WO2024169858A1 - Six-membered nitrogen heterocyclic compound and use thereof - Google Patents

Six-membered nitrogen heterocyclic compound and use thereof Download PDF

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Publication number
WO2024169858A1
WO2024169858A1 PCT/CN2024/076641 CN2024076641W WO2024169858A1 WO 2024169858 A1 WO2024169858 A1 WO 2024169858A1 CN 2024076641 W CN2024076641 W CN 2024076641W WO 2024169858 A1 WO2024169858 A1 WO 2024169858A1
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membered
alkyl
deuterium
deuterated
substituents
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PCT/CN2024/076641
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French (fr)
Chinese (zh)
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陈俐娟
贾涛
王太津
李钢
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成都赜灵生物医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of chemical medicine and relates to a class of six-membered nitrogen heterocyclic compounds and uses thereof.
  • Inflammasomes are a class of protein complexes that can recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) in cells.
  • PAMPs pathogen-associated molecular patterns
  • DAMPs damage-associated molecular patterns
  • the assembly of inflammasomes triggers proteolysis, cleaving dormant procaspase-1 into active caspase-1, converting cytokine precursors pro-IL-1 ⁇ and pro-IL-18 into mature, biologically active IL-1 ⁇ and IL-18, respectively, and regulating the expression of inflammation-related genes to produce various biological effects.
  • As a receptor of the body's innate immunity, inflammasome activation can resist pathogen infection and stress injury, but its uncontrolled activation can also cause amplification of inflammatory effects and organ damage.
  • NOD nucleotide-binding oligomerization domain
  • NLRP3 pyrin domain-containing protein 3
  • the NLRP3 inflammasome is composed of a sensor (NLRP3), an adapter (ASC, also known as PYCARD), and an effector (caspase 1).
  • Classic NLRP3 inflammasome activation is activated by two signals co-stimulated. The first signal activates the TLR4 (Toll-like receptor 4) signaling pathway, promotes the nuclear entry of NF- ⁇ B, induces the production of precursors such as IL-1 ⁇ and IL-18, and induces post-translational modification of NLRP3.
  • TLR4 Toll-like receptor 4
  • the second signal promotes the formation of the NLRP3/ASC/pro-caspase-1 complex, that is, when activated, it aggregates with apoptosis-associated specklike protein (ASC) containing a caspase activation and recruitment domain. ASC then interacts with cysteine protease caspase-1 to form a complex called inflammasome.
  • ASC apoptosis-associated specklike protein
  • the pro-caspase (pro-caspase-1) is self-cleaved into an activated form. 2
  • the activated caspase-1 cleaves the pro-inflammatory cytokines IL-1 ⁇ and IL-18, converting them into active forms of IL-1 ⁇ and IL-18 and releasing them into the extracellular space, recruiting inflammatory cells to aggregate and amplifying the inflammatory response.
  • ASC speck-like protein can also recruit and activate caspase-8, cleaving the pro-forms of IL- ⁇ and IL-18 to convert them into mature forms and trigger cell pyroptosis.
  • Non-classical NLRP3 inflammasome activation is independent of TLR4 signaling pathway activation. It is initiated by caspase-11 directly recognizing intracellular LPS, initiating NLRP3 inflammasome activation, promoting the activation and release of Gasdermin D, and thus mediating cell death.
  • Abnormal activation of NLRP3 is associated with many diseases, including inflammasome-related diseases, immunological diseases, inflammatory diseases, nervous system diseases, autoimmune diseases and/or autoinflammatory diseases, cancer, chronic metabolic diseases, etc. diseases and neurological related diseases.
  • cryptopyrin-associated periodic syndrome CACS
  • Muckle-Wells syndrome MFS
  • familial cold autoinflammatory syndrome FCAS
  • NOMID neonatal-onset multisystem inflammatory disease
  • FMF familial Mediterranean fever
  • non-alcoholic steatohepatitis alcoholic liver disease
  • graft-versus-host disease multiple sclerosis (MS), rheumatoid arthritis, type I/type II diabetes and related complications (such as nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial
  • the present invention develops a class of six-membered nitrogen heterocyclic compounds, which can be used to treat NLRP3-related diseases.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable form thereof, wherein the structure of formula I is as follows:
  • X is selected from NR 7a
  • Y is selected from C( ⁇ O);
  • X is independently selected from CR 7b or N, and Y is selected from N;
  • R2 and R3 , R3 and R4 , or R4 and R5 together with the atoms to which they are attached form a group substituted with 0 to 6 a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle or a 5-6 membered heteroaromatic ring substituted with a substituent selected from the group consisting of deuterium, halogen, -OH, -NH2 , -CN, oxo, C1-6 alkyl, C1-6 fluoroalkyl, C1-6 deuterated alkyl, -OC1-6 alkyl, -OC1-6 fluoroalkyl, -OC1-6 deuterated alkyl, C3-6 cycloalkyl, C3-6 fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-6 membered cycloalkyl; when R2 and R3 , R3 and R4 , or R4
  • L (the left end is connected to the azine ring, and the right end is connected to R 6 ) is selected from -(CH 2 ) n1 -, O, -(CH 2 ) n1 -NH-, -NH-(CH 2 ) n1 -, -NH-CH(CH 2 ) n1 (CH 3 )-, and n1 is an integer selected from 0-3;
  • R 8a and R 8b are independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: C 1-4 alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, 3-6-membered cycloalkylmethylene or 4-6-membered heterocycloalkylmethylene; in R 8a and R 8b , the substituents are selected from deuterium, halogen, -N(R 10a R 10b ), -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 deuterated alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 3-6-membered cycloalkylmethylene or 4-6-membered heterocycloalkylmethylene; R 8a , R In 8b , the 4-6 membered heterocycloal
  • R 8a and R 8b and the atoms to which they are attached form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents; when R 8a and R 8b and the atoms to which they are attached form a ring, the substituents are selected from: deuterium, halogen, -N(R 11a R 11b ), -OH, -CN, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl; when R 8a and R 8b and the atoms to which they are attached form a ring, the 3-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S and O, and the 4-6 membered heterocycloalkyl in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S and O;
  • R 7a is selected from hydrogen or the following groups optionally substituted by 0-6 substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 7a , the substituent is selected from: hydrogen, deuterium, halogen, -OH, -NH 2 or -CN; in R 7a , the 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O;
  • R 7b is selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OR 9a , -COR 9a , -COOR 9a , -CONHR 9a , -CON(R 9b R 9c ), -N(R 9b R 9c ), -NR 9a COR 9b , -SO 2 R 9a or the following groups optionally substituted by 0-6 substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 7b , the substituent is selected from: hydrogen, deuterium, halogen, -OH, -NH 2 or -CN; in R 7b , the 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl contains 1 to 3 heteroatoms selected from
  • R 9a , R 9b and R 9c are independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 9a , R 9b and R 9c , the substituent is selected from: deuterium, halogen, -OH, -NH 2 or CN; in R 9a , R 9b and R 9c , the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S and O;
  • R 10a , R 10b , R 11a and R 11b are independently selected from hydrogen or C 1-4 alkyl
  • the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotopically labeled substances, metabolites or prodrugs.
  • R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-6 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, wherein the substituents are selected from deuterium, halogen, -OH, -NH 2 or -CN.
  • R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, F, Cl, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, 3-6 membered cycloalkyl, wherein the substituents are selected from: deuterium, F, Cl, -OH, -NH 2 or -CN.
  • R1 , R2 , R4 and R5 are independently selected from hydrogen, deuterium, F, Cl, -OH, -CH3 , fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.
  • R 3 is selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted by 0-6 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 3 , the substituent is selected from: deuterium, halogen, -OH, -NH 2 , -CN, -CF 3 or cyclopropyl; in R 3 , the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O.
  • R 3 is selected from hydrogen, deuterium, F, Cl, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 3 , the substituent is selected from: deuterium, F, Cl, -OH, -NH 2 , -CF 3 , -CN or cyclopropyl; in R 3 , the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1 to 2 heteroatoms selected from at least one of N, S and O.
  • R3 is selected from hydrogen, deuterium, F, Cl, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl.
  • R2 and R3 , R3 and R4 , or R4 and R5 can form, together with the atoms to which they are connected, a 5-6-membered alkane ring, a benzene ring, a 5-6-membered alkane heterocycle, or a 5-6-membered heteroaromatic ring substituted with 0-6 substituents, wherein the substituents are selected from: deuterium, halogen, -OH, -NH2 , -CN, oxo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 deuterated alkyl, -OC1-4 alkyl, -O-fluoro C1-4 alkyl, -O-deuterated C1-4 alkyl, 3-6 -membered cycloalkyl or 3-6 -membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a
  • R2 and R3 , R3 and R4 , or R4 and R5 together with the atoms to which they are attached form a group substituted with 0-3 substituents.
  • the substituent is selected from: deuterium, F, Cl, -OH, -NH2 , -CN, oxo, C1-4 alkyl, C1-4 fluoroalkyl , C1-4 deuterated alkyl, -OC1-4 alkyl, -O-fluoro C1-4 alkyl , -O -deuterated C1-4 alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.
  • R2 and R3 or R3 and R4 together with the atoms to which they are attached form a group substituted with 0-3 substituents.
  • the substituent is selected from: deuterium, F, Cl, -OH, -NH2 , -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.
  • R 12 is selected from deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, -OC 1-4 alkyl , -OC 1-4 fluoroalkyl, -OC 1-4 deuterated alkyl, -SC 1-4 alkyl, -SC 1-4 fluoroalkyl, -SC 1-4 deuterated alkyl , 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl; n2 is selected from an integer of 0-6.
  • R12 is selected from: deuterium, F, Cl, -OH, -NH2 , -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl; n2 is selected from an integer of 0-3.
  • R 7a is selected from hydrogen or the following groups optionally substituted by 0-3 substituents: C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 7a , the substituents are selected from: hydrogen, deuterium, halogen, -OH, -NH 2 or -CN.
  • R 7b is selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OR 9a , -COR 9a , -COOR 9a , -CONHR 9a , -CON(R 9b R 9c ), -N(R 9b R 9c ), -SO 2 R 9a or the following groups optionally substituted with 0-3 substituents: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 9a , R 9b and R 9c are independently selected from hydrogen, deuterium or the following groups substituted with 0-3 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl;
  • R 7a is selected from hydrogen or C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, carboxyl, C 1-4 alkoxycarbonyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkoxy, Alkoxycarbonyl, C 1-4 deuterated alkoxycarbonyl, 3-6 membered cycloalkyl, 3-6 membered fluorinated cycloalkyl, phenyl, pyridyl or X1 and X2 are independently selected from CH, N; X3 is selected from NC1-4alkyl , NH, S, O.
  • R 7b is selected from hydrogen, deuterium, halogen, -NH 2 , -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, carboxyl, C 1-4 alkoxycarbonyl, C 1-4 fluoroalkoxycarbonyl, C 1-4 deuterated alkoxycarbonyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, phenyl, 6-membered nitrogen heteroaryl, -CONHR 9a ;
  • R 9a is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl;
  • X 4 and X 5 are independently selected from CH
  • R 7a is selected from hydrogen, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, pyridyl,
  • X1 is selected from N;
  • X2 is selected from CH, N;
  • X3 is selected from N-methyl, S, O.
  • L (the left end is connected to the azine ring, and the right end is connected to R 6 ) is selected from O, -NH-, -NH-CH 2 -, and -NH-CH(CH 3) -.
  • the substituent is selected from fluorine, chlorine, hydroxyl, cyano, oxo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 deuterated alkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, C1-4 deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino, dimethylamino,
  • R 6 is selected from the following structures:
  • R 13a and R 13b are independently selected from R 8a , halogen, oxo, —OR 8a , —SR 8a , —C( ⁇ O)R 8a , —OC( ⁇ O)R 8a , —C( ⁇ O)OR 8a , —C( ⁇ O)NR 8a R 8b , —NR 8a C( ⁇ O)R 8b , —NR 8a R 8b , —SO 2 R 8a , —SO 2 NR 8a R 8b , —NR 8a SO 2 R 8b , —CN; n3 is an integer of 0-6.
  • R 13a and R 13b are independently selected from fluorine, chlorine, hydroxyl, cyano, oxo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino, dimethylamino,
  • R 6 is selected from the following structures:
  • the present invention also provides some specific compounds, which are selected from:
  • R 3 in addition to the aforementioned R 3 being selected from hydrogen, deuterium, F, Cl, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl, R 3 can also be selected from propynyl, fluoropropynyl, cyclopropylalkynyl, pyridyl, fluoropyridyl, pyrimidinyl, fluoropyrimidinyl.
  • R6 in the compound represented by formula I, except for the aforementioned R 6 is selected from:
  • R6 can also be selected from the following structures:
  • R6 in the compound represented by formula I, except for the aforementioned R 6 is selected from:
  • R6 can also be selected from the following structures:
  • the present invention also provides some specific compounds, which are selected from:
  • R6 in the compound represented by formula I, except for the aforementioned R 6 is selected from: and R6 is selected from:
  • R6 can also be selected from the following structures:
  • the present invention also provides some specific compounds, which are selected from:
  • the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula I or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug as an active ingredient, supplemented with a pharmaceutically acceptable carrier.
  • a further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, the method comprising The invention relates to combining a compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (2005).
  • the pharmaceutical composition can be administered in any form as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient.
  • it can be prepared into various suitable dosage forms according to the administration route.
  • the administration of the compounds or pharmaceutical compositions of the present invention may be combined with another therapeutic method.
  • the other therapeutic method may be selected from, but not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.
  • the present invention also relates to a pharmaceutical preparation, which uses the above-mentioned compound of formula I or its pharmaceutically acceptable form, or a mixture thereof, or a pharmaceutical composition of the present invention as an active ingredient.
  • the preparation is in the form of a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • a further object of the present invention is to provide an article of manufacture, for example, in the form of a kit.
  • Articles of manufacture as used herein are intended to include, but are not limited to, kits and packages.
  • the article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent, the first therapeutic agent comprising: a compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.
  • the first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and/or individual/batch sales.
  • the first container is intended to cover bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing or dispensing pharmaceutical products.
  • the second container is a container for accommodating the first container and optional package instructions.
  • the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.
  • the package instructions may be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion means, or they may be placed inside the second container without any physical tool for adhesion to the first container.
  • the package instructions are located outside the second container. When located outside the second container, it is preferred that the package instructions are physically adhered via a cable tie, glue, staples, or other adhesion means. Alternatively, it may abut or contact the outside of the second container without physical adhesion.
  • the package insert is a trademark, label, indicia, etc., which lists information related to the pharmaceutical composition located in the first container.
  • the information listed is generally determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is to be sold.
  • the package insert specifically lists the indications for which the pharmaceutical composition is approved.
  • the package insert can be made of any material from which information contained therein or thereon can be read.
  • the package insert is a printable material (eg, paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (eg, printed or applied).
  • the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating NLRP3-related diseases.
  • the present invention provides a method for preventing or treating NLRP3-related diseases, comprising administering the compound of formula I or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of the present invention to an individual in need thereof.
  • the present invention provides a method for preventing or treating NLRP3-related diseases in combination with the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention and another treatment method, wherein the other treatment method includes but is not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.
  • the NLRP3-related disease includes: inflammatory disease, autoimmune disease, cardiovascular disease, cancer, renal disease, gastrointestinal disease, respiratory disease, endocrine disease or central nervous system disease.
  • the NLRP3-related diseases include: cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I/type II diabetes and related complications (e.g., nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, r
  • the compounds of the present invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat NLRP3-related diseases.
  • the present invention provides a class of six-membered nitrogen heterocyclic compounds, which can be used to prepare NLRP3 inflammasome inhibitors, providing a new approach for treating NLRP3-related diseases.
  • compositions comprising "a” pharmaceutically acceptable excipient can be interpreted as indicating that the composition includes “one or more” pharmaceutically acceptable excipients.
  • C 1-4 should be understood to cover any sub-ranges and each point value therein, such as C 2-4 , C 3-4 , C 1-2 , C 1-3 , C 1-4 , etc., as well as C 1 , C 2 , C 3 , C 4 , etc.
  • halogen means fluorine, chlorine, bromine or iodine.
  • alkyl includes a linear or branched monovalent saturated hydrocarbon group.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
  • C1-4 in “ C1-4 alkyl” refers to a group containing 1, 2, 3 or 4 carbon atoms arranged in a linear or branched form.
  • cycloalkyl refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group.
  • Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decalinyl, etc.
  • monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cycl
  • C 3-12 cycloalkyl refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12).
  • the cycloalkyl or cycloalkylene group in the present invention is optionally substituted by one or more substituents described in the present invention.
  • fluoroalkyl refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by fluorine atoms.
  • C 1-4 fluoroalkyl refers to a C 1-4 alkyl group optionally substituted by one or more (e.g., 1-3) fluorine atoms. It will be understood by those skilled in the art that when there are more than one fluorine atom substituents, the fluorine atoms may be the same or different, and may be located on the same or different C atoms.
  • haloalkyl groups include, for example, -CH 2 F, -CHF 2 , -CF 3 , -C 2 F 5 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , etc.
  • the fluoroalkyl group in the present invention is optionally substituted by one or more substituents described in the present invention.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 13C and 14C ); isotopes of chlorine (e.g., 37Cl); isotopes of iodine (e.g., 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 17O and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 34S ).
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H )
  • isotopes of carbon e.g., 13C and 14C
  • isotopes of chlorine e.g.
  • polymorph refers to different solid crystalline phases produced by the presence of two or more different molecular arrangements in the solid state of certain compounds of the present invention.
  • Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.
  • crystallization will produce a solvate of the compound of the present invention.
  • solvate used in the present invention refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules.
  • the solvent may be water, in which case the solvate is a hydrate.
  • the solvent may be an organic solvent.
  • the compound of the present invention may exist as a hydrate, including a single hydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, etc., and corresponding solvated forms.
  • the compound of the present invention may form a true solvate, but in some cases, it may also retain only adventitious water or a mixture of water plus a portion of an adventitious solvent.
  • the compound of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compound of the present invention are also included within the scope of the present invention.
  • the present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • stereoisomer means an isomer formed due to at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three, or four) asymmetric centers it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It is to be understood that the scope of the present invention encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
  • pharmaceutically acceptable salts include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts.
  • Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable acid addition salts” refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.
  • organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, thiazolyl salt, thiazolyl salt, oxalate ...
  • the invention relates to pharmaceutically acceptable base addition salts, such as succinate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc.
  • base addition salts such as succinate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, na
  • Salts derived from inorganic bases include but are not limited to sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc.
  • Preferred inorganic salts are ammonium salts, sodium salts, calcium salts and magnesium salts.
  • the salt derived from organic base includes but is not limited to the following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclo
  • esters refers to esters derived from the compounds described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • the compounds of the present invention themselves may also be esters.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • nitrogen-containing heterocycles are capable of forming nitrogen oxides.
  • nitrogen-containing heterocycles that are capable of forming nitrogen oxides.
  • tertiary amines are capable of forming nitrogen oxides.
  • the synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane.
  • peroxyacids such as peracetic acid and metachloroperbenzoic acid (mCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane such as dimethyl dioxirane.
  • metabolites refer to substances formed in the body when a compound of the present invention is administered. Metabolites can be identified by techniques known in the art, and their activity can be characterized by experimental methods. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with mammals for a period of time sufficient to produce their metabolites.
  • prodrug refers to certain derivatives of the compounds of the present invention that can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered into or onto the body.
  • prodrugs will be functional group derivatives of the compound that are easily converted into the desired therapeutically active compound in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain parts known to those skilled in the art as "pro-moieties” (e.g., as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).
  • pharmaceutical composition refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved or accepted by relevant governmental regulatory authorities for use in humans or livestock.
  • drug combination refers to drug treatments obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of the active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • non-fixed combination refers to the simultaneous administration, combined administration or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapies, for example the administration of three or more active ingredients.
  • tumor includes but is not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the lung, adenocarcinoma of the lung, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, rhinitis cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition, or preventing such disorder or condition. or one or more symptoms of such a disorder or condition.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, tetramethylsilane (TMS) as the internal standard, and chemical shifts are given in units of 10 -6 (ppm).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).
  • HPLC determinations were performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5wn, chromatographic column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150X 4.5mm, 5ym chromatographic column).
  • the thin layer chromatography silica gel plate used was Qingdao Ocean GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the thin layer chromatography separation and purification product used a 0.4mm-0.5mm silica gel plate.
  • the reactions were carried out under an argon atmosphere or a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 L.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and the operation is repeated 3 times.
  • Step 3 Add compound INT1c (15.0 g, 65.5 mmol) and K 2 CO 3 (18.1 g, 131 mmol) to MeCN (150 mL), then add Me 2 SO 4 (9.9 g, 78.6 mmol), and stir overnight at 60°C under nitrogen protection. Cool the reaction mixture to room temperature, filter, add silica gel (30 g) to the filtrate, then concentrate to dryness under reduced pressure, and separate by column chromatography.
  • Step 4 Compound INT1d (13.7 g, 56.4 mmol), bis-pinacol borate (17.2 g, 67.7 mmol), KOAc (11.1 g, 113 mmol) and Pd(PPh 3 )Cl 2 (2.00 g, 2.82 mmol) were added to dioxane (137 mL) and reacted at 90° C. for 12 h under nitrogen protection.
  • Step 3 Compound INT2c (3 g, 14.26 mmol) was placed in a three-necked flask, nitrogen was protected, anhydrous DMF (30 mL) was added, the reaction was placed in an ice bath, NaH (1.15 g, 28.79 mmol) was slowly added, and the reaction was restored to room temperature for 1 h after the addition, and then iodomethane (2.02 g, 14.26 mmol) was slowly added dropwise, and the reaction was allowed to proceed overnight at room temperature after the addition.
  • Step 1 Dissolve compound 3-bromo-2-hydroxybenzaldehyde INT3a (25.0 g, 104.65 mmol), CH 3 I (60.63 g, 373.14 mmol), K 2 CO 3 (34.38 g, 248.76 mmol) in DMF (200 mL), heat to 50°C and react for 3 hours. Add water to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent from the filtrate under reduced pressure to obtain the target compound INT3b (yellow oily liquid, 22.5 g, yield: 84%), without further purification, MS/ESI [M+H] + : 215.1.
  • Step 4 Compound INT3d (4.7 g, 19.50 mmol) and 2-(difluoromethanesulfonyl)pyridine INT3e (5.65 g, 29.25 mmol) were dissolved in DMF (30 mL), cooled to -50°C, and a DMF solution of potassium tert-butoxide was added under nitrogen protection, and the temperature was raised to -40°C. After reacting for 3 hours, a saturated aqueous ammonium chloride solution (26 ml) was added to quench the reaction, and then 3N HCl (26 ml) was added. The temperature was raised to room temperature, and the reaction was extracted with ethyl acetate.
  • Step 5 Under nitrogen protection, compound INT3f (1.92 g, 6.98 mmol), bipyralidone (2.66 g, 10.47 mmol), PdCl 2 (dppf) (0.57 g, 0.7 mmol), potassium acetate (2.05 g, 20.94 mmol) were dissolved in 1,4-dioxane solution and refluxed at 100°C overnight. After the reaction was completed, the temperature was restored to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure.
  • Step 1 Add CuBr 2 (66 g, 223 mmol) to EtOAc (120 mL) and stir at 80°C for 10 minutes. Then dissolve compound INT4a (10 g, 136 mmol) in chloroform (120 mL) and add it to the above suspension, reflux at 80°C for overnight reaction. After the reaction is complete, concentrate under reduced pressure, slurry the residue with EtOAc (200 mL) for 0.5 h, filter, and concentrate the filtrate to dryness to obtain the target compound INT4b (7.3 g).
  • Step 2 Add compound INT4b (7.3 g, 25 mmol) and Li 2 CO 3 (11 g, 150 mmol) to DMF (70 mL) and stir at 100°C for 6 h. After the reaction is complete, filter the mixture, adjust the pH of the filtrate to 1 with aqueous hydrochloric acid, extract with EtOAc (150 mL ⁇ 3), wash the organic phase with saturated brine, dry over anhydrous Na 2 SO 4 , filter, and concentrate to obtain the target compound INT4c (5.5 g).
  • Step 3 Compound INT4c (5.5 g, 26 mmol) and K 2 CO 3 (7.17 g, 52 mmol) were added to MeCN (60 mL), and then Me 2 SO 4 (4.1 g, 33 mmol) was added, and stirred at 60°C overnight under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, and silica gel was added to the filtrate, and then concentrated to dryness under reduced pressure.
  • Step 4 Add compound INT4d (1g, 4.4mmol), bis-pinacol borate (2.2g, 8.8mmol), KOAc (1.7g, 17.6mmol) and Pd(dppf)Cl 2 (322mg, 0.44mmol) to dioxane (15mL), and react at 90°C for 12h under nitrogen protection.
  • Step 1 Weigh INT5a (21.7 g, 90.8 mmol), LiOH.H 2 O (11.4 g, 272 mmol), Pd 2 (dba) 3 (1.7 g, 1.82 mmol) and BippyPhos (1.8 g, 3.63 mmol) into a flask, then add dioxane (220 mL) and water (22 mL), replace with N 2 three times, and reflux at 100°C for overnight. The reaction mixture was cooled to room temperature, filtered through a layer of celite, and then rinsed with EtOAc (100 mL).
  • Step 2 Compound INT5b (14.0 g, 79.5 mmol) was dissolved in toluene (280 mL), cooled to 0°C, and then NaH (6.36 g, 159 mmol, 60%) was added in batches. After addition, the mixture was stirred at 0°C for 1 h. Then I2 (20.2 g, 79.5 mmol) was added in batches to the above suspension. After addition, the mixture was stirred at 0°C for 1 h.
  • Step 3 Compound INT5c (20.7 g, 68.5 mmol) and K 2 CO 3 (18.9 g, 137 mmol) were added to acetone (200 mL), and then MeI (14.6 g, 103 mmol) was added, and stirred at 25°C overnight. After the reaction was complete, the mixture was filtered, and then silica gel was added to the filtrate, and the mixture was concentrated to dryness under reduced pressure.
  • Step 4 Compound INT5d (6.10 g, 19.3 mmol), 2-(dicyclohexylphosphino)biphenyl (0.676 g, 1.93 mmol), Pd(OAc) 2 (0.433 g, 1.93 mmol) and Et 3 N (5.86 g, 57.9 mmol) were added to anhydrous dioxane (60 mL), and then pinacol borane (4.94 g, 38.6 mmol) was added, and the reaction was refluxed at 110° C. under nitrogen protection overnight.
  • Step 1 Add compound INT8a (4.75 g, 21.8 mmol), paraformaldehyde (1.31 g, 43.6 mmol) and acetic acid (0.26 g, 4.36 mmol) to methanol (50 mL), then add sodium cyanoborohydride (2.74 g, 43.6 mmol) and stir at 50°C for 1 h.
  • Step 2 Dissolve compound INT8b (4.67 g, 20.1 mmol) in dioxane (25 mL), then add HCl/dioxane (25 mL, 101 mmol, 4.0 M), stir at 25 °C for 1 h, and after the reaction is completed, dry under reduced pressure to obtain the target product INT8 (4.60 g, 22.4 mmol, yield 111%);
  • Step 1 Compound INT10a (500 mg, 1.6 mmol), cyclopropylboronic acid (505 mg, 5.87 mmol) and potassium carbonate (883 mg, 6.39 mmol) were mixed in dioxane (10 mL) and water (5 mL), and Pd(dppf)Cl 2 (65.9 mg, 0.080 mmol) was added under nitrogen. The mixture was stirred at 120°C under nitrogen for sufficient reaction. After cooling to room temperature, ethyl acetate (20 mL) was added for dilution, and the organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a crude compound INT10b, which was used directly in the next step.
  • Step 2 At room temperature, K 2 CO 3 (601.8 mg, 4.4 mmol) was added to a solution of compound INT12b (470 mg, 2.19 mmol) in acetonitrile (10 mL). The mixture was stirred at room temperature for 0.5 hours, and 2-(trimethylsilyl)ethoxymethyl chloride (438.1 mg, 2.63 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature for 3 hours. TLC detected that the reaction was complete. Water was added to the mixed solution, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 Add compound INT12c (301 mg, 0.87 mmol), (BPin) 2 (330 mg, 1.3 mmol), Pd(dppf)Cl 2 (65.9 mg, 0.09 mmol), Cs 2 CO 3 (567.2 mg, 1.74 mmol), 1,4-dioxane (8 mL) to a dry flask, reflux at 100°C overnight under nitrogen protection, return to room temperature after the reaction is complete, add water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, remove excess solvent from the filtrate under reduced pressure, and separate the residue by column chromatography to obtain the target compound INT12 (colorless oily liquid 103 mg).
  • Step 2 Compound 1c (2 g, 6.6 mmol) and Lawesson's reagent (4.8 g, 12 mmol) were dissolved in 50 ml of toluene and reacted at 110°C for 12 h.
  • the target product was generated by LC-MS monitoring, and the solvent was removed by concentration under reduced pressure.
  • Step 4 Dissolve compound 1e (174 mg, 0.5 mmol) in 5 ml THF and cool to 0°C. Add m-CPBA (433 mg, 2.5 mmol) and react at room temperature overnight. LC-MS monitoring shows that compound 1e is completely converted into compound 1f. The reaction is not treated and is directly used in the next step.
  • Step 6 Dissolve compound 1h (7 mg, 0.02 mmol) in 1 ml DCM and cool to -10°C. Add BBr 3 (1M, 0.1 ml) and react at -10°C for 3 h. LC-MS monitors the completion of the reaction. Add methanol to quench the reaction, concentrate under reduced pressure to remove the solvent, and purify on a TLC plate to obtain the target compound 1 (5 mg).
  • Step 2 Compound 3c (97 mg, 0.68 mmol) was placed in a reaction bottle, glacial acetic acid (10 mL) was added, the temperature was lowered to 0°C, and liquid bromine (0.5 mL) was slowly added dropwise. After the addition was completed, the mixture was stirred at room temperature for 0.5 h. LCMS detection showed that the reaction was complete, and an aqueous sodium thiosulfate solution was added to quench the reaction, and the pH was adjusted to 8-9 with a saturated sodium bicarbonate aqueous solution, and ethyl acetate was added.
  • Step 4 Compound 3e (68 mg, 0.29 mmol) was placed in a reaction bottle, dichloromethane (7 mL) was added, the reaction was placed in an ice bath, m-CPBA (99 mg, 0.58 mmol) was slowly added, the ice bath was removed after the addition, and the reaction was carried out at room temperature for 10 h.
  • LCMS monitoring showed that the reaction was complete, saturated sodium thiosulfate aqueous solution was added to quench the reaction, dichloromethane was added for extraction, the organic phases were combined and concentrated to obtain a crude product 3f (46 mg), which was directly used in the next step reaction;
  • LC-MS: ESI [M+H] + 267.9.
  • Step 1 Compound 3e (800 mg, 3.39 mmol), compound 26a (694 mg, 3.72 mmol), Pd(dppf)Cl 2 (248 mg, 0.34 mmol), cesium carbonate (4.41 g, 13.6 mmol), dioxane (20 mL) and water (5 mL) were placed in a reaction bottle, protected by nitrogen, and stirred at 100°C for 15 h.
  • Step 2 Compound 26b (200 mg, 0.67 mol) was dissolved in dichloromethane (15 mL), cooled to 0-5°C, and m-CPBA (204 mg, 1.01 mol, 85% purity) was added. After addition, the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, a saturated sodium bicarbonate aqueous solution (20 mL) was added and stirred for 5 minutes. The aqueous phase was extracted twice with dichloromethane (10 mL).
  • Step 4 Compound 26d (45 mg, 0.12 mmol) and dichloromethane (10 mL) were placed in a reaction bottle, protected by nitrogen, cooled to -10 °C, and 2M dichloromethane solution of boron tribromide (0.18 mL, 0.37 mmol) was added, and the reaction was kept warm for 1 h.
  • Example 40 6-(2-Hydroxy-4-(trifluoromethoxy)phenyl)-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
  • THP-1 cells Wuhan Punosai Life Science Technology Co., Ltd.
  • PMA Sigma-Aldrich
  • RPMI medium Hyclone
  • LPS Sigma-Aldrich
  • Opti-MEM medium Gibco
  • Nigericin Invivogen
  • Human IL-1 ⁇ ELISA kit 4A Biotech
  • reference compound MCC950 MedChemExpress (MCE).
  • THP-1 cells were inoculated in 48-well plates at a cell density of 2x10 5 /mL in RPMI medium containing PMA (10 ⁇ M) and placed in an incubator at 37°C and 5% CO 2 for overnight induction. The next day, the medium was replaced with Opti-MEM medium containing 1 ⁇ g/mL LPS; 3 hours later, the drug was added for 40 minutes; Nigericin (10 ⁇ M) was added for 40 minutes; the cell supernatant was collected for ELISA analysis.
  • Compound MCC950 was purchased from MCE. The experimental results are shown in Table 2.
  • the compounds of the present invention have good inhibitory activity on NLRP3 inflammasome, and the preferred compounds 2, 4 and 13 have better inhibitory effects on NLRP3 inflammasome than MCC950.
  • PBMC Human peripheral blood mononuclear cells
  • RPMI 1640 medium containing 10% FBS and antibiotics before stimulation.
  • the medium was changed to reduced serum medium and LPS with an action concentration of 1ug/ml was added for 3h, drug stimulation for 40min, and nigericin with a concentration of 10uM for 40min.
  • the cell supernatant was collected and the production of IL-1 ⁇ was detected by ELISA.
  • the compounds of the present invention have good inhibitory activity on the production of IL-1 ⁇ by human PBMC cells, and the preferred compound 2 has an inhibitory activity IC 50 on the production of IL-1 ⁇ by human PBMC cells that is better than MCC950.
  • CHO cells stably expressing hERG were cultured in a cell culture flask and placed in an incubator at 37°C and 5% CO 2. When the cell density grew to 60-80%, the cell culture medium was removed, and the cells were washed once with PBS and then digested with Detachin. After complete digestion, the cells were neutralized with culture medium, centrifuged, the supernatant was removed, and the cells were resuspended with culture medium. The cell density was adjusted to 2-5 ⁇ 10 6 /mL for later use.
  • Compound preparation Dilute the compound stock solution with 100% DMSO, that is, take 10 ⁇ L of the compound stock solution and add it to 20 ⁇ L DMSO, and dilute it 3 times continuously to 6 concentrations. Take 4 ⁇ L of the 6 concentrations of the compound respectively and add it to 396 ⁇ L of extracellular fluid, that is, dilute it 100 times to get 6 intermediate concentrations. Then take 80 ⁇ L of the 6 intermediate concentration compounds respectively and add them to 320 ⁇ L of extracellular fluid, that is, dilute it 5 times to the final concentration to be tested. The highest test concentration is 40 ⁇ M, and there are 6 concentrations of 40, 13.33, 4.44, 1.48, 0.49 and 0.16 ⁇ M respectively. The DMSO content in the final test concentration does not exceed 0.2%, and this concentration of DMSO has no effect on the hERG potassium channel.
  • the compound preparation is completed by the Bravo instrument throughout the dilution process.
  • Electrophysiological recording process The single-cell high-impedance sealing and whole-cell pattern formation process are all automatically completed by the Qpatch instrument. After obtaining the whole-cell recording mode, the cell is clamped at -80 mV. Before giving a 5-second +40 mV depolarizing stimulus, a 50-millisecond -50 mV pre-voltage is given, and then repolarizes to -50 mV for 5 seconds, and then returns to -80 mV. This voltage stimulus is applied every 15 seconds. After recording for 2 minutes, the extracellular solution is given for 5 minutes of recording, and then the drug administration process begins. The compound concentration starts from the lowest test concentration, and each test concentration is given for 2.5 minutes, and the continuous After all concentrations were given, 3 ⁇ M Cisapride, a positive control compound, was given. At least 3 cells (n ⁇ 3) were tested for each concentration.
  • X is the Log value of the test sample concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • Sample preparation Weigh the compound and add DMSO to dissolve it, then add sodium chloride solution for injection to prepare the compound solution for administration.
  • Sample collection 6 Balb/c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), male, 3 intravenous administration (IV), 3 gavage administration (PO), about 0.05mL of blood was collected at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h and 48h after administration, the collected blood was centrifuged at 3500rpm for 15min, the supernatant plasma was collected, and it was frozen at -40°C for testing.
  • the blood concentration was quantitatively analyzed by LC-MS/MS analysis method, and pharmacokinetic parameters such as peak time (Cmax), area under the drug-time curve (AUC (0-t)), half-life (T 1/2 ), clearance (CL), tissue distribution (Vdss), bioavailability (F), etc.
  • Cmax peak time
  • AUC (0-t) area under the drug-time curve
  • T 1/2 half-life
  • CL clearance
  • Vdss tissue distribution
  • F bioavailability
  • Compounds 1, 2, 11, 23 and 25 of the present invention have good pharmacokinetic properties in Balb/c mice, including good oral bioavailability, exposure, half-life and clearance.
  • mice 7-8 weeks old Balb/c mice were orally administered 25 mg/kg compound or vehicle control (sterile 0.9% NaCl solution), and 1 hour later, 10 mg/kg LPS (Sigma, L2880) was intraperitoneally injected. The survival status of the mice was observed every 12 hours for 72 hours, and the 72-hour survival rate of the mice was obtained.
  • compound or vehicle control sterile 0.9% NaCl solution
  • LPS Sigma, L2880
  • the compounds of the present invention have good in vivo therapeutic effects on LPS-induced mice and can increase the survival rate of LPS-induced mice.
  • the survival rate of compounds 2, 4 and 20 on LPS-induced mice is better than that of the reference compound MCC950.
  • Experimental plan The brain-to-blood ratio of the compound was investigated by monitoring the content of the compound in the mouse brain and plasma.
  • Standard curve range 10 ⁇ 10000ng ⁇ ml -1 .
  • Drug content in brain measured value ⁇ 0.03 ⁇ (M3-M1)/[(M2-M1) ⁇ (M3-M4)].
  • Some compounds of the present invention have the potential to enter the brain, especially compound 2, whose brain-to-blood ratios reached 0.44 and 0.53 at 1 hour and 6 hours, respectively.

