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WO2024179393A1 - Sulfoximine compounds and application thereof as lrrk2 protein kinase inhibitors - Google Patents

Sulfoximine compounds and application thereof as lrrk2 protein kinase inhibitors Download PDF

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WO2024179393A1
WO2024179393A1 PCT/CN2024/078490 CN2024078490W WO2024179393A1 WO 2024179393 A1 WO2024179393 A1 WO 2024179393A1 CN 2024078490 W CN2024078490 W CN 2024078490W WO 2024179393 A1 WO2024179393 A1 WO 2024179393A1
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amine
amino
compound
thiopyran
pyrazol
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PCT/CN2024/078490
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French (fr)
Chinese (zh)
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朱振东
李旭珂
牛德强
蒋毅
张青
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科辉智药(深圳)新药研究中心有限公司
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Publication of WO2024179393A1 publication Critical patent/WO2024179393A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, and in particular to a class of sulfoximide compounds and stereoisomers, tautomers or pharmaceutically acceptable salts thereof, preparation methods thereof and pharmaceutical compositions containing the compounds.
  • the present invention also relates to the use of the compounds as LRRK2 protein kinase inhibitors.
  • LRRK2 Leucine-rich repeat kinase 2
  • PD Parkinson's disease
  • LRRK2 gene mutations were found to be associated with Parkinson's disease (PD) as early as 2004.
  • LRRK2 gene mutations are commonly found in the G2019S and I2020T in the kinase active region and the R1441G/C/H and Y1699C mutations in the GTPase region. These mutations can lead to increased LRRK2 protein kinase activity and induce a variety of pathological changes, including increased synuclein and TAU protein phosphorylation, nervous system inflammation, and neuronal mitochondrial dysfunction.
  • Parkinson’s disease is the second largest neurodegenerative disease after Alzheimer’s Disease, with more than 10 million patients worldwide, but no effective treatment has been found so far. 10% of PD patients have a clear family history, of which LRRK2 mutation is the most common cause. This mutation occurs in about 5% of familial PD and 1% of non-familial PD, and the clinical manifestations caused by these mutations are no different from those of sporadic PD. In addition, LRRK2 mutations can also lead to pathological changes in TAU protein, and pathological changes in TAU are a major feature of Alzheimer’s disease. LRRK2 is believed to be located in the upstream stage of the pathogenesis of neurodegenerative diseases and also plays an important role in other neurodegenerative diseases. Therefore, the development of LRRK2-specific inhibitors has become one of the effective ways to treat PD and other neurodegenerative diseases.
  • the inventors have found through research that the sulfoximide compounds of the present invention exhibit good inhibitory activity against protein kinases; moreover, the compounds also exhibit good water solubility.
  • the present invention provides a compound having a structure of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • A is selected from optionally substituted C1-6 alkyl, C3-8 cycloalkyl, C6-14 aryl, 5-12 membered heteroaryl, 3-8 membered heterocyclyl, 5-18 membered bridged ring group or 5-18 membered spirocyclyl, wherein the substituent is selected from deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, 3-8 membered heterocyclyl, C1-4 alkylphosphoryl, C1-4 alkylsulfonyl, cyano, hydroxy, oxo, mercapto, amino and halogen;
  • L represents absence (covalent bond), -O-, -NH-, -N(C 1-4 alkyl)-, -S-, -S(O)-, or -S(O) 2 -;
  • R1 is hydrogen, or substituted or unsubstituted C1-4 alkyl, C3-6 cycloalkyl, wherein the substituent is selected from deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, oxo, cyano, hydroxyl, amino, dimethylamino, hydroxylamino, halogen;
  • R2 and R3 are each independently selected from hydrogen, deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, 3-8 membered heterocyclic group, cyano, hydroxyl and halogen;
  • Ra is selected from hydrogen, amino, trifluoromethyl, halogen, cyano, C 1-3 alkyl, acetyl, C 1-3 alkylphosphoryl and C 1-3 alkylsulfonyl;
  • Rb is selected from hydrogen, amino and C 1-3 alkylamino
  • Ra, Rb and the C atom to which they are attached together form a 5- to 6-membered aromatic ring, a 5- to 8-membered heteroaromatic ring or a 5- to 8-membered heterocyclic ring;
  • n is selected from 0, 1 and 2.
  • the compound of formula (I) has the following structure of formula (II):
  • the compound of formula I has the following structure:
  • A, L, R 1 , R 2 , R 3 and n are as defined above, X and Y are each independently selected from C and N, Indicates a double bond or a single bond.
  • A may preferably be the following structure:
  • the wavy line indicates the position connected to the parent core compound.
  • a pharmaceutical composition which comprises a compound of formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof according to the present invention.
  • the compound of formula (I) has the above-mentioned structure (II) or (III).
  • the compound of formula (I) is the above-mentioned specific compound.
  • the compound itself includes its isotopic form, for example, a compound in which the hydrogen atom of the compound of formula (I) is replaced by deuterium, an isotope of hydrogen.
  • the compound itself also includes its solvate and hydrate forms.
  • LRRK2 protein kinase-related disease refers to a disease in which the development or symptoms of the disease are related to the signal transmission, mediation, regulation or adjustment of the LRRK2 protein kinase.
  • LRRK2 protein kinase-related diseases include the following disease types: neurodegenerative diseases, immune-related diseases and cancer.
  • the LRRK2 protein kinase-related disease is selected from Parkinson's disease, Alzheimer's disease, Hennessy's disease, and other diseases. Huntington's disease, Crohn's disease, inflammatory bowel disease, tuberculosis, leprosy, melanoma, non-melanoma skin cancer, and breast cancer.
  • a method for treating or preventing LRRK2 protein kinase-related diseases comprising administering the compound of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.
  • Diseases to which the compounds, compositions and methods described herein relate include, but are not limited to, Parkinson's disease, Alzheimer's disease, Huntington's disease, Crohn's disease, inflammatory bowel disease, colitis, tuberculosis, leprosy, melanoma, non-melanoma skin cancer and breast cancer.
  • alkyl is used to represent a straight or branched saturated hydrocarbon group, for example, C1-3 alkyl refers to a saturated hydrocarbon group containing 1 to 3 carbon atoms, C1-4 alkyl refers to a saturated hydrocarbon group containing 1 to 4 carbon atoms, and C1-6 alkyl refers to a saturated hydrocarbon group containing 1 to 6 carbon atoms, including straight, branched or cyclic alkyl groups.
  • the alkyl group herein is preferably C1-10 alkyl, C1-8 alkyl, C1-6 alkyl or C1-4 alkyl.
  • alkoxy refers to an alkyl-O-.
  • C 1-6 alkoxy is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and tert-butoxy.
  • C 1-10 alkoxy refers to an -O-alkyl group, and the alkyl group includes linear, branched and cyclic alkyl groups, and the number of carbon atoms thereof is 1 to 10.
  • alkoxy examples include methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy and cyclopropoxy), tert-butoxy, and the like.
  • Preferred alkoxy groups herein include C 1-10 alkoxy, C 1-8 alkoxy, C 1-6 alkoxy and C 1-4 alkoxy.
  • cycloalkyl refers to a cyclized alkyl group based on a non-aromatic carbocyclic ring.
  • the cycloalkyl group may include a monocyclic, bicyclic or polycyclic system.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • C3-8 cycloalkyl groups refer to cycloalkyl groups containing 3 to 8 carbon atoms.
  • Preferred cycloalkyl groups herein are C3-8 cycloalkyl groups and C3-6 cycloalkyl groups.
  • heterocycloalkyl refers to a non-aromatic heterocycloalkyl group in which 1 or 2 or 3 ring-forming carbon atoms are substituted by heteroatoms selected from O, N and S atoms.
  • the heterocycloalkyl group preferably has 3, 4, 5 , 6, 7 or 8 ring-forming atoms.
  • Preferred heterocyclyl groups herein are C 3-8 heterocyclyl groups or C 3-6 heterocyclyl groups.
  • Aryl refers to an aromatic carbocyclic group, including monocyclic, bicyclic, tricyclic or polycyclic aromatic hydrocarbons, such as phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.
  • Aryl is preferably a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon having 6 to 14 or 6 to 12 ring members. or tricyclic ring system.
  • at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members.
  • Substituted aryl means that at least one hydrogen atom on the phenyl ring of the aryl is replaced by a non-hydrogen moiety, and the substituent of the aryl can be halogen, C 1-10 alkoxy, -CN, -OH, -SH, -NH 2 , C 1-6 alkyl.
  • Preferred aryl groups include phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl.
  • aralkyl or “arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, etc.
  • the fused aryl can be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring.
  • heteroaryl means a 5-12 membered aromatic monocyclic or aromatic bicyclic or aromatic polycyclic heterocyclic ring, which is fully unsaturated, partially unsaturated, and contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.
  • the heteroaryl herein is preferably a 5-12 membered heteroaryl.
  • the heteroaryl herein preferably has 1 or 2 or 3 heteroatoms independently selected from N, O and S.
  • the heteroaryl herein includes a 5-, 6- or 7-membered aromatic monocyclic ring or an 8-, 9-, 10-, 11- or 12-membered aromatic bicyclic or aromatic polycyclic heterocyclic ring; preferably, any heterocyclic ring defined above is fused to a benzene ring.
  • Nitrogen and sulfur heteroatoms may be optionally oxidized.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent).
  • the heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic group described herein can be substituted on carbon or nitrogen atom.
  • the nitrogen in the heterocycle can be optionally quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other.
  • aromatic hetero groups includes but is not limited to acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiopyranyl, benzoxazolyl, benzoxazoline, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazoline, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, quinolyl , decahydroquinolinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolinyl, indoliziny
  • heteroaryl may also include a biaryl structure formed by the above-defined “aryl” and a monocyclic “heteroaryl”, such as but not limited to "-phenylbipyridyl-", “-phenylbipyrimidyl-", “-pyridylbiphenyl-”, “-pyridylbipyrimidyl-", “-pyrimidylbiphenyl-”.
  • C 1-4 alkylphosphoryl group refers to a phosphoryl group substituted with a C 1-4 alkyl group, and the two alkyl groups on the phosphoryl group may be the same or different.
  • C 1-4 alkylsulfonyl group refers to a sulfonyl group substituted with a C 1-4 alkyl group.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Bridged ring group refers to a polycyclic group of 5 to 18 members, preferably 5 to 14 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other. More preferably, it is a 6 to 14-membered, and even more preferably a 7 to 10-membered bridged ring group. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, pyridone or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or pyridone, more preferably a bicyclic or tricyclic.
  • the bridged ring group herein allows 1, 2 or 3 of the ring atoms to be heteroatoms selected from N, O, S, SO and/or S(O) 2 .
  • Spirocyclyl refers to a polycyclic group of 5 to 18 members, preferably 6 to 12 members, containing two or more cyclic structures, sharing one carbon atom with each other. According to the number of constituent rings, it can be divided into bicyclic and tricyclic, preferably bicyclic. Spirocyclyl herein allows 1, 2 or 3 of the ring atoms to be heteroatoms selected from N, O, S, SO and/or S(O) 2 .
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt” as used herein refers to salts that enable the compounds of the present invention to maintain their original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salts of the compounds represented by formula (I) may be salts formed by a carboxyl group or an amine group (mainly an amine group) and a suitable base or acid, such as a salt formed with a suitable base (including a metal salt, an ammonium salt), or a salt formed with a suitable acid.
  • the compounds of the present invention preferably form salts with a suitable acid, and the acid may be selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, Fruit acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid and aspartic acid, preferably methanesulfonic acid or hydrochloric acid.
  • the acid may be selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propi
  • the phrase "pharmaceutically acceptable carrier” means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate or stearic acid) or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another.
  • a pharmaceutical substance, composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate or stearic acid) or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another.
  • manufacturing aid e.g., lubricant, talc, magnesium, calcium or zinc stearate or stearic acid
  • solvent encapsulating substance e.g., solvent encapsulating substance, which is involved
  • composition means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form.
  • adjuents such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form.
  • TLC refers to thin layer chromatography
  • the instrument used for liquid chromatography-mass spectrometry was Shimadzu LCMS-2020, and the instrument used for preparative high performance liquid chromatography (Prep-HPLC) was Bonna-Agela FLEXA FL-H100G.
  • Thin layer chromatography The thin layer chromatography silica gel plate used for (TLC) was Yantai Huanghai HSGF254 thin layer chromatography silica gel plate, the specifications used for reaction monitoring were 2.5 ⁇ 8cm, the coating thickness was 0.2 ⁇ 0.03mm, the specifications used for separation and purification were 20 ⁇ 20cm, the coating thickness was 0.4–0.5mm.
  • the silica gel column chromatography method used Qingdao Marine Silica Gel 100–200 mesh or 200–300 mesh silica gel as the carrier.
  • Step 1 Synthesis of intermediate Amine-1-c:4-nitro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
  • Step 2 Synthesis of intermediate Amine-1-d: 5-chloro-4-nitro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
  • Step 3 Synthesis of intermediate Amine-1-e: 4-(5-chloro-4-nitro-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1-oxide
  • Step 4 Synthesis of intermediate Amine-1-fA: N-((1s,4s)-(4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-oxytetrahydro-2H-1 ⁇ 6 -thiopyran-1-ylidene)-2,2,2-trifluoroacetamide and intermediate Amine-1-fB: N-((1r,4r)-(4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-oxytetrahydro-2H-1 ⁇ 6 -thiopyran-1-ylidene)-2,2,2-trifluoroacetamide
  • the first eluted component is white solid Amine-1-f-A (340 mg, 34%)
  • the second eluting fraction was a colorless oily substance, Amine-1-f-B (320 mg, 32%).
  • Step 5 Synthesis of intermediate Amine-1-g: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-iminohexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 7 Synthesis of fragment Amine-1: (1s, 4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-iminohexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 1 Synthesis of intermediate Amine-2-a: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 2 Synthesis of intermediate Amine-2: (1s, 4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the implementation method is the same as Amine-2, and acetaldehyde is used to replace paraformaldehyde to obtain the target compound.
  • the stereo configuration of Amine-3-a is determined by X-ray single crystal diffraction.
  • Step 1 Synthesis of intermediate Amine-4-a: tetrahydrothiopyran-4-toluenesulfonate
  • Step 4 Synthesis of intermediate Amine-4-cA: (1s, 4s)-1-imino-4-(4-nitro-1H-pyrazol-1-yl)hexahydro-1 ⁇ 6 -thiopyran 1-oxide and intermediate Amine-4-cB: (1r, 4r)-1-imino-4-(4-nitro-1H-pyrazol-1-yl)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the first eluting fraction, Amine-4-c-B was a white solid (192 mg, 18%).
  • the second eluting component, Amine-4-c-A was a white solid (287 mg, 27%);
  • Step 5 Synthesis of fragment Amine-4: (1s, 4s)-4-(4-amino-1H-pyrazol-1-yl)-1-iminohexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the implementation method is the same as Amine-2, and the fragment Amine-1-g is replaced by the fragment Amine-4-c-A to obtain the target compound.
  • the implementation method is the same as Amine-2, replacing Amine-1-g with Amine-4-c-A and replacing paraformaldehyde with acetaldehyde to obtain the target compound.
  • Step 1 Synthesis of intermediate Amine-7-a: 4-nitro-5-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
  • 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (147 mg, 0.262 mmol) was added to a solution of 1,4-dioxane (4 mL) and water (0.4 mL) containing Amine-1-d (500 mg, 2.02 mmol), methylboric acid (363 mg, 6.06 mmol) and potassium carbonate (836 mg, 6.06 mmol). The mixture was reacted at 90 °C for 16 hours under a nitrogen atmosphere. The reaction was complete when monitored by TLC.
  • the mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (5 mL ⁇ 2), the filtrate was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether elution solution containing 25% ethyl acetate) to obtain the intermediate Amine-7-a as a white solid (320 mg, 70%).
  • Step 3 Synthesis of intermediates Amine-7-cA: (1s, 4s)-1-imino-4-(4-nitro-5-methyl-1H-pyrazol-1-yl)-hexahydro-1 ⁇ 6 -thiopyran 1-oxide and Amine-7-cB: (1r, 4r)-1-imino-4-(4-nitro-5-methyl-1H-pyrazol-1-yl)-hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the first component, Amine-7-c-B was a white solid (196 mg, 37%).
  • the second component is Amine-7-c-A which is a white solid (235 mg, 44%).
  • Step 4 Synthesis of fragment Amine-7: (1s, 4s)-1-imino-4-(4-amino-5-methyl-1H-pyrazol-1-yl)-hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Implementation method The implementation method is the same as Amine-2, replacing Amine-1-g with the intermediate Amine-7-c-A to obtain the target product.
  • Implementation method The implementation method is the same as Amine-2, replacing Amine-1-g with the intermediate Amine-7-c-A, and replacing paraformaldehyde with acetaldehyde to obtain the target product.
  • Step 1 Synthesis of intermediate Amine-10-a: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-(isopropylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 2 Synthesis of fragment Amine-10: (1s, 4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-(isopropylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Implementation method The implementation method is the same as Amine-10, replacing Amine-10-a with Amine-11-a to obtain the target product.
  • Implementation method The implementation method is the same as Amine-10, replacing 2-iodoisopropane with 2-bromo-N,N-dimethylethane-1-amine hydrobromide to obtain the target product.
  • Methylmagnesium bromide (3M dissolved in tetrahydrofuran, 7.7ml, 23mmol) was added to a suspension of compound 1-a (1,4-cyclohexanedione monoethylene glycol acetal) (2g, 12.8mmol) in anhydrous tetrahydrofuran (20ml) at -60°C, and the reaction mixture was stirred at -60°C for 20 minutes, then heated to -30°C for 30 minutes, and then stirred at 0°C for 30 minutes. TLC monitored the reaction to be complete. The reaction mixture was quenched with saturated ammonium chloride solution (10ml) and extracted with ethyl acetate (20ml).
  • Step 3 Synthesis of intermediates 1-d: (1r, 4r)-1-methylcyclohexane-1,4-diol and 1-e: (1s, 4s)-1-methylcyclohexane-1,4-diol
  • Step 4 Synthesis of Intermediate 1-g: (1s, 4s)-4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-methylcyclohexan-1-ol and Intermediate 1-h: (1s, 4s)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)oxy)-1-methylcyclohexan-1-ol
  • reaction mixture was quenched with saturated ammonium chloride solution (10 ml) and extracted with ethyl acetate (10 ml x 2).
  • the organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was separated and purified by silica gel column chromatography (eluted with n-hexane containing 6%-12.5% ethyl acetate) to obtain two groups of compounds: colorless oil 1-g (first effluent component) (28 mg, 12%);
  • Step 5 Synthesis of Compound 1: (1s, 4s)-4-(5-chloro-4-((4-(((1s, 4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • N,N-diisopropylethylamine (1.42 g, 10.95 mmol) was added to a solution of 1-f (2,4-dichloro-5-(trifluoromethyl)pyrimidine) (949 mg, 4.37 mmol) and 2-b (2-methoxymethylaniline) (500 mg, 3.65 mmol) in isopropanol (20 mL).
  • the mixture was reacted at 80 °C for 12 hours. TLC monitored the reaction to be complete. The mixture was concentrated under reduced pressure, and the residue was partitioned between water (15 mL) and dichloromethane (20 mL).
  • the first component is a yellow solid 2-d: 4-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidin-2-amine (320 mg, 28%).
  • the second component was a white solid 2-c: 2-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidin-4-amine (670 mg, 58%).
  • Step 3 Synthesis of Compound 2A: (1s, 4s)-1-imino-4-(4-((4-(2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Trifluoroacetic acid (3.8 mg) was added to a solution of fragment Amine-4 (72 mg, 0.34 mmol) and intermediate 2-c (2-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidine-4-amine) (107 mg, 0.34 mmol) in isopropanol (3 mL). The mixture was reacted at 80°C for 16 hours. TLC monitored the reaction to be complete. The mixture was partitioned between saturated sodium bicarbonate solution (5 mL) and ethyl acetate (10 mL), the organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent containing 8% methanol in dichloromethane) to give compound 2A as a white solid (14.2 mg, 8.5%).
  • Step 1 Synthesis of intermediate 3-c: 2-chloro-N-(2-(methylsulfonyl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • reaction mixture was dispersed in water (10 mL) and ethyl acetate (10 mL), the organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether containing 25% ethyl acetate) to obtain intermediate 3-c as a white solid (86 mg, 68%).
  • Step 2 Synthesis of intermediate 3-d: 4-(5-chloro-4-((4-(2-(methylsulfonyl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 3 Synthesis of Compound 3: (1s, 4s)-4-(5-chloro-4-((4-((2-(methylsulfonyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 1 Synthesis of intermediate 4-a: (1s, 4s)-4-(5-chloro-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • Step 2 Synthesis of Compound 4: (1s, 4s)-4-(5-chloro-4-((4-(4-hydroxy-4-methylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide
  • the intermediate 1-e is replaced by the fragment 2-(methylsulfonyl)ethylamine hydrochloride, and the fragment Amine-2 is replaced by the fragment Amine-1 to obtain the title compound.
  • the intermediate 1-e is replaced by the fragment 2-(methylsulfonyl)ethylamine hydrochloride, and Amine-1-f-B is replaced by Amine-1-f-A in the synthesis of the fragment Amine-1 to obtain the title compound.
  • intermediate 1-e is replaced by 2-(methylsulfonyl)ethylamine hydrochloride
  • Amine-1-f-B is replaced by Amine-1-f-A in the synthesis of fragment Amine-1 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-1 to obtain the title compound.
  • intermediate 2-d is replaced by intermediate 1-a
  • intermediate 2-b is replaced by intermediate 14-e
  • fragment Amine-2 is replaced by fragment Amine-1 to obtain the title compound.
  • dimethylphosphine oxide ethylamine hydrochloride is used to replace intermediate 1-e to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-1 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-3 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-10 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-11 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-12 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-4 to obtain the title compound.
  • intermediate 1-e is used to replace intermediate 3-b to obtain the title compound.
  • the starting material 3-a is replaced by 2,4,5-trichloropyrimidine, and the intermediate 3-b is replaced by the intermediate 2-b to obtain the title compound.
  • the starting material 3-a is replaced by 2,4,5-trichloropyrimidine, and the intermediate 3-b is replaced by the intermediate 1-e to obtain the title compound.
  • the starting material 3-a is replaced by 2,4-dichloro-5-methylpyrimidine, and the intermediate 3-b is replaced by the intermediate 1-e to obtain the title compound.
  • fragment Amine-2 was used to replace fragment Amine-4 to obtain the title compound.
  • intermediate 1-e is replaced by methylamine hydrochloride to obtain the title compound.
  • methylamine hydrochloride is used to replace intermediate 1-e, and in the synthesis of fragment Amine-2, Amine-1-f-B is used to replace Amine-1-f-A to obtain the title compound.
  • intermediate 1-e is replaced by (2-aminophenyl)dimethylphosphine oxide
  • fragment Amine-2 is replaced by fragment Amine-4 to obtain the title compound.
  • intermediate 1-d was used to replace intermediate 1-e to obtain the title compound.
  • fragment Amine-1 was used to replace fragment Amine-4 to obtain the title compound.
  • fragment Amine-4 was replaced by fragment Amine-7 to obtain the title compound.
  • fragment Amine-4 was replaced by fragment Amine-7
  • fragment Amine-7-c-A was replaced by fragment Amine-7-c-B in the synthesis of fragment Amine-7 to obtain the title compound.
  • fragment Amine-4 was replaced by fragment Amine-5 to obtain the title compound.
  • fragment Amine-4 was replaced by fragment Amine-6 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-9 to obtain the title compound.
  • fragment Amine-2 was replaced by fragment Amine-12 to obtain the title compound.
  • fragment Amine-3 was used to replace fragment Amine-4 to obtain the title compound.
  • 1,4-dioxaspiro[4.5]decan-8-ol was used to replace intermediate 1-e
  • fragment Amine-3 was used to replace fragment Amine-2 to obtain the title compound.
  • 1,4-dioxaspiro[4.5]decan-8-ol was used to replace intermediate 1-e
  • fragment Amine-3 was used to replace fragment Amine-2 to obtain the title compound.
  • intermediate 1-e was replaced by ethyl 4-hydroxypiperidine-1-carboxylate, and fragment Amine-2 was replaced by fragment Amine-3 to obtain the title compound.
  • intermediate 4-b is replaced by morpholine to obtain the title compound.
  • intermediate 2-b was replaced by 4-amino-1-methylcyclohexane-1-ol, and fragment Amine-4 was replaced by fragment Amine-3 to obtain the title compound.
  • intermediate 4-b was replaced with N,N-dimethylpiperidin-4-amine to obtain the title compound.
  • intermediate 4-b was replaced with piperidin-4-ylmethanol to obtain the title compound.
  • tetrakis(triphenylphosphine)palladium (7.5 mg, 0.0065 mmol) was added to acetonitrile (1 ml) and water (0.5 mL) containing 4-a((1s, 4s)-4-(5-chloro-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1 ⁇ 6 -thiopyran 1-oxide) (30 mg, 0.065 mmol), 39-a(3-(methoxymethyl)phenylboronic acid) (12 mg, 0.072 mmol) and sodium carbonate (14 mg, 0.13 mmol).
  • the reaction system was replaced with nitrogen three times and heated to 90° C. for 18 hours.
  • the reaction was complete when monitored by TLC.
  • the mixture was concentrated under reduced pressure and the residue was distributed between dichloromethane (10 mL) and water (10 mL).
  • the organic phase was collected, dichloromethane was added to the aqueous phase for extraction (10 mL x 2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by preparative TLC (dichloromethane elution solution containing 3% methanol) to obtain compound 39 as a white solid (11.8 mg, 33%).
  • methylboronic acid was replaced with ethylboronic acid in the synthesis of fragment Amine-7 to obtain the title compound.
  • intermediate 4-b is replaced by N,N-dimethylethylenediamine to obtain the title compound.
  • ethylene glycol monomethyl ether is used to replace intermediate 4-b, and sodium hydride is used to replace N,N-diisopropylethylamine in step 2 to obtain the title compound.
  • intermediate 1-e is replaced by 1-Boc-3-hydroxypyrrolidine, and fragment Amine-2 is replaced by fragment Amine-3, and the title compound is obtained after deprotection.
  • intermediate 1-e is replaced by tert-butyl cis-(4-hydroxymethyl)cyclohexylcarbamate, and fragment Amine-2 is replaced by fragment Amine-3, and the title compound is obtained after deprotection.
  • intermediate 1-e is replaced by trans-(4-hydroxymethyl)cyclohexylcarbamic acid tert-butyl ester, and fragment Amine-2 is replaced by fragment Amine-3, and the title compound is obtained after deprotection.
  • the starting material 3-a is replaced by 2,4,5-trichloropyrimidine
  • the intermediate 3-b is replaced by the intermediate 1-d
  • the fragment Amine-2 is replaced by the fragment Amine-3 to obtain the title compound.
  • intermediate 4-b is replaced by N-Boc-4-piperidinemethanol, and N,N-diisopropylethylamine is replaced by sodium hydride in step 2, and the title compound is obtained after deprotection.
  • 1-methyl-4-piperidinol is used to replace intermediate 4-b, and sodium hydride is used to replace N,N-diisopropylethylamine in step 2 to obtain the title compound.
  • the starting material 3-a was replaced by 2,4,5-trichloropyrimidine, the intermediate 3-b was replaced by (2-aminophenyl) dimethylphosphine oxide, and the fragment Amine-2 was replaced by the fragment Amine-3 to obtain the title compound.
  • Example 52 Determination of the solubility of the compound in water and dilute hydrochloric acid
  • the compound was dissolved in acetonitrile (LCMS pure) and prepared into the following concentration gradient standard samples: 1000 ⁇ g/mL, 500 ⁇ g/mL, 250 ⁇ g/mL, 125 ⁇ g/mL, 62.5 ⁇ g/mL, 31.25 ⁇ g/mL.
  • the standard sample and the sample to be tested were analyzed by Shimadzu LCMS-2020, chromatographic column: Shim-pack GIST 5 ⁇ m C18 2.1*50nm; mobile phase: A: water, B: methanol; flow rate: 0.3mL/min. Gradient of B: 0min: 10%; 0-1.0min: 10%; 1.0-2.5min: 95%; 3.0-4.0min: 95%; 4.0-4.1min: 10%; 4.1-6.0min: 10%.
  • the relationship between the concentration and peak area of the standard sample is made into a standard curve, and the concentration of the sample to be tested is calibrated using this standard curve.
  • Compound solubility concentration of the sample to be tested ⁇ 10
  • the compound of the present invention has good solubility in water, and has even better solubility in dilute hydrochloric acid simulating gastric acid.
  • the ADP-Glo method was used to detect the inhibitory effect of the compound on the activity of LRRK2 kinase.
  • the compound was diluted with 1 ⁇ kinase buffer, 3 ⁇ L of 1mM compound DMSO storage solution was added to 57 ⁇ L 1 ⁇ kinase buffer D, and the compound was diluted 5 times with 1 ⁇ kinase buffer. 1 ⁇ L of the compound diluted with kinase buffer was added to the Greiner 384-well plate, and a DMSO blank control group and a buffer background group were set up.
  • IC 50 ranges of some compounds in the LRRK2 kinase activity assay are provided in Table 2 below: (IC 50 ranges: A ⁇ 0.1 ⁇ M; B: 0.1-0.5 ⁇ M; C: > 0.5 ⁇ M):
  • Biological test example-2 Inhibition rate detection of endogenous phosphorylated LRRK2 (S935) in cells
  • A549 cells with high expression of LRRK2 were resuspended in serum-free 1640 medium at a density of 1 ⁇ 10 ⁇ 6 cells/ml, and 1 ml was inoculated in each well of a 12-well plate and cultured at 37°C, 5% carbon dioxide for 6-8 hours. 1 ⁇ L of compound DMSO storage solution or DMSO (volume ratio of 0.1%) was added, mixed, and cultured at 37°C, 5% carbon dioxide for 15 hours. Cells were collected, and 50 ⁇ L RIPA III lysis buffer was added to each sample to lyse the cells on ice for 15 minutes, centrifuged at 4°C, 13000 rpm for 30 minutes, and the supernatant was taken.
  • the concentration of cell lysate was measured by BCA, and the concentration of all samples was normalized. 5 ⁇ loading buffer was added and 95°C for 10 minutes. WB was used to detect the content of endogenous LRRK2 phosphorylated S935.
  • the phosphorylated LRRK2 (S935) antibody was Abcam#133450. Image J was used to count the signal intensity of phosphorylated LRRK2 (S935), and beta-actin was used to normalize the phosphorylated LRRK2 (S935) signal in the sample for data analysis.
  • Table 3 below provides the inhibition rates of some compounds on LRRK2 (S935) activity in cells at a concentration of 10 ⁇ M:
  • Table 4 below provides the IC 50 ranges of the inhibitory activity of some compounds on LRRK2 (S935) in cells: (IC 50 range: A ⁇ 0.1 ⁇ M; B: 0.1-0.5 ⁇ M; C: > 0.5 ⁇ M)

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Abstract

The present invention provides a class of sulfoximine compounds represented by formula (I) and a use thereof as LRRK2 protein kinase inhibitors.

