WO2024109922A1 - Bridged ring pyridazine compound and use thereof - Google Patents

Bridged ring pyridazine compound and use thereof Download PDF

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WO2024109922A1
WO2024109922A1 PCT/CN2023/133933 CN2023133933W WO2024109922A1 WO 2024109922 A1 WO2024109922 A1 WO 2024109922A1 CN 2023133933 W CN2023133933 W CN 2023133933W WO 2024109922 A1 WO2024109922 A1 WO 2024109922A1
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membered
alkyl
deuterium
substituents
compound
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PCT/CN2023/133933
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French (fr)
Chinese (zh)
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贾涛
王太津
黄浩
李钢
陈俐娟
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of chemical medicine and relates to a class of bridged ring pyridazine compounds and a preparation method thereof and use thereof in medicine.
  • 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, inflammatory diseases, neurological diseases, autoimmune diseases and/or autoinflammatory diseases, cancer, chronic metabolic diseases and neurological related diseases, such as 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/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 myo
  • the object of the present invention is to invent a class of bridged cyclic pyridazine compounds, or stereoisomers, solvates, metabolites, deuterated substances, prodrugs, pharmaceutically acceptable salts or cocrystals thereof, and pharmaceutical compositions containing the same, for the treatment of NLRP3-related diseases.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable form thereof, wherein the structure of formula I is as follows:
  • 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 alkyl ring; when R2 and R3 , R3 and R4 , or R
  • X is selected from O, -NR 7a -, -C(R 7b R 7c )-, -CH 2 C(R 7b R 7c )- or -C(R 7b R 7c )CH 2 -;
  • 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;
  • R 7a is selected from hydrogen, deuterium, -COR 9a , -CONHR 9a , -CON(R 9b R 9c ), -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, 6 membered aryl, 5-6 membered heteroaryl; in R 7a , the substituent is selected from 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 and R 7c are selected from hydrogen, deuterium, fluorine, -OH, -NH 2 , -CN or C 1-4 alkyl;
  • 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 12a R 12b ), -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, wherein the substituents are selected from: deuterium, halogen, -N(R 12a R 12b ), -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 alkyl heterocyclic ring 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 heteroatom selected from N, S, and O;
  • R 12a and R 12b are independently selected from hydrogen or C 1-4 alkyl
  • R 9a , R 9b and R 9c are independently selected from the following groups 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, 6-membered aryl, 5-6-membered heteroaryl, wherein 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 and 5-6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O;
  • R 9b and R 9c and the atoms to which they are attached form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents, wherein the substituents are selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylmethylene or 4-6 membered heterocycloalkylmethylene; when R 9b and R 9c and the atoms to which they are attached form a ring, the 3-6 membered alkyl heterocyclic ring contains 1 to 3 heteroatoms selected from at least one of N, S and O, and the 4-6 membered heterocycloalkyl and 4-6 membered heterocycloalkylmethylene in the substituents contain 1 to 3 heteroatoms selected from at least one of N, S and O;
  • 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, and 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.
  • 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.
  • 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 substituents are 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.
  • R 3 is selected from hydrogen, deuterium, -CH 3 , fluoromethyl, deuterated methyl, -SCH 3 , fluoromethylthio, deuterated methylthio, -OCH 3 , fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, F, and Cl.
  • R2 and R3 , R3 and R4 , or R4 and R5 together with the atoms to which they are connected, form a 5-6-membered cycloalkane, 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, C1-4 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
  • the 5-6 membered heterocyclic ring and the 5-6 membered heteroaromatic ring contain 1 to 2 heteroatoms selected from at least one of N, S and O.
  • 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 alkyl ring.
  • 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, -NH 2 , -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 alkyl ring.
  • R 10 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.
  • R10 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.
  • X is selected from O, -NR7a- , -C( R7bR7c )-, -CH2C ( R7bR7c )- or -C( R7bR7c ) CH2- ;
  • R7a is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3-6 -membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-membered aryl, 5-6-membered heteroaryl;
  • the substituent is selected from deuterium, fluorine, -OH, -NH2 or -CN;
  • the 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl contains 1 to 2 heteroatoms selected from at least one of N, S and O;
  • X is selected from O, NR 7a , CH 2 , CH 2 CH 2 ; and R 7a is selected from hydrogen, deuterium, methyl, fluoromethyl, and deuterated methyl.
  • L is selected from O, -NH-, -NH-CH 2 -, and -NH-CHCH 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 11a and R 11b 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 11a and R 11b 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 11a and R 11b are independently selected from H
  • R 6 is selected from the following structures:
  • R 6 is selected from the following structures:
  • the present invention also provides some specific compounds represented by the above formula I, which are selected from:
  • the present invention also provides some specific compounds represented by the above formula I, which are selected from:
  • the present invention also provides some specific compounds represented by the above formula I, which are selected from:
  • the compound represented by the above formula I or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug is an active ingredient, assisted by 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, which comprises combining any 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 present invention also relates to a pharmaceutical preparation comprising any compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention.
  • the preparation is in the form of a solid preparation, a semisolid 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: any 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, label, etc., which lists information related to the pharmaceutical composition located in the first container.
  • the listed information is usually determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the area where the product is to be sold.
  • the package insert specifically lists the indications for which the pharmaceutical composition is approved.
  • the package insert may be made of any material, and the information contained therein or thereon may be read from the material.
  • the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which a material (e.g., printed) may be formed.
  • the above-mentioned methods for preventing and/or treating NLRP3-related diseases include: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine system diseases or central nervous system diseases.
  • 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
  • CAPS cryptopyrin-
  • the present invention provides a class of compounds with a bridged ring and pyridazine skeleton.
  • the compounds and compositions can be used to prepare NLRP3 inflammasome inhibitors, providing a new approach for treating NLRP3-related diseases.
  • Activity experiments have shown that the compounds of the present invention have good inhibitory activity on IL-1 ⁇ production in human PBMC cells, good pharmacokinetic properties, and the potential for brain penetration.
  • compositions comprising "a” pharmaceutically acceptable excipient can be interpreted as indicating that the composition includes “one or more” pharmaceutically acceptable excipients.
  • C 1-6 should be understood to include any sub-ranges and each point value therein, such as C 2-5 , C 3-4 , C1-2, C 1-3 , C 1-4 , C 1-5 , etc., as well as C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc.
  • C 3-10 should also be understood in a similar manner, for example, it can include any sub-ranges and point values contained therein, such as C 3-9 , C 6-9 , C 6-8 , C 6-7 , C 7-10 , C 7-9 , C7-8, C 8-9 , etc., as well as C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , 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, decahydronaphthyl, etc.
  • monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooct
  • heterocycloalkyl refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, for example: fused, bridged or spiro) non-aromatic group, whose ring atoms are composed of carbon atoms and at least one (e.g. 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur. If the valence bond requirements are met, the heterocycloalkyl group can be connected to the rest of the molecule through any ring atom.
  • haloalkyl refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by halogen.
  • C 1-6 haloalkyl refers to a C 1-6 alkyl group optionally substituted by one or more (e.g., 1-3) halogens. It will be appreciated by those skilled in the art that when there are more than one halogen substituent, the halogens 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 , -CCl 3 , -C 2 F 5 , -C 2 Cl 5 , -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 , etc.
  • the haloalkyl 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.
  • substituted means that one or more hydrogen atoms in a group are replaced by the same or different substituents.
  • substituents are independently selected from groups comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert- butoxy, -SCH3, -SC2H5 , carbaldehyde , -C(O) CH3 , cyano, nitro, -CF3 , -OCF3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.
  • 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.
  • Some 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 solvates of the compounds 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 compounds of the present invention may exist as hydrates, including single hydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms.
  • the compounds of the present invention may form true solvates, but in some cases, only adventitious water or a mixture of water plus a portion of an adventitious solvent may be retained.
  • the compounds of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
  • the present invention also covers the present invention
  • polymorph refers to all possible crystalline forms or polymorphs of a compound, 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 can retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base which can retain the biological effectiveness of the free acid without other side effects. These salts can be prepared by methods known in the art.
  • 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, as nitrogen requires an available lone pair of electrons to oxidize to the oxide.
  • nitrogen-containing heterocycles that are capable of forming nitrogen oxides.
  • tertiary amines are capable of forming nitrogen oxides.
  • Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxirane.
  • peroxyacids such as peracetic acid and m-chloroperbenzoic acid (mCPBA)
  • hydrogen peroxide such as peracetic acid and m-chloroperbenzoic acid (mCPBA)
  • alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxirane dioxirane
  • metabolite refers to a substance formed in vivo when a compound of the present invention is administered.
  • the metabolites of a compound 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, enzymatic hydrolysis, 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 a mammal 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 to the body or thereon.
  • prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo.
  • 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 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 therapy, for example the administration of three or more active ingredients.
  • treating means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • the reagents and raw materials used in the examples of the present invention are commercially available.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR is determined by a Bruker AVANCE-400 nuclear magnetic spectrometer, the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard is tetramethylsilane (TMS), and the chemical shift is 10 -6 The units are given in ppm.
  • 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 1 Add compound 1a (10 g, 1 eq.) and freshly distilled cyclopentadiene (1.1 eq.) into a reaction flask, add DCM (100 ml) to dissolve, and stir at room temperature for 24 h. Monitor the progress of the reaction by TLC. When the raw material 1a is completely reacted, spin dry the solvent to obtain compound 1b.
  • 1 H NMR (CDCl 3 ) 2.02-2.03 (m, 1H), 2.19-2.21 (m, 1H), 3.71 (s, 6H), 3.86-3.87 (m, 2H), 6.97 (t, J 1.88 Hz, 2H).
  • Step 2 Compound 1b (1 equiv), palladium carbon (10%), and THF were added to a reaction flask, replaced with a hydrogen balloon three times, reacted at room temperature, and the reaction progress was monitored by LC-MS. After about 1 hour, the raw material 1b was completely reacted, the reaction solution was passed through a diatomaceous earth pad, and the filtrate was dried to obtain compound 1c.
  • 1 H NMR (CDCl 3 ) 1.15-1.26 (m, 3H), 1.53-1.56 (m, 1H), 1.76-1.78 (m, 1H), 3.21 (s, 2H), 3.70 (s, 6H).
  • Step 3 Add compound 1c (560 mg, 1.0 eq.), tetrahydrofuran (6 ml), water (2 ml), methanol (2 ml), and sodium hydroxide (2.5 eq.) to a reaction flask, react at room temperature overnight, and monitor the reaction progress by LC-Ms. After the reaction is completed, add 2M hydrochloric acid to adjust the pH to 5 and spin dry. Soak in methanol, pass through a diatomaceous earth pad, and spin dry the resulting liquid to obtain compound 1d.
  • Step 4 Add compound 1d and trifluoroacetic anhydride into the sealed tube and react at 65°C for 12 hours. The reaction is complete. Afterwards, the reaction solution was spin dried to obtain compound 1e.
  • LC-MS: ESI [M+H] + 165.1.
  • Step 6 Add compound 1f (2.5 g) and phosphorus oxychloride (15 ml) to a reaction flask, replace with a nitrogen balloon three times, and react at 100°C overnight. After the reaction is completed, add the reaction solution dropwise to 50 ml of room temperature water, and add solid potassium carbonate to adjust the pH to 7. Extract with EA three times, combine the organic phases, dry, filter, dry-load, and column chromatography to obtain compound 1g.
  • LC-MS: ESI [M+H] + 215.1.
  • Step 7 Add compound 1g (107mg, 1.0eq.), (R)-1-methyl-3-aminopiperidine dihydrochloride (CAS: 1157849-50-7) (1.0eq.), palladium acetate (0.2eq.), race-BINAP (0.6eq.), cesium carbonate (5.0eq.), and anhydrous toluene (5ml) into a reaction tube, replace with a nitrogen balloon three times, and react at 110°C for 12h. After the reaction is completed, the reaction solution is passed through a celite pad, concentrated, and separated by preparative TLC to obtain the target product 1h.
  • LC-MS: ESI [M+H] + 293.2.
  • Step 8 Add compound 1h (29 mg, 1.0 eq.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS: 1072951-50-8) (1.5 eq.), Pd(dppf)Cl 2 (0.1 eq.), cesium carbonate (3.0 eq.), dioxane (2 ml), and deoxygenated water (0.2 ml) into a reaction tube, replace with a nitrogen balloon three times, and react at 100° C. for 12 h. After the reaction is completed, the reaction solution is passed through a celite pad, concentrated, and separated by preparative TLC to obtain the target product 1.
  • Example 12 4-(4-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-methylpiperidin-3-yl)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-amine
  • Step 3 Compound 28c (15.0 g, 65.5 mmol) and K 2 CO 3 (18.1 g, 131 mmol) were added to MeCN (150 mL), and then Me 2 SO 4 (9.9 g, 78.6 mmol) was added, and stirred at 60°C overnight under nitrogen protection.
  • Step 5 Compound 1h (29 mg, 1.0 eq.), 28e (1.5 eq.), Pd(dppf)Cl 2 (0.1 eq.), cesium carbonate (3.0 eq.), dioxane (2 ml), and deoxygenated water (0.2 ml) were added to a reaction tube, replaced with a nitrogen balloon three times, and reacted at 100°C for 12 h. After the reaction was completed, the reaction solution was passed through a celite pad, concentrated, and separated by preparative TLC to obtain the target product 28f.
  • Step 1 Weigh 29a (25.0 g, 231 mmol), pyridine (21.6 g, 277 mmol) and dichloromethane (125 mL) into a flask, cool to 0°C, then slowly drop Tf 2 O (71.7 g, 254 mmol), stir at room temperature for 1 h, filter, wash the filter cake with dichloromethane (20 mL), collect the filtrate to obtain a dichloromethane solution (light yellow) of the target compound 29b.
  • Step 2 Compound 29c (50.9 g, 254 mmol) and triethylamine (70.1 g, 693 mmol) were dissolved in dichloromethane (250 mL), and the dichloromethane solution of the above compound 29b was added dropwise at room temperature, and stirred overnight at room temperature. After the reaction was complete, silica gel was added, concentrated under reduced pressure, and dried by spin drying.
  • Step 5 Compound 29f (400 mg, 1.04 mmol), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS: 1072951-50-8) (235 mg, 1.14 mmol), Cs 2 CO 3 (678 mg, 2.08 mmol) and Pd(dppf)Cl 2 (36.6 mg, 0.05 mmol) were added to dioxane (4 mL) and water (0.8 mL), and the mixture was refluxed at 100°C under nitrogen protection overnight. After the reaction was complete, silica gel was added to the reaction solution, and the mixture was concentrated under reduced pressure and dried by spin drying.
  • MS/ESI [M+H] + 509.2.
  • Step 1 Add CuBr 2 (66 g, 223 mmol) to EtOAc (120 mL) and stir at 80°C for 10 minutes. Then, compound 38a (10 g, 136 mmol) was dissolved in chloroform (120 mL) and added to the above suspension, and refluxed at 80°C for overnight reaction. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was slurried with EtOAc (200 mL) for 0.5 h, filtered, and the filtrate was concentrated to dryness to obtain the target compound 38b (7.3 g).
  • Step 2 Compound 38b (7.3 g, 25 mmol) and Li 2 CO 3 (11 g, 150 mmol) were added to DMF (70 mL) and stirred at 100°C for 6 h. After the reaction was complete, the mixture was filtered, the filtrate was adjusted to pH 1 with aqueous hydrochloric acid, extracted with EtOAc (150 mL ⁇ 3), the organic phase was washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the target compound 38c (5.5 g).
  • Step 3 Compound 38c (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 5 Add compound 19h (150 mg, 0.4 mmol), compound 38e (164 mg, 0.6 mmol), Pd(dppf)Cl 2 (29 mg, 0.04 mmol), cesium carbonate (391 mg, 1.2 mmol), dioxane (4 ml) and deoxygenated water (0.4 ml) to the reaction bottle, replace the nitrogen atmosphere, and react at 100°C for 12 hours. Pass through a celite pad, add silica gel to mix the sample, concentrate under reduced pressure to dry powder, and obtain the target compound 38f (50 mg) by column chromatography.
  • Step 1 Add compound 39a (10 g, 50 mmol), Na 2 CO 3 (11 g, 102 mmol), THF (120 ml), H 2 O (30 ml) to a reaction flask, cool to 0°C in an ice-water bath, add CbzCl (11.4 g, 67 mmol) dropwise, and monitor the reaction progress by TLC. The reaction is complete after about 5 hours. Most of the THF is evaporated off, and the mixture is extracted with EA three times, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. Add silica gel to prepare dry powder, and column chromatography is performed to obtain the target product 39b (14 g).
  • Example 51 2-(4-(((1R)-3-(3,3-difluoroazetidin-1-yl)cyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-ethanolphthalic acid-1-yl)-5-(trifluoromethoxy)phenol
  • Step 2 4M KOH aqueous solution (100mL, 400mmol, 5.0eq.) was added to a solution of compound 52b (30.64g, 79.1mmol) in EtOH (1.0L). The resulting solution was heated at 60°C for 2 hours and then cooled to room temperature. The reaction mixture was neutralized with 3M hydrochloric acid aqueous solution and concentrated under reduced pressure. The crude residue was dissolved in ether (100mL). Washed with water (1 x 100mL) and saturated NaCl aqueous solution (1 x 100mL). The organic layer was dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to obtain compound 52c.
  • the third step a solution of compound 52c (5.00 g, 20.7 mmol, 1.0 eq.), sodium chloro-2,2-difluoroacetate (7.07 g, 51.9 mmol, 2.50 eq.) and cesium carbonate (11.5 g, 41.5 mmol, 2.0 eq.) in water (20 mL) and N,N-dimethylformamide (80 mL) was heated at 100 ° C for 12 hours. After completion, the reaction mixture was cooled to room temperature and the reaction mixture was diluted and washed with EtOAc. The organic phase was washed with water and brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in hexane to give compound 52d as a yellow solid.
  • Step 5 Add compound 19h (150 mg, 0.4 mmol), compound 52e (198 mg, 0.6 mmol), Pd(dppf)Cl 2 (29 mg, 0.04 mmol), cesium carbonate (391 mg, 1.2 mmol), dioxane (4 ml) and deoxygenated water (0.4 ml) to the reaction bottle, replace the nitrogen atmosphere, and react at 100°C for 12 hours. Pass through a celite pad, add silica gel to mix the sample, concentrate under reduced pressure to dry powder, and obtain the target compound 52f (98 mg) by column chromatography.
  • Example 58 2-(4-((((R)-1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
  • Example 62 5-(4-((((R)-1-[(R)-1-hydroxypropan-2-yl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol and
  • Step 6 Compound 62f was chiral split to obtain compound 62 and compound 63.
  • the splitting method was: instrument-Waters 150Prep-SFC, column model: Chiralcel AD Column, mobile phase A: carbon dioxide, mobile phase B: 0.1% ammonia in isopropanol, gradient: 70% mobile phase B, pressure: 100 bar, flow rate: 100 mL/min.
  • Step 2 Add compound 68b (393 mg, 1 mmol), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS: 1072951-50-8) (309 mg, 1.5 mmol), Pd(dppf)Cl 2 (51 mg, 0.1 mmol), and carbonic acid to the reaction flask.
  • Cesium (694 mg, 3 mmol), dioxane (5 ml) and deoxygenated water (0.5 ml) were replaced with nitrogen atmosphere and reacted at 100°C for 12 h.
  • the mixture was passed through a celite pad and mixed with silica gel, and concentrated to dry powder under reduced pressure.
  • Example 70 (R)-5-(difluoromethoxy)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)phenol
  • Step 2 At room temperature, K 2 CO 3 (601.8 mg, 4.4 mmol) was added to a solution of compound 71b (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 Compound 71c (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), and 1,4-dioxane (8 mL) were added to a dry flask. Under nitrogen protection, the mixture was refluxed at 100°C overnight. After the reaction was complete, 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 excess solvent was removed from the filtrate under reduced pressure.
  • Step 4 Add compound 29f (82 mg, 0.21 mmol) and compound 71d (98 mg, 0.25 mmol), Cs 2 CO 3 (136.9 mg, 0.42 mmol), Pd(dppf)Cl 2 (15.4 mg, 0.02 mmol) into a dry reaction flask, replace nitrogen three times, add dioxane/H 2 O (3 mL/0.5 mL) under nitrogen protection, and react at 105°C overnight. After the reaction is complete, the reaction solution is restored to At room temperature, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the excess solvent was concentrated under reduced pressure. Compound 71f (yellow solid, 46 mg) was separated by column chromatography. LC-MS: 613.6 [M+H] + .
  • Step 5 Add compound 71f (46 mg, 0.08 mmol), DCM (0.5 mL), and HCl in dioxane (4 M) (1 mL) to a dry reaction bottle, react at room temperature for 3 h, remove excess solvent under reduced pressure, and separate by column chromatography to obtain compound 71 (yellow solid, 12 mg).
  • Step 1 Add compound 18h (132 mg, 0.45 mmol) and compound 71d (211.7 mg, 0.54 mmol), Cs 2 CO 3 (440 mg, 1.35 mmol), Pd(dppf)Cl 2 (36.6 mg, 0.05 mmol) to a dry reaction flask, replace nitrogen three times, add dioxane/H 2 O (4 mL/0.5 mL) under nitrogen protection, and react at 105°C overnight. After the reaction is complete, the reaction solution is returned to room temperature, water is added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the excess solvent is concentrated under reduced pressure. Compound 72a (yellow solid, 79 mg) is separated by column chromatography. LC-MS: 523.6 [M+H] + .
  • Step 2 Add compound 72a (79 mg, 0.15 mmol), DCM (1 mL), HCl in dioxane (4 M) (1 mL) to a dry reaction bottle, react at room temperature for 3 h, remove excess solvent under reduced pressure, and separate compound 72 (yellow solid, 10.2 mg) by column chromatography.
  • LC-MS 393.3 [M+H] + .
  • Example 78 2-(4-(((R)-1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-3-methyl-5-(trifluoromethyl)phenol
  • Step 1 Weigh 78a (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).
  • Step 2 Compound 78b (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 the addition, the mixture was stirred at 0°C for 1 h. I2 (20.2 g, 79.5 mmol) was then added in batches to the above suspension. After the addition, the mixture was stirred at 0°C for 1 h.
  • Step 3 Compound 78c (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 overnight at 25° C. 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 78d (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 mixture was refluxed at 110° C. under nitrogen protection overnight.
  • Step 1 Compound 29c (10.0 g, 49.9 mmol) and K 2 CO 3 (13.8 g, 99.8 mmol) were added to MeCN (100 mL), and then deuterated bromoethane (6.83 g, 59.9 mmol) was added and stirred at room temperature overnight. After the reaction was complete, the mixture was filtered and the filtrate was dried by rotary evaporation. The filter cake was dissolved in EtOAc (100 mL), washed with water (30 mL ⁇ 3), and the organic phase was collected and dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated to dryness to obtain the target compound 79a (10.1 g, 43.3 mmol, light brown solid, yield 87%).
  • 1 H NMR 400 MHz, CDCl 3 ) ⁇ 4.99 (s, 1H), 3.73 (s, 1H), 2.54–2.21 (m, 4H), 1.74–1.52 (m, 4H), 1.45 (s, 9H
  • Step 2 Compound 79a (10.1 g, 43.3 mmol) was dissolved in dioxane (50 mL), and then HCl/dioxane (65 mL, 4.0 M) was slowly added, and stirred at room temperature for 1 h. Then, the mixture was concentrated under reduced pressure and dried to obtain the target compound 79b (9.20 g, 44.6 mmol, white solid, yield 100%).
  • Step 5 Compound 80e (122 mg, 0.28 mmol) and DCM (2 ml) were added to the reaction flask, cooled to -5°C, 1M BBr 3 (0.2 ml, 2 mmol) was added dropwise, reacted at -5°C for 2 h, and methanol was added dropwise to quench the reaction.
  • THP-1 cells Wuhan Pronosai Life Science Technology Co., Ltd.
  • PMA Sigma-Aldrich
  • RPMI medium Hyclone
  • LPS Sigma-Aldrich
  • Opti-MEM medium Gibco
  • Nigericin Invivogen
  • Human IL-1 ⁇ ELISA detection 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 with RPMI medium containing PMA (10 ⁇ M) and placed in a 37°C, 5% CO 2 incubator for induction overnight. The next day, the culture medium was replaced with Opti-MEM medium containing 1 ⁇ g/mL LPS; after 3h, the drug was added for 40min; Nigericin (10 ⁇ M) was added for 40min; the cell supernatant was collected for ELISA analysis.
  • Compound MCC950 was purchased from MCE, and Ref-1 was synthesized according to the synthesis method of Example 63 in patent WO2021193897. The experimental results are shown in Table 2 below.
  • the compounds of the present invention have good inhibitory activity on NLRP3 inflammasome, especially compounds 38 and 39 have better inhibitory effects on NLRP3 inflammasome than reference compounds MCC950 and Ref-1.
  • 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 aspirated, and the cells were washed once with PBS and then digested with Detachin. After complete digestion, the cells were neutralized by adding culture medium, then centrifuged, the supernatant was aspirated, and the cells were resuspended in 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, 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. After all concentrations are given continuously, the positive control compound 3 ⁇ M Cisapride is given. At least 3 cells (n ⁇ 3) are 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
  • the compounds of the present invention have good pharmacokinetic properties in Balb/c mice, including good oral Oral bioavailability, exposure, half-life and clearance, etc.
  • mice 7-8 weeks old Balb/c mice were orally administered 25mg/kg or 50mg/kg of the compound or a solvent control (sterile 0.9% NaCl solution), and 1 hour later, 10mg/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. The experimental results are shown in Table 5.
  • the compounds of the present invention have good in vivo therapeutic effects on LPS-induced septic mice and can increase the survival rate of LPS-induced septic mice.
  • the survival rate of compound 39 on LPS-induced septic 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)].
  • 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 39 has an inhibitory activity IC 50 on the production of IL-1 ⁇ by human PBMC cells that is better than MCC950.