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Abstract

Disclosed are a six-membered nitrogen heterocyclic compound and use thereof, which belong to the technical field of chemical pharmaceuticals. The six-membered nitrogen heterocyclic compound represented by formula I provided by the present invention can be used as an NLRP3 inhibitor, and has high activity and excellent pharmacokinetic properties, thereby providing a new way for treating NLRP3-related diseases.

Description

六元氮杂环类化合物及其用途Six-membered nitrogen heterocyclic compounds and uses thereof 技术领域Technical Field
本发明属于化学医药领域，涉及一类六元氮杂环类化合物及其用途。The invention belongs to the field of chemical medicine and relates to a class of six-membered nitrogen heterocyclic compounds and uses thereof.
背景技术Background Art
炎症小体是一类可识别细胞内病原相关分子模式(pathogen associated molecular patterns,PAMPs)或损伤相关分子模式(damage associated molecular patterns,DAMPs)等的蛋白复合物，炎症小体的组装引发蛋白水解，将休眠的procaspase-1裂解为有活性的caspase-1，将细胞因子前体pro-IL-1β和pro-IL-18分别转化为成熟的、具有生物学活性的IL-1β和IL-18，调控炎症相关基因表达等方式产生各种生物学效应。作为机体固有免疫的感受器，炎症小体活化可以抵抗病原体感染和应激损伤，但其活化失控也能造成炎症效应的放大和器官损伤。目前对核苷酸结合寡聚化结构域(nucleotide-binding oligomerization domain,NOD)样受体家族含pyrin结构域蛋白3(NOD-like receptor family,pyrin domain-containing protein 3，NLRP3)炎症小体的研究最为热门。Inflammasomes are a class of protein complexes that can recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) in cells. The assembly of inflammasomes triggers proteolysis, cleaving dormant procaspase-1 into active caspase-1, converting cytokine precursors pro-IL-1β and pro-IL-18 into mature, biologically active IL-1β and IL-18, respectively, and regulating the expression of inflammation-related genes to produce various biological effects. As a receptor of the body's innate immunity, inflammasome activation can resist pathogen infection and stress injury, but its uncontrolled activation can also cause amplification of inflammatory effects and organ damage. Currently, the research on nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome is the most popular.
NLRP3炎性小体由传感器(NLRP3)、适配器(ASC，也被称为PYCARD)和一个效应体(caspase 1)组成。经典的NLRP3炎性小体活化由两种信号共同刺激激活，第一信号激活TLR4(Toll like receptor4)信号通路，促进NF-κB入核，诱导IL-1β和IL-18等前体的产生,并诱导NLRP3的翻译后修饰。第二信号促进NLRP3/ASC/pro-caspase-1复合体形成，即在被激活时与含有半胱天冬酶活化和募集结构域的凋亡相关斑点样蛋白(ASC，Apoptosis-Associated Specklike Protein containing a CARD)聚合，ASC再与cysteine protease caspase-1相互作用形成称为炎性体的复合物，前体形式的半胱天冬酶(pro-caspase-1)自剪切成活化形式，2活化的半胱天冬酶-1(caspase-1)切割前体形式的促炎细胞因子IL-1β和IL-18，使其转化为活性形式的IL-1β和IL-18并释放到胞外，募集炎症细胞聚集，扩大炎症反应。ASC斑点样蛋白还可以募集并活化胱天蛋白酶-8(caspase-8)，切割前体形式的IL-Ιβ和IL-18使其转变为成熟形式并引发细胞焦亡。非经典的NLRP3炎性小体活化不依赖于TLR4信号通路活化，它是由半胱天冬酶-11直接识别胞内的LPS，启动NLRP3炎性小体活化，促进Gasdermin D的活化与释放从而介导细胞死亡。The NLRP3 inflammasome is composed of a sensor (NLRP3), an adapter (ASC, also known as PYCARD), and an effector (caspase 1). Classic NLRP3 inflammasome activation is activated by two signals co-stimulated. The first signal activates the TLR4 (Toll-like receptor 4) signaling pathway, promotes the nuclear entry of NF-κB, induces the production of precursors such as IL-1β and IL-18, and induces post-translational modification of NLRP3. The second signal promotes the formation of the NLRP3/ASC/pro-caspase-1 complex, that is, when activated, it aggregates with apoptosis-associated specklike protein (ASC) containing a caspase activation and recruitment domain. ASC then interacts with cysteine protease caspase-1 to form a complex called inflammasome. The pro-caspase (pro-caspase-1) is self-cleaved into an activated form. 2 The activated caspase-1 cleaves the pro-inflammatory cytokines IL-1β and IL-18, converting them into active forms of IL-1β and IL-18 and releasing them into the extracellular space, recruiting inflammatory cells to aggregate and amplifying the inflammatory response. ASC speck-like protein can also recruit and activate caspase-8, cleaving the pro-forms of IL-Ιβ and IL-18 to convert them into mature forms and trigger cell pyroptosis. Non-classical NLRP3 inflammasome activation is independent of TLR4 signaling pathway activation. It is initiated by caspase-11 directly recognizing intracellular LPS, initiating NLRP3 inflammasome activation, promoting the activation and release of Gasdermin D, and thus mediating cell death.
NLRP3的异常活化与许多疾病相关，主要包括炎性体相关疾病、免疫学疾病、炎症性疾病、神经系统疾病、自身免疫性疾病和或自身炎症性疾病、癌症、慢性代谢性疾 病以及神经相关疾病。例如隐热蛋白相关周期综合征(CAPS)、穆克尔-韦尔斯综合征(MWS)、家族性寒冷性自身炎性综合征(FCAS)、新生儿发病多系统炎性疾病(NOMID)、家族性地中海热(FMF)、非酒精性脂肪性肝炎、酒精性肝病、移植物抗宿主病、多发性硬化(MS)、类风湿性关节炎、I型/II型糖尿病及相关并发症(例如肾病、视网膜病)、牛皮癣、阿尔茨海默氏病、动脉粥样硬化、痛风、慢性肾疾病、脓毒症、肝纤维化、特发性肺纤维化、癫痫、神经病理性疼痛、抑郁症、帕金森病、哮喘、急性心肌梗塞、红斑狼疮、类风湿关节炎、克罗恩氏病、溃疡性结肠炎、炎症性肠病、类风湿性关节炎、强制性脊髓炎、支气管哮喘、急性呼吸窘迫综合征、慢性阻塞性肺部疾病或者缺血性中风。NLRP3处于细胞因子的上游，可以从根源上阻断炎症，因此开发新的NLRP3炎性小体抑制剂具有较高的研究价值。Abnormal activation of NLRP3 is associated with many diseases, including inflammasome-related diseases, immunological diseases, inflammatory diseases, nervous system diseases, autoimmune diseases and/or autoinflammatory diseases, cancer, chronic metabolic diseases, etc. diseases and neurological related diseases. For example, cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I/type II diabetes and related complications (such as nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing myelitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease or ischemic stroke. NLRP3 is upstream of cytokines and can block inflammation at the source, so the development of new NLRP3 inflammasome inhibitors has high research value.
发明内容Summary of the invention
本发明开发了一类六元氮杂环类化合物，其能够用于治疗NLRP3相关疾病。The present invention develops a class of six-membered nitrogen heterocyclic compounds, which can be used to treat NLRP3-related diseases.
第一方面，本发明提供了式Ⅰ所示化合物或其药学上可接受的形式，所述式Ⅰ结构如下：
In the first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable form thereof, wherein the structure of formula I is as follows:
其中：in:
为单键时，X选自NR7a，Y选自C(＝O)； When it is a single bond, X is selected from NR 7a , and Y is selected from C(═O);
为双键时，X独立选自CR7b或者N，Y选自N； When it is a double bond, X is independently selected from CR 7b or N, and Y is selected from N;
R1、R2、R4和R5独立地选自氢、氘、卤素、-OH、-NH2、-CN或任选被0-6个取代基取代的以下基团：C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-NHC(＝O)-C1-6烷基、-(C＝O)NH-C1-6烷基、C2-6烯基、C2-6炔基、3-6元环烷基；R1、R2、R4和R5中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC(=O)-C 1-6 alkyl, -(C=O)NH-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl; among R 1 , R 2 , R 4 and R 5 , the substituent is selected from deuterium, halogen, -OH, -NH 2 or -CN;
R3选自氢、氘、卤素、-OH、-NH2、-CN或任选被0-6个取代基取代的以下基团：C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-NHC(＝O)-C1-6烷基、-(C＝O)NH-C1-6烷基、C2-6烯基、C2-6炔基、3-6元环烷基、5-6元杂环烷基、苯基、5-6元杂芳基；R3中，所述取代基选自：氘、卤素、-OH、-NH2、-CN或3-6元环烷基；R3中，所述5-6元杂环烷基、5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子；R 3 is selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted by 0-6 substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC(=O)-C 1-6 alkyl, -(C=O)NH-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6-membered cycloalkyl, 5-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 3 , the substituent is selected from deuterium, halogen, -OH, -NH 2 , -CN or 3-6-membered cycloalkyl; in R 3 , the 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O;
或者，R2与R3、R3与R4或者R4与R5与它们所连接的原子一起形成被0-6个取代 基取代的5-6元烷烃环、苯环、5-6元烷烃杂环或者5-6元杂芳环，所述取代基选自：氘、卤素、-OH、-NH2、-CN、氧代基、C1-6烷基、C1-6氟代烷基、C1-6氘代烷基、-O-C1-6烷基、-O-C1-6氟代烷基、-O-C1-6氘代烷基、C3-6环烷基、C3-6氟代环烷基，或者同一碳原子连接的2个所述取代基形成3-6元环烷基；R2与R3、R3与R4或者R4与R5与它们所连接的原子相连成环时，所述5-6元烷烃杂环、5-6元杂芳环含有1～3个选自N、S、O中至少一个的杂原子；Alternatively, R2 and R3 , R3 and R4 , or R4 and R5 together with the atoms to which they are attached form a group substituted with 0 to 6 a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle or a 5-6 membered heteroaromatic ring substituted with a substituent selected from the group consisting of deuterium, halogen, -OH, -NH2 , -CN, oxo, C1-6 alkyl, C1-6 fluoroalkyl, C1-6 deuterated alkyl, -OC1-6 alkyl, -OC1-6 fluoroalkyl, -OC1-6 deuterated alkyl, C3-6 cycloalkyl, C3-6 fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-6 membered cycloalkyl; when R2 and R3 , R3 and R4 , or R4 and R5 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocycle or the 5-6 membered heteroaromatic ring contains 1 to 3 heteroatoms selected from at least one of N, S and O;
L(左端与嗪环相连，右端与R6相连)选自-(CH2)n1-、O、-(CH2)n1-NH-、-NH-(CH2)n1-、-NH-CH(CH2)n1(CH3)-，n1为选自0-3的整数；L (the left end is connected to the azine ring, and the right end is connected to R 6 ) is selected from -(CH 2 ) n1 -, O, -(CH 2 ) n1 -NH-, -NH-(CH 2 ) n1 -, -NH-CH(CH 2 ) n1 (CH 3 )-, and n1 is an integer selected from 0-3;
R6选自被0-6个取代基取代的6～10元芳基、5～10元杂芳基、3-8元杂环烷基、3-8元环烷基、6～10元螺环烷基、6～10元杂螺环烷基、6～10元桥环烷基、6～10元杂桥环烷基、C1-6烷基；R6中，所述取代基选自R8a、卤素、氧代基、-OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aC(＝O)R8b、-NR8aR8b、-SO2R8a、-SO2NR8aR8b、-NR8aSO2R8b、-CN；R6中，所述5～10元杂芳基、3-8元杂环烷基、6～10元杂螺环烷基、6～10元杂桥环烷基含有1～3个选自N、S、O中至少一个的杂原子； R6 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, and C1-6 alkyl substituted with 0-6 substituents; in R6 , the substituent is selected from R8a , halogen, oxo, -OR8a , -SR8a , -C(=O) R8a , -OC ( =O ) R8a , -C(=O ) OR8a, -C(=O)NR8aR8b , -NR8aC ( =O)R8b , -NR8aR8b , -SO2R8a , -SO2NR8aR8b , -NR8aSO2R8b , -CN; in R 6 , the 5- to 10-membered heteroaryl, 3- to 8-membered heterocycloalkyl, 6- to 10-membered heterospirocycloalkyl, and 6- to 10-membered heterobridged cycloalkyl contain 1 to 3 heteroatoms selected from at least one of N, S, and O;
R8a和R8b独立地选自氢、氘或者被0-6个取代基取代的以下基团：C1-4烷基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基、3-6元环烷基亚甲基或者4-6元杂环烷基亚甲基；R8a、R8b中，所述取代基选自：氘、卤素、-N(R10aR10b)、-OH、-CN、C1-4烷基、C1-4烷氧基、C1-4氘代烷基、3-6元环烷基、4-6元杂环烷基、3-6元环烷基亚甲基或者4-6元杂环烷基亚甲基；R8a、R8b中，所述4-6元杂环烷基、5-6元杂芳基、4-6元杂环烷基亚甲基含有1～3个选自N、S、O中至少一个的杂原子，所述取代基中4-6元杂环烷基、4-6元杂环烷基亚甲基含有1～3个选自N、S、O中至少一个的杂原子；R 8a and R 8b are independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: C 1-4 alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, 3-6-membered cycloalkylmethylene or 4-6-membered heterocycloalkylmethylene; in R 8a and R 8b , the substituents are selected from deuterium, halogen, -N(R 10a R 10b ), -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 deuterated alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 3-6-membered cycloalkylmethylene or 4-6-membered heterocycloalkylmethylene; R 8a , R In 8b , the 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkylmethylene contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkylmethylene in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S, and O;
或者，R8a与R8b与它们所连接的原子形成被0-6个取代基取代的3-6元烷基杂环；R8a与R8b与它们所连接的原子相连成环时，所述取代基选自：氘、卤素、-N(R11aR11b)、-OH、-CN、C1-4烷基、3-6元环烷基、4-6元杂环烷基；R8a与R8b与它们所连接的原子相连成环时，所述3-6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子，所述取代基中4-6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；Alternatively, R 8a and R 8b and the atoms to which they are attached form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents; when R 8a and R 8b and the atoms to which they are attached form a ring, the substituents are selected from: deuterium, halogen, -N(R 11a R 11b ), -OH, -CN, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl; when R 8a and R 8b and the atoms to which they are attached form a ring, the 3-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S and O, and the 4-6 membered heterocycloalkyl in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S and O;
R7a选自氢或者任选被0-6个取代基取代的以下基团：C1-6烷基、C2-6烯基、C2-6炔基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R7a中，所述取代基选自：氢、氘、卤素、-OH、-NH2或-CN；R7a中，所述4-6元杂环烷基、5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子；R 7a is selected from hydrogen or the following groups optionally substituted by 0-6 substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 7a , the substituent is selected from: hydrogen, deuterium, halogen, -OH, -NH 2 or -CN; in R 7a , the 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O;
R7b选自氢、氘、卤素、-NH2、-CN、-OR9a、-COR9a、-COOR9a、-CONHR9a、-CON(R9bR9c)、 -N(R9bR9c)、-NR9aCOR9b、-SO2R9a或者任选被0-6个取代基取代的以下基团：C1-6烷基、C2-6烯基、C2-6炔基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R7b中，所述取代基选自：氢、氘、卤素、-OH、-NH2或-CN；R7b中，所述4-6元杂环烷基、5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子；R 7b is selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OR 9a , -COR 9a , -COOR 9a , -CONHR 9a , -CON(R 9b R 9c ), -N(R 9b R 9c ), -NR 9a COR 9b , -SO 2 R 9a or the following groups optionally substituted by 0-6 substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 7b , the substituent is selected from: hydrogen, deuterium, halogen, -OH, -NH 2 or -CN; in R 7b , the 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O;
R9a、R9b和R9c独立地选自氢、氘或者被0-6个取代基取代的以下基团：C1-4烷基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R9a、R9b和R9c中，所述取代基选自：氘、卤素、-OH、-NH2或者CN；R9a、R9b和R9c中，所述取代基中4-6元杂环烷基或5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子；R 9a , R 9b and R 9c are independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 9a , R 9b and R 9c , the substituent is selected from: deuterium, halogen, -OH, -NH 2 or CN; in R 9a , R 9b and R 9c , the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S and O;
R10a、R10b、R11a和R11b独立地选自氢或C1-4烷基；R 10a , R 10b , R 11a and R 11b are independently selected from hydrogen or C 1-4 alkyl;
所述药学上可接受的形式选自药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药。The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotopically labeled substances, metabolites or prodrugs.
在本发明的一些实施例中，式Ⅰ所示化合物中，R1、R2、R4和R5独立地选自氢、氘、卤素、-OH、-NH2、-CN或者任选被0-6个取代基取代的以下基团：C1-4烷基、-O-C1-4烷基、-S-C1-4烷基、C2-4烯基、C2-4炔基、3-6元环烷基，所述取代基选自：氘、卤素、-OH、-NH2或-CN。In some embodiments of the present invention, in the compound of formula I, R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-6 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, wherein the substituents are selected from deuterium, halogen, -OH, -NH 2 or -CN.
在本发明的一些优选实施例中，式Ⅰ所示化合物中，R1、R2、R4和R5独立地选自氢、氘、F、Cl、-OH、-NH2、-CN或者任选被0-3个取代基取代的以下基团：C1-4烷基、-O-C1-4烷基、-S-C1-4烷基、3-6元环烷基，所述取代基选自：氘、F、Cl、-OH、-NH2或-CN。In some preferred embodiments of the present invention, in the compound represented by formula I, R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, F, Cl, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, 3-6 membered cycloalkyl, wherein the substituents are selected from: deuterium, F, Cl, -OH, -NH 2 or -CN.
在本发明的一些更优选实施例中，式Ⅰ所示化合物中，R1、R2、R4和R5独立地选自氢、氘、F、Cl、-OH、-CH3、氟代甲基、氘代甲基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基、氟代环丙基。In some more preferred embodiments of the present invention, in the compound of formula I, R1 , R2 , R4 and R5 are independently selected from hydrogen, deuterium, F, Cl, -OH, -CH3 , fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.
在本发明的一些实施例中，式Ⅰ所示化合物中，R3选自氢、氘、卤素、-OH、-NH2、-CN或任选被0-6个取代基取代的以下基团：C1-4烷基、-O-C1-4烷基、-S-C1-4烷基、C2-4烯基、C2-4炔基、3-6元环烷基、5-6元杂环烷基、苯基、5-6元杂芳基；R3中，所述取代基选自：氘、卤素、-OH、-NH2、-CN、-CF3或者环丙基；R3中，所述5-6元杂环烷基、5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子。In some embodiments of the present invention, in the compound represented by formula I, R 3 is selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted by 0-6 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 3 , the substituent is selected from: deuterium, halogen, -OH, -NH 2 , -CN, -CF 3 or cyclopropyl; in R 3 , the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O.
在本发明的一些优选实施例中，式Ⅰ所示化合物中，R3选自氢、氘、F、Cl、-CN或任选被0-3个取代基取代的以下基团：C1-4烷基、-O-C1-4烷基、-S-C1-4烷基、C2-4烯基、C2-4炔基、3-6元环烷基、5-6元杂环烷基、苯基、5-6元杂芳基；R3中，所述取代基选自：氘、F、Cl、-OH、-NH2、-CF3、-CN或环丙基；R3中，所述5-6元杂环烷基、5-6元杂芳基含有1～2个选自N、S、O中至少一个的杂原子。 In some preferred embodiments of the present invention, in the compound represented by formula I, R 3 is selected from hydrogen, deuterium, F, Cl, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 3 , the substituent is selected from: deuterium, F, Cl, -OH, -NH 2 , -CF 3 , -CN or cyclopropyl; in R 3 , the 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl contain 1 to 2 heteroatoms selected from at least one of N, S and O.
在本发明的一些更优选实施例中，式Ⅰ所示化合物中，R3选自氢、氘、F、Cl、甲基、氟代甲基、氘代甲基、甲硫基、氟代甲硫基、氘代甲硫基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基、氟代环丙基、乙烯基、乙炔基、苯基、氟代苯基、氘代苯基。In some more preferred embodiments of the present invention, in the compound represented by formula I, R3 is selected from hydrogen, deuterium, F, Cl, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl.
在本发明的一些实施例中，式Ⅰ所示化合物中，R2与R3、R3与R4或者R4与R5可以与它们所连接的原子一起形成被0-6个取代基取代的5-6元烷烃环、苯环、5-6元烷烃杂环或者5-6元杂芳环，所述取代基选自：氘、卤素、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-氟代C1-4烷基、-O-氘代C1-4烷基、3-6元环烷基或3-6元氟代环烷基，或者同一碳原子连接的2个所述取代基形成3-4元环烷基；R2与R3、R3与R4或者R4与R5与它们所连接的原子相连成环时，所述5-6元烷烃杂环、5-6元杂芳环含有1～2个选自N、S、O中至少一个的杂原子。In some embodiments of the present invention, in the compound of formula I, R2 and R3 , R3 and R4 , or R4 and R5 can form, together with the atoms to which they are connected, a 5-6-membered alkane ring, a benzene ring, a 5-6-membered alkane heterocycle, or a 5-6-membered heteroaromatic ring substituted with 0-6 substituents, wherein the substituents are selected from: deuterium, halogen, -OH, -NH2 , -CN, oxo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 deuterated alkyl, -OC1-4 alkyl, -O-fluoro C1-4 alkyl, -O-deuterated C1-4 alkyl, 3-6 -membered cycloalkyl or 3-6 -membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 -membered cycloalkyl; R2 and R3, R3 and R4, or R4 and R5 can form a 5-6 -membered alkane ring, a benzene ring, a 5-6-membered alkane heterocycle, or a 5-6-membered heteroaromatic ring substituted with 0-6 substituents, wherein the substituents are selected from: deuterium, halogen, -OH, -NH2, -CN, oxo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 deuterated alkyl, -OC1-4 alkyl, -O-fluoro C1-4 alkyl, -O-deuterated C1-4 alkyl, 3-6 - membered cycloalkyl or 3-6 -membered fluorocycloalkyl; When the 5- to 6-membered alkane heterocyclic ring and the 5- to 6-membered heteroaromatic ring are connected to form a ring, the 5- to 6-membered alkane heterocyclic ring and the 5- to 6-membered heteroaromatic ring contain 1 to 2 heteroatoms selected from at least one of N, S and O.
在本发明的一些实施例中，式Ⅰ所示化合物中，R2与R3、R3与R4或者R4与R5与它们所连接的原子一起形成被0-3个取代基取代的 所述取代基选自：氘、F、Cl、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-氟代C1-4烷基、-O-氘代C1-4烷基、3-6元环烷基或3-6元氟代环烷基，或者同一碳原子连接的2个所述取代基形成3-4元环烷基。In some embodiments of the present invention, in the compound of formula I, R2 and R3 , R3 and R4 , or R4 and R5 together with the atoms to which they are attached form a group substituted with 0-3 substituents. The substituent is selected from: deuterium, F, Cl, -OH, -NH2 , -CN, oxo, C1-4 alkyl, C1-4 fluoroalkyl , C1-4 deuterated alkyl, -OC1-4 alkyl, -O-fluoro C1-4 alkyl , -O -deuterated C1-4 alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.
在本发明的一些实施例中，式Ⅰ所示化合物中，R2与R3或者R3与R4与它们所连接的原子一起形成被0-3个取代基取代的 所述取代基选自：氘、F、Cl、-OH、-NH2、-CN、氧代基、甲基、氟代甲基、氘代甲基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基或氟代环丙基，或者同一碳原子连接的2个所述取代基形成3-4元环烷基。In some embodiments of the present invention, in the compound of formula I, R2 and R3 or R3 and R4 together with the atoms to which they are attached form a group substituted with 0-3 substituents. The substituent is selected from: deuterium, F, Cl, -OH, -NH2 , -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.
在本发明的一些实施例中，式Ⅰ所示化合物中，结构单元选自：