Description

亚砜酰亚胺化合物及其作为LRRK2蛋白激酶抑制剂的应用Sulfoximide compounds and their use as LRRK2 protein kinase inhibitors
本申请要求于2023年02月27日提交到中国国家知识产权局、申请号为202310216460.7、发明名称为“亚砜酰亚胺化合物及其作为LRRK2蛋白激酶抑制剂的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims priority to a Chinese patent application filed with the State Intellectual Property Office of China on February 27, 2023, with application number 202310216460.7 and invention name “Sulfothimide compounds and their use as LRRK2 protein kinase inhibitors”, the entire contents of which are incorporated by reference into this application.
技术领域Technical Field
本发明涉及药物化学领域，具体涉及一类亚砜酰亚胺化合物及其立体异构体、互变异构体或药学上可接受的盐，它们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该类化合物用作LRRK2蛋白激酶抑制剂的用途。The present invention relates to the field of pharmaceutical chemistry, and in particular to a class of sulfoximide compounds and stereoisomers, tautomers or pharmaceutically acceptable salts thereof, preparation methods thereof and pharmaceutical compositions containing the compounds. The present invention also relates to the use of the compounds as LRRK2 protein kinase inhibitors.
背景技术Background Art
富亮氨酸重复激酶2(LRRK2)是LRRK2基因的蛋白产物，属于丝氨酸/苏氨酸蛋白激酶。虽然LRRK2蛋白的功能在目前尚不完全清楚，但早在2004年LRRK2基因突变就被发现与帕金森氏病(PD)有关。LRRK2基因突变常见于激酶活性区域的G2019S和I2020T以及GTP酶区域的R1441G/C/H和Y1699C突变，这些突变均可导致LRRK2蛋白激酶活性升高，引发多种病理改变，包括增加synuclein和TAU蛋白磷酸化、神经系统炎症以及神经元线粒体功能失调。Leucine-rich repeat kinase 2 (LRRK2) is the protein product of the LRRK2 gene and is a serine/threonine protein kinase. Although the function of LRRK2 protein is not fully understood at present, LRRK2 gene mutations were found to be associated with Parkinson's disease (PD) as early as 2004. LRRK2 gene mutations are commonly found in the G2019S and I2020T in the kinase active region and the R1441G/C/H and Y1699C mutations in the GTPase region. These mutations can lead to increased LRRK2 protein kinase activity and induce a variety of pathological changes, including increased synuclein and TAU protein phosphorylation, nervous system inflammation, and neuronal mitochondrial dysfunction.
帕金森病(PD)是仅次于老年痴呆症(Alzheimer’s Disease)的第二大神经系统退行性疾病，在全球有1000多万患者，但至今尚未发现有效治疗。10％的PD患者有明显家族史，其中LRRK2突变是最常见的原因。该突变发生在约5％的家族性PD以及1％的非家族性PD，这些突变引起的临床表现与散发型PD没有区别。此外LRRK2突变还可以导致TAU蛋白的病理改变，而TAU的病理改变是老年痴呆症的一大特征。LRRK2被认为位于神经退行性疾病发病机理的上游阶段，对其他神经退行性疾病也起着重要作用。因此开发LRRK2特异性抑制剂成为治疗PD以及其它神经退行性疾病的有效途径之一。Parkinson’s disease (PD) is the second largest neurodegenerative disease after Alzheimer’s Disease, with more than 10 million patients worldwide, but no effective treatment has been found so far. 10% of PD patients have a clear family history, of which LRRK2 mutation is the most common cause. This mutation occurs in about 5% of familial PD and 1% of non-familial PD, and the clinical manifestations caused by these mutations are no different from those of sporadic PD. In addition, LRRK2 mutations can also lead to pathological changes in TAU protein, and pathological changes in TAU are a major feature of Alzheimer’s disease. LRRK2 is believed to be located in the upstream stage of the pathogenesis of neurodegenerative diseases and also plays an important role in other neurodegenerative diseases. Therefore, the development of LRRK2-specific inhibitors has become one of the effective ways to treat PD and other neurodegenerative diseases.
现有的LRRK2蛋白激酶化合物在酶抑制活性上还不能让人满意，或者水溶性不够好，不能够满足药物开发的要求。因此，现有技术中仍迫切需要具有良好的蛋白激酶抑制活性和/或良好的水溶性的化合物。Existing LRRK2 protein kinase compounds are not satisfactory in terms of enzyme inhibitory activity, or their water solubility is not good enough to meet the requirements of drug development. Therefore, there is still an urgent need in the prior art for compounds with good protein kinase inhibitory activity and/or good water solubility.
发明内容 Summary of the invention
本发明人经研究发现，本发明的亚砜酰亚胺化合物针对蛋白激酶展现了很好的抑制活性；而且，该类化合物也展示了良好的水溶性。The inventors have found through research that the sulfoximide compounds of the present invention exhibit good inhibitory activity against protein kinases; moreover, the compounds also exhibit good water solubility.
基于上述研究发现，在第一方面，本发明提供了一种具有式(I)结构的化合物或其立体异构体、互变异构体或药学上可接受的盐：
Based on the above research findings, in the first aspect, the present invention provides a compound having a structure of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
其中，in,
A选自任选取代的C1～6烷基、C3～8环烷基、C6～14芳基、5～12元杂芳基、3～8元杂环基、5～18元桥环基或5～18元螺环基，其中所述取代基选自氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、3～8元杂环基、C1～4烷基磷酰基、C1～4烷基磺酰基、氰基、羟基、氧代、巯基、氨基和卤素；A is selected from optionally substituted C1-6 alkyl, C3-8 cycloalkyl, C6-14 aryl, 5-12 membered heteroaryl, 3-8 membered heterocyclyl, 5-18 membered bridged ring group or 5-18 membered spirocyclyl, wherein the substituent is selected from deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, 3-8 membered heterocyclyl, C1-4 alkylphosphoryl, C1-4 alkylsulfonyl, cyano, hydroxy, oxo, mercapto, amino and halogen;
L表示不存在(共价键)、-O-、-NH-、-N(C1～4烷基)-、-S-、-S(O)-或者-S(O)2-；L represents absence (covalent bond), -O-, -NH-, -N(C 1-4 alkyl)-, -S-, -S(O)-, or -S(O) 2 -;
R1是氢，或者是取代或未取代的C1～4烷基、C3～6环烷基，其中所述取代基选自氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、氧代、氰基、羟基、氨基、二甲氨基、羟胺基、卤素； R1 is hydrogen, or substituted or unsubstituted C1-4 alkyl, C3-6 cycloalkyl, wherein the substituent is selected from deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, oxo, cyano, hydroxyl, amino, dimethylamino, hydroxylamino, halogen;
R2和R3各自独立地选自氢、氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、3～8元杂环基、氰基、羟基和卤素； R2 and R3 are each independently selected from hydrogen, deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, 3-8 membered heterocyclic group, cyano, hydroxyl and halogen;
Ra选自氢、氨基、三氟甲基、卤素、氰基、C1～3烷基、乙酰基、C1～3烷基磷酰基和C1～3烷基磺酰基；Ra is selected from hydrogen, amino, trifluoromethyl, halogen, cyano, C 1-3 alkyl, acetyl, C 1-3 alkylphosphoryl and C 1-3 alkylsulfonyl;
Rb选自氢、氨基和C1～3烷基氨基；Rb is selected from hydrogen, amino and C 1-3 alkylamino;
或者，Ra、Rb和它们所连接的C原子一起形成5～6元芳环、5～8元杂芳环或5～8元杂环；Alternatively, Ra, Rb and the C atom to which they are attached together form a 5- to 6-membered aromatic ring, a 5- to 8-membered heteroaromatic ring or a 5- to 8-membered heterocyclic ring;
n选自0、1和2。n is selected from 0, 1 and 2.
更具体地，在一些实施方案中，所述式(I)化合物具有以下式(II)结构：
More specifically, in some embodiments, the compound of formula (I) has the following structure of formula (II):
其中，A、L、R1、R2、R3、Ra和n具有如上所述的定义。wherein A, L, R 1 , R 2 , R 3 , Ra and n have the same meanings as described above.
在另一些实施方案中，所述式I化合物具有以下式(III)结构：
In other embodiments, the compound of formula I has the following structure:
其中，A、L、R1、R2、R3和n具有如上所述的定义，X、Y各自独立地选自C和N，表示双键或者单键。wherein A, L, R 1 , R 2 , R 3 and n are as defined above, X and Y are each independently selected from C and N, Indicates a double bond or a single bond.
在本文中，A可优选为以下的结构：Herein, A may preferably be the following structure:
其中，上述波浪线表示与母核化合物相连接的位置。 The wavy line indicates the position connected to the parent core compound.
本发明中优选以下化合物或其可药用盐：





The following compounds or their pharmaceutically acceptable salts are preferred in the present invention:





在本发明的另一个方面，提供了一种药物组合物，其包含本发明所述的式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐。在一些实施方案中，所述式(I)化合物具有上述(II)或(III)结构。在另一些实施方案中，所述式(I)化合物为上述具体的化合物。In another aspect of the present invention, a pharmaceutical composition is provided, which comprises a compound of formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof according to the present invention. In some embodiments, the compound of formula (I) has the above-mentioned structure (II) or (III). In other embodiments, the compound of formula (I) is the above-mentioned specific compound.
在本文中，化合物本身包括其同位素形式，例如式(I)化合物的氢原子被氢的同位素氘取代后的化合物。另一方面，化合物本身还包括其溶剂化物、水合物形式。Herein, the compound itself includes its isotopic form, for example, a compound in which the hydrogen atom of the compound of formula (I) is replaced by deuterium, an isotope of hydrogen. On the other hand, the compound itself also includes its solvate and hydrate forms.
在本发明的又一个方面，提供了本发明的上述化合物或其立体异构体、互变异构体或药学上可接受的盐或其药物组合物在制备用作LRRK2蛋白激酶抑制剂的药物中的应用。In another aspect of the present invention, provided is the use of the above-mentioned compound of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt or pharmaceutical composition thereof in the preparation of a drug used as an LRRK2 protein kinase inhibitor.
在本发明的又一个方面，提供了本发明的上述化合物或其立体异构体、互变异构体或药学上可接受的盐或其药物组合物在制备用于治疗或预防LRRK2蛋白激酶相关疾病的药物中的应用。所述LRRK2蛋白激酶相关疾病是指疾病发展或症状与LRRK2蛋白激酶的信号传递、介导、调节或调整有关的疾病。LRRK2蛋白激酶相关疾病的实例有下列疾病类型：神经退行性疾病、免疫相关疾病和癌症。优选地，所述LRRK2蛋白激酶相关疾病选自帕金森病、阿尔茨海默病、亨 廷顿病、克罗恩病、炎症性肠病、结核病、麻风病、黑色素瘤、非黑色素瘤皮肤癌和乳腺癌。In another aspect of the present invention, there is provided the use of the above-mentioned compound of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of a drug for treating or preventing LRRK2 protein kinase-related diseases. The LRRK2 protein kinase-related disease refers to a disease in which the development or symptoms of the disease are related to the signal transmission, mediation, regulation or adjustment of the LRRK2 protein kinase. Examples of LRRK2 protein kinase-related diseases include the following disease types: neurodegenerative diseases, immune-related diseases and cancer. Preferably, the LRRK2 protein kinase-related disease is selected from Parkinson's disease, Alzheimer's disease, Hennessy's disease, and other diseases. Huntington's disease, Crohn's disease, inflammatory bowel disease, tuberculosis, leprosy, melanoma, non-melanoma skin cancer, and breast cancer.
在本发明的另一方面，提供了一种治疗或预防LRRK2蛋白激酶相关疾病的方法，包括向有此需要的对象给予本发明所述的化合物或其立体异构体、互变异构体或药学上可接受的盐或其药物组合物。In another aspect of the present invention, a method for treating or preventing LRRK2 protein kinase-related diseases is provided, comprising administering the compound of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need thereof.
就本文所述的化合物、组合物和方法中所涉及的疾病而言，其包括但不局限于帕金森病、阿尔茨海默病、亨廷顿病、克罗恩病、炎症性肠病、结肠炎、结核病、麻风病、黑色素瘤、非黑色素瘤皮肤癌和乳腺癌。Diseases to which the compounds, compositions and methods described herein relate include, but are not limited to, Parkinson's disease, Alzheimer's disease, Huntington's disease, Crohn's disease, inflammatory bowel disease, colitis, tuberculosis, leprosy, melanoma, non-melanoma skin cancer and breast cancer.
本文中的用语“任选取代”或“取代或未取代的”是指A、R1等所述基团可以被所述取代基取代，也可以不被所述取代基取代，即并不仅限于被所列举的取代基取代的情况，也包括不被所列举的取代基取代的情况。The term "optionally substituted" or "substituted or unsubstituted" herein means that the groups such as A and R1 may be substituted by the substituents or may not be substituted by the substituents, i.e., it is not limited to the case of being substituted by the listed substituents, but also includes the case of not being substituted by the listed substituents.
术语“烷基”用于表示直链或支链的饱和烃基，例如，C1～3烷基是指含有1～3个碳原子的饱和烃基，C1～4烷基是指含有1～4个碳原子的饱和烃基，C1～6的烷基是指含有1～6个碳原子的饱和烃基，包括直连、支链或者环状的烷基。本文中的烷基优选C1～10烷基、C1～8烷基、C1～6烷基或C1～4烷基。The term "alkyl" is used to represent a straight or branched saturated hydrocarbon group, for example, C1-3 alkyl refers to a saturated hydrocarbon group containing 1 to 3 carbon atoms, C1-4 alkyl refers to a saturated hydrocarbon group containing 1 to 4 carbon atoms, and C1-6 alkyl refers to a saturated hydrocarbon group containing 1 to 6 carbon atoms, including straight, branched or cyclic alkyl groups. The alkyl group herein is preferably C1-10 alkyl, C1-8 alkyl, C1-6 alkyl or C1-4 alkyl.
术语“烷氧基”是指烷基-O-。“C1～6烷氧基”意欲包括C1、C2、C3、C4、C5、C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地，“C1～10烷氧基”是指-O-烷基基团，烷基包括直链、支链和环状烷基，其碳原子数为1～10个。烷氧基的例子包括甲氧基，乙氧基，丙氧基(如，正丙氧基、异丙氧基和环丙氧基)，叔丁氧基等。本文中优选的烷氧基包括C1～10烷氧基、C1～8烷氧基、C1～6烷氧基和C1～4烷氧基。The term "alkoxy" refers to an alkyl-O-. "C 1-6 alkoxy" is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and tert-butoxy. Similarly, "C 1-10 alkoxy" refers to an -O-alkyl group, and the alkyl group includes linear, branched and cyclic alkyl groups, and the number of carbon atoms thereof is 1 to 10. Examples of alkoxy include methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy and cyclopropoxy), tert-butoxy, and the like. Preferred alkoxy groups herein include C 1-10 alkoxy, C 1-8 alkoxy, C 1-6 alkoxy and C 1-4 alkoxy.
术语“环烷基”指基于非芳族碳环的环化烷基。环烷基可以包括单环、二环或多环系统。环烷基的例子包括环丙基、环丁基、环戊基、环己基、环庚基等，C3～8环烷基是指含有3～8个碳原子的环烷基。本文中优选的环烷基是C3～8环烷基、C3～6环烷基。The term "cycloalkyl" refers to a cyclized alkyl group based on a non-aromatic carbocyclic ring. The cycloalkyl group may include a monocyclic, bicyclic or polycyclic system. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. C3-8 cycloalkyl groups refer to cycloalkyl groups containing 3 to 8 carbon atoms. Preferred cycloalkyl groups herein are C3-8 cycloalkyl groups and C3-6 cycloalkyl groups.
术语“杂环烷基”或“杂环基”是指非芳族杂环烷基，其中1个或2个或3个成环碳原子被选自O、N和S原子的杂原子所取代。杂环烷基优选具有3、4、5、6、7或8个成环原子。本文中优选的杂环基是C3～8杂环基或C3～6杂环基。The term "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic heterocycloalkyl group in which 1 or 2 or 3 ring-forming carbon atoms are substituted by heteroatoms selected from O, N and S atoms. The heterocycloalkyl group preferably has 3, 4, 5 , 6, 7 or 8 ring-forming atoms. Preferred heterocyclyl groups herein are C 3-8 heterocyclyl groups or C 3-6 heterocyclyl groups.
“芳基”是指芳族碳环基，包括单环、二环、三环或多环芳烃，例如苯基，萘基，蒽基，菲基等。芳基优选为具有6至14个或6至12个环成员的单环、二环 或三环的环系统。优选地，所述系统中的至少一个环为芳族的且其中所述系统中的每个环含有3至7个环成员。“取代的芳基”是指在芳基的苯环上至少一个氢原子被非氢部分取代，芳基的取代基可以是卤素、C1～10烷氧基、-CN、-OH、-SH、-NH2、C1～6烷基。优选的芳基包括苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。"Aryl" refers to an aromatic carbocyclic group, including monocyclic, bicyclic, tricyclic or polycyclic aromatic hydrocarbons, such as phenyl, naphthyl, anthracenyl, phenanthrenyl, etc. Aryl is preferably a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon having 6 to 14 or 6 to 12 ring members. or tricyclic ring system. Preferably, at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. "Substituted aryl" means that at least one hydrogen atom on the phenyl ring of the aryl is replaced by a non-hydrogen moiety, and the substituent of the aryl can be halogen, C 1-10 alkoxy, -CN, -OH, -SH, -NH 2 , C 1-6 alkyl. Preferred aryl groups include phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, etc. The fused aryl can be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring.
术语“杂芳基”意指5-12元的芳香单环或芳香二环或芳香多环杂环，其为完全不饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子。本文中的杂芳基优选为5～12元杂芳基。本文中的杂芳基优选具有1或2个或3个独立地选自N、O和S的杂原子。优选地，本文中的杂芳基包括5元、6元或7元的芳香单环或8元、9元、10元、11元、12元的芳香二环或芳香多环杂环；优选上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子可为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。芳杂基的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻喃基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、喹啉基、十氢喹啉基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、 2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻喃基、噻唑并吡啶基、噻喃并噻唑基、噻喃并噁唑基、噻喃并咪唑基、噻喃基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构，例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、“-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”。The term "heteroaryl" means a 5-12 membered aromatic monocyclic or aromatic bicyclic or aromatic polycyclic heterocyclic ring, which is fully unsaturated, partially unsaturated, and contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The heteroaryl herein is preferably a 5-12 membered heteroaryl. The heteroaryl herein preferably has 1 or 2 or 3 heteroatoms independently selected from N, O and S. Preferably, the heteroaryl herein includes a 5-, 6- or 7-membered aromatic monocyclic ring or an 8-, 9-, 10-, 11- or 12-membered aromatic bicyclic or aromatic polycyclic heterocyclic ring; preferably, any heterocyclic ring defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent). The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic group described herein can be substituted on carbon or nitrogen atom. The nitrogen in the heterocycle can be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. The embodiment of aromatic hetero groups includes but is not limited to acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiopyranyl, benzoxazolyl, benzoxazoline, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazoline, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, quinolyl , decahydroquinolinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl , isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perimelinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenanthroline, oxazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidine, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthracenyl, thiazolyl, thiapyranyl, thiazolopyridyl, thiapyranothiazolyl, thiapyranooxazolyl, thiapyranoimidazolyl, thiapyranyl, triazinyl, 1 , 2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-quinolyl, 2,3-dihydro-benzofuranyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The term "heteroaryl" may also include a biaryl structure formed by the above-defined "aryl" and a monocyclic "heteroaryl", such as but not limited to "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidyl-", "-pyrimidylbiphenyl-".
术语“C1～4烷基磷酰基”是指C1～4烷基取代的磷酰基，磷酰基上的两个烷基可以相同也可以不同。The term "C 1-4 alkylphosphoryl group" refers to a phosphoryl group substituted with a C 1-4 alkyl group, and the two alkyl groups on the phosphoryl group may be the same or different.
术语“C1～4烷基磺酰基”是指C1～4烷基取代的磺酰基。The term "C 1-4 alkylsulfonyl group" refers to a sulfonyl group substituted with a C 1-4 alkyl group.
术语“卤素”包括氟、氯、溴和碘。The term "halogen" includes fluorine, chlorine, bromine and iodine.
“桥环基”指5至18元、优选5至14元，含有两个或两个以上环状结构，彼此共用两个不直接相连接的碳原子的多环基团。更优选为6至14元，还更优选为7至10元桥环基。根据组成环的数目可以分为双环、三环、吡啶酮或多环桥杂环基，优选为双环、三环或吡啶酮，更优选为双环或三环。本文中的桥环基允许其中1个、2个或3个环原子为选自N、O、S、SO和/或S(O)2的杂原子。"Bridged ring group" refers to a polycyclic group of 5 to 18 members, preferably 5 to 14 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other. More preferably, it is a 6 to 14-membered, and even more preferably a 7 to 10-membered bridged ring group. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, pyridone or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or pyridone, more preferably a bicyclic or tricyclic. The bridged ring group herein allows 1, 2 or 3 of the ring atoms to be heteroatoms selected from N, O, S, SO and/or S(O) 2 .
“螺环基”指5至18元、优选6至12元，含有两个或两个以上环状结构，彼此共用一个碳原子的多环基团。根据组成环的数目可以分为双环、三环，优选为双环。本文中的螺环基允许其中1个、2个或3个环原子为选自N、O、S、SO和/或S(O)2的杂原子。"Spirocyclyl" refers to a polycyclic group of 5 to 18 members, preferably 6 to 12 members, containing two or more cyclic structures, sharing one carbon atom with each other. According to the number of constituent rings, it can be divided into bicyclic and tricyclic, preferably bicyclic. Spirocyclyl herein allows 1, 2 or 3 of the ring atoms to be heteroatoms selected from N, O, S, SO and/or S(O) 2 .
本文中所用术语“药学上可接受的盐”或“可药用盐”是指使本发明化合物能保持原有生物活性并且适合于医药用途的盐类。式(I)所表示的化合物的可药用的盐可以是通过羧基或胺基(主要是胺基)与合适的碱或酸所形成的盐，例如与合适的碱形成的盐(包括金属盐、铵盐)、或者与合适的酸形成的盐。本发明的化合物优选与合适的酸形成盐，所述酸可选自：盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹 果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘磺酸、三氟乙酸和天冬氨酸，优选为甲磺酸或盐酸。The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" as used herein refers to salts that enable the compounds of the present invention to maintain their original biological activity and are suitable for medical use. The pharmaceutically acceptable salts of the compounds represented by formula (I) may be salts formed by a carboxyl group or an amine group (mainly an amine group) and a suitable base or acid, such as a salt formed with a suitable base (including a metal salt, an ammonium salt), or a salt formed with a suitable acid. The compounds of the present invention preferably form salts with a suitable acid, and the acid may be selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, Fruit acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid and aspartic acid, preferably methanesulfonic acid or hydrochloric acid.
本文使用的术语“治疗”包括导致改善病症、疾病、障碍等的任何效果，例如减轻、减少、调节、改善或消除，或改善其症状。As used herein, the term "treat," ...
本文使用的短语“可药用载体”意指药用物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质，其涉及将主体化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutical substance, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium, calcium or zinc stearate or stearic acid) or solvent encapsulating substance, which is involved in carrying or transporting the subject compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
术语“药物组合物”意指包含本发明化合物与至少一种其它可药用载体的组合物。“药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质，包括(即)佐剂、赋形剂或媒介物，诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂，这取决于给药模式和剂型的性质。The term "pharmaceutical composition" means a composition comprising a compound of the present invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including (i.e.) adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form.
术语“TLC”是指薄层色谱；The term “TLC” refers to thin layer chromatography;
为更好地阐述本发明所采取的技术手段及其效果，以下结合非限制性实施例来进一步说明本发明。本发明的实施例，包括实施例中提供的描述，旨在说明本发明的实施方式，其并非旨在限制任何权利要求的范围。根据本发明，本领域技术人员将理解，在不脱离本发明的精神和范围的情况下，可以对所公开的具体实施方案进行许多改变并仍然能获得相同或相似的结果。In order to better illustrate the technical means and effects adopted by the present invention, the present invention is further described below in conjunction with non-limiting examples. The embodiments of the present invention, including the descriptions provided in the embodiments, are intended to illustrate the embodiments of the present invention and are not intended to limit the scope of any claims. According to the present invention, those skilled in the art will understand that many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of the present invention and still achieve the same or similar results.
除非另有说明，所有材料/试剂均从商业供应商处获得，无需进一步纯化即可使用。下述实施例的化合物结构是通过核磁共振(NMR)和/或液相色谱质谱联用(LC_MS)来表征和确定的。Unless otherwise specified, all materials/reagents were obtained from commercial suppliers and used without further purification. The structures of the compounds in the following examples were characterized and confirmed by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS).
1H NMR波谱通过Bruker Avance 400MHz波谱仪上在室温下记录，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)或氘水(D2O)。化学位移值(δ)以ppm为单位，用四甲基硅烷(TMS)或残留溶剂峰作为内标，耦合常数(J)以赫兹(Hz)为单位，1H NMR谱图中峰型的多重性缩写如下：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、qn(五重峰)、m(多重峰)、br(宽峰)。 1 H NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer at room temperature, and the solvents used for the determination were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) or deuterated water (D 2 O). Chemical shift values (δ) are in ppm, with tetramethylsilane (TMS) or residual solvent peak as internal standard, coupling constants (J) are in Hertz (Hz), and the multiplicity abbreviations of peak types in 1 H NMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), m (multiplet), br (broad peak).
液相色谱质谱联用(LC_MS)使用的仪器是Shimadzu LCMS-2020，制备型高效液相色谱(Prep-HPLC)使用的仪器是Bonna-Agela FLEXA FL-H100G。薄层色谱 (TLC)所使用的薄层层析硅胶板是烟台黄海HSGF254薄层层析硅胶板，反应监测所用的规格为2.5×8cm，其涂层厚度为0.2±0.03mm，分离纯化所用的规格为20×20cm，其涂层厚度为0.4–0.5mm。硅胶柱层析色谱法使用的是青岛海洋硅胶100–200目或200–300目硅胶为载体。The instrument used for liquid chromatography-mass spectrometry (LC_MS) was Shimadzu LCMS-2020, and the instrument used for preparative high performance liquid chromatography (Prep-HPLC) was Bonna-Agela FLEXA FL-H100G. Thin layer chromatography The thin layer chromatography silica gel plate used for (TLC) was Yantai Huanghai HSGF254 thin layer chromatography silica gel plate, the specifications used for reaction monitoring were 2.5×8cm, the coating thickness was 0.2±0.03mm, the specifications used for separation and purification were 20×20cm, the coating thickness was 0.4–0.5mm. The silica gel column chromatography method used Qingdao Marine Silica Gel 100–200 mesh or 200–300 mesh silica gel as the carrier.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention.
合成实施例：Synthesis Example:
片段Amine-1Fragment Amine-1
(1s,4s)-4-(4-氨基-5-氯-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
实施方式:
Implementation method:
步骤1：中间体Amine-1-c:4-硝基-1-(四氢-2H-噻喃-4-基)-1H-吡唑的合成
Step 1: Synthesis of intermediate Amine-1-c:4-nitro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
向含有四氢-2H-噻喃-4-醇(1g,8.46mmol),4-硝基吡唑(957mg,8.46mmol)，三苯基磷(4.4g,16.9mmol)的四氢呋喃(20mL)溶液于0℃及氮气氛围下加入偶氮二甲酸二乙酯(2.9g,16.9mmol)。混合物继续在0℃及氮气氛围下反应5小时。TLC监测反应完全。混合物分配于二氯甲烷(100mL)和水(100mL)中。收集有机相，饱和氯化钠溶液(20ml)洗涤，无水硫酸钠干燥，减压浓缩，所得粗品经硅胶柱层析(13％乙酸乙酯的石油醚洗脱溶液)纯化得到中间体Amine-1-c为白色固体(1.13g,63％)。To a tetrahydrofuran (20 mL) solution containing tetrahydro-2H-thiopyran-4-ol (1 g, 8.46 mmol), 4-nitropyrazole (957 mg, 8.46 mmol), triphenylphosphine (4.4 g, 16.9 mmol) was added diethyl azodicarboxylate (2.9 g, 16.9 mmol) at 0°C under nitrogen atmosphere. The mixture continued to react for 5 hours at 0°C under nitrogen atmosphere. TLC monitored the reaction to be complete. The mixture was partitioned between dichloromethane (100 mL) and water (100 mL). The organic phase was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (13% ethyl acetate in petroleum ether elution solution) to obtain the intermediate Amine-1-c as a white solid (1.13 g, 63%).
LC_MS:(ES+):m/z 214.0[M+H]+.LC_MS:(ES + ):m/z 214.0[M+H] + .
步骤2：中间体Amine-1-d:5-氯-4-硝基-1-(四氢-2H-噻喃-4-基)-1H-吡唑的合成
Step 2: Synthesis of intermediate Amine-1-d: 5-chloro-4-nitro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
向含有4-硝基-1-(四氢-2H-噻喃-4-基)-1H-吡唑(1g,4.69mmol)的四氢呋喃(20ml)悬浮液中于-60℃及氮气氛围中加入双(三甲基硅基)胺锂(11.7ml,11.72mmol)。混合物继续在-60℃搅拌30分钟后，逐滴加入六氯乙烷(2.8g,11.72mmol)的四氢呋喃(10ml)并继续搅拌一小时。TLC监测反应完全。向反应液中加入饱和碳酸氢钠溶液(30mL)及乙酸乙酯(30mL)。收集有机相，无水硫酸钠干燥，减压浓缩，得到中间体Amine-1-d为白色固体(990mg,78％)。To a suspension of 4-nitro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole (1 g, 4.69 mmol) in tetrahydrofuran (20 ml) was added lithium bis(trimethylsilyl)amide (11.7 ml, 11.72 mmol) at -60°C in a nitrogen atmosphere. The mixture was stirred at -60°C for 30 minutes, and then hexachloroethane (2.8 g, 11.72 mmol) in tetrahydrofuran (10 ml) was added dropwise and stirred for one hour. TLC monitored the reaction to be complete. Saturated sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL) were added to the reaction solution. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate Amine-1-d as a white solid (990 mg, 78%).
LC_MS:(ES+):m/z 247.8[M+H]+.LC_MS:(ES + ):m/z 247.8[M+H] + .
步骤3：中间体Amine-1-e:4-(5-氯-4-硝基-1H-吡唑-1-基)四氢-2H-噻喃1-氧化物的合成
Step 3: Synthesis of intermediate Amine-1-e: 4-(5-chloro-4-nitro-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1-oxide
向5-氯-4-硝基-1-(四氢-2H-噻喃-4-基)-1H-吡唑(300mg,1.21mmol)的甲醇混悬液中于0℃加入高碘酸钠(259mg,1.21mmol)的水溶液(2mL)，混合物在0℃下反应2小时后继续于室温反应15小时。TLC监测反应完全。混合物减压浓缩，剩余物分配于二氯甲烷(10mL)和水(10mL)中。收集有机相，向水相中加入二氯甲烷萃取(10mL x 2)，合并有机相，用饱和氯化钠溶液洗涤(20mL),无水硫酸钠干燥，减压浓缩，得到中间体Amine-1-e为白色固体(300mg,94％),无需进一步纯化可直接用于下一步反应。To a methanol suspension of 5-chloro-4-nitro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole (300 mg, 1.21 mmol) was added an aqueous solution (2 mL) of sodium periodate (259 mg, 1.21 mmol) at 0°C. The mixture was reacted at 0°C for 2 hours and then at room temperature for 15 hours. TLC monitored the reaction to be complete. The mixture was concentrated under reduced pressure, and the residue was distributed between dichloromethane (10 mL) and water (10 mL). The organic phase was collected, and dichloromethane was added to the aqueous phase for extraction (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate Amine-1-e as a white solid (300 mg, 94%), which can be directly used in the next step without further purification.
LC_MS:(ES+):m/z 263.8[M+H]+.LC_MS:(ES + ):m/z 263.8[M+H] + .
步骤4：中间体Amine-1-f-A:N-((1s,4s)-(4-(5-氯-4-硝基-1H-吡唑-1-基)-1-氧化四氢-2H-1λ6-噻喃-1-亚基)-2,2,2-三氟乙酰胺和中间体Amine-1-f-B:N-((1r,4r)-(4-(5-氯-4-硝基-1H-吡唑-1-基)-1-氧化四氢-2H-1λ6-噻喃-1-亚基)-2,2,2-三氟乙酰胺的合成
Step 4: Synthesis of intermediate Amine-1-fA: N-((1s,4s)-(4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-oxytetrahydro-2H-1λ 6 -thiopyran-1-ylidene)-2,2,2-trifluoroacetamide and intermediate Amine-1-fB: N-((1r,4r)-(4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-oxytetrahydro-2H-1λ 6 -thiopyran-1-ylidene)-2,2,2-trifluoroacetamide
将含有4-(5-氯-4-硝基-1H-吡唑-1-基)四氢-2H-噻喃1-氧化物(700mg,2.66mmol),2,2,2-三氟乙酰胺(450mg,3.98mmol),氧化镁(425mg,10.62mmol),二聚醋酸铑(II)(176mg,0.40mmol)及碘苯二乙酸(1.28g,3.98mmol)的二氯甲烷(15mL)溶液在氮气氛围下反应15小时。TLC监测反应完全。混合物经硅藻土过滤,滤饼用二氯甲烷(5mL x 2)洗涤，滤液合并后减压浓缩，所得粗品经硅胶柱层析(30-50％乙酸乙酯的石油醚洗脱溶液)纯化得到两个顺反异构体组分(顺反构型的确定参考Amine-3-a)：A solution of 4-(5-chloro-4-nitro-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1-oxide (700 mg, 2.66 mmol), 2,2,2-trifluoroacetamide (450 mg, 3.98 mmol), magnesium oxide (425 mg, 10.62 mmol), dimerized rhodium (II) acetate (176 mg, 0.40 mmol) and iodophenyl diacetic acid (1.28 g, 3.98 mmol) in dichloromethane (15 mL) was reacted under nitrogen atmosphere for 15 hours. TLC monitored the reaction to be complete. The mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane (5 mL x 2), the filtrates were combined and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (30-50% ethyl acetate in petroleum ether elution solution) to obtain two cis-trans isomer components (the determination of cis-trans configuration refers to Amine-3-a):
第一洗脱组分为白色固体Amine-1-f-A(340mg,34％)The first eluted component is white solid Amine-1-f-A (340 mg, 34%)
LC_MS:(ES+):m/z 374.8[M+H]+.LC_MS:(ES + ):m/z 374.8[M+H] + .
第二洗脱组分为无色油状物Amine-1-f-B(320mg,32％).The second eluting fraction was a colorless oily substance, Amine-1-f-B (320 mg, 32%).
LC_MS:(ES+):m/z 374.8[M+H]+. LC_MS:(ES + ):m/z 374.8[M+H] + .
步骤5：中间体Amine-1-g:(1s,4s)-4-(5-氯-4-硝基-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物的合成
Step 5: Synthesis of intermediate Amine-1-g: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
将含有Amine-1-f-A(300mg,0.80mmol)及氢氧化锂一水合物(168mg,4.00mmol)的四氢呋喃(4mL)及水(1mL)溶液于室温下搅拌30min。TLC监测反应完全。混合物分配于乙酸乙酯(10mL)及水(10mL)中。收集有机相，无水硫酸钠干燥，减压浓缩，得到中间体Amine-1-g为白色固体(214mg,96％),无需纯化，可直接用于下一步反应。A solution of tetrahydrofuran (4 mL) and water (1 mL) containing Amine-1-f-A (300 mg, 0.80 mmol) and lithium hydroxide monohydrate (168 mg, 4.00 mmol) was stirred at room temperature for 30 min. TLC monitored the reaction to be complete. The mixture was distributed between ethyl acetate (10 mL) and water (10 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate Amine-1-g as a white solid (214 mg, 96%), which can be directly used in the next step without purification.
LC_MS:(ES+):m/z 279.0[M+H]+.LC_MS:(ES + ):m/z 279.0[M+H] + .
步骤七:片段Amine-1:(1s,4s)-4-(4-氨基-5-氯-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物的合成
Step 7: Synthesis of fragment Amine-1: (1s, 4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
将含有Amine-1-g(40mg,0.14mmol),铁粉(79mg,1.41mmol),氯化铵(38mg,0.71mmol)的甲醇(4mL)和水(1mL)混合溶液加热至回流反应两小时。TLC监测反应完全。混合物经过滤除去铁粉后用乙醇(5ml×2)洗涤滤饼，滤液合并后减压浓缩，得到片段Amine-1为红色固体(30mg,粗品)，无需进一步纯化，可直接用于下一步反应。A mixed solution of methanol (4 mL) and water (1 mL) containing Amine-1-g (40 mg, 0.14 mmol), iron powder (79 mg, 1.41 mmol), ammonium chloride (38 mg, 0.71 mmol) was heated to reflux for two hours. The reaction was completed by TLC monitoring. The mixture was filtered to remove the iron powder and the filter cake was washed with ethanol (5 ml × 2). The filtrates were combined and concentrated under reduced pressure to obtain the fragment Amine-1 as a red solid (30 mg, crude product), which could be directly used in the next step without further purification.
LC_MS:(ES+):m/z 249.0[M+H]+.LC_MS:(ES + ):m/z 249.0[M+H] + .
片段Amine-2Fragment Amine-2
(1s,4s)-4-(4-氨基-5-氯-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式:
Implementation method:
步骤1：中间体Amine-2-a:(1s,4s)-4-(5-氯-4-硝基-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step 1: Synthesis of intermediate Amine-2-a: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