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Abstract

Disclosed are a bridged ring pyridazine compound and the use thereof, which compound and use belong to the technical field of chemical medicine. Provided is a bridged ring pyridazine compound as represented by formula I, which compound can be used as an NLRP3 inhibitor, and has high activity and good pharmacokinetic properties.

Description

桥环并哒嗪类化合物及其用途Bridged ring and pyridazine compounds and uses thereof 技术领域Technical Field
本发明属于化学医药领域，涉及一类桥环并哒嗪类化合物及其制备方法和在医药中的用途。The invention belongs to the field of chemical medicine and relates to a class of bridged ring pyridazine compounds and a preparation method thereof and use thereof in medicine.
背景技术Background technique
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) inflammasomes 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, inflammatory diseases, neurological diseases, autoimmune diseases and/or autoinflammatory diseases, cancer, chronic metabolic diseases and neurological related diseases, such as 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/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. 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
本发明的目的在于发明一类桥环并哒嗪化合物，或者其立体异构体、溶剂化物、代谢产物、氘代物、前药、药学上可接受的盐或共晶，包含其的药物组合物，以用于治疗NLRP3相关疾病。The object of the present invention is to invent a class of bridged cyclic pyridazine compounds, or stereoisomers, solvates, metabolites, deuterated substances, prodrugs, pharmaceutically acceptable salts or cocrystals thereof, and pharmaceutical compositions containing the same, for the treatment of NLRP3-related diseases.
第一方面，本发明提供一种式I所示的化合物或其药学上可接受的形式，所述式Ⅰ结构如下：
In a first aspect, the present invention provides a compound represented by formula I or a pharmaceutically acceptable form thereof, wherein the structure of formula I is as follows:
其中：in:
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元烷基环；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 alkyl ring; 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;
X选自O、-NR7a-、-C(R7bR7c)-、-CH2C(R7bR7c)-或者-C(R7bR7c)CH2-；X is selected from O, -NR 7a -, -C(R 7b R 7c )-, -CH 2 C(R 7b R 7c )- or -C(R 7b R 7c )CH 2 -;
L选自-(CH2)n1-、O、-(CH2)n1-NH-、-NH-(CH2)n1-、-NH-CH(CH2)n1CH3-，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, 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 , and -CN; R In 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;
R7a选自氢、氘、-COR9a、-CONHR9a、-CON(R9bR9c)、-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、6元芳基、5-6元杂芳基；R7a中，所述取代基选自：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, deuterium, -COR 9a , -CONHR 9a , -CON(R 9b R 9c ), -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, 6 membered aryl, 5-6 membered heteroaryl; in R 7a , the substituent is selected from 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和R7c选自氢、氘、氟、-OH、-NH2、-CN或者C1-4烷基；R 7b and R 7c are selected from hydrogen, deuterium, fluorine, -OH, -NH 2 , -CN or C 1-4 alkyl;
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(R12aR12b)、-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 12a R 12b ), -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，所述取代基选自选自：氘、卤素、-N(R12aR12b)、-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元烷基杂环含有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, wherein the substituents are selected from: deuterium, halogen, -N(R 12a R 12b ), -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 alkyl heterocyclic ring 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 heteroatom selected from N, S, and O;
R12a和R12b独立地选自氢或C1-4烷基；R 12a and R 12b are independently selected from hydrogen or C 1-4 alkyl;
R9a、R9b和R9c独立地选自被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、6元芳基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH2或-CN；R9a、R9b和R9c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 9a , R 9b and R 9c are independently selected from the following groups 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, 6-membered aryl, 5-6-membered heteroaryl, wherein 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 and 5-6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O;
或者，R9b与R9c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，所述取代基选自：氘、卤素、-NH2、-OH、-CN、C1-4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；R9b与R9c与它们所连接的原子相连成环时，所述3-6元烷基杂环含有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；Alternatively, R 9b and R 9c and the atoms to which they are attached form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents, wherein the substituents are selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylmethylene or 4-6 membered heterocycloalkylmethylene; when R 9b and R 9c and the atoms to which they are attached form a ring, the 3-6 membered alkyl heterocyclic ring contains 1 to 3 heteroatoms selected from at least one of N, S and O, and the 4-6 membered heterocycloalkyl and 4-6 membered heterocycloalkylmethylene in the substituents contain 1 to 3 heteroatoms selected from at least one of N, S and O;
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.
在本发明一些实施例中，上述式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 represented by the above 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, and the substituents are selected from: deuterium, halogen, -OH, -NH 2 or -CN.
在本发明一些优选实施例中，上述式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 the above 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.
在本发明一些更优选实施例中，上述式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, 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.
在本发明一些实施例中，上述式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 the above 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.
在本发明一些优选实施例中，上述式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 the above 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 substituents are 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.
在本发明一些更优选实施例中，上述式I所示化合物中，R3选自氢、氘、-CH3、氟代甲基、氘代甲基、-SCH3、氟代甲硫基、氘代甲硫基、-OCH3、氟代甲氧基、氘代甲氧基、环丙基、氟代环丙基、F、Cl。In some more preferred embodiments of the present invention, in the compound of formula I, R 3 is selected from hydrogen, deuterium, -CH 3 , fluoromethyl, deuterated methyl, -SCH 3 , fluoromethylthio, deuterated methylthio, -OCH 3 , fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, F, and Cl.
在本发明一些实施例中，上述式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0-6个取代基取代的5-6元环烷烃、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元烷基环；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 , together with the atoms to which they are connected, form a 5-6-membered cycloalkane, 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, C1-4 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 alkyl ring; R2 and R3, R3 and R4 , or R4 and R5, together with the atoms to which they are connected, form a 5-6-membered cycloalkane, 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, C1-4 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 5 and the atoms to which they are connected are connected to form a ring, the 5-6 membered heterocyclic ring and the 5-6 membered heteroaromatic ring contain 1 to 2 heteroatoms selected from at least one of N, S and O.
在本发明一些优选实施例中，上述式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元烷基环。In some preferred embodiments of the present invention, in the compound represented by the above 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 alkyl ring.
在本发明一些更优选实施例中，上述式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元烷基环。In some more preferred embodiments of the present invention, in the compound represented by the above 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, -NH 2 , -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 alkyl ring.
在本发明一些实施例中，上述式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 the above formula I, the structural unit Selected from:
R10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 10 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.
在本发明一些优选实施例中，上述式I所示化合物中，R10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, R10 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.
在本发明一些更优选实施例中，上述式I所示化合物中，结构单元选自：
In some more preferred embodiments of the present invention, in the compound represented by the above formula I, the structural unit Selected from:
在本发明一些更优选实施例中，上述式I所示化合物中，结构单元选自：

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

在本发明一些实施例中，上述式I所示化合物中，X选自O、-NR7a-、-C(R7bR7c)-、-CH2C(R7bR7c)-或者-C(R7bR7c)CH2-；R7a选自氢、氘或者任选被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、6元芳基、5-6元杂芳基；R7a中，所述取代基选自：氘、氟、-OH、-NH2或-CN；R7a中，所述4-6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；R7b和R7c选自氢、氘、氟、-OH、-NH2、-CN或者C1-4烷基。In some embodiments of the present invention, in the compound represented by the above formula I, X is selected from O, -NR7a- , -C( R7bR7c )-, -CH2C ( R7bR7c )- or -C( R7bR7c ) CH2- ; R7a is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3-6 -membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-membered aryl, 5-6-membered heteroaryl; in R7a , the substituent is selected from deuterium, fluorine, -OH, -NH2 or -CN; in R7a , the 4-6-membered heterocycloalkyl, 5-6-membered heteroaryl contains 1 to 2 heteroatoms selected from at least one of N, S and O; R7b and R7c are selected from hydrogen, deuterium, fluorine, -OH, -NH2 , -CN or C 1-4 alkyl.
在本发明一些优选实施例中，上述式I所示化合物中，X选自O、NR7a、CH2、CH2CH2；R7a选自氢、氘、甲基、氟代甲基、氘代甲基。In some preferred embodiments of the present invention, in the compound represented by the above formula I, X is selected from O, NR 7a , CH 2 , CH 2 CH 2 ; and R 7a is selected from hydrogen, deuterium, methyl, fluoromethyl, and deuterated methyl.
在本发明一些实施例中，上述式I所示化合物中，L选自O、-NH-、-NH-CH2-、-NH-CHCH3-。In some embodiments of the present invention, in the compound represented by the above formula I, L is selected from O, -NH-, -NH-CH 2 -, and -NH-CHCH 3 -.
在本发明一些实施例中，上述式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,
在本发明一些实施例中，上述式I所示化合物中，R6中，所述取代基选自 In some embodiments of the present invention, in the compound represented by the above formula I, in R 6 , the substituent is selected from
在本发明一些实施例中，上述式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 the above formula I, R 6 is selected from the following structures:

R11a和R11b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 11a and R 11b 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.
在本发明一些优选实施例中，上述式I所示化合物中，R11a和R11b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 the above formula I, R 11a and R 11b 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.
在本发明一些更优选实施例中，上述式I所示化合物中，R11a和R11b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 represented by the above formula I, R 11a and R 11b 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,
在本发明一些更优选实施例中，上述式I所示化合物中，R11a和R11b独立地选自H、 In some more preferred embodiments of the present invention, in the compound represented by the above formula I, R 11a and R 11b are independently selected from H,
在本发明一些实施例中，上述式I所示化合物中，R6选自以下结构：

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

在本发明一些实施例中，上述式I所示化合物中，R6选自以下结构： In some embodiments of the present invention, in the compound represented by the above formula I, R 6 is selected from the following structures:
本发明还提供了一些上述式I所示的具体化合物，其选自：

The present invention also provides some specific compounds represented by the above formula I, which are selected from:

本发明还提供了一些上述式I所示的具体化合物，其选自：

The present invention also provides some specific compounds represented by the above formula I, which are selected from:

本发明还提供了一些上述式I所示的具体化合物，其选自：
The present invention also provides some specific compounds represented by the above formula I, which are selected from:
在本发明一些实施方案中，上述式I所示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 some embodiments of the present invention, the compound represented by the above formula I or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug is an active ingredient, assisted by 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的任意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, which comprises combining any 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.
本发明还涉及一种药物制剂，其包含式I的任意化合物或其药学上可接受的形式、或它们的混合物作为活性成分，或者本发明的药物组合物。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 comprising any compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention. In some embodiments, the preparation is in the form of a solid preparation, a semisolid 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的任意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: any 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(例如印刷在本发明的一些实施方案中，提供了上述式I所示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，及其药物组合物，在制备用于预防和/或治疗NLRP3相关疾病的药物中的用途。The package insert is a trademark, label, label, etc., which lists information related to the pharmaceutical composition located in the first container. The listed information is usually determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the area where the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert may be made of any material, and the information contained therein or thereon may be read from the material. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which a material (e.g., printed) may be formed. In some embodiments of the present invention, there is provided a compound shown in the above formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug thereof, and a pharmaceutical composition thereof, for use in the preparation of a medicament for preventing and/or treating NLRP3-related diseases.
在本发明一些实施方案中，上述用于预防和/或治疗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 of the present invention, the above-mentioned methods for preventing and/or treating NLRP3-related diseases include: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine system diseases or central nervous system diseases.
在本发明一些实施方案中，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 of the present invention, 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.
本发明的有益效果：Beneficial effects of the present invention:
本发明提供了一类骨架为桥环并哒嗪的化合物，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；活性实验证明，本发明化合物对人PBMC细胞IL-1β产生具有良好的抑制活性，具有良好的药代动力学性质，以及具有脑渗透的潜力。The present invention provides a class of compounds with a bridged ring and pyridazine skeleton. The compounds and compositions can be used to prepare NLRP3 inflammasome inhibitors, providing a new approach for treating NLRP3-related diseases. Activity experiments have shown that the compounds of the present invention have good inhibitory activity on IL-1β production in human PBMC cells, good pharmacokinetic properties, and the potential for brain penetration.
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, the meanings of all technical and scientific terms used herein are intended to be the same as those commonly understood by those skilled in the art. The terms "include,""comprises,""has,""contains," or "involves," and other variations thereof herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps. It should be understood by those skilled in the art that the above terms, such as "includes," encompass 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.
当公开了数值范围的下限和上限时，落入该范围中的任何数值和任何包括的范围都被具体公开。特别地，本文公开的值的每个取值范围(以形式“约a至b”，或同等的，“大约a至b”，或同等的，“约a-b”)，应理解为表示涵盖于较宽范围中的每个数值和范围。When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values disclosed herein (in the form of "about a to b", or equivalently, "approximately a to b", or equivalently, "about a-b"), should be understood to represent each value and range encompassed in the broader range.
例如，表述“C1-6”应理解为涵盖其中的任意亚范围以及每个点值，例如C2-5、C3-4、C1-2、C1-3、C1-4、C1-5等，以及C1、C2、C3、C4、C5、C6等。例如，表述“C3-10”也应当以类似的方式理解，例如可以涵盖包含于其中的任意亚范围和点值，例如C3-9、C6-9、C6-8、C6-7、C7-10、C7-9、C7-8、C8-9等以及C3、C4、C5、C6、C7、C8、C9、C10等。For example, the expression "C 1-6 " should be understood to include any sub-ranges and each point value therein, such as C 2-5 , C 3-4 , C1-2, C 1-3 , C 1-4 , C 1-5 , etc., as well as C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , etc. For example, the expression "C 3-10 " should also be understood in a similar manner, for example, it can include any sub-ranges and point values contained therein, such as C 3-9 , C 6-9 , C 6-8 , C 6-7 , C 7-10 , C 7-9 , C7-8, C 8-9 , etc., as well as C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , 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。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, decahydronaphthyl, etc.
在本发明中，除非另有说明，“杂环烷基”、“亚杂环烷基”或“杂环”是指饱和或部分饱和的，单环或多环(诸如双环，例如：并环、桥环或螺环)的非芳香族基团，其环原子由碳原子以及至少一个(例如1、2、3或4个)选自氮、氧和硫的杂原子构成。如果满足价键要求，杂环烷基可以通过任意一个环原子与分子的其余部分连接。In the present invention, unless otherwise specified, "heterocycloalkyl", "heterocycloalkylene" or "heterocycle" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, for example: fused, bridged or spiro) non-aromatic group, whose ring atoms are composed of carbon atoms and at least one (e.g. 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur. If the valence bond requirements are met, the heterocycloalkyl group can be connected to the rest of the molecule through any ring atom.
在本发明中，除非另有说明，“卤代烷基”指上文所述的烷基，其中一个或多个氢原子被卤素代替。例如，术语“C1-6卤代烷基”指任选地被一个或多个(如1-3个)卤素取代的C1-6烷基。本领域技术人员应当理解，当卤素取代基多于一个时，卤素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、-CCl3、-C2F5、-C2Cl5、-CH2CF3、-CH2Cl或-CH2CH2CF3等。本发明中的卤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, "haloalkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by halogen. For example, the term "C 1-6 haloalkyl" refers to a C 1-6 alkyl group optionally substituted by one or more (e.g., 1-3) halogens. It will be appreciated by those skilled in the art that when there are more than one halogen substituent, the halogens 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 , -CCl 3 , -C 2 F 5 , -C 2 Cl 5 , -CH 2 CF 3 , -CH 2 Cl or -CH 2 CH 2 CF 3 , etc. The haloalkyl 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.
在本发明中，除非另有说明，“氧代基”或“＝O”是指其与相连碳原子一起形成C＝O。In the present invention, unless otherwise specified, "oxo" or "=O" means that it and the attached carbon atom together form C=O.
在本发明中，除非另有说明，“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于卤素(F、Cl、Br或I)、羟基、胺基、C1-8烷基、C3-7环烷基、-OR’、-SR’、＝O、＝S、-C(O)R’、-C(S)R’、＝NR’、-C(O)OR’、-C(S)OR’、-NR’R”、-C(O)NR’R”、氰基、硝基、-S(O)2R’、-O-S(O)2OR’、-O-S(O)2R’、-OP(O)(OR’)(OR”)；其中R’和R”独立地选自-H、C1-8烷基、C1-8卤代烷基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH3、-SC2H5、甲醛基、-C(O)CH3、氰基、硝基、-CF3、-OCF3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。In the present invention, unless otherwise specified, "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), hydroxyl, amine, C 1-8 alkyl, C 3-7 cycloalkyl, -OR', -SR', =O, =S, -C(O)R', -C(S)R', =NR', -C(O)OR', -C(S)OR', -NR'R", -C(O)NR'R", cyano, nitro, -S(O) 2 R', -OS(O) 2 OR', -OS(O) 2 R', -OP(O)(OR')(OR"); wherein R' and R" are independently selected from -H, C 1-8 alkyl, C 1-8 haloalkyl. In some embodiments, substituents are independently selected from groups comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert- butoxy, -SCH3, -SC2H5 , carbaldehyde , -C(O) CH3 , cyano, nitro, -CF3 , -OCF3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.
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. Some 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 solvates of the compounds 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 compounds of the present invention may exist as hydrates, including single hydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases, only adventitious water or a mixture of water plus a portion of an adventitious solvent may be retained. The compounds of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention. The present invention also covers the present invention The term "polymorph" refers to all possible crystalline forms or polymorphs of a compound, 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。“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。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 can retain the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base which can retain the biological effectiveness of the free acid without other side effects. These salts can be prepared by methods known in the art.
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。Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming nitrogen oxides, as nitrogen requires an available lone pair of electrons to oxidize to the oxide. 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. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxirane. Such methods for the preparation of nitroxides have been extensively described and reviewed in the literature.
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, "metabolite" refers to a substance formed in vivo when a compound of the present invention is administered. The metabolites of a compound 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, enzymatic hydrolysis, 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 a mammal 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。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 to the body or thereon. Usually such prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo.
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 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 therapy, for example the administration of three or more active ingredients.
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。As used herein, unless otherwise indicated, "treating" means reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
在不违背符合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。On the basis of not 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 ways
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 the embodiments. Those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For parts, it shall be carried out according to the technology or conditions described in the literature in this field or according to the product manual.
本发明实施例中所用试剂和原料均市售可得。The reagents and raw materials used in the examples of the present invention are commercially available.
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 structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR is determined by a Bruker AVANCE-400 nuclear magnetic spectrometer, the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard is tetramethylsilane (TMS), and the chemical shift is 10 -6 The units are given in 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.
实施例1：2-(4-((((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 1: 2-(4-((((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
第一步：将化合物1a(10g,1eq.)，新蒸馏环戊二烯(1.1eq.)加入反应瓶中，加入DCM(100ml)溶解，室温搅拌24h。TLC监测反应进度，待原料1a完全反应，旋干溶剂即得化合物1b。1H NMR(CDCl3)2.02-2.03(m,1H)，2.19-2.21(m,1H)，3.71(s,6H)，3.86-3.87(m，2H)，6.97(t，J＝1.88Hz，2H)。Step 1: Add compound 1a (10 g, 1 eq.) and freshly distilled cyclopentadiene (1.1 eq.) into a reaction flask, add DCM (100 ml) to dissolve, and stir at room temperature for 24 h. Monitor the progress of the reaction by TLC. When the raw material 1a is completely reacted, spin dry the solvent to obtain compound 1b. 1 H NMR (CDCl 3 ) 2.02-2.03 (m, 1H), 2.19-2.21 (m, 1H), 3.71 (s, 6H), 3.86-3.87 (m, 2H), 6.97 (t, J=1.88 Hz, 2H).
第二步：将化合物1b(1equiv)，钯碳(10％)，THF加入反应瓶中，氢气球置换三次，室温反应，LC-MS监测反应进度。约1h，原料1b完全反应，将反应液过硅藻土垫，旋干滤液即得化合物1c。1H NMR(CDCl3)1.15-1.26(m，3H)，1.53-1.56(m，1H),1.76-1.78(m，1H)，3.21(s,2H),3.70(s，6H)。Step 2: Compound 1b (1 equiv), palladium carbon (10%), and THF were added to a reaction flask, replaced with a hydrogen balloon three times, reacted at room temperature, and the reaction progress was monitored by LC-MS. After about 1 hour, the raw material 1b was completely reacted, the reaction solution was passed through a diatomaceous earth pad, and the filtrate was dried to obtain compound 1c. 1 H NMR (CDCl 3 ) 1.15-1.26 (m, 3H), 1.53-1.56 (m, 1H), 1.76-1.78 (m, 1H), 3.21 (s, 2H), 3.70 (s, 6H).
第三步：将化合物1c(560mg，1.0eq.)，四氢呋喃(6ml)，水(2ml)，甲醇(2ml)，氢氧化钠(2.5eq.)加入反应瓶中，室温反应过夜，Lc-Ms监测反应进度。反应完成后，加2M盐酸调节pH至5，旋干。加甲醇浸泡，过硅藻土垫，所得液体旋干即得化合物1d。1H-NMR(d6-DMSO)0.98-1.02(m，2H)，1.27-1.30(m，1H),1.68-1.70(m，2H)，3.16(s,1H)，3.23(s,2H)。LC-MS:ESI[M-H]-＝181.0。Step 3: Add compound 1c (560 mg, 1.0 eq.), tetrahydrofuran (6 ml), water (2 ml), methanol (2 ml), and sodium hydroxide (2.5 eq.) to a reaction flask, react at room temperature overnight, and monitor the reaction progress by LC-Ms. After the reaction is completed, add 2M hydrochloric acid to adjust the pH to 5 and spin dry. Soak in methanol, pass through a diatomaceous earth pad, and spin dry the resulting liquid to obtain compound 1d. 1 H-NMR (d6-DMSO) 0.98-1.02 (m, 2H), 1.27-1.30 (m, 1H), 1.68-1.70 (m, 2H), 3.16 (s, 1H), 3.23 (s, 2H). LC-MS: ESI [MH] - = 181.0.
第四步：将化合物1d，三氟乙酸酐加入到封管中，65℃条件下反应12h。反应完成 后，将反应液旋干即得化合物1e。LC-MS:ESI[M+H]+＝165.1。Step 4: Add compound 1d and trifluoroacetic anhydride into the sealed tube and react at 65°C for 12 hours. The reaction is complete. Afterwards, the reaction solution was spin dried to obtain compound 1e. LC-MS: ESI [M+H] + = 165.1.
第五步：将化合物1e(7.7g)，冰醋酸(70ml)，水(35ml)加到反应瓶中，而后在搅拌状态下加入水合肼(5.0eq.)，100℃下反应12h。反应完成后，将反应液旋干得粗品。粗品用叔丁基甲基醚打浆即得化合物1f。LC-MS:ESI[M+H]+＝179.1。Step 5: Add compound 1e (7.7 g), glacial acetic acid (70 ml), and water (35 ml) to a reaction flask, then add hydrazine hydrate (5.0 eq.) under stirring, and react at 100°C for 12 h. After the reaction is completed, the reaction solution is spin-dried to obtain a crude product. The crude product is slurried with tert-butyl methyl ether to obtain compound 1f. LC-MS: ESI [M+H] + = 179.1.
第六步：将化合物1f(2.5g)，三氯氧磷(15ml)加入反应瓶中，氮气球置换三次，100℃反应过夜。反应完成后，将反应液滴加到50ml室温水中，加固体碳酸钾调节pH至7。用EA萃取三次，合并有机相，干燥，过滤，干法上样，柱层析即得化合物1g。LC-MS:ESI[M+H]+＝215.1。Step 6: Add compound 1f (2.5 g) and phosphorus oxychloride (15 ml) to a reaction flask, replace with a nitrogen balloon three times, and react at 100°C overnight. After the reaction is completed, add the reaction solution dropwise to 50 ml of room temperature water, and add solid potassium carbonate to adjust the pH to 7. Extract with EA three times, combine the organic phases, dry, filter, dry-load, and column chromatography to obtain compound 1g. LC-MS: ESI [M+H] + = 215.1.
第七步：将化合物1g(107mg，1.0eq.)，(R)-1-甲基-3-氨基哌啶双盐酸盐(CAS：1157849-50-7)(1.0eq.)，醋酸钯(0.2eq.)，race-BINAP(0.6eq.)，碳酸铯(5.0eq.)，无水甲苯(5ml)加入反应管中，氮气球置换三次，110℃反应12h。反应完成后，将反应液过硅藻土垫，浓缩，用制备TLC分离即得目标产物1h。LC-MS:ESI[M+H]+＝293.2。Step 7: Add compound 1g (107mg, 1.0eq.), (R)-1-methyl-3-aminopiperidine dihydrochloride (CAS: 1157849-50-7) (1.0eq.), palladium acetate (0.2eq.), race-BINAP (0.6eq.), cesium carbonate (5.0eq.), and anhydrous toluene (5ml) into a reaction tube, replace with a nitrogen balloon three times, and react at 110°C for 12h. After the reaction is completed, the reaction solution is passed through a celite pad, concentrated, and separated by preparative TLC to obtain the target product 1h. LC-MS: ESI [M+H] + = 293.2.
第八步：将化合物1h(29mg，1.0eq.)，[2-羟基-4-(三氟甲基)苯基]硼酸(CAS:1072951-50-8)(1.5eq.)，Pd(dppf)Cl2(0.1eq.)，碳酸铯(3.0eq.)，二氧六环(2ml)，脱氧水(0.2ml)加入反应管中，氮气球置换三次，100℃反应12h。反应完成后，将反应液过硅藻土垫，浓缩，用制备TLC分离即得目标产物1。1H NMR(CDCl3)1.20(m,2H),1.32(m,3H),1.53(m,1H),1.60-1.68(m,3H),2.24-1.97(m,4H),2.48(m,4H),2.72(m,1H),3.74(m,1H),3.80(s,1H),4.66(m,1H),7.09(d,J＝8.2Hz,1H)7.29-7.23(m,2H),δ7.61(d,J＝8.2Hz,1H)。Step 8: Add compound 1h (29 mg, 1.0 eq.), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS: 1072951-50-8) (1.5 eq.), Pd(dppf)Cl 2 (0.1 eq.), cesium carbonate (3.0 eq.), dioxane (2 ml), and deoxygenated water (0.2 ml) into a reaction tube, replace with a nitrogen balloon three times, and react at 100° C. for 12 h. After the reaction is completed, the reaction solution is passed through a celite pad, concentrated, and separated by preparative TLC to obtain the target product 1. 1 H NMR (CDCl 3 ) 1.20 (m, 2H), 1.32 (m, 3H), 1.53 (m, 1H), 1.60-1.68 (m, 3H), 2.24-1.97 (m, 4H), 2.48 (m, 4H), 2.72 (m, 1H), 3.74 (m, 1H), 3.80 (s, 1H), 4.66 (m, 1H), 7.09 (d, J=8.2 Hz, 1H) 7.29-7.23 (m, 2H), δ7.61 (d, J=8.2 Hz, 1H).
实施例2：2-(4-(((R)-1-乙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 2: 2-(4-(((R)-1-ethylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-乙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝433.2。1H NMR(400MHz,Chloroform-d)δ7.66(d,J＝8.2Hz,1H),7.33(d,J＝1.8Hz,1H),7.20–7.08(m,1H),5.29(s,1H),4.57–4.36(m,1H),3.94–3.77(m,1H),3.42(d,J＝5.2Hz,1H),2.68(m,2H),2.61–2.35(m,2H),2.32–2.03(m,3H),1.99–1.81(m,1H),1.81–1.73(m,2H),1.74–1.55(m,4H),1.51–1.38(m,1H),1.36–1.20(m,2H),1.10(q,J＝7.1Hz,3H)。The preparation method of 2-(4-(((R)-1-ethylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol is as follows: Example 1. MS/ESI[M+H] + =433.2. 1 H NMR (400 MHz, Chloroform-d) δ7.66 (d, J=8.2 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.20-7.08 (m, 1H), 5.29 (s, 1H), 4.57-4.36 (m, 1H), 3.94-3.77 (m, 1H), 3.42 (d, J=5.2 Hz, 1H), 2.68 (m, 2H), 2.61–2.35 (m, 2H), 2.32–2.03 (m, 3H), 1.99–1.81 (m, 1H), 1.81–1.73 (m, 2H), 1.74–1.55 (m, 4H), 1.51–1.38 (m, 1H), 1.36–1.20 (m, 2H), 1.10 (q, J=7.1 Hz, 3H).