In some embodiments of the present invention, in the compound represented by formula I, the structural unit Selected from:

R12选自氘、卤素、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-C1-4氟代烷基、-O-C1-4氘代烷基、-S-C1-4烷基、-S-C1-4氟代烷基、-S-C1-4氘代烷基、3-6元环烷基、3-6元氟代环烷基；n2选自0-6的整数。R 12 is selected from deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, -OC 1-4 alkyl , -OC 1-4 fluoroalkyl, -OC 1-4 deuterated alkyl, -SC 1-4 alkyl, -SC 1-4 fluoroalkyl, -SC 1-4 deuterated alkyl , 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl; n2 is selected from an integer of 0-6.
在本发明的一些优选实施例中，式Ⅰ所示化合物中，R12选自：氘、F、Cl、-OH、-NH2、-CN、氧代基、甲基、氟代甲基、氘代甲基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基或氟代环丙基；n2选自0-3的整数。In some preferred embodiments of the present invention, in the compound of formula I, R12 is selected from: deuterium, F, Cl, -OH, -NH2 , -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl; n2 is selected from an integer of 0-3.
在本发明的一些最优选实施例中，式Ⅰ所示化合物中，结构单元选自：

In some of the most preferred embodiments of the present invention, in the compounds represented by formula I, the structural unit Selected from:

在本发明的一些实施例中，R7a选自氢或者任选被0-3个取代基取代的以下基团：C1-4烷基、C2-6烯基、C2-6炔基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R7a中，所述取代基选自：氢、氘、卤素、-OH、-NH2或-CN。In some embodiments of the present invention, R 7a is selected from hydrogen or the following groups optionally substituted by 0-3 substituents: C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 7a , the substituents are selected from: hydrogen, deuterium, halogen, -OH, -NH 2 or -CN.
在本发明的一些实施例中，R7b选自氢、氘、卤素、-NH2、-CN、-OR9a、-COR9a、-COOR9a、-CONHR9a、-CON(R9bR9c)、-N(R9bR9c)、-SO2R9a或者任选被0-3个取代基取代的以下基团：C1-4烷基、C2-4烯基、C2-4炔基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R9a、R9b和R9c独立地选自氢、氘或者被0-3个取代基取代的以下基团：C1-4烷基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R9a、R9b和R9c中，所述取代基选自：氘、卤素、-OH、-NH2或者CN。In some embodiments of the present invention, R 7b is selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OR 9a , -COR 9a , -COOR 9a , -CONHR 9a , -CON(R 9b R 9c ), -N(R 9b R 9c ), -SO 2 R 9a or the following groups optionally substituted with 0-3 substituents: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 9a , R 9b and R 9c are independently selected from hydrogen, deuterium or the following groups substituted with 0-3 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; R 9a , R 9b and R 9c are independently selected from hydrogen, deuterium or the following groups substituted with 0-3 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; In 9c , the substituent is selected from: deuterium, halogen, -OH, -NH2 or CN.
在本发明的一些优选实施例中，R7a选自氢或者C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4烷氧基、C1-4氟代烷氧基、C1-4氘代烷氧基、羧基、C1-4烷氧羰基、C1-4氟代 烷氧羰基、C1-4氘代烷氧羰基、3～6元环烷基、3～6元氟代环烷基、苯基、吡啶基或者X1和X2独立地选自CH、N；X3选自N-C1-4烷基、NH、S、O。In some preferred embodiments of the present invention, R 7a is selected from hydrogen or C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, carboxyl, C 1-4 alkoxycarbonyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkoxy, Alkoxycarbonyl, C 1-4 deuterated alkoxycarbonyl, 3-6 membered cycloalkyl, 3-6 membered fluorinated cycloalkyl, phenyl, pyridyl or X1 and X2 are independently selected from CH, N; X3 is selected from NC1-4alkyl , NH, S, O.
在本发明的一些优选实施例中，R7b选自氢、氘、卤素、-NH2、-CN、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4烷氧基、C1-4氟代烷氧基、C1-4氘代烷氧基、羧基、C1-4烷氧羰基、C1-4氟代烷氧羰基、C1-4氘代烷氧羰基、3～6元环烷基、3～6元氟代环烷基、苯基、六元氮杂芳基、-CONHR9a；R9a选自氢、氘、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、3～6元环烷基、3～6元氟代环烷基；X4和X5独立地选自CH、N；X6选自N-C1-4烷基、NH、S、O。In some preferred embodiments of the present invention, R 7b is selected from hydrogen, deuterium, halogen, -NH 2 , -CN, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, carboxyl, C 1-4 alkoxycarbonyl, C 1-4 fluoroalkoxycarbonyl, C 1-4 deuterated alkoxycarbonyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, phenyl, 6-membered nitrogen heteroaryl, -CONHR 9a ; R 9a is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl; X 4 and X 5 are independently selected from CH, N; X 6 is selected from NC 1-4 alkyl, NH, S, O.
在本发明的一些优选实施例中，R7a选自氢、甲基、氘代甲基、氟代甲基、乙基、氟代乙基、异丙基、氟代异丙基、环丙基氟代环丙基、环己基、氟代环己基、苯基、吡啶基、X1选自N；X2选自CH、N；X3选自N-甲基、S、O。In some preferred embodiments of the present invention, R 7a is selected from hydrogen, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, pyridyl, X1 is selected from N; X2 is selected from CH, N; X3 is selected from N-methyl, S, O.
在本发明的一些优选实施例中，R7b选自氢、氘、F、Cl、氰基、氨基、甲基、氘代甲基、氟代甲基、乙基、氟代乙基、异丙基、氟代异丙基、甲氧基、氘代甲氧基、氟代甲氧基、羧基、甲氧羰基、氟代甲氧羰基、氘代甲氧羰基、乙氧羰基、氟代乙氧羰基、环丙基、氟代环丙基、环己基、氟代环己基、苯基、吡啶基、-CONHR9a；R9a选自氢、氘、甲基、氟代甲基、氘代甲基、环丙基、氟代环丙基；X4选自N；X5选自CH、N；X6选自N-甲基、S、O。In some preferred embodiments of the present invention, R 7b is selected from hydrogen, deuterium, F, Cl, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, methoxy, deuterated methoxy, fluoromethoxy, carboxyl, methoxycarbonyl, fluoromethoxycarbonyl, deuterated methoxycarbonyl, ethoxycarbonyl, fluoroethoxycarbonyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, pyridyl, -CONHR 9a ; R 9a is selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, cyclopropyl, fluorocyclopropyl; X 4 is selected from N; X 5 is selected from CH, N; X 6 is selected from N-methyl, S, O.
在本发明的一些最优选实施例中，结构单元选自：
或者 In some most preferred embodiments of the present invention, the structural unit Selected from:
or
在本发明的一些实施例中，式Ⅰ所示化合物中，L(左端与嗪环相连，右端与R6相连)选自O、-NH-、-NH-CH2-、-NH-CH(CH3)-。In some embodiments of the present invention, in the compound represented by formula I, L (the left end is connected to the azine ring, and the right end is connected to R 6 ) is selected from O, -NH-, -NH-CH 2 -, and -NH-CH(CH 3) -.
在本发明的一些实施例中，式Ⅰ所示化合物中，R6中，所述取代基选自氟、氯、羟基、氰基、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4烷氧基、C1-4氟代烷氧基、C1-4氘代烷氧基、3～6元环烷基、3～6元氟代环烷基、氨基、二甲基氨基、 In some embodiments of the present invention, in the compound of formula I, in R6 , the substituent is selected from fluorine, chlorine, hydroxyl, cyano, oxo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 deuterated alkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, C1-4 deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino, dimethylamino,
在本发明的一些实施例中，式Ⅰ所示化合物中，R6选自以下所述的结构：
In some embodiments of the present invention, in the compound represented by formula I, R 6 is selected from the following structures:
R13a和R13b独立地选自R8a、卤素、氧代基、-OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aC(＝O)R8b、-NR8aR8b、-SO2R8a、-SO2NR8aR8b、-NR8aSO2R8b、-CN；n3为0-6的整数。 R 13a and R 13b are independently selected from R 8a , halogen, oxo, —OR 8a , —SR 8a , —C(═O)R 8a , —OC(═O)R 8a , —C(═O)OR 8a , —C(═O)NR 8a R 8b , —NR 8a C(═O)R 8b , —NR 8a R 8b , —SO 2 R 8a , —SO 2 NR 8a R 8b , —NR 8a SO 2 R 8b , —CN; n3 is an integer of 0-6.
在本发明的一些优选实施例中，式Ⅰ所示化合物中，R13a和R13b独立地选自R8a、氟、氧代基、-OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aC(＝O)R8b、-NR8aR8b、-SO2R8a、-SO2NR8aR8b、-NR8aSO2R8b、-CN；n3为0-3的整数。In some preferred embodiments of the present invention, in the compound represented by formula I, R 13a and R 13b are independently selected from R 8a , fluorine, oxo, -OR 8a , -SR 8a , -C(＝O)R 8a , -OC(＝O)R 8a , -C(＝O)OR 8a , -C(＝O)NR 8a R 8b , -NR 8a C(＝O)R 8b , -NR 8a R 8b , -SO 2 R 8a , -SO 2 NR 8a R 8b , -NR 8a SO 2 R 8b , -CN; n3 is an integer of 0-3.
在本发明的一些更优选实施例中，式Ⅰ所示化合物中，R13a和R13b独立地选自氟、氯、羟基、氰基、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4烷氧基、C1-4氟代烷氧基、C1-4氘代烷氧基、3～6元环烷基、3～6元氟代环烷基、氨基、二甲基氨基、 In some more preferred embodiments of the present invention, in the compound of formula I, R 13a and R 13b are independently selected from fluorine, chlorine, hydroxyl, cyano, oxo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino, dimethylamino,
在本发明的一些最优选实施例中，式Ⅰ所示化合物中，R6选自以下结构：

In some most preferred embodiments of the present invention, in the compound represented by formula I, R 6 is selected from the following structures:

本发明还提供了一些具体化合物，所述化合物选自：
The present invention also provides some specific compounds, which are selected from:
在本发明的一些更优选实施例中，式Ⅰ所示化合物中，除前述的R3选自氢、氘、F、Cl、甲基、氟代甲基、氘代甲基、甲硫基、氟代甲硫基、氘代甲硫基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基、氟代环丙基、乙烯基、乙炔基、苯基、氟代苯基、氘代苯基外，R3还能选自丙炔基、氟代丙炔基、环丙基炔基、吡啶基、氟代吡啶基、嘧啶基、氟代嘧啶基。In some more preferred embodiments of the present invention, in the compounds represented by formula I, in addition to the aforementioned R 3 being selected from hydrogen, deuterium, F, Cl, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl, R 3 can also be selected from propynyl, fluoropropynyl, cyclopropylalkynyl, pyridyl, fluoropyridyl, pyrimidinyl, fluoropyrimidinyl.
在本发明的一些最优选实施例中，式Ⅰ所示化合物中，除前述的结构单元选自：外，结构单元还能选自： In some of the most preferred embodiments of the present invention, in the compounds represented by formula I, except for the aforementioned structural units Selected from: In addition, the structural unit You can also choose from:
在本发明的一些实施例中，式Ⅰ所示化合物中，除前述的R6选自： 外，R6还能选自以下所述的结构： In some embodiments of the present invention, in the compound represented by formula I, except for the aforementioned R 6 is selected from: In addition, R6 can also be selected from the following structures:
在本发明的一些最优选实施例中，式Ⅰ所示化合物中，除前述的R6选自： 外，R6还能选自以下结构： In some of the most preferred embodiments of the present invention, in the compound represented by formula I, except for the aforementioned R 6 is selected from: In addition, R6 can also be selected from the following structures:
本发明还提供了一些具体化合物，所述化合物选自：
The present invention also provides some specific compounds, which are selected from:
在本发明的一些最优选实施例中，式Ⅰ所示化合物中，除前述的结构单元选自：以及结构单元选自：外，结构单元还能选自： In some of the most preferred embodiments of the present invention, in the compounds represented by formula I, except for the aforementioned structural units Selected from: And structural units Selected from: In addition, the structural unit You can also choose from:
在本发明的一些最优选实施例中，式Ⅰ所示化合物中，除前述的R6选自： 以及R6选自：外，R6还能选自以下结构： In some of the most preferred embodiments of the present invention, in the compound represented by formula I, except for the aforementioned R 6 is selected from: and R6 is selected from: In addition, R6 can also be selected from the following structures:
本发明还提供了一些具体化合物，所述化合物选自：
The present invention also provides some specific compounds, which are selected from:
第二方面，本发明提供了一种药物组合物，其以前述式I化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药为活性成分，辅以药学上可接受的载体。In a second aspect, the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula I or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug as an active ingredient, supplemented with a pharmaceutically acceptable carrier.
本发明的进一步的目的在于提供一种制备本发明的药物组合物的方法，所述方法包 括将含式I化合物或其药学上可接受的形式、或者它们的混合物、与一种或多种药学上可接受的载体组合。A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, the method comprising The invention relates to combining a compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.
在本发明的药物组合物中可使用的药学上可接受的载体为药学上可接受的载体，适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(2005)中所述。The pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier. Examples of suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (2005).
药物组合物可以以任意形式施用，只要其实现预防、减轻、防止或者治愈人类或动物患者的症状即可。例如，可根据给药途径制成各种适宜的剂型。The pharmaceutical composition can be administered in any form as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient. For example, it can be prepared into various suitable dosage forms according to the administration route.
在另一些实施方案中，本发明的化合物或药物组合物的施用可以与另外的治疗方法组合。所述另外的治疗方法可以选自，但不限于：放射疗法、化疗疗法、免疫疗法，或其组合。In other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention may be combined with another therapeutic method. The other therapeutic method may be selected from, but not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.
本发明还涉及一种药物制剂，其以上述式I化合物或其药学上可接受的形式、或它们的混合物、或者本发明的药物组合物作为活性成分。在一些实施方案中，所述制剂的形式为固体制剂、半固体制剂、液体制剂或气态制剂。The present invention also relates to a pharmaceutical preparation, which uses the above-mentioned compound of formula I or its pharmaceutically acceptable form, or a mixture thereof, or a pharmaceutical composition of the present invention as an active ingredient. In some embodiments, the preparation is in the form of a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
本发明的进一步的目的在于提供一种制品，例如以试剂盒形式提供。本文所用的制品意图包括但不限于药盒和包装。本发明的制品包含：(a)第一容器；(b)位于第一容器中的药物组合物，其中所述组合物包含：第一治疗剂，所述第一治疗剂包括：含式I化合物或其药学上可接受的形式、或者它们的混合物；(c)任选存在的包装说明书，其说明所述药物组合物可用于治疗肿瘤病症(如下文所定义)；和(d)第二容器。A further object of the present invention is to provide an article of manufacture, for example, in the form of a kit. Articles of manufacture as used herein are intended to include, but are not limited to, kits and packages. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent, the first therapeutic agent comprising: a compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.
所述第一容器为用于容纳药物组合物的容器。此容器可用于制备、储存、运输和/或独立/批量销售。第一容器意图涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如用于乳膏制品)，或者用于制备、容纳、储存或分配药物产品的任何其它容器。The first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and/or individual/batch sales. The first container is intended to cover bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing or dispensing pharmaceutical products.
所述第二容器为用于容纳所述第一容器和任选包装说明书的容器。所述第二容器的实例包括但不限于盒(例如纸盒或塑料盒)、箱、纸箱、袋(例如纸袋或塑料袋)、小袋和粗布袋。所述包装说明书可经由扎带、胶水、U形钉或别的粘附方式物理粘附于所述第一容器的外部，或者其可放在所述第二容器的内部，而无需与所述第一容器粘附的任何物理工具。或者，所述包装说明书位于所述第二容器的外面。当位于所述第二容器的外面时，优选的是所述包装说明书经由扎带、胶水、U形钉或别的粘附方式物理粘附。或者，其可邻接或接触所述第二容器的外部，而无需物理粘附。The second container is a container for accommodating the first container and optional package instructions. Examples of the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package instructions may be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion means, or they may be placed inside the second container without any physical tool for adhesion to the first container. Alternatively, the package instructions are located outside the second container. When located outside the second container, it is preferred that the package instructions are physically adhered via a cable tie, glue, staples, or other adhesion means. Alternatively, it may abut or contact the outside of the second container without physical adhesion.
所述包装说明书为商标、标签、标示等，其列举了与位于所述第一容器内的药物组合物相关的信息。所列出的信息通常由管辖待销售所述制品的区域的管理机构(例如美国食品与药品管理局)决定。优选所述包装说明书具体列出了所述药物组合物获准用于的适应症。所述包装说明书可由任何材料制成，可从所述材料上读取包含于其中或其上 的信息。优选所述包装说明书为可印刷材料(例如纸、塑料、卡纸板、箔、胶粘纸或塑料等)，其上可形成(例如印刷或施涂)所需信息。The package insert is a trademark, label, indicia, etc., which lists information related to the pharmaceutical composition located in the first container. The information listed is generally determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material from which information contained therein or thereon can be read. Preferably, the package insert is a printable material (eg, paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (eg, printed or applied).
第三方面，本发明提供前述式I化合物，及相关具体化合物或其药学上可接受的形式、或者本发明的药物组合物在制备用于预防或治疗NLRP3相关疾病的药物中的用途。In a third aspect, the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating NLRP3-related diseases.
本发明提供一种用于预防或治疗NLRP3相关疾病的方法，所述方法包括向有此需要的个体施用上述式I化合物或其药学上可接受的形式、或者本发明的药物组合物。The present invention provides a method for preventing or treating NLRP3-related diseases, comprising administering the compound of formula I or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of the present invention to an individual in need thereof.
本发明提供上述式I化合物或其药学上可接受的形式或者本发明的药物组合物与另外的治疗方法组合用于预防或治疗NLRP3相关疾病的方法，所述另外的治疗方法包括但不限于：放射疗法、化疗疗法，免疫疗法、或其组合。The present invention provides a method for preventing or treating NLRP3-related diseases in combination with the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention and another treatment method, wherein the other treatment method includes but is not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.
在一些实施方案中，所述NLRP3相关疾病包括：炎性疾病、自身免疫疾病、心血管系统疾病、癌症、肾系统疾病、胃肠道疾病、呼吸系统疾病、内分泌系统疾病或者中枢神经系统疾病。In some embodiments, the NLRP3-related disease includes: inflammatory disease, autoimmune disease, cardiovascular disease, cancer, renal disease, gastrointestinal disease, respiratory disease, endocrine disease or central nervous system disease.
在一些实施方案中，所述NLRP3相关疾病包括：隐热蛋白相关周期综合征(CAPS)、穆克尔-韦尔斯综合征(MWS)、家族性寒冷性自身炎性综合征(FCAS)、新生儿发病多系统炎性疾病(NOMID)、家族性地中海热(FMF)、非酒精性脂肪性肝炎、酒精性肝病、移植物抗宿主病、多发性硬化(MS)、类风湿性关节炎、I型/II型糖尿病及相关并发症(例如肾病、视网膜病)、牛皮癣、阿尔茨海默氏病、动脉粥样硬化、痛风、慢性肾疾病、脓毒症、肝纤维化、特发性肺纤维化、癫痫、神经病理性疼痛、抑郁症、帕金森病、哮喘、急性心肌梗塞、红斑狼疮、类风湿关节炎、克罗恩氏病、溃疡性结肠炎、炎症性肠病、类风湿性关节炎、强制性脊髓炎、支气管哮喘、急性呼吸窘迫综合征、慢性阻塞性肺部疾病或者缺血性中风。In some embodiments, the NLRP3-related diseases include: cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I/type II diabetes and related complications (e.g., nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing myelitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke.
在进一步优选的实施方案中，本发明的化合物可以与放化疗或免疫疗法联用以预防或治NLRP3相关疾病。In a further preferred embodiment, the compounds of the present invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat NLRP3-related diseases.
本发明的有益效果：Beneficial effects of the present invention:
本发明提供了一类六元氮杂环类化合物，该类化合物及组合物能够用于制备NLRP3炎性小体抑制剂，为治疗NLRP3相关疾病提供了新途径。The present invention provides a class of six-membered nitrogen heterocyclic compounds, which can be used to prepare NLRP3 inflammasome inhibitors, providing a new approach for treating NLRP3-related diseases.
术语定义：Definition of terms:
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的或开放式的，且不排除其它未列举的元素 或方法步骤。本领域技术人员应当理解，上述术语如“包括”涵盖“由…组成”的含义。Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The terms "include", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements. Those skilled in the art will appreciate that the above terms such as "comprising" include the meaning of "consisting of".
在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的赋型剂的组合物，可以被解释为表示该组合物包括“一种或多种”药学上可接受的赋型剂。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Therefore, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the composition includes "one or more" pharmaceutically acceptable excipients.
例如，表述“C1-4”应理解为涵盖其中的任意亚范围以及每个点值，例如C2-4、C3-4、C1-2、C1-3、C1-4等，以及C1、C2、C3、C4等。For example, the expression "C 1-4 " should be understood to cover any sub-ranges and each point value therein, such as C 2-4 , C 3-4 , C 1-2 , C 1-3 , C 1-4 , etc., as well as C 1 , C 2 , C 3 , C 4 , etc.
本文中使用，除非另有说明，表示单键或者双键。As used herein, unless otherwise stated, Indicates a single bond or a double bond.
在本发明中，除非另有说明，卤素是指氟、氯、溴或碘。In the present invention, unless otherwise specified, halogen means fluorine, chlorine, bromine or iodine.
在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“C1-4烷基”中的C1-4是指包含有1、2、3或4个碳原子的直链或支链形式排列的基团。In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, C1-4 in " C1-4 alkyl" refers to a group containing 1, 2, 3 or 4 carbon atoms arranged in a linear or branched form.
在本发明中，除非另有说明，“环烷基”、“碳环”或“亚环烷基”是指饱和或部分饱和的，单环或多环(诸如双环)的非芳香族烃基。常见的环烷基包括(但不限于)单环环烷基，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环丁烯、环戊烯、环己烯等；或双环环烷基，包括稠环、桥环或螺环，诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基、双环[5.2.0]壬基、十氢化萘基等。例如，“C 3-12环烷基”指具有3-12个环碳原子(如3、4、5、6、7、8、9、10、11或12个)的环烷基。本发明中的环烷基或亚环烷基任选地被一个或多个本发明所描述的取代基取代。In the present invention, unless otherwise specified, "cycloalkyl", "carbocycle" or "cycloalkylene" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decalinyl, etc. For example, "C 3-12 cycloalkyl" refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12). The cycloalkyl or cycloalkylene group in the present invention is optionally substituted by one or more substituents described in the present invention.
在本发明中，除非另有说明，“氟代烷基”指上文所述的烷基，其中一个或多个氢原子被氟原子代替。例如，术语“C1-4氟代烷基”指任选地被一个或多个(如1-3个)氟原子取代的C1-4烷基。本领域技术人员应当理解，当氟原子取代基多于一个时，氟原子可以相同也可以不同，并且可以位于相同或不同的C原子上。卤代烷基的实例有例如-CH2F、-CHF2、-CF3、-C2F5、-CH2CF3、-CH2CH2CF3等。本发明中的氟代烷基任选地被一个或多个本发明所描述的取代基取代。In the present invention, unless otherwise specified, "fluoroalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by fluorine atoms. For example, the term "C 1-4 fluoroalkyl" refers to a C 1-4 alkyl group optionally substituted by one or more (e.g., 1-3) fluorine atoms. It will be understood by those skilled in the art that when there are more than one fluorine atom substituents, the fluorine atoms may be the same or different, and may be located on the same or different C atoms. Examples of haloalkyl groups include, for example, -CH 2 F, -CHF 2 , -CF 3 , -C 2 F 5 , -CH 2 CF 3 , -CH 2 CH 2 CF 3 , etc. The fluoroalkyl group in the present invention is optionally substituted by one or more substituents described in the present invention.
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(2H)、氚(3H))；碳的同位素(例如13C及14C)；氯的同位素(例如37Cl)；碘的同位素(例如125I)；氮的同位素(例如13N及15N)；氧的同位素(例如17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如34S)。 The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g., 13C and 14C ); isotopes of chlorine (e.g., 37Cl); isotopes of iodine (e.g., 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 17O and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 34S ).
在本发明中，“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同的固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单一水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真是的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。本发明还涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。In the present invention, "polymorph" refers to different solid crystalline phases produced by the presence of two or more different molecular arrangements in the solid state of certain compounds of the present invention. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof. Generally, crystallization will produce a solvate of the compound of the present invention. The term "solvate" used in the present invention refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compound of the present invention may exist as a hydrate, including a single hydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, etc., and corresponding solvated forms. The compound of the present invention may form a true solvate, but in some cases, it may also retain only adventitious water or a mixture of water plus a portion of an adventitious solvent. The compound of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compound of the present invention are also included within the scope of the present invention. The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
在本发明中，“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体。要理解，本发明的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。In the present invention, "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It is to be understood that the scope of the present invention encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
在本发明中，药学上可接受的盐包括其酸加成盐及碱加成盐。适合的酸加成盐由形成药学可接受盐的酸来形成。适合的碱加成盐由形成药学可接受盐的碱来形成。适合的盐的综述参见例如“Remington′s Pharmaceutical Sciences”，Mack Publishing Company,Easton,Pa.,(2005)；和“药用盐手册：性质、选择和应用”(Handbook of Pharmaceutical Salts：Properties,Selection,and Use)，Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草 酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-胺基水杨酸盐、萘二磺酸盐等。这些盐可通过本专利已知的方法制备。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱己咖啡因。这些盐可通过本专利已知的方法制备。In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. For a review of suitable salts, see, for example, "Remington's Pharmaceutical Sciences", Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, thiazolyl salt, thiazolyl salt, oxalate ... The invention relates to pharmaceutically acceptable base addition salts, such as succinate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in this patent. "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include but are not limited to sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts and magnesium salts. The salt derived from organic base includes but is not limited to the following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline hexyl caffeine. These salts can be prepared by methods known to this patent.
在本发明中，除非另有说明，“酯”指衍生自本文所描述的化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。In the present invention, unless otherwise indicated, "ester" refers to esters derived from the compounds described herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form). The compounds of the present invention themselves may also be esters.
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成氮氧化物。本领域技术人员会识别能够形成氮氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成氮氧化物。用于制备杂环和叔胺的氮氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(mCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备氮氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750(A.R.Katritzky和A.J.Boulton,Eds.,Academic Press)；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392(A.R.Katritzky和A.J.Boulton,Eds.,Academic Press)。Those skilled in the art will appreciate that, since nitrogen requires available lone pairs of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles are capable of forming nitrogen oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitrogen oxides. The synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane. These methods for preparing nitrogen oxides have been widely described and reviewed in the literature, see, for example: T.L.Gilchrist, Comprehensive Organic Synthesis, vol.7, pp.748-750 (A.R.Katritzky and A.J.Boulton, Eds., Academic Press); and G.W.H.Cheeseman and E.S.G.Werstiuk, Advances in Heterocyclic Chemistry, vol.22, pp.390-392 (A.R.Katritzky and A.J.Boulton, Eds., Academic Press).
在本发明中，“代谢物”指在给药本发明的化合物时体内形成的物质。化合物的代 谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过试验的方法进行表征。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。In the present invention, "metabolites" refer to substances formed in the body when a compound of the present invention is administered. Metabolites can be identified by techniques known in the art, and their activity can be characterized by experimental methods. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with mammals for a period of time sufficient to produce their metabolites.
在本发明中，“前药”指本发明化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其它信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。In the present invention, "prodrug" refers to certain derivatives of the compounds of the present invention that can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered into or onto the body. Typically such prodrugs will be functional group derivatives of the compound that are easily converted into the desired therapeutically active compound in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain parts known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收，进而发挥生物活性。In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可或为接受供人类或家畜使用的佐剂、载体、赋型剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved or accepted by relevant governmental regulatory authorities for use in humans or livestock.
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其他治疗”、“施用其他治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。As used herein, the terms "drug combination", "drug combination", "combination therapy", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, combined administration or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapies, for example the administration of three or more active ingredients.
在本发明中，除非另有说明，“肿瘤”包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻炎癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。In the present invention, unless otherwise specified, "tumor" includes but is not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the lung, adenocarcinoma of the lung, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, rhinitis cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.
在本发明中，除非另有说明，“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一种或多种症状的进展，或预防这样的病症或病况 或者这样的病症或病况的一种或多种症状。In the present invention, unless otherwise indicated, "treating" means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition, or preventing such disorder or condition. or one or more symptoms of such a disorder or condition.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.
具体实施方式DETAILED DESCRIPTION
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。The scheme of the present invention will be explained below in conjunction with embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are followed.
表1本发明中字母缩写及其含义