将含有Amine-1-g(20mg,0.072mmol),多聚甲醛(17mg,0.57mmol),三乙基硅烷(25mg,0.21mmol)及三氟乙酸(25mg,0.22mmol)的乙腈(1ml)溶液于35℃搅拌15小时。TLC监测反应完全。混合物分配于乙酸乙酯(10ml)和水(10ml)中。收集有机相，水相加入乙酸乙酯(10ml x 2)萃取后合并有机相。饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经制备TLC(含1.5％甲醇的二氯甲烷洗脱溶液)纯化，得到Amine-2-a为黄色固体(15mg,71％)。A solution of Amine-1-g (20 mg, 0.072 mmol), paraformaldehyde (17 mg, 0.57 mmol), triethylsilane (25 mg, 0.21 mmol) and trifluoroacetic acid (25 mg, 0.22 mmol) in acetonitrile (1 ml) was stirred at 35 °C for 15 hours. TLC monitored the reaction to be complete. The mixture was distributed between ethyl acetate (10 ml) and water (10 ml). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (10 ml x 2) and the organic phases were combined. Wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by preparative TLC (dichloromethane elution solution containing 1.5% methanol) to obtain Amine-2-a as a yellow solid (15 mg, 71%).
LC_MS:(ES+):m/z 293.0[M+H]+.LC_MS:(ES + ):m/z 293.0[M+H] + .
1H NMR(400MHz,DMSO-d6):δ2.38-2.48(m,4H),2.81(s,3H),3.67-3.82(m,4H),4.95-5.02(m,1H),8.58(s,1H). 1 H NMR (400MHz, DMSO-d6): δ2.38-2.48(m,4H),2.81(s,3H),3.67-3.82(m,4H),4.95-5.02(m,1H),8.58(s ,1H).
步骤2：中间体Amine-2:(1s,4s)-4-(4-氨基-5-氯-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step 2: Synthesis of intermediate Amine-2: (1s, 4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
将含有Amine-2-a(40mg,0.14mmol),铁粉(79mg,1.41mmol),氯化铵(38mg,0.71mmol)的甲醇(4mL)和水(1mL)混合溶液加热至回流并反应两小时。TLC监测反应完全。混合物经过滤除去铁粉后用乙醇(5ml×2)洗涤滤饼，滤液合并后减压浓缩，得到片段Amine-2为红色固体(32mg,粗品)，无需进一步纯化，可直接用于下一步反应。A mixed solution of methanol (4 mL) and water (1 mL) containing Amine-2-a (40 mg, 0.14 mmol), iron powder (79 mg, 1.41 mmol), ammonium chloride (38 mg, 0.71 mmol) was heated to reflux and reacted for two hours. TLC monitored the reaction to be complete. The mixture was filtered to remove the iron powder and the filter cake was washed with ethanol (5 ml × 2). The filtrates were combined and concentrated under reduced pressure to obtain the fragment Amine-2 as a red solid (32 mg, crude product), which could be directly used in the next step without further purification.
LC_MS:(ES+):m/z 262.9[M+H]+.LC_MS:(ES + ):m/z 262.9[M+H] + .
片段Amine-3Fragment Amine-3
(1s,4s)-4-(4-氨基-5-氯-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式:
Implementation method:
实施方式同Amine-2，用乙醛替换多聚甲醛，得到目标化合物。其中Amine-3-a经X-单晶衍射确定其立体构型。The implementation method is the same as Amine-2, and acetaldehyde is used to replace paraformaldehyde to obtain the target compound. The stereo configuration of Amine-3-a is determined by X-ray single crystal diffraction.
LC_MS:(ES+):m/z 277.0[M+H]+.LC_MS:(ES + ):m/z 277.0[M+H] + .
片段Amine-4Clip Amine-4
(1s,4s)-4-(4-氨基-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
实施方式:
Implementation method:
步骤1：中间体Amine-4-a:四氢噻喃-4-对甲苯磺酸酯的合成
Step 1: Synthesis of intermediate Amine-4-a: tetrahydrothiopyran-4-toluenesulfonate
向含有4-硫代环己醇(1.0g,8.46mmol)、三乙胺(1.3g,12.70mmol)、DMAP(103.9mg,0.85mmol)的二氯甲烷(20mL)溶液于0℃分批加入对甲苯磺酰氯(1.7g,8.88mmol)。混合物逐渐升温至室温并反应16小时。TLC监测反应完全。混合物分配于水(20mL)中。收集有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。得到中间体Amine-4-a为棕色固体(2.02g,88％)，无需进一步纯化，可直接用于下一步反应。To a solution of 4-thiocyclohexanol (1.0 g, 8.46 mmol), triethylamine (1.3 g, 12.70 mmol), and DMAP (103.9 mg, 0.85 mmol) in dichloromethane (20 mL) was added in batches at 0°C to p-toluenesulfonyl chloride (1.7 g, 8.88 mmol). The mixture was gradually warmed to room temperature and reacted for 16 hours. TLC monitored the reaction to be complete. The mixture was distributed in water (20 mL). The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The intermediate Amine-4-a was obtained as a brown solid (2.02 g, 88%), which can be directly used in the next step without further purification.
1H NMR(400MHz,DMSO-d6)δ7.81(d,J＝8.2Hz,2H),7.48(d,J＝8.1Hz,2H),4.59(ddd,J＝11.9,8.2,3.4Hz,1H),2.70–2.62(m,2H),2.59–2.51(m,2H),2.42(s,3H),1.99–1.90(m,2H),1.78–1.68(m,2H). 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J＝8.2Hz,2H),7.48(d,J＝8.1Hz,2H),4.59(ddd,J＝11.9,8.2,3.4Hz,1H ),2.70–2.62(m,2H),2.59–2.51(m,2H),2.42(s,3H),1.99–1.90(m,2H),1.78–1.68(m,2H).
步骤2：中间体Amine-1-c:4-硝基-1-(四氢-2H-噻喃-4-基)-1H-吡唑的合成
Step 2: Synthesis of intermediate Amine-1-c:4-nitro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
向含有四氢噻喃-4-对甲苯磺酸酯(2.00g,7.34mmol)，4-硝基吡唑(871.5mg,7.71mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入碳酸钾(1.52g,11.01mmol)。混合物于80℃下加热16小时。TLC监测反应完全。混合物分配于乙酸乙酯(30 mL)和水(30mL)中。收集有机相，水相中加入乙酸乙酯(20mL×2)萃取后合并有机相。饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经柱层析纯化(含25％乙酸乙酯的石油醚洗脱溶液)得到中间体Amine-1-c为白色固体(1.03g,66％)。Potassium carbonate (1.52 g, 11.01 mmol) was added to a solution of tetrahydrothiopyran-4-p-toluenesulfonate (2.00 g, 7.34 mmol) and 4-nitropyrazole (871.5 mg, 7.71 mmol) in N,N-dimethylformamide (20 mL). The mixture was heated at 80°C for 16 hours. The reaction was complete as monitored by TLC. The mixture was partitioned between ethyl acetate (30 mL) and water (30 mL). Collect the organic phase, add ethyl acetate (20 mL × 2) to the aqueous phase for extraction and combine the organic phases. Wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by column chromatography (petroleum ether elution solution containing 25% ethyl acetate) to obtain the intermediate Amine-1-c as a white solid (1.03 g, 66%).
1H NMR(400MHz,CDCl3)δ8.16(s,1H),8.08(s,1H),4.16(tt,J＝11.8,3.5Hz,1H),2.91–2.78(m,4H),2.48(dd,J＝13.0,3.3Hz,2H),2.13(ddd,J＝24.4,12.0,4.3Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.16 (s, 1H), 8.08 (s, 1H), 4.16 (tt, J = 11.8, 3.5Hz, 1H), 2.91–2.78 (m, 4H), 2.48 ( dd,J＝13.0,3.3Hz,2H),2.13(ddd,J＝24.4,12.0,4.3Hz,2H).
步骤3：中间体Amine-4-b:4-(4-硝基-1H-吡唑-1-基)四氢-2H-噻喃1-氧化物的合成
Step 3: Synthesis of intermediate Amine-4-b: 4-(4-nitro-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1-oxide
向含有Amine-1-c(1.00g,4.69mmol)的甲醇溶液于冰浴条件下分批加入高碘酸钠(1.05g,4.92mmol)。混合物逐渐升温至室温反应8小时。TLC监测反应完全。混合物经过滤后收集滤液，滤饼经甲醇(10mL×2)洗涤后合并滤液。减压浓缩。得到中间体Amine-4-b为白色固体(1.11g,98％)，无需进一步纯化，可直接用于下一步反应。Sodium periodate (1.05 g, 4.92 mmol) was added in batches to a methanol solution containing Amine-1-c (1.00 g, 4.69 mmol) under ice bath conditions. The mixture was gradually heated to room temperature and reacted for 8 hours. TLC monitored the reaction to be complete. The mixture was filtered and the filtrate was collected. The filter cake was washed with methanol (10 mL × 2) and the filtrate was combined. Concentrated under reduced pressure. The intermediate Amine-4-b was obtained as a white solid (1.11 g, 98%), which can be directly used in the next step without further purification.
1H NMR(400MHz,DMSO)δ8.99(s,1H),8.32(s,1H),4.51(tt,J＝11.8,3.4Hz,1H),3.05(d,J＝12.6Hz,2H),2.88(dd,J＝13.5,2.7Hz,2H),2.60(td,J＝13.5,2.3Hz,2H),2.09–1.99(m,2H). 1 H NMR (400MHz, DMSO) δ8.99 (s, 1H), 8.32 (s, 1H), 4.51 (tt, J = 11.8, 3.4Hz, 1H), 3.05 (d, J = 12.6Hz, 2H), 2.88(dd,J＝13.5,2.7Hz,2H),2.60(td,J＝13.5,2.3Hz,2H),2.09–1.99(m,2H).
步骤4：中间体Amine-4-c-A:(1s,4s)-1-亚氨基-4-(4-硝基-1H-吡唑-1-基)六氢-1λ6-噻喃1-氧化物和中间体Amine-4-c-B:(1r,4r)-1-亚氨基-4-(4-硝基-1H-吡唑-1-基)六氢-1λ6-噻喃1-氧化物的合成
Step 4: Synthesis of intermediate Amine-4-cA: (1s, 4s)-1-imino-4-(4-nitro-1H-pyrazol-1-yl)hexahydro-1λ 6 -thiopyran 1-oxide and intermediate Amine-4-cB: (1r, 4r)-1-imino-4-(4-nitro-1H-pyrazol-1-yl)hexahydro-1λ 6 -thiopyran 1-oxide
向含有Amine-4-b(1.00g,4.36mmol)的甲醇(10mL)和N,N-二甲基甲酰胺(5mL)溶液依次加入氨基甲酸铵(851mg,10.90mmol)及碘苯二乙酸(4.22g,13.08mmol)。混合物于室温反应1.5小时。TLC监测反应完全。混合物分配于饱和碳酸氢钠溶液(10mL)和乙酸乙酯(30mL)中，继续于室温搅拌0.5小时，收集有机相。饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经柱层析纯化(含9％甲醇的二氯甲烷洗脱溶液)得到两个顺反异构体组分：To a solution of methanol (10 mL) and N,N-dimethylformamide (5 mL) containing Amine-4-b (1.00 g, 4.36 mmol) were added ammonium carbamate (851 mg, 10.90 mmol) and iodophenyl diacetic acid (4.22 g, 13.08 mmol) in sequence. The mixture was reacted at room temperature for 1.5 hours. TLC monitored the reaction to be complete. The mixture was distributed between a saturated sodium bicarbonate solution (10 mL) and ethyl acetate (30 mL), and continued to stir at room temperature for 0.5 hours, and the organic phase was collected. Washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent containing 9% methanol in dichloromethane) to obtain two cis-trans isomer components:
第一流出组分Amine-4-c-B为白色固体(192mg,18％)。The first eluting fraction, Amine-4-c-B, was a white solid (192 mg, 18%).
LC_MS:(ES+):m/z 245.1[M+H]+.LC_MS:(ES + ):m/z 245.1[M+H] + .
1H NMR(400MHz,DMSO)δ8.97(s,1H),8.32(s,1H),4.67(tt,J＝11.3,3.6Hz,1H),3.70(s,1H),3.28(d,J＝12.7Hz,2H),3.13(d,J＝12.3Hz,2H),2.44(dd,J＝19.0,7.6Hz,2H),2.28(d,J＝11.5Hz,2H). 1 H NMR (400MHz, DMSO) δ8.97(s,1H),8.32(s,1H),4.67(tt,J＝11.3,3.6Hz,1H),3.70(s,1H),3.28(d,J =12.7Hz,2H),3.13(d,J＝12.3Hz,2H),2.44(dd,J＝19.0,7.6Hz,2H),2.28(d,J＝11.5Hz,2H).
第二流出组分Amine-4-c-A为白色固体(287mg,27％)；The second eluting component, Amine-4-c-A, was a white solid (287 mg, 27%);
LC_MS:(ES+):m/z 245.1[M+H]+.LC_MS:(ES + ):m/z 245.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.32(s,1H),4.71–4.59(m,1H),3.85(s,1H),3.27–3.18(m,2H),3.12(d,J＝13.5Hz,2H),2.43(td,J＝13.9,3.0Hz,2H),2.30(dd,J＝14.1,3.3Hz,2H). 1 H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.32(s,1H),4.71–4.59(m,1H),3.85(s,1H),3.27–3.18(m,2H) ,3.12(d,J＝13.5Hz,2H),2.43(td,J＝13.9,3.0Hz,2H),2.30(dd,J＝14.1,3.3Hz,2H).
步骤5：片段Amine-4:(1s,4s)-4-(4-氨基-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物的合成
Step 5: Synthesis of fragment Amine-4: (1s, 4s)-4-(4-amino-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
向含有Amine-4-c-A(80mg,0.32mmol)的甲醇(5mL)溶液加入5％Pd/C,混合物于氢气氛围下反应8小时。TLC监测反应完全。混合物经硅藻土过滤，滤饼用甲醇(5mL×2)洗涤后合并滤液,无水硫酸钠干燥，减压浓缩，得到红色固体Amine-4(52mg,74％)，无需进一步纯化，可直接用于下一步反应。5% Pd/C was added to a methanol (5 mL) solution containing Amine-4-c-A (80 mg, 0.32 mmol), and the mixture was reacted under a hydrogen atmosphere for 8 hours. TLC monitored the reaction to be complete. The mixture was filtered through diatomaceous earth, the filter cake was washed with methanol (5 mL × 2), and the filtrate was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a red solid Amine-4 (52 mg, 74%), which could be directly used in the next step without further purification.
LC_MS:(ES+):m/z 215.0[M+H]+. LC_MS:(ES+):m/z 215.0[M+H] + .
片段Amine-5Clip Amine-5
(1s,4s)-4-(4-氨基-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式:实施方式同Amine-2，用片段Amine-4-c-A替换片段Amine-1-g，得到目标化合物。Implementation method: The implementation method is the same as Amine-2, and the fragment Amine-1-g is replaced by the fragment Amine-4-c-A to obtain the target compound.
LC_MS:(ES+):m/z 228.9[M+H]+.LC_MS:(ES + ):m/z 228.9[M+H] + .
片段Amine-6Clip Amine-6
(1s,4s)-4-(4-氨基-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式:Implementation method:
实施方式同Amine-2，用Amine-4-c-A替换Amine-1-g，用乙醛替换多聚甲醛，得到目标化合物。The implementation method is the same as Amine-2, replacing Amine-1-g with Amine-4-c-A and replacing paraformaldehyde with acetaldehyde to obtain the target compound.
LC_MS:(ES+):m/z 242.9[M+H]+.LC_MS:(ES + ):m/z 242.9[M+H] + .
片段Amine-7Clip Amine-7
(1s,4s)-4-(4-氨基-5-甲基-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
实施方式:
Implementation method:
步骤1：中间体Amine-7-a:4-硝基-5-甲基-1-(四氢-2H-噻喃-4-基)-1H-吡唑的合成
Step 1: Synthesis of intermediate Amine-7-a: 4-nitro-5-methyl-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazole
向含有Amine-1-d(500mg,2.02mmol)、甲基硼酸(363mg,6.06mmol)和碳酸钾(836mg,6.06mmol)的1,4-二氧六环(4mL)和水(0.4mL)溶液中添加1,1'-双二苯基膦二茂铁二氯化钯(147mg,0.262mmol)。混合物于氮气氛围和90℃下反应16小时。TLC监测反应完全。混合物经硅藻土过滤，滤饼以乙酸乙酯(5mL×2)洗涤后合并滤液，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经硅胶柱层析(含25％乙酸乙酯的石油醚洗脱溶液)纯化得到中间体Amine-7-a为白色固体(320mg,70％)。1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (147 mg, 0.262 mmol) was added to a solution of 1,4-dioxane (4 mL) and water (0.4 mL) containing Amine-1-d (500 mg, 2.02 mmol), methylboric acid (363 mg, 6.06 mmol) and potassium carbonate (836 mg, 6.06 mmol). The mixture was reacted at 90 °C for 16 hours under a nitrogen atmosphere. The reaction was complete when monitored by TLC. The mixture was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (5 mL × 2), the filtrate was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether elution solution containing 25% ethyl acetate) to obtain the intermediate Amine-7-a as a white solid (320 mg, 70%).
LC_MS:(ES+):m/z 227.9[M+H]+.LC_MS:(ES + ):m/z 227.9[M+H] + .
1H NMR(400MHz,CDCl3)δ8.10(s,1H),4.05(tt,J＝11.5,3.6Hz,1H),2.91–2.78(m,4H),2.67(s,3H),2.38(ddd,J＝16.2,12.1,5.0Hz,2H),2.18(dd,J＝13.3,3.3Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.10 (s, 1H), 4.05 (tt, J = 11.5, 3.6Hz, 1H), 2.91–2.78 (m, 4H), 2.67 (s, 3H), 2.38 ( ddd,J＝16.2,12.1,5.0Hz,2H),2.18(dd,J＝13.3,3.3Hz,2H).
步骤2：中间体Amine-7-b:4-(4-硝基-5-甲基-1H-吡唑-1-基)四氢-2H-噻喃1-氧化物的合成
Step 2: Synthesis of intermediate Amine-7-b: 4-(4-nitro-5-methyl-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1-oxide
向含有Amine-7-a(320mg,1.41mmol)的甲醇(10mL)溶液中加入高碘酸钠(332mg,1.55mmol)。混合物于室温下反应6小时。TLC监测反应完全。混合物经过滤后收集滤液，滤饼以二氯甲烷(5mL×2)洗涤后合并滤液。滤液减压浓缩， 得到中间体Amine-7-b为白色固体(240mg,粗品)，无需进一步纯化，可直接用于下一步反应。Sodium periodate (332 mg, 1.55 mmol) was added to a methanol (10 mL) solution containing Amine-7-a (320 mg, 1.41 mmol). The mixture was reacted at room temperature for 6 hours. TLC monitored the reaction to be complete. The mixture was filtered and the filtrate was collected. The filter cake was washed with dichloromethane (5 mL × 2) and the filtrate was combined. The filtrate was concentrated under reduced pressure. The intermediate Amine-7-b was obtained as a white solid (240 mg, crude product), which was directly used in the next step without further purification.
LC_MS:(ES+):m/z 243.95[M+H]+.LC_MS:(ES + ):m/z 243.95[M+H] + .
步骤3：中间体Amine-7-c-A:(1s,4s)-1-亚氨基-4-(4-硝基-5-甲基-1H-吡唑-1-基)-六氢-1λ6-噻喃1-氧化物和Amine-7-c-B:(1r,4r)-1-亚氨基-4-(4-硝基-5-甲基-1H-吡唑-1-基)-六氢-1λ6-噻喃1-氧化物合成
Step 3: Synthesis of intermediates Amine-7-cA: (1s, 4s)-1-imino-4-(4-nitro-5-methyl-1H-pyrazol-1-yl)-hexahydro-1λ 6 -thiopyran 1-oxide and Amine-7-cB: (1r, 4r)-1-imino-4-(4-nitro-5-methyl-1H-pyrazol-1-yl)-hexahydro-1λ 6 -thiopyran 1-oxide
向含有Amine-7-b(500mg,2.06mmol)的甲醇(10mL)和N,N-二甲基甲酰胺(5mL)溶液依次加入氨基甲酸铵(401mg,5.14mmol)，碘苯二乙酸(1.99g,6.18mmol)。混合物于室温下反应3小时。TLC监测反应完全。混合物减压浓缩，剩余物用饱和碳酸氢钠溶液(10mL)和乙酸乙酯(15mL)稀释，收集有机相，水相加入乙酸乙酯(10mL×2)萃取后合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经硅胶柱层析(含7％甲醇的二氯甲烷洗脱溶液)纯化，得到两个顺反异构体组分：To a solution of methanol (10 mL) and N,N-dimethylformamide (5 mL) containing Amine-7-b (500 mg, 2.06 mmol) were added ammonium carbamate (401 mg, 5.14 mmol) and iodophenyl diacetic acid (1.99 g, 6.18 mmol) in sequence. The mixture was reacted at room temperature for 3 hours. TLC monitored the reaction to be complete. The mixture was concentrated under reduced pressure, and the residue was diluted with saturated sodium bicarbonate solution (10 mL) and ethyl acetate (15 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (10 mL × 2) and then the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent containing 7% methanol in dichloromethane) to obtain two cis-trans isomer components:
第一组分Amine-7-c-B为白色固体(196mg,37％),The first component, Amine-7-c-B, was a white solid (196 mg, 37%).
1H NMR(400MHz,DMSO)δ8.28(s,1H),4.82–4.72(m,1H),3.67(s,1H),3.30(d,2H),3.13(d,J＝12.2Hz,2H),2.66(s,3H),2.45(d,J＝11.5Hz,2H),2.10(d,J＝12.4Hz,2H). 1 H NMR (400MHz, DMSO) δ8.28 (s, 1H), 4.82–4.72 (m, 1H), 3.67 (s, 1H), 3.30 (d, 2H), 3.13 (d, J＝12.2Hz, 2H ),2.66(s,3H),2.45(d,J＝11.5Hz,2H),2.10(d,J＝12.4Hz,2H).
第二组分为Amine-7-c-A为白色固体(235mg,44％),The second component is Amine-7-c-A which is a white solid (235 mg, 44%).
1H NMR(400MHz,DMSO)δ8.29(s,1H),4.75(s,1H),3.86(s,1H),3.25(d,J＝12.3Hz,2H),3.13(d,J＝12.4Hz,2H),2.66(s,3H),2.43(dd,J＝24.4,12.5Hz,2H),2.14(d,J＝12.1Hz,2H). 1 H NMR (400MHz, DMSO) δ8.29 (s, 1H), 4.75 (s, 1H), 3.86 (s, 1H), 3.25 (d, J = 12.3Hz, 2H), 3.13 (d, J = 12.4 Hz,2H),2.66(s,3H),2.43(dd,J＝24.4,12.5Hz,2H),2.14(d,J＝12.1Hz,2H).
步骤4：片段Amine-7:(1s,4s)-1-亚氨基-4-(4-氨基-5-甲基-1H-吡唑-1-基)-六氢-1λ6-噻喃1-氧化物的合成
Step 4: Synthesis of fragment Amine-7: (1s, 4s)-1-imino-4-(4-amino-5-methyl-1H-pyrazol-1-yl)-hexahydro-1λ 6 -thiopyran 1-oxide
向含有Amine-7-c-A(80mg,0.31mmol)的甲醇(5mL)中加入5％Pd/C,混合物于氢气氛围及室温条件下反应3小时。混合物经硅藻土过滤后收集滤液，滤饼以甲醇(5mL×2)洗涤后合并滤液，减压浓缩，得到片段Amine-7为红色固体(57mg,粗品)，无需进一步纯化，可直接用于下一步反应。5% Pd/C was added to methanol (5 mL) containing Amine-7-c-A (80 mg, 0.31 mmol), and the mixture was reacted under hydrogen atmosphere at room temperature for 3 hours. The mixture was filtered through diatomaceous earth and the filtrate was collected. The filter cake was washed with methanol (5 mL × 2) and the filtrate was combined and concentrated under reduced pressure to obtain fragment Amine-7 as a red solid (57 mg, crude product), which can be directly used in the next step without further purification.
LC_MS:(ES+):m/z 228.95[M+H]+.LC_MS:(ES + ):m/z 228.95[M+H] + .
片段Amine-8Clip Amine-8
(1s,4s)-4-(4-氨基-5-甲基-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式:实施方式同Amine-2，用中间体Amine-7-c-A替换Amine-1-g，得到目标产物。Implementation method: The implementation method is the same as Amine-2, replacing Amine-1-g with the intermediate Amine-7-c-A to obtain the target product.
LC_MS:(ES+):m/z 223.15[M+H]+.LC_MS:(ES + ):m/z 223.15[M+H] + .
片段Amine-9Clip Amine-9
(1s,4s)-4-(4-氨基-5-甲基-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-5-methyl-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式:实施方式同Amine-2，用中间体Amine-7-c-A替换Amine-1-g，将多聚甲醛替换为乙醛，得到目标产物。Implementation method: The implementation method is the same as Amine-2, replacing Amine-1-g with the intermediate Amine-7-c-A, and replacing paraformaldehyde with acetaldehyde to obtain the target product.
LC_MS:(ES+):m/z 257.10[M+H]+.LC_MS:(ES + ):m/z 257.10[M+H] + .
片段Amine-10Clip Amine-10
(1s,4s)-4-(4-氨基-5-氯-1H-吡唑-1-基)-1-(异丙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-(isopropylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式:
Implementation method:
步骤1：中间体Amine-10-a:(1s,4s)-4-(5-氯-4-硝基-1H-吡唑-1-基)-1-(异丙基亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step 1: Synthesis of intermediate Amine-10-a: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-(isopropylimino)hexahydro-1λ 6 -thiopyran 1-oxide
向含有Amine-1-g(50mg,0.18mmol)和2-碘异丙烷(305mg,1.79mmol)的乙腈(2ml)溶液中加入碳酸钾(371mg,2.69mmol)，反应混合物加热至90℃下密封搅拌反应48小时。TLC监测反应完全。反应混合物用水(10ml)和乙酸乙酯(10ml)萃取。收集有机层，饱和氯化钠溶液(10ml)洗，有机相用无水硫酸钠干燥，减压浓缩。剩余物经制备TLC(含5％甲醇的二氯甲烷洗脱溶液)纯化得到中间体Amine-10-a为淡黄色固体(10.5mg,18％)。Potassium carbonate (371 mg, 2.69 mmol) was added to a solution of Amine-1-g (50 mg, 0.18 mmol) and 2-iodoisopropane (305 mg, 1.79 mmol) in acetonitrile (2 ml), and the reaction mixture was heated to 90 ° C and stirred for 48 hours. TLC monitored the reaction to be complete. The reaction mixture was extracted with water (10 ml) and ethyl acetate (10 ml). The organic layer was collected, washed with saturated sodium chloride solution (10 ml), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane elution solution containing 5% methanol) to obtain the intermediate Amine-10-a as a light yellow solid (10.5 mg, 18%).
LC_MS:(ES+):m/z 321.05[M+H]+.LC_MS:(ES + ):m/z 321.05[M+H] + .
1H NMR(400MHz,CDCl3):δ8.21(s,1H),4.70-4.64(m,1H),3.65-3.59(m,1H),3.54-3.48(m,2H),3.19-3.12(m,2H),2.71-2.62(m,2H),2.43-2.37(m,2H),1.22(d,J＝6.0Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ8.21(s,1H),4.70-4.64(m,1H),3.65-3.59(m,1H),3.54-3.48(m,2H),3.19-3.12( m,2H),2.71-2.62(m,2H),2.43-2.37(m,2H),1.22(d,J＝6.0Hz,6H).
步骤2：片段Amine-10:(1s,4s)-4-(4-氨基-5-氯-1H-吡唑-1-基)-1-(异丙基亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step 2: Synthesis of fragment Amine-10: (1s, 4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-(isopropylimino)hexahydro-1λ 6 -thiopyran 1-oxide
将含有Amine-10-a(21mg,65umol),铁粉(37mg,0.65mmol),氯化铵(18mg,0.33mmol)的乙醇(1mL)和水(0.25mL)混合溶液加热至回流并反应两小时。TLC监测反应完全。混合物经过滤除去铁粉后用乙醇(5ml×2)洗涤滤饼， 滤液合并后减压浓缩，剩余物经制备TLC(含5％甲醇的二氯甲烷洗脱溶液)纯化得到片段Amine-10为白色固体(15mg,79％)。A mixed solution of ethanol (1 mL) and water (0.25 mL) containing Amine-10-a (21 mg, 65 umol), iron powder (37 mg, 0.65 mmol), ammonium chloride (18 mg, 0.33 mmol) was heated to reflux and reacted for two hours. TLC monitored the reaction to be complete. The mixture was filtered to remove the iron powder and the filter cake was washed with ethanol (5 ml × 2). The filtrates were combined and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent containing 5% methanol in dichloromethane) to obtain fragment Amine-10 as a white solid (15 mg, 79%).
LC_MS:(ES+):m/z 291.15[M+H]+.LC_MS:(ES + ):m/z 291.15[M+H] + .
片段Amine-11Clip Amine-11
(1s,4s)-4-(4-氨基-5-氯-1H-吡唑-1-基)-1-((2,2,2-三氟乙基)亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-((2,2,2-trifluoroethyl)imino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式:实施方式同Amine-10，用Amine-11-a替换Amine-10-a，得到目标产物。Implementation method: The implementation method is the same as Amine-10, replacing Amine-10-a with Amine-11-a to obtain the target product.
LC_MS:(ES+):m/z 331.05[M+H]+.LC_MS:(ES + ):m/z 331.05[M+H] + .
其中Amine-11-a的合成方法如下：
The synthesis method of Amine-11-a is as follows:
步骤：中间体Amine-11-a:(1s,4s)-4-(5-氯-4-硝基-1H-吡唑-1-基)-1-((2,2,2-三氟乙基)亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step: Synthesis of intermediate Amine-11-a: (1s, 4s)-4-(5-chloro-4-nitro-1H-pyrazol-1-yl)-1-((2,2,2-trifluoroethyl)imino)hexahydro-1λ 6 -thiopyran 1-oxide
冰浴条件下向含有Amine-1-g(35mg,0.12mmol)的三氟乙酸(1.2g,10.55mmol)溶液中加入硼氢化钠(48.5mg,1.25mmol)，反应混合物室温下搅拌反应5小时。TLC监测反应完全。反应混合物用饱和碳酸氢钠溶液(10ml)和二氯甲烷(10ml)萃取。收集有机层，饱和氯化钠溶液(10ml)洗，有机相用无水硫酸钠干燥， 减压浓缩。剩余物经制备TLC(100％乙酸乙酯洗脱溶液)纯化得到中间体Amine-11-a为淡黄色固体(8.5mg,19％)。Sodium borohydride (48.5 mg, 1.25 mmol) was added to a solution of trifluoroacetic acid (1.2 g, 10.55 mmol) containing Amine-1-g (35 mg, 0.12 mmol) under ice bath conditions, and the reaction mixture was stirred at room temperature for 5 hours. TLC monitored the reaction to be complete. The reaction mixture was extracted with saturated sodium bicarbonate solution (10 ml) and dichloromethane (10 ml). The organic layer was collected, washed with saturated sodium chloride solution (10 ml), and the organic phase was dried over anhydrous sodium sulfate. The residue was purified by preparative TLC (100% ethyl acetate eluent) to give intermediate Amine-11-a as a light yellow solid (8.5 mg, 19%).
LC_MS:(ES+):m/z 361.05[M+H]+.LC_MS:(ES + ):m/z 361.05[M+H] + .
片段Amine-12Clip Amine-12
(1s,4s)-4-(4-氨基-5-氯-1H-吡唑-1-基)-1-((2-(二甲基氨基)乙基)亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-amino-5-chloro-1H-pyrazol-1-yl)-1-((2-(dimethylamino)ethyl)imino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式:实施方式同Amine-10，用2-溴-N,N-二甲基乙烷-1-胺氢溴酸盐替换2-碘异丙烷，得到目标产物。Implementation method: The implementation method is the same as Amine-10, replacing 2-iodoisopropane with 2-bromo-N,N-dimethylethane-1-amine hydrobromide to obtain the target product.
LC_MS:(ES+):m/z 320.1[M+H]+.LC_MS:(ES + ):m/z 320.1[M+H] + .
实施例1Example 1
(1s,4s)-4-(5-氯-4-((4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施步骤(实施方法一)：
Implementation steps (implementation method 1):
步骤1：中间体1-b:8-甲基-1,4-二氧杂螺[4.5]癸-8-醇的合成
Step 1: Synthesis of Intermediate 1-b: 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol
-60℃下向含有化合物1-a(1,4-环己二酮单乙二醇缩酮)(2g,12.8mmol)的无水四氢呋喃(20ml)的悬浮液中加入甲基溴化镁(3M溶在四氢呋喃中,7.7ml,23mmol)，反应混合物在-60℃下搅拌反应20分钟，然后升至-30℃搅拌30分钟，再在0℃搅拌反应30分钟。TLC监测反应完全。反应混合物用饱和氯化铵溶液(10ml)淬灭，乙酸乙酯(20ml)萃取。收集有机层，饱和氯化钠溶液(20ml)洗涤，无水硫酸钠干燥，减压浓缩得到中间体1-b为无色油状物(1.4g,63％)，未经进一步纯化直接用于下一步。Methylmagnesium bromide (3M dissolved in tetrahydrofuran, 7.7ml, 23mmol) was added to a suspension of compound 1-a (1,4-cyclohexanedione monoethylene glycol acetal) (2g, 12.8mmol) in anhydrous tetrahydrofuran (20ml) at -60°C, and the reaction mixture was stirred at -60°C for 20 minutes, then heated to -30°C for 30 minutes, and then stirred at 0°C for 30 minutes. TLC monitored the reaction to be complete. The reaction mixture was quenched with saturated ammonium chloride solution (10ml) and extracted with ethyl acetate (20ml). The organic layer was collected, washed with saturated sodium chloride solution (20ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 1-b as a colorless oil (1.4g, 63%), which was used directly in the next step without further purification.
步骤2：中间体1-c:4-羟基-4-甲基环己酮的合成
Step 2: Synthesis of Intermediate 1-c: 4-Hydroxy-4-methylcyclohexanone
将含有化合物1-b(8-甲基-1,4-二氧杂螺[4.5]癸-8-醇)(1.4g,8.1mmol)和对甲苯磺酸吡啶鎓(408.6mg,1.63mmol)的丙酮(16ml)和水(8ml)的悬浮物在60℃氮气保护下搅拌反应13小时。TLC监测反应完全。反应混合物冷至室温，加入 水(50ml)淬灭，乙酸乙酯(30ml x 2)萃取。合并有机层，保饱和氯化钠溶液(20ml)洗涤，无水硫酸钠干燥，减压浓缩，所得粗品经硅胶柱层析(用含15％乙酸乙酯的正己烷洗脱)分离纯化得到中间体1-c为黄色油状物(630mg,57％)。A suspension of compound 1-b (8-methyl-1,4-dioxaspiro[4.5]dec-8-ol) (1.4 g, 8.1 mmol) and pyridinium p-toluenesulfonate (408.6 mg, 1.63 mmol) in acetone (16 ml) and water (8 ml) was stirred at 60°C under nitrogen protection for 13 hours. The reaction was complete when monitored by TLC. The reaction mixture was cooled to room temperature and added The mixture was quenched with water (50 ml) and extracted with ethyl acetate (30 ml x 2). The organic layers were combined, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluted with n-hexane containing 15% ethyl acetate) to obtain intermediate 1-c as a yellow oil (630 mg, 57%).