实施例3：2-(4-(((R)-1-(环丙基甲基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻 苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 3: 2-(4-(((R)-1-(cyclopropylmethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methyl- 1-Benzenedimethazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-(环丙基甲基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝459.2。1H NMR(400MHz,Chloroform-d)δ7.68(d,J＝8.2Hz,1H),7.33(d,J＝1.8Hz,1H),7.20–7.10(m,1H),5.31(m,1H),4.54(d,J＝11.8Hz,1H),3.94–3.83(m,1H),3.50(s,1H),3.07–2.74(m,2H),2.62(m,1H),2.33(m,3H),2.25–2.06(m,2H),1.93(m,2H),1.84–1.74(m,2H),1.64(m,3H),1.51–1.38(m,1H),1.36–1.22(m,2H),0.91(m,1H),0.56(t,J＝7.3Hz,2H),0.16(m,2H)。The preparation method of 2-(4-(((R)-1-(cyclopropylmethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was referred to Example 1. MS/ESI[M+H] + =459.2. 1 H NMR (400 MHz, Chloroform-d) δ7.68 (d, J=8.2 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.20-7.10 (m, 1H), 5.31 (m, 1H), 4.54 (d, J=11.8 Hz, 1H), 3.94-3.83 (m, 1H), 3.50 (s, 1H), 3.07-2.74 (m, 2H ),2.62(m,1H),2.33(m,3H),2.25–2.06(m,2H),1.93(m,2H),1.84–1.74(m,2H),1.64(m,3H),1.51–1.38(m,1H),1.36–1.22(m,2H),0.91(m,1H),0.56(t,J＝7.3Hz,2H),0.16(m,2H).
实施例4：2-(4-(((R)-1-环丁基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 4: 2-(4-(((R)-1-cyclobutylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-环丁基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝459.2。1H NMR(400MHz,Chloroform-d)δ7.66(d,J＝8.3Hz,1H),7.33(d,J＝1.8Hz,1H),7.15(dd,J＝8.4,1.9Hz,1H),5.26(s,1H),3.89(s,1H),3.55–3.32(m,1H),2.77(p,J＝7.6Hz,1H),2.68–2.53(m,2H),2.45–2.30(m,1H),2.28–2.09(m,2H),2.09–1.99(m,3H),1.99–1.50(m,12H),1.51–1.40(m,1H),1.37–1.19(m,2H)。The preparation method of 2-(4-(((R)-1-cyclobutylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + = 459.2. 1 H NMR (400 MHz, Chloroform-d) δ7.66 (d, J=8.3 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.15 (dd, J=8.4, 1.9 Hz, 1H), 5.26 (s, 1H), 3.89 (s, 1H), 3.55–3.32 (m, 1H), 2.77 (p, J=7.6 Hz, 1H), 2.68–2.53 (m, 2H), 2.45–2.30 (m, 1H), 2.28–2.09 (m, 2H), 2.09–1.99 (m, 3H), 1.99–1.50 (m, 12H), 1.51–1.40 (m, 1H), 1.37–1.19 (m, 2H).
实施例5：2-(4-(((R)-1-(氧杂环丁烷-3-基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 5: 2-(4-(((R)-1-(oxetane-3-yl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-(氧杂环丁烷-3-基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯 二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝461.2。1H NMR(400MHz,Chloroform-d)δ7.45–7.32(m,2H),7.20–7.11(m,1H),5.41(s,1H),4.74–4.66(m,3H),4.59(t,J＝6.2Hz,1H),4.54(s,1H),3.60–3.51(m,2H),3.11(t,J＝2.6Hz,1H),2.58(d,J＝13.7Hz,2H),2.44(d,J＝11.0Hz,1H),2.07(d,J＝20.0Hz,5H),2.02–1.82(m,4H),1.82–1.60(m,2H),1.55–1.35(m,4H),1.34–1.20(m,2H)。2-(4-(((R)-1-(oxetan-3-yl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphenyl The preparation method of dimethazin-1-yl)-5-(trifluoromethyl)phenol is as described in Example 1. MS/ESI [M+H] + = 461.2. 1 H NMR (400 MHz, Chloroform-d) δ7.45–7.32 (m, 2H), 7.20–7.11 (m, 1H), 5.41 (s, 1H), 4.74–4.66 (m, 3H), 4.59 (t, J=6.2 Hz, 1H), 4.54 (s, 1H), 3.60–3.51 (m, 2H), 3.11 (t, J=2.6 Hz, 1H), 2.58 (d, J=13.7 Hz, 2H), 2.44 (d, J=11.0 Hz, 1H), 2.07 (d, J=20.0 Hz, 5H), 2.02–1.82 (m, 4H), 1.82–1.60 (m, 2H), 1.55–1.35 (m, 4H), 1.34–1.20 (m, 2H).
实施例6：2-(4-(((R)-1-环丙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 6: 2-(4-(((R)-1-cyclopropylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-环丙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝445.2。The preparation method of 2-(4-(((R)-1-cyclopropylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + = 445.2.
实施例7：2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 7: 2-(4-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝420.2。1H NMR(400MHz,Chloroform-d)δ7.65(dd,J＝8.3,4.3Hz,1H),7.33(s,1H),7.16(d,J＝8.2,1H),4.38(dd,J＝16.6,6.7Hz,1H),4.07–3.94(m,1H),3.93–3.84(m,1H),3.58–3.45(m,1H),3.44–3.28(br,1H),2.30–2.06(m,4H),1.89–1.70(m,3H),1.68–1.51(m,3H),1.51–1.38(m,3H),1.38–1.21(m,3H)。The preparation method of 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + =420.2. 1 H NMR (400 MHz, Chloroform-d) δ7.65 (dd, J=8.3, 4.3 Hz, 1H), 7.33 (s, 1H), 7.16 (d, J=8.2, 1H), 4.38 (dd, J=16.6, 6.7 Hz, 1H), 4.07–3.94 (m, 1H), 3.93–3.84 (m, 1H), 3.58–3.45 (m, 1H), 3.44–3.28 (br, 1H), 2.30–2.06 (m, 4H), 1.89–1.70 (m, 3H), 1.68–1.51 (m, 3H), 1.51–1.38 (m, 3H), 1.38–1.21 (m, 3H).
实施例8：2-(4-(((1s，3s)-3-羟基-3-甲基环丁基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 8: 2-(4-(((1s, 3s)-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((1s，3s)-3-羟基-3-甲基环丁基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝406.2。1H NMR (400MHz,Chloroform-d)δ7.57(d,J＝8.2Hz,1H),7.27(d,J＝1.9Hz,1H),7.09(d,J＝8.2Hz,1H),4.70(s,1H),4.26(h,J＝7.6Hz,1H),3.80(d,J＝3.8Hz,1H),3.32(s,1H),2.69(q,J＝9.9Hz,2H),2.21–1.97(m,4H),1.70(d,J＝9.4Hz,2H),1.55(d,J＝9.3Hz,2H),1.41(s,3H),1.35(d,J＝6.7Hz,1H),1.21(d,J＝17.6Hz,3H)。The preparation method of 2-(4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was as described in Example 1. MS/ESI[M+H] + =406.2. 1 H NMR (400 MHz, Chloroform-d) δ7.57 (d, J = 8.2 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 4.70 (s, 1H), 4.26 (h, J = 7.6 Hz, 1H), 3.80 (d, J = 3.8 Hz, 1H), 3.32 (s, 1H), 2.69 (q, J = 9.9 Hz, 2H), 2.21–1.97 (m, 4H), 1.70 (d, J = 9.4 Hz, 2H), 1.55 (d, J = 9.3 Hz, 2H), 1.41 (s, 3H), 1.35 (d, J = 6.7 Hz, 1H), 1.21 (d, J = 17.6 Hz, 3H).
实施例9：5-环丙基-2-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)苯酚
Example 9: 5-cyclopropyl-2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)phenol
5-环丙基-2-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝391.2。The preparation method of 5-cyclopropyl-2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)phenol was as described in Example 1. MS/ESI [M+H] + = 391.2.
实施例10：3-甲基-2-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 10: 3-methyl-2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
3-甲基-2-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝433.2。The preparation method of 3-methyl-2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was referred to Example 1. MS/ESI [M+H] + = 433.2.
实施例11：5-氯-2-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)苯酚
Example 11: 5-Chloro-2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)phenol
5-氯-2-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝385.2。The preparation method of 5-chloro-2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + = 385.2.
实施例12：4-(4-氯-2-(三氟甲基)苯基)-N-((R)-1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-甲基邻苯二嗪-1-胺
Example 12: 4-(4-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-methylpiperidin-3-yl)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-amine
4-(4-氯-2-(三氟甲基)苯基)-N-((R)-1-甲基哌啶-3-基)-5,6,7,8-四氢-5,8-甲基邻苯二嗪-1-胺的制备方法参考实施例1。MS/ESI[M+H]+＝437.2。The preparation method of 4-(4-chloro-2-(trifluoromethyl)phenyl)-N-((R)-1-methylpiperidin-3-yl)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-amine was prepared by referring to Example 1. MS/ESI [M+H] + = 437.2.
实施例13：2-(4-(((R)-1-异丙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 13: 2-(4-(((R)-1-isopropylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-异丙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝447.2。The preparation method of 2-(4-(((R)-1-isopropylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was referred to Example 1. MS/ESI [M+H] + = 447.2.
实施例14：2-(4-(((R)-1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 14: 2-(4-(((R)-1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝449.2。The preparation method of 2-(4-(((R)-1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was referred to Example 1. MS/ESI [M+H] + = 449.2.
实施例15：2-((3R)-3-((4-(2-羟基-4-(三氟甲基)苯基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)氨基)哌啶-1-基)乙腈
Example 15: 2-((3R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)amino)piperidin-1-yl)acetonitrile
2-((3R)-3-((4-(2-羟基-4-(三氟甲基)苯基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)氨基)哌啶-1-基)乙腈的制备方法参考实施例1。MS/ESI[M+H]+＝444.2。1H NMR(400MHz,Chloroform-d)δ7.66(d,J＝8.2Hz,1H),7.33(d,J＝1.8Hz,1H),7.16(dd,J＝8.2,2.1Hz,1H),4.79(s,1H),4.63–4.43(m,1H),3.90(d,J＝3.8Hz,1H),3.58(dd,J＝5.6,2.8Hz,2H),3.39(d,J＝3.5Hz,1H),2.97(m,1H),2.78–2.47(m,3H),2.29–2.08(m,2H),1.93–1.68(m,5H),1.68–1.57(m,1H),1.50–1.35(m,1H),1.34–1.20(m,2H)。The preparation method of 2-((3R)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)amino)piperidin-1-yl)acetonitrile was prepared by reference to Example 1. MS/ESI[M+H] + =444.2. 1 H NMR (400 MHz, Chloroform-d) δ7.66 (d, J=8.2 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.16 (dd, J=8.2, 2.1 Hz, 1H), 4.79 (s, 1H), 4.63–4.43 (m, 1H), 3.90 (d, J=3.8 Hz, 1H), 3.58 (dd, J=5.6, 2.8 Hz, 2H), 3.39 (d, J=3.5 Hz, 1H), 2.97 (m, 1H), 2.78–2.47 (m, 3H), 2.29–2.08 (m, 2H), 1.93–1.68 (m, 5H), 1.68–1.57 (m, 1H), 1.50–1.35 (m, 1H), 1.34–1.20 (m, 2H).
实施例16：2-(4-(((3R)-1-(四氢呋喃-3-基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲 基邻苯二甲酸-1-基)-5-(三氟甲基)苯酚
Example 16: 2-(4-(((3R)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methane 1-(trifluoromethyl)phthalate
2-(4-(((3R)-1-(四氢呋喃-3-基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲酸-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝475.2。The preparation method of 2-(4-(((3R)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalic acid-1-yl)-5-(trifluoromethyl)phenol was referred to Example 1. MS/ESI [M+H] + = 475.2.
实施例17：2-(4-(((R)-1-(2-羟基-2-甲基丙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 17: 2-(4-(((R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-(2-羟基-2-甲基丙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝477.2。The preparation method of 2-(4-(((R)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was referred to Example 1. MS/ESI [M+H] + = 477.2.
实施例18：(R)-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 18: (R)-2-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-ethylphthalazin-1-yl)-5-(trifluoromethyl)phenol
第一步：将化合物1a(30g,375mmol)和化合物18a(50g,352mmol)溶于超干THF(250mL)中，反应液加热至60℃反应12小时。反应完全后，浓缩反应液除去溶剂，残留物经柱层析分离纯化(PE/EA 20:1 to 10:1)得到化合物18b(61g)。MS/ESI[M+H]+＝223.2。Step 1: Compound 1a (30 g, 375 mmol) and compound 18a (50 g, 352 mmol) were dissolved in ultra-dry THF (250 mL), and the reaction solution was heated to 60°C for 12 hours. After the reaction was complete, the reaction solution was concentrated to remove the solvent, and the residue was purified by column chromatography (PE/EA 20:1 to 10:1) to obtain compound 18b (61 g). MS/ESI [M+H] + = 223.2.
第二步：将化合物18b(61g,274mmol)溶于EA(610.O mL)中，加入Pd/C(6.04g)，室温下氢气氛中反应1.5小时。反应完全后，硅藻土过滤，滤液浓缩后得化合物18c(63.0g)，无需纯化，直接用于下一步。MS/ESI[M+H]+＝225.2。Step 2: Compound 18b (61 g, 274 mmol) was dissolved in EA (610.0 mL), Pd/C (6.04 g) was added, and the mixture was reacted in a hydrogen atmosphere at room temperature for 1.5 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound 18c (63.0 g), which was used directly in the next step without purification. MS/ESI [M+H] + = 225.2.
第三步：将化合物18c(63g,281mmol)溶于MeOH(500mL)中，加入NaOH 水溶液(10％，170mL)，60℃反应8小时。反应完全后，除去MeOH，以盐酸调pH到1，用EtOAc(300mL X 3)萃取，无水硫酸钠干燥，浓缩后得到化合物18d(43g,白色固体)。MS/ESI[M+H]+＝197.2。Step 3: Dissolve compound 18c (63 g, 281 mmol) in MeOH (500 mL) and add NaOH Aqueous solution (10%, 170 mL), react at 60°C for 8 hours. After the reaction is complete, remove MeOH, adjust pH to 1 with hydrochloric acid, extract with EtOAc (300 mL x 3), dry over anhydrous sodium sulfate, and concentrate to obtain compound 18d (43 g, white solid). MS/ESI [M+H] + = 197.2.
第四步：将化合物18d(43g，218mmol)与醋酸酐(232mL)混合，100℃反应4小时。反应完全后，冷至室温，浓缩反应液后得到化合物18e(37g，白色固体)。MS/ESI[M+H]+＝179.1。Step 4: Compound 18d (43 g, 218 mmol) was mixed with acetic anhydride (232 mL) and reacted at 100° C. for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and the reaction solution was concentrated to obtain compound 18e (37 g, white solid). MS/ESI [M+H] + = 179.1.
第五步：将化合物18e(37g，188mmol)，乙酸钠(22.8g，282mmol)与水合肼(14g，282mmol)混合于乙酸/水溶液中(500mL，50％)，100℃反应16小时。反应完全后，冷至室温，过滤得到白色固体，经过水、MTBE洗涤后，干燥得到化合物18f(34g)。MS/ESI[M+H]+＝193.2。Step 5: Compound 18e (37 g, 188 mmol), sodium acetate (22.8 g, 282 mmol) and hydrazine hydrate (14 g, 282 mmol) were mixed in acetic acid/water solution (500 mL, 50%) and reacted at 100°C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered to obtain a white solid, which was washed with water and MTBE and dried to obtain compound 18f (34 g). MS/ESI [M+H] + = 193.2.
第六步：将化合物18f(34g，176mmol)与POCl3(190mL)混合，110℃反应12小时。反应完全后，冷至室温，浓缩反应液后得到粗品，打浆得到化合物18g(25.5g，白色固体)。MS/ESI[M+H]+＝230.1。1H NMR(400MHz,DMSO-d6)δ3.38–3.35(m,2H),1.92–1.84(m,4H),1.35–1.27(m,4H).Step 6: Compound 18f (34 g, 176 mmol) was mixed with POCl 3 (190 mL) and reacted at 110° C. for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and the reaction solution was concentrated to obtain a crude product, which was then slurried to obtain compound 18g (25.5 g, white solid). MS/ESI [M+H] + = 230.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.38–3.35 (m, 2H), 1.92–1.84 (m, 4H), 1.35–1.27 (m, 4H).
(R)-2-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-乙基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝433.2。1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.45(d,J＝7.8Hz,1H),7.30–7.13(m,2H),6.13(d,J＝7.8Hz,1H),4.33–4.11(m,1H),3.38(s,1H),3.07–2.96(m,1H),2.71–2.61(m,1H),2.21(s,3H),1.96–1.82(m,3H),1.81–1.62(m,5H),1.57(q,J＝12.1Hz,1H),1.45–1.32(m,1H),1.32–1.15(m,5H)。The preparation method of (R)-2-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-ethylphthalazin-1-yl)-5-(trifluoromethyl)phenol was as described in Example 1. MS/ESI [M+H] + = 433.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.30–7.13 (m, 2H), 6.13 (d, J = 7.8 Hz, 1H), 4.33–4.11 (m, 1H), 3.38 (s, 1H), 3.07–2.96 (m, 1H), 2.71–2.61 (m, 1H), 2.21 (s, 3H), 1.96–1.82 (m, 3H), 1.81–1.62 (m, 5H), 1.57 (q, J = 12.1 Hz, 1H), 1.45–1.32 (m, 1H), 1.32–1.15 (m, 5H).
实施例19：2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7,8-四氢-5,8-乙基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 19: 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydro-5,8-ethylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7,8-四氢-5,8-乙基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝433.2。1H NMR(400MHz,Chloroform-d)δ7.39–7.31(m,2H),7.16(d,J＝8.0Hz,1H),4.52(d,J＝6.4Hz,1H),4.07–3.91(m,1H),3.56–3.42(m,2H),3.09–2.97(m,1H),2.15(t,J＝12.8Hz,2H),1.96–1.82(m,4H),1.82–1.71(m,3H),1.53–1.33(m,7H),1.33–1.23(m,3H)。The preparation method of 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydro-5,8-ethylphthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + =433.2. 1 H NMR (400 MHz, Chloroform-d) δ7.39–7.31 (m, 2H), 7.16 (d, J=8.0 Hz, 1H), 4.52 (d, J=6.4 Hz, 1H), 4.07–3.91 (m, 1H), 3.56–3.42 (m, 2H), 3.09–2.97 (m, 1H), 2.15 (t, J=12.8 Hz, 2H), 1.96–1.82 (m, 4H), 1.82–1.71 (m, 3H), 1.53–1.33 (m, 7H), 1.33–1.23 (m, 3H).
实施例20：2-(9-甲基-4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-二氨基酞 嗪-1-基)-5-(三氟甲基)苯酚
Example 20: 2-(9-methyl-4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-diaminophthalide Oxazine-1-yl)-5-(trifluoromethyl)phenol
2-(9-甲基-4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-二氨基酞嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝434.2。The preparation method of 2-(9-methyl-4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-diaminophthalazin-1-yl)-5-(trifluoromethyl)phenol was referred to Example 1. MS/ESI [M+H] + = 434.2.
实施例21：2-(4-(((R)-1-环丁基哌啶-3-基)氨基)-9-甲基-5,6,7,8-四氢-5,8-二氨基酞嗪-1-基)-5-(三氟甲基)苯酚
Example 21: 2-(4-(((R)-1-cyclobutylpiperidin-3-yl)amino)-9-methyl-5,6,7,8-tetrahydro-5,8-diaminophthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-环丁基哌啶-3-基)氨基)-9-甲基-5,6,7,8-四氢-5,8-二氨基酞嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝474.2。The preparation method of 2-(4-(((R)-1-cyclobutylpiperidin-3-yl)amino)-9-methyl-5,6,7,8-tetrahydro-5,8-diaminophthalazin-1-yl)-5-(trifluoromethyl)phenol was referred to Example 1. MS/ESI [M+H] + = 474.2.
实施例22：2-(4-(((R)-1-乙基哌啶-3-基)氨基)-9-甲基-5,6,7,8-四氢-5,8-二氨基酞嗪-1-基)-5-(三氟甲基)苯酚
Example 22: 2-(4-(((R)-1-ethylpiperidin-3-yl)amino)-9-methyl-5,6,7,8-tetrahydro-5,8-diaminophthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-乙基哌啶-3-基)氨基)-9-甲基-5,6,7,8-四氢-5,8-二氨基酞嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝448.2。The preparation method of 2-(4-(((R)-1-ethylpiperidin-3-yl)amino)-9-methyl-5,6,7,8-tetrahydro-5,8-diaminophthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + = 448.2.
实施例23：2-(4-(((1R，2R)-2-羟基环己基)氨基)-9-甲基-5,6,7,8-四氢-5,8-二氨基酞嗪-1-基)-5-(三氟甲基)苯酚
Example 23: 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-9-methyl-5,6,7,8-tetrahydro-5,8-diaminophthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((1R，2R)-2-羟基环己基)氨基)-9-甲基-5,6,7,8-四氢-5,8-二氨基酞嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝435.2。 The preparation method of 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-9-methyl-5,6,7,8-tetrahydro-5,8-diaminophthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + =435.2.
实施例24：2-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-环氧邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 24: 2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-环氧邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝421.2。The preparation method of 2-(4-(((R)-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + = 421.2.
实施例25：2-(4-(((R)-1-乙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-环氧邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 25: 2-(4-(((R)-1-ethylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-乙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-环氧邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝435.2。The preparation method of 2-(4-(((R)-1-ethylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + = 435.2.
实施例26：2-(4-(((R)-1-环丁基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-环氧邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 26: 2-(4-(((R)-1-cyclobutylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((R)-1-环丁基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-环氧邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝461.2。The preparation method of 2-(4-(((R)-1-cyclobutylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + = 461.2.
实施例27：2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7,8-四氢-5,8-环氧邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 27: 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7,8-四氢-5,8-环氧邻苯二甲嗪-1-基) -5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝422.2。2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydro-5,8-epoxyphthalazin-1-yl) - The preparation method of 5-(trifluoromethyl)phenol is as described in Example 1. MS/ESI [M+H] + = 422.2.