Table 1 Abbreviations and their meanings in the present invention

本发明所述化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)内标为四甲基硅烷(TMS)化学位移是以10-6(ppm)作为单位给出。The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, tetramethylsilane (TMS) as the internal standard, and chemical shifts are given in units of 10 -6 (ppm).
MS的测定用Agilent SQD(ESI)质谱仪(生产商：Agilent，信号：6110)。MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfirc C18,150X 4.6mm,5wn,色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18,150X 4.5mm,5ym色谱柱)。HPLC determinations were performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5wn, chromatographic column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150X 4.5mm, 5ym chromatographic column).
薄层层析硅胶板使用青岛海洋GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.2mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm硅胶板。The thin layer chromatography silica gel plate used was Qingdao Ocean GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the thin layer chromatography separation and purification product used a 0.4mm-0.5mm silica gel plate.
柱层析一般使用青岛海洋100-200、200-300目硅胶为载体。Column chromatography generally uses Qingdao Ocean 100-200, 200-300 mesh silica gel as the carrier.
以下实施例中无特殊说明，反应均在氩气氛围或氮气氛围下进行。氩气氛围或氮气氛围是指反应瓶连接一个约1L容积的氩气或氮气气球。氢气氛围是指反应瓶连接一个约1L容积的氢气气球。氢化反应通常抽真空，充入氢气，反复操作3次。Unless otherwise specified in the following examples, the reactions were carried out under an argon atmosphere or a nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L. Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 L. The hydrogenation reaction is usually evacuated, filled with hydrogen, and the operation is repeated 3 times.
中间体INT1：2-(4-甲氧基苯并[b]噻吩-5-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
Intermediate INT1: 2-(4-methoxybenzo[b]thiophene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
第一步：将CuBr2(146.5g,656mmol)加入到EtOAc(250mL)中，80℃搅拌10分钟。然后将化合物INT1a(25.0g,164mmol)溶于氯仿(250mL)中再加入到上述悬浮液中，80℃回流反应过夜。反应完全后减压浓缩，残余物用EtOAc(500mL)打浆0.5h，过滤，滤液浓缩至干得到目标化合物INT1b(46.0g,148mmol，浅棕色固体，产率90％),MS:[M+H]+＝309.0,311.0,313.0。Step 1: Add CuBr 2 (146.5 g, 656 mmol) to EtOAc (250 mL) and stir at 80°C for 10 minutes. Then dissolve compound INT1a (25.0 g, 164 mmol) in chloroform (250 mL) and add to the above suspension, reflux at 80°C overnight. After the reaction is complete, concentrate under reduced pressure, slurry the residue with EtOAc (500 mL) for 0.5 h, filter, and concentrate the filtrate to dryness to obtain the target compound INT1b (46.0 g, 148 mmol, light brown solid, yield 90%), MS: [M+H] + = 309.0, 311.0, 313.0.
第二步：将化合物INT1b(45.0g,145mmol)和Li2CO3(26.8g,363mmol)加入到DMF(450mL)中，100℃搅拌6h。反应完全后过滤，滤液用盐酸水溶液(900mL,0.5N)处理，EtOAc(400mL×2)萃取，有机相再用水(300mL×2)洗涤，无水Na2SO4干燥，过滤，浓缩得到目标化合物INT1c(31.0g,135mmol，浅棕色固体，产率93％)，MS:[M-H]-＝227.0,229.0。Step 2: Add compound INT1b (45.0 g, 145 mmol) and Li 2 CO 3 (26.8 g, 363 mmol) to DMF (450 mL) and stir at 100°C for 6 h. After the reaction is complete, filter and treat the filtrate with aqueous hydrochloric acid (900 mL, 0.5 N), extract with EtOAc (400 mL×2), wash the organic phase with water (300 mL×2), dry over anhydrous Na 2 SO 4 , filter and concentrate to obtain the target compound INT1c (31.0 g, 135 mmol, light brown solid, yield 93%), MS: [MH] - = 227.0, 229.0.
第三步：将化合物INT1c(15.0g,65.5mmol)和K2CO3(18.1g,131mmol)加入到MeCN(150mL)中，然后加入Me2SO4(9.9g,78.6mmol),氮气保护下60℃搅拌过夜。反应降温至室温，过滤，向滤液中加入硅胶(30g)，然后减压浓缩至干，用柱层析分离 (PE:EtOAc＝10:1)得到目标化合物INT1d(13.7g,56.4mmol，白色固体，产率86％),1H NMR(400MHz,CDCl3)δ7.51-7.46(m,2H),7.45-7.42(m,2H),4.00(s,3H)。Step 3: Add compound INT1c (15.0 g, 65.5 mmol) and K 2 CO 3 (18.1 g, 131 mmol) to MeCN (150 mL), then add Me 2 SO 4 (9.9 g, 78.6 mmol), and stir overnight at 60°C under nitrogen protection. Cool the reaction mixture to room temperature, filter, add silica gel (30 g) to the filtrate, then concentrate to dryness under reduced pressure, and separate by column chromatography. (PE:EtOAc=10:1) to give the target compound INT1d (13.7 g, 56.4 mmol, white solid, yield 86%), 1 H NMR (400 MHz, CDCl 3 ) δ7.51-7.46 (m, 2H), 7.45-7.42 (m, 2H), 4.00 (s, 3H).
第四步：将化合物INT1d(13.7g,56.4mmol),双联频哪醇硼酸酯(17.2g,67.7mmol),KOAc(11.1g,113mmol)和Pd(PPh3)Cl2(2.00g,2.82mmol)加入到二氧六环(137mL)中，氮气保护下90℃反应12h。反应后过滤，滤液中加入30g硅胶，减压浓缩旋干，用柱层析分离(PE:EtOAc＝30:1)得到目标化合物INT1(7.6g,26.2mmol，无色固体，产率46％),1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.49(d,J＝5.6Hz,1H),7.35(d,J＝5.2Hz,1H),4.00(s,3H),1.39(s,12H)。Step 4: Compound INT1d (13.7 g, 56.4 mmol), bis-pinacol borate (17.2 g, 67.7 mmol), KOAc (11.1 g, 113 mmol) and Pd(PPh 3 )Cl 2 (2.00 g, 2.82 mmol) were added to dioxane (137 mL) and reacted at 90° C. for 12 h under nitrogen protection. After the reaction, the reaction mixture was filtered, 30 g of silica gel was added to the filtrate, the mixture was concentrated under reduced pressure and dried, and the target compound INT1 (7.6 g, 26.2 mmol, colorless solid, yield 46%) was obtained by column chromatography (PE:EtOAc=30:1), 1 H NMR (400 MHz, CDCl 3 )δ7.67(d, J=8.0 Hz, 1H), 7.61(d, J=8.0 Hz, 1H), 7.49(d, J=5.6 Hz, 1H), 7.35(d, J=5.2 Hz, 1H), 4.00(s, 3H), 1.39(s, 12H).
中间体INT2：6-溴-3-氯-4-甲基-1,2,4-三嗪-5(4H)-酮
Intermediate INT2: 6-bromo-3-chloro-4-methyl-1,2,4-triazine-5(4H)-one
第一步：将化合物INT2a(10g,57.15mmol)，氯化亚铜(11g，111.11mmol)置于封管中，后加入亚硝酸叔丁酯(12g，116.50mmol)，乙腈(35mL)，加完后迅速密封封管，升温至80℃下反应4h，反应结束后浓缩反应液，残余物经柱层析纯化，10％EA：PE洗脱产物，浓缩，得淡黄色固体产物INT2b(5.31g)。LC-MS:ESI[M+H]+＝193.0。Step 1: Compound INT2a (10 g, 57.15 mmol) and cuprous chloride (11 g, 111.11 mmol) were placed in a sealed tube, and then tert-butyl nitrite (12 g, 116.50 mmol) and acetonitrile (35 mL) were added. After the addition, the tube was quickly sealed and heated to 80°C for 4 h. After the reaction, the reaction solution was concentrated and the residue was purified by column chromatography. The product was eluted with 10% EA:PE and concentrated to obtain a light yellow solid product INT2b (5.31 g). LC-MS: ESI [M+H] + = 193.0.
第二步：将化合物INT2b(5.31g，25.24mmol)置于反应瓶中，加入醋酸(25mL)，后置于冰浴中，缓慢滴加双氧水(5mL)，加完后缓慢恢复至室温下反应过夜，反应结束后加入硫代硫酸钠水溶液淬灭反应，后加入EA,5％TEA萃取，浓缩有机相，残余物经柱层析纯化，得淡黄色固体产物INT2c(5.12g)。LC-MS:ESI[M+H]+＝209.1。Step 2: Compound INT2b (5.31 g, 25.24 mmol) was placed in a reaction bottle, acetic acid (25 mL) was added, and then placed in an ice bath, and hydrogen peroxide (5 mL) was slowly added dropwise. After the addition, the mixture was slowly returned to room temperature and reacted overnight. After the reaction was completed, sodium thiosulfate aqueous solution was added to quench the reaction, and then EA and 5% TEA were added for extraction. The organic phase was concentrated, and the residue was purified by column chromatography to obtain a light yellow solid product INT2c (5.12 g). LC-MS: ESI [M+H] + = 209.1.
第三步：将化合物INT2c(3g，14.26mmol)置于三口瓶中，氮气保护，加入无水DMF(30mL)，反应置于冰浴中，缓慢加入NaH(1.15g，28.79mmol)，加完后恢复至室温下反应1h，后缓慢滴加碘甲烷(2.02g,14.26mmol)，加完后室温下反应过夜。反应结束后加水淬灭反应，加入EA萃取，饱和食盐水洗，干燥，浓缩，残余物经柱层析纯化，得白色固体产物INT2(0.8g)。LC-MS:ESI[M+H]+＝224.0。1H NMR(400MHz,DMSO-d6)δ3.45(s,3H)。Step 3: Compound INT2c (3 g, 14.26 mmol) was placed in a three-necked flask, nitrogen was protected, anhydrous DMF (30 mL) was added, the reaction was placed in an ice bath, NaH (1.15 g, 28.79 mmol) was slowly added, and the reaction was restored to room temperature for 1 h after the addition, and then iodomethane (2.02 g, 14.26 mmol) was slowly added dropwise, and the reaction was allowed to proceed overnight at room temperature after the addition. After the reaction was completed, water was added to quench the reaction, EA was added for extraction, saturated brine was added for washing, drying, and concentration, and the residue was purified by column chromatography to obtain a white solid product INT2 (0.8 g). LC-MS: ESI [M + H] + = 224.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.45 (s, 3H).
中间体INT3：2-(1-(二氟亚甲基)-4-甲氧基-2,3-二氢-1H-茚-5-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
Intermediate INT3: 2-(1-(difluoromethylene)-4-methoxy-2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
第一步：将化合物3-溴-2-羟基苯甲醛INT3a(25.0g,104.65mmol),CH3I(60.63g,373.14mmol),K2CO3(34.38g,248.76mmol)溶于DMF(200mL)中,加热到50℃反应3小时。反应液中加入水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，得到目标化合物INT3b(黄色油状液体,22.5g,产率：84％)，无需进一步纯化，MS/ESI[M+H]+:215.1。Step 1: Dissolve compound 3-bromo-2-hydroxybenzaldehyde INT3a (25.0 g, 104.65 mmol), CH 3 I (60.63 g, 373.14 mmol), K 2 CO 3 (34.38 g, 248.76 mmol) in DMF (200 mL), heat to 50°C and react for 3 hours. Add water to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent from the filtrate under reduced pressure to obtain the target compound INT3b (yellow oily liquid, 22.5 g, yield: 84%), without further purification, MS/ESI [M+H] + : 215.1.
第二步：在0℃下，将Et3N(12.71g,125.58mmol)滴加到HCOOH(14.45g,313.95mmol)中，随后室温反应30分钟，然后加入溶有化合物INT3b(22.5g,104.65mmol)和丙二酸环(亚)异丙酯(15.08g,104.65mmol)的DMF(200mL)溶液,加热到100℃反应过夜。反应液中加入NaOH水溶液，调节pH＝9，乙酸乙酯萃取，水相加入HCl水溶液(3M)，调节pH＝5,乙酸乙酯萃取,合并有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，残留物柱层析分离(PE:EA＝5:1)得到目标化合物INT3c(白色固体，20.3g,产率：75％),MS/ESI[M+H]+:259.1。Step 2: At 0°C, Et 3 N (12.71 g, 125.58 mmol) was added dropwise to HCOOH (14.45 g, 313.95 mmol), followed by reaction at room temperature for 30 minutes, and then a DMF (200 mL) solution containing compound INT3b (22.5 g, 104.65 mmol) and cycloisopropyl malonate (15.08 g, 104.65 mmol) was added, and the mixture was heated to 100°C for reaction overnight. NaOH aqueous solution was added to the reaction solution to adjust pH=9, and ethyl acetate was used for extraction. HCl aqueous solution (3 M) was added to the aqueous phase to adjust pH=5, and ethyl acetate was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA=5:1) to obtain the target compound INT3c (white solid, 20.3 g, yield: 75%), MS/ESI [M+H] + : 259.1.
第三步：将多聚磷酸(200g)加热到90℃，加入化合物INT3c(20.3g,78.34mmol),反应一小时后停止加热，加入水溶液，待溶液冷却至室温，二氯甲烷萃取，饱和NaCl水溶液洗涤有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，残留物柱层析分离(PE:EA＝5:1)得到目标化合物INT3d(黄色固体，9.7g,产率：51.3％),MS/ESI[M+H]+:241.1。Step 3: Heat polyphosphoric acid (200 g) to 90°C, add compound INT3c (20.3 g, 78.34 mmol), stop heating after one hour of reaction, add aqueous solution, wait for the solution to cool to room temperature, extract with dichloromethane, wash the organic phase with saturated NaCl aqueous solution, dry over anhydrous sodium sulfate, filter, remove the solvent from the filtrate under reduced pressure, and separate the residue by column chromatography (PE:EA=5:1) to obtain the target compound INT3d (yellow solid, 9.7 g, yield: 51.3%), MS/ESI[M+H] + : 241.1.
第四步：将化合物INT3d(4.7g,19.50mmol),2-(二氟甲烷磺酰基)吡啶INT3e(5.65g,29.25mmol)溶于DMF(30mL)中，冷却至-50℃，氮气保护下加入叔丁醇钾的DMF溶液,升温至-40℃，反应3小时后，加入饱和氯化铵水溶液(26ml)淬灭，随后加入3N HCl(26ml),升温至室温，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，残留物柱层析分离(PE:EA＝20:1)得到目标化合物INT3f(黄色油状液体，1.92g,产率：35.8％)1H NMR(400MHz,CDCl3)δ7.53(d,J＝7.7Hz,1H),7.11(d,J＝7.7Hz,1H),3.75(s,3H),3.01-2.95(m,2H),2.76-2.65(m,2H)。 Step 4: Compound INT3d (4.7 g, 19.50 mmol) and 2-(difluoromethanesulfonyl)pyridine INT3e (5.65 g, 29.25 mmol) were dissolved in DMF (30 mL), cooled to -50°C, and a DMF solution of potassium tert-butoxide was added under nitrogen protection, and the temperature was raised to -40°C. After reacting for 3 hours, a saturated aqueous ammonium chloride solution (26 ml) was added to quench the reaction, and then 3N HCl (26 ml) was added. The temperature was raised to room temperature, and the reaction was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA=20:1) to obtain the target compound INT3f (yellow oily liquid, 1.92 g, yield: 35.8%). 1 H NMR (400 MHz, CDCl 3 )δ7.53(d,J＝7.7Hz,1H),7.11(d,J＝7.7Hz,1H),3.75(s,3H),3.01-2.95(m,2H),2.76-2.65(m,2H).
第五步：氮气保护下，将化合物INT3f(1.92g,6.98mmol)，联硼酸频那醇酯(2.66g,10.47mmol)，PdCl2(dppf)(0.57g,0.7mmol)，乙酸钾(2.05g,20.94mmol)溶于1,4-二氧六环溶液中，100℃回流过夜，反应完全后，恢复至室温，加水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，残留物柱层析分离(PE:EA＝10:1)得到目标化合物INT3(黄色固体，1.02g,产率：45.4％)。1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),3.81(s,3H),2.97-2.82(m,2H),2.62-2.51(m,2H),1.30(s,12H)。Step 5: Under nitrogen protection, compound INT3f (1.92 g, 6.98 mmol), bipyralidone (2.66 g, 10.47 mmol), PdCl 2 (dppf) (0.57 g, 0.7 mmol), potassium acetate (2.05 g, 20.94 mmol) were dissolved in 1,4-dioxane solution and refluxed at 100°C overnight. After the reaction was completed, the temperature was restored to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (PE:EA=10:1) to obtain the target compound INT3 (yellow solid, 1.02 g, yield: 45.4%). 1 H NMR (400MHz, CDCl 3 ) δ7.60 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 2.97-2.82 (m, 2H), 2.62-2.51 (m, 2H), 1.30 (s, 12H).
中间体INT4：2-(4-甲氧基苯并呋喃-5-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
Intermediate INT4: 2-(4-methoxybenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
第一步：将CuBr2(66g,223mmol)加入到EtOAc(120mL)中，80℃搅拌10分钟。然后将化合物INT4a(10g,136mmol)溶于氯仿(120mL)中再加入到上述悬浮液中，80℃回流反应过夜。反应完全后减压浓缩，残余物用EtOAc(200mL)打浆0.5h，过滤，滤液浓缩至干得到目标化合物INT4b(7.3g)。1H NMR(400MHz,Chloroform-d)δ7.39(d,J＝1.8Hz,1H),6.76(dt,J＝4.7,2.1Hz,1H),3.12(m,2H),3.05-2.98(m,2H)。Step 1: Add CuBr 2 (66 g, 223 mmol) to EtOAc (120 mL) and stir at 80°C for 10 minutes. Then dissolve compound INT4a (10 g, 136 mmol) in chloroform (120 mL) and add it to the above suspension, reflux at 80°C for overnight reaction. After the reaction is complete, concentrate under reduced pressure, slurry the residue with EtOAc (200 mL) for 0.5 h, filter, and concentrate the filtrate to dryness to obtain the target compound INT4b (7.3 g). 1 H NMR (400 MHz, Chloroform-d) δ7.39 (d, J＝1.8 Hz, 1H), 6.76 (dt, J＝4.7, 2.1 Hz, 1H), 3.12 (m, 2H), 3.05-2.98 (m, 2H).
第二步：将化合物INT4b(7.3g,25mmol)和Li2CO3(11g,150mmol)加入到DMF(70mL)中，100℃搅拌6h。反应完全后过滤，滤液用盐酸水溶液调节pH至1，EtOAc(150mL×3)萃取，有机相再用饱和食盐水洗涤，无水Na2SO4干燥，过滤，浓缩得到目标化合物INT4c(5.5g)。1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝2.2Hz,1H),7.34(d,J＝8.7Hz,1H),7.02(dd,J＝8.7,0.9Hz,1H),6.89(dd,J＝2.2,1.0Hz,1H),5.94(s,1H)。Step 2: Add compound INT4b (7.3 g, 25 mmol) and Li 2 CO 3 (11 g, 150 mmol) to DMF (70 mL) and stir at 100°C for 6 h. After the reaction is complete, filter the mixture, adjust the pH of the filtrate to 1 with aqueous hydrochloric acid, extract with EtOAc (150 mL×3), wash the organic phase with saturated brine, dry over anhydrous Na 2 SO 4 , filter, and concentrate to obtain the target compound INT4c (5.5 g). 1 H NMR (400 MHz, Chloroform-d) δ7.55 (d, J＝2.2 Hz, 1H), 7.34 (d, J＝8.7 Hz, 1H), 7.02 (dd, J＝8.7, 0.9 Hz, 1H), 6.89 (dd, J＝2.2, 1.0 Hz, 1H), 5.94 (s, 1H).
第三步：将化合物INT4c(5.5g,26mmol)和K2CO3(7.17g,52mmol)加入到MeCN(60mL)中，然后加入Me2SO4(4.1g,33mmol),氮气保护下60℃搅拌过夜。反应降温至室温，过滤，向滤液中加入硅胶，然后减压浓缩至干，柱层析分离(PE:EtOAc＝10:1)得到目标化合物INT4d(5g),1H NMR(400MHz,Chloroform-d)δ7.56(d,J＝2.3Hz,1H),7.42(d,J＝8.7Hz,1H),7.12(dd,J＝8.7,1.0Hz,1H),6.91(dd,J＝2.4,1.0Hz,1H),4.08(s,3H)。Step 3: Compound INT4c (5.5 g, 26 mmol) and K 2 CO 3 (7.17 g, 52 mmol) were added to MeCN (60 mL), and then Me 2 SO 4 (4.1 g, 33 mmol) was added, and stirred at 60°C overnight under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, and silica gel was added to the filtrate, and then concentrated to dryness under reduced pressure. The target compound INT4d (5 g) was obtained by column chromatography separation (PE: EtOAc = 10: 1), 1 H NMR (400 MHz, Chloroform-d) δ7.56 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.12 (dd, J = 8.7, 1.0 Hz, 1H), 6.91 (dd, J = 2.4, 1.0 Hz, 1H), 4.08 (s, 3H).
第四步：将化合物INT4d(1g,4.4mmol),双联频哪醇硼酸酯(2.2g,8.8mmol),KOAc(1.7g,17.6mmol)和Pd(dppf)Cl2(322mg,0.44mmol)加入到二氧六环(15mL)中，氮气保护下90℃反应12h。反应后过滤，滤液中加入硅胶，减压浓缩旋干，柱层析分离(PE:EtOAc＝10:1)得到目标化合物INT4(410mg),1H NMR(400MHz,Chloroform-d) δ7.63(d,J＝8.3Hz,1H),7.54(d,J＝2.2Hz,1H),7.22(dd,J＝8.3,1.0Hz,1H),6.90(dd,J＝2.2,1.0Hz,1H),4.05(s,3H),1.37(s,12H)。Step 4: Add compound INT4d (1g, 4.4mmol), bis-pinacol borate (2.2g, 8.8mmol), KOAc (1.7g, 17.6mmol) and Pd(dppf)Cl 2 (322mg, 0.44mmol) to dioxane (15mL), and react at 90°C for 12h under nitrogen protection. After the reaction, filter, add silica gel to the filtrate, concentrate under reduced pressure and spin dry, and separate by column chromatography (PE:EtOAc＝10:1) to obtain the target compound INT4 (410mg), 1H NMR (400MHz, Chloroform-d) δ7.63(d,J＝8.3Hz,1H),7.54(d,J＝2.2Hz,1H),7.22(dd,J＝8.3,1.0Hz,1H),6.90(dd,J＝2.2,1.0Hz,1H),4.05(s,3H),1.37(s,12H).
中间体INT5：2-(2-甲氧基-6-甲基-4-三氟甲基苯基)-4，4，5，5-四甲基-1，3，2-二氧杂硼烷
Intermediate INT5: 2-(2-methoxy-6-methyl-4-trifluoromethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
第一步：称取INT5a(21.7g,90.8mmol)，LiOH.H2O(11.4g，272mmol),Pd2(dba)3(1.7g,1.82mmol)和BippyPhos(1.8g,3.63mmol)加入到烧瓶中，然后加入二氧六环(220mL)和水(22mL),用N2置换三次，100℃回流反应过夜。反应冷却至室温，垫一层硅藻土过滤，然后用EtOAc(100mL)淋洗，滤液用1M盐酸洗涤(50mL)，收集有机相，用无水Na2SO4干燥，加硅胶减压旋干过柱纯化(PE:EtOAc＝5：1,KMnO4显色)，得到目标化合物INT5b(14.1g,80.0mmol，淡黄色液体，产率88％),MS:[M-H]+＝175.0。Step 1: Weigh INT5a (21.7 g, 90.8 mmol), LiOH.H 2 O (11.4 g, 272 mmol), Pd 2 (dba) 3 (1.7 g, 1.82 mmol) and BippyPhos (1.8 g, 3.63 mmol) into a flask, then add dioxane (220 mL) and water (22 mL), replace with N 2 three times, and reflux at 100°C for overnight. The reaction mixture was cooled to room temperature, filtered through a layer of celite, and then rinsed with EtOAc (100 mL). The filtrate was washed with 1 M hydrochloric acid (50 mL), and the organic phase was collected, dried over anhydrous Na 2 SO 4 , added with silica gel and dried under reduced pressure, and purified by column chromatography (PE:EtOAc=5:1, KMnO 4 color development) to obtain the target compound INT5b (14.1 g, 80.0 mmol, light yellow liquid, yield 88%), MS: [MH] + =175.0.
第二步：将化合物INT5b(14.0g,79.5mmol)溶于甲苯(280mL)，降温冷却至0℃，然后分批加入NaH(6.36g，159mmol，60％),加毕，0℃保温搅拌反应1h。然后向上述悬浮液中分批加入I2(20.2g，79.5mmol)，加毕0℃保温搅拌反应1h。反应完全后用水淬灭，用2M盐酸调pH～5，用EtOAc萃取，无水Na2SO4干燥，过滤，滤液减压旋干，用柱层析分离(PE:EtOAc＝5:1，KMnO4显色)得到目标化合物INT5c(20.7g,68.5mmol，淡黄色固体，产率86％)，MS:[M-H]-＝301。Step 2: Compound INT5b (14.0 g, 79.5 mmol) was dissolved in toluene (280 mL), cooled to 0°C, and then NaH (6.36 g, 159 mmol, 60%) was added in batches. After addition, the mixture was stirred at 0°C for 1 h. Then I2 (20.2 g, 79.5 mmol) was added in batches to the above suspension. After addition, the mixture was stirred at 0°C for 1 h. After the reaction was complete, the mixture was quenched with water, the pH was adjusted to 5 with 2M hydrochloric acid, extracted with EtOAc, dried over anhydrous Na 2 SO 4 , filtered, the filtrate was dried under reduced pressure, and separated by column chromatography (PE:EtOAc=5:1, KMnO 4 for color development) to obtain the target compound INT5c (20.7 g, 68.5 mmol, light yellow solid, yield 86%), MS: [MH] - = 301.
第三步：将化合物INT5c(20.7g,68.5mmol)和K2CO3(18.9g,137mmol)加入到丙酮(200mL)中，然后加入MeI(14.6g,103mmol),25℃下搅拌过夜。反应完全后过滤，然后向滤液中加入硅胶，减压浓缩至干，用柱层析分离(PE:EtOAc＝20:1，紫外显色)得到目标化合物INT5d(6.20g,19.6mmol，白色固体，产率29％),1H NMR(400MHz,CDCl3)δ7.13(s,1H),6.82(s,1H),3.93(s,3H),2.53(s,3H)。Step 3: Compound INT5c (20.7 g, 68.5 mmol) and K 2 CO 3 (18.9 g, 137 mmol) were added to acetone (200 mL), and then MeI (14.6 g, 103 mmol) was added, and stirred at 25°C overnight. After the reaction was complete, the mixture was filtered, and then silica gel was added to the filtrate, and the mixture was concentrated to dryness under reduced pressure. The target compound INT5d (6.20 g, 19.6 mmol, white solid, yield 29%) was obtained by column chromatography (PE:EtOAc=20:1, UV color development), 1 H NMR (400 MHz, CDCl 3 )δ7.13(s,1H),6.82(s,1H),3.93(s,3H),2.53(s,3H).
第四步：将化合物INT5d(6.10g,19.3mmol),2-(二环己基膦基)联苯(0.676g,1.93mmol),Pd(OAc)2(0.433g,1.93mmol)和Et3N(5.86g,57.9mmol)加入到无水二氧六环(60mL)中，然后再加入频哪醇硼烷(4.94g,38.6mmol),氮气保护下110℃回流反应过夜。反应完全后，向反应液中加入硅胶，减压浓缩旋干，用柱层析分离(PE:EtOAc＝20:1，KMnO4显色)得到目标化合物INT5(4.9g,15.5mmol，淡黄色固体，产率80％),1H NMR(400MHz,CDCl3)δ7.00(s,1H),6.83(s,1H),3.81(s,3H),2.39(s,3H),1.39(s,12H)。Step 4: Compound INT5d (6.10 g, 19.3 mmol), 2-(dicyclohexylphosphino)biphenyl (0.676 g, 1.93 mmol), Pd(OAc) 2 (0.433 g, 1.93 mmol) and Et 3 N (5.86 g, 57.9 mmol) were added to anhydrous dioxane (60 mL), and then pinacol borane (4.94 g, 38.6 mmol) was added, and the reaction was refluxed at 110° C. under nitrogen protection overnight. After the reaction was completed, silica gel was added to the reaction solution, concentrated under reduced pressure and dried, and separated by column chromatography (PE:EtOAc=20:1, KMnO4 color development) to obtain the target compound INT5 (4.9 g, 15.5 mmol, light yellow solid, yield 80%), 1 H NMR (400 MHz, CDCl 3 )δ7.00(s,1H),6.83(s,1H),3.81(s,3H),2.39(s,3H),1.39(s,12H).
中间体INT6：2-(4-氯-2-甲氧基-6-甲基苯基)-4,4,5-5-四甲基-1,3,2-二氧杂硼烷
Intermediate INT6: 2-(4-chloro-2-methoxy-6-methylphenyl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane
2-(4-氯-2-甲氧基-6-甲基苯基)-4,4,5-5-四甲基-1,3,2-二氧杂硼烷的制备参考中间体INT5。MS/ESI[M+H]+:283.2。The preparation of 2-(4-chloro-2-methoxy-6-methylphenyl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane was based on intermediate INT5. MS/ESI [M+H] + : 283.2.
中间体INT7：2-(4-乙炔基-2-(甲氧基甲氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
Intermediate INT7: 2-(4-ethynyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
第一步：干燥烧瓶中加入化合物INT7a(2.0g,9.35mmol),HBr(48％)(18mL),将得到的混合溶液在100℃下搅拌过夜。反应完成后，混合溶液恢复至室温，加水淬灭，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压条件下浓缩滤液。残留物通过柱色谱法纯化，得到化合物INT7b(1.13g,60％)。LC-MS:ESI[M+H]+＝200.9。Step 1: Add compound INT7a (2.0 g, 9.35 mmol) and HBr (48%) (18 mL) to a dry flask, and stir the resulting mixed solution at 100°C overnight. After the reaction is completed, the mixed solution is returned to room temperature, quenched with water, extracted three times with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography to obtain compound INT7b (1.13 g, 60%). LC-MS: ESI [M+H] + = 200.9.
第二步：干燥烧瓶中加入化合物INT7b(1.13g,5.65mmol并溶于THF(20mL),降温至0℃,加入NaH(60％)(339.2mg,8.48mmol),搅拌20min,加入MOMCl(797.1mg,8.48mmol),反应4h,加入饱和NH4Cl水溶液淬灭,分液，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压条件下浓缩滤液。残留物通过柱色谱法纯化，得到化合物INT7c(1.24g,90％)。LC-MS:ESI[M+H]+＝245.1。Step 2: Add compound INT7b (1.13 g, 5.65 mmol) to a dry flask and dissolve in THF (20 mL), cool to 0°C, add NaH (60%) (339.2 mg, 8.48 mmol), stir for 20 min, add MOMCl (797.1 mg, 8.48 mmol), react for 4 h, add saturated NH4Cl aqueous solution to quench, separate the layers, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by column chromatography to obtain compound INT7c (1.24 g, 90%). LC-MS: ESI [M+H] + = 245.1.
第三步：干燥烧瓶中加入化合物INT7c(1.24g,5.08mmol),(Bpin)2(1.55g,6.1mmol),Pd(dppf)Cl2(36.6mg,0.05mmol),KOAc(1.0g,10.2mmol),1,4-dioxane(20mL),100℃下搅拌过夜。反应完成后，混合溶液恢复至室温，加水，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压条件下浓缩滤液。残留物通过柱色谱法纯化，得到化合物INT7d(684mg,46％)。LC-MS:ESI[M+H]+＝293.1。Step 3: Add compound INT7c (1.24 g, 5.08 mmol), (Bpin) 2 (1.55 g, 6.1 mmol), Pd(dppf)Cl 2 (36.6 mg, 0.05 mmol), KOAc (1.0 g, 10.2 mmol), 1,4-dioxane (20 mL) to a dry flask and stir overnight at 100°C. After the reaction is completed, the mixed solution is returned to room temperature, water is added, and ethyl acetate is extracted three times. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography to obtain compound INT7d (684 mg, 46%). LC-MS: ESI [M+H] + = 293.1.
第四步：室温下，向化合物INT7d(684mg,2.34mmol)的MeOH(8mL)溶液中加入K2CO3(646.8mg,4.68mmol),化合物INT7e(539.2mg,2.81mmol),室温下反应3h,减压条件下浓缩除去多余溶剂,加水溶解,DCM萃取,无水硫酸钠干燥，过滤，减压条件下浓缩滤液。残留物通过柱色谱法纯化,得到化合物INT7(366mg,54％)。LC-MS:ESI[M+H]+＝289.2。Step 4: At room temperature, add K 2 CO 3 (646.8 mg, 4.68 mmol) and compound INT7e (539.2 mg, 2.81 mmol) to a solution of compound INT7d (684 mg, 2.34 mmol) in MeOH (8 mL), react at room temperature for 3 h, concentrate under reduced pressure to remove excess solvent, add water to dissolve, extract with DCM, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by column chromatography to obtain compound INT7 (366 mg, 54%). LC-MS: ESI [M+H] + = 289.2.
中间体INT8：(3R，5R)-5-氟-1-甲基六氢吡啶-3-胺双盐酸盐
Intermediate INT8: (3R, 5R)-5-fluoro-1-methylhexahydropyridine-3-amine dihydrochloride