步骤3：中间体1-d:(1r,4r)-1-甲基环己烷-1,4-二醇和1-e:(1s,4s)-1-甲基环己烷-1,4-二醇的合成
Step 3: Synthesis of intermediates 1-d: (1r, 4r)-1-methylcyclohexane-1,4-diol and 1-e: (1s, 4s)-1-methylcyclohexane-1,4-diol
0℃下向含有化合物1-c(4-羟基-4-甲基环己酮)(630mg,4.9mmol)的甲醇(6ml)悬浮液中加入硼氢化钠(372.1mg,9.5mmol)，反应混合物在室温下搅拌反应12小时。TLC监测反应完全。反应混合物用水(0.5ml)淬灭，减压浓缩，所得粗品经硅胶柱层析(用含4％甲醇的二氯甲烷洗脱)分离纯化得到白色固体1-d(80mg,12％)Sodium borohydride (372.1 mg, 9.5 mmol) was added to a suspension of compound 1-c (4-hydroxy-4-methylcyclohexanone) (630 mg, 4.9 mmol) in methanol (6 ml) at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. TLC monitored the reaction to be complete. The reaction mixture was quenched with water (0.5 ml) and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluted with dichloromethane containing 4% methanol) to obtain a white solid 1-d (80 mg, 12%).
1H NMR(400MHz,CDCl3):δ4.04–3.71(m,1H),1.89(dq,J＝16.0,9.6,6.7Hz,2H),1.89(dq,J＝16.0,9.6,6.7Hz,2H),1.59–1.36(m,6H),1.26(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ4.04–3.71 (m, 1H), 1.89 (dq, J＝16.0, 9.6, 6.7Hz, 2H), 1.89 (dq, J＝16.0, 9.6, 6.7Hz, 2H),1.59–1.36(m,6H),1.26(s,3H).
以及白色固体1-e(400mg,60％)；and white solid 1-e (400 mg, 60%);
1H NMR(400MHz,CDCl3):δ3.60(tt,J＝9.7,4.1Hz,1H),1.81–1.72(m,2H),1.72–1.58(m,4H),1.55–1.37(m,4H),1.22(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ3.60 (tt, J = 9.7, 4.1Hz, 1H), 1.81–1.72 (m, 2H), 1.72–1.58 (m, 4H), 1.55–1.37 (m, 4H),1.22(s,3H).
步骤4:中间体1-g:(1s,4s)-4-((2-氯-5-(三氟甲基)嘧啶-4-基)氧基)-1-甲基环己-1-醇和中间体1-h:(1s,4s)-4-((4-氯-5-(三氟甲基)嘧啶-2-基)氧基)-1-甲基环己-1-醇的合成
Step 4: Synthesis of Intermediate 1-g: (1s, 4s)-4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-methylcyclohexan-1-ol and Intermediate 1-h: (1s, 4s)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)oxy)-1-methylcyclohexan-1-ol
0℃氮气保护下向含有化合物1-e((1s,4s)-1-甲基环己烷-1,4-二醇)(100mg,0.77mmol)的四氢呋喃(3ml)溶液中加入氢化钠(60％,68mg,1.69mmol),混合物缓慢升至室温后搅拌反应30分钟，然后将反应液滴加到2,4-二氯-5-(三氟甲基)嘧啶(334mg,1.54mmol)的四氢呋喃(2ml)溶液中，反应液在室温下搅拌反应16 小时。TLC监测反应完全。反应混合物用饱和氯化铵溶液(10ml)淬灭，乙酸乙酯(10ml x 2)萃取。收集有机层，饱和氯化钠溶液(20ml)洗涤，无水硫酸钠干燥，减压浓缩，所得粗品经硅胶柱层析(用含6％-12.5％乙酸乙酯的正己烷洗脱)分离纯化得到两组化合物：无色油状物1-g(第一流出组分)(28mg,12％)；Sodium hydride (60%, 68 mg, 1.69 mmol) was added to a tetrahydrofuran (3 ml) solution containing compound 1-e ((1s, 4s)-1-methylcyclohexane-1,4-diol) (100 mg, 0.77 mmol) under nitrogen protection at 0°C. The mixture was slowly heated to room temperature and stirred for 30 minutes. The reaction solution was then added dropwise to a tetrahydrofuran (2 ml) solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (334 mg, 1.54 mmol). The reaction solution was stirred at room temperature for 16 minutes. hours. TLC monitored the reaction to be complete. The reaction mixture was quenched with saturated ammonium chloride solution (10 ml) and extracted with ethyl acetate (10 ml x 2). The organic layer was collected, washed with saturated sodium chloride solution (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluted with n-hexane containing 6%-12.5% ethyl acetate) to obtain two groups of compounds: colorless oil 1-g (first effluent component) (28 mg, 12%);
LC_MS:(ES+):m/z 311.0[M+H]+.LC_MS:(ES + ):m/z 311.0[M+H] + .
和无色油状物1-h(第二流出组分)(52mg,21％)。and colorless oil 1-h (second eluting fraction) (52 mg, 21%).
LC_MS:(ES+):m/z 311.0[M+H]+.LC_MS:(ES + ):m/z 311.0[M+H] + .
步骤5：化合物1:(1s,4s)-4-(5-氯-4-((4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step 5: Synthesis of Compound 1: (1s, 4s)-4-(5-chloro-4-((4-(((1s, 4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
向含有中间体1-g((1s,4s)-4-((2-氯-5-(三氟甲基)嘧啶-4-基)氧基)-1-甲基环己-1-醇)(30.0mg,96umol)和片段Amine-2(21.0mg,80umol)的乙醇(30mL)溶液中加入氯化铵(13mg,241umol)，反应液加热至100℃搅拌反应16小时。TLC监测反应完全。反应液减压浓缩后残余物用乙酸乙酯(10mL)和饱和碳酸钠溶液(10mL)稀释，收集有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经制备TLC(含5％甲醇的二氯甲烷洗脱溶液)纯化得到化合物1为白色固体(26mg,60％)。To an ethanol (30 mL) solution containing intermediate 1-g ((1s, 4s)-4-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)oxy)-1-methylcyclohexan-1-ol) (30.0 mg, 96 umol) and fragment Amine-2 (21.0 mg, 80 umol) was added ammonium chloride (13 mg, 241 umol), and the reaction solution was heated to 100 ° C and stirred for 16 hours. TLC monitored the reaction to be complete. After the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate (10 mL) and saturated sodium carbonate solution (10 mL), the organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane elution solution containing 5% methanol) to obtain compound 1 as a white solid (26 mg, 60%).
LC_MS:(ES+):m/z 537.2[M+H]+.LC_MS:(ES + ):m/z 537.2[M+H] + .
1H NMR(400MHz,CDCl3):δ9.56-9.31(m,1H),8.42(s,1H),7.78(s,1H),5.18-4.87(m,1H),4.78-4.73(m,1H),4.22(s,1H),3.26-3.16(m,4H),2.67(s,3H),2.46-2.36(m,2H),2.19-2.15(m,2H),1.77-1.58(m,6H),1.41-1.25(m,2H),1.12(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ9.56-9.31(m,1H),8.42(s,1H),7.78(s,1H),5.18-4.87(m,1H),4.78-4.73(m, 1H),4.22(s,1H),3.26-3.16(m,4H),2.67(s,3H),2.46-2.36(m,2H),2.19-2.15(m,2H),1.77-1.58(m, 6H),1.41-1.25(m,2H),1.12(s,3H).
实施例2 Example 2
(1s,4s)-1-亚氨基-4-(4-((4-(2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-1-Imino-4-(4-((4-(2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)hexahydro-1λ 6 -thiopyran 1-oxide
实施步骤(实施方法二)：
Implementation steps (implementation method 2):
步骤1:中间体2-b:2-(甲氧基甲基)苯胺的合成
Step 1: Synthesis of Intermediate 2-b: 2-(methoxymethyl)aniline
向含有2-a(2-羟甲基苯胺)(4.0g,29.16mmol)的无水甲醇(30mL)溶液中于0℃逐滴加入浓硫酸。混合物于50℃反应5小时。TLC监测反应完全。向反应液于0℃加入饱和碳酸氢钠溶液调节pH至中性。混合物分配于二氯甲烷(30mL)中，收集有机相。水相加入二氯甲烷(20mL x 2)萃取后合并有机相。饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经硅胶柱层析纯化(含10％-15％乙酸乙酯的石油醚洗脱溶液)得到中间体2-b为黄色油状物(2.96g,74％)。Concentrated sulfuric acid was added dropwise to a solution of anhydrous methanol (30 mL) containing 2-a (2-hydroxymethylaniline) (4.0 g, 29.16 mmol) at 0°C. The mixture was reacted at 50°C for 5 hours. TLC monitored the reaction to be complete. Saturated sodium bicarbonate solution was added to the reaction solution at 0°C to adjust the pH to neutral. The mixture was distributed in dichloromethane (30 mL) and the organic phase was collected. The aqueous phase was extracted with dichloromethane (20 mL x 2) and the organic phases were combined. Wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether elution solution containing 10%-15% ethyl acetate) to obtain intermediate 2-b as a yellow oil (2.96 g, 74%).
LC_MS:(ES+):m/z 179.1[M+41+H]+.LC_MS:(ES + ):m/z 179.1[M+41+H] + .
步骤2：中间体2-c:2-氯-N-(2-(甲氧甲基)苯基)-5-(三氟乙基)嘧啶-4-胺的合成
Step 2: Synthesis of Intermediate 2-c: 2-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidin-4-amine
向含有1-f(2,4-二氯-5-(三氟甲基)嘧啶)(949mg,4.37mmol)和2-b(2-甲氧甲基苯胺)(500mg,3.65mmol)的异丙醇(20mL)溶液中加入N,N-二异丙基乙胺(1.42g,10.95mmol)。混合物于80℃反应12小时。TLC监测反应完全。混合物减压浓缩，剩余物分配于水(15mL)和二氯甲烷(20mL)中。收集有机相，水相加入二氯甲烷(20mL x 2)萃取后合并有机相。饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经制备HPLC纯化(C18柱，流动相为含10％～90％乙腈的水溶液)得到两个组分：N,N-diisopropylethylamine (1.42 g, 10.95 mmol) was added to a solution of 1-f (2,4-dichloro-5-(trifluoromethyl)pyrimidine) (949 mg, 4.37 mmol) and 2-b (2-methoxymethylaniline) (500 mg, 3.65 mmol) in isopropanol (20 mL). The mixture was reacted at 80 °C for 12 hours. TLC monitored the reaction to be complete. The mixture was concentrated under reduced pressure, and the residue was partitioned between water (15 mL) and dichloromethane (20 mL). The organic phase was collected, and the aqueous phase was extracted with dichloromethane (20 mL x 2) and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18 column, mobile phase was an aqueous solution containing 10% to 90% acetonitrile) to obtain two components:
第一组分为黄色固体2-d：4-氯-N-(2-(甲氧甲基)苯基)-5-(三氟乙基)嘧啶-2-胺(320mg,28％)。The first component is a yellow solid 2-d: 4-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidin-2-amine (320 mg, 28%).
LC_MS:(ES+):m/z 317.9,358.9[M+H]+.LC_MS:(ES + ):m/z 317.9,358.9[M+H] + .
1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.55(s,1H),8.14(d,J＝8.2Hz,1H),7.50–7.32(m,1H),7.32–7.18(m,1H),7.18–7.01(m,1H),4.57(s,2H),3.44(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.76 (s, 1H), 8.55 (s, 1H), 8.14 (d, J = 8.2Hz, 1H), 7.50–7.32 (m, 1H), 7.32–7.18 ( m,1H),7.18–7.01(m,1H),4.57(s,2H),3.44(s,3H).
第二组分为白色固体2-c：2-氯-N-(2-(甲氧甲基)苯基)-5-(三氟乙基)嘧啶-4-胺(670mg,58％)。The second component was a white solid 2-c: 2-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidin-4-amine (670 mg, 58%).
LC_MS:(ES+):m/z 317.9,358.9[M+H]+.LC_MS:(ES + ):m/z 317.9,358.9[M+H] + .
1H NMR(400MHz,CDCl3)δ9.07(s,1H),8.42(s,1H),8.20(d,J＝8.3Hz,1H),7.42(dd,J＝11.4,4.3Hz,1H),7.24(d,J＝7.7Hz,1H),7.16(t,J＝7.4Hz,1H),4.53(s,2H),3.46(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.07 (s, 1H), 8.42 (s, 1H), 8.20 (d, J = 8.3Hz, 1H), 7.42 (dd, J = 11.4, 4.3Hz, 1H) ,7.24(d,J＝7.7Hz,1H),7.16(t,J＝7.4Hz,1H),4.53(s,2H),3.46(s,3H).
步骤3：化合物2A:(1s,4s)-1-亚氨基-4-(4-((4-(2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)六氢-1λ6-噻喃1-氧化物的合成
Step 3: Synthesis of Compound 2A: (1s, 4s)-1-imino-4-(4-((4-(2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)hexahydro-1λ 6 -thiopyran 1-oxide
向含有片段Amine-4(72mg,0.34mmol)和中间体2-c(2-氯-N-(2-(甲氧甲基)苯基)-5-(三氟乙基)嘧啶-4-胺)(107mg,0.34mmol)的异丙醇(3mL)溶液中加入三氟乙酸(3.8mg)。混合物于80℃反应16小时。TLC监测反应完全。混合物分配于饱和碳酸氢钠溶液(5mL)和乙酸乙酯(10mL)中，收集有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经制备TLC(含8％甲醇的二氯甲烷洗脱溶液)纯化得到化合物2A为白色固体(14.2mg,8.5％)。Trifluoroacetic acid (3.8 mg) was added to a solution of fragment Amine-4 (72 mg, 0.34 mmol) and intermediate 2-c (2-chloro-N-(2-(methoxymethyl)phenyl)-5-(trifluoroethyl)pyrimidine-4-amine) (107 mg, 0.34 mmol) in isopropanol (3 mL). The mixture was reacted at 80°C for 16 hours. TLC monitored the reaction to be complete. The mixture was partitioned between saturated sodium bicarbonate solution (5 mL) and ethyl acetate (10 mL), the organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent containing 8% methanol in dichloromethane) to give compound 2A as a white solid (14.2 mg, 8.5%).
LC_MS:(ES+):m/z 496.15[M+H]+.LC_MS:(ES + ):m/z 496.15[M+H] + .
1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.24(s,1H),7.84(s,1H),7.56(s,1H),7.32(t,J＝7.4Hz,2H),7.25(s,1H),7.14(s,1H),4.43(s,2H),4.11(m,1H),3.38(s,3H),3.32(m,2H),3.05(m,2H),2.49(m,2H),2.36(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.27 (s, 1H), 8.24 (s, 1H), 7.84 (s, 1H), 7.56 (s, 1H), 7.32 (t, J = 7.4Hz, 2H) ,7.25(s,1H),7.14(s,1H),4.43(s,2H),4.11(m,1H),3.38(s,3H),3.32(m,2H),3.05(m,2H), 2.49(m,2H),2.36(m,2H).
(1r,4r)-1-亚氨基-4-(4-((4-(2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)六氢-1λ6-噻喃1-氧化物
(1r,4r)-1-Imino-4-(4-((4-(2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)hexahydro-1λ 6 -thiopyran 1-oxide
实施步骤：按实施方法二，在片段Amine-4合成中用片段Amine-4-c-B替换片段Amine-4-c-A，获得标题化合物。Implementation steps: According to implementation method 2, fragment Amine-4-c-A is replaced by fragment Amine-4-c-B in the synthesis of fragment Amine-4 to obtain the title compound.
LC_MS:(ES+):m/z 496.15[M+H]+. LC_MS:(ES + ):m/z 496.15[M+H] + .
1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.24(s,1H),7.84(s,1H),7.56(s,1H),7.32(t,J＝7.4Hz,2H),7.25(s,1H),7.14(s,1H),4.43(s,2H),4.11(m,1H),3.38(s,3H),3.32(m,2H),3.05(m,2H),2.49(m,2H),2.36(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.27 (s, 1H), 8.24 (s, 1H), 7.84 (s, 1H), 7.56 (s, 1H), 7.32 (t, J = 7.4Hz, 2H) ,7.25(s,1H),7.14(s,1H),4.43(s,2H),4.11(m,1H),3.38(s,3H),3.32(m,2H),3.05(m,2H), 2.49(m,2H),2.36(m,2H).
实施例3Example 3
(1s,4s)-4-(5-氯-4-((4-((2-(甲基磺酰基)乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((2-(methylsulfonyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施步骤(实施方法三)：
Implementation steps (implementation method three):
步骤一：中间体3-c:2-氯-N-(2-(甲磺酰)乙基)-7-((2-(三甲基硅基)乙氧)甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
Step 1: Synthesis of intermediate 3-c: 2-chloro-N-(2-(methylsulfonyl)ethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
0℃下向含有中间体3-a(2,4-二氯-7-(((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶)(100mg,0.315mmol)和2-(甲磺酰基)乙-1-胺盐酸盐(75.2mg,0.473mmol)和N,N-二甲基甲酰胺(2ml)溶液加入氢化钠(60％,19mg,0.46mmol)，反应液在0℃下搅拌反应18小时。TLC监测反应完全。反应混合物分散于水(10mL)及乙酸乙酯(10mL)中，收集有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，所得粗品经硅胶柱层析(用含25％乙酸乙酯的石油醚洗脱)分离纯化得到中间体3-c为白色固体(86mg,68％)。Sodium hydride (60%, 19 mg, 0.46 mmol) was added to a solution containing intermediate 3-a (2,4-dichloro-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine) (100 mg, 0.315 mmol) and 2-(methylsulfonyl)ethan-1-amine hydrochloride (75.2 mg, 0.473 mmol) and N,N-dimethylformamide (2 ml) at 0°C, and the reaction solution was stirred at 0°C for 18 hours. The reaction was completed by TLC monitoring. The reaction mixture was dispersed in water (10 mL) and ethyl acetate (10 mL), the organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether containing 25% ethyl acetate) to obtain intermediate 3-c as a white solid (86 mg, 68%).
LC_MS:(ES+):m/z 405.1[M+H]+.LC_MS:(ES + ):m/z 405.1[M+H] + .
步骤二：中间体3-d:4-(5-氯-4-((4-(2-(甲基磺酰基)乙基)氨基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step 2: Synthesis of intermediate 3-d: 4-(5-chloro-4-((4-(2-(methylsulfonyl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
向含有中间体3-c(46mg,0.114mmol),片段Amine-2(30mg,0.114mmol),1,1'-联萘-2,2'-双二苯膦(14mg,0.023mmol),碳酸铯(74mg,0.228mmol)的甲苯溶液(1mL)加入三二亚苄基丙酮二钯(10.4mg,0.011mmol),混合物经三次抽换气后，于氮气氛围及110℃下反应15小时。TLC监测反应完全。混合物冷却至室温后，分散于水(10mL)及乙酸乙酯(10mL)中。收集有机相，饱和氯化 钠溶液洗涤，无水硫酸钠干燥，减压浓缩，剩余物经制备TLC(含5％甲醇的二氯甲烷洗脱溶液)纯化得到中间体3-d为黄色固体(17mg,24％)。To a toluene solution (1 mL) containing intermediate 3-c (46 mg, 0.114 mmol), fragment Amine-2 (30 mg, 0.114 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (14 mg, 0.023 mmol), cesium carbonate (74 mg, 0.228 mmol) was added tris(dibenzylideneacetone dipalladium) (10.4 mg, 0.011 mmol). After the mixture was evacuated three times, it was reacted at 110°C in a nitrogen atmosphere for 15 hours. The reaction was monitored by TLC. After the mixture was cooled to room temperature, it was dispersed in water (10 mL) and ethyl acetate (10 mL). The organic phase was collected and saturated with chlorinated The residue was washed with sodium solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (eluent containing 5% methanol in dichloromethane) to give intermediate 3-d as a yellow solid (17 mg, 24%).
LC_MS:(ES+):m/z 631.05[M+H]+.LC_MS:(ES + ):m/z 631.05[M+H] + .
步骤三：化合物3:(1s,4s)-4-(5-氯-4-((4-((2-(甲基磺酰基)乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step 3: Synthesis of Compound 3: (1s, 4s)-4-(5-chloro-4-((4-((2-(methylsulfonyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
将含有中间体3-d(17mg,0.027mmol),三氟乙酸(1mL)的二氯甲烷(1mL)溶液于室温反应3小时。TLC监测反应完全。混合物减压浓缩，剩余物加入至氨水(2mL)和乙酸乙酯(2mL)的混合液中。混合物于30℃反应16小时。TLC监测反应完全。收集有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经制备TLC(含7％甲醇的二氯甲烷洗脱溶液)纯化，得到化合物3为黄色固体(7.7mg,57％)。A solution of dichloromethane (1 mL) containing intermediate 3-d (17 mg, 0.027 mmol) and trifluoroacetic acid (1 mL) was reacted at room temperature for 3 hours. TLC monitored the reaction to be complete. The mixture was concentrated under reduced pressure, and the residue was added to a mixture of ammonia water (2 mL) and ethyl acetate (2 mL). The mixture was reacted at 30°C for 16 hours. TLC monitored the reaction to be complete. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane elution solution containing 7% methanol) to obtain compound 3 as a yellow solid (7.7 mg, 57%).
LC_MS:(ES+):m/z 501.1[M+H]+.LC_MS:(ES + ):m/z 501.1[M+H] + .
1H NMR(400MHz,DMSO-d6):δ10.96(s,1H),7.88(s,1H),7.73(s,1H),7.44(t,J＝5.2Hz,1H),6.74-6.73(m,1H),6.34-6.32(m,1H),4.74-4.67(m,1H),3.79-3.74(m,2H),3.44(t,J＝6.8Hz,2H),3.30-3.21(m,4H),3.00(s,3H),2.67(s,3H),2.45-2.36(m,2H),2.20-2.15(m,2H). 1 H NMR (400MHz, DMSO-d6): δ10.96 (s, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.44 (t, J = 5.2Hz, 1H), 6.74-6.73 ( m,1H),6.34-6.32(m,1H),4.74-4.67(m,1H),3.79-3.74(m,2H),3.44(t,J＝6.8Hz,2H),3.30-3.21(m, 4H),3.00(s,3H),2.67(s,3H),2.45-2.36(m,2H),2.20-2.15(m,2H).
实施例4Example 4
(1s,4s)-4-(5-氯-4-((4-(4-羟基-4-甲基哌啶-1-基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(4-hydroxy-4-methylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施步骤(实施方法四)：
Implementation steps (implementation method 4):
步骤一：中间体4-a:(1s,4s)-4-(5-氯-4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step 1: Synthesis of intermediate 4-a: (1s, 4s)-4-(5-chloro-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
在0℃，氮气保护下向含有1-f(2,4-二氯-5-(三氟甲基)嘧啶)(356mg,1.64mmol)的叔丁醇(5ml)和1,2-二氯乙烷(5ml)溶液中加入氯化锌(1.96ml,1.96mmol,1N in THF)溶液。混合物于0℃下反应1小时后加入片段Amine-3(455mg,1.64mmol)和三乙胺(183mg,1.8mmol)。混合物于氮气氛围和室温下反应15小时，TLC监测反应完全。混合物经加入乙酸乙酯(20mL)和水(20mL)稀释，收集有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经硅胶柱层析(含20％乙酸乙酯的石油醚洗脱溶液)纯化得到中间体4-a为白色固体(400mg,53％)。LC_MS:(ES+):m/z 457.05[M+H]+. At 0°C, under nitrogen protection, a solution of zinc chloride (1.96ml, 1.96mmol, 1N in THF) was added to a solution of tert-butanol (5ml) and 1,2-dichloroethane (5ml) containing 1-f (2,4-dichloro-5-(trifluoromethyl)pyrimidine) (356mg, 1.64mmol). The mixture was reacted at 0°C for 1 hour, and then fragment Amine-3 (455mg, 1.64mmol) and triethylamine (183mg, 1.8mmol) were added. The mixture was reacted under nitrogen atmosphere and room temperature for 15 hours, and the reaction was complete when monitored by TLC. The mixture was diluted by adding ethyl acetate (20mL) and water (20mL), and the organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether elution solution containing 20% ethyl acetate) to obtain intermediate 4-a as a white solid (400mg, 53%). LC_MS:(ES + ):m/z 457.05[M+H] + .
1H NMR(400MHz,CDCl3):δ8.60-8.55(m,1H),8.10-8.05(m,1H),7.00(s,1H),4.61-4.55(m,1H),3.67-3.61(m,2H),3.19-3.13(m,4H),2.64-2.56(m,2H),2.47-2.40(m,2H),1.25(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ8.60-8.55(m,1H),8.10-8.05(m,1H),7.00(s,1H),4.61-4.55(m,1H),3.67-3.61( m,2H),3.19-3.13(m,4H),2.64-2.56(m,2H),2.47-2.40(m,2H),1.25(t,J＝7.2Hz,3H).
步骤二：化合物4:(1s,4s)-4-(5-氯-4-((4-(4-羟基-4-甲基哌啶-1-基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物的合成
Step 2: Synthesis of Compound 4: (1s, 4s)-4-(5-chloro-4-((4-(4-hydroxy-4-methylpiperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
向含有中间体4-a(20mg,0.044mmol)和N,N-二异丙基乙胺(11.4mg,0.088mmol)的1,4-二氧六环溶液(1ml)中加入4-甲基哌啶-4-醇(6mg,0.052mmol)。反应液在90℃下反应3小时，TLC监测反应完全。混合物经加入乙酸乙酯(20mL)和水(20mL)稀释，收集有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。剩余物经剩余物经制备TLC(含3％甲醇的二氯甲烷洗脱溶液)纯化得到化合物4为白色固体(14.2mg,8.5％)。4-Methylpiperidin-4-ol (6 mg, 0.052 mmol) was added to a 1,4-dioxane solution (1 ml) containing intermediate 4-a (20 mg, 0.044 mmol) and N,N-diisopropylethylamine (11.4 mg, 0.088 mmol). The reaction solution was reacted at 90°C for 3 hours, and the reaction was complete after TLC monitoring. The mixture was diluted by adding ethyl acetate (20 mL) and water (20 mL), and the organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane elution solution containing 3% methanol) to obtain compound 4 as a white solid (14.2 mg, 8.5%).
LC_MS:(ES+):m/z 536.01[M+H]+.LC_MS:(ES + ):m/z 536.01[M+H] + .
1H NMR(400MHz,CD3OD):δ8.21(s,1H),7.81(s,1H),4.82-4.75(m,1H),3.88-3.84(m,2H),3.55-3.52(m,2H),3.47-3.42(m,2H),3.37-3.33(m,2H),3.19-3.14(m,2H),2.66-2.57(m,2H),2.36-2.32(m,2H),1.67-1.56(m,4H),1.24-1.19(m,6H). 1 H NMR (400MHz, CD 3 OD): δ8.21(s,1H),7.81(s,1H),4.82-4.75(m,1H),3.88-3.84(m,2H),3.55-3.52(m ,2H),3.47-3.42(m,2H),3.37-3.33(m,2H),3.19-3.14(m,2H),2.66-2.57(m,2H),2.36-2.32(m,2H),1.67 -1.56(m,4H),1.24-1.19(m,6H).
实施例5Example 5
(1s,4s)-4-(5-氯-4-((4-((2-(甲基磺酰基)乙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((2-(methylsulfonyl)ethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段2-(甲砜基)乙胺盐酸盐替换中间体1-e，用片段Amine-1替换片段Amine-2，获得标题化合物。According to implementation method 1, the intermediate 1-e is replaced by the fragment 2-(methylsulfonyl)ethylamine hydrochloride, and the fragment Amine-2 is replaced by the fragment Amine-1 to obtain the title compound.
LC_MS:(ES+):m/z 516.0[M+H]+.LC_MS:(ES + ):m/z 516.0[M+H] + .
1H NMR(400MHz,CDCl3):δ8.20(s,1H),7.96(s,1H),7.00-6.82(m,1H),6.02-5.90(m,1H),4.61-4.55(m,1H),4.09-4.04(m,2H),3.66-3.60(m,2H),3.38(t,J＝6.0Hz,2H),3.18-3.11(m,2H),2.97(s,3H),2.69-2.61(m,2H),2.52-2.44(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ8.20(s,1H),7.96(s,1H),7.00-6.82(m,1H),6.02-5.90(m,1H),4.61-4.55(m, 1H),4.09-4.04(m,2H),3.66-3.60(m,2H),3.38(t,J＝6.0Hz,2H),3.18-3.11(m,2H),2.97(s,3H),2.69 -2.61(m,2H),2.52-2.44(m,2H).
(1r,4r)-4-(5-氯-4-((4-((2-(甲基磺酰基)乙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物
(1r,4r)-4-(5-chloro-4-((4-((2-(methylsulfonyl)ethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段2-(甲砜基)乙胺盐酸盐替换中间体1-e，在片段Amine-1合成中用Amine-1-f-B替换Amine-1-f-A，获得标题化合物。According to implementation method 1, the intermediate 1-e is replaced by the fragment 2-(methylsulfonyl)ethylamine hydrochloride, and Amine-1-f-B is replaced by Amine-1-f-A in the synthesis of the fragment Amine-1 to obtain the title compound.
LC_MS:(ES+):m/z 516.0[M+H]+.LC_MS:(ES + ):m/z 516.0[M+H] + .
1H NMR(400MHz,DMSO-d6):δ9.01-8.86(m,2H),8.16(s,1H),7.76(s,1H),7.15(t,J＝5.0Hz,1H),4.75-4.70(m,1H),3.84-3.70(m,2H),3.40-3.38(m,2H),3.31(s,3H),3.13-3.10(m,2H),2.98-2.92(m,2H),2.47-2.44(m,2H),2.13-2.10(m,2H). 1 H NMR (400MHz, DMSO-d6): δ9.01-8.86(m,2H),8.16(s,1H),7.76(s,1H),7.15(t,J＝5.0Hz,1H),4.75- 4.70(m,1H),3.84-3.70(m,2H),3.40-3.38(m,2H),3.31(s,3H),3.13-3.10(m,2H),2.98-2.92(m,2H), 2.47-2.44(m,2H),2.13-2.10(m,2H).
实施例6Example 6
(1s,4s)-4-(5-氯-4-((4-((2-(甲基磺酰基)乙基)氨基)-5-(三氟甲基)吡啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((2-(methylsulfonyl)ethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用2-(甲砜基)乙胺盐酸盐替换中间体1-e，获得标题化合物。LC_MS:(ES+):m/z 530.2[M+H]+.According to implementation method 1, 2-(methylsulfonyl)ethylamine hydrochloride was used to replace intermediate 1-e to obtain the title compound. LC_MS: (ES + ): m/z 530.2 [M+H] + .
1H NMR(400MHz,DMSO-d6):δ9.12-8.96(m,1H),8.16(s,1H),7.79(s,1H),7.21-7.17(m,1H),4.75-4.70(m,1H),3.80-3.71(m,2H),3.33(s,3H),3.30-3.21(m,4H),2.95-2.87(m,2H),2.66(s,3H),2.40-2.34(m,2H),2.19-2.16(m,2H). 1 H NMR (400MHz, DMSO-d6): δ9.12-8.96(m,1H),8.16(s,1H),7.79(s,1H),7.21-7.17(m,1H),4.75-4.70(m ,1H),3.80-3.71(m,2H),3.33(s,3H),3.30-3.21(m,4H),2.95-2.87(m,2H),2.66(s,3H),2.40-2.34(m ,2H),2.19-2.16(m,2H).
(1r,4r)-4-(5-氯-4-((4-((2-(甲基磺酰基)乙基)氨基)-5-(三氟甲基)吡啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1r,4r)-4-(5-chloro-4-((4-((2-(methylsulfonyl)ethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用2-(甲砜基)乙胺盐酸盐替换中间体1-e，在片段Amine-1合成中用Amine-1-f-B替换Amine-1-f-A，获得标题化合物。According to implementation method 1, intermediate 1-e is replaced by 2-(methylsulfonyl)ethylamine hydrochloride, and Amine-1-f-B is replaced by Amine-1-f-A in the synthesis of fragment Amine-1 to obtain the title compound.
LC_MS:(ES+):m/z 530.0[M+H]+. LC_MS:(ES + ):m/z 530.0[M+H] + .
1H NMR(400MHz,DMSO-d6):δ9.05(brs,1H),8.15(s,1H),7.75(s,1H),7.15(t,J＝4.8Hz,1H),4.78-4.70(m,1H),3.71(brs,2H),3.36(s,3H),3.35-3.32(m,4H),2.93(brs,2H),2.65(s,3H),2.42-2.30(m,2H),2.10-2.07(m,2H). 1 H NMR (400MHz, DMSO-d6): δ9.05 (brs, 1H), 8.15 (s, 1H), 7.75 (s, 1H), 7.15 (t, J = 4.8Hz, 1H), 4.78-4.70 ( m,1H),3.71(brs,2H),3.36(s,3H),3.35-3.32(m,4H),2.93(brs,2H),2.65(s,3H),2.42-2.30(m,2H) ,2.10-2.07(m,2H).
实施例7Example 7
(1s,4s)-4-(5-氯-4-((4-((2-(甲基磺酰基)乙基)氨基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((2-(methylsulfonyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
按实施方法三，用片段Amine-1替换片段Amine-2，获得标题化合物。According to implementation method 3, fragment Amine-2 was replaced by fragment Amine-1 to obtain the title compound.
LC_MS:(ES+):m/z 487.2[M+H]+.LC_MS:(ES + ):m/z 487.2[M+H] + .
1H NMR(400MHz,CD3OD):δ7.87(s,1H),6.95(d,J＝3.6Hz,1H),6.56(d,J＝3.6Hz,1H),4.97-4.92(m,1H),4.10-4.04(m,2H),3.97(t,J＝6.8Hz,2H),3.87-3.80(m,2H),3.45(t,J＝7.0Hz,2H),2.99(s,3H),2.76-2.68(m,2H),2.60-2.54(m,2H). 1 H NMR (400MHz, CD 3 OD): δ7.87 (s, 1H), 6.95 (d, J = 3.6Hz, 1H), 6.56 (d, J = 3.6Hz, 1H), 4.97-4.92 (m, 1H),4.10-4.04(m,2H),3.97(t,J＝6.8Hz,2H),3.87-3.80(m,2H),3.45(t,J＝7.0Hz,2H),2.99(s,3H ),2.76-2.68(m,2H),2.60-2.54(m,2H).
实施例8Example 8
(2-((2-((5-氯-1-((1s,4s)-1-亚氨基-1-氧化四氢-1λ6-噻喃-4-基)-1H-吡唑-4-基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)乙基)二甲基氧化膦
(2-((2-((5-chloro-1-((1s,4s)-1-imino-1-oxytetrahydro-1λ 6 -thiopyran-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)ethyl)dimethylphosphine oxide