实施例28：5-(4-((((R)-1-甲基哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-甲基邻苯二甲嗪-1-基)苯并噻吩-4-醇
Example 28: 5-(4-((((R)-1-methylpiperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-methylphthalazin-1-yl)benzothiophene-4-ol
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28a(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28b(46.0g,148mmol，浅棕色固体，产率90％),MS/ESI[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 28a (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 28b (46.0 g, 148 mmol, light brown solid, yield 90%), MS/ESI [M+H] + = 309.0, 311.0, 313.0.
第二步：将化合物28b(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28c(31.0g,135mmol，浅棕色固体，产率93％)，MS/ESI[M+H]+＝227.0,229.0。Step 2: Compound 28b (45.0 g, 145 mmol) and Li 2 CO 3 (26.8 g, 363 mmol) were added to DMF (450 mL) and stirred at 100° C. for 6 h. After the reaction was complete, the mixture was filtered, and the filtrate was treated with aqueous hydrochloric acid (900 mL, 0.5 N), extracted with EtOAc (400 mL×2), and the organic phase was washed with water (300 mL×2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the target compound 28c (31.0 g, 135 mmol, light brown solid, yield 93%), MS/ESI [M+H] + = 227.0, 229.0.
第三步：将化合物28c(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28d(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: Compound 28c (15.0 g, 65.5 mmol) and K 2 CO 3 (18.1 g, 131 mmol) were added to MeCN (150 mL), and then Me 2 SO 4 (9.9 g, 78.6 mmol) was added, and stirred at 60°C overnight under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, and silica gel (30 g) was added to the filtrate, and then concentrated to dryness under reduced pressure, and separated by column chromatography (PE: EtOAc = 10: 1) to obtain the target compound 28d (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28d(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28e(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 28d (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 28e (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).
第五步：将化合物1h(29mg，1.0eq.)，28e(1.5eq.)，Pd(dppf)Cl2(0.1eq.)，碳酸铯(3.0eq.)，二氧六环(2ml)，脱氧水(0.2ml)加入反应管中，氮气球置换三次，100℃反应12h。反应完成后，将反应液过硅藻土垫，浓缩，用制备TLC分离即得目标产物28f。Step 5: Compound 1h (29 mg, 1.0 eq.), 28e (1.5 eq.), Pd(dppf)Cl 2 (0.1 eq.), cesium carbonate (3.0 eq.), dioxane (2 ml), and deoxygenated water (0.2 ml) were added to a reaction tube, replaced with a nitrogen balloon three times, and reacted at 100°C for 12 h. After the reaction was completed, the reaction solution was passed through a celite pad, concentrated, and separated by preparative TLC to obtain the target product 28f.
第六步：将上一步所得化合物28f溶解在适量二氯甲烷中，往体系内滴加三溴化硼溶液(1M)，室温下反应1h后进行LC/MS检测。将反应液在冰水中淬灭，调节pH至弱酸性，二氯甲烷萃取浓缩后进行柱层析纯化得化合物28(22mg)。MS/ESI[M+H]+＝407.2。1H NMR(400MHz,CDCl3)δ7.69(d,J＝5.5Hz,1H),7.56(d,J＝8.5Hz,1H),7.40(d,J＝8.5Hz,1H),7.32(d,J＝5.5Hz,1H),5.11(s,1H),4.69–4.20(m,1H),3.94(d,J＝2.6Hz,1H),3.45(s,1H),2.60(d,J＝29.0Hz,3H),2.30(d,J＝3.8Hz,3H),2.24–2.03(m,3H),1.93–1.72(m,3H),1.60(dd,J＝24.0,10.9Hz,3H),1.52–1.40(m,1H),1.28(dt,J＝20.4,5.7Hz,1H)。Step 6: Dissolve the compound 28f obtained in the previous step in an appropriate amount of dichloromethane, add boron tribromide solution (1M) dropwise into the system, react at room temperature for 1 hour, and then perform LC/MS detection. The reaction solution was quenched in ice water, the pH was adjusted to weak acidity, extracted and concentrated with dichloromethane, and then purified by column chromatography to obtain compound 28 (22 mg). MS/ESI[M+H] + ＝407.2. 1 H NMR (400MHz,CDCl 3 )δ7.69(d,J＝5.5Hz,1H),7.56(d,J＝8.5Hz,1H),7.40(d,J＝8.5Hz,1H),7.32(d,J＝5.5Hz,1H),5.11(s,1H),4.69–4.20(m,1H),3.94(d,J＝2.6Hz,1H),3.45(s,1H),2.60(d,J＝29.0Hz,3H),2.30(d,J＝3.8Hz,3H),2.24–2.03(m,3H),1.93–1.72(m,3H),1.60(dd,J＝24.0,10.9Hz,3H),1.52–1.40(m,1H),1.28(dt,J＝20.4,5.7Hz,1H).
实施例29：(R)-2-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 29: (R)-2-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
第一步：称取29a(25.0g,231mmol)，吡啶(21.6g，277mmol)和二氯甲烷(125mL)加入到烧瓶中，降温至0℃，然后慢慢滴加Tf2O(71.7g,254mmol)，加毕室温搅拌反应1h。过滤，滤饼用二氯甲烷(20mL)洗涤，收集滤液得到目标化合物29b的二氯甲烷溶液(淡黄色)。Step 1: Weigh 29a (25.0 g, 231 mmol), pyridine (21.6 g, 277 mmol) and dichloromethane (125 mL) into a flask, cool to 0°C, then slowly drop Tf 2 O (71.7 g, 254 mmol), stir at room temperature for 1 h, filter, wash the filter cake with dichloromethane (20 mL), collect the filtrate to obtain a dichloromethane solution (light yellow) of the target compound 29b.
第二步：将化合物29c(50.9g,254mmol)和三乙胺(70.1g,693mmol)溶于二氯甲烷(250mL)中，室温滴加上述化合物29b的二氯甲烷溶液，加毕室温搅拌过夜。反应完全后加入硅胶减压浓缩旋干，用柱层析分离(PE:EtOAc＝3:1，碘显)得到目标化合物29d(20.0g,68.9mmol，淡黄色固体，两步收率30％)，MS/ESI[M+H]+＝291.1。Step 2: Compound 29c (50.9 g, 254 mmol) and triethylamine (70.1 g, 693 mmol) were dissolved in dichloromethane (250 mL), and the dichloromethane solution of the above compound 29b was added dropwise at room temperature, and stirred overnight at room temperature. After the reaction was complete, silica gel was added, concentrated under reduced pressure, and dried by spin drying. The target compound 29d (20.0 g, 68.9 mmol, light yellow solid, two-step yield 30%) was obtained by column chromatography (PE: EtOAc = 3: 1, iodine development), MS/ESI [M + H] + = 291.1.
第三步：将化合物29d(20.0g,68.9mmol)溶于乙酸乙酯(100mL)中，然后加入HCl/EtOAc(86mL,345mmol,4.0M),室温搅拌1h。反应完全后减压浓缩旋干得到目标化合物29e(15.6g,59.3mmol，白色固体，产率86％)，MS/ESI[M+H]+＝191.2。 Step 3: Compound 29d (20.0 g, 68.9 mmol) was dissolved in ethyl acetate (100 mL), and then HCl/EtOAc (86 mL, 345 mmol, 4.0 M) was added and stirred at room temperature for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure and dried to give the target compound 29e (15.6 g, 59.3 mmol, white solid, yield 86%), MS/ESI [M+H] + = 191.2.
第四步：将化合物29e(1.38g,5.26mmol),18g(1.10g,4.78mmol),Cs2CO3(3.11g,9.56mmol),Pd(OAc)2(110mg,0.480mmol)和BINAP(300mg,0.480mmol)加入到无水甲苯(10mL)中，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(DCM:EtOAc＝3:1)得到目标化合物29f(700mg,1.83mmol，淡黄色粘稠固体，产率35％),MS/ESI[M+H]+＝383.1。Step 4: Compound 29e (1.38 g, 5.26 mmol), 18 g (1.10 g, 4.78 mmol), Cs 2 CO 3 (3.11 g, 9.56 mmol), Pd(OAc) 2 (110 mg, 0.480 mmol) and BINAP (300 mg, 0.480 mmol) were added to anhydrous toluene (10 mL), and refluxed at 110° C. under nitrogen protection for overnight reaction. After the reaction was complete, silica gel was added to the reaction solution, and the mixture was concentrated under reduced pressure and dried by spin drying. The target compound 29f (700 mg, 1.83 mmol, light yellow viscous solid, yield 35%) was obtained by column chromatography (DCM: EtOAc = 3:1), MS/ESI [M+H] + = 383.1.
第五步：将化合物29f(400mg,1.04mmol),[2-羟基-4-(三氟甲基)苯基]硼酸(CAS:1072951-50-8)(235mg,1.14mmol),Cs2CO3(678mg,2.08mmol)和Pd(dppf)Cl2(36.6mg,0.05mmol)加入到二氧六环(4mL)和水(0.8mL)中，氮气保护下100℃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(DCM:EtOAc＝3:1)得到目标化合物29(700mg,0.390mmol，白色固体，产率15％)。1H NMR(400MHz,CDCl3)δ7.37(dd,J＝7.1,4.9Hz,2H),7.20–7.12(m,1H),5.21(s,1H),4.53(s,1H),3.55(s,1H),3.03(s,1H),2.80–2.41(m,7H),2.38–2.06(m,2H),1.99–1.82(m,5H),1.74–1.62(m,3H),1.48–1.37(m,4H)。MS/ESI[M+H]+＝509.2。Step 5: Compound 29f (400 mg, 1.04 mmol), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS: 1072951-50-8) (235 mg, 1.14 mmol), Cs 2 CO 3 (678 mg, 2.08 mmol) and Pd(dppf)Cl 2 (36.6 mg, 0.05 mmol) were added to dioxane (4 mL) and water (0.8 mL), and the mixture was refluxed at 100°C under nitrogen protection overnight. After the reaction was complete, silica gel was added to the reaction solution, and the mixture was concentrated under reduced pressure and dried by spin drying. The target compound 29 (700 mg, 0.390 mmol, white solid, yield 15%) was obtained by column chromatography (DCM: EtOAc = 3:1). 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (dd, J=7.1, 4.9 Hz, 2H), 7.20–7.12 (m, 1H), 5.21 (s, 1H), 4.53 (s, 1H), 3.55 (s, 1H), 3.03 (s, 1H), 2.80–2.41 (m, 7H), 2.38–2.06 (m, 2H), 1.99–1.82 (m, 5H), 1.74–1.62 (m, 3H), 1.48–1.37 (m, 4H). MS/ESI [M+H] + = 509.2.
实施例30：(R)-5-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并噻吩-4-醇
Example 30: (R)-5-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzothiophene-4-ol
(R)-5-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并噻吩-4-醇的制备方法参考实施例28。MS/ESI[M+H]+＝421.2。1H NMR(400MHz,CDCl3)δ7.68(d,J＝5.5Hz,1H),7.41(d,J＝8.4Hz,1H),7.33(d,J＝5.5Hz,1H),7.26(s,1H),5.23(s,1H),4.51(s,1H),3.64(s,1H),3.12(s,1H),2.60(d,J＝52.9Hz,3H),2.40–2.07(m,4H),2.05–1.75(m,6H),1.63(s,2H),1.49–1.36(m,4H)。The preparation method of (R)-5-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzothiophene-4-ol was referred to Example 28. MS/ESI [M+H] + = 421.2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 5.5 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 5.5 Hz, 1H), 7.26 (s, 1H), 5.23 (s, 1H), 4.51 (s, 1H), 3.64 (s, 1H), 3.12 (s, 1H), 2.60 (d, J = 52.9 Hz, 3H), 2.40–2.07 (m, 4H), 2.05–1.75 (m, 6H), 1.63 (s, 2H), 1.49–1.36 (m, 4H).
实施例31：5-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并噻吩-4-醇
Example 31: 5-(4-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzothiophene-4-ol
5-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并噻吩-4-醇的制备方法参考实施例28。MS/ESI[M+H]+＝422.2。1H NMR(400MHz,CDCl3)δ7.69(d,J＝5.3Hz,1H),7.41(d,J＝8.4Hz,1H),7.35(d,J＝5.5Hz,1H),7.23(d,J＝8.4Hz,1H),4.59(s,1H),4.02(s,1H),3.58(d,J＝27.7Hz,2H),3.11(s,1H),2.22–2.09 (m,2H),1.97–1.69(m,7H),1.48–1.28(m,8H)。The preparation method of 5-(4-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzothiophen-4-ol is shown in Example 28. MS/ESI [M+H] + = 422.2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 (d, J = 5.3 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 5.5 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.59 (s, 1H), 4.02 (s, 1H), 3.58 (d, J = 27.7 Hz, 2H), 3.11 (s, 1H), 2.22-2.09 (m, 2H), 1.97–1.69 (m, 7H), 1.48–1.28 (m, 8H).
实施例32：2-(4-(((1R，3S)-3-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 32: 2-(4-(((1R,3S)-3-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((1R，3S)-3-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝434.2。1H NMR(400MHz,Chloroform-d)δ7.40–7.32(m,2H),7.15(dd,J＝8.1,1.5Hz,1H),5.27(s,1H),4.38(dd,J＝8.5,4.5Hz,1H),4.03(s,1H),3.52(t,J＝2.7Hz,1H),3.01(d,J＝2.7Hz,1H),2.28(d,J＝12.4Hz,1H),2.02–1.75(m,7H),1.62–1.33(m,8H)。The preparation method of 2-(4-(((1R,3S)-3-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol was prepared by referring to Example 1. MS/ESI [M+H] + = 434.2. 1 H NMR (400 MHz, Chloroform-d) δ 7.40–7.32 (m, 2H), 7.15 (dd, J = 8.1, 1.5 Hz, 1H), 5.27 (s, 1H), 4.38 (dd, J = 8.5, 4.5 Hz, 1H), 4.03 (s, 1H), 3.52 (t, J = 2.7 Hz, 1H), 3.01 (d, J = 2.7 Hz, 1H), 2.28 (d, J = 12.4 Hz, 1H), 2.02–1.75 (m, 7H), 1.62–1.33 (m, 8H).
实施例33：(R)-2-(4-((1-(2,2,2-三氟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 33: (R)-2-(4-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
(R)-2-(4-((1-(2,2,2-三氟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝501.2。1H NMR(400MHz,Chloroform-d)δ7.34(s,1H),7.30(d,J＝8.0Hz,1H),7.17–7.08(m,1H),4.45(s,2H),3.43–3.34(m,1H),3.32–3.18(m,2H),3.15–2.95(m,4H),1.98–1.84(m,4H),1.84–1.73(m,3H),1.39–1.17(m,6H)。The preparation method of (R)-2-(4-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol was as described in Example 1. MS/ESI [M+H] + = 501.2. 1 H NMR (400 MHz, Chloroform-d) δ7.34 (s, 1H), 7.30 (d, J＝8.0 Hz, 1H), 7.17–7.08 (m, 1H), 4.45 (s, 2H), 3.43–3.34 (m, 1H), 3.32–3.18 (m, 2H), 3.15–2.95 (m, 4H), 1.98–1.84 (m, 4H), 1.84–1.73 (m, 3H), 1.39–1.17 (m, 6H).
实施例34：(R)-5-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并噻吩-4-醇
Example 34: (R)-5-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzothiophene-4-ol
(R)-5-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并噻吩-4-醇的制备参考实施例28。MS/ESI[M+H]+＝497.2。1H NMR(400MHz,CDCl3)δ7.65(d,J＝5.5Hz,1H),7.38(d,J＝8.4Hz,1H),7.31(d,J＝5.5Hz,1H),7.23(d,J＝1.2Hz,1H),5.07(s,1H),4.50(s,1H),3.62(s,1H),3.00(s,1H),2.74–2.62(m,3H),2.57–2.42(m,3H),2.37–2.24(m,1H),2.13(s,1H),1.92–1.79(m,5H),1.66(dd,J＝18.1,9.2Hz,4H),1.41(t,J＝8.3Hz,4H)。 Preparation of (R)-5-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzothiophene-4-ol Reference Example 28. MS/ESI [M+H] + = 497.2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (d, J = 5.5 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 5.5 Hz, 1H), 7.23 (d, J = 1.2 Hz, 1H), 5.07 (s, 1H), 4.50 (s, 1H), 3.62 (s, 1H), 3.00 (s, 1H), 2.74–2.62 (m, 3H), 2.57–2.42 (m, 3H), 2.37–2.24 (m, 1H), 2.13 (s, 1H), 1.92–1.79 (m, 5H), 1.66 (dd, J = 18.1, 9.2 Hz, 4H), 1.41 (t, J = 8.3 Hz, 4H).
实施例35：(R)-5-氯-2-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯酚
Example 35: (R)-5-chloro-2-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)phenol
(R)-5-氯-2-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯酚的制备方法参考实施例1。MS/ESI[M+H]+＝475.2。1H NMR(400MHz,CDCl3)δ12.09(s,1H),7.20(d,J＝8.3Hz,1H),7.11(d,J＝2.1Hz,1H),6.89(dd,J＝8.4,2.1Hz,1H),5.15(s,1H),4.52(s,1H),3.54(s,1H),3.02(s,1H),2.75–2.56(m,5H),2.51–2.27(m,3H),2.14(s,1H),1.95–1.82(m,5H),1.67(dd,J＝14.8,10.2Hz,3H),1.41(s,4H)。The preparation method of (R)-5-chloro-2-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)phenol was as described in Example 1. MS/ESI [M+H] + = 475.2. 1 H NMR (400 MHz, CDCl 3 ) δ 12.09 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 2.1 Hz, 1H), 6.89 (dd, J = 8.4, 2.1 Hz, 1H), 5.15 (s, 1H), 4.52 (s, 1H), 3.54 (s, 1H), 3.02 (s, 1H), 2.75–2.56 (m, 5H), 2.51–2.27 (m, 3H), 2.14 (s, 1H), 1.95–1.82 (m, 5H), 1.67 (dd, J = 14.8, 10.2 Hz, 3H), 1.41 (s, 4H).
实施例36：(R)-4-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-3-羟基苄腈
Example 36: (R)-4-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-3-hydroxybenzonitrile
(R)-4-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-3-羟基苄腈的制备方法参考实施例28。MS/ESI[M+H]+＝466.2。1H NMR(400MHz,Chloroform-d)δ7.41–7.33(m,2H),7.19(dd,J＝8.0,1.7Hz,1H),5.26(s,1H),4.53(s,1H),3.15–2.91(m,1H),2.80–2.57(m,5H),2.57–2.41(m,2H),2.40–2.24(m,1H),2.22–2.05(m,1H),2.02–1.80(m,6H),1.54–1.36(m,5H),1.35–1.27(m,2H)。The preparation method of (R)-4-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-3-hydroxybenzonitrile was prepared by reference to Example 28. MS/ESI [M+H] + = 466.2. 1 H NMR (400 MHz, Chloroform-d) δ7.41–7.33 (m, 2H), 7.19 (dd, J=8.0, 1.7 Hz, 1H), 5.26 (s, 1H), 4.53 (s, 1H), 3.15–2.91 (m, 1H), 2.80–2.57 (m, 5H), 2.57–2.41 (m, 2H), 2.40–2.24 (m, 1H), 2.22–2.05 (m, 1H), 2.02–1.80 (m, 6H), 1.54–1.36 (m, 5H), 1.35–1.27 (m, 2H).
实施例37：3-羟基-4-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苄腈
Example 37: 3-Hydroxy-4-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzonitrile
3-羟基-4-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苄腈的制备方法参考实施例28。MS/ESI[M+H]+＝391.2。1H NMR(400MHz,Chloroform-d)δ7.38(d,J＝1.6Hz,1H),7.33(d,J＝8.0Hz,1H),7.19(dd,J＝8.0,1.5Hz,1H),4.70(s,1H),4.02(s,1H),3.62–3.40(m,2H),3.09(s,1H),2.17(t,J＝13.6Hz,2H), 1.96–1.83(m,4H),1.83–1.71(m,3H),1.55–1.32(m,4H),1.31–1.18(m,4H)。The preparation method of 3-hydroxy-4-(4-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzonitrile is shown in Example 28. MS/ESI[M+H] + =391.2. 1 H NMR (400 MHz, Chloroform-d) δ7.38 (d, J=1.6 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.19 (dd, J=8.0, 1.5 Hz, 1H), 4.70 (s, 1H), 4.02 (s, 1H), 3.62-3.40 (m, 2H), 3.09 (s, 1H), 2.17 (t, J=13.6 Hz, 2H), 1.96–1.83(m,4H),1.83–1.71(m,3H),1.55–1.32(m,4H),1.31–1.18(m,4H).
实施例38：5-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-乙醇邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 38: 5-(4-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-ethanolphthalazin-1-yl)benzofuran-4-ol
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38a(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38b(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, compound 38a (10 g, 136 mmol) was dissolved in chloroform (120 mL) and added to the above suspension, and refluxed at 80°C for overnight reaction. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was slurried with EtOAc (200 mL) for 0.5 h, filtered, and the filtrate was concentrated to dryness to obtain the target compound 38b (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38b(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38c(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: Compound 38b (7.3 g, 25 mmol) and Li 2 CO 3 (11 g, 150 mmol) were added to DMF (70 mL) and stirred at 100°C for 6 h. After the reaction was complete, the mixture was filtered, the filtrate was adjusted to pH 1 with aqueous hydrochloric acid, extracted with EtOAc (150 mL×3), the organic phase was washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain the target compound 38c (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38c(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38d(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 38c (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 38d (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38d(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38e(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: Compound 38d (1 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) were added to dioxane (15 mL) and reacted at 90° C. for 12 h under nitrogen protection. After the reaction, the reaction mixture was filtered and silica gel was added to the filtrate. The mixture was concentrated under reduced pressure and then spin-dried. The title compound 38e (410 mg) was obtained by column chromatography (PE:EtOAc=10:1). 1 H NMR (400 MHz, Chloroform-d) δ7.63 (d, J=8.3 Hz, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.22 (dd, J=8.3, 1.0 Hz, 1H), 6.90 (dd, J=2.2, 1.0 Hz, 1H), 4.05 (s, 3H), 1.37 (s, 12H).
第五步：向反应瓶中加入化合物19h(150mg，0.4mmol)，化合物38e(164mg，0.6mmol)，Pd(dppf)Cl2(29mg,0.04mmol)，碳酸铯(391mg，1.2mmol)，二氧六环(4ml)和脱氧水(0.4ml)，置换氮气氛围，100℃反应12h。过硅藻土垫，加硅胶拌样，减压浓缩至干粉，柱层析得目标化合物38f(50mg)。Step 5: Add compound 19h (150 mg, 0.4 mmol), compound 38e (164 mg, 0.6 mmol), Pd(dppf)Cl 2 (29 mg, 0.04 mmol), cesium carbonate (391 mg, 1.2 mmol), dioxane (4 ml) and deoxygenated water (0.4 ml) to the reaction bottle, replace the nitrogen atmosphere, and react at 100°C for 12 hours. Pass through a celite pad, add silica gel to mix the sample, concentrate under reduced pressure to dry powder, and obtain the target compound 38f (50 mg) by column chromatography.