第一步：将化合物INT8a(4.75g,21.8mmol)、多聚甲醛(1.31g,43.6mmol)和醋酸(0.26g,4.36mmol)加入到甲醇(50mL)中，然后加入氰基硼氢化钠(2.74g,43.6mmol)，50℃搅拌1h。反应完全后加入硅胶拌样旋干，过柱纯化(DCM:MeOH＝10:1,碘显)得到化合物INT8b(4.67g,20.1mmol，收率92％)；1H NMR(400MHz,CDCl3-d)δ4.92-4.64(m,2H),3.99(s,1H),2.77-2.39(m,3H),2.30(s,3H),1.94-1.80(m,1H),1.45(s,9H)；LC-MS:ESI[M+H]+＝233.0。Step 1: Add compound INT8a (4.75 g, 21.8 mmol), paraformaldehyde (1.31 g, 43.6 mmol) and acetic acid (0.26 g, 4.36 mmol) to methanol (50 mL), then add sodium cyanoborohydride (2.74 g, 43.6 mmol) and stir at 50°C for 1 h. After the reaction was complete, silica gel was added, the sample was mixed and dried in a spin-drying process, and purified by column chromatography (DCM:MeOH=10:1, iodine development) to obtain compound INT8b (4.67 g, 20.1 mmol, yield 92%); 1 H NMR (400 MHz, CDCl 3 -d) δ4.92-4.64 (m, 2H), 3.99 (s, 1H), 2.77-2.39 (m, 3H), 2.30 (s, 3H), 1.94-1.80 (m, 1H), 1.45 (s, 9H); LC-MS: ESI[M+H] + ＝233.0.
第二步：将化合物INT8b(4.67g,20.1mmol)溶于到二氧六环(25mL)中，然后加入HCl/二氧六环(25mL,101mmol,4.0M)，25℃搅拌1h，反应完成后减压旋干得到目标产物INT8(4.60g,22.4mmol,收率111％)；1H NMR(400MHz,CD3OD-d4)δ5.37-5.24(m,1H),4.98-4.89(m,1H),3.92-3.77(m,3H),3.51(dd,J＝39.2,13.9Hz,1H),3.06(s,3H),2.63-2.55(m,1H),2.15-1.98(m,1H)；LC-MS:ESI[M+H]+＝133.0。Step 2: Dissolve compound INT8b (4.67 g, 20.1 mmol) in dioxane (25 mL), then add HCl/dioxane (25 mL, 101 mmol, 4.0 M), stir at 25 °C for 1 h, and after the reaction is completed, dry under reduced pressure to obtain the target product INT8 (4.60 g, 22.4 mmol, yield 111%); 1 H NMR (400 MHz, CD 3 OD-d 4 ) δ 5.37-5.24 (m, 1H), 4.98-4.89 (m, 1H), 3.92-3.77 (m, 3H), 3.51 (dd, J＝39.2, 13.9 Hz, 1H), 3.06 (s, 3H), 2.63-2.55 (m, 1H), 2.15-1.98 (m, 1H); LC-MS: ESI[M+H] + =133.0.
中间体INT9：2-(2-氟-6-甲氧基-4-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
Intermediate INT9: 2-(2-fluoro-6-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
2-(2-氟-6-甲氧基-4-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷的制备参考中间体INT5。MS/ESI[M+H]+:321.2。The preparation of 2-(2-fluoro-6-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was based on intermediate INT5. MS/ESI [M+H] + : 321.2.
中间体INT10：2-(4-环丙基-2-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
Intermediate INT10: 2-(4-cyclopropyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
第一步：将化合物INT10a(500mg,1.6mmol)，环丙基硼酸(505mg,5.87mmol)和碳酸钾(883mg,6.39mmol)混合于二氧六烷(10mL)和水(5mL)中，在氮气下加入Pd(dppf)Cl2(65.9mg,0.080mmol)，混合物在氮气下120℃搅拌充分反应。冷却至室温后，加入乙酸乙酯(20mL)稀释，有机相通过盐水(30mL)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到化合物INT10b粗品，直接用于下一步。Step 1: Compound INT10a (500 mg, 1.6 mmol), cyclopropylboronic acid (505 mg, 5.87 mmol) and potassium carbonate (883 mg, 6.39 mmol) were mixed in dioxane (10 mL) and water (5 mL), and Pd(dppf)Cl 2 (65.9 mg, 0.080 mmol) was added under nitrogen. The mixture was stirred at 120°C under nitrogen for sufficient reaction. After cooling to room temperature, ethyl acetate (20 mL) was added for dilution, and the organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a crude compound INT10b, which was used directly in the next step.
第二步：将化合物INT10b(1.2g,4.4mmol),双联频哪醇硼酸酯(2.2g,8.8mmol),KOAc(1.7g,17.6mmol)和Pd(dppf)Cl2(322mg,0.44mmol)加入到二氧六环(15mL)中，氮气保护下90℃反应12h。反应后过滤，滤液中加入硅胶，减压浓缩旋干，柱层析分离(PE:EtOAc＝10:1)得到目标化合物INT10(0.82g)。Step 2: Add compound INT10b (1.2 g, 4.4 mmol), bis-pinacol borate (2.2 g, 8.8 mmol), KOAc (1.7 g, 17.6 mmol) and Pd(dppf)Cl 2 (322 mg, 0.44 mmol) to dioxane (15 mL), and react at 90°C for 12 h under nitrogen protection. After the reaction, filter, add silica gel to the filtrate, concentrate under reduced pressure and spin dry, and separate by column chromatography (PE: EtOAc = 10: 1) to obtain the target compound INT10 (0.82 g).
中间体INT11：(3R，5R)-1-乙基-5-氟哌啶-3-胺盐酸盐
Intermediate INT11: (3R, 5R)-1-ethyl-5-fluoropiperidin-3-amine hydrochloride
(3R，5R)-1-乙基-5-氟哌啶-3-胺盐酸盐的制备参考中间体INT8。MS/ESI[M+H]+:147.2。The preparation of (3R,5R)-1-ethyl-5-fluoropiperidin-3-amine hydrochloride was based on intermediate INT8. MS/ESI [M+H] + : 147.2.
中间体INT12：三甲基(2-(((5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-2,3-二氢苯并呋喃-4-基)氧基)甲氧基)乙基)硅烷
Intermediate INT12: trimethyl(2-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-yl)oxy)methoxy)ethyl)silane
第一步：在-40℃下，向化合物INT12a(500mg，3.68mmol)的甲醇(10mL)溶液中添加三溴吡啶(1.18g，3.68mmol)。将得到的混合物在-40℃下搅拌0.5小时，然后加热至室温并搅拌16小时。反应完成后，将反应混合物溶解在乙酸乙酯(100mL)中。有机层用1N盐酸(25mL×2)洗涤，然后用饱和食盐水(25mL)洗涤，用无水硫酸钠干燥，过滤，并在减压下浓缩滤液。残留物通过柱色谱法纯化，得到化合物INT12b(黄色固体470mg)。LC-MS:212.8[M-H]-。The first step: at -40 ° C, to a solution of compound INT12a (500 mg, 3.68 mmol) in methanol (10 mL) was added tribromopyridine (1.18 g, 3.68 mmol). The resulting mixture was stirred at -40 ° C for 0.5 hours, then heated to room temperature and stirred for 16 hours. After the reaction was completed, the reaction mixture was dissolved in ethyl acetate (100 mL). The organic layer was washed with 1N hydrochloric acid (25 mL × 2), then washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound INT12b (yellow solid 470 mg). LC-MS: 212.8 [MH] - .
第二步：室温下，向化合物INT12b的(470mg，2.19mmol)的乙腈(10mL)溶液中加入K2CO3(601.8mg,4.4mmol)。将混合物在室温下搅拌0.5小时，并将2-(三甲基硅烷基)乙氧甲基氯(438.1mg,2.63mmol)逐滴加入到混合物中。将混合物在室温下搅拌3小时。TLC检测反应完全。混合液中加入水，并用乙酸乙酯萃取。有机相用盐水洗涤，无水硫酸钠干燥，过滤，减压下浓缩滤液。柱层析纯化得化合物INT12c(黄色油状液体，301mg)。1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),5.16(s,2H),4.61-4.57(m,2H),3.87-3.76(m,2H),3.29-3.22(m,2H),0.99-0.96(m,2H),0.03(s,9H)。Step 2: At room temperature, K 2 CO 3 (601.8 mg, 4.4 mmol) was added to a solution of compound INT12b (470 mg, 2.19 mmol) in acetonitrile (10 mL). The mixture was stirred at room temperature for 0.5 hours, and 2-(trimethylsilyl)ethoxymethyl chloride (438.1 mg, 2.63 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature for 3 hours. TLC detected that the reaction was complete. Water was added to the mixed solution, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography purification gave compound INT12c (yellow oily liquid, 301 mg). 1 H NMR (400MHz, CDCl 3 ) δ7.38 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.16 (s, 2H), 4.61-4.57 (m, 2H), 3.87-3.76 (m, 2H), 3.29-3.22 (m, 2H), 0.99-0.96 (m,2H),0.03(s,9H).
第三步：干燥烧瓶中加入化合物INT12c(301mg,0.87mmol)，(BPin)2(330mg,1.3mmol)，Pd(dppf)Cl2(65.9mg,0.09mmol)，Cs2CO3(567.2mg,1.74mmol),1,4-dioxane(8mL)，氮气保护下，100℃回流过夜，反应完全后，恢复至室温，加水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压除去多余溶剂，残留物柱层析分离得到目标化合物INT12(无色油状液体103mg)。1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.0Hz, 1H),6.58(d,J＝8.0Hz,1H),5.15(s,2H),4.61-4.57(m,2H),3.85-3.80(m,2H),3.28-3.19(m,2H),1.32(s,12H),1.00-0.95(m,2H),0.03(s,9H)。Step 3: Add compound INT12c (301 mg, 0.87 mmol), (BPin) 2 (330 mg, 1.3 mmol), Pd(dppf)Cl 2 (65.9 mg, 0.09 mmol), Cs 2 CO 3 (567.2 mg, 1.74 mmol), 1,4-dioxane (8 mL) to a dry flask, reflux at 100°C overnight under nitrogen protection, return to room temperature after the reaction is complete, add water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, remove excess solvent from the filtrate under reduced pressure, and separate the residue by column chromatography to obtain the target compound INT12 (colorless oily liquid 103 mg). 1 H NMR (400 MHz, CDCl 3 )δ7.58(d,J＝8.0 Hz, 1H), 6.58 (d, J = 8.0Hz, 1H), 5.15 (s, 2H), 4.61-4.57 (m, 2H), 3.85-3.80 (m, 2H), 3.28-3.19 (m, 2H), 1.32 (s, 12H), 1.00-0.95 (m, 2H), 0.03 (s, 9H).
实施例1：(R)-6-(2-羟基-4-(三氟甲基)苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 1: (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
第一步：将化合物1a(2.7g,13mmol)、化合物1b(5g,26mmol)、Pd(dppf)Cl2(952mg，1.3mmol)，碳酸铯(13g，39mmol)，溶解于45mL 1，4-二氧六环和4.5ml水中。氮气条件下，100℃搅拌过夜。LC-MS监测目标产物生成。将反应液过滤，滤液减压浓缩除去溶剂，粗品用甲醇/二氯甲烷体系柱层析纯化即得目标产物1c(2.8g)，MS/ESI[M+H]+＝302.2。Step 1: Dissolve compound 1a (2.7 g, 13 mmol), compound 1b (5 g, 26 mmol), Pd(dppf)Cl 2 (952 mg, 1.3 mmol), and cesium carbonate (13 g, 39 mmol) in 45 mL of 1,4-dioxane and 4.5 ml of water. Stir overnight at 100 °C under nitrogen. LC-MS monitors the formation of the target product. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to remove the solvent. The crude product is purified by methanol/dichloromethane column chromatography to obtain the target product 1c (2.8 g), MS/ESI [M+H] + = 302.2.
第二步：将化合物1c(2g,6.6mmol)、劳森试剂(4.8g，12mmol)，溶解于50ml甲苯中，110℃反应12h。LC-MS监测目标产物生成，减压浓缩除去溶剂，柱层析纯化即得目标产物1d(860mg)，MS/ESI[M+H]+＝334.3。Step 2: Compound 1c (2 g, 6.6 mmol) and Lawesson's reagent (4.8 g, 12 mmol) were dissolved in 50 ml of toluene and reacted at 110°C for 12 h. The target product was generated by LC-MS monitoring, and the solvent was removed by concentration under reduced pressure. The target product 1d (860 mg) was obtained by column chromatography purification, MS/ESI [M+H] + = 334.3.
第三步：将化合物1d(860mg，2.6mmol)，DBU(517mg，3.4mmol)，溶解于15ml THF和1.5ml乙腈中，降温至0℃。加入碘甲烷(480mg，3.4mmol)，0℃反应5min。移除冰浴，室温反应过夜。点板监测，减压浓缩除去溶剂，柱层析纯化即得化合物1e(410mg)，MS/ESI[M+H]+＝348.3。Step 3: Dissolve compound 1d (860 mg, 2.6 mmol) and DBU (517 mg, 3.4 mmol) in 15 ml THF and 1.5 ml acetonitrile, and cool to 0°C. Add iodomethane (480 mg, 3.4 mmol) and react at 0°C for 5 min. Remove the ice bath and react at room temperature overnight. Monitor with a plate spot, concentrate under reduced pressure to remove the solvent, and purify by column chromatography to obtain compound 1e (410 mg), MS/ESI [M+H] + = 348.3.
第四步：将化合物1e(174mg，0.5mmol)溶于5ml THF中，降温至0℃。加入m-CPBA(433mg，2.5mmol)，室温反应过夜。LC-MS监测化合物1e完全转化为化合物1f，反应不做处理，直接用于下一步反应。Step 4: Dissolve compound 1e (174 mg, 0.5 mmol) in 5 ml THF and cool to 0°C. Add m-CPBA (433 mg, 2.5 mmol) and react at room temperature overnight. LC-MS monitoring shows that compound 1e is completely converted into compound 1f. The reaction is not treated and is directly used in the next step.
第五步：在上一步反应液中加入化合物1g(171mg，1.5mmol)，DIEA(968mg，7.5mmol)，70℃反应过夜。减压浓缩除去溶剂，残留物用EA和水稀释，萃取三次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩除去溶剂，柱层析纯化即得化合物1h(7mg)，MS/ESI[M+H]+＝398.3。Step 5: Compound 1g (171 mg, 1.5 mmol) and DIEA (968 mg, 7.5 mmol) were added to the reaction solution of the previous step, and the mixture was reacted at 70°C overnight. The solvent was removed by concentration under reduced pressure, and the residue was diluted with EA and water, extracted three times, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and purified by column chromatography to obtain compound 1h (7 mg), MS/ESI [M+H] + = 398.3.
第六步：将化合物1h(7mg，0.02mmol)溶于1ml DCM中，降温至-10℃。加入BBr3(1M，0.1ml)，-10℃反应3h，LC-MS监测反应完成。加甲醇淬灭反应，减压浓缩除去溶剂，经TLC板纯化即得目标化合物1(5mg)。MS/ESI[M+H]+＝384.3，1H NMR(400MHz,Methanol-d4)δ8.63(d,J＝8.2Hz,1H),7.10-6.93(m,2H),4.49(s,1H),4.34-4.16 (m,1H),3.39(s,3H),3.00-2.85(m,1H),2.68-2.50(m,1H),2.24(s,3H),2.17-2.01(m,1H),1.97-1.84(m,1H),1.80-1.70(m,1H),1.69-1.54(m,1H),1.57-1.43(m,2H)。Step 6: Dissolve compound 1h (7 mg, 0.02 mmol) in 1 ml DCM and cool to -10°C. Add BBr 3 (1M, 0.1 ml) and react at -10°C for 3 h. LC-MS monitors the completion of the reaction. Add methanol to quench the reaction, concentrate under reduced pressure to remove the solvent, and purify on a TLC plate to obtain the target compound 1 (5 mg). MS/ESI [M+H] + = 384.3, 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.63 (d, J = 8.2 Hz, 1H), 7.10-6.93 (m, 2H), 4.49 (s, 1H), 4.34-4.16 (m,1H),3.39(s,3H),3.00-2.85(m,1H),2.68-2.50(m,1H),2.24(s,3H),2.17-2.01(m,1H),1.97-1.84(m,1H),1.80-1.70(m,1H),1.69-1.54(m,1H) ),1.57-1.43(m,2H).
实施例2：(R)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 2: (R)-6-(4-hydroxybenzo[b]thiophene-5-yl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
第一步：将化合物INT2(77mg,0.34mmol)、INT1(149mg,0.51mmol)、Pd(dppf)Cl2(13mg,0.02mmol)、碳酸铯(222mg,0.69mmol)、二氧六环(12mL)和水(2mL)置于反应瓶中，氮气保护，100℃搅拌15h。反应完成，降温至室温，残余物经硅胶柱层析纯化得化合物2a(90mg)；LC-MS:ESI[M+H]+＝308.0。Step 1: Compound INT2 (77 mg, 0.34 mmol), INT1 (149 mg, 0.51 mmol), Pd(dppf)Cl 2 (13 mg, 0.02 mmol), cesium carbonate (222 mg, 0.69 mmol), dioxane (12 mL) and water (2 mL) were placed in a reaction bottle, protected by nitrogen, and stirred at 100°C for 15 h. After the reaction was completed, the temperature was lowered to room temperature, and the residue was purified by silica gel column chromatography to obtain compound 2a (90 mg); LC-MS: ESI [M+H] + = 308.0.
第二步：将化合物2a(90mg,0.29mmol)和化合物2b(50mg,0.44mmol),Pd(OAc)2(6mg,0.03mmol)，BINAP(37mg,0.06mmol)，Cs2CO3(190mg,0.59mmol)，1,4-二氧六环(10mL)置于反应瓶中,氮气保护，升温至100℃反应12h。反应完成，浓缩除去溶剂，残余物经硅胶柱层析纯化得目标化合物2c(37mg)；LC-MS:ESI[M+H]+＝386.0。Step 2: Compound 2a (90 mg, 0.29 mmol) and compound 2b (50 mg, 0.44 mmol), Pd(OAc) 2 (6 mg, 0.03 mmol), BINAP (37 mg, 0.06 mmol), Cs 2 CO 3 (190 mg, 0.59 mmol), 1,4-dioxane (10 mL) were placed in a reaction bottle, protected by nitrogen, and heated to 100°C for 12 h. After the reaction was completed, the solvent was removed by concentration, and the residue was purified by silica gel column chromatography to obtain the target compound 2c (37 mg); LC-MS: ESI [M+H] + = 386.0.
第三步：将化合物2c(37mg,0.10mmol)置于反应瓶中，加入DCM(10mL),降温至-10℃，随后缓慢滴加BBr3(120mg,0.48mmol),加完后维持-10℃反应3h。MS监测，反应完成，加甲醇淬灭反应，浓缩反应液除去溶剂，残余物经柱层析纯化得目标化合物2(22mg,31.1％)；LC-MS:ESI[M+H]+＝371.9。1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),7.74(d,J＝4.0Hz,1H),7.70(d,J＝4.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.27(d,J＝8.0Hz,1H),3.20(s,3H),2.68(s,3H),1.91-1.88(m,2H),1.70-1.68(m,2H),1.18(t,J＝8.0Hz,4H)。Step 3: Compound 2c (37 mg, 0.10 mmol) was placed in a reaction bottle, DCM (10 mL) was added, the temperature was lowered to -10°C, and then BBr 3 (120 mg, 0.48 mmol) was slowly added dropwise, and the temperature was maintained at -10°C for 3 h after the addition was complete. MS monitoring showed that the reaction was complete, methanol was added to quench the reaction, the reaction solution was concentrated to remove the solvent, and the residue was purified by column chromatography to obtain the target compound 2 (22 mg, 31.1%); LC-MS: ESI [M+H] + = 371.9. 1 H NMR (400MHz, DMSO-d 6 ) δ10.24(s,1H),7.74(d,J＝4.0Hz,1H),7.70(d,J＝4.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.27(d,J＝8.0Hz,1H),3.20(s,3H),2.68(s, 3H), 1.91-1.88 (m, 2H), 1.70-1.68 (m, 2H), 1.18 (t, J = 8.0Hz, 4H).
实施例3：(R)-6-(4-羟基苯并呋喃-5-基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 3: (R)-6-(4-hydroxybenzofuran-5-yl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
第一步：将化合物3b(3g,28,53mmol)溶于乙醇(15ml)中，加入乙醛酸3a(40％的甲苯溶液，8.5mL)，升温至90℃下反应2h，随后冷却至室温，过滤反应液，滤饼用乙醇洗，烘干滤饼，将滤饼溶于乙酸中，加入乙醇钠，升温至110℃下反应过夜，冷却至室 温，浓缩反应液，加入乙酸乙酯，用三乙胺调pH至中性，取有机相，浓缩，柱层析纯化得化合物3c(黄色固体，97mg)；LC-MS:ESI[M+H]+＝144.1。Step 1: Compound 3b (3 g, 28, 53 mmol) was dissolved in ethanol (15 ml), glyoxylic acid 3a (40% toluene solution, 8.5 mL) was added, the temperature was raised to 90 °C for reaction for 2 h, then cooled to room temperature, the reaction solution was filtered, the filter cake was washed with ethanol, the filter cake was dried, the filter cake was dissolved in acetic acid, sodium ethoxide was added, the temperature was raised to 110 °C for reaction overnight, and the reaction mixture was cooled to room temperature. The reaction solution was concentrated and ethyl acetate was added. The pH was adjusted to neutral with triethylamine. The organic phase was collected, concentrated and purified by column chromatography to obtain compound 3c (yellow solid, 97 mg); LC-MS: ESI [M+H] + = 144.1.
第二步：将化合物3c(97mg,0.68mmol)置于反应瓶中，加入冰醋酸(10mL)，降温至0℃，缓慢滴加液溴(0.5mL)，滴毕，室温下搅拌0.5h。LCMS检测，反应完全，加入硫代硫酸钠水溶液淬灭反应，再用饱和碳酸氢钠水溶液调pH至8-9，加入乙酸乙酯，取有机相，水相复萃，合并有机相，浓缩，残余物经柱层析纯化得化合物3d(黄色固体，80mg)；LC-MS:ESI[M+H]+＝222.9。Step 2: Compound 3c (97 mg, 0.68 mmol) was placed in a reaction bottle, glacial acetic acid (10 mL) was added, the temperature was lowered to 0°C, and liquid bromine (0.5 mL) was slowly added dropwise. After the addition was completed, the mixture was stirred at room temperature for 0.5 h. LCMS detection showed that the reaction was complete, and an aqueous sodium thiosulfate solution was added to quench the reaction, and the pH was adjusted to 8-9 with a saturated sodium bicarbonate aqueous solution, and ethyl acetate was added. The organic phase was taken, the aqueous phase was re-extracted, the organic phases were combined, and the residue was purified by column chromatography to obtain compound 3d (yellow solid, 80 mg); LC-MS: ESI [M+H] + = 222.9.
第三步：将化合物3d(80mg,0.36mmol)溶于2mol/L氢氧化钠水溶液(5mL)中，缓慢滴加碘甲烷(77mg,0.54mmol)，加完后维持室温下反应12h。TLC监测反应完全，加EA萃取2次，合并有机相，浓缩，残余物经柱层析纯化得化合物3e(浅黄色油状，68mg)；LC-MS:ESI[M+H]+＝237.0。Step 3: Compound 3d (80 mg, 0.36 mmol) was dissolved in 2 mol/L sodium hydroxide aqueous solution (5 mL), and iodomethane (77 mg, 0.54 mmol) was slowly added dropwise. After the addition, the reaction was maintained at room temperature for 12 h. The reaction was complete by TLC monitoring, and EA was added for 2 extractions. The organic phases were combined and concentrated, and the residue was purified by column chromatography to obtain compound 3e (light yellow oil, 68 mg); LC-MS: ESI [M+H] + = 237.0.
第四步：将化合物3e(68mg,0.29mmol)置于反应瓶中，加入二氯甲烷(7mL)，反应置于冰浴中，缓慢加入m-CPBA(99mg,0.58mmol)，加完后撤去冰浴，室温下反应10h，LCMS监测，反应完全，加入饱和硫代硫酸钠水溶液淬灭反应，加入二氯甲烷萃取，合并有机相，浓缩，得粗品产物3f(46mg)，直接用于下一步反应；LC-MS:ESI[M+H]+＝267.9。Step 4: Compound 3e (68 mg, 0.29 mmol) was placed in a reaction bottle, dichloromethane (7 mL) was added, the reaction was placed in an ice bath, m-CPBA (99 mg, 0.58 mmol) was slowly added, the ice bath was removed after the addition, and the reaction was carried out at room temperature for 10 h. LCMS monitoring showed that the reaction was complete, saturated sodium thiosulfate aqueous solution was added to quench the reaction, dichloromethane was added for extraction, the organic phases were combined and concentrated to obtain a crude product 3f (46 mg), which was directly used in the next step reaction; LC-MS: ESI [M+H] + = 267.9.
第五步：将化合物3f(46mg,0.17mmol),化合2b(29mg,0.26mmol)置于反应瓶中,加入DMF(5mL)，后缓慢加入DIEA(44mg,0.34mmol)，升温至60℃下反应10h,LCMS监测，反应完全，直接浓缩反应液，残余物经柱层析纯化得化合物3g(无色油状产物，31mg)；LC-MS:ESI[M+H]+＝303.1。Step 5: Compound 3f (46 mg, 0.17 mmol) and compound 2b (29 mg, 0.26 mmol) were placed in a reaction bottle, DMF (5 mL) was added, and DIEA (44 mg, 0.34 mmol) was slowly added. The temperature was raised to 60°C and the reaction was carried out for 10 h. After LCMS monitoring, the reaction was complete. The reaction solution was directly concentrated and the residue was purified by column chromatography to obtain compound 3g (colorless oily product, 31 mg); LC-MS: ESI [M+H] + = 303.1.
第六步：将化合物3g(31mg,0.10mmol)，化合物INT4(42mg,0.15mmol)，Pd(dppf)2Cl2(3.75mg,0.05mmol)，Cs2CO3(67mg,0.21mmol)依次加入反应瓶中，加入1,4-二氧六环/水＝4:1(10mL)，氮气保护，升温至100℃下反应10h，LCMS监测反应完全，浓缩反应液，残余物经薄层色谱板纯化得化合物3h(19mg)；LC-MS:ESI[M+H]+＝370.0。Step 6: Compound 3g (31 mg, 0.10 mmol), compound INT4 (42 mg, 0.15 mmol), Pd(dppf) 2 Cl 2 (3.75 mg, 0.05 mmol), and Cs 2 CO 3 (67 mg, 0.21 mmol) were added to a reaction flask in sequence, and 1,4-dioxane/water = 4:1 (10 mL) was added. Under nitrogen protection, the temperature was raised to 100° C. and the reaction was carried out for 10 h. The reaction was completed after monitoring by LCMS. The reaction solution was concentrated and the residue was purified by thin layer chromatography to obtain compound 3h (19 mg); LC-MS: ESI [M+H] + = 370.0.
第七步：将化合物3h(19mg,0.05mmol)置于反应瓶中，加入无水DCM(5mL)，降温至-10℃下反应3h,LCMS监测反应完全，浓缩反应液，残余物经薄层色谱板纯化得化合物3(8mg)；LC-MS:ESI[M+H]+＝356.1。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),7.87(d,J＝4.0Hz,1H),7.16(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.10(d,J＝4.0Hz,1H),3.11(s,3H),2.67-2.44(m,2H),2.15(s,3H),2.14-2.10(m,2H),1.68-1.62(m,2H),1.50-1.46(m,2H)。 Step 7: Compound 3h (19 mg, 0.05 mmol) was placed in a reaction bottle, anhydrous DCM (5 mL) was added, the temperature was lowered to -10°C and the reaction was carried out for 3 h. The reaction was completed after monitoring by LCMS. The reaction solution was concentrated and the residue was purified by TLC to obtain compound 3 (8 mg); LC-MS: ESI [M+H] + = 356.1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.34(s,1H),7.87(d,J＝4.0Hz,1H),7.16(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.10(d,J＝4.0Hz,1H),3.11(s,3H),2.67-2.4 4(m,2H),2.15(s,3H),2.14-2.10(m,2H),1.68-1.62(m,2H),1.50-1.46(m,2H).
实施例4：(R)-3-((1-乙基哌啶-3-基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 4: (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-3-((1-乙基哌啶-3-基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝386.1。1H NMR(400MHz,DMSO)δ8.27(s,1H),7.69(q,J＝5.6Hz,2H),7.56(d,J＝8.2Hz,1H),7.24(d,J＝8.2Hz,1H),3.88-3.79(m,3H),3.04-3.02(m,1H),2.79-2.76(m,1H),2.41(q,J＝7.1Hz,2H),1.96-1.89(m,3H),1.77-1.69(m,1H),1.57-1.54(m,1H),1.40-1.37(m,1H),1.02(t,J＝7.2Hz,3H)。The preparation method of (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =386.1. 1 H NMR (400MHz, DMSO) δ8.27 (s, 1H), 7.69 (q, J = 5.6Hz, 2H), 7.56 (d, J = 8.2Hz, 1H), 7.24 (d, J = 8.2Hz, 1H), 3.88-3.79 (m, 3H), 3.04-3.02 (m, 1H), 2.79-2.76 (m,1H),2.41(q,J＝7.1Hz,2H),1.96-1.89(m,3H),1.77-1.69(m,1H),1.57-1.54(m,1H),1.40-1.37(m,1H),1.02(t,J＝7.2Hz,3H).
实施例5：(R)-6-(4-羟基苯并[b]噻吩-5-基)-3-((1-异丙基哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 5: (R)-6-(4-hydroxybenzo[b]thiophene-5-yl)-3-((1-isopropylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-6-(4-羟基苯并[b]噻吩-5-基)-3-((1-异丙基哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝400.2。1H NMR(400MHz,Methanol-d4)δ8.57(d,J＝8.8Hz,1H),7.46(d,J＝5.5Hz,1H),7.33(d,J＝5.5Hz,1H),7.27(d,J＝8.8Hz,1H),4.44-4.28(m,1H),3.63-3.50(m,1H),3.45-3.39(m,1H),3.37(s,3H),3.31-3.24(m,1H),2.95-2.74(m,2H),2.17-1.97(m,2H),1.89-1.60(m,2H),1.27(dd,J＝6.7,2.6Hz,6H)。The preparation method of (R)-6-(4-hydroxybenzo[b]thiophen-5-yl)-3-((1-isopropylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =400.2. 1 H NMR (400MHz, Methanol-d 4 ) δ8.57(d,J＝8.8Hz,1H),7.46(d,J＝5.5Hz,1H),7.33(d,J＝5.5Hz,1H),7.27(d,J＝8.8Hz,1H),4.44-4.28(m,1H),3.63-3.50(m,1H) ,3.45-3.39(m,1H),3.37(s,3H),3.31-3.24(m,1H),2.95-2.74(m,2H),2.17-1.97(m,2H),1.89-1.60(m,2H),1.27(dd,J＝6.7,2.6Hz,6H).
实施例6：(R)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-3-((1-(氧杂环丁烷-3-基)哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 6: (R)-6-(4-hydroxybenzo[b]thiophene-5-yl)-4-methyl-3-((1-(oxetane-3-yl)piperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
(R)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-3-((1-(氧杂环丁烷-3-基)哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝414.1。The preparation method of (R)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-3-((1-(oxetan-3-yl)piperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =414.1.
实施例7：6-(4-羟基苯并[b]噻吩-5-基)-3-(((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 7: 6-(4-Hydroxybenzo[b]thiophen-5-yl)-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
6-(4-羟基苯并[b]噻吩-5-基)-3-(((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝373.2。1H NMR(400MHz,DMSO)δ10.64(s),7.74(d,J＝5.6Hz,1H),7.68(d,J＝5.8Hz,1H),7.63(d,J＝8.4Hz,1H),7.28-7.23(m,1H),3.82(s,3H),1.92(d,J＝6.5Hz,2H),1.66(s,2H),1.25-1.23(m,6H)。The preparation method of 6-(4-hydroxybenzo[b]thiophen-5-yl)-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =373.2. 1 H NMR (400 MHz, DMSO) δ10.64 (s), 7.74 (d, J=5.6 Hz, 1H), 7.68 (d, J=5.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.28-7.23 (m, 1H), 3.82 (s, 3H), 1.92 (d, J=6.5 Hz, 2H), 1.66 (s, 2H), 1.25-1.23 (m, 6H).
实施例8：3-(((1R，3R)-3-羟基-3-甲基环己基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 8: 3-(((1R,3R)-3-hydroxy-3-methylcyclohexyl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one
3-(((1R，3R)-3-羟基-3-甲基环己基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝367.2。The preparation method of 3-(((1R,3R)-3-hydroxy-3-methylcyclohexyl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =367.2.
实施例9：3-(((1R，3R)-3-羟基-3-甲基环戊基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 9: 3-(((1R,3R)-3-hydroxy-3-methylcyclopentyl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one
3-(((1R，3R)-3-羟基-3-甲基环戊基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝373.2。The preparation method of 3-(((1R,3R)-3-hydroxy-3-methylcyclopentyl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =373.2.
实施例10：(S)-3-((2,3-二羟丙基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 10: (S)-3-((2,3-dihydroxypropyl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one
(S)-3-((2,3-二羟丙基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝349.2。The preparation method of (S)-3-((2,3-dihydroxypropyl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =349.2.