按实施方法二，用中间体1-a替换中间体2-d，用中间体14-e替换中间体2-b，用片段Amine-1替换片段Amine-2，获得标题化合物。According to implementation method 2, intermediate 2-d is replaced by intermediate 1-a, intermediate 2-b is replaced by intermediate 14-e, and fragment Amine-2 is replaced by fragment Amine-1 to obtain the title compound.
LC_MS:(ES+):m/z 514.2[M+H]+.LC_MS:(ES + ):m/z 514.2[M+H] + .
1H NMR(400MHz,CDCl3):δ8.15(s,1H),8.06(s,1H),4.60-4.55(m,1H),4.01-3.92(m,2H),3.68-3.62(m,2H),3.17-3.11(m,2H),2.68-2.60(m,2H),2.51-2.45(m,2H),2.15-2.09(m,2H),1.58(d,J＝12.4Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ8.15(s,1H),8.06(s,1H),4.60-4.55(m,1H),4.01-3.92(m,2H),3.68-3.62(m, 2H),3.17-3.11(m,2H),2.68-2.60(m,2H),2.51-2.45(m,2H),2.15-2.09(m,2H),1.58(d,J＝12.4Hz,6H) .
实施例9Embodiment 9
(2-((2-(5-氯-1-((1s,4s)-1-(甲基亚氨基)-1-氧化四氢-1λ6-噻喃-4-基)-1H-吡唑-4-基)氨基)-5-(三氟甲基)嘧啶-4-基氨基)乙基)二甲基氧化膦
(2-((2-(5-chloro-1-((1s,4s)-1-(methylimino)-1-oxidotetrahydro-1λ 6 -thiopyran-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-ylamino)ethyl)dimethylphosphine oxide
按实施方法二，用二甲基氧化膦乙胺盐酸盐替换中间体1-e，获得标题化合物。According to Embodiment 2, dimethylphosphine oxide ethylamine hydrochloride is used to replace intermediate 1-e to obtain the title compound.
LC_MS:(ES+):m/z 528.1[M+H]+.LC_MS:(ES + ):m/z 528.1[M+H] + .
1H NMR(400MHz,CDCl3):δ8.16(s,1H),8.07(s,1H),4.59-4.56(m,1H), 1 H NMR (400MHz, CDCl 3 ): δ8.16(s,1H),8.07(s,1H),4.59-4.56(m,1H),
3.99-3.93(m,2H),3.70-3.65(m,2H),3.21-3.16(m,2H),2.84(s,3H),2.58-2.40(m,4H),2.15-2.09(m,2H),1.57(d,J＝12.8Hz,6H).3.99-3.93(m,2H),3.70-3.65(m,2H),3.21-3.16(m,2H),2.84(s,3H),2.58-2.40(m,4H),2.15-2.09(m,2H ),1.57(d,J＝12.8Hz,6H).
实施例10Example 10
(1s,4s)-4-(5-氯-4-((4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段Amine-1替换片段Amine-2，获得标题化合物。According to implementation method 1, fragment Amine-2 was replaced by fragment Amine-1 to obtain the title compound.
LC_MS:(ES+):m/z 523.5[M+H]+.LC_MS:(ES + ):m/z 523.5[M+H] + .
1H NMR(400MHz,CD3OD):δ8.30(s,1H),7.83(s,1H),5.34-5.03(m,1H),4.96-4.80(m,1H),3.46-3.33(m,4H),2.68-2.59(m,2H),2.38-2.33(m,2H),1.92-1.88(m,4H),1.78-1.75(m,2H),1.52-1.49(m,2H),1.23(s,3H). 1 H NMR (400MHz, CD 3 OD): δ8.30(s,1H),7.83(s,1H),5.34-5.03(m,1H),4.96-4.80(m,1H),3.46-3.33(m ,4H),2.68-2.59(m,2H),2.38-2.33(m,2H),1.92-1.88(m,4H),1.78-1.75(m,2H),1.52-1.49(m,2H),1.23 (s,3H).
实施例11Embodiment 11
(1s,4s)-4-(5-氯-4-((4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段Amine-3替换片段Amine-2，获得标题化合物。According to implementation method 1, fragment Amine-2 was replaced by fragment Amine-3 to obtain the title compound.
LC_MS:(ES+):m/z 551.5[M+H]+.LC_MS:(ES + ):m/z 551.5[M+H] + .
1H NMR(400MHz,CD3OD):δ8.30(brs,1H),7.83(brs,1H),5.20-4.99(m,1H),4.79-4.69(m,1H),3.54-3.51(m,2H),3.39-3.31(m,2H),3.19-3.14(m,2H),2.65-2.55(m,2H),2.37-2.32(m,2H),1.95-1.68(m,6H),1.56-1.41(m,2H),1.23-1.20(m,6H). 1 H NMR (400MHz, CD 3 OD): δ8.30(brs,1H),7.83(brs,1H),5.20-4.99(m,1H),4.79-4.69(m,1H),3.54-3.51(m ,2H),3.39-3.31(m,2H),3.19-3.14(m,2H),2.65-2.55(m,2H),2.37-2.32(m,2H),1.95-1.68(m,6H),1.56 -1.41(m,2H),1.23-1.20(m,6H).
实施例12 Example 12
(1s,4s)-4-(5-氯-4-((4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(异丙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(isopropylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段Amine-10替换片段Amine-2，获得标题化合物。According to implementation method 1, fragment Amine-2 was replaced by fragment Amine-10 to obtain the title compound.
LC_MS:(ES+):m/z 565.5[M+H]+.LC_MS:(ES + ):m/z 565.5[M+H] + .
1H NMR(400MHz,CD3OD):δ8.32(s,1H),7.85(s,1H),4.66-4.60(m,2H),3.70-3.64(m,1H),3.56-3.51(m,2H),3.39-3.36(m,2H),2.68-2.59(m,2H),2.37-2.34(m,2H),1.94-1.77(m,6H),1.54-1.48(m,2H),1.26(s,3H),1.22(d,J＝6.0Hz,6H). 1 H NMR (400MHz, CD 3 OD): δ8.32(s,1H),7.85(s,1H),4.66-4.60(m,2H),3.70-3.64(m,1H),3.56-3.51(m ,2H),3.39-3.36(m,2H),2.68-2.59(m,2H),2.37-2.34(m,2H),1.94-1.77(m,6H),1.54-1.48(m,2H),1.26 (s,3H),1.22(d,J＝6.0Hz,6H).
实施例13Example 13
(1s,4s)-4-(5-氯-4-((4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-((2,2,2-三氟乙基)亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-((2,2,2-trifluoroethyl)imino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段Amine-11替换片段Amine-2，获得标题化合物。According to implementation method 1, fragment Amine-2 was replaced by fragment Amine-11 to obtain the title compound.
LC_MS:(ES+):m/z 605.45[M+H]+.LC_MS:(ES + ):m/z 605.45[M+H] + .
1H NMR(400MHz,CD3OD):δ8.29(s,1H),7.84(s,1H),5.29-5.02(m,1H),4.81-4.78(m,1H),3.72-3.65(m,2H),3.60-3.48(m,2H),3.44-3.37(m,2H), 2.68-2.58(m,2H),2.40-2.35(m,2H),2.02-1.82(m,4H),1.78-1.72(m,2H),1.57-1.42(m,2H),1.23(s,3H). 1 H NMR (400MHz, CD 3 OD): δ8.29(s,1H),7.84(s,1H),5.29-5.02(m,1H),4.81-4.78(m,1H),3.72-3.65(m ,2H),3.60-3.48(m,2H),3.44-3.37(m,2H), 2.68-2.58(m,2H),2.40-2.35(m,2H),2.02-1.82(m,4H),1.78-1.72(m,2H),1.57-1.42(m,2H),1.23(s,3H ).
实施例14Embodiment 14
(1s,4s)-4-(5-氯-4-((4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-((2-(二甲基氨基)乙基)亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-((2-(dimethylamino)ethyl)imino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段Amine-12替换片段Amine-2，获得标题化合物。According to implementation method 1, fragment Amine-2 was replaced by fragment Amine-12 to obtain the title compound.
LC_MS:(ES+):m/z 594.50[M+H]+.LC_MS:(ES + ):m/z 594.50[M+H] + .
1H NMR(400MHz,CD3OD):δ8.30(s,1H),7.84(s,1H),4.82-4.76(m,1H),3.65-3.57(m,2H),3.42-3.34(m,5H),3.17-3.13(m,2H),2.83(s,6H),2.67-2.58(m,2H),2.41-2.36(m,2H),1.93-1.75(m,6H),1.56-1.46(m,2H),1.29(s,3H). 1 H NMR (400MHz, CD 3 OD): δ8.30(s,1H),7.84(s,1H),4.82-4.76(m,1H),3.65-3.57(m,2H),3.42-3.34(m ,5H),3.17-3.13(m,2H),2.83(s,6H),2.67-2.58(m,2H),2.41-2.36(m,2H),1.93-1.75(m,6H),1.56-1.46 (m,2H),1.29(s,3H).
实施例15Embodiment 15
(1s,4s)-4-(4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段Amine-4替换片段Amine-2，获得标题化合物。 According to implementation method 1, fragment Amine-2 was replaced by fragment Amine-4 to obtain the title compound.
LC_MS:(ES+):m/z 503.75[M+H]+.LC_MS:(ES + ):m/z 503.75[M+H] + .
1H NMR(400MHz,DMSO-d6):δ10.10-9.88(m,1H),8.48-8.41(m,1H),7.99-7.83(m,1H),7.61(s,1H),5.16-5.10(m,1H),4.59-4.52(m,1H),4.24(s,1H),3.31-3.26(m,4H),2.67(s,3H),2.33-2.27(m,4H),1.84-1.81(m,4H),1.64-1.58(m,2H),1.47-1.42(m,2H),1.17-1.15(m,3H). 1 H NMR (400MHz, DMSO-d6): δ10.10-9.88(m,1H),8.48-8.41(m,1H),7.99-7.83(m,1H),7.61(s,1H),5.16-5.10 (m,1H),4.59-4.52(m,1H),4.24(s,1H),3.31-3.26(m,4H),2.67(s,3H),2.33-2.27(m,4H),1.84-1.81 (m,4H),1.64-1.58(m,2H),1.47-1.42(m,2H),1.17-1.15(m,3H).
实施例16Example 16
(1s,4s)-4-(5-氯-4-((4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法三，用中间体1-e替换中间体3-b，获得标题化合物。According to implementation method 3, intermediate 1-e is used to replace intermediate 3-b to obtain the title compound.
LC_MS:(ES+):m/z 508.35[M+H]+.LC_MS:(ES + ):m/z 508.35[M+H] + .
1H NMR(400MHz,CD3OD):δ8.00(s,1H),6.85(d,J＝3.6Hz,1H),6.31(d,J＝3.2Hz,1H),5.22-5.15(m,1H),4.81-4.75(m,1H),3.60-3.56(m,2H),3.38-3.34(m,2H),2.81(s,3H),2.65-2.56(m,2H),2.39-2.34(m,2H),1.96-1.92(m,4H),1.81-1.77(m,2H),1.59-1.51(m,2H),1.25(s,3H). 1 H NMR (400MHz, CD 3 OD): δ8.00 (s, 1H), 6.85 (d, J = 3.6Hz, 1H), 6.31 (d, J = 3.2Hz, 1H), 5.22-5.15 (m, 1H),4.81-4.75(m,1H),3.60-3.56(m,2H),3.38-3.34(m,2H),2.81(s,3H),2.65-2.56(m,2H),2.39-2.34( m,2H),1.96-1.92(m,4H),1.81-1.77(m,2H),1.59-1.51(m,2H),1.25(s,3H).
实施例17Embodiment 17
(1s,4s)-4-(5-氯-4-((5-氯-5-((2-(甲氧基甲基)苯基)氨基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((5-chloro-5-((2-(methoxymethyl)phenyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法三，用2,4,5-三氯嘧啶替换起始原料3-a，用中间体2-b替换中间体3-b，获得标题化合物。According to implementation method three, the starting material 3-a is replaced by 2,4,5-trichloropyrimidine, and the intermediate 3-b is replaced by the intermediate 2-b to obtain the title compound.
LC_MS:(ES+):m/z 510.15[M+H]+.LC_MS:(ES + ):m/z 510.15[M+H] + .
1H NMR(400MHz,CD3OD):δ8.04-7.97(m,2H),7.84-7.80(m,2H),7.67(s,1H),7.32-7.28(m,2H),7.12(t,J＝7.4Hz,1H),4.78-4.70(m,1H),4.52(s,2H),3.56-3.52(m,2H),3.42(s,3H),3.35-3.34(m,1H),3.28-3.27(m,1H),2.80(s,3H),2.58-2.55(m,2H),2.34-2.29(m,2H). 1 H NMR (400MHz, CD 3 OD): δ8.04-7.97(m,2H),7.84-7.80(m,2H),7.67(s,1H),7.32-7.28(m,2H),7.12(t ,J＝7.4Hz,1H),4.78-4.70(m,1H),4.52(s,2H),3.56-3.52(m,2H),3.42(s,3H),3.35-3.34(m,1H), 3.28-3.27(m,1H),2.80(s,3H),2.58-2.55(m,2H),2.34-2.29(m,2H).
实施例18Embodiment 18
(1s,4s)-4-(5-氯-4-(5-氟-4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-(5-fluoro-4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法三，用2,4-二氯-5-氟嘧啶替换起始原料3-a，用中间体1-e替换中间体3-b，获得标题化合物。According to implementation method three, 2,4-dichloro-5-fluoropyrimidine was used to replace the starting material 3-a, and the intermediate 1-e was used to replace the intermediate 3-b to obtain the title compound.
LC_MS:(ES+):m/z 487.35[M+H]+.LC_MS:(ES + ):m/z 487.35[M+H] + .
1H NMR(400MHz,CD3OD):δ7.96(d,J＝3.2Hz,1H),7.81(s,1H),5.10-5.03(m,1H),4.77-4.74(m,1H),3.58-3.52(m,2H),3.35-3.32(m,1H),3.30-3.28(m,1H), 2.80(s,3H),2.64-2.54(m,2H),2.37-2.32(m,2H),1.93-1.88(m,4H),1.79-1.75(m,2H),1.55-1.48(m,2H),1.23(s,3H). 1 H NMR (400MHz, CD 3 OD): δ7.96 (d, J = 3.2Hz, 1H), 7.81 (s, 1H), 5.10-5.03 (m, 1H), 4.77-4.74 (m, 1H), 3.58-3.52(m,2H),3.35-3.32(m,1H),3.30-3.28(m,1H), 2.80(s,3H),2.64-2.54(m,2H),2.37-2.32(m,2H),1.93-1.88(m,4H),1.79-1.75(m,2H),1.55-1.48(m,2H ),1.23(s,3H).
实施例19Embodiment 19
(1s,4s)-4-(5-氯-4-((5-氯-4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((5-chloro-4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法三，用2,4,5-三氯嘧啶替换起始原料3-a，用中间体1-e替换中间体3-b，获得标题化合物。According to implementation method three, the starting material 3-a is replaced by 2,4,5-trichloropyrimidine, and the intermediate 3-b is replaced by the intermediate 1-e to obtain the title compound.
LC_MS:(ES+):m/z 503.20[M+H]+.LC_MS:(ES + ):m/z 503.20[M+H] + .
1H NMR(400MHz,CD3OD):δ8.04(s,1H),7.82(s,1H),5.06(brs,1H),4.81-4.75(m,1H),3.58-3.52(m,2H),3.35-3.32(m,1H),3.30-3.28(m,1H),2.80(s,3H),2.64-2.55(m,2H),2.38-2.32(m,2H),1.93-1.85(m,4H),1.80-1.76(m,2H),1.54-1.47(m,2H),1.23(s,3H). 1 H NMR (400MHz, CD 3 OD): δ8.04(s,1H),7.82(s,1H),5.06(brs,1H),4.81-4.75(m,1H),3.58-3.52(m,2H ),3.35-3.32(m,1H),3.30-3.28(m,1H),2.80(s,3H),2.64-2.55(m,2H),2.38-2.32(m,2H),1.93-1.85(m ,4H),1.80-1.76(m,2H),1.54-1.47(m,2H),1.23(s,3H).
实施例20Embodiment 20
(1s,4s)-4-(5-氯-4-((4-(((1s,4S)-4-羟基-4-甲基环己基)氧基)-5-甲基嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1s,4S)-4-hydroxy-4-methylcyclohexyl)oxy)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法三，用2,4-二氯-5-甲基嘧啶替换起始原料3-a，用中间体1-e替换中间体3-b，获得标题化合物。According to implementation method three, the starting material 3-a is replaced by 2,4-dichloro-5-methylpyrimidine, and the intermediate 3-b is replaced by the intermediate 1-e to obtain the title compound.
LC_MS:(ES+):m/z 483.2[M+H]+.LC_MS:(ES + ):m/z 483.2[M+H] + .
1H NMR(400MHz,CD3OD):δ7.83-7.81(m,2H),5.08-5.01(m,1H),4.80-4.73(m,1H),3.58-3.53(m,2H),3.35-3.34(m,2H),2.80(s,3H),2.61-2.58(m,2H),2.38-2.33(m,2H),1.99(s,3H),1.88-1.86(m,4H),1.77-1.74(m,2H),1.55-1.50(m,2H),1.24(s,3H). 1 H NMR (400MHz, CD 3 OD): δ7.83-7.81(m,2H),5.08-5.01(m,1H),4.80-4.73(m,1H),3.58-3.53(m,2H),3.35 -3.34(m,2H),2.80(s,3H),2.61-2.58(m,2H),2.38-2.33(m,2H),1.99(s,3H),1.88-1.86(m,4H),1.77 -1.74(m,2H),1.55-1.50(m,2H),1.24(s,3H).
实施例21Embodiment 21
(1s,4s)-4-(5-氯-4-((4-((2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法二，用片段Amine-2替换片段Amine-4，获得标题化合物。According to implementation method 2, fragment Amine-2 was used to replace fragment Amine-4 to obtain the title compound.
LC_MS:(ES+):m/z 544.4[M+H]+.LC_MS:(ES + ):m/z 544.4[M+H] + .
1H NMR(400MHz,DMSO-d6):δ9.16-9.12(m,1H),8.57(s,1H),8.34(s,1H),7.70-7.66(m,1H),7.52-7.36(m,1H),7.33-7.13(m,3H),4.82-4.61(m,1H),4.53-4.35(m,2H),3.29-3.23(m,7H),2.67(s,3H),2.38-2.32(m,2H),2.12-2.10(m,2H). 1 H NMR (400MHz, DMSO-d6): δ9.16-9.12(m,1H),8.57(s,1H),8.34(s,1H),7.70-7.66(m,1H),7.52-7.36(m ,1H),7.33-7.13(m,3H),4.82-4.61(m,1H),4.53-4.35(m,2H),3.29-3.23(m,7H),2.67(s,3H),2.38-2.32 (m,2H),2.12-2.10(m,2H).
实施例22Embodiment 22
(1s,4s)-4-(5-氯-4-((4-(甲基氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用甲胺盐酸盐替换中间体1-e，获得标题化合物。According to implementation method 1, intermediate 1-e is replaced by methylamine hydrochloride to obtain the title compound.
LC_MS:(ES+):m/z 438.1[M+H]+.LC_MS:(ES + ):m/z 438.1[M+H] + .
1H NMR(400MHz,DMSO-d6):δ9.01(brs,1H),8.09(s,1H),7.87(brs,1H),7.03(s,1H),4.75-4.70(m,1H),3.28-3.21(m,4H),2.83(s,3H),2.66(s,3H),2.44-2.34(m,2H),2.19-2.14(m,2H). 1 H NMR (400MHz, DMSO-d6): δ9.01(brs,1H),8.09(s,1H),7.87(brs,1H),7.03(s,1H),4.75-4.70(m,1H), 3.28-3.21(m,4H),2.83(s,3H),2.66(s,3H),2.44-2.34(m,2H),2.19-2.14(m,2H).
(1r,4r)-4-(5-氯-4-((4-(甲基氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1r,4r)-4-(5-chloro-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用甲胺盐酸盐替换中间体1-e，在片段Amine-2合成中，用Amine-1-f-B替换Amine-1-f-A，获得标题化合物。According to implementation method 1, methylamine hydrochloride is used to replace intermediate 1-e, and in the synthesis of fragment Amine-2, Amine-1-f-B is used to replace Amine-1-f-A to obtain the title compound.
LC_MS:(ES+):m/z 438.1[M+H]+.LC_MS:(ES + ):m/z 438.1[M+H] + .
1H NMR(400MHz,CDCl3):δ8.14(s,1H),8.13(s,1H),6.82(brs,1H),5.27(brs,1H),4.58-4.49(m,1H),3.61-3.56(m,2H),3.14-3.07(m,5H),2.86(s,3H),2.63-2.60(m,2H),2.40-2.37(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ8.14(s,1H),8.13(s,1H),6.82(brs,1H),5.27(brs,1H),4.58-4.49(m,1H),3.61 -3.56(m,2H),3.14-3.07(m,5H),2.86(s,3H),2.63-2.60(m,2H),2.40-2.37(m,2H).
实施例23Embodiment 23
(2-((2-(5-氯-1-((1s,4s)-1-(甲基亚氨基)-1-氧化四氢-1λ6-噻喃-4-基)-1H-吡唑-4-基)氨基)-5-(三氟甲基)嘧啶-4-基氨基)苯基)二甲基氧化膦
(2-((2-(5-chloro-1-((1s,4s)-1-(methylimino)-1-oxidotetrahydro-1λ 6 -thiopyran-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-ylamino)phenyl)dimethylphosphine oxide
按实施方法二，用(2-氨基苯基)二甲基氧化膦替换中间体1-e，用片段Amine-2替换片段Amine-4，获得标题化合物。According to implementation method 2, intermediate 1-e is replaced by (2-aminophenyl)dimethylphosphine oxide, and fragment Amine-2 is replaced by fragment Amine-4 to obtain the title compound.
LC_MS:(ES+):m/z 576.55[M+H]+.LC_MS:(ES + ):m/z 576.55[M+H] + .
1H NMR(400MHz,CD3OD):δ8.28(s,1H),8.12-8.08(m,1H),7.68(s,1H),7.54-7.49(m,1H),7.35(t,J＝8.0Hz,1H),7.16-7.12(m,1H),4.80-4.76(m,1H),3.58-3.53(m,2H),3.36-3.35(m,2H),2.81(s,3H),2.36-2.31(m,2H),2.65-2.56(m,2H),1.81(d,J＝13.6Hz,6H). 1 H NMR (400MHz, CD 3 OD): δ8.28(s,1H),8.12-8.08(m,1H),7.68(s,1H),7.54-7.49(m,1H),7.35(t,J ＝8.0Hz,1H),7.16-7.12(m,1H),4.80-4.76(m,1H),3.58-3.53(m,2H),3.36-3.35(m,2H),2.81(s,3H), 2.36-2.31(m,2H),2.65-2.56(m,2H),1.81(d,J＝13.6Hz,6H).
实施例24Embodiment 24
(1s,4s)-4-(5-氯-4-((4-(((1r,4R)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1r,4R)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用中间体1-d替换中间体1-e，获得标题化合物。 According to implementation method 1, intermediate 1-d was used to replace intermediate 1-e to obtain the title compound.
LC_MS:(ES+):m/z 537.50[M+H]+.LC_MS:(ES + ):m/z 537.50[M+H] + .
1H NMR(400MHz,CD3OD):δ8.30(s,1H),7.84(s,1H),5.45-5.27(m,1H),4.83-4.80(m,1H),3.59-3.51(m,2H),3.35-3.34(m,2H),2.80(s,3H),2.60-2.57(m,2H),2.38-2.33(m,2H),2.03-1.92(m,2H),1.76-1.70(m,4H),1.54-1.50(m,2H),1.22(s,3H). 1 H NMR (400MHz, CD 3 OD): δ8.30(s,1H),7.84(s,1H),5.45-5.27(m,1H),4.83-4.80(m,1H),3.59-3.51(m ,2H),3.35-3.34(m,2H),2.80(s,3H),2.60-2.57(m,2H),2.38-2.33(m,2H),2.03-1.92(m,2H),1.76-1.70 (m,4H),1.54-1.50(m,2H),1.22(s,3H).
实施例25Embodiment 25
(1s,4s)-4-(5-氯-4-((4-((2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
按实施方法二，用片段Amine-1替换片段Amine-4，获得标题化合物。According to implementation method 2, fragment Amine-1 was used to replace fragment Amine-4 to obtain the title compound.
LC_MS:(ES+):m/z 529.9[M+H]+.LC_MS:(ES + ):m/z 529.9[M+H] + .
1H NMR(400MHz,CDCl3)δ8.72(s,1H),8.27(s,1H),7.99(s,1H),7.83(s,1H),7.35(t,J＝7.7Hz,1H),7.27(s,1H),7.17(t,J＝7.4Hz,1H),4.54(td,J＝7.1,4.1Hz,1H),4.50(s,2H),3.66–3.57(m,2H),3.45(s,3H),3.18–3.09(m,2H),2.68–2.58(m,2H),2.50–2.40(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.72(s,1H),8.27(s,1H),7.99(s,1H),7.83(s,1H),7.35(t,J＝7.7Hz,1H) ,7.27(s,1H),7.17(t,J＝7.4Hz,1H),4.54(td,J＝7.1,4.1Hz,1H),4.50(s,2H),3.66–3.57(m,2H), 3.45(s,3H),3.18–3.09(m,2H),2.68–2.58(m,2H),2.50–2.40(m,2H).
实施例26Embodiment 26
(1s,4s)-1-亚氨基-4-(4-((4-((2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-5-甲基-1H-吡唑-1-基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-1-Imino-4-(4-((4-((2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法二，用片段Amine-7替换片段Amine-4，获得标题化合物。According to implementation method 2, fragment Amine-4 was replaced by fragment Amine-7 to obtain the title compound.
LC_MS:(ES+):m/z 510.2[M+H]+.LC_MS:(ES + ):m/z 510.2[M+H] + .
1H NMR(400MHz,CDCl3)δ8.46(s,1H),8.19(s,1H),7.94(s,1H),7.49(s,1H),7.13(s,1H),6.99(s,1H),6.40(s,1H),4.41(s,2H),4.25(s,1H),3.59(d,J＝10.2Hz,2H),3.37(s,3H),3.09–3.01(m,2H),2.53(m,2H),2.34(m,2H),2.08(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.46(s,1H),8.19(s,1H),7.94(s,1H),7.49(s,1H),7.13(s,1H),6.99(s, 1H),6.40(s,1H),4.41(s,2H),4.25(s,1H),3.59(d,J＝10.2Hz,2H),3.37(s,3H),3.09–3.01(m,2H ),2.53(m,2H),2.34(m,2H),2.08(s,3H).
(1r,4r)-1-亚氨基-4-(4-((4-((2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-5-甲基-1H-吡唑-1-基)六氢-1λ6-噻喃1-氧化物
(1r,4r)-1-Imino-4-(4-((4-((2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法二，用片段Amine-7替换片段Amine-4，在片段Amine-7合成中用片段Amine-7-c-B替换片段Amine-7-c-A，获得标题化合物。According to implementation method 2, fragment Amine-4 was replaced by fragment Amine-7, and fragment Amine-7-c-A was replaced by fragment Amine-7-c-B in the synthesis of fragment Amine-7 to obtain the title compound.
LC_MS:(ES+):m/z 510.2[M+H]+.LC_MS:(ES + ):m/z 510.2[M+H] + .
1H NMR(400MHz,CDCl3)δ8.52(s,1H),8.26(s,1H),8.02(s,1H),7.56(s,1H),7.23–7.19(m,1H),7.09–7.02(m,1H),6.37(s,1H),4.48(s,2H),4.38–4.24(m,2H),3.71–3.63(m,2H),3.43(s,3H),3.16–3.07(m,2H),2.65–2.57(m,2H),2.46–2.36(m,2H),2.14(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.52(s,1H),8.26(s,1H),8.02(s,1H),7.56(s,1H),7.23–7.19(m,1H),7.09– 7.02(m,1H),6.37(s,1H),4.48(s,2H),4.38–4.24(m,2H),3.71–3.63(m,2H),3.43(s,3H),3.16–3.07( m,2H),2.65–2.57(m,2H),2.46–2.36(m,2H),2.14(s,3H).
实施例27 Embodiment 27
(1s,4s)-4-(4-((4-((2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(甲基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-((4-((2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(methylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法二，用片段Amine-5替换片段Amine-4，获得标题化合物。According to implementation method 2, fragment Amine-4 was replaced by fragment Amine-5 to obtain the title compound.
LC_MS:(ES+):m/z 510.25[M+H]+.LC_MS:(ES + ):m/z 510.25[M+H] + .
1H NMR(400MHz,CDCl3)δ8.33(s,2H),7.93(s,1H),7.64(s,1H),7.40(m,2H),7.34(d,J＝6.9Hz,1H),7.22(s,1H),7.12(s,1H),4.52(s,2H),4.29–4.14(m,1H),3.55–3.37(m,5H),3.15–3.04(m,2H),2.87(s,3H),2.41(dd,J＝11.9,5.6Hz,2H),1.30(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.33 (s, 2H), 7.93 (s, 1H), 7.64 (s, 1H), 7.40 (m, 2H), 7.34 (d, J = 6.9Hz, 1H) ,7.22(s,1H),7.12(s,1H),4.52(s,2H),4.29–4.14(m,1H),3.55–3.37(m,5H),3.15–3.04(m,2H),2.87 (s,3H),2.41(dd,J＝11.9,5.6Hz,2H),1.30(m,2H).
实施例28Embodiment 28
(1s,4s)-1-(乙基亚氨基)-4-(4-((4-((2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-1-(ethylimino)-4-(4-((4-((2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法二，用片段Amine-6替换片段Amine-4，获得标题化合物。According to implementation method 2, fragment Amine-4 was replaced by fragment Amine-6 to obtain the title compound.
LC_MS:(ES+):m/z 524.25[M+H]+.LC_MS:(ES + ):m/z 524.25[M+H] + .
1H NMR(400MHz,CDCl3)δ8.30(s,2H),7.91(s,1H),7.63(s,1H),7.38(m,2H),7.30(s,1H),7.21(s,1H),7.07(s,1H),4.49(s,2H),4.20(m,1H),3.44(s,3H),3.38 (m,2H),3.17(q,J＝7.2Hz,2H),3.09(m,2H),2.39(m,2H),1.25(t,J＝7.2Hz,5H). 1 H NMR (400MHz, CDCl 3 ) δ8.30(s,2H),7.91(s,1H),7.63(s,1H),7.38(m,2H),7.30(s,1H),7.21(s, 1H),7.07(s,1H),4.49(s,2H),4.20(m,1H),3.44(s,3H),3.38 (m,2H),3.17(q,J＝7.2Hz,2H),3.09(m,2H),2.39(m,2H),1.25(t,J＝7.2Hz,5H).
实施例29Embodiment 29
(1s,4s)-4-(5-氯-4-((4-(((1r,4R)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1r,4R)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段Amine-9替换片段Amine-2，获得标题化合物。According to implementation method 1, fragment Amine-2 was replaced by fragment Amine-9 to obtain the title compound.
LC_MS:(ES+):m/z 551.45[M+H]+.LC_MS:(ES + ):m/z 551.45[M+H] + .
1H NMR(400MHz,CD3OD)δ8.30(brs,1H),7.81(s,1H),5.57-5.46(m,1H),4.83-4.76(m,1H),3.55-3.51(m,2H),3.37-3.31(m,2H),3.19-3.14(m,2H),2.65-2.56(m,2H),2.37-2.32(m,2H),2.01-1.69(m,6H),1.57-1.46(m,2H),1.24-1.20(m,6H). 1 H NMR (400MHz, CD 3 OD) δ8.30(brs,1H),7.81(s,1H),5.57-5.46(m,1H),4.83-4.76(m,1H),3.55-3.51(m, 2H),3.37-3.31(m,2H),3.19-3.14(m,2H),2.65-2.56(m,2H),2.37-2.32(m,2H),2.01-1.69(m,6H),1.57- 1.46(m,2H),1.24-1.20(m,6H).
实施例30Embodiment 30
(1s,4s)-4-(5-氯-4-((4-(((1r,4R)-4-羟基-4-甲基环己基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-((2-(二甲基氨基)乙基)亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(((1r,4R)-4-hydroxy-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-((2-(dimethylamino)ethyl)imino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用片段Amine-12替换片段Amine-2，获得标题化合物。According to implementation method 1, fragment Amine-2 was replaced by fragment Amine-12 to obtain the title compound.
LC_MS:(ES+):m/z 595.45[M+H]+.LC_MS:(ES + ):m/z 595.45[M+H] + .
1H NMR(400MHz,CD3OD):δ8.29(s,1H),7.82(s,1H),5.41-5.19(m,1H),4.58-4.51(m,1H),3.65-3.57(m,2H),3.44-3.38(m,4H),3.23-3.21(m,2H),2.88(s,6H),2.64-2.54(m,2H),2.41-2.36(m,2H),2.01-1.93(m,2H),1.83-1.72(m,4H),1.54-1.48(m,2H),1.22(s,3H). 1 H NMR (400MHz, CD 3 OD): δ8.29(s,1H),7.82(s,1H),5.41-5.19(m,1H),4.58-4.51(m,1H),3.65-3.57(m ,2H),3.44-3.38(m,4H),3.23-3.21(m,2H),2.88(s,6H),2.64-2.54(m,2H),2.41-2.36(m,2H),2.01-1.93 (m,2H),1.83-1.72(m,4H),1.54-1.48(m,2H),1.22(s,3H).
实施例31Embodiment 31
(1s,4s)-4-(5-氯-4-((4-((2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法二，用片段Amine-3替换片段Amine-4，获得标题化合物。According to implementation method 2, fragment Amine-3 was used to replace fragment Amine-4 to obtain the title compound.
LC_MS:(ES+):m/z 559.20[M+H]+.LC_MS:(ES + ):m/z 559.20[M+H] + .
1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.30(s,1H),8.02(s,1H),7.87(s,1H),7.35(t,J＝7.4Hz,1H),7.25(s,1H),7.14(t,J＝7.4Hz,1H),6.58(s,1H),4.53(td,J＝7.4,3.8Hz,1H),4.49(s,2H),3.65–3.56(m,2H),3.44(s,3H),3.20–3.08(m,4H),2.63–2.52(m,2H),2.39(ddd,J＝13.9,8.3,3.9Hz,2H),1.24(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.51 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.35 (t, J = 7.4Hz, 1H) ,7.25(s,1H),7.14(t,J＝7.4Hz,1H),6.58(s,1H),4.53(td,J＝7.4,3.8Hz,1H),4.49(s,2H),3.65– 3.56(m,2H),3.44(s,3H),3.20–3.08(m,4H),2.63–2.52(m,2H),2.39(ddd,J＝13.9,8.3,3.9Hz,2H),1.24( t,J＝7.2Hz,3H).
实施例32Embodiment 32
(1s,4s)-4-(4-((4-((1,4-二氧杂螺[4.5]癸-8-基)氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-5-氯-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-((4-((1,4-dioxaspiro[4.5]dec-8-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-chloro-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用1,4-二氧杂螺[4.5]癸-8-醇替换中间体1-e，用片段Amine-3替换片段Amine-2，获得标题化合物。According to implementation method 1, 1,4-dioxaspiro[4.5]decan-8-ol was used to replace intermediate 1-e, and fragment Amine-3 was used to replace fragment Amine-2 to obtain the title compound.
LC_MS:(ES+):m/z 579.30[M+H]+.LC_MS:(ES + ):m/z 579.30[M+H] + .
1H NMR(400MHz,CDCl3)δ8.35(s,1H),8.00(s,1H),6.75(s,2H),5.34(d,J＝2.7Hz,1H),4.63–4.48(m,1H),4.05–3.92(m,3H),3.71–3.52(m,2H),3.17(dd,J＝14.3,7.1Hz,2H),3.15–3.10(m,1H),2.69–2.51(m,2H),2.50–2.34(m,2H),2.09–1.85(m,5H),1.66(dd,J＝12.0,5.9Hz,2H),1.25(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.35 (s, 1H), 8.00 (s, 1H), 6.75 (s, 2H), 5.34 (d, J = 2.7Hz, 1H), 4.63–4.48 (m, 1H),4.05–3.92(m,3H),3.71–3.52(m,2H),3.17(dd,J＝14.3,7.1Hz,2H),3.15–3.10(m,1H),2.69–2.51(m, 2H),2.50–2.34(m,2H),2.09–1.85(m,5H),1.66(dd,J＝12.0,5.9Hz,2H),1.25(t,J＝7.2Hz,3H).
实施例33Embodiment 33
4-((2-((5-氯-1-((1s,4s)-1-(乙基亚氨基)-1-氧化四氢-1λ6-噻喃-4-基)-1H-吡唑-4-基)氨基)-5-(三氟甲基)嘧啶-4-基)氧基)环己烷-1-酮
4-((2-((5-chloro-1-((1s,4s)-1-(ethylimino)-1-oxidotetrahydro-1λ 6 -thiopyran-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)cyclohexane-1-one
按实施方法一，用1,4-二氧杂螺[4.5]癸-8-醇替换中间体1-e，用片段Amine-3替换片段Amine-2，获得标题化合物。According to implementation method 1, 1,4-dioxaspiro[4.5]decan-8-ol was used to replace intermediate 1-e, and fragment Amine-3 was used to replace fragment Amine-2 to obtain the title compound.
LC_MS:(ES+):m/z 535.15[M+H]+.LC_MS:(ES + ):m/z 535.15[M+H] + .
1H NMR(400MHz,CDCl3)δ8.41(s,1H),8.01(s,1H),6.87(s,1H),6.58(s,1H),5.61(d,J＝0.6Hz,1H),4.57(ddd,J＝11.0,7.4,4.0Hz,1H),3.68–3.57(m,2H),3.21–3.15(m,2H),3.13(dd,J＝9.3,3.7Hz,1H),2.75–2.65(m,2H),2.60(dtd,J＝ 10.4,8.3,3.5Hz,2H),2.49–2.34(m,5H),2.17–2.06(m,2H),1.25(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.41 (s, 1H), 8.01 (s, 1H), 6.87 (s, 1H), 6.58 (s, 1H), 5.61 (d, J = 0.6Hz, 1H) ,4.57(ddd,J＝11.0,7.4,4.0Hz,1H),3.68–3.57(m,2H),3.21–3.15(m,2H),3.13(dd,J＝9.3,3.7Hz,1H),2.75 –2.65(m,2H),2.60(dtd,J＝ 10.4,8.3,3.5Hz,2H),2.49–2.34(m,5H),2.17–2.06(m,2H),1.25(t,J=7.2Hz,3H).