第六步：向反应瓶中加入化合物38f(50mg，0.1mmol)，置换氮气，加入DCM(2ml)，降温至-78℃，滴加1M BBr3(0.4ml，0.4mmol)，升温至-20℃反应2h后降温至-78℃，滴加甲醇淬灭反应。旋干溶剂，用制备板分离得目标产物38。MS/ESI[M+H]+＝406.5。1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),7.97(d,J＝2.2Hz,1H),7.29–7.18(m,3H),3.85–3.70(m,2H),2.91(d,J＝3.0Hz,1H),2.04–1.90(m,2H),1.89–1.67(m,6H),1.47–1.16(m,9H)。Step 6: Add compound 38f (50 mg, 0.1 mmol) to the reaction bottle, replace nitrogen, add DCM (2 ml), cool to -78°C, drop 1M BBr 3 (0.4 ml, 0.4 mmol), heat to -20°C for 2 h, cool to -78°C, drop methanol to quench the reaction. The solvent was spin-dried, and the target product 38 was isolated using a preparative plate. MS/ESI [M+H] + = 406.5. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.68 (s, 1H), 7.97 (d, J=2.2 Hz, 1H), 7.29–7.18 (m, 3H), 3.85–3.70 (m, 2H), 2.91 (d, J=3.0 Hz, 1H), 2.04–1.90 (m, 2H), 1.89–1.67 (m, 6H), 1.47–1.16 (m, 9H).
实施例39：(R)-5-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-乙醇邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 39: (R)-5-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-ethanolphthalazin-1-yl)benzofuran-4-ol
第一步：反应瓶中加入化合物39a(10g，50mmol)，Na2CO3(11g，102mmol)，THF(120ml)，H2O(30ml)，冰水浴降温至0℃，逐滴加入CbzCl(11.4g，67mmol)，TLC监测反应进度。约5h，反应完全。旋蒸掉大部分THF，用EA萃取三次，饱和食盐水洗涤，无水硫酸钠干燥，过滤。加硅胶制干粉，柱层析即得目标产物39b(14g)。Step 1: Add compound 39a (10 g, 50 mmol), Na 2 CO 3 (11 g, 102 mmol), THF (120 ml), H 2 O (30 ml) to a reaction flask, cool to 0°C in an ice-water bath, add CbzCl (11.4 g, 67 mmol) dropwise, and monitor the reaction progress by TLC. The reaction is complete after about 5 hours. Most of the THF is evaporated off, and the mixture is extracted with EA three times, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. Add silica gel to prepare dry powder, and column chromatography is performed to obtain the target product 39b (14 g).
第二步：反应瓶中加入化合物39b(14g，42mmol)，DCM(140ml)，盐酸二氧六环溶液(4M，140ml)，室温反应，TLC监测反应进度。约2h，反应完全。减压旋蒸掉溶剂，所得产物39c(9.8g)直接用于下一步反应，MS/ESI[M+H]+＝234.1。Step 2: Compound 39b (14 g, 42 mmol), DCM (140 ml), and dioxane hydrochloride solution (4 M, 140 ml) were added to the reaction flask and reacted at room temperature. The reaction progress was monitored by TLC. The reaction was completed after about 2 h. The solvent was evaporated under reduced pressure. The obtained product 39c (9.8 g) was directly used for the next step reaction. MS/ESI [M+H] + = 234.1.
第三步：上步所得产物39c(9.8g，42mmol)，加入ACN(120ml)，碳酸铯(68g，210mmol)，化合物39d(16g，67mmol)。90℃反应16h，TLC监测反应进度。过滤，滤液减压浓缩，加硅胶制干粉，柱层析即得目标化合物39e(8.7g)，MS/ESI[M+H]+＝393.2。 Step 3: Add ACN (120 ml), cesium carbonate (68 g, 210 mmol), and compound 39d (16 g, 67 mmol) to the product 39c (9.8 g, 42 mmol) obtained in the previous step. React at 90°C for 16 h, and monitor the reaction progress by TLC. Filter, concentrate the filtrate under reduced pressure, add silica gel to prepare dry powder, and obtain the target compound 39e (8.7 g) by column chromatography, MS/ESI [M+H] + = 393.2.
第四步：反应瓶中加入化合物39e(8.7g，22.1mmol)，甲醇(80ml)，Pd/C(0.87g，10％)。用氢气球置换反应体系为氢气氛围，室温反应过夜。待反应完全，反应液过硅藻土垫，将滤液减压浓缩，加硅胶制干粉，柱层析即得目标化合物39f(4.8g)。MS/ESI[M+H]+＝259.2.HNMR(400MHz，CDCl3)83.68(t，J＝6.6Hz，2H)，2.85-2.74(m，2H)，2.67-2.58(m，1H)，2.46(t，J＝6.4Hz，2H)，2.11-2.01(m,1H)，1.94-1.83(m，1H)，1.83-1.71(m，4H)，1.68-1.58(m，1H)，1.56-1.43(m，1H)，1.09-0.96(m，1H)，0.88-0.79(m，9H)，0.04-0.04(m，6H)。Step 4: Add compound 39e (8.7 g, 22.1 mmol), methanol (80 ml), and Pd/C (0.87 g, 10%) to the reaction flask. Replace the reaction system with hydrogen atmosphere using a hydrogen balloon and react at room temperature overnight. After the reaction is complete, pass the reaction solution through a celite pad, concentrate the filtrate under reduced pressure, add silica gel to prepare dry powder, and obtain the target compound 39f (4.8 g) by column chromatography. MS/ESI[M+H] + =259.2. H NMR (400 MHz, CDCl3) 83.68 (t, J=6.6 Hz, 2H), 2.85-2.74 (m, 2H), 2.67-2.58 (m, 1H), 2.46 (t, J=6.4 Hz, 2H), 2.11-2.01 (m, 1H), 1.94-1.83 (m, 1H), 1.83-1.71 (m, 4H), 1.68-1.58 (m, 1H), 1.56-1.43 (m, 1H), 1.09-0.96 (m, 1H), 0.88-0.79 (m, 9H), 0.04-0.04 (m, 6H).
第五步：向反应瓶中加入18g(460mg,2mmol)，39f(470mg，1.82mmol),Pd(OAc)2(45mg，0.2mmol)，BINAP(249mg，0.4mmol)，碳酸铯(0.98g，6mmol)和甲苯(10ml)，置换为氮气氛围，110℃反应过夜。过硅藻土垫，加硅胶拌样，减压浓缩至干粉，柱层析得目标化合物39g(320mg)，MS/ESI[M+H]+＝452.1。Step 5: 18g (460mg, 2mmol), 39f (470mg, 1.82mmol), Pd(OAc) 2 (45mg, 0.2mmol), BINAP (249mg, 0.4mmol), cesium carbonate (0.98g, 6mmol) and toluene (10ml) were added to the reaction bottle, replaced with nitrogen atmosphere, and reacted at 110°C overnight. Passed through a celite pad, added silica gel to mix the sample, concentrated under reduced pressure to dry powder, and column chromatography was performed to obtain the target compound 39g (320mg), MS/ESI [M+H] + = 452.1.
第六步：向反应瓶中加入化合物39g(320mg，0.71mmol)，化合物38e(291mg，1.1mmol)，Pd(dppf)Cl2(51mg,0.07mmol)，碳酸铯(694mg，2.13mmol)，二氧六环(5ml)和脱氧水(0.5ml)，置换为氮气氛围，100℃反应12h。过硅藻土垫，加硅胶拌样，减压浓缩至干粉，柱层析得目标化合物39h(65mg),MS/ESI[M+H]+＝563.5。Step 6: Add compound 39g (320 mg, 0.71 mmol), compound 38e (291 mg, 1.1 mmol), Pd(dppf)Cl 2 (51 mg, 0.07 mmol), cesium carbonate (694 mg, 2.13 mmol), dioxane (5 ml) and deoxygenated water (0.5 ml) into the reaction bottle, replace with nitrogen atmosphere, react at 100°C for 12 h. Pass through celite pad, add silica gel to mix, concentrate under reduced pressure to dry powder, and obtain the target compound 39h (65 mg) by column chromatography, MS/ESI [M+H] + = 563.5.
第七步：向反应瓶中加入化合物39h(65mg，0.12mmol)，TBAF(47mg，0.18mmol)，THF(5ml)，室温反应3h。加硅胶拌样，减压浓缩至干粉，柱层析即得目标化合物39i(20mg)，MS/ESI[M+H]+＝449.6。Step 7: Add compound 39h (65 mg, 0.12 mmol), TBAF (47 mg, 0.18 mmol), THF (5 ml) to the reaction bottle, react at room temperature for 3 h, add silica gel to mix, concentrate under reduced pressure to dry powder, and obtain the target compound 39i (20 mg) by column chromatography, MS/ESI [M+H] + = 449.6.
第八步：向反应瓶中加入化合物39i(20mg，0.04mmol)，置换氮气，加入DCM(2ml)，降温至-5℃，滴加1M BBr3(0.2ml，2mmol)，-5℃反应2h，滴加甲醇淬灭反应。旋干溶剂，制备液相分离得目标产物39，MS/ESI[M+H]+＝435.4。1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝2.2Hz,1H),7.22(d,J＝8.6Hz,1H),7.08(dd,J＝8.6,0.9Hz,1H),7.04(dd,J＝2.2,0.9Hz,1H),4.89(s,1H),4.51(s,1H),3.80–3.55(m,3H),3.01(s,1H),2.82(s,1H),2.59(t,J＝5.4Hz,4H),2.45(s,2H),2.29–2.10(m,1H),2.01(d,J＝6.1Hz,2H),1.85(m,3H),1.44(m,3H),1.28(m,4H)。Step 8: Add compound 39i (20 mg, 0.04 mmol) to the reaction flask, replace nitrogen, add DCM (2 ml), cool to -5°C, dropwise add 1M BBr 3 (0.2 ml, 2 mmol), react at -5°C for 2 h, dropwise add methanol to quench the reaction, spin dry the solvent, and separate the target product 39 by preparative liquid phase separation, MS/ESI [M+H] + = 435.4. 1 H NMR (400 MHz, Chloroform-d) δ7.55 (d, J=2.2 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 7.08 (dd, J=8.6, 0.9 Hz, 1H), 7.04 (dd, J=2.2, 0.9 Hz, 1H), 4.89 (s, 1H), 4.51 (s, 1H), 3.80–3.55 (m, 3H), 3.01 (s, 1H), 2.82 (s, 1H), 2.59 (t, J=5.4 Hz, 4H), 2.45 (s, 2H), 2.29–2.10 (m, 1H), 2.01 (d, J=6.1 Hz, 2H), 1.85 (m, 3H), 1.44 (m, 3H), 1.28 (m, 4H).
实施例40：(R)-5-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 40: (R)-5-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
(R)-5-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲 嗪-1-基)苯并呋喃-4-醇的制备方法参考实施例28。MS/ESI[M+H]+＝466.2。(R)-5-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalic acid The preparation method of (4-oxazine-1-yl)benzofuran-4-ol is shown in Example 28. MS/ESI [M+H] + = 466.2.
实施例41：(R)-5-氯-2-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯酚
Example 41: (R)-5-chloro-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)phenol
(R)-5-氯-2-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯酚的制备方法参考实施例39。MS/ESI[M+H]+＝429.2。The preparation method of (R)-5-chloro-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)phenol was described in Example 39. MS/ESI [M+H] + = 429.2.
实施例42：(R)-2-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-甲基苯酚
Example 42: (R)-2-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-methylphenol
(R)-2-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-甲基苯酚的制备参考实施例1。MS/ESI[M+H]+＝455.3。1H NMR(400MHz,CDCl3)δ7.17(d,J＝7.5Hz,1H),6.94(s,1H),6.73(d,J＝7.6Hz,1H),5.09(s,1H),4.52(s,1H),3.59(s,1H),3.02(s,1H),2.74–2.47(m,6H),2.35(s,3H),1.87(dd,J＝24.4,11.0Hz,4H),1.74–1.62(m,3H),1.44(d,J＝20.0Hz,4H),1.28(d,J＝21.2Hz,4H)。Preparation of (R)-2-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-methylphenol Reference Example 1. MS/ESI [M+H] + = 455.3. 1 H NMR (400 MHz, CDCl 3 ) δ 7.17 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.09 (s, 1H), 4.52 (s, 1H), 3.59 (s, 1H), 3.02 (s, 1H), 2.74-2.47 (m, 6H), 2.35 (s, 3H), 1.87 (dd, J = 24.4, 11.0 Hz, 4H), 1.74-1.62 (m, 3H), 1.44 (d, J = 20.0 Hz, 4H), 1.28 (d, J = 21.2 Hz, 4H).
实施例43：(R)-2-(4-((1-环丁基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 43: (R)-2-(4-((1-cyclobutylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
(R)-2-(4-((1-环丁基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备参考实施例1。MS/ESI[M+H]+＝473.3。1H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.46–7.35(m,2H),7.21–7.13(m,1H),5.55–5.33(m,1H),4.50(s,1H),3.56(s,1H),3.10(s,1H),2.85–2.71(m,1H),2.72–2.57(m,2H),2.51–2.29(m,1H),2.15–2.00(m,3H),2.01–1.84(m,5H),1.80–1.55(m,5H),1.55–1.40(m,4H),1.37–1.23(m,2H)。Preparation of (R)-2-(4-((1-cyclobutylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol Reference Example 1. MS/ESI [M+H] + = 473.3. 1 H NMR (400 MHz, Chloroform-d) δ8.04 (s, 1H), 7.46–7.35 (m, 2H), 7.21–7.13 (m, 1H), 5.55–5.33 (m, 1H), 4.50 (s, 1H), 3.56 (s, 1H), 3.10 (s, 1H), 2.85–2.71 (m, 1H), 2.72–2.57 (m, 2H), 2.51–2.29 (m, 1H), 2.15–2.00 (m, 3H), 2.01–1.84 (m, 5H), 1.80–1.55 (m, 5H), 1.55–1.40 (m, 4H), 1.37–1.23 (m, 2H).
实施例44：(S)-3-((4-(2-羟基-4-(三氟甲基)苯基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)氨基)丙烷-1,2-二醇
Example 44: (S)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)amino)propane-1,2-diol
(S)-3-((4-(2-羟基-4-(三氟甲基)苯基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)氨基)丙烷-1,2-二醇的制备参考实施例1。MS/ESI[M+H]+＝410.2。1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.46(d,J＝7.7Hz,1H),7.32–7.16(m,2H),6.75(s,1H),4.13(q,J＝5.2Hz,1H),3.77(dt,J＝10.3,5.1Hz,1H),3.60(dt,J＝12.7,5.0Hz,1H),3.46–3.38(m,5H),3.17(d,J＝3.4Hz,1H),2.73(d,J＝2.7Hz,1H),1.71(dq,J＝30.1,11.8,9.8Hz,4H),1.36–1.12(m,5H)。Preparation of (S)-3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)amino)propane-1,2-diol Reference Example 1. MS/ESI [M+H] + = 410.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.32–7.16 (m, 2H), 6.75 (s, 1H), 4.13 (q, J = 5.2 Hz, 1H), 3.77 (dt, J = 10.3, 5.1 Hz, 1H), 3.60 (dt, J = 12.7, 5.0 Hz, 1H), 3.46–3.38 (m, 5H), 3.17 (d, J = 3.4 Hz, 1H), 2.73 (d, J = 2.7 Hz, 1H), 1.71 (dq, J = 30.1, 11.8, 9.8 Hz, 4H), 1.36–1.12 (m, 5H).
实施例45：(R)-2-(4-((1-(氧杂环丁烷-3-基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 45: (R)-2-(4-((1-(oxetane-3-yl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
(R)-2-(4-((1-(氧杂环丁烷-3-基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备参考实施例1。MS/ESI[M+H]+＝475.2。1H NMR(400MHz,Chloroform-d)δ7.45–7.31(m,2H),7.21–7.08(m,1H),5.41(s,1H),4.73–4.65(m,2H),4.59(t,J＝6.2Hz,1H),4.54(s,1H),3.59–3.52(m,2H),3.11(t,J＝2.6Hz,1H),2.58(s,2H),2.44(d,J＝11.1Hz,1H),2.07(d,J＝20.0Hz,4H),2.02–1.91(m,3H),1.92–1.81(m,2H),1.81–1.60(m,3H),1.52–1.34(m,4H),1.33–1.22(m,1H)。Preparation of (R)-2-(4-((1-(oxetan-3-yl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol Reference Example 1. MS/ESI [M+H] + = 475.2. 1 H NMR (400 MHz, Chloroform-d) δ7.45–7.31 (m, 2H), 7.21–7.08 (m, 1H), 5.41 (s, 1H), 4.73–4.65 (m, 2H), 4.59 (t, J=6.2 Hz, 1H), 4.54 (s, 1H), 3.59–3.52 (m, 2H), 3.11 (t, J=2.6 Hz, 1H), 2.58 (s, 2H), 2.44 (d, J=11.1 Hz, 1H), 2.07 (d, J=20.0 Hz, 4H), 2.02–1.91 (m, 3H), 1.92–1.81 (m, 2H), 1.81–1.60 (m, 3H), 1.52–1.34 (m, 4H), 1.33–1.22 (m, 1H).
实施例46：(R)-2-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 46: (R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
(R)-2-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备参考实施例39。MS/ESI[M+H]+＝463.2。1H NMR(400MHz,DMSO-d6)δ7.44(d,J＝7.7Hz,1H),7.30–7.14(m,2H),6.11(d,J＝7.8Hz,1H),4.41(s,1H),4.20(dq,J＝9.3,4.6Hz,1H),3.50(t,J＝6.2Hz,28H),3.07(dd,J＝10.5,3.8Hz,1H),2.79–2.67(m,2H),2.42(t,J＝6.3Hz,2H),2.08–1.95(m,2H),1.94–1.86(m,1H),1.80–1.62(m,5H),1.61–1.48(m,1H),1.48–1.34(m,1H),1.34–1.15(m,5H)。 Preparation of (R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol Reference Example 39. MS/ESI [M+H] + = 463.2. 1 H NMR (400 MHz, DMSO-d 6 )δ7.44(d,J＝7.7Hz,1H),7.30–7.14(m,2H),6.11(d,J＝7.8Hz,1H),4.41(s,1H),4.20(dq,J＝9.3,4.6Hz,1H),3.50(t,J＝6.2Hz,28H),3.07(dd,J＝10.5,3.8Hz,1H),2.79–2.67(m,2H),2.42(t,J＝6.3Hz,2H),2.08–1.95(m,2H),1.94–1.86(m,1H),1.80–1.62(m,5H),1.61–1.48(m,1H),1.48–1.34(m,1H),1.34–1.15(m,5H).
实施例47：(R)-5-(4-((四氢呋喃-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 47: (R)-5-(4-((tetrahydrofuran-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
(R)-5-(4-((四氢呋喃-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例38。MS/ESI[M+H]+＝378.2。1H NMR(400MHz,Chloroform-d)δ9.20(s,1H),7.57(d,J＝2.1Hz,1H),7.21–7.15(m,1H),7.14(s,1H),7.11(d,J＝8.5Hz,1H),4.81–4.63(m,1H),4.51(d,J＝13.6Hz,1H),4.46–4.26(m,2H),4.12–3.90(m,2H),3.75–3.63(m,2H),3.55–3.39(m,2H),2.27–1.98(m,2H),1.85–1.55(m,4H),1.48–1.14(m,3H)。Preparation of (R)-5-(4-((tetrahydrofuran-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol Reference Example 38. MS/ESI [M+H] + = 378.2. 1 H NMR (400 MHz, Chloroform-d) δ9.20 (s, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.21–7.15 (m, 1H), 7.14 (s, 1H), 7.11 (d, J = 8.5 Hz, 1H), 4.81–4.63 (m, 1H), 4.51 (d, J = 13.6 Hz, 1H), 4.46–4.26 (m, 2H), 4.12–3.90 (m, 2H), 3.75–3.63 (m, 2H), 3.55–3.39 (m, 2H), 2.27–1.98 (m, 2H), 1.85–1.55 (m, 4H), 1.48–1.14 (m, 3H).
实施例48：(S)-5-氯-2-(4-((四氢呋喃-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯酚
Example 48: (S)-5-chloro-2-(4-((tetrahydrofuran-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)phenol
(S)-5-氯-2-(4-((四氢呋喃-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯酚的制备参考实施例1。MS/ESI[M+H]+＝372.2。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.32–7.16(m,1H),7.00–6.87(m,2H),6.49(d,J＝5.7Hz,1H),4.64–4.54(m,1H),3.99(dd,J＝8.9,6.2Hz,1H),3.89(td,J＝8.0,6.3Hz,1H),3.74(td,J＝8.0,6.3Hz,1H),3.63(dd,J＝8.8,4.6Hz,1H),3.43(t,J＝2.6Hz,1H),2.76(t,J＝2.6Hz,1H),2.31–2.17(m,1H),2.07–1.89(m,1H),1.79–1.62(m,4H),1.33–1.16(m,4H)。Preparation of (S)-5-chloro-2-(4-((tetrahydrofuran-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)phenol Reference Example 1. MS/ESI [M+H] + = 372.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 7.32–7.16 (m, 1H), 7.00–6.87 (m, 2H), 6.49 (d, J=5.7 Hz, 1H), 4.64–4.54 (m, 1H), 3.99 (dd, J=8.9, 6.2 Hz, 1H), 3.89 (td, J=8.0, 6.3 Hz, 1H), 3.74 (td, J= 8.0,6.3Hz,1H),3.63(dd,J＝8.8,4.6Hz,1H),3.43(t,J＝2.6Hz,1H),2.76(t,J＝2.6Hz,1H),2.31–2.17(m,1H),2.07–1.89(m,1H),1.79–1.62(m,4H),1.33–1.16(m,4H).
实施例49：5-氯-2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯酚
Example 49: 5-Chloro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)phenol
5-氯-2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯酚的制备参考实施例1。MS/ESI[M+H]+＝400.2。Preparation of 5-chloro-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)phenol Reference Example 1. MS/ESI [M+H] + = 400.2.
实施例50：2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1- 基)-5-(三氟甲氧基)苯酚
Example 50: 2-(4-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazine-1-yl 5-(Trifluoromethoxy)phenol
2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲氧基)苯酚的制备参考实施例1。MS/ESI[M+H]+＝450.2。Preparation of 2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethoxy)phenol Reference Example 1. MS/ESI [M+H] + = 450.2.
实施例51：2-(4-(((1R)-3-(3,3-二氟氮杂环丁烷-1-基)环己基)氨基)-5,6,7-8-四氢-5,8-乙醇邻苯二甲酸-1-基)-5-(三氟甲氧基)苯酚
Example 51: 2-(4-(((1R)-3-(3,3-difluoroazetidin-1-yl)cyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-ethanolphthalic acid-1-yl)-5-(trifluoromethoxy)phenol
2-(4-(((1R)-3-(3,3-二氟氮杂环丁烷-1-基)环己基)氨基)-5,6,7-8-四氢-5,8-乙醇邻苯二甲酸-1-基)-5-(三氟甲氧基)苯酚的制备参考实施例1。MS/ESI[M+H]+＝525.2。1H NMR(400MHz,CD3OD)δ7.26(d,J＝8.4Hz,1H),6.78(d,J＝8.4Hz,1H),6.73(s,1H),4.22(dd,J＝11.3,7.4Hz,1H),3.09-3.01(m,1H),2.85-2.77(s,1H),2.76–2.56(m,4H),2.52–2.30(m,2H),2.14-2.07(m,1H),1.99-1.88(m,2H),1.80–1.56(m,6H),1.52-1.44(m,1H),1.28–1.20(m,6H)。Preparation of 2-(4-(((1R)-3-(3,3-difluoroazetidin-1-yl)cyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-ethanolphthalic acid-1-yl)-5-(trifluoromethoxy)phenol Reference Example 1. MS/ESI [M+H] + = 525.2. 1 H NMR (400 MHz, CD 3 OD) δ 7.26 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 4.22 (dd, J = 11.3, 7.4 Hz, 1H), 3.09-3.01 (m, 1H), 2.85-2.77 (s, 1H), 2.76-2.56 (m, 4H), 2.52-2.30 (m, 2H), 2.14-2.07 (m, 1H), 1.99-1.88 (m, 2H), 1.80-1.56 (m, 6H), 1.52-1.44 (m, 1H), 1.28-1.20 (m, 6H).
实施例52：5-(二氟甲氧基)-2-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯酚
Example 52: 5-(Difluoromethoxy)-2-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)phenol
第一步：将化合物52a(15.32g，81.1mmol)、对甲苯磺酰氯(17.07g，89.5mmol，1.1eq.)和碳酸钾(33.81g，245mmol，3.0eq.)在丙酮(200mL)中的混合物在65℃下加热24小时。First step: A mixture of compound 52a (15.32 g, 81.1 mmol), p-toluenesulfonyl chloride (17.07 g, 89.5 mmol, 1.1 eq.) and potassium carbonate (33.81 g, 245 mmol, 3.0 eq.) in acetone (200 mL) was heated at 65° C. for 24 hours.
然后向反应液中加入氯甲基甲醚(40mL 6M/L二甲氧基乙烷溶液，240mmol，3.0eq.)。再搅拌24小时并将反应混合物冷却至室温。过滤并减压浓缩，将所得残留物溶于乙醚(100mL)中。用水(1 x 100mL)和饱和NaCl水溶液(1 x 100％mL)洗涤。无水硫 酸钠干燥有机层。过滤并减压浓缩。通过柱层析纯化粗残留物得到化合物52b。Then, chloromethyl methyl ether (40 mL of 6M/L dimethoxyethane solution, 240 mmol, 3.0 eq.) was added to the reaction solution. Stir for another 24 hours and cool the reaction mixture to room temperature. Filter and concentrate under reduced pressure, and dissolve the resulting residue in ether (100 mL). Wash with water (1 x 100 mL) and saturated aqueous NaCl solution (1 x 100% mL). Anhydrous sulfur The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford compound 52b.
