeled compound, metabolite or prodrug, or the pharmaceutical composition of claim 18; and
    b)任选存在的包装和/或说明书。b) Optional packaging and/or instructions.
  20. 权利要求1-17中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者权利要求18所述的药物组合物或者权利要求19所述的药盒在制备用于预防或治疗与Axl和/或Mer相关的疾病(特别是肿瘤疾病)的药物中的用途。The compound according to any one of claims 1-17 or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled The compound, metabolite or prodrug or the pharmaceutical composition described in claim 18 or the kit described in claim 19 are used in the preparation of medicines for preventing or treating diseases (especially tumor diseases) related to Axl and/or Mer use in .
  21. 制备权利要求1-17中任一项所述的化合物的方法，其包括反应路线1所示的步骤：The method for preparing the compound described in any one of claims 1-17, it comprises the steps shown in reaction scheme 1:
    反应路线1Reaction scheme 1
    Figure PCTCN2022109584-appb-100023
    Figure PCTCN2022109584-appb-100023
    其中，R 1、R 2、R 3、R 4、R 5、X和m如权利要求1-17中任一项所定义。 Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , X and m are as defined in any one of claims 1-17.
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CN109348715A (en) * 2016-03-28 2019-02-15 因赛特公司 Pyrrolotriazine compounds as TAM inhibitor
CN110627796A (en) * 2018-06-21 2019-12-31 北京越之康泰生物医药科技有限公司 Nitrogenous heterocyclic derivative and application thereof in medicine
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EP3067356A1 (en) * 2013-11-08 2016-09-14 ONO Pharmaceutical Co., Ltd. Pyrrolo pyrimidine derivative
CN109348715A (en) * 2016-03-28 2019-02-15 因赛特公司 Pyrrolotriazine compounds as TAM inhibitor
CN108250200A (en) * 2016-12-28 2018-07-06 中国科学院上海药物研究所 A kind of compound and its preparation and application with Axl inhibitory activity
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