实施例11：(R)-4-乙基-6-(4-羟基苯并[b]噻吩-5-基)-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 11: (R)-4-ethyl-6-(4-hydroxybenzo[b]thiophene-5-yl)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
(R)-4-乙基-6-(4-羟基苯并[b]噻吩-5-基)-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝386.2。1H NMR(400MHz,MeOD)δ7.55(d,J＝8.0Hz,1H),7.51(d,J＝4.0Hz,1H),7.49(s,1H),7.21(d,J＝8.0Hz,1H),4.37-4.28(m,1H),3.79(q,J＝8.0,4.0Hz,2H),2.97-2.86(m,2H),2.66(s,3H),2.06-1.91(m,2H),1.89-1.76(m,2H),1.68-1.65(m,1H),1.01(t,J＝8.0Hz,3H)。The preparation method of (R)-4-ethyl-6-(4-hydroxybenzo[b]thiophen-5-yl)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =386.2. 1 H NMR (400MHz, MeOD) δ7.55(d,J＝8.0Hz,1H),7.51(d,J＝4.0Hz,1H),7.49(s,1H),7.21(d,J＝8.0Hz,1H),4.37-4.28(m,1H),3.79(q,J＝8.0,4.0Hz,2H),2.9 7-2.86(m,2H),2.66(s,3H),2.06-1.91(m,2H),1.89-1.76(m,2H),1.68-1.65(m,1H),1.01(t,J＝8.0Hz,3H).
实施例12：(R)-6-(4-羟基苯并[b]噻吩-5-基)-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 12: (R)-6-(4-hydroxybenzo[b]thiophene-5-yl)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
(R)-6-(4-羟基苯并[b]噻吩-5-基)-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝358.2。1H NMR(400MHz,DMSO)δ13.13(s,1h),7.69(d,J＝8.0Hz,1h),7.60(d,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.30(s,1H),3.99(s,1H),2.35-2.32(m,1H),2.30(s,3H),2.26-2.16(m,1H),1.80-1.73(m,2H),1.55-1.45(m,2H)。The preparation method of (R)-6-(4-hydroxybenzo[b]thiophen-5-yl)-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =358.2. 1 H NMR (400MHz, DMSO) δ13.13(s,1h),7.69(d,J＝8.0Hz,1h),7.60(d,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.30(s,1H),3.99(s,1H), 2.35-2.32(m,1H),2.30(s,3H),2.26-2.16(m,1H),1.80-1.73(m,2H),1.55-1.45(m,2H).
实施例13：(R)-6-(2-羟基-6-甲基-4-(三氟甲基)苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 13: (R)-6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
(R)-6-(2-羟基-6-甲基-4-(三氟甲基)苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝398.2。1H NMR(400MHz,DMSO)δ8.34(s,1H),7.12(s,1H),7.09(s,1H),4.70-4.65(m,1H),3.18(s,3H),2.23-2.19(m,1H),2.15(s,3H),2.05-1.94(m,2H),1.79-1.73(m,1H),1.59-1.35(m,2H),1.12(s,3H)。The preparation method of (R)-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 398.2. 1 H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 4.70-4.65 (m, 1H), 3.18 (s, 3H), 2.23-2.19 (m, 1H), 2.15 (s, 3H), 2.05-1.94 (m, 2H), 1.79-1.73 (m, 1H), 1.59-1.35 (m, 2H), 1.12 (s, 3H).
实施例14：(R)-3-((1-乙基哌啶-3-基)氨基)-6-(2-羟基-6-甲基-4-(三氟甲基)苯基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 14: (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-3-((1-乙基哌啶-3-基)氨基)-6-(2-羟基-6-甲基-4-(三氟甲基)苯基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝412.2。The preparation method of (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 412.2.
实施例15：(R)-6-(2-羟基-6-甲基-4-(三氟甲基)苯基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 15: (R)-6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-6-(2-羟基-6-甲基-4-(三氟甲基)苯基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝428.2。The preparation method of (R)-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 428.2.
实施例16：6-(2-羟基-6-甲基-4-(三氟甲基)苯基)-3-((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 16: 6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-3-((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
6-(2-羟基-6-甲基-4-(三氟甲基)苯基)-3-((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝399.2。The preparation method of 6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-3-((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 399.2.
实施例17：(R)-6-(4-乙炔基-2-羟基苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 17: (R)-6-(4-ethynyl-2-hydroxyphenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
(R)-6-(4-乙炔基-2-羟基苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝340.2。The preparation method of (R)-6-(4-ethynyl-2-hydroxyphenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 340.2.
实施例18：(R)-3-((1-乙基哌啶-3-基)氨基)-6-(4-乙炔基-2-羟基苯基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 18: (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-3-((1-乙基哌啶-3-基)氨基)-6-(4-乙炔基-2-羟基苯基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝354.2。The preparation method of (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 354.2.
实施例19：6-(4-乙炔基-2-羟基苯基)-3-(((1R，2R)-2-羟基环己基)氨基)-4-甲基 -1,2,4-三嗪-5(4H)-酮
Example 19: 6-(4-ethynyl-2-hydroxyphenyl)-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl -1,2,4-Triazine-5(4H)-one
6-(4-乙炔基-2-羟基苯基)-3-(((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝341.2。The preparation method of 6-(4-ethynyl-2-hydroxyphenyl)-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 341.2.
实施例20：(R)-6-(2-羟基-4-(三氟甲氧基)苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 20: (R)-6-(2-hydroxy-4-(trifluoromethoxy)phenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
(R)-6-(2-羟基-4-(三氟甲氧基)苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝400.2。1H NMR(400MHz,CD3OD)δ7.58(d,J＝8.6Hz,1H),6.96(d,J＝8.6Hz,1H),6.89(s,1H),4.24(s,1H),3.69-3.62(m,1H),3.56(s,1H),3.50-3.42(m,1H),3.37(s,1H),2.86(s,3H),2.16-2.99(m,3H),1.95-1.80(m,2H),1.76-1.62(m,1H)。The preparation method of (R)-6-(2-hydroxy-4-(trifluoromethoxy)phenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 400.2. 1 H NMR (400MHz, CD 3 OD) δ7.58(d,J＝8.6Hz,1H),6.96(d,J＝8.6Hz,1H),6.89(s,1H),4.24(s,1H),3.69-3.62(m,1H),3.56(s,1H),3.50-3.42(m,1H),3.3 7(s,1H),2.86(s,3H),2.16-2.99(m,3H),1.95-1.80(m,2H),1.76-1.62(m,1H).
实施例21：(R)-6-(2-氟-6-羟基-4-(三氟甲基)苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 21: (R)-6-(2-Fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
(R)-6-(2-氟-6-羟基-4-(三氟甲基)苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝402.2。The preparation method of (R)-6-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 402.2.
实施例22：6-(2-氟-6-羟基-4-(三氟甲基)苯基)-3-((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 22: 6-(2-Fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-3-((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
6-(2-氟-6-羟基-4-(三氟甲基)苯基)-3-((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝403.2。 The preparation method of 6-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-3-((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 403.2.
实施例23：(R)-6-(4-环丙基-2-羟基苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 23: (R)-6-(4-cyclopropyl-2-hydroxyphenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
(R)-6-(4-环丙基-2-羟基苯基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝356.2。1H NMR(400MHz,MeOD)δ7.19(d,J＝8.0Hz,1H),6.70(dd,J＝8.0,4.0Hz,1H),6.64(s,1H),4.20-4.17(m,1H),3.64(d,J＝8.0Hz,1H),3.33(s,3H),2.88-2.85(m,1H),2.82(s,3H),2.79-2.77(m,1H),2.10-1.99(m,2H),1.89-1.82(m,2H),1.66-1.604(m,1H),1.01-0.94(m,2H),0.70-0.63(m,2H)。The preparation method of (R)-6-(4-cyclopropyl-2-hydroxyphenyl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 356.2. 1 H NMR (400MHz, MeOD) δ7.19(d,J＝8.0Hz,1H),6.70(dd,J＝8.0,4.0Hz,1H),6.64(s,1H),4.20-4.17(m,1H),3.64(d,J＝8.0Hz,1H),3.33(s,3H),2.88-2.85( m,1H),2.82(s,3H),2.79-2.77(m,1H),2.10-1.99(m,2H),1.89-1.82(m,2H),1.66-1.604(m,1H),1.01-0.94(m,2H),0.70-0.63(m,2H).
实施例24：6-(4-环丙基-2-羟基苯基)-3-(((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 24: 6-(4-cyclopropyl-2-hydroxyphenyl)-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
6-(4-环丙基-2-羟基苯基)-3-(((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝357.2。The preparation method of 6-(4-cyclopropyl-2-hydroxyphenyl)-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI [M+H] + = 357.2.
实施例25：(R)-6-(4-羟基苯并[b]噻吩-5-基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 25: (R)-6-(4-hydroxybenzo[b]thiophen-5-yl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-6-(4-羟基苯并[b]噻吩-5-基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备方法参考实施例2。MS/ESI[M+H]+＝402.1。1H NMR(400MHz,DMSO)δ7.71(dd,J＝12.5,5.6Hz,2H),7.59(d,J＝8.3Hz,1H),7.28(d,J＝8.2Hz,1H),6.80(d,J＝8.4Hz,1H),4.44(s,1H),4.06-4.03(m,1H),3.52(t,J＝6.2Hz,2H),3.19(s,3H),2.86(d,J＝9.3Hz,1H),2.59-2.57(m,1H),2.45(t,J＝6.2Hz,2H),2.30-2.25(m,1H),1.73-1.63(m,2H),1.62-1.47(m,2H)。The preparation method of (R)-6-(4-hydroxybenzo[b]thiophen-5-yl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one was referred to Example 2. MS/ESI[M+H] + =402.1. 1 H NMR (400MHz, DMSO) δ7.71(dd,J＝12.5,5.6Hz,2H),7.59(d,J＝8.3Hz,1H),7.28(d,J＝8.2Hz,1H),6.80(d,J＝8.4Hz,1H),4.44(s,1H),4.06-4.03(m,1H),3.5 2(t,J＝6.2Hz,2H),3.19(s,3H),2.86(d,J＝9.3Hz,1H),2.59-2.57(m,1H),2.45(t,J＝6.2Hz,2H),2.30-2.25(m,1H),1.73-1.63(m,2H),1.62-1.47(m, 2H).
实施例26：6-(4-氯-2-羟基苯基)-3-{[(3R)-1-甲基六氢吡啶-3-基]氨基}-4-甲基-5H,4H-1,2,4-三嗪-5-酮
Example 26: 6-(4-chloro-2-hydroxyphenyl)-3-{[(3R)-1-methylpiperidin-3-yl]amino}-4-methyl-5H,4H-1,2,4-triazine-5-one
第一步：将化合物3e(800mg,3.39mmol)、化合物26a(694mg,3.72mmol)、Pd(dppf)Cl2(248mg,0.34mmol)、碳酸铯(4.41g,13.6mmol)、二氧六环(20mL)和水(5mL)置于反应瓶中，氮气保护，100℃搅拌15h。反应完成，降温至室温，直接加入硅胶拌样，经硅胶柱层析(石油醚：乙酸乙酯＝1：0-2.5：1)纯化得6-(4-氯-2-甲氧基苯基)-4-甲基-3-(甲基硫基)-5H,4H-1,2,4-三嗪-5-酮26b(590mg，59.0％)；LC-MS:ESI[M+H]+＝297.9。Step 1: Compound 3e (800 mg, 3.39 mmol), compound 26a (694 mg, 3.72 mmol), Pd(dppf)Cl 2 (248 mg, 0.34 mmol), cesium carbonate (4.41 g, 13.6 mmol), dioxane (20 mL) and water (5 mL) were placed in a reaction bottle, protected by nitrogen, and stirred at 100°C for 15 h. After the reaction was completed, the temperature was cooled to room temperature, and silica gel was directly added to mix the sample, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 0-2.5: 1) to obtain 6-(4-chloro-2-methoxyphenyl)-4-methyl-3-(methylthio)-5H,4H-1,2,4-triazine-5-one 26b (590 mg, 59.0%); LC-MS: ESI [M+H] + = 297.9.
第二步：将化合物26b(200mg,0.67mol)溶解于二氯甲烷(15mL)中，降温至0-5℃，加入m-CPBA(204mg，1.01mol，85％纯度)，加毕，室温反应0.5h。反应完成加入饱和碳酸氢钠水溶液(20mL)搅拌5分钟，分液，水相继续用二氯甲烷(10mL)萃取两次，合并有机相，依次用饱和硫代硫酸钠水溶液、饱和食盐水溶液洗涤，无水硫酸钠干燥、过滤、旋干得粗品化合物26c，直接用于下一步，未做进一步纯化；LC-MS:ESI[M+H]+＝313.9。Step 2: Compound 26b (200 mg, 0.67 mol) was dissolved in dichloromethane (15 mL), cooled to 0-5°C, and m-CPBA (204 mg, 1.01 mol, 85% purity) was added. After addition, the mixture was reacted at room temperature for 0.5 h. After the reaction was completed, a saturated sodium bicarbonate aqueous solution (20 mL) was added and stirred for 5 minutes. The aqueous phase was extracted twice with dichloromethane (10 mL). The organic phases were combined and washed with a saturated sodium thiosulfate aqueous solution and a saturated saline solution in turn, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude compound 26c, which was used directly in the next step without further purification; LC-MS: ESI [M+H] + = 313.9.
第三步：将化合物26c(200mg,粗品)置于反应瓶中，加入DIEA(260mg,2.01mmol)，DMAP(8mg,0.06mmol)和(3R)-1-甲基六氢吡啶-3-胺2b(229mg,2.01mmol)，加毕60℃反应12h。旋干溶剂，所得粗品经硅胶柱层析(二氯甲烷：甲醇＝1：0-7：1)纯化得化合物26d(45mg,18.0％两步产率)；LC-MS:ESI[M+H]+＝363.9。Step 3: Compound 26c (200 mg, crude product) was placed in a reaction bottle, DIEA (260 mg, 2.01 mmol), DMAP (8 mg, 0.06 mmol) and (3R)-1-methylhexahydropyridine-3-amine 2b (229 mg, 2.01 mmol) were added, and the mixture was reacted at 60°C for 12 h. The solvent was dried, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 1: 0-7: 1) to obtain compound 26d (45 mg, 18.0% two-step yield); LC-MS: ESI [M+H] + = 363.9.
第四步：将化合物26d(45mg,0.12mmol)和二氯甲烷(10mL)置于反应瓶中，氮气保护，降温至-10℃，加入2M的三溴化硼的二氯甲烷溶液(0.18mL,0.37mmol)，保温反应1h。反应完成，加入甲醇(4mL)淬灭反应，然后加入0.2mL氨水调节pH＝9-10，旋干溶剂，残余物经硅胶柱层析(二氯甲烷：甲醇＝1：0-9：1)纯化得化合物26(22mg,51.2％)；1H NMR(400MHz,Methanol-d4)δ8.57(d,J＝8.8Hz,1H),6.91(d,J＝2.4Hz,1H),6.86(dd,J＝8.8,2.4Hz,1H),4.41-4.29(m,1H),3.47(s,3H),3.37-3.32(m,1H),3.06-2.97(m,1H),2.67-2.46(m,5H),2.12-2.03(m,1H),2.01-1.92(m,1H),1.86-1.74(m,1H),1.73-1.60(m,1H)；LC-MS:ESI[M+H]+＝350.0。 Step 4: Compound 26d (45 mg, 0.12 mmol) and dichloromethane (10 mL) were placed in a reaction bottle, protected by nitrogen, cooled to -10 °C, and 2M dichloromethane solution of boron tribromide (0.18 mL, 0.37 mmol) was added, and the reaction was kept warm for 1 h. After the reaction was completed, methanol (4 mL) was added to quench the reaction, and then 0.2 mL of ammonia water was added to adjust the pH to 9-10, the solvent was dried, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 1: 0-9: 1) to obtain compound 26 (22 mg, 51.2%); 1 H NMR (400 MHz, Methanol-d 4 )δ8.57(d,J＝8.8Hz,1H),6.91(d,J＝2.4Hz,1H),6.86(dd,J＝8.8,2.4Hz,1H),4.41-4.29(m,1H),3.47(s,3H),3.37-3.32(m,1H),3.06-2.97(m,1H),2.6 7-2.46(m,5H),2.12-2.03(m,1H),2.01-1.92(m,1H),1.86-1.74(m,1H),1.73-1.60(m,1H); LC-MS: ESI[M+H] + =350.0.
实施例27：6-(4-氯-2-羟基苯基)-3-{[(3R)-1-乙基六氢吡啶-3-基]氨基}-4-甲基-5H,4H-1,2,4-三嗪-5-酮
Example 27: 6-(4-chloro-2-hydroxyphenyl)-3-{[(3R)-1-ethylpiperidin-3-yl]amino}-4-methyl-5H,4H-1,2,4-triazine-5-one
6-(4-氯-2-羟基苯基)-3-{[(3R)-1-乙基六氢吡啶-3-基]氨基}-4-甲基-5H,4H-1,2,4-三嗪-5-酮的制备参考实施例26，得到化合物27(18mg,13.7％)；1H NMR(400MHz,Methanol-d4)δ8.48(d,J＝8.4Hz,1H),6.80(d,J＝2.4Hz,1H),6.74(dd,J＝8.4,2.4Hz,1H),4.31-4.19(m,1H),3.35(s,3H),3.15-3.06(m,1H),2.85-2.71(m,1H),2.63-2.47(m,2H),2.32-2.18(m,2H),2.01-1.88(m,1H),1.83-1.74(m,1H),1.71-1.59(m,1H),1.58-1.44(m,1H),1.08(t,J＝7.2Hz,3H)；LC-MS:ESI[M+H]+＝364.0。Preparation of 6-(4-chloro-2-hydroxyphenyl)-3-{[(3R)-1-ethylpiperidin-3-yl]amino}-4-methyl-5H,4H-1,2,4-triazine-5-one Referring to Example 26, Compound 27 (18 mg, 13.7%) was obtained; 1 H NMR (400 MHz, Methanol-d 4 )δ8.48(d,J＝8.4Hz,1H),6.80(d,J＝2.4Hz,1H),6.74(dd,J＝8.4,2.4Hz,1H),4.31-4.19(m,1H),3.35(s,3H),3.15-3.06(m,1H),2.85-2.71(m,1H),2.6 3-2.47(m,2H),2.32-2.18(m,2H),2.01-1.88(m,1H),1.83-1.74(m,1H),1.71-1.59(m,1H),1.58-1.44(m,1H),1.08(t,J＝7.2Hz,3H); LC-MS:ESI[M+H ] + = 364.0.
实施例28：3-羟基-4-(3-{[(3R)-1-乙基六氢吡啶-3-基]氨基}-4-甲基-5-氧亚基-1,2,4-三嗪-6-基)苯-1-甲腈
Example 28: 3-Hydroxy-4-(3-{[(3R)-1-ethylpiperidin-3-yl]amino}-4-methyl-5-oxyde-1,2,4-triazin-6-yl)benzene-1-carbonitrile
3-羟基-4-(3-{[(3R)-1-乙基六氢吡啶-3-基]氨基}-4-甲基-5-氧亚基-1,2,4-三嗪-6-基)苯-1-甲腈的制备参考实施例26，得到化合物28(4mg)，LC-MS:ESI[M+H]+＝341.3。Preparation of 3-hydroxy-4-(3-{[(3R)-1-ethylpiperidin-3-yl]amino}-4-methyl-5-oxyylidene-1,2,4-triazin-6-yl)benzene-1-carbonitrile Referring to Example 26, Compound 28 (4 mg) was obtained. LC-MS: ESI [M+H] + = 341.3.
实施例29：(R)-4-(3-((1-乙基哌啶-3-基)氨基)-4-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-6-基)-3-羟基苯甲腈
Example 29: (R)-4-(3-((1-ethylpiperidin-3-yl)amino)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazine-6-yl)-3-hydroxybenzonitrile
(R)-4-(3-((1-乙基哌啶-3-基)氨基)-4-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-6-基)-3-羟基苯甲腈的制备方法参考实施例26，得到化合物29(16mg,11.7％)；1H NMR(400MHz,Methanol-d4)δ8.64(d,J＝8.4Hz,1H),7.13-7.05(m,2H),4.34-4.22(m,1H),3.37(s, 3H),3.05-2.96(m,1H),2.73-2.60(m,1H),2.48-2.34(m,2H),2.21-2.05(m,2H),1.98-1.86(m,1H),1.79-1.69(m,1H),1.67-1.45(m,2H),1.04(t,J＝7.2Hz,4H)；LC-MS:ESI[M+H]+＝355.0。The preparation method of (R)-4-(3-((1-ethylpiperidin-3-yl)amino)-4-methyl-5-oxo-4,5-dihydro-1,2,4-triazine-6-yl)-3-hydroxybenzonitrile was prepared by referring to Example 26 to obtain Compound 29 (16 mg, 11.7%); 1 H NMR (400 MHz, Methanol-d 4 )δ8.64(d,J＝8.4Hz,1H),7.13-7.05(m,2H),4.34-4.22(m,1H),3.37(s, 3H),3.05-2.96(m,1H),2.73-2.60(m,1H),2.48-2.34(m,2H),2.21-2.05(m,2H),1.98-1.86(m,1H),1.79-1.69(m,1H),1.67-1.45(m,2H),1.04( t, J=7.2Hz, 4H); LC-MS: ESI[M+H] + =355.0.
实施例30：6-(4-羟基苯并[b]噻吩-5-基)-3-{[(3R,5R)-5-氟-1-甲基六氢吡啶-3-基]氨基}-4-甲基-5H,4H-1,2,4-三嗪-5-酮
Example 30: 6-(4-Hydroxybenzo[b]thiophene-5-yl)-3-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-4-methyl-5H,4H-1,2,4-triazine-5-one
6-(4-羟基苯并[b]噻吩-5-基)-3-{[(3R,5R)-5-氟-1-甲基六氢吡啶-3-基]氨基}-4-甲基-5H,4H-1,2,4-三嗪-5-酮的制备参考实施例26，得到化合物30(1.9mg,9.7％)；1H NMR(400MHz,Methanol-d4)δ8.58(d,J＝8.8Hz,1H),7.47(d,J＝5.6Hz,1H),7.33-7.24(m,2H),4.97-4.81(m,1H),4.60-4.52(m,1H),3.39(s,3H),3.14-3.07(m,1H),2.99-2.90(m,1H),2.41-2.33(m,1H),2.30(s,3H),2.26-2.20(m,1H),1.96-1.93(m,1H),1.80-1.73(m,1H)；LC-MS:ESI[M+H]+＝390.0。Preparation of 6-(4-hydroxybenzo[b]thiophen-5-yl)-3-{[(3R,5R)-5-fluoro-1-methylpiperidin-3-yl]amino}-4-methyl-5H,4H-1,2,4-triazine-5-one Referring to Example 26, Compound 30 (1.9 mg, 9.7%) was obtained; 1 H NMR (400 MHz, Methanol-d 4 )δ8.58(d,J＝8.8Hz,1H),7.47(d,J＝5.6Hz,1H),7.33-7.24(m,2H),4.97-4.81(m,1H),4.60-4.52(m,1H),3.39(s,3H),3.14-3.07(m,1H),2.99-2.90 (m,1H),2.41-2.33(m,1H),2.30(s,3H),2.26-2.20(m,1H),1.96-1.93(m,1H),1.80-1.73(m,1H); LC-MS: ESI[M+H] + =390.0.
实施例31：3-(((1R，2R)-2-氨基环己基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 31: 3-(((1R,2R)-2-aminocyclohexyl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one
3-(((1R，2R)-2-氨基环己基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例26。1H NMR(400MHz,MeOD)δ8.57(d,J＝8.0Hz,1H),7.46(d,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.27(d,J＝8.0Hz,1H),4.26-4.19(m,1H),3.40(s,3H),2.09-2.06(d,J＝12.0Hz,2H),1.80(d,J＝12.0Hz,2H),1.58-1.44(m,2H),1.39-1.31(m,3H)，LC-MS:ESI[M+H]+＝390.0。Preparation of 3-(((1R,2R)-2-aminocyclohexyl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one Reference Example 26. 1 H NMR (400MHz, MeOD) δ8.57(d,J＝8.0Hz,1H),7.46(d,J＝8.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.27(d,J＝8.0Hz,1H),4.26-4.19(m,1H),3.40(s,3H),2.09-2. 06 (d, J = 12.0 Hz, 2H), 1.80 (d, J = 12.0 Hz, 2H), 1.58-1.44 (m, 2H), 1.39-1.31 (m, 3H), LC-MS: ESI [M+H] + = 390.0.
实施例32：3-(((3R，5R)-1-乙基-5-氟哌啶-3-基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 32: 3-(((3R,5R)-1-ethyl-5-fluoropiperidin-3-yl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one
3-(((3R，5R)-1-乙基-5-氟哌啶-3-基)氨基)-6-(4-羟基苯并[b]噻吩-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例26，得到化合物32(4.7mg,11.7％)；1H NMR(400MHz,Methanol-d4)δ8.58(d,J＝8.8Hz,1H),7.47(d,J＝5.6Hz,1H),7.31(d,J＝5.6Hz,1H),7.26(d,J＝8.8Hz,1H),4.96-4.80(m,1H),4.61-4.52(m,1H),3.38(s,3H),3.18-3.11(m,1H),3.04-2.95(m,1H),2.51(q,J＝7.2Hz,2H),2.31-2.20(m,1H),2.16-2.09(m,1H),1.99-1.90(m,1H),1.54-1.47(m,1H),1.06(d,J＝7.2Hz,3H)；LC-MS:ESI[M+H]+＝404.0。Preparation of 3-(((3R,5R)-1-ethyl-5-fluoropiperidin-3-yl)amino)-6-(4-hydroxybenzo[b]thiophen-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one Reference Example 26 to obtain Compound 32 (4.7 mg, 11.7%); 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.58 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 5.6 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 4.96-4.80 (m, 1H), 4.61-4.52 (m, 1H), 3.38 (s, 3H), 3.18-3.11 (m, 1 LC-MS: ESI[M+H] + =404.0.
实施例33：(R)-3-((1-乙基哌啶-3-基)氨基)-6-(2-羟基-4-(三氟甲基)苯基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 33: (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-3-((1-乙基哌啶-3-基)氨基)-6-(2-羟基-4-(三氟甲基)苯基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例26。1H NMR(400MHz,MeOD)δ8.62(d,J＝8.0Hz,1H),7.04(s,1H),7.01(d,J＝8.0Hz,1H),4.31-4.22(m,1H),3.38(s,3H),2.99(d,J＝8.0Hz,1H),2.44-2.38(m,2H),2.15-2.07(m,2H),1.93-1.89(m,1H),1.78-1.69(m,1H),1.66-1.58(m,1H),1.57-1.49(m,1H),1.04(t,J＝8.0Hz,3H)，LC-MS：ESI[M+H]+＝414.0。Preparation of (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one Reference Example 26. 1 H NMR (400MHz, MeOD) δ8.62(d,J＝8.0Hz,1H),7.04(s,1H),7.01(d,J＝8.0Hz,1H),4.31-4.22(m,1H),3.38(s,3H),2.99(d,J＝8.0Hz,1H),2.44-2.38(m,2H ), 2.15-2.07(m,2H),1.93-1.89(m,1H),1.78-1.69(m,1H),1.66-1.58(m,1H),1.57-1.49(m,1H),1.04(t,J=8.0Hz,3H), LC-MS: ESI[M+H] + =414.0.
实施例34：(R)-6-(4-羟基-2,3-二氢苯并呋喃-5-基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮
Example 34: (R)-6-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazine-5(4H)-one
(R)-6-(4-羟基-2,3-二氢苯并呋喃-5-基)-4-甲基-3-((1-甲基哌啶-3-基)氨基)-1,2,4-三嗪-5(4H)-酮的制备参考实施例2。LC-MS/ESI[M+H]+＝358.2。 Preparation of (R)-6-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-3-((1-methylpiperidin-3-yl)amino)-1,2,4-triazin-5(4H)-one Reference Example 2. LC-MS/ESI [M+H] + = 358.2.
实施例35：(R)-3-((1-乙基哌啶-3-基)氨基)-6-(4-羟基-2,3-二氢苯并呋喃-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 35: (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-3-((1-乙基哌啶-3-基)氨基)-6-(4-羟基-2,3-二氢苯并呋喃-5-基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例2。LC-MS/ESI[M+H]+＝372.2。Preparation of (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. LC-MS/ESI [M+H] + = 372.2.
实施例36：(R)-6-(4-羟基-2,3-二氢苯并呋喃-5-基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 36: (R)-6-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-6-(4-羟基-2,3-二氢苯并呋喃-5-基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例2。LC-MS/ESI[M+H]+＝388.2。Preparation of (R)-6-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. LC-MS/ESI [M+H] + = 388.2.
实施例37：(R)-6-(4-环丙基-2-羟基苯基)-3-((1-乙基哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 37: (R)-6-(4-cyclopropyl-2-hydroxyphenyl)-3-((1-ethylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-6-(4-环丙基-2-羟基苯基)-3-((1-乙基哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例2。LC-MS/ESI[M+H]+＝370.2。Preparation of (R)-6-(4-cyclopropyl-2-hydroxyphenyl)-3-((1-ethylpiperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. LC-MS/ESI [M+H] + = 370.2.
实施例38：(R)-6-(4-环丙基-2-羟基苯基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 38: (R)-6-(4-cyclopropyl-2-hydroxyphenyl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-6-(4-环丙基-2-羟基苯基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例2。LC-MS/ESI[M+H]+＝386.2。Preparation of (R)-6-(4-cyclopropyl-2-hydroxyphenyl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. LC-MS/ESI [M+H] + = 386.2.
实施例39：(R)-3-((1-乙基哌啶-3-基)氨基)-6-(2-羟基-4-(三氟甲氧基)苯基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 39: (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-4-(trifluoromethoxy)phenyl)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-3-((1-乙基哌啶-3-基)氨基)-6-(2-羟基-4-(三氟甲氧基)苯基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例2。LC-MS/ESI[M+H]+＝414.2。Preparation of (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-4-(trifluoromethoxy)phenyl)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. LC-MS/ESI [M+H] + = 414.2.
实施例40：6-(2-羟基-4-(三氟甲氧基)苯基)-3-(((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 40: 6-(2-Hydroxy-4-(trifluoromethoxy)phenyl)-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
(6-(2-羟基-4-(三氟甲氧基)苯基)-3-(((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例2。LC-MS/ESI[M+H]+＝401.2。Preparation of (6-(2-hydroxy-4-(trifluoromethoxy)phenyl)-3-(((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. LC-MS/ESI [M+H] + =401.2.
实施例41：(R)-6-(2-羟基-4-(三氟甲氧基)苯基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 41: (R)-6-(2-hydroxy-4-(trifluoromethoxy)phenyl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
(R)-6-(2-羟基-4-(三氟甲氧基)苯基)-3-((1-(2-羟乙基)哌啶-3-基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例2。LC-MS/ESI[M+H]+＝430.2。Preparation of (R)-6-(2-hydroxy-4-(trifluoromethoxy)phenyl)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. LC-MS/ESI [M+H] + = 430.2.
实施例42：6-(4-羟基-2,3-二氢苯并呋喃-5-基)-3-((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮
Example 42: 6-(4-Hydroxy-2,3-dihydrobenzofuran-5-yl)-3-((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazine-5(4H)-one
6-(4-羟基-2,3-二氢苯并呋喃-5-基)-3-((1R，2R)-2-羟基环己基)氨基)-4-甲基-1,2,4-三嗪-5(4H)-酮的制备参考实施例2。LC-MS/ESI[M+H]+＝359.2。Preparation of 6-(4-hydroxy-2,3-dihydrobenzofuran-5-yl)-3-((1R,2R)-2-hydroxycyclohexyl)amino)-4-methyl-1,2,4-triazin-5(4H)-one Reference Example 2. LC-MS/ESI [M+H] + =359.2.
生物活性测试：Biological activity test:
1、人类单核细胞中的NLRP3炎症体抑制活性测定1. Assay of NLRP3 inflammasome inhibitory activity in human monocytes
试剂：THP-1细胞：武汉普诺赛生命科技有限公司，PMA:Sigma-Aldrich，RPMI培养基:Hyclone，LPS:Sigma-Aldrich，Opti-MEM培养基:Gibco，Nigericin:Invivogen， Human IL-1βELISA检测试剂盒：4A Biotech，参考化合物MCC950：MedChemExpress(MCE)。Reagents: THP-1 cells: Wuhan Punosai Life Science Technology Co., Ltd., PMA: Sigma-Aldrich, RPMI medium: Hyclone, LPS: Sigma-Aldrich, Opti-MEM medium: Gibco, Nigericin: Invivogen, Human IL-1β ELISA kit: 4A Biotech, reference compound MCC950: MedChemExpress (MCE).
实验方法：将THP-1细胞用含PMA(10μM)的RPMI培养基，按2x105/mL的细胞密度，将细胞接种于48孔板，置于37℃、5％CO2孵箱诱导过夜。次日将培养基更换为含1μg/mL LPS的Opti-MEM培养基；3h后，加入药物作用40min；加入Nigericin(10μM)作用40min；收集细胞上清用于ELISA分析。化合物MCC950由MCE公司购买。实验结果如下表2。
Experimental method: THP-1 cells were inoculated in 48-well plates at a cell density of 2x10 5 /mL in RPMI medium containing PMA (10μM) and placed in an incubator at 37°C and 5% CO 2 for overnight induction. The next day, the medium was replaced with Opti-MEM medium containing 1μg/mL LPS; 3 hours later, the drug was added for 40 minutes; Nigericin (10μM) was added for 40 minutes; the cell supernatant was collected for ELISA analysis. Compound MCC950 was purchased from MCE. The experimental results are shown in Table 2.
表2 NLRP3炎症体抑制活性