第二步：向化合物52b(30.64g，79.1mmol)在EtOH(1.0L)的溶液中加入4M KOH水溶液(100mL，400mmol，5.0eq.)。将所得溶液在60℃下加热2小时，然后冷却至室温。用3M盐酸水溶液中和反应混合物，并在减压下浓缩。将粗残渣溶于乙醚(100mL)中。用水(1 x 100mL)和饱和NaCl水溶液(1 x 100mL)洗涤。无水硫酸钠干燥有机层。过滤并减压浓缩。通过柱层析纯化粗残留物得到化合物52c。1HNMR(500MHz,CDCl3):δ＝3.52(s,3H),5.11(s,1H)，5.22(s,2H)，6.40(dd,J＝2.8,8.6Hz,1H)，6.70(d,J＝2.8Hz,1H),7.35ppm(d,J＝8.6Hz,1H)。Step 2: 4M KOH aqueous solution (100mL, 400mmol, 5.0eq.) was added to a solution of compound 52b (30.64g, 79.1mmol) in EtOH (1.0L). The resulting solution was heated at 60°C for 2 hours and then cooled to room temperature. The reaction mixture was neutralized with 3M hydrochloric acid aqueous solution and concentrated under reduced pressure. The crude residue was dissolved in ether (100mL). Washed with water (1 x 100mL) and saturated NaCl aqueous solution (1 x 100mL). The organic layer was dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to obtain compound 52c. 1 H NMR (500 MHz, CDCl 3 ): δ＝3.52 (s, 3H), 5.11 (s, 1H), 5.22 (s, 2H), 6.40 (dd, J＝2.8, 8.6 Hz, 1H), 6.70 (d, J＝2.8 Hz, 1H), 7.35 ppm (d, J＝8.6 Hz, 1H).
第三步：将化合物52c(5.00g，20.7mmol，1.0eq.)、氯-2,2-二氟乙酸钠(7.07g，51.9mmol，2.50eq.)和碳酸铯(11.5g，41.5mmol，2.0eq.)在水(20mL)和N，N-二甲基甲酰胺(80mL)的溶液在100℃下加热12小时。完成后，将反应混合物冷却至室温并用EtOAc稀释洗涤反应混合物。用水和盐水洗涤有机相，用Na2SO4干燥，过滤，并在减压下浓缩。粗残留物通过硅胶柱色谱法纯化，用0-50％EtOAc在己烷中洗脱，得到黄色固体的化合物52d。The third step: a solution of compound 52c (5.00 g, 20.7 mmol, 1.0 eq.), sodium chloro-2,2-difluoroacetate (7.07 g, 51.9 mmol, 2.50 eq.) and cesium carbonate (11.5 g, 41.5 mmol, 2.0 eq.) in water (20 mL) and N,N-dimethylformamide (80 mL) was heated at 100 ° C for 12 hours. After completion, the reaction mixture was cooled to room temperature and the reaction mixture was diluted and washed with EtOAc. The organic phase was washed with water and brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in hexane to give compound 52d as a yellow solid.
第四步：将化合物52d(1.24g,4.4mmol),双联硼酸频哪醇酯(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52e(682mg)。Step 4: Compound 52d (1.24 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) were added to dioxane (15 mL) and reacted at 90°C for 12 h under nitrogen protection. After the reaction, the mixture was filtered, silica gel was added to the filtrate, and the mixture was concentrated under reduced pressure and dried, and separated by column chromatography (PE:EtOAc=10:1) to obtain the target compound 52e (682 mg).
第五步：向反应瓶中加入化合物19h(150mg，0.4mmol)，化合物52e(198mg，0.6mmol)，Pd(dppf)Cl2(29mg,0.04mmol)，碳酸铯(391mg，1.2mmol)，二氧六环(4ml)和脱氧水(0.4ml)，置换氮气氛围，100℃反应12h。过硅藻土垫，加硅胶拌样，减压浓缩至干粉，柱层析得目标化合物52f(98mg)。Step 5: Add compound 19h (150 mg, 0.4 mmol), compound 52e (198 mg, 0.6 mmol), Pd(dppf)Cl 2 (29 mg, 0.04 mmol), cesium carbonate (391 mg, 1.2 mmol), dioxane (4 ml) and deoxygenated water (0.4 ml) to the reaction bottle, replace the nitrogen atmosphere, and react at 100°C for 12 hours. Pass through a celite pad, add silica gel to mix the sample, concentrate under reduced pressure to dry powder, and obtain the target compound 52f (98 mg) by column chromatography.
第六步：将化合物52f(98mg)加入氯化氢的二氧六环溶液(1ml，1M/L)中，室温搅拌1小时后加入饱和碳酸氢钠溶液调节至弱碱性，二氯甲烷萃取。有机相合并后旋干，柱层析纯化得化合物52(35mg)。MS/ESI[M+H]+＝432.2。Step 6: Compound 52f (98 mg) was added to a solution of hydrogen chloride in dioxane (1 ml, 1 M/L), stirred at room temperature for 1 hour, and then saturated sodium bicarbonate solution was added to adjust to weak alkalinity, and extracted with dichloromethane. The organic phases were combined and dried, and purified by column chromatography to obtain compound 52 (35 mg). MS/ESI [M+H] + = 432.2.
实施例53：(R)-2-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(二氟甲氧基)苯酚
Example 53: (R)-2-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(difluoromethoxy)phenol
(R)-2-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲 嗪-1-基)-5-(二氟甲氧基)苯酚的制备参照实施例52。MS/ESI[M+H]+＝507.2。(R)-2-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalic acid The preparation of 4-(4-oxazin-1-yl)-5-(difluoromethoxy)phenol refers to Example 52. MS/ESI [M+H] + = 507.2.
实施例54：(R)-2-(4-((1-(2-氟-2-甲基丙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 54: (R)-2-(4-((1-(2-fluoro-2-methylpropyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
(R)-2-(4-((1-(2-氟-2-甲基丙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备参照实施例1。MS/ESI[M+H]+＝493.2。1H NMR(400MHz,Chloroform-d)δ7.46–7.30(m,2H),7.15(dd,J＝8.2,1.8Hz,1H),5.55(d,J＝8.0Hz,1H),4.56–4.40(m,1H),3.54(t,J＝2.7Hz,1H),3.02(t,J＝2.6Hz,1H),2.83(s,2H),2.75–2.63(m,1H),2.51(s,1H),2.46(s,1H),2.44–2.30(m,1H),2.03–1.80(m,5H),1.81–1.67(m,1H),1.60(s,3H),1.42(d,J＝8.7Hz,6H),1.27(m,1H)。The preparation of (R)-2-(4-((1-(2-fluoro-2-methylpropyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol was carried out according to Example 1. MS/ESI [M+H] + = 493.2. 1 H NMR (400 MHz, Chloroform-d) δ7.46–7.30 (m, 2H), 7.15 (dd, J=8.2, 1.8 Hz, 1H), 5.55 (d, J=8.0 Hz, 1H), 4.56–4.40 (m, 1H), 3.54 (t, J=2.7 Hz, 1H), 3.02 (t, J=2.6 Hz, 1H), 2.83 (s, 2H), 2.75–2.63 (m, 1H), 2.51 (s, 1H), 2.46 (s, 1H), 2.44–2.30 (m, 1H), 2.03–1.80 (m, 5H), 1.81–1.67 (m, 1H), 1.60 (s, 3H), 1.42 (d, J=8.7 Hz, 6H), 1.27 (m, 1H).
实施例55：(R)-2-(4-(((1-(2,2-二氟基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 55: (R)-2-(4-(((1-(2,2-difluoro)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
(R)-2-(4-(((1-(2,2-二氟基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备参照实施例1。MS/ESI[M+H]+＝493.2。1H NMR(400MHz,Chloroform-d)δ7.44–7.31(m,2H),7.15(dd,J＝8.5,1.7Hz,1H),5.47–5.30(m,1H),4.57–4.43(m,1H),3.54(t,J＝2.7Hz,1H),3.01(d,J＝2.9Hz,1H),2.81(d,J＝3.4Hz,3H),2.78–2.65(m,2H),2.57–2.35(m,1H),1.96–1.81(m,4H),1.74–1.51(m,5H),1.51–1.35(m,4H),1.32–1.16(m,3H)。The preparation of (R)-2-(4-(((1-(2,2-difluoro)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol was carried out according to Example 1. MS/ESI [M+H] + = 493.2. 1 H NMR (400 MHz, Chloroform-d) δ7.44–7.31 (m, 2H), 7.15 (dd, J=8.5, 1.7 Hz, 1H), 5.47–5.30 (m, 1H), 4.57–4.43 (m, 1H), 3.54 (t, J=2.7 Hz, 1H), 3.01 (d, J=2.9 Hz, 1H), 2.81 (d, J=3.4 Hz, 3H), 2.78–2.65 (m, 2H), 2.57–2.35 (m, 1H), 1.96–1.81 (m, 4H), 1.74–1.51 (m, 5H), 1.51–1.35 (m, 4H), 1.32–1.16 (m, 3H).
实施例56：(R)-2-(4-(((1-(2,2-二氟乙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 56: (R)-2-(4-(((1-(2,2-difluoroethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
(R)-2-(4-(((1-(2,2-二氟乙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备参照实施例1。MS/ESI[M+H]+＝493.2。1H NMR(400 MHz,MeOD)δ7.60(d,J＝7.9Hz,1H),7.38(d,J＝8.0Hz,1H),7.32(s,1H),6.34(tt,J＝54.2,3.8Hz,1H),4.41(ddd,J＝13.8,9.8,3.8Hz,1H),3.76–3.61(m,2H),3.56–3.39(m,3H),3.00(dd,J＝25.5,13.3Hz,3H),2.20(dt,J＝8.5,7.5Hz,1H),2.02(dddd,J＝30.0,26.2,13.4,7.5Hz,6H),1.84–1.72(m,1H),1.52–1.39(m,4H)。The preparation of (R)-2-(4-(((1-(2,2-difluoroethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol was carried out according to Example 1. MS/ESI [M+H] + = 493.2. 1 H NMR (400 MHz, MeOD) δ7.60 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 6.34 (tt, J = 54.2, 3.8 Hz, 1H), 4.41 (ddd, J = 13.8, 9.8, 3.8 Hz, 1H), 3.76–3.61 (m, 2H), 3.56–3.39 (m, 3H), 3.00 (dd, J = 25.5, 13.3 Hz, 3H), 2.20 (dt, J = 8.5, 7.5 Hz, 1H), 2.02 (dddd, J = 30.0, 26.2, 13.4, 7.5 Hz, 6H), 1.84–1.72 (m, 1H), 1.52–1.39 (m, 4H).
实施例57：5-甲基-2-(4-((((R)-1-甲基哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-甲基邻苯二甲嗪-1-基)苯酚
Example 57: 5-methyl-2-(4-((((R)-1-methylpiperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-methylphthalazin-1-yl)phenol
5-甲基-2-(4-((((R)-1-甲基哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-甲基邻苯二甲嗪-1-基)苯酚的制备参照实施例1。MS/ESI[M+H]+＝493.2。The preparation of 5-methyl-2-(4-((((R)-1-methylpiperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-methylphthalazin-1-yl)phenol was carried out according to Example 1. MS/ESI [M+H] + =493.2.
实施例58：2-(4-((((R)-1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 58: 2-(4-((((R)-1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-((((R)-1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备参照实施例29。MS/ESI[M+H]+＝495.2。1H NMR(400MHz,CDCl3)δ13.58(s,1H),7.67(d,J＝8.2Hz,1H),7.33(d,J＝1.1Hz,1H),7.16(d,J＝8.2Hz,1H),5.04(s,1H),4.50(s,1H),3.90(s,1H),3.38(d,J＝4.5Hz,1H),2.91–2.60(m,4H),2.60–2.28(m,4H),2.27–2.09(m,3H),1.91–1.58(m,6H),1.38(ddd,J＝52.3,7.7,4.9Hz,2H)。The preparation of 2-(4-((((R)-1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol was carried out according to Example 29. MS/ESI [M+H] + = 495.2. 1 H NMR (400 MHz, CDCl 3 )δ13.58(s,1H),7.67(d,J＝8.2Hz,1H),7.33(d,J＝1.1Hz,1H),7.16(d,J＝8.2Hz,1H),5.04(s,1H),4.50(s,1H),3.90(s,1H),3.38(d,J＝4.5Hz,1H),2.91–2.60(m,4H),2.60–2.28(m,4H),2.27–2.09(m,3H),1.91–1.58(m,6H),1.38(ddd,J＝52.3,7.7,4.9Hz,2H).
实施例59：5-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-甲基邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 59: 5-(4-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-methylphthalazin-1-yl)benzofuran-4-ol
5-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-甲基邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例38。MS/ESI[M+H]+＝392.2。1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝2.2Hz,1H),7.50(dd,J＝8.7,5.2Hz,1H),7.09(d,J＝8.7Hz,1H),7.04(d,J＝2.1Hz,1H),4.26(dd,J＝14.1,6.4Hz,1H),3.95(s,2H),3.56–3.45(m, 1H),3.37(d,J＝9.5Hz,1H),2.27–2.17(m,2H),2.17–2.05(m,3H),1.78(m,3H),1.73–1.46(m,3H),1.47–1.34(m,2H),1.34–1.27(m,2H)。Preparation of 5-(4-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-methylphthalazin-1-yl)benzofuran-4-ol Reference Example 38. MS/ESI [M+H] + = 392.2. 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 8.7, 5.2 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 4.26 (dd, J = 14.1, 6.4 Hz, 1H), 3.95 (s, 2H), 3.56-3.45 (m, 1H), 3.37 (d, J＝9.5Hz, 1H), 2.27–2.17 (m, 2H), 2.17–2.05 (m, 3H), 1.78 (m, 3H), 1.73–1.46 (m, 3H), 1.47–1.34 (m, 2H), 1.34–1.27 (m, 2H).
实施例60：(S)-5-(4-((四氢呋喃-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 60: (S)-5-(4-((tetrahydrofuran-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
(S)-5-(4-((四氢呋喃-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例38。MS/ESI[M+H]+＝378.2。1H NMR(400MHz,Chloroform-d)δ9.20(s,1H),7.57(d,J＝2.1Hz,1H),7.21–7.15(m,1H),7.14(s,1H),7.11(d,J＝8.5Hz,1H),4.81–4.63(m,1H),4.51(d,J＝13.6Hz,1H),4.46–4.26(m,2H),4.12–3.90(m,2H),3.75–3.63(m,2H),3.55–3.39(m,2H),2.27–1.98(m,2H),1.85–1.55(m,4H),1.48–1.14(m,3H)。Preparation of (S)-5-(4-((tetrahydrofuran-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol Reference Example 38. MS/ESI [M+H] + = 378.2. 1 H NMR (400 MHz, Chloroform-d) δ9.20 (s, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.21–7.15 (m, 1H), 7.14 (s, 1H), 7.11 (d, J = 8.5 Hz, 1H), 4.81–4.63 (m, 1H), 4.51 (d, J = 13.6 Hz, 1H), 4.46–4.26 (m, 2H), 4.12–3.90 (m, 2H), 3.75–3.63 (m, 2H), 3.55–3.39 (m, 2H), 2.27–1.98 (m, 2H), 1.85–1.55 (m, 4H), 1.48–1.14 (m, 3H).
实施例61：(R)-2-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚对甲苯磺酸盐
Example 61: (R)-2-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol p-toluenesulfonate
将化合物29(80.0mg,0.157mmol)加入到EtOAc(1.6mL)中,体系为悬浊液。将TsOH(108mg)溶于EtOAc(1mL)中配成溶液，然后将此溶液慢慢滴加到上述悬浊液中，体系溶清，然后又有少量固体析出，滴毕后室温搅拌2h。过滤，滤液用EtOAc(0.5mL)淋洗得到粘稠的固体，固体用少量乙腈溶解，加入水冻干即得到目标化合物61(89.0mg,0.104mmol，白色固体，产率66％)。MS/ESI[M+H]+＝509.2。1H NMR(400MHz,MeOD)δ7.71(d,J＝8.2Hz,4H),7.60(d,J＝7.9Hz,1H),7.37(d,J＝8.0Hz,1H),7.30(s,1H),7.24(d,J＝8.0Hz,4H),4.49(s,1H),3.81(s,2H),3.71–3.52(m,2H),3.12–2.83(m,7H),2.37(s,6H),2.20(dd,J＝27.7,14.8Hz,2H),2.05–1.81(m,6H),1.43(t,J＝9.4Hz,4H)。Compound 29 (80.0 mg, 0.157 mmol) was added to EtOAc (1.6 mL) to form a suspension. TsOH (108 mg) was dissolved in EtOAc (1 mL) to prepare a solution, and then the solution was slowly added dropwise to the suspension to make the system clear, and then a small amount of solid precipitated. After the addition, the mixture was stirred at room temperature for 2 h. The mixture was filtered and the filtrate was rinsed with EtOAc (0.5 mL) to obtain a viscous solid. The solid was dissolved with a small amount of acetonitrile and lyophilized with water to obtain the target compound 61 (89.0 mg, 0.104 mmol, white solid, yield 66%). MS/ESI[M+H] + ＝509.2. 1H NMR (400 MHz, MeOD) δ7.71 (d, J＝8.2 Hz, 4H), 7.60 (d, J＝7.9 Hz, 1H), 7.37 (d, J＝8.0 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J＝8.0 Hz, 4H), 4.49 (s, 1H), 3.81 (s, 2H), 3.71–3.52 (m, 2H), 3.12–2.83 (m, 7H), 2.37 (s, 6H), 2.20 (dd, J＝27.7, 14.8 Hz, 2H), 2.05–1.81 (m, 6H), 1.43 (t, J＝9.4 Hz, 4H).
实施例62：5-(4-((((R)-1-[(R)-1-羟基丙-2-基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇和Example 62: 5-(4-((((R)-1-[(R)-1-hydroxypropan-2-yl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol and
实施例63：5-(4-((((R)-1-[(S)-1-羟基丙-2-基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 63: 5-(4-((((R)-1-[(S)-1-hydroxypropan-2-yl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
第一步：将化合物29c(200mg,1mmol)和化合物62a(138mg,1mmol)溶解于8mLDMF中，然后加入碳酸钾(276mg,2mmol)和碘化钾(166mg,1mmol),反应液在室温下搅拌3小时。TLC监测反应完全。将反应液加水稀释，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析得到产物62b(230mg,产率：89.1％)。MS/ESI[M+H]+＝259.1。Step 1: Compound 29c (200 mg, 1 mmol) and compound 62a (138 mg, 1 mmol) were dissolved in 8 mL DMF, and potassium carbonate (276 mg, 2 mmol) and potassium iodide (166 mg, 1 mmol) were added. The reaction solution was stirred at room temperature for 3 hours. TLC monitored the reaction to be complete. The reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography to obtain product 62b (230 mg, yield: 89.1%). MS/ESI [M+H] + = 259.1.
第二步：将化合物62b(1.4g,5.4mmol)溶解于15mL氯化氢/乙酸乙酯(2M)中，室温下搅拌1小时。TLC监测反应完全。将反应液减压浓缩，得到粗品产物62c(1.2g,产率：100％)。MS/ESI[M+H]+＝159.1。Step 2: Compound 62b (1.4 g, 5.4 mmol) was dissolved in 15 mL of hydrogen chloride/ethyl acetate (2 M) and stirred at room temperature for 1 hour. TLC monitored the reaction to be complete. The reaction solution was concentrated under reduced pressure to obtain a crude product 62c (1.2 g, yield: 100%). MS/ESI [M+H] + = 159.1.
第三步：向反应瓶中加入18g(460mg,2mmol)，62c(288mg，1.82mmol),Pd(OAc)2(45mg，0.2mmol)，BINAP(249mg，0.4mmol)，碳酸铯(0.98g，6mmol)和甲苯(10ml)，置换为氮气氛围，110℃反应过夜。过硅藻土垫，加硅胶拌样，减压浓缩至干粉，柱层析得目标化合物62d(249mg)，MS/ESI[M+H]+＝351.2。Step 3: 18 g (460 mg, 2 mmol), 62c (288 mg, 1.82 mmol), Pd(OAc) 2 (45 mg, 0.2 mmol), BINAP (249 mg, 0.4 mmol), cesium carbonate (0.98 g, 6 mmol) and toluene (10 ml) were added to the reaction bottle, replaced with nitrogen atmosphere, and reacted at 110° C. overnight. Passed through a celite pad, added silica gel to mix the sample, concentrated under reduced pressure to dry powder, and column chromatography was performed to obtain the target compound 62d (249 mg), MS/ESI [M+H] + = 351.2.
第四步：向反应瓶中加入化合物62d(249mg，0.71mmol)，化合物38e(291mg，1.1mmol)，Pd(dppf)Cl2(51mg,0.07mmol)，碳酸铯(694mg，2.13mmol)，二氧六环(5ml)和脱氧水(0.5ml)，置换为氮气氛围，100℃反应12h。过硅藻土垫，加硅胶拌样，减压浓缩至干粉，柱层析得目标化合物62e(87mg),MS/ESI[M+H]+＝462.3。Step 4: Add compound 62d (249 mg, 0.71 mmol), compound 38e (291 mg, 1.1 mmol), Pd(dppf)Cl 2 (51 mg, 0.07 mmol), cesium carbonate (694 mg, 2.13 mmol), dioxane (5 ml) and deoxygenated water (0.5 ml) to the reaction bottle, replace with nitrogen atmosphere, react at 100°C for 12 h. Pass through a celite pad, add silica gel to mix the sample, concentrate under reduced pressure to dry powder, and obtain the target compound 62e (87 mg) by column chromatography, MS/ESI [M+H] + = 462.3.
第五步：向反应瓶中加入化合物62e(92mg，0.2mmol)，置换氮气，加入DCM(2ml)，降温至-5℃，滴加1M BBr3(0.2ml，2mmol)，-5℃反应2h，滴加甲醇淬灭反应。旋干溶剂，制备液相分离得目标产物62f，MS/ESI[M+H]+＝448.2。1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝2.2Hz,1H),7.22(d,J＝8.6Hz,1H),7.08(d,J＝8.6Hz,1H), 7.04(d,J＝2.2Hz,1H),4.82(d,J＝39.1Hz,1H),4.50(s,1H),3.63(s,1H),3.48–3.31(m,2H),3.08–2.94(m,2H),2.94–2.77(m,2H),2.78–2.58(m,2H),2.56–2.32(m,2H),1.99–1.78(m,5H),1.78–1.53(m,5H),1.50–1.34(m,3H),1.34–1.27(m,2H)。Step 5: Add compound 62e (92 mg, 0.2 mmol) to the reaction bottle, replace nitrogen, add DCM (2 ml), cool to -5°C, add 1M BBr 3 (0.2 ml, 2 mmol), react at -5°C for 2 h, and add methanol to quench the reaction. The solvent was spin-dried, and the target product 62f was obtained by preparative liquid separation. MS/ESI [M+H] + = 448.2. 1 H NMR (400 MHz, Chloroform-d) δ7.55 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 4.82 (d, J = 39.1 Hz, 1H), 4.50 (s, 1H), 3.63 (s, 1H), 3.48–3.31 (m, 2H), 3.08–2.94 (m, 2H), 2.94–2.77 (m, 2H), 2.78–2.58 (m, 2H), 2.56–2.32 (m, 2H), 1.99–1.78 (m, 5H), 1.78–1.53 (m, 5H), 1.50–1.34 (m, 3H), 1.34–1.27 (m, 2H).
第六步：化合物62f通过手性拆分得到化合物62和化合物63。拆分方法为：仪器-Waters 150Prep-SFC，柱子型号：Chiralcel AD Column，流动相A：二氧化碳，流动相B：0.1％氨水的异丙醇，梯度：70％流动相B，压力：100bar，流速：100mL/min。Step 6: Compound 62f was chiral split to obtain compound 62 and compound 63. The splitting method was: instrument-Waters 150Prep-SFC, column model: Chiralcel AD Column, mobile phase A: carbon dioxide, mobile phase B: 0.1% ammonia in isopropanol, gradient: 70% mobile phase B, pressure: 100 bar, flow rate: 100 mL/min.
实施例64：5-(4-((((R)-1-((R)-2-羟丙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-乙醇邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 64: 5-(4-((((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-ethanolphthalazin-1-yl)benzofuran-4-ol
5-(4-((((R)-1-((R)-2-羟丙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-乙醇邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例62。MS/ESI[M+H]+＝448.2。Preparation of 5-(4-((((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-ethanolphthalazin-1-yl)benzofuran-4-ol Reference Example 62. MS/ESI [M+H] + = 448.2.
实施例65：5-(4-((((R)-1-((S)-2-羟丙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-乙醇邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 65: 5-(4-((((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-ethanolphthalazin-1-yl)benzofuran-4-ol
5-(4-((((R)-1-((S)-2-羟丙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-乙醇邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例62。MS/ESI[M+H]+＝448.2。Preparation of 5-(4-((((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-ethanolphthalazin-1-yl)benzofuran-4-ol Reference Example 62. MS/ESI [M+H] + = 448.2.
实施例66：(R)-5-(4-((1-(2-羟基-2-甲基丙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 66: (R)-5-(4-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