实施例34Embodiment 34
4-((2-((5-氯-1-((1s,4s)-1-(乙基亚氨基)-1-氧化四氢-1λ6-噻喃-4-基)-1H-吡唑-4-基)氨基)-5-(三氟甲基)嘧啶-4-基)氧基)哌啶-1-甲酸乙酯
4-((2-((5-chloro-1-((1s,4s)-1-(ethylimino)-1-oxidotetrahydro-1λ 6 -thiopyran-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)oxy)piperidine-1-carboxylic acid ethyl ester
按实施方法一，用4-羟基哌啶-1-甲酸乙酯替换中间体1-e，用片段Amine-3替换片段Amine-2，获得标题化合物。According to implementation method 1, intermediate 1-e was replaced by ethyl 4-hydroxypiperidine-1-carboxylate, and fragment Amine-2 was replaced by fragment Amine-3 to obtain the title compound.
LC_MS:(ES+):m/z 594.25[M+H]+.LC_MS:(ES + ):m/z 594.25[M+H] + .
1H NMR(400MHz,CDCl3)δ8.38(s,1H),7.98(s,1H),5.44(d,J＝2.9Hz,1H),4.67–4.48(m,1H),4.16(q,J＝7.1Hz,2H),3.64(dd,J＝24.3,11.6Hz,4H),3.58–3.49(m,2H),3.17(q,J＝7.2Hz,4H),3.13(dd,J＝9.2,3.4Hz,2H),2.60(ddd,J＝14.8,10.5,3.3Hz,2H),2.42(ddd,J＝13.2,8.0,3.6Hz,2H),1.99–1.84(m,4H),1.28(t,J＝7.1Hz,3H),1.25(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.38 (s, 1H), 7.98 (s, 1H), 5.44 (d, J = 2.9Hz, 1H), 4.67–4.48 (m, 1H), 4.16 (q, J＝7.1Hz,2H),3.64(dd,J＝24.3,11.6Hz,4H),3.58–3.49(m,2H),3.17(q,J＝7.2Hz,4H), 3.13(dd,J＝9.2,3.4Hz,2H),2.60(ddd,J＝14.8,10.5,3.3Hz,2H),2.42(ddd,J＝13.2,8.0,3.6Hz,2H),1.99–1.84( m,4H),1.28(t,J＝7.1Hz,3H),1.25(t,J＝7.2Hz,3H).
实施例35Embodiment 35
(1s,4s)-4-(5-氯-4-((4-吗啉-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-morpholin-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法四，用吗啉替换中间体4-b，获得标题化合物。According to implementation method 4, intermediate 4-b is replaced by morpholine to obtain the title compound.
LC_MS:(ES+):m/z 508.3[M+H]+.LC_MS:(ES + ):m/z 508.3[M+H] + .
1H NMR(400MHz,CD3OD):δ8.26(s,1H),7.79(s,1H),4.90-4.72(m,1H),3.73-3.72(m,4H),3.60-3.51(m,6H),3.36-3.35(m,2H),3.21-3.11(m,2H),2.60-2.54(m,2H),2.36-2.31(m,2H),1.22(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.26(s,1H),7.79(s,1H),4.90-4.72(m,1H),3.73-3.72(m,4H),3.60-3.51(m ,6H),3.36-3.35(m,2H),3.21-3.11(m,2H),2.60-2.54(m,2H),2.36-2.31(m,2H),1.22(t,J＝7.2Hz,3H ).
实施例36Embodiment 36
(1s,4s)-4-(5-氯-4-((4-((4-羟基-4-甲基环己基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((4-hydroxy-4-methylcyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法二，用4-氨基-1-甲基环己烷-1-醇替换中间体2-b，用片段Amine-3替换片段Amine-4，获得标题化合物。According to implementation method 2, intermediate 2-b was replaced by 4-amino-1-methylcyclohexane-1-ol, and fragment Amine-4 was replaced by fragment Amine-3 to obtain the title compound.
LC_MS:(ES+):m/z 550.25[M+H]+.LC_MS:(ES + ):m/z 550.25[M+H] + .
1H NMR(400MHz,CDCl3)δ8.04(s,1H),8.01(s,1H),7.94(s,1H),6.81(m,1H),5.02(s,1H),4.61(d,J＝4.1Hz,1H),4.50(s,1H),3.58–3.51(m,2H),3.09(dd,J＝13.9,6.7Hz,4H),1.83(m,2H),1.69(m,2H),1.59(d,J＝12.1Hz,2H),1.48(d,J＝12.8Hz,2H),1.22(s,3H),1.19–1.15(m,5H),0.78(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.04(s,1H),8.01(s,1H),7.94(s,1H),6.81(m,1H),5.02(s,1H),4.61(d, J＝4.1Hz,1H),4.50(s,1H),3.58–3.51(m,2H),3.09(dd,J＝13.9,6.7Hz,4H),1.83(m,2H),1.69(m,2H ),1.59(d,J＝12.1Hz,2H),1.48(d,J＝12.8Hz,2H),1.22(s,3H),1.19–1.15(m,5H),0.78(m,2H).
实施例37Embodiment 37
(1s,4s)-4-(5-氯-4-((4-(4-(二甲基氨基)哌啶-1-基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(4-(dimethylamino)piperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法四，用N,N-二甲基哌啶-4-胺替换中间体4-b，获得标题化合物。LC_MS:(ES+):m/z 549.2[M+H]+.According to implementation method 4, intermediate 4-b was replaced with N,N-dimethylpiperidin-4-amine to obtain the title compound. LC_MS: (ES + ): m/z 549.2 [M+H] + .
1H NMR(400MHz,CD3OD):δ8.26(s,1H),7.83(s,1H),4.81-4.76(m,1H),4.34-3.27(m,2H),3.55-3.51(m,2H),3.36-3.30(m,2H),3.19-3.14(m,2H),3.04-2.97(m,2H),2.89-2.81(m,1H),2.64-2.56(m,2H),2.53(s,6H),2.37-2.32(m,2H),2.04-2.02(m,2H),1,62-1.56(m,2H),1.22(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.26(s,1H),7.83(s,1H),4.81-4.76(m,1H),4.34-3.27(m,2H),3.55-3.51(m ,2H),3.36-3.30(m,2H),3.19-3.14(m,2H),3.04-2.97(m,2H),2.89-2.81(m,1H),2.64-2.56(m,2H),2.53 (s,6H),2.37-2.32(m,2H),2.04-2.02(m,2H),1,62-1.56(m,2H),1.22(t,J=7.2Hz,3H).
实施例38Embodiment 38
(1s,4s)-4-(5-氯-4-((4-(4-(羟甲基)哌啶-1-基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(4-(hydroxymethyl)piperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法四，用哌啶-4-基甲醇替换中间体4-b，获得标题化合物。According to Embodiment 4, intermediate 4-b was replaced with piperidin-4-ylmethanol to obtain the title compound.
LC_MS:(ES+):m/z 536.15[M+H]+. LC_MS:(ES + ):m/z 536.15[M+H] + .
1H NMR(400MHz,CD3OD):δ8.21(s,1H),7.82(s,1H),4.80-4.76(m,1H),4.25-4.21(m,2H),3.56-3.50(m,2H),3.42(d,J＝6.0Hz,2H),3.36-3.31(m,2H),3.19-3.13(m,2H),2.99(t,J＝13.0Hz,2H),2.62-2.54(m,2H),2.37-2.32(m,2H),1.79-1.74(m,3H),1.31-1.26(m,2H),1.22(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.21(s,1H),7.82(s,1H),4.80-4.76(m,1H),4.25-4.21(m,2H),3.56-3.50(m ,2H),3.42(d,J＝6.0Hz,2H),3.36-3.31(m,2H),3.19-3.13(m,2H),2.99(t,J＝13.0Hz,2H),2.62-2.54( m,2H),2.37-2.32(m,2H),1.79-1.74(m,3H),1.31-1.26(m,2H),1.22(t,J＝7.2Hz,3H).
实施例39Embodiment 39
(1s,4s)-4-(5-氯-4-((4-(3-(甲氧基甲基)苯基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(3-(methoxymethyl)phenyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
实施方式：
Implementation method:
在氮气保护下向含有4-a((1s,4s)-4-(5-氯-4-((4-氯-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物)(30mg,0.065mmol)，39-a(3-(甲氧基甲基)苯基硼酸)(12mg,0.072mmol)和碳酸钠(14mg,0.13mmol)的乙腈(1ml)和水(0.5mL)中加入四(三苯基膦)钯(7.5mg,0.0065mmol)。反应体系氮气置换3次，加热至90℃反应18小时。TLC监测反应完全。混合物减压浓缩，剩余物分配于二氯甲烷(10mL)和水(10mL)中。收集有机相，向水相中加入二氯甲烷萃取(10mL x 2)，合并有机相，用饱和氯化钠溶液洗涤(20mL),无水硫酸钠干燥，减压浓缩。剩余物经剩余物经制备TLC(含3％甲醇的二氯甲烷洗脱溶液)纯化得到化合物39为白色固体(11.8mg,33％)。Under nitrogen protection, tetrakis(triphenylphosphine)palladium (7.5 mg, 0.0065 mmol) was added to acetonitrile (1 ml) and water (0.5 mL) containing 4-a((1s, 4s)-4-(5-chloro-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide) (30 mg, 0.065 mmol), 39-a(3-(methoxymethyl)phenylboronic acid) (12 mg, 0.072 mmol) and sodium carbonate (14 mg, 0.13 mmol). The reaction system was replaced with nitrogen three times and heated to 90° C. for 18 hours. The reaction was complete when monitored by TLC. The mixture was concentrated under reduced pressure and the residue was distributed between dichloromethane (10 mL) and water (10 mL). The organic phase was collected, dichloromethane was added to the aqueous phase for extraction (10 mL x 2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane elution solution containing 3% methanol) to obtain compound 39 as a white solid (11.8 mg, 33%).
LC_MS:(ES+):m/z 543.8[M+H]+. LC_MS:(ES + ):m/z 543.8[M+H] + .
1H NMR(400MHz,CD3OD):δ8.69(s,1H),7.91(s,1H),7.55-7.44(m,4H),4.80-4.74(m,1H),4.52(s,2H),3.55-3.50(m,2H),3.39(s,3H),3.35-3.34(m,2H),3.18-3.13(m,2H),2.65-2.59(m,2H),2.36-2.32(m,2H),1.21(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.69(s,1H),7.91(s,1H),7.55-7.44(m,4H),4.80-4.74(m,1H),4.52(s,2H ),3.55-3.50(m,2H),3.39(s,3H),3.35-3.34(m,2H),3.18-3.13(m,2H),2.65-2.59(m,2H),2.36-2.32(m ,2H),1.21(t,J＝7.2Hz,3H).
实施例40Embodiment 40
(1s,4s)-4-(5-乙基-4-((4-((2-(甲氧基甲基)苯基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-亚氨基六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-ethyl-4-((4-((2-(methoxymethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-iminohexahydro-1λ 6 -thiopyran 1-oxide
按实施方法二，在片段Amine-7合成中用乙基硼酸替换甲基硼酸，获得标题化合物。According to Embodiment 2, methylboronic acid was replaced with ethylboronic acid in the synthesis of fragment Amine-7 to obtain the title compound.
LC_MS:(ES+):m/z 524.20[M+H]+.LC_MS:(ES + ):m/z 524.20[M+H] + .
1H NMR(400MHz,CDCl3)δ8.30(s,2H),7.91(s,1H),7.62(s,1H),7.38(dd,J＝11.5,3.9Hz,2H),7.34–7.29(m,1H),7.15(m,1H),4.49(s,2H),4.38–4.03(m,1H),3.44(s,3H),3.17(q,J＝7.2Hz,2H),3.08(m,2H),2.38(m,2H),1.25(t,J＝7.2Hz,5H). 1 H NMR (400MHz, CDCl 3 ) δ8.30 (s, 2H), 7.91 (s, 1H), 7.62 (s, 1H), 7.38 (dd, J = 11.5, 3.9Hz, 2H), 7.34–7.29 ( m,1H),7.15(m,1H),4.49(s,2H),4.38–4.03(m,1H),3.44(s,3H),3.17(q,J＝7.2Hz,2H),3.08(m ,2H),2.38(m,2H),1.25(t,J＝7.2Hz,5H).
实施例41Embodiment 41
(1s,4s)-4-(5-氯-4-((4-((2-(二甲基氨基)乙基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((2-(dimethylamino)ethyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法四，用N,N-二甲基乙二胺替换中间体4-b，获得标题化合物。According to implementation method 4, intermediate 4-b is replaced by N,N-dimethylethylenediamine to obtain the title compound.
LC_MS:(ES+):m/z 509.95[M+H]+.LC_MS:(ES + ):m/z 509.95[M+H] + .
1H NMR(400MHz,CD3OD):δ8.04(s,1H),7.80(s,1H),4.82-4.73(m,1H),3.65-3.59(m,2H),3.56-3.51(m,2H),3.36-3.33(m,2H),3.19-3.14(m,2H),2.69-2.55(m,4H),2.38-2.32(m,8H),1.22(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.04(s,1H),7.80(s,1H),4.82-4.73(m,1H),3.65-3.59(m,2H),3.56-3.51(m ,2H),3.36-3.33(m,2H),3.19-3.14(m,2H),2.69-2.55(m,4H),2.38-2.32(m,8H),1.22(t,J＝7.2Hz,3H ).
实施例42Embodiment 42
(1s,4s)-4-(5-氯-4-((4-(2-甲氧基乙氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(2-methoxyethoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法四，用乙二醇单甲醚替换中间体4-b，在步骤二中用氢化钠替换N,N-二异丙基乙胺，获得标题化合物。According to implementation method 4, ethylene glycol monomethyl ether is used to replace intermediate 4-b, and sodium hydride is used to replace N,N-diisopropylethylamine in step 2 to obtain the title compound.
LC_MS:(ES+):m/z 497.05[M+H]+.LC_MS:(ES + ):m/z 497.05[M+H] + .
1H NMR(400MHz,CD3OD):δ8.32(s,1H),7.85(s,1H),4.83-4.76(m,1H),4.62-4.48(m,2H),3.74-3.73(m,2H),3.56-3.55(m,2H),3.39-3.36(m,5H),3.19-3.14(m,2H),2.65-2.55(m,2H),2.37-2.32(m,2H),1.22(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.32(s,1H),7.85(s,1H),4.83-4.76(m,1H),4.62-4.48(m,2H),3.74-3.73(m ,2H),3.56-3.55(m,2H),3.39-3.36(m,5H),3.19-3.14(m,2H),2.65-2.55(m,2H),2.37-2.32(m,2H),1.22 (t,J＝7.2Hz,3H).
实施例43Embodiment 43
(1s,4s)-4-(5-氯-4-((4-(吡咯烷-3-基氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(pyrrolidin-3-yloxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用1-Boc-3-羟基吡咯烷替换中间体1-e，用片段Amine-3替换片段Amine-2，经脱保护后获得标题化合物。According to implementation method 1, intermediate 1-e is replaced by 1-Boc-3-hydroxypyrrolidine, and fragment Amine-2 is replaced by fragment Amine-3, and the title compound is obtained after deprotection.
LC_MS:(ES+):m/z 508.15[M+H]+.LC_MS:(ES + ):m/z 508.15[M+H] + .
1H NMR(400MHz,CDCl3):δ8.35–8.26(m,1H),8.03(s,1H),5.28(td,J＝4.3,0.7Hz,1H),4.62(s,1H),4.11(ddd,J＝18.1,11.8,5.5Hz,1H),3.63–3.51(m,6H),3.10(d,J＝7.3Hz,3H),2.62–2.47(m,2H),2.36(ddd,J＝14.1,6.6,2.3Hz,2H),2.28(t,J＝7.5Hz,2H),2.17–2.12(m,2H),1.98–1.91(m,3H). 1 H NMR (400MHz, CDCl 3 ): δ8.35–8.26 (m, 1H), 8.03 (s, 1H), 5.28 (td, J = 4.3, 0.7Hz, 1H), 4.62 (s, 1H), 4.11 (ddd,J＝18.1,11.8,5.5Hz,1H),3.63–3.51(m,6H),3.10(d,J＝7.3Hz,3H),2.62–2.47(m,2H),2.36(ddd,J ＝14.1,6.6,2.3Hz,2H),2.28(t,J＝7.5Hz,2H),2.17–2.12(m,2H),1.98–1.91(m,3H).
实施例44Embodiment 44
(1s,4s)-4-(4-((4-(((1s,4s)-4-氨基环己基)甲氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-5-氯-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-((4-(((1s,4s)-4-aminocyclohexyl)methoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-chloro-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用顺式-(4-羟甲基)环己基氨基甲酸叔丁酯替换中间体1-e，用片段Amine-3替换片段Amine-2，经脱保护后获得标题化合物。According to implementation method 1, intermediate 1-e is replaced by tert-butyl cis-(4-hydroxymethyl)cyclohexylcarbamate, and fragment Amine-2 is replaced by fragment Amine-3, and the title compound is obtained after deprotection.
LC_MS:(ES+):m/z 550.20[M+H]+.LC_MS:(ES + ):m/z 550.20[M+H] + .
1H NMR(400MHz,CDCl3):δ11.94(s,1H),8.44(m,2H),8.32(s,1H),7.96(s,1H),4.70(m,1H),4.35(dd,J＝8.2,5.0Hz,2H),3.69(dd,J＝19.1,12.4Hz,2H),3.47(dd,J＝9.3,4.6Hz,2H),3.21(dd,J＝13.9,6.9Hz,2H),3.12(m,3H),2.67–2.55(m,2H),2.47(dd,J＝8.7,8.0Hz,2H),2.06–1.96(m,4H),1.83(dd,J＝9.7,5.8Hz,2H),1.71(m,3H). 1 H NMR (400 MHz, CDCl 3 ): δ11.94(s,1H),8.44(m,2H),8.32(s,1H),7.96(s,1H),4.70(m,1H),4.35(dd,J＝8.2,5.0Hz,2H),3.69(dd,J＝19.1,12.4Hz,2H),3.47(dd,J＝9.3,4.6 Hz,2H),3.21(dd,J＝13.9,6.9Hz,2H),3.12(m,3H),2.67–2.55(m,2H),2.47(dd,J＝8.7,8.0Hz,2H),2.06–1.96(m,4H),1.83(dd,J＝9.7,5.8Hz,2H),1.71(m ,3H).
实施例45Embodiment 45
(1s,4s)-4-(4-((4-(((1r,4r)-4-氨基环己基)甲氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-5-氯-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(4-((4-(((1r,4r)-4-aminocyclohexyl)methoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-chloro-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法一，用反式-(4-羟甲基)环己基氨基甲酸叔丁酯替换中间体1-e，用片段Amine-3替换片段Amine-2，经脱保护后获得标题化合物。According to implementation method 1, intermediate 1-e is replaced by trans-(4-hydroxymethyl)cyclohexylcarbamic acid tert-butyl ester, and fragment Amine-2 is replaced by fragment Amine-3, and the title compound is obtained after deprotection.
LC_MS:(ES+):m/z 550.20[M+H]+.LC_MS:(ES + ):m/z 550.20[M+H] + .
1H NMR(400MHz,CDCl3):δ11.97(s,1H),8.53–8.39(m,2H),8.35(s,1H),7.98(d,J＝1.1Hz,1H),4.80–4.64(m,1H),4.22(d,J＝4.8Hz,2H),3.76–3.63(m,2H),3.60–3.36(m,2H),3.22(dd,J＝14.3,7.1Hz,2H),3.12(m,3H),2.70–2.56(m,2H),2.47(dd,J＝13.0,7.0Hz,2H),2.11–1.98(m,4H),1.91(d,J＝15.9Hz,2H),1.70–1.56(m,3H). 1 H NMR (400 MHz, CDCl 3 ): δ11.97(s,1H),8.53–8.39(m,2H),8.35(s,1H),7.98(d,J＝1.1Hz,1H),4.80–4.64(m,1H),4.22(d,J＝4.8Hz,2H),3.76–3.63(m,2H),3.60–3.36(m, 2H),3.22(dd,J＝14.3,7.1Hz,2H),3.12(m,3H),2.70–2.56(m,2H),2.47(dd,J＝13.0,7.0Hz,2H),2.11–1.98(m,4H),1.91(d,J＝15.9Hz,2H),1.70–1.56 (m,3H).
实施例46Embodiment 46
(1s,4s)-4-(5-氯-4-((4-((4-羟基双环[2.2.2]辛-1-基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((4-hydroxybicyclo[2.2.2]oct-1-yl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法四，用4-氨基双环[2.2.2]-1-辛醇盐酸盐替换中间体4-b，获得标题化合物。According to Embodiment 4, 4-aminobicyclo[2.2.2]-1-octanol hydrochloride was used to replace intermediate 4-b to obtain the title compound.
LC_MS:(ES+):m/z 562.20[M+H]+.LC_MS:(ES + ):m/z 562.20[M+H] + .
1H NMR(400MHz,CD3OD):δ8.04(s,1H),7.72(s,1H),4.86-4.31(m,1H),3.59-3.56(m,2H),3.41-3.36(m,2H),3.22-3.16(m,2H),2.7-261(m,2H),2.41-2.36(m,2H),2.09-2.06(m,6H),1.71(s,6H),1.24(t,J＝8.0Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.04(s,1H),7.72(s,1H),4.86-4.31(m,1H),3.59-3.56(m,2H),3.41-3.36(m ,2H),3.22-3.16(m,2H),2.7-261(m,2H),2.41-2.36(m,2H),2.09-2.06(m,6H),1.71(s,6H),1.24(t ,J＝8.0Hz,3H).
实施例47Embodiment 47
(1s,4s)-4-(5-氯-4-((5-氯-4-((((1r,4R)-4-羟基-4-甲基环己基)氧基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((5-chloro-4-((((1r,4R)-4-hydroxy-4-methylcyclohexyl)oxy)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法三，用2,4,5-三氯嘧啶替换起始原料3-a，用中间体1-d替换中间体3-b，用片段Amine-3替换片段Amine-2，获得标题化合物。According to implementation method three, the starting material 3-a is replaced by 2,4,5-trichloropyrimidine, the intermediate 3-b is replaced by the intermediate 1-d, and the fragment Amine-2 is replaced by the fragment Amine-3 to obtain the title compound.
LC_MS:(ES+):m/z 517.00[M+H]+. LC_MS:(ES + ):m/z 517.00[M+H] + .
1H NMR(400MHz,CD3OD):δ8.07(s,1H),7.82(s,1H),5.29(brs,1H),4.83-4.79(m,1H),3.60-3.57(m,2H),3.43-3.36(m,2H),3.23-3.17(m,2H),2.67-2.58(m,2H),2.40-2.34(m,2H),2.05-1.98(m,2H),1.84-1.74(m,4H),1.59-1.53(m,2H),1.27-1.23(m,6H). 1 H NMR (400MHz, CD 3 OD): δ8.07(s,1H),7.82(s,1H),5.29(brs,1H),4.83-4.79(m,1H),3.60-3.57(m,2H ),3.43-3.36(m,2H),3.23-3.17(m,2H),2.67-2.58(m,2H),2.40-2.34(m,2H),2.05-1.98(m,2H),1.84-1.74 (m,4H),1.59-1.53(m,2H),1.27-1.23(m,6H).
实施例48Embodiment 48
(1s,4s)-4-(5-氯-4-((4-((4-羟基环己基)甲氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((4-hydroxycyclohexyl)methoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法四，用4-(羟甲基)环己醇替换中间体4-b，在步骤二中用氢化钠替换N,N-二异丙基乙胺，获得标题化合物。According to implementation method 4, 4-(hydroxymethyl)cyclohexanol is used to replace intermediate 4-b, and sodium hydride is used to replace N,N-diisopropylethylamine in step 2 to obtain the title compound.
LC_MS:(ES+):m/z 551.15[M+H]+.LC_MS:(ES + ):m/z 551.15[M+H] + .
1H NMR(400MHz,CD3OD):δ8.32(s,1H),7.87(s,1H),4.85-4.78(m,1H),4.32-4.19(m,2H),3.58-3.48(m,3H),3.39-3.35(m,2H),3.21-3.16(m,2H),2.67-2.58(m,2H),2.39-2.31(m,2H),2.02-1.75(m,5H),1.62-1.58(m,1H),1.31-1.22(m,6H). 1 H NMR (400MHz, CD 3 OD): δ8.32(s,1H),7.87(s,1H),4.85-4.78(m,1H),4.32-4.19(m,2H),3.58-3.48(m ,3H),3.39-3.35(m,2H),3.21-3.16(m,2H),2.67-2.58(m,2H),2.39-2.31(m,2H),2.02-1.75(m,5H),1.62 -1.58(m,1H),1.31-1.22(m,6H).
实施例49Embodiment 49
(1s,4s)-4-(5-氯-4-((4-(哌啶-4-基甲氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-(piperidin-4-ylmethoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法四，用N-Boc-4-哌啶甲醇替换中间体4-b，在步骤二中用氢化钠替换N,N-二异丙基乙胺，经脱保护后获得标题化合物。According to implementation method 4, intermediate 4-b is replaced by N-Boc-4-piperidinemethanol, and N,N-diisopropylethylamine is replaced by sodium hydride in step 2, and the title compound is obtained after deprotection.
LC_MS:(ES+):m/z 536.50[M+H]+.LC_MS:(ES + ):m/z 536.50[M+H] + .
1H NMR(400MHz,CD3OD):δ8.37(s,1H),7.95-7.85(m,1H),4.86-4.80(m,1H),4.44-4.34(m,2H),3.59-3.65(m,2H),3.49-3.45(m,2H),3.42-3.38(m,2H),3.23-3.17(m,2H),3.09-2.98(m,2H),2.68-2.58(m,2H),2.40-2.36(m,2H),2.24-2.17(m,1H),2.06-2.03(m,2H),1.64-1.61(m,2H),1.25(t,J＝14.4Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.37(s,1H),7.95-7.85(m,1H),4.86-4.80(m,1H),4.44-4.34(m,2H),3.59-3.65 (m,2H),3.49-3.45(m,2H),3.42-3.38(m,2H),3.23-3.17(m,2H),3.09-2.98(m,2H),2.68-2.58(m,2H) ,2.40-2.36(m,2H),2.24-2.17(m,1H),2.06-2.03(m,2H),1.64-1.61(m,2H),1.25(t,J＝14.4Hz,3H).
实施例50Embodiment 50
(1s,4s)-4-(5-氯-4-((4-((1-甲基哌啶-4-基)甲氧基)-5-(三氟甲基)嘧啶-2-基)氨基)-1H-吡唑-1-基)-1-(乙基亚氨基)六氢-1λ6-噻喃1-氧化物
(1s,4s)-4-(5-chloro-4-((4-((1-methylpiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-1-(ethylimino)hexahydro-1λ 6 -thiopyran 1-oxide
按实施方法四，用1-甲基-4-哌啶甲醇替换中间体4-b，在步骤二中用氢化钠替换N,N-二异丙基乙胺，获得标题化合物。According to implementation method 4, 1-methyl-4-piperidinol is used to replace intermediate 4-b, and sodium hydride is used to replace N,N-diisopropylethylamine in step 2 to obtain the title compound.
LC_MS:(ES+):m/z 550.35[M+H]+. LC_MS:(ES + ):m/z 550.35[M+H] + .
1H NMR(400MHz,CD3OD):δ8.33(s,1H),7.91-7.86(m,1H),4.82-4.74(m,1H),4.41-4.31(m,2H),3.55-3.41(m,4H),3.36-3.34(m,2H),3.19-3.14(m,2H),2.95-2.89(m,2H),2.78(s,3H),2.61-2.58(m,2H),2.37-2.32(m,2H),2.05-1.94(m,3H),1.66-1.62(m,2H),1.22(t,J＝8.0Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.33(s,1H),7.91-7.86(m,1H),4.82-4.74(m,1H),4.41-4.31(m,2H),3.55-3.41 (m,4H),3.36-3.34(m,2H),3.19-3.14(m,2H),2.95-2.89(m,2H),2.78(s,3H),2.61-2.58(m,2H),2.37 -2.32(m,2H),2.05-1.94(m,3H),1.66-1.62(m,2H),1.22(t,J＝8.0Hz,3H).
实施例51Embodiment 51
(2-((5-氯-2-((5-氯-1-((1s,4s)-1-(乙基亚氨基)-1-氧化六氢-1λ6-噻喃-4-基)-1H-吡唑-4-基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦
(2-((5-chloro-2-((5-chloro-1-((1s,4s)-1-(ethylimino)-1-oxidohexahydro-1λ 6 -thiopyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
按实施方法三，用2,4,5-三氯嘧啶替换起始原料3-a，用(2-氨基苯基)二甲基氧化膦替换中间体3-b，用片段Amine-3替换片段Amine-2，获得标题化合物。LC_MS:(ES+):m/z 556.05[M+H]+.According to implementation method 3, the starting material 3-a was replaced by 2,4,5-trichloropyrimidine, the intermediate 3-b was replaced by (2-aminophenyl) dimethylphosphine oxide, and the fragment Amine-2 was replaced by the fragment Amine-3 to obtain the title compound. LC_MS: (ES + ): m/z 556.05 [M+H] + .
1H NMR(400MHz,CD3OD):δ8.38(s,1H),8.02(s,1H),7.69(s,1H),7.61-7.56(m,1H),7.50(t,J＝7.2Hz,1H),7.26-7.21(m,1H),4.79-4.72(m,1H),3.59-3.52(m,2H),3.38-3.34(m,2H),3.2-3.15(m,2H),2.64-2.54(m,2H),2.35-2.29(m,2H),1.84(d,J＝13.6Hz,6H),1.22(t,J＝6.8Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ8.38 (s, 1H), 8.02 (s, 1H), 7.69 (s, 1H), 7.61-7.56 (m, 1H), 7.50 (t, J = 7.2 Hz,1H),7.26-7.21(m,1H),4.79-4.72(m,1H),3.59-3.52(m,2H),3.38-3.34(m,2H),3.2-3.15(m,2H), 2.64-2.54(m,2H),2.35-2.29(m,2H),1.84(d,J＝13.6Hz,6H),1.22(t,J＝6.8Hz,3H).
实施例52：化合物在水和稀盐酸中溶解度的测定Example 52: Determination of the solubility of the compound in water and dilute hydrochloric acid
标准样品的配制：Preparation of standard samples:
将化合物溶解于乙腈(LCMS纯)中，配成如下浓度梯度标准样品：1000μg/mL，500μg/mL，250μg/mL，125μg/mL，62.5μg/mL，31.25μg/mL。The compound was dissolved in acetonitrile (LCMS pure) and prepared into the following concentration gradient standard samples: 1000 μg/mL, 500 μg/mL, 250 μg/mL, 125 μg/mL, 62.5 μg/mL, 31.25 μg/mL.
水中待测样品制备： Preparation of test samples in water:
称取待测物粉末1.0mg左右，加入0.3mL超纯水(pH～6)中，室温充分震荡过夜，离心，取上清，用乙腈稀释10倍。混合均匀后进样分析。Weigh about 1.0 mg of the powder of the substance to be tested, add it to 0.3 mL of ultrapure water (pH ~ 6), shake it thoroughly at room temperature overnight, centrifuge it, take the supernatant, dilute it 10 times with acetonitrile, mix it evenly, and then inject it for analysis.
稀盐酸中待测样品制备：Preparation of samples to be tested in dilute hydrochloric acid:
吸取153.8μL 6M HCl，加入20mL水，混匀制成稀盐酸溶液A(pH～1.5)。称取待测物粉末1.0mg左右，加入0.3mL稀盐酸溶液A，室温充分震荡1h，离心，取上清，用乙腈稀释10倍。混合均匀后进样分析。Take 153.8μL 6M HCl, add 20mL water, mix well to make dilute hydrochloric acid solution A (pH ~ 1.5). Weigh about 1.0mg of the powder of the substance to be tested, add 0.3mL of dilute hydrochloric acid solution A, shake thoroughly at room temperature for 1h, centrifuge, take the supernatant, and dilute 10 times with acetonitrile. Mix well and inject for analysis.
分析方法：Analytical methods:
将标准样品和待测样品用岛津LCMS-2020分析，色谱柱：Shim-pack GIST 5μm C18 2.1*50nm；流动相：A：水，B：甲醇；流速：0.3mL/min。B的梯度：0min:10％；0-1.0min:10％；1.0-2.5min:95％；3.0-4.0min:95％；4.0-4.1min:10％；4.1-6.0min:10％。The standard sample and the sample to be tested were analyzed by Shimadzu LCMS-2020, chromatographic column: Shim-pack GIST 5μm C18 2.1*50nm; mobile phase: A: water, B: methanol; flow rate: 0.3mL/min. Gradient of B: 0min: 10%; 0-1.0min: 10%; 1.0-2.5min: 95%; 3.0-4.0min: 95%; 4.0-4.1min: 10%; 4.1-6.0min: 10%.
数据处理：Data processing:
将标准样品的浓度/峰面积的关系制成标准曲线，用此标准曲线定标待测样品的浓度。The relationship between the concentration and peak area of the standard sample is made into a standard curve, and the concentration of the sample to be tested is calibrated using this standard curve.
化合物溶解度＝待测样品的浓度×10Compound solubility = concentration of the sample to be tested × 10
在下表1提供了一些化合物的溶解度数据：The solubility data of some compounds are provided in Table 1 below:
表1化合物的溶解度数据
Table 1 Solubility data of compounds
由上述结果可知，本发明的化合物在水中具备良好的溶解度，在模拟胃酸的稀盐酸中的溶解度更好。It can be seen from the above results that the compound of the present invention has good solubility in water, and has even better solubility in dilute hydrochloric acid simulating gastric acid.
生物活性测试实施例： Biological activity test example:
生物测试实施例-1：LRRK2激酶活性抑制实验:Biological test example-1: LRRK2 kinase activity inhibition experiment:
采用ADP-Glo方法检测化合物对LRRK2激酶的活性抑制作用。化合物用1×激酶缓冲液稀释，3μL 1mM化合物DMSO储存液加入57μL 1×激酶缓冲液D，用1×激酶缓冲液5倍稀释化合物。取1μL激酶缓冲液稀释的化合物加入Greiner384孔板中，设置DMSO空白对照组和缓冲液背景组。用1×激酶缓冲液激酶溶液(激酶浓度滴定和S/N＝10确定激酶稀释比例)，加入2μL 2.5倍终浓度的激酶溶液，以1000g的转速离心孔板30秒，室温放置15分钟。在1×激酶缓冲液中配制2.5倍终浓度的ATP和激酶底物的混合溶液，加入2μL 2.5倍终浓度的ATP和激酶底物的混合溶液，开始反应。以1000g转速离心孔板30秒，密封孔板，室温放置1小时。加入5μL ADP-Glo试剂，室温下孵育40分钟；再加入10μL检测试剂，室温下孵育40分钟。在Biotek Synergy H1微孔板检测仪上检测发光信号值。换算抑制率％＝100-(化合物信号值-背景信号值)/(空白对照信号值-背景信号值)×100。剂量反应通过GraphPad 6.0 nonlinear regression curve log[inhibitor]vs.response—Variable slope(four parameters)拟合曲线得到IC50值。The ADP-Glo method was used to detect the inhibitory effect of the compound on the activity of LRRK2 kinase. The compound was diluted with 1× kinase buffer, 3μL of 1mM compound DMSO storage solution was added to 57μL 1× kinase buffer D, and the compound was diluted 5 times with 1× kinase buffer. 1μL of the compound diluted with kinase buffer was added to the Greiner 384-well plate, and a DMSO blank control group and a buffer background group were set up. Use 1× kinase buffer kinase solution (kinase concentration titration and S/N=10 to determine the kinase dilution ratio), add 2μL of 2.5 times the final concentration of kinase solution, centrifuge the plate at 1000g for 30 seconds, and place at room temperature for 15 minutes. Prepare a mixed solution of ATP and kinase substrate at 2.5 times the final concentration in 1× kinase buffer, add 2μL of 2.5 times the final concentration of ATP and kinase substrate, and start the reaction. Centrifuge the plate at 1000g for 30 seconds, seal the plate, and place at room temperature for 1 hour. Add 5 μL ADP-Glo reagent and incubate at room temperature for 40 minutes; then add 10 μL detection reagent and incubate at room temperature for 40 minutes. Detect the luminescent signal value on the Biotek Synergy H1 microplate reader. Conversion inhibition rate % = 100-(compound signal value-background signal value)/(blank control signal value-background signal value) × 100. The dose response was obtained by fitting the curve of GraphPad 6.0 nonlinear regression curve log[inhibitor]vs.response—Variable slope(four parameters) to obtain the IC 50 value.
在下表2中提供了一些化合物在LRRK2激酶活性测定中的IC50区间：(IC50区间：A<0.1μM；B:0.1-0.5μM；C:>0.5μM)：The IC 50 ranges of some compounds in the LRRK2 kinase activity assay are provided in Table 2 below: (IC 50 ranges: A < 0.1 μM; B: 0.1-0.5 μM; C: > 0.5 μM):
表2化合物的LRRK2激酶活性测定中的IC50