Table 2 NLRP3 inflammasome inhibitory activity

结论：本发明化合物对NLRP3炎症体具有较好的抑制活性，优选化合物2、4和13等对NLRP3炎症体抑制作用优于MCC950。Conclusion: The compounds of the present invention have good inhibitory activity on NLRP3 inflammasome, and the preferred compounds 2, 4 and 13 have better inhibitory effects on NLRP3 inflammasome than MCC950.
2、化合物对人PBMC细胞IL-1β产生抑制活性测定2. Determination of the inhibitory activity of compounds on IL-1β production in human PBMC cells
取人外周血单核细胞(PBMC)，在含10％FBS和抗生素的RPMI 1640培养基中刺激前培养过夜。第二日换液为减血清培养基并添加作用浓度1ug/ml的LPS刺激3h，药物刺激40min，浓度10uM的nigericin作用40min，收集细胞上清，ELISA法检测IL-1β的生成量。Human peripheral blood mononuclear cells (PBMC) were cultured overnight in RPMI 1640 medium containing 10% FBS and antibiotics before stimulation. On the second day, the medium was changed to reduced serum medium and LPS with an action concentration of 1ug/ml was added for 3h, drug stimulation for 40min, and nigericin with a concentration of 10uM for 40min. The cell supernatant was collected and the production of IL-1β was detected by ELISA.
实验结果如下表3。The experimental results are shown in Table 3 below.
表3化合物对PBMC细胞IL-1β抑制结果
Table 3 Inhibition results of compounds on PBMC cell IL-1β
结论：本发明化合物对人PBMC细胞IL-1β产生具有较好的抑制活性，优选化合物2等对人PBMC细胞IL-1β产生抑制活性IC50优于MCC950。Conclusion: The compounds of the present invention have good inhibitory activity on the production of IL-1β by human PBMC cells, and the preferred compound 2 has an inhibitory activity IC 50 on the production of IL-1β by human PBMC cells that is better than MCC950.
3、化合物对hERG钾离子通道的抑制实验3. Inhibition experiment of compounds on hERG potassium channel
细胞培养和处理：稳定表达hERG的CHO细胞培养于细胞培养瓶中，置于37℃，5％CO2的培养箱培养。待细胞密度生长至60～80％，吸走细胞培养液，用PBS洗一遍后加入Detachin消化。待消化完全后加入培养液中和，然后离心，吸走上清液，再加入培养液重悬，调节细胞密度为2～5×106/mL备用。Cell culture and treatment: CHO cells stably expressing hERG were cultured in a cell culture flask and placed in an incubator at 37°C and 5% CO 2. When the cell density grew to 60-80%, the cell culture medium was removed, and the cells were washed once with PBS and then digested with Detachin. After complete digestion, the cells were neutralized with culture medium, centrifuged, the supernatant was removed, and the cells were resuspended with culture medium. The cell density was adjusted to 2-5×10 6 /mL for later use.
化合物准备：将化合物母液用100％DMSO进行稀释，即取10μL化合物母液加入到20μLDMSO中，3倍连续稀释至6个浓度。分别取4μL的6个浓度的化合物，加入到396μL细胞外液中，即100倍稀释得到6个中间浓度。再分别取80μL的6个中间浓度化合物，加入到320μL细胞外液中，即5倍稀释至需要测试的最终浓度。最高测试浓度为40μM，依次分别为40，13.33，4.44，1.48，0.49和0.16μM共6个浓度。最终测试浓度中的DMSO含量不超过0.2％，此浓度的DMSO对hERG钾通道没有影响。化合物准备由Bravo仪器完成整个稀释过程。Compound preparation: Dilute the compound stock solution with 100% DMSO, that is, take 10 μL of the compound stock solution and add it to 20 μL DMSO, and dilute it 3 times continuously to 6 concentrations. Take 4 μL of the 6 concentrations of the compound respectively and add it to 396 μL of extracellular fluid, that is, dilute it 100 times to get 6 intermediate concentrations. Then take 80 μL of the 6 intermediate concentration compounds respectively and add them to 320 μL of extracellular fluid, that is, dilute it 5 times to the final concentration to be tested. The highest test concentration is 40 μM, and there are 6 concentrations of 40, 13.33, 4.44, 1.48, 0.49 and 0.16 μM respectively. The DMSO content in the final test concentration does not exceed 0.2%, and this concentration of DMSO has no effect on the hERG potassium channel. The compound preparation is completed by the Bravo instrument throughout the dilution process.
电生理记录过程：单细胞高阻抗封接和全细胞模式形成过程全部由Qpatch仪器自动完成，在获得全细胞记录模式后，细胞钳制在-80毫伏，在给予一个5秒的+40毫伏去极化刺激前，先给予一个50毫秒的-50毫伏前置电压，然后复极化到-50毫伏维持5秒，再回到-80毫伏。每15秒施加此电压刺激，记录2分钟后给予细胞外液记录5分钟，然后开始给药过程，化合物浓度从最低测试浓度开始，每个测试浓度给予2.5分钟，连 续给完所有浓度后，给予阳性对照化合物3μM Cisapride。每个浓度至少测试3个细胞(n≥3)。Electrophysiological recording process: The single-cell high-impedance sealing and whole-cell pattern formation process are all automatically completed by the Qpatch instrument. After obtaining the whole-cell recording mode, the cell is clamped at -80 mV. Before giving a 5-second +40 mV depolarizing stimulus, a 50-millisecond -50 mV pre-voltage is given, and then repolarizes to -50 mV for 5 seconds, and then returns to -80 mV. This voltage stimulus is applied every 15 seconds. After recording for 2 minutes, the extracellular solution is given for 5 minutes of recording, and then the drug administration process begins. The compound concentration starts from the lowest test concentration, and each test concentration is given for 2.5 minutes, and the continuous After all concentrations were given, 3 μM Cisapride, a positive control compound, was given. At least 3 cells (n≥3) were tested for each concentration.
数据处理：数据分析处理采用GraphPad Prism 5.0和Excel软件。化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Data processing: GraphPad Prism 5.0 and Excel software were used for data analysis. The IC50 of the compound was calculated using GraphPad Prism 5 software by fitting the following equation:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。实验结果如下表4。Among them, X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively. The experimental results are shown in Table 4.
表4化合物对hERG钾离子通道抑制结果
Table 4 Inhibition results of compounds on hERG potassium ion channel
结论：本发明化合物2、4、20和25等对hERG钾离子通道抑制作用较弱。Conclusion: Compounds 2, 4, 20 and 25 of the present invention have weak inhibitory effects on hERG potassium ion channels.
4、化合物在Balb/c小鼠体内的药代动力学评价4. Pharmacokinetic evaluation of the compound in Balb/c mice
实验目的：了解化合物的药代动力学情况。Experimental purpose: To understand the pharmacokinetics of the compound.
实验依据：化学药物非临床药代动力学研究技术指导原则，2014年。Experimental basis: Technical guidelines for non-clinical pharmacokinetic studies of chemical drugs, 2014.
实验方案：通过Balb/c小鼠静脉给药和灌胃给药，考察化合物的药代动力学情况。Experimental plan: The pharmacokinetics of the compound were investigated by intravenous and oral administration to Balb/c mice.
样品配制：称量化合物加DMSO溶解，再加注射用氯化钠溶液，配化合物溶待给药用。Sample preparation: Weigh the compound and add DMSO to dissolve it, then add sodium chloride solution for injection to prepare the compound solution for administration.
样品采集：6只Balb/c小鼠(成都达硕实验动物有限公司，许可证号：SCXK(川)2020-030)，雄性，3只静脉给药(IV)、3只灌胃给药(PO)，给药后5min、15min、30min、1h、2h、4h、6h、8h、10h、24h和48h采集约0.05mL血液，将收集的血液3500rpm化合物离心15min，收集上清血浆，-40℃冻存待测。以LC-MS/MS分析方法定量分析血药浓度，计算药代动力学参数，如达峰时间(Cmax)，药时曲线下面积(AUC(0-t))，半衰期(T1/2)，清除率(CL)，组织分部(Vdss)，生物利用度(F)等。药代动力学评价结果如下表5。Sample collection: 6 Balb/c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), male, 3 intravenous administration (IV), 3 gavage administration (PO), about 0.05mL of blood was collected at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h and 48h after administration, the collected blood was centrifuged at 3500rpm for 15min, the supernatant plasma was collected, and it was frozen at -40℃ for testing. The blood concentration was quantitatively analyzed by LC-MS/MS analysis method, and pharmacokinetic parameters such as peak time (Cmax), area under the drug-time curve (AUC (0-t)), half-life (T 1/2 ), clearance (CL), tissue distribution (Vdss), bioavailability (F), etc. The results of pharmacokinetic evaluation are shown in Table 5 below.
表5化合物在Balb/c小鼠体内的药代动力学测试结果

Table 5 Pharmacokinetic test results of the compounds in Balb/c mice

结论：本发明化合物1、2、11、23和25等在Balb/c小鼠体内具有良好的药代动力学性质，包括良好的口服生物利用度、暴露量、半衰期和清除率等。Conclusion: Compounds 1, 2, 11, 23 and 25 of the present invention have good pharmacokinetic properties in Balb/c mice, including good oral bioavailability, exposure, half-life and clearance.
5、LPS诱导小鼠模型评价5. Evaluation of LPS-induced mouse model
实验方法：7-8周Balb/c小鼠口服25mg/kg化合物或者溶媒对照(无菌0.9％Nacl溶液)，1h后腹腔注射10mg/kg LPS(Sigma,L2880)。每隔12h观察小鼠生存状态，持续72h，得到小鼠72h存活率。Experimental method: 7-8 weeks old Balb/c mice were orally administered 25 mg/kg compound or vehicle control (sterile 0.9% NaCl solution), and 1 hour later, 10 mg/kg LPS (Sigma, L2880) was intraperitoneally injected. The survival status of the mice was observed every 12 hours for 72 hours, and the 72-hour survival rate of the mice was obtained.
表6化合物对LPS诱导小鼠的存活率影响
Table 6 Effects of compounds on the survival rate of LPS-induced mice
结论：本发明化合物对LPS诱导小鼠具有较好的体内疗效，能够增加LPS诱导小鼠的存活率，尤其是同等剂量下化合物2、4和20等对LPS诱导小鼠的存活率优于参考化合物MCC950。Conclusion: The compounds of the present invention have good in vivo therapeutic effects on LPS-induced mice and can increase the survival rate of LPS-induced mice. In particular, at the same dose, the survival rate of compounds 2, 4 and 20 on LPS-induced mice is better than that of the reference compound MCC950.
6、化合物体内脑血比评价6. Evaluation of the brain-blood ratio of compounds in vivo
实验目的：获得化合物的脑血比。Experimental purpose: To obtain the brain-to-blood ratio of the compound.
实验方案：通过监测化合物在小鼠脑和血浆中的含量，考察化合物的脑血比。Experimental plan: The brain-to-blood ratio of the compound was investigated by monitoring the content of the compound in the mouse brain and plasma.
实验步骤：称量化合物，加少量DMSO，再加入注射用氯化钠溶液，配成1mg·mL-1的化合物溶液，待给药用。按10mg·kg-1口服给药，给药后1h、6h分别采集全血和全脑(n＝3)。全血离心3500rpm 15min，收集上清血浆。称取离心管重量为M1，装入 全脑的离心管重量为M2，加水匀浆后离心管重量为M3，取出30μL匀浆后离心管重量为M4。取30μL血浆和30μL脑匀浆于离心管中，加入120μL含20ng·ml-1内标SAHA的乙腈沉淀，涡旋30s，于13000rpm离心15min，取上清装进样瓶待测。Experimental steps: Weigh the compound, add a small amount of DMSO, and then add sodium chloride solution for injection to prepare a 1 mg·mL -1 compound solution for administration. Orally administer 10 mg·kg -1 , and collect whole blood and whole brain (n=3) 1h and 6h after administration. Centrifuge the whole blood at 3500rpm for 15min, and collect the supernatant plasma. Weigh the centrifuge tube as M1 and put it into The weight of the whole brain centrifuge tube is M2, the weight of the centrifuge tube after adding water homogenate is M3, and the weight of the centrifuge tube after taking out 30μL of homogenate is M4. Take 30μL of plasma and 30μL of brain homogenate in a centrifuge tube, add 120μL of acetonitrile containing 20ng·ml -1 internal standard SAHA to precipitate, vortex for 30s, centrifuge at 13000rpm for 15min, and take the supernatant into the injection bottle for testing.
标准曲线范围：10～10000ng·ml-1。Standard curve range: 10～10000ng·ml -1 .
脑中药物含量＝实测值×0.03×(M3-M1)/[(M2-M1)×(M3-M4)]。Drug content in brain = measured value × 0.03 × (M3-M1)/[(M2-M1) × (M3-M4)].
化合物脑血比结果如下表7所示。The results of the brain-to-blood ratios of the compounds are shown in Table 7 below.
表7化合物给药后小鼠脑血比测试结果
Table 7 Results of brain-to-blood ratio test in mice after administration of compounds
结论：本发明部分化合物具有入脑的潜力，尤其是化合物2在1小时和6小时脑血比分别达到了0.44和0.53。 Conclusion: Some compounds of the present invention have the potential to enter the brain, especially compound 2, whose brain-to-blood ratios reached 0.44 and 0.53 at 1 hour and 6 hours, respectively.