Table 2 IC 50 of compounds in LRRK2 kinase activity assay

生物测试实施例-2：细胞中内源性磷酸化LRRK2(S935)的抑制率检测Biological test example-2: Inhibition rate detection of endogenous phosphorylated LRRK2 (S935) in cells
LRRK2高表达的A549细胞按1×10^6细胞/毫升的密度重悬于无血清的1640培养基中，每孔1毫升接种于12孔板中，37℃，5％二氧化碳条件下培养6-8小时。加入1微升化合物的DMSO储存液或DMSO(体积比为0.1％)，混匀，37℃，5％二氧化碳条件下培养15小时。收集细胞，每个样品加入50μL RIPA III裂解液冰上裂解细胞15分钟，4℃13000rpm离心30分钟，取上清，BCA测细胞裂解液浓度，所有样品浓度归一化。加入5×上样缓冲液，95℃10分钟。WB检测内源性LRRK2磷酸化S935的含量，磷酸化LRRK2(S935)抗体为Abcam#133450。Image J统计磷酸化LRRK2(S935)信号强度，用beta actin来归一样品中磷酸化LRRK2(S935)信号，数据分析。A549 cells with high expression of LRRK2 were resuspended in serum-free 1640 medium at a density of 1×10^6 cells/ml, and 1 ml was inoculated in each well of a 12-well plate and cultured at 37°C, 5% carbon dioxide for 6-8 hours. 1 μL of compound DMSO storage solution or DMSO (volume ratio of 0.1%) was added, mixed, and cultured at 37°C, 5% carbon dioxide for 15 hours. Cells were collected, and 50 μL RIPA III lysis buffer was added to each sample to lyse the cells on ice for 15 minutes, centrifuged at 4°C, 13000 rpm for 30 minutes, and the supernatant was taken. The concentration of cell lysate was measured by BCA, and the concentration of all samples was normalized. 5× loading buffer was added and 95°C for 10 minutes. WB was used to detect the content of endogenous LRRK2 phosphorylated S935. The phosphorylated LRRK2 (S935) antibody was Abcam#133450. Image J was used to count the signal intensity of phosphorylated LRRK2 (S935), and beta-actin was used to normalize the phosphorylated LRRK2 (S935) signal in the sample for data analysis.
下表3中提供了一些化合物在10μM浓度下对细胞中LRRK2(S935)活性的抑制率：Table 3 below provides the inhibition rates of some compounds on LRRK2 (S935) activity in cells at a concentration of 10 μM:
(区间：A>80％；B:40-80％；C:<40％；)(Interval: A>80%; B:40-80%; C:<40%;)
表3化合物对LRRK2(S935)活性的抑制率

Table 3 Inhibition rate of compounds on LRRK2 (S935) activity

下表4中提供了一些化合物在细胞中LRRK2(S935)的抑制活性IC50区间：(IC50区间：A<0.1μM；B:0.1-0.5μM；C:>0.5μM)Table 4 below provides the IC 50 ranges of the inhibitory activity of some compounds on LRRK2 (S935) in cells: (IC 50 range: A < 0.1 μM; B: 0.1-0.5 μM; C: > 0.5 μM)
表4化合物在细胞中对LRRK2(S935)的抑制活性IC50

Table 4 Inhibitory activity of compounds on LRRK2 (S935) in cells IC 50

出于清楚和理解的目的,已经通过说明和示例的方式详细描述了前述公开。对于本领域技术人员而言显而易见的是,可以在所附申请专利范围的范围内实施改变和修改。因此,应该理解的是,以上描述旨在是说明性的而非限制性的。所以,本公开的范围不应参照以上描述来确定,而应该参照所附申请专利范围以及这些申请专利范围有权要求的等效物的全部范围来确定。 For the purpose of clarity and understanding, the foregoing disclosure has been described in detail by way of illustration and example. It will be apparent to those skilled in the art that changes and modifications may be implemented within the scope of the appended claims. Therefore, it should be understood that the above description is intended to be illustrative rather than restrictive. Therefore, the scope of the present disclosure should not be determined with reference to the above description, but should be determined with reference to the appended claims and the full scope of equivalents to which these claims are entitled.

Claims (10)

  1. 式(I)化合物，或其立体异构体、互变异构体或药学上可接受的盐：
    A compound of formula (I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
    其中，in,
    A选自任选取代的C1～6烷基、C3～8环烷基、C6～14芳基、5～12元杂芳基、3～8元杂环基、5～18元桥环基或5～18元螺环基，其中所述取代基选自氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、3～8元杂环基、C1～4烷基磷酰基、C1～4烷基磺酰基、氰基、羟基、氧代、巯基、氨基和卤素；A is selected from optionally substituted C1-6 alkyl, C3-8 cycloalkyl, C6-14 aryl, 5-12 membered heteroaryl, 3-8 membered heterocyclyl, 5-18 membered bridged ring group or 5-18 membered spirocyclyl, wherein the substituent is selected from deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, 3-8 membered heterocyclyl, C1-4 alkylphosphoryl, C1-4 alkylsulfonyl, cyano, hydroxy, oxo, mercapto, amino and halogen;
    L表示不存在(共价键)、-O-、-NH-、-N(C1～4烷基)-、-S-、-S(O)-或者-S(O)2-；L represents absence (covalent bond), -O-, -NH-, -N(C 1-4 alkyl)-, -S-, -S(O)-, or -S(O) 2 -;
    R1是氢，或者是取代或未取代的C1～4烷基、C3～6环烷基，其中所述取代基选自氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、氧代、氰基、羟基、氨基、二甲氨基、羟胺基、卤素； R1 is hydrogen, or substituted or unsubstituted C1-4 alkyl, C3-6 cycloalkyl, wherein the substituent is selected from deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, oxo, cyano, hydroxyl, amino, dimethylamino, hydroxylamino, halogen;
    R2和R3各自独立地选自氢、氘、C1～4烷基、C1～10烷氧基、C3～6环烷基、3～8元杂环基、氰基、羟基和卤素； R2 and R3 are each independently selected from hydrogen, deuterium, C1-4 alkyl, C1-10 alkoxy, C3-6 cycloalkyl, 3-8 membered heterocyclic group, cyano, hydroxyl and halogen;
    Ra选自氢、氨基、三氟甲基、卤素、氰基、C1～3烷基、乙酰基、C1～3烷基磷酰基和C1～3烷基磺酰基；Ra is selected from hydrogen, amino, trifluoromethyl, halogen, cyano, C 1-3 alkyl, acetyl, C 1-3 alkylphosphoryl and C 1-3 alkylsulfonyl;
    Rb选自氢、氨基和C1～3烷基氨基；Rb is selected from hydrogen, amino and C 1-3 alkylamino;
    或者，Ra、Rb和它们所连接的C原子一起形成5～6元芳环、5～8元杂芳环或5～8元杂环；Alternatively, Ra, Rb and the C atom to which they are attached together form a 5- to 6-membered aromatic ring, a 5- to 8-membered heteroaromatic ring or a 5- to 8-membered heterocyclic ring;
    n选自0、1和2。n is selected from 0, 1 and 2.
  2. 根据权利要求1所述的式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐，其中所述式(I)化合物具有式(II)所示的结构：
    The compound of formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (I) has the structure shown in formula (II):
    其中，A、L、R1、R2、R3、Ra和n具有如权利要求1中所述的定义。wherein A, L, R 1 , R 2 , R 3 , Ra and n have the same meanings as defined in claim 1.
  3. 根据权利要求1所述的式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐，其中所述式(I)化合物具有式(III)所示的结构：
    The compound of formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (I) has the structure shown in formula (III):
    其中，A、L、R1、R2、R3和n具有如权利要求1中所述的定义，X、Y各自独立地选自C和N，表示双键或者单键。wherein A, L, R 1 , R 2 , R 3 and n are as defined in claim 1, X and Y are each independently selected from C and N, Indicates a double bond or a single bond.
  4. 根据权利要求1-3中任一项所述的化合物或其立体异构体、互变异构体或药学上可接受的盐，其中A选自以下结构：
    The compound according to any one of claims 1 to 3 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein A is selected from the following structures:
  5. 根据权利要求1-4中任一项所述的化合物或其立体异构体、互变异构体或药学上可接受的盐，其中L选自-O-和-NH-。The compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein L is selected from -O- and -NH-.
  6. 根据权利要求1-5中任一项所述的化合物或其立体异构体、互变异构体或药学上可接受的盐，其中所述化合物选自：





    The compound according to any one of claims 1 to 5 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein the compound is selected from:





  7. 一种药物组合物，其包含权利要求1至6中任一项所述的化合物或其立体异构体、互变异构体或药学上可接受的盐，以及任选的可药用载体。A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer or pharmaceutically acceptable salt, and optionally a pharmaceutically acceptable carrier.
  8. 根据权利要求1至7中任一项所述的化合物或其立体异构体、互变异构体或药学上可接受的盐在制备用作LRRK2蛋白激酶抑制剂的药物中的应用。 Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer or pharmaceutically acceptable salt in the preparation of a medicament for use as an LRRK2 protein kinase inhibitor.
  9. 根据权利要求1至7中任一项所述的化合物或其立体异构体、互变异构体或药学上可接受的盐在制备用于治疗或预防LRRK2蛋白激酶相关疾病的药物中的应用。Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer or pharmaceutically acceptable salt in the preparation of a medicament for treating or preventing LRRK2 protein kinase-related diseases.
  10. 根据权利要求9所述的应用，其中所述LRRK2蛋白激酶相关疾病选自神经退行性疾病、免疫相关疾病和癌症，优选地，所述疾病选自帕金森病、阿尔茨海默病、亨廷顿病、克罗恩病、炎症性肠病、结肠炎、结核病、麻风病、黑色素瘤、非黑色素瘤皮肤癌和乳腺癌。 The use according to claim 9, wherein the LRRK2 protein kinase-related disease is selected from neurodegenerative diseases, immune-related diseases and cancer, preferably, the disease is selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, Crohn's disease, inflammatory bowel disease, colitis, tuberculosis, leprosy, melanoma, non-melanoma skin cancer and breast cancer.
PCT/CN2024/078490 2023-02-27 2024-02-26 Sulfoximine compounds and application thereof as lrrk2 protein kinase inhibitors WO2024179393A1 (en)

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