Claims (25)

  1. 式Ⅰ所示化合物或其药学上可接受的形式，其特征在于：所述式Ⅰ结构如下：
    The compound represented by formula I or a pharmaceutically acceptable form thereof, characterized in that: the structure of formula I is as follows:
    其中：in:
    为单键时，X选自NR7a，Y选自C(＝O)； When it is a single bond, X is selected from NR 7a , and Y is selected from C(═O);
    为双键时，X独立选自CR7b或者N，Y选自N； When it is a double bond, X is independently selected from CR 7b or N, and Y is selected from N;
    R1、R2、R4和R5独立地选自氢、氘、卤素、-OH、-NH2、-CN或任选被0-6个取代基取代的以下基团：C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-NHC(＝O)-C1-6烷基、-(C＝O)NH-C1-6烷基、C2-6烯基、C2-6炔基、3-6元环烷基；R1、R2、R4和R5中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-6 substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC(=O)-C 1-6 alkyl, -(C=O)NH-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl; among R 1 , R 2 , R 4 and R 5 , the substituent is selected from deuterium, halogen, -OH, -NH 2 or -CN;
    R3选自氢、氘、卤素、-OH、-NH2、-CN或任选被0-6个取代基取代的以下基团：C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、-NHC(＝O)-C1-6烷基、-(C＝O)NH-C1-6烷基、C2-6烯基、C2-6炔基、3-6元环烷基、5-6元杂环烷基、苯基、5-6元杂芳基；R3中，所述取代基选自：氘、卤素、-OH、-NH2、-CN或3-6元环烷基；R3中，所述5-6元杂环烷基、5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子；R 3 is selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted by 0-6 substituents: C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC(=O)-C 1-6 alkyl, -(C=O)NH-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6-membered cycloalkyl, 5-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 3 , the substituent is selected from deuterium, halogen, -OH, -NH 2 , -CN or 3-6-membered cycloalkyl; in R 3 , the 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O;
    或者，R2与R3、R3与R4或者R4与R5与它们所连接的原子一起形成被0-6个取代基取代的5-6元烷烃环、苯环、5-6元烷烃杂环或者5-6元杂芳环，所述取代基选自：氘、卤素、-OH、-NH2、-CN、氧代基、C1-6烷基、C1-6氟代烷基、C1-6氘代烷基、-O-C1-6烷基、-O-C1-6氟代烷基、-O-C1-6氘代烷基、C3-6环烷基、C3-6氟代环烷基，或者同一碳原子连接的2个所述取代基形成3-6元环烷基；R2与R3、R3与R4或者R4与R5与它们所连接的原子相连成环时，所述5-6元烷烃杂环、5-6元杂芳环含有1～3个选自N、S、O中至少一个的杂原子；Alternatively, R2 and R3 , R3 and R4 , or R4 and R5 , together with the atoms to which they are attached, form a 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle, or a 5-6 membered heteroaromatic ring substituted with 0-6 substituents, wherein the substituents are selected from the group consisting of deuterium, halogen, -OH, -NH2 , -CN, oxo, C1-6 alkyl, C1-6 fluoroalkyl, C1-6 deuterated alkyl, -OC1-6 alkyl, -OC1-6 fluoroalkyl , -OC1-6 deuterated alkyl, C3-6 cycloalkyl , C3-6 fluorocycloalkyl, or two of the substituents attached to the same carbon atom form a 3-6 membered cycloalkyl; ... When 5 is connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocyclic ring and the 5-6 membered heteroaromatic ring contain 1 to 3 heteroatoms selected from at least one of N, S and O;
    L选自-(CH2)n1-、O、-(CH2)n1-NH-、-NH-(CH2)n1-、-NH-CH(CH2)n1(CH3)-，n1为选自0-3的整数；L is selected from -(CH 2 ) n1 -, O, -(CH 2 ) n1 -NH-, -NH-(CH 2 ) n1 -, -NH-CH(CH 2 ) n1 (CH 3 )-, and n1 is an integer selected from 0 to 3;
    R6选自被0-6个取代基取代的6～10元芳基、5～10元杂芳基、3-8元杂环烷基、3-8元环烷基、6～10元螺环烷基、6～10元杂螺环烷基、6～10元桥环烷基、 6～10元杂桥环烷基、C1-6烷基；R6中，所述取代基选自R8a、卤素、氧代基、-OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aC(＝O)R8b、-NR8aR8b、-SO2R8a、-SO2NR8aR8b、-NR8aSO2R8b、-CN；R6中，所述5～10元杂芳基、3-8元杂环烷基、6～10元杂螺环烷基、6～10元杂桥环烷基含有1～3个选自N、S、O中至少一个的杂原子； R6 is selected from 6-10 membered aryl substituted with 0-6 substituents, 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 3-8 membered cycloalkyl, 6-10 membered spirocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered bridged cycloalkyl, 6-10 membered heterobridged cycloalkyl, C 1-6 alkyl; in R 6 , the substituent is selected from R 8a , halogen, oxo, -OR 8a , -SR 8a , -C(＝O)R 8a , -OC(＝O)R 8a , -C(＝O)OR 8a , -C(＝O)NR 8a R 8b , -NR 8a C(＝O)R 8b , -NR 8a R 8b , -SO 2 R 8a , -SO 2 NR 8a R 8b , -NR 8a SO 2 R 8b , -CN; in R 6 , the 5-10 membered heteroaryl, 3-8 membered heterocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered heterobridged cycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S and O;
    R8a和R8b独立地选自氢、氘或者被0-6个取代基取代的以下基团：C1-4烷基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基、3-6元环烷基亚甲基或者4-6元杂环烷基亚甲基；R8a、R8b中，所述取代基选自：氘、卤素、-N(R10aR10b)、-OH、-CN、C1-4烷基、C1-4烷氧基、C1-4氘代烷基、3-6元环烷基、4-6元杂环烷基、3-6元环烷基亚甲基或者4-6元杂环烷基亚甲基；R8a、R8b中，所述4-6元杂环烷基、5-6元杂芳基、4-6元杂环烷基亚甲基含有1～3个选自N、S、O中至少一个的杂原子，所述取代基中4-6元杂环烷基、4-6元杂环烷基亚甲基含有1～3个选自N、S、O中至少一个的杂原子；R 8a and R 8b are independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: C 1-4 alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, 3-6-membered cycloalkylmethylene or 4-6-membered heterocycloalkylmethylene; in R 8a and R 8b , the substituents are selected from deuterium, halogen, -N(R 10a R 10b ), -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 deuterated alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 3-6-membered cycloalkylmethylene or 4-6-membered heterocycloalkylmethylene; R 8a , R In 8b , the 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkylmethylene contains 1 to 3 heteroatoms selected from at least one of N, S, and O, and the 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkylmethylene in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S, and O;
    或者，R8a与R8b与它们所连接的原子形成被0-6个取代基取代的3-6元烷基杂环；R8a与R8b与它们所连接的原子相连成环时，所述取代基选自：氘、卤素、-N(R11aR11b)、-OH、-CN、C1-4烷基、3-6元环烷基、4-6元杂环烷基；R8a与R8b与它们所连接的原子相连成环时，所述3-6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子，所述取代基中4-6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；Alternatively, R 8a and R 8b and the atoms to which they are attached form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents; when R 8a and R 8b and the atoms to which they are attached form a ring, the substituents are selected from: deuterium, halogen, -N(R 11a R 11b ), -OH, -CN, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl; when R 8a and R 8b and the atoms to which they are attached form a ring, the 3-6 membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S and O, and the 4-6 membered heterocycloalkyl in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S and O;
    R7a选自氢或者任选被0-6个取代基取代的以下基团：C1-6烷基、C2-6烯基、C2-6炔基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R7a中，所述取代基选自：氢、氘、卤素、-OH、-NH2或-CN；R7a中，所述4-6元杂环烷基、5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子；R 7a is selected from hydrogen or the following groups optionally substituted by 0-6 substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 7a , the substituent is selected from: hydrogen, deuterium, halogen, -OH, -NH 2 or -CN; in R 7a , the 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O;
    R7b选自氢、氘、卤素、-NH2、-CN、-OR9a、-COR9a、-COOR9a、-CONHR9a、-CON(R9bR9c)、-N(R9bR9c)、-NR9aCOR9b、-SO2R9a或者任选被0-6个取代基取代的以下基团：C1-6烷基、C2-6烯基、C2-6炔基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R7b中，所述取代基选自：氢、氘、卤素、-OH、-NH2或-CN；R7b中，所述4-6元杂环烷基、5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子；R 7b is selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OR 9a , -COR 9a , -COOR 9a , -CONHR 9a , -CON(R 9b R 9c ), -N(R 9b R 9c ), -NR 9a COR 9b , -SO 2 R 9a or the following groups optionally substituted with 0-6 substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 7b , the substituent is selected from hydrogen, deuterium, halogen, -OH, -NH 2 or -CN; in R 7b , the 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl contains 1 to 3 heteroatoms selected from at least one of N, S and O;
    R9a、R9b和R9c独立地选自氢、氘或者被0-6个取代基取代的以下基团：C1-4烷基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R9a、R9b和R9c中， 所述取代基选自：氘、卤素、-OH、-NH2或者CN；R9a、R9b和R9c中，所述取代基中4-6元杂环烷基或5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子；R 9a , R 9b and R 9c are independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; among R 9a , R 9b and R 9c , The substituent is selected from: deuterium, halogen, -OH, -NH2 or CN; in R9a , R9b and R9c , the 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl in the substituent contains 1 to 3 heteroatoms selected from at least one of N, S and O;
    R10a、R10b、R11a和R11b独立地选自氢或C1-4烷基；R 10a , R 10b , R 11a and R 11b are independently selected from hydrogen or C 1-4 alkyl;
    所述药学上可接受的形式选自药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药。The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites or prodrugs.
  2. 根据权利要求1所述的化合物，其特征在于：The compound according to claim 1, characterized in that:
    R1、R2、R4和R5独立地选自氢、氘、卤素、-OH、-NH2、-CN或者任选被0-6个取代基取代的以下基团：C1-4烷基、-O-C1-4烷基、-S-C1-4烷基、C2-4烯基、C2-4炔基、3-6元环烷基，所述取代基选自：氘、卤素、-OH、-NH2或-CN；R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-6 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl;
    优选的，R1、R2、R4和R5独立地选自氢、氘、F、Cl、-OH、-NH2、-CN或者任选被0-3个取代基取代的以下基团：C1-4烷基、-O-C1-4烷基、-S-C1-4烷基、3-6元环烷基，所述取代基选自：氘、F、Cl、-OH、-NH2或-CN；Preferably, R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, F, Cl, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, 3-6 membered cycloalkyl, wherein the substituents are selected from: deuterium, F, Cl, -OH, -NH 2 or -CN;
    更优选的，R1、R2、R4和R5独立地选自氢、氘、F、Cl、-OH、-CH3、氟代甲基、氘代甲基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基、氟代环丙基。More preferably, R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, deuterium, F, Cl, -OH, -CH 3 , fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.
  3. 根据权利要求1或2所述的化合物，其特征在于：The compound according to claim 1 or 2, characterized in that:
    R3选自氢、氘、卤素、-OH、-NH2、-CN或任选被0-6个取代基取代的以下基团：C1-4烷基、-O-C1-4烷基、-S-C1-4烷基、C2-4烯基、C2-4炔基、3-6元环烷基、5-6元杂环烷基、苯基、5-6元杂芳基；R3中，所述取代基选自：氘、卤素、-OH、-NH2、-CN、-CF3或者环丙基；R3中，所述5-6元杂环烷基、5-6元杂芳基含有1～3个选自N、S、O中至少一个的杂原子；R 3 is selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted by 0-6 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6-membered cycloalkyl, 5-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 3 , the substituent is selected from deuterium, halogen, -OH, -NH 2 , -CN, -CF 3 or cyclopropyl; in R 3 , the 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O;
    优选的，R3选自氢、氘、F、Cl、-CN或任选被0-3个取代基取代的以下基团：C1-4烷基、-O-C1-4烷基、-S-C1-4烷基、C2-4烯基、C2-4炔基、3-6元环烷基、5-6元杂环烷基、苯基、5-6元杂芳基；R3中，所述取代基选自：氘、F、Cl、-OH、-NH2、-CF3、-CN或环丙基；R3中，所述5-6元杂环烷基、5-6元杂芳基含有1～2个选自N、S、O中至少一个的杂原子；Preferably, R 3 is selected from hydrogen, deuterium, F, Cl, -CN or the following groups optionally substituted by 0-3 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6-membered cycloalkyl, 5-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 3 , the substituent is selected from: deuterium, F, Cl, -OH, -NH 2 , -CF 3 , -CN or cyclopropyl; in R 3 , the 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl contain 1 to 2 heteroatoms selected from at least one of N, S and O;
    更优选的，R3选自氢、氘、F、Cl、甲基、氟代甲基、氘代甲基、甲硫基、氟代甲硫基、氘代甲硫基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基、氟代环丙基、乙烯基、乙炔基、苯基、氟代苯基、氘代苯基。More preferably, R 3 is selected from hydrogen, deuterium, F, Cl, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl.
  4. 根据权利要求1～3任一项所述的化合物，其特征在于：The compound according to any one of claims 1 to 3, characterized in that:
    R2与R3、R3与R4或者R4与R5可以与它们所连接的原子一起形成被0-6个 取代基取代的5-6元烷烃环、苯环、5-6元烷烃杂环或者5-6元杂芳环，所述取代基选自：氘、卤素、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-氟代C1-4烷基、-O-氘代C1-4烷基、3-6元环烷基或3-6元氟代环烷基，或者同一碳原子连接的2个所述取代基形成3-4元环烷基；R2与R3、R3与R4或者R4与R5与它们所连接的原子相连成环时，所述5-6元烷烃杂环、5-6元杂芳环含有1～2个选自N、S、O中至少一个的杂原子； R2 and R3 , R3 and R4 , or R4 and R5 together with the atoms to which they are attached may form a group consisting of 0-6 atoms. A 5-6 membered alkane ring, a benzene ring, a 5-6 membered alkane heterocycle or a 5-6 membered heteroaromatic ring substituted with a substituent, wherein the substituent is selected from: deuterium, halogen, -OH, -NH2 , -CN, oxo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 deuterated alkyl, -OC1-4 alkyl, -O-fluoro C1-4 alkyl, -O-deuterated C1-4 alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl; when R2 and R3 , R3 and R4 , or R4 and R5 are connected to the atoms to which they are connected to form a ring, the 5-6 membered alkane heterocycle or the 5-6 membered heteroaromatic ring contains 1 to 2 heteroatoms selected from at least one of N, S and O;
    优选的，R2与R3、R3与R4或者R4与R5与它们所连接的原子一起形成被0-3个取代基取代的 所述取代基选自：氘、F、Cl、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-氟代C1-4烷基、-O-氘代C1-4烷基、3-6元环烷基或3-6元氟代环烷基，或者同一碳原子连接的2个所述取代基形成3-4元环烷基；Preferably, R2 and R3 , R3 and R4 , or R4 and R5 together with the atoms to which they are attached form a group substituted with 0-3 substituents. The substituent is selected from: deuterium, F, Cl, -OH, -NH 2 , -CN, oxo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, -OC 1-4 alkyl, -O-fluoro C 1-4 alkyl, -O-deuterated C 1-4 alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl;
    更优选的，R2与R3或者R3与R4与它们所连接的原子一起形成被0-3个取代基取代的 所述取代基选自：氘、F、Cl、-OH、-NH2、-CN、氧代基、甲基、氟代甲基、氘代甲基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基或氟代环丙基，或者同一碳原子连接的2个所述取代基形成3-4元环烷基。More preferably, R2 and R3 or R3 and R4 together with the atoms to which they are attached form a group substituted with 0 to 3 substituents. The substituent is selected from: deuterium, F, Cl, -OH, -NH2 , -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.
  5. 根据权利要求1～4任一项所述的化合物，其特征在于：结构单元选自：

    The compound according to any one of claims 1 to 4, characterized in that: Selected from:

    R12选自氘、卤素、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-C1-4氟代烷基、-O-C1-4氘代烷基、-S-C1-4烷基、-S-C1-4氟代烷基、-S-C1-4氘代烷基、3-6元环烷基、3-6元氟代环烷基；n2选自0-6的整数；R 12 is selected from deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, -OC 1-4 alkyl , -OC 1-4 fluoroalkyl, -OC 1-4 deuterated alkyl, -SC 1-4 alkyl, -SC 1-4 fluoroalkyl, -SC 1-4 deuterated alkyl , 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl; n2 is selected from an integer of 0-6;
    优选的，R12选自：氘、F、Cl、-OH、-NH2、-CN、氧代基、甲基、氟代甲基、氘代甲基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基或氟代环丙基；n2选自0-3的整数。Preferably, R 12 is selected from: deuterium, F, Cl, -OH, -NH 2 , -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl; n2 is selected from an integer of 0-3.
  6. 根据权利要求1～5任一项所述的化合物，其特征在于：结构单元选自：

    The compound according to any one of claims 1 to 5, characterized in that: Selected from:

  7. 根据权利要求1～6任一项所述的化合物，其特征在于：The compound according to any one of claims 1 to 6, characterized in that:
    R7a选自氢或者任选被0-3个取代基取代的以下基团：C1-4烷基、C2-6烯基、C2-6炔基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R7a中，所述取代基选自：氢、氘、卤素、-OH、-NH2或-CN；R7b选自氢、氘、卤素、-NH2、-CN、-OR9a、-COR9a、-COOR9a、-CONHR9a、-CON(R9bR9c)、-N(R9bR9c)、-SO2R9a或者任选被0-3个取代基取代的以下基团：C1-4烷基、C2-4烯基、C2-4炔基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R9a、R9b和R9c独立地选自氢、氘或者被0-3个取代基取代的以下基团：C1-4烷基、3-6元环烷基、4-6元杂环烷基、苯基、5-6元杂芳基；R9a、R9b和R9c中，所述取代基选自：氘、卤素、-OH、-NH2或者CN；R 7a is selected from hydrogen or the following groups optionally substituted by 0-3 substituents: C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 7a , the substituent is selected from hydrogen, deuterium, halogen, -OH, -NH 2 or -CN; R 7b is selected from hydrogen, deuterium, halogen, -NH 2 , -CN, -OR 9a , -COR 9a , -COOR 9a , -CONHR 9a , -CON(R 9b R 9c ), -N(R 9b R 9c ) , -SO 2 R 9a or the following groups optionally substituted by 0-3 substituents: C 1-4 alkyl, C 2-4 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; in R 7a , the substituent is selected from hydrogen, deuterium, halogen, -OH, -NH 2 or -CN; R 9a , R 9b and R 9c are independently selected from hydrogen, deuterium or the following groups substituted with 0-3 substituents: C 1-4 alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; R 9a , R 9b and R 9c are independently selected from hydrogen, deuterium or the following groups substituted with 0-3 substituents: C 1-4 alkyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; in R 9a , R 9b and R 9c , the substituents are selected from deuterium, halogen, -OH, -NH 2 or CN;
    优选的，R7a选自氢或者C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4烷氧 基、C1-4氟代烷氧基、C1-4氘代烷氧基、羧基、C1-4烷氧羰基、C1-4氟代烷氧羰基、C1-4氘代烷氧羰基、3～6元环烷基、3～6元氟代环烷基、苯基、吡啶基或者X1和X2独立地选自CH、N；X3选自N-C1-4烷基、NH、S、O；R7b选自氢、氘、卤素、-NH2、-CN、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4烷氧基、C1-4氟代烷氧基、C1-4氘代烷氧基、羧基、C1-4烷氧羰基、C1-4氟代烷氧羰基、C1-4氘代烷氧羰基、3～6元环烷基、3～6元氟代环烷基、苯基、六元氮杂芳基、-CONHR9a；R9a选自氢、氘、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、3～6元环烷基、3～6元氟代环烷基；X4和X5独立地选自CH、N；X6选自N-C1-4烷基、NH、S、O；Preferably, R 7a is selected from hydrogen or C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy alkyl, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, carboxyl, C 1-4 alkoxycarbonyl , C 1-4 fluoroalkoxycarbonyl, C 1-4 deuterated alkoxycarbonyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, phenyl, pyridyl or X1 and X2 are independently selected from CH, N; X3 is selected from NC1-4 alkyl, NH, S, O; R7b is selected from hydrogen, deuterium, halogen, -NH2 , -CN, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 deuterated alkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, C1-4 deuterated alkoxy, carboxyl, C1-4 alkoxycarbonyl, C1-4 fluoroalkoxycarbonyl, C1-4 deuterated alkoxycarbonyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, phenyl, 6-membered nitrogen heteroaryl, -CONHR 9a ; R 9a is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl; X 4 and X 5 are independently selected from CH, N; X 6 is selected from NC 1-4 alkyl, NH, S, O;
    更优选的，R7a选自氢、甲基、氘代甲基、氟代甲基、乙基、氟代乙基、异丙基、氟代异丙基、环丙基氟代环丙基、环己基、氟代环己基、苯基、吡啶基、X1选自N；X2选自CH、N；X3选自N-甲基、S、O；R7b选自氢、氘、F、Cl、氰基、氨基、甲基、氘代甲基、氟代甲基、乙基、氟代乙基、异丙基、氟代异丙基、甲氧基、氘代甲氧基、氟代甲氧基、羧基、甲氧羰基、氟代甲氧羰基、氘代甲氧羰基、乙氧羰基、氟代乙氧羰基、环丙基、氟代环丙基、环己基、氟代环己基、苯基、吡啶基、-CONHR9a；R9a选自氢、氘、甲基、氟代甲基、氘代甲基、环丙基、氟代环丙基；X4选自N；X5选自CH、N；X6选自N-甲基、S、O。More preferably, R 7a is selected from hydrogen, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, pyridyl, X1 is selected from N; X2 is selected from CH, N; X3 is selected from N-methyl, S, O; R7b is selected from hydrogen, deuterium, F, Cl, cyano, amino, methyl, deuterated methyl, fluoromethyl, ethyl, fluoroethyl, isopropyl, fluoroisopropyl, methoxy, deuterated methoxy, fluoromethoxy, carboxyl, methoxycarbonyl, fluoromethoxycarbonyl, deuterated methoxycarbonyl, ethoxycarbonyl, fluoroethoxycarbonyl, cyclopropyl, fluorocyclopropyl, cyclohexyl, fluorocyclohexyl, phenyl, pyridyl, -CONHR 9a ; R 9a is selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, cyclopropyl, fluorocyclopropyl; X 4 is selected from N; X 5 is selected from CH, N; X 6 is selected from N-methyl, S, O.
  8. 根据权利要求1～7任一项所述的化合物，其特征在于：结构单元选自：

    The compound according to any one of claims 1 to 7, characterized in that: Selected from:

  9. 根据权利要求1～8任一项所述的化合物，其特征在于：L选自O、-NH-、-NH-CH2-、-NH-CH(CH3)-。The compound according to any one of claims 1 to 8, characterized in that L is selected from O, -NH-, -NH-CH 2 -, and -NH-CH(CH 3) -.
  10. 根据权利要求1～9任一项所述的化合物，其特征在于：R6中，所述取代基选自氟、氯、羟基、氰基、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4烷氧基、C1-4氟代烷氧基、C1-4氘代烷氧基、3～6元环烷基、3～6元氟代环烷基、氨基、二甲基氨基、 The compound according to any one of claims 1 to 9, characterized in that: in R 6 , the substituent is selected from fluorine, chlorine, hydroxyl, cyano, oxo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino, dimethylamino,
  11. 根据权利要求1～10任一项所述的化合物，其特征在于：R6选自以下所述的结构：
    The compound according to any one of claims 1 to 10, characterized in that: R 6 is selected from the following structures:
    R13a和R13b独立地选自R8a、卤素、氧代基、-OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aC(＝O)R8b、-NR8aR8b、-SO2R8a、-SO2NR8aR8b、-NR8aSO2R8b、-CN；n3为0-6的整数；R 13a and R 13b are independently selected from R 8a , halogen, oxo, —OR 8a , —SR 8a , —C(═O)R 8a , —OC(═O)R 8a , —C(═O)OR 8a , —C(═O)NR 8a R 8b , —NR 8a C(═O)R 8b , —NR 8a R 8b , —SO 2 R 8a , —SO 2 NR 8a R 8b , —NR 8a SO 2 R 8b , —CN; n3 is an integer from 0 to 6;
    优选的，R13a和R13b独立地选自R8a、氟、氧代基、-OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aC(＝O)R8b、-NR8aR8b、-SO2R8a、-SO2NR8aR8b、-NR8aSO2R8b、-CN；n3为0-3的整数；Preferably, R 13a and R 13b are independently selected from R 8a , fluorine, oxo, -OR 8a , -SR 8a , -C(═O)R 8a , -OC(═O)R 8a , -C(═O)OR 8a , -C(═O)NR 8a R 8b , -NR 8a C(═O)R 8b , -NR 8a R 8b , -SO 2 R 8a , -SO 2 NR 8a R 8b , -NR 8a SO 2 R 8b , -CN; n3 is an integer of 0-3;
    更优选的，R13a和R13b独立地选自氟、氯、羟基、氰基、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4烷氧基、C1-4氟代烷氧基、C1-4氘代烷氧基、3～6元环烷基、3～6元氟代环烷基、氨基、二甲基氨基、 More preferably, R 13a and R 13b are independently selected from fluorine, chlorine, hydroxyl, cyano, oxo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, amino, dimethylamino,
  12. 根据权利要求1～11任一项所述的化合物，其特征在于：R6选自以下结构：

    The compound according to any one of claims 1 to 11, characterized in that: R 6 is selected from the following structures:

  13. 据权利要求1～12任一项所述的化合物，其特征在于：所述化合物选自：

    The compound according to any one of claims 1 to 12, characterized in that the compound is selected from:

  14. 根据权利要求3所述的化合物，其特征在于：R3还能选自丙炔基、氟代丙炔基、环丙基炔基、吡啶基、氟代吡啶基、嘧啶基、氟代嘧啶基。The compound according to claim 3, characterized in that: R 3 can also be selected from propynyl, fluoropropynyl, cyclopropylalkynyl, pyridyl, fluoropyridyl, pyrimidinyl, fluoropyrimidinyl.
  15. 根据权利要求6所述的化合物，其特征在于：结构单元还能选自： The compound according to claim 6, characterized in that: You can also choose from:
  16. 根据权利要求11所述的化合物，其特征在于：R6还能选自以下所述的结构： The compound according to claim 11, characterized in that: R 6 can also be selected from the following structures:
  17. 根据权利要求12所述的化合物，其特征在于：R6还能选自以下结构： The compound according to claim 12, characterized in that: R 6 can also be selected from the following structures:
  18. 据权利要求1～12或14～17任一项所述的化合物，其特征在于：所述化合物选自：
    The compound according to any one of claims 1 to 12 or 14 to 17, characterized in that the compound is selected from:
  19. 根据权利要求6所述的化合物，其特征在于：结构单元还能选自： The compound according to claim 6, characterized in that: You can also choose from:
  20. 根据权利要求12或17所述的化合物，其特征在于：R6还能选自以下结构： The compound according to claim 12 or 17, characterized in that: R 6 can also be selected from the following structures:
  21. 据权利要求1～12、14～17或19～20任一项所述的化合物，其特征在于：所述化合物选自：
    The compound according to any one of claims 1 to 12, 14 to 17 or 19 to 20, characterized in that the compound is selected from:
  22. 药物组合物，其特征在于：其是以权利要求1～21任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药为活性成分，辅以药学上可接受的载体。A pharmaceutical composition, characterized in that it uses the compound according to any one of claims 1 to 21 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug as an active ingredient, assisted by a pharmaceutically acceptable carrier.
  23. 权利要求1～21任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药，及权利要求22所述的药物组合物，在制备用于预防和/或治疗NLRP3相关疾病的药物中的用途。Use of the compound according to any one of claims 1 to 21 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug, and the pharmaceutical composition according to claim 22 in the preparation of a medicament for preventing and/or treating NLRP3-related diseases.
  24. 根据权利要求23所述的用途，其特征在于：所述NLRP3相关疾病包括：炎性疾病、自身免疫疾病、心血管系统疾病、癌症、肾系统疾病、胃肠道疾病、呼吸系统疾病、内分泌系统疾病或者中枢神经系统疾病。The use according to claim 23 is characterized in that: the NLRP3-related diseases include: inflammatory diseases, autoimmune diseases, cardiovascular system diseases, cancer, renal system diseases, gastrointestinal diseases, respiratory system diseases, endocrine system diseases or central nervous system diseases.
  25. 根据权利要求24所述的用途，其特征在于：所述NLRP3相关疾病包括：隐热蛋白相关周期综合征、穆克尔-韦尔斯综合征、家族性寒冷性自身炎性综合征、新生儿发病多系统炎性疾病、家族性地中海热、非酒精性脂肪性肝炎、酒精性肝病、移植物抗宿主病、多发性硬化、类风湿性关节炎、I型/II型糖尿病及相关并发症、牛皮癣、阿尔茨海默氏病、动脉粥样硬化、痛风、慢性肾疾病、脓毒 症、肝纤维化、特发性肺纤维化、癫痫、神经病理性疼痛、抑郁症、帕金森病、哮喘、急性心肌梗塞、红斑狼疮、类风湿关节炎、克罗恩氏病、溃疡性结肠炎、炎症性肠病、类风湿性关节炎、强制性脊髓炎、支气管哮喘、急性呼吸窘迫综合征、慢性阻塞性肺部疾病或者缺血性中风。 The use according to claim 24 is characterized in that: the NLRP3-related diseases include: cryptopyrin-associated periodic syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, neonatal multisystem inflammatory disease, familial Mediterranean fever, non-alcoholic fatty hepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis, rheumatoid arthritis, type I/type II diabetes and related complications, psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis encephalitis, hepatic fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing myelitis, bronchial asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, or ischemic stroke.
PCT/CN2024/076641 2023-02-17 2024-02-07 Six-membered nitrogen heterocyclic compound and use thereof WO2024169858A1 (en)

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