(R)-5-(4-((1-(2-羟基-2-甲基丙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例62。MS/ESI[M+H]+＝463.3。Preparation of (R)-5-(4-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol Reference Example 62. MS/ESI [M+H] + = 463.3.
实施例67：2-(4-(((1R，3S)-3-羟基环己基)氨基)-5,6,7-8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 67: 2-(4-(((1R,3S)-3-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol
2-(4-(((1R，3S)-3-羟基环己基)氨基)-5,6,7-8-四氢-5,8-甲基邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚的制备参考实施例1。MS/ESI[M+H]+＝420.2。MS/ESI[M+H]+＝420.2。1H NMR(400MHz,Chloroform-d)δ7.66(d,J＝8.2Hz,1H),7.33(d,J＝1.8Hz,1H),7.15(dd,J＝8.3,1.8Hz,1H),5.04(s,1H),4.46–4.22(m,1H),4.15–3.94(m,1H),3.94–3.81(m,1H),3.46–3.20(m,1H),2.39–2.15(m,2H),2.15–2.05(m,1H),2.05–1.82(m,3H),1.81–1.72(m,2H),1.67–1.56(m,2H),1.57–1.39(m,4H),1.34–1.21(m,2H)。Preparation of 2-(4-(((1R,3S)-3-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol Reference Example 1. MS/ESI[M+H] + =420.2. MS/ESI[M+H] + =420.2. 1 H NMR (400 MHz, Chloroform-d) δ7.66 (d, J=8.2 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.15 (dd, J=8.3, 1.8 Hz, 1H), 5.04 (s, 1H), 4.46–4.22 (m, 1H), 4.15–3.94 (m, 1H), 3.94–3.81 (m, 1H), 3.46–3.20 (m, 1H), 2.39–2.15 (m, 2H), 2.15–2.05 (m, 1H), 2.05–1.82 (m, 3H), 1.81–1.72 (m, 2H), 1.67–1.56 (m, 2H), 1.57–1.39 (m, 4H), 1.34–1.21 (m, 2H).
实施例68：(R)-2-(4-(哌啶-3-基氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲基)苯酚
Example 68: (R)-2-(4-(piperidin-3-ylamino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethyl)phenol
第一步：向反应瓶中加入18g(460mg,2mmol)，68a(400mg，2mmol),Pd(OAc)2(45mg，0.2mmol)，BINAP(249mg，0.4mmol)，碳酸铯(0.98g，6mmol)和甲苯(10ml)，置换为氮气氛围，110℃反应过夜。过硅藻土垫，加硅胶拌样，减压浓缩至干粉，柱层析得目标化合物68b(412mg)，MS/ESI[M+H]+＝393.2。Step 1: Add 18g (460mg, 2mmol), 68a (400mg, 2mmol), Pd(OAc) 2 (45mg, 0.2mmol), BINAP (249mg, 0.4mmol), cesium carbonate (0.98g, 6mmol) and toluene (10ml) to a reaction bottle, replace with nitrogen atmosphere, react overnight at 110°C. Pass through a celite pad, add silica gel to mix, concentrate under reduced pressure to dry powder, and obtain the target compound 68b (412mg) by column chromatography, MS/ESI [M+H] + = 393.2.
第二步：向反应瓶中加入化合物68b(393mg，1mmol)，[2-羟基-4-(三氟甲基)苯基]硼酸(CAS:1072951-50-8)(309mg，1.5mmol)，Pd(dppf)Cl2(51mg,0.1mmol)，碳酸 铯(694mg，3mmol)，二氧六环(5ml)和脱氧水(0.5ml)，置换为氮气氛围，100℃反应12h。过硅藻土垫，加硅胶拌样，减压浓缩至干粉，柱层析得目标化合物68c(127mg),MS/ESI[M+H]+＝519.3。Step 2: Add compound 68b (393 mg, 1 mmol), [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (CAS: 1072951-50-8) (309 mg, 1.5 mmol), Pd(dppf)Cl 2 (51 mg, 0.1 mmol), and carbonic acid to the reaction flask. Cesium (694 mg, 3 mmol), dioxane (5 ml) and deoxygenated water (0.5 ml) were replaced with nitrogen atmosphere and reacted at 100°C for 12 h. The mixture was passed through a celite pad and mixed with silica gel, and concentrated to dry powder under reduced pressure. The target compound 68c (127 mg) was obtained by column chromatography, MS/ESI [M+H] + = 519.3.
第三步：将化合物68c(127mg)加入HCl的二氧六环溶液(2mL，1M/L)中，室温搅拌1小时。反应完全后加入饱和氯化钠溶液将pH调至弱碱性，二氯甲烷萃取，有机相干燥旋干后柱层析纯化得化合物68(76mg)。MS/ESI[M+H]+＝419.3。1H NMR(400MHz,Chloroform-d)δ7.40–7.35(m,2H),7.15(dd,J＝8.1,1.9,1H),5.24(m,1H),4.37(m,1H),3.53(t,J＝2.6Hz,1H),3.21(dd,J＝11.8,3.1Hz,1H),3.11(d,J＝3.2Hz,1H),2.94–2.78(m,3H),1.98–1.81(m,6H),1.76(m,2H),1.58(m,1H),1.49–1.34(m,4H)。Step 3: Compound 68c (127 mg) was added to a solution of HCl in dioxane (2 mL, 1 M/L) and stirred at room temperature for 1 hour. After the reaction was complete, a saturated sodium chloride solution was added to adjust the pH to a weakly alkaline state, and the mixture was extracted with dichloromethane. The organic phase was dried and purified by column chromatography to obtain compound 68 (76 mg). MS/ESI [M+H] + = 419.3. 1 H NMR (400 MHz, Chloroform-d) δ7.40–7.35 (m, 2H), 7.15 (dd, J=8.1, 1.9, 1H), 5.24 (m, 1H), 4.37 (m, 1H), 3.53 (t, J=2.6 Hz, 1H), 3.21 (dd, J=11.8, 3.1 Hz, 1H), 3.11 (d, J=3.2 Hz, 1H), 2.94–2.78 (m, 3H), 1.98–1.81 (m, 6H), 1.76 (m, 2H), 1.58 (m, 1H), 1.49–1.34 (m, 4H).
实施例69：(R)-2-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲氧基)苯酚
Example 69: (R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethoxy)phenol
(R)-2-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-5-(三氟甲氧基)苯酚的制备参考实施例39。MS/ESI[M+H]+＝479.3。1H NMR(400MHz,CD3OD)δ7.25(d,J＝8.4Hz,1H),6.74(d,J＝7.6Hz,1H),6.72(s,1H),4.30–4.22(m,1H),3.65–3.57(m,2H),3.08–2.95(m,1H),2.84-2.76(m,1H),2.64-2.57(m,1H),2.56-2.41(m,2H),2.37-2.15(m,2H),1.92-1.82(m,1H),1.81–1.64(m,6H),1.63-1.53(m,1H),1.54-1.43(m,1H),1.33–1.14(m,5H)。Preparation of (R)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-5-(trifluoromethoxy)phenol Reference Example 39. MS/ESI [M+H] + = 479.3. 1 H NMR (400 MHz, CD 3 OD) δ7.25 (d, J=8.4 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.30–4.22 (m, 1H), 3.65–3.57 (m, 2H), 3.08–2.95 (m, 1H), 2.84-2.76 (m, 1H), 2.64-2.57 (m, 1H), 2.56-2.41 (m, 2H), 2.37-2.15 (m, 2H), 1.92-1.82 (m, 1H), 1.81–1.64 (m, 6H), 1.63-1.53 (m, 1H), 1.54-1.43 (m, 1H), 1.33–1.14 (m, 5H).
实施例70：(R)-5-(二氟甲氧基)-2-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯酚
Example 70: (R)-5-(difluoromethoxy)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)phenol
(R)-5-(二氟甲氧基)-2-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯酚的制备参考实施例39。MS/ESI[M+H]+＝461.2。Preparation of (R)-5-(difluoromethoxy)-2-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)phenol Reference Example 39. MS/ESI [M+H] + = 461.2.
实施例71：(R)-5-(4-((1-(3,3-二氟环丁基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-2,3-二氢苯并呋喃-4-醇
Example 71: (R)-5-(4-((1-(3,3-difluorocyclobutyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-2,3-dihydrobenzofuran-4-ol
第一步：在-40℃下，向化合物71a(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71b(黄色固体470mg)。LC-MS:212.8[M-H]-。The first step: at -40 ° C, to a solution of compound 71a (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 obtain compound 71b (yellow solid 470 mg). LC-MS: 212.8 [MH] - .
第二步：室温下，向化合物71b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71c(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 71b (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 was used to purify compound 71c (yellow oily liquid, 301 mg). 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 (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71c(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71d(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: Compound 71c (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), and 1,4-dioxane (8 mL) were added to a dry flask. Under nitrogen protection, the mixture was refluxed at 100°C overnight. After the reaction was complete, 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 excess solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography to obtain the target compound 71d (103 mg of colorless oily liquid). 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 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).
第四步：干燥反应瓶中加入化合物29f(82mg,0.21mmol)和化合物71d(98mg,0.25mmol),Cs2CO3(136.9mg,0.42mmol),Pd(dppf)Cl2(15.4mg,0.02mmol),抽换氮气三次，氮气保护下加入dioxane/H2O(3mL/0.5mL),105℃反应过夜。反应完全后，反应液恢复至 室温，加入水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩多余溶剂，柱层析分离得化合物71f(黄色固体，46mg).LC-MS:613.6[M+H]+。Step 4: Add compound 29f (82 mg, 0.21 mmol) and compound 71d (98 mg, 0.25 mmol), Cs 2 CO 3 (136.9 mg, 0.42 mmol), Pd(dppf)Cl 2 (15.4 mg, 0.02 mmol) into a dry reaction flask, replace nitrogen three times, add dioxane/H 2 O (3 mL/0.5 mL) under nitrogen protection, and react at 105°C overnight. After the reaction is complete, the reaction solution is restored to At room temperature, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the excess solvent was concentrated under reduced pressure. Compound 71f (yellow solid, 46 mg) was separated by column chromatography. LC-MS: 613.6 [M+H] + .
第五步：干燥反应瓶中加入化合物71f(46mg,0.08mmol),DCM(0.5mL),HCl in dioxane(4M)(1mL),室温反应3h,减压除去多余溶剂，柱层析分离得化合物71(黄色固体，12mg)。LC-MS:483.6[M+H]+。1H NMR(400MHz,MeOD)δ7.03(d,J＝8.1Hz,1H),6.39(d,J＝8.2Hz,1H),4.68-4.53(m,3H),4.44(s,1H),3.84-3.79(m,2H),3.73(dd,J＝11.7,5.1Hz,1H),3.39-3.35(m,1H),3.25–3.15(m,4H),3.01(s,2H),2.24–2.14(m,1H),2.02(dd,J＝17.9,12.4Hz,3H),1.90-1.77(m,,6H),1.41–1.34(m,6H)。Step 5: Add compound 71f (46 mg, 0.08 mmol), DCM (0.5 mL), and HCl in dioxane (4 M) (1 mL) to a dry reaction bottle, react at room temperature for 3 h, remove excess solvent under reduced pressure, and separate by column chromatography to obtain compound 71 (yellow solid, 12 mg). LC-MS: 483.6 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.03 (d, J = 8.1 Hz, 1H), 6.39 (d, J = 8.2 Hz, 1H), 4.68-4.53 (m, 3H), 4.44 (s, 1H), 3.84-3.79 (m, 2H), 3.73 (dd, J = 11.7, 5.1 Hz, 1H), 3.39-3.35 (m, 1H), 3.25-3.15 (m, 4H), 3.01 (s, 2H), 2.24-2.14 (m, 1H), 2.02 (dd, J = 17.9, 12.4 Hz, 3H), 1.90-1.77 (m,, 6H), 1.41-1.34 (m, 6H).
实施例72：(R)-5-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-2,3-二氢苯并呋喃-4-醇
Example 72: (R)-5-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-2,3-dihydrobenzofuran-4-ol
第一步：干燥反应瓶中加入化合物18h(132mg,0.45mmol)和化合物71d(211.7mg,0.54mmol),Cs2CO3(440mg,1.35mmol),Pd(dppf)Cl2(36.6mg,0.05mmol),抽换氮气三次，氮气保护下加入dioxane/H2O(4mL/0.5mL),105℃反应过夜。反应完全后，反应液恢复至室温，加入水，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩多余溶剂，柱层析分离得化合物72a(黄色固体，79mg).LC-MS:523.6[M+H]+。Step 1: Add compound 18h (132 mg, 0.45 mmol) and compound 71d (211.7 mg, 0.54 mmol), Cs 2 CO 3 (440 mg, 1.35 mmol), Pd(dppf)Cl 2 (36.6 mg, 0.05 mmol) to a dry reaction flask, replace nitrogen three times, add dioxane/H 2 O (4 mL/0.5 mL) under nitrogen protection, and react at 105°C overnight. After the reaction is complete, the reaction solution is returned to room temperature, water is added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the excess solvent is concentrated under reduced pressure. Compound 72a (yellow solid, 79 mg) is separated by column chromatography. LC-MS: 523.6 [M+H] + .
第二步：干燥反应瓶中加入化合物72a(79mg,0.15mmol),DCM(1mL),HCl in dioxane(4M)(1mL),室温反应3h,减压除去多余溶剂，柱层析分离得化合物72(黄色固体，10.2mg)。LC-MS:393.3[M+H]+。1H NMR(400MHz,MeOD)δ7.43(d,J＝8.4Hz,1H),6.39(d,J＝8.4Hz,1H),4.67–4.53(m,3H),4.32–4.21(m,1H),3.85(d,J＝8.2Hz,1H),3.61(d,J＝14.4Hz,1H),3.25–3.15(m,2H),3.09(d,J＝9.3Hz,1H),2.71(s,1H),2.37(s,3H),2.21(s,1H),2.22–2.00(m,3H),1.90-1.79(m,1H),1.78–1.65(m,2H),1.59(d,J＝8.8Hz,1H),1.53(s,1H),1.40–1.23(m,4H)。Step 2: Add compound 72a (79 mg, 0.15 mmol), DCM (1 mL), HCl in dioxane (4 M) (1 mL) to a dry reaction bottle, react at room temperature for 3 h, remove excess solvent under reduced pressure, and separate compound 72 (yellow solid, 10.2 mg) by column chromatography. LC-MS: 393.3 [M+H] + . 1 H NMR (400 MHz, MeOD) δ7.43 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 4.67–4.53 (m, 3H), 4.32–4.21 (m, 1H), 3.85 (d, J = 8.2 Hz, 1H), 3.61 (d, J = 14.4 Hz, 1H), 3.25–3.15 (m, 2H), 3. 09(d, J＝9.3Hz,1H),2.71(s,1H),2.37(s,3H),2.21(s,1H),2.22–2.00(m,3H),1.90-1.79(m,1H),1.78–1.65(m,2H),1.59(d, J＝8.8Hz,1H),1.53(s,1H),1.40–1.23(m,4H).
实施例73：(R)-5-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-2,3-二氢苯并呋喃-4-醇
Example 73: (R)-5-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-2,3-dihydrobenzofuran-4-ol
(R)-5-(4-((1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-2,3-二氢苯并呋喃-4-醇的制备参考实施例71。MS/ESI[M+H]+＝437.2。Preparation of (R)-5-(4-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-2,3-dihydrobenzofuran-4-ol Reference Example 71. MS/ESI [M+H] + = 437.2.
实施例74：5-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-2,3-二氢苯并呋喃-4-醇
Example 74: 5-(4-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-2,3-dihydrobenzofuran-4-ol
5-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-2,3-二氢苯并呋喃-4-醇的制备参考实施例71。MS/ESI[M+H]+＝408.2。Preparation of 5-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-2,3-dihydrobenzofuran-4-ol Reference Example 71. MS/ESI [M+H] + = 408.2.
实施例75：(R)-5-(4-((1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 75: (R)-5-(4-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
5-(4-(((1R，2R)-2-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)-2,3-二氢苯并呋喃-4-醇的制备参考实施例38。MS/ESI[M+H]+＝405.2。Preparation of 5-(4-(((1R,2R)-2-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)-2,3-dihydrobenzofuran-4-ol Reference Example 38. MS/ESI [M+H] + = 405.2.
实施例76：5-(4-(((1R，3S)-3-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 76: 5-(4-(((1R,3S)-3-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
5-(4-(((1R，3S)-3-羟基环己基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例38。MS/ESI[M+H]+＝406.2。1H NMR(400MHz,MeOD)δ7.72(d,J＝2.2Hz,1H),7.25(d,J＝8.5Hz,1H),7.16(d,J＝8.5Hz,1H),7.03(d,J＝2.1Hz,1H),4.62(s,1H),4.19–4.09(m,1H),3.82–3.70(m,1H),3.38(d,J＝2.7Hz,1H),3.12– 3.05(m,1H),2.37(d,J＝12.3Hz,1H),2.05(d,J＝4.7Hz,1H),2.00–1.77(m,6H),1.44–1.31(m,8H)。Preparation of 5-(4-(((1R,3S)-3-hydroxycyclohexyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol Reference Example 38. MS/ESI[M+H] + =406.2. 1 H NMR (400 MHz, MeOD) δ7.72 (d, J=2.2 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.03 (d, J=2.1 Hz, 1H), 4.62 (s, 1H), 4.19-4.09 (m, 1H), 3.82-3.70 (m, 1H), 3.38 (d, J=2.7 Hz, 1H), 3.12- 3.05 (m, 1H), 2.37 (d, J = 12.3 Hz, 1H), 2.05 (d, J = 4.7 Hz, 1H), 2.00–1.77 (m, 6H), 1.44–1.31 (m, 8H).
实施例77：(R)-5-(4-((1-乙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 77: (R)-5-(4-((1-ethylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
(R)-5-(4-((1-乙基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例38。MS/ESI[M+H]+＝419.2。1H NMR(400MHz,Chloroform-d)δ8.56(s,1H),7.56(d,J＝2.2Hz,1H),7.23(d,J＝8.5Hz,1H),7.10(d,J＝8.6Hz,1H),7.04(d,J＝2.1Hz,1H),6.78(br,1H),4.87(s,2H),3.69–3.42(m,4H),3.01(m,2H),2.96–2.85(m,1H),2.61(t,J＝11.5Hz,1H),2.38(m,1H),2.23(m,1H),1.96–1.64(m,6H),1.44(d,J＝8.4Hz,2H),1.34(m,4H)。Preparation of (R)-5-(4-((1-ethylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol Reference Example 38. MS/ESI [M+H] + = 419.2. 1 H NMR (400 MHz, Chloroform-d) δ8.56 (s, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.78 (br, 1H), 4.87 (s, 2H), 3.69–3.42 (m, 4H), 3.01 (m, 2H), 2.96–2.85 (m, 1H), 2.61 (t, J = 11.5 Hz, 1H), 2.38 (m, 1H), 2.23 (m, 1H), 1.96–1.64 (m, 6H), 1.44 (d, J = 8.4 Hz, 2H), 1.34 (m, 4H).
实施例78：2-(4-(((R)-1-(2-羟乙基)哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)-3-甲基-5-(三氟甲基)苯酚
Example 78: 2-(4-(((R)-1-(2-hydroxyethyl)piperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)-3-methyl-5-(trifluoromethyl)phenol
第一步：称取78a(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78b(14.1g,80.0mmol，淡黄色液体，产率88％),MS/ESI[M+H]+＝175.0。Step 1: Weigh 78a (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). 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 for color development) to obtain the target compound 78b (14.1 g, 80.0 mmol, light yellow liquid, yield 88%), MS/ESI[M+H] + ＝175.0.
第二步：将化合物78b(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78c(20.7g,68.5 mmol，淡黄色固体，产率86％)，MS:[M-H]-＝301。Step 2: Compound 78b (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 the addition, the mixture was stirred at 0°C for 1 h. I2 (20.2 g, 79.5 mmol) was then added in batches to the above suspension. After the 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 78c (20.7 g, 68.5 mmol, light yellow solid, yield 86%), MS: [MH] − ＝301.
第三步：将化合物78c(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78d(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 78c (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 overnight at 25° C. 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 78d (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78d(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78e(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 78d (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 mixture 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 for color development) to obtain the target compound 78e (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).
第五步：反应瓶中加入化合物39g(451mg，1mmol)，化合物78e(520mg，1.5mmol)，Pd(dppf)Cl2(73.2mg，0.1mmol)，碳酸铯(978mg，3mmol)，二氧六环(10ml)，脱氧水(2ml)。将体系置换为氮气氛围，100℃反应过夜。反应液过硅藻土垫，滤液减压浓缩，加硅胶拌样，柱层析即得目标产物78f(90mg)，MS/ESI[M+H]+＝635.3。Step 5: Add compound 39g (451 mg, 1 mmol), compound 78e (520 mg, 1.5 mmol), Pd(dppf)Cl 2 (73.2 mg, 0.1 mmol), cesium carbonate (978 mg, 3 mmol), dioxane (10 ml), and deoxygenated water (2 ml) into the reaction flask. Replace the system with nitrogen atmosphere and react at 100°C overnight. Pass the reaction solution through a celite pad, concentrate the filtrate under reduced pressure, add silica gel to mix the sample, and obtain the target product 78f (90 mg) by column chromatography, MS/ESI [M+H] + = 635.3.
第六步：向反应瓶中加入化合物78f(90mg，0.14mmol)，TBAF(73mg，0.28mmol)，THF(3ml)，室温反应2h。待反应完成，加硅胶拌样，柱层析即得目标产物78g(61mg),MS/ESI[M+H]+＝521.5。Step 6: Add compound 78f (90 mg, 0.14 mmol), TBAF (73 mg, 0.28 mmol), and THF (3 ml) to the reaction bottle and react at room temperature for 2 h. After the reaction is complete, add silica gel to mix the sample and column chromatography to obtain the target product 78 g (61 mg), MS/ESI [M+H] + = 521.5.
第七步：反应瓶中加入化合物78g(61mg，0.12mmol)，DCM(2ml)，降温至-5℃，滴加1M BBr3(0.2ml，2mmol)，-5℃反应2h，滴加甲醇淬灭反应。加硅胶拌样，柱层析即得目标产物78(31mg),MS/ESI[M+H]+＝477.0.1H NMR(400MHz,Chloroform-d)δ7.03(d,J＝7.3Hz,1H),6.99(d,J＝5.7Hz,1H),4.94(s,1H),4.44(s,1H),3.77–3.52(m,3H),3.07–2.94(m,1H),2.94–2.80(m,1H),2.74–2.34(m,7H),2.10(s,3H),1.92–1.49(m,8H),1.49–1.18(m,4H)。Step 7: Compound 78g (61 mg, 0.12 mmol) and DCM (2 ml) were added to the reaction bottle, cooled to -5°C, 1M BBr 3 (0.2 ml, 2 mmol) was added dropwise, reacted at -5°C for 2 h, and methanol was added dropwise to quench the reaction. Silica gel was added to the sample and the target product 78 (31 mg) was obtained by column chromatography, MS/ESI [M+H] + = 477.0. 1H NMR (400 MHz, Chloroform-d) δ7.03 (d, J = 7.3 Hz, 1H), 6.99 (d, J = 5.7 Hz, 1H), 4.94 (s, 1H), 4.44 (s, 1H), 3.77–3.52 (m, 3H), 3.07–2.94 (m, 1H), 2.94–2.80 (m, 1H), 2.74–2.34 (m, 7H), 2.10 (s, 3H), 1.92–1.49 (m, 8H), 1.49–1.18 (m, 4H).
实施例79：(R)-5-(4-((1-(乙基-d5)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 79: (R)-5-(4-((1-(ethyl-d5)piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
第一步：将化合物29c(10.0g,49.9mmol)和K2CO3(13.8g,99.8mmol)加入到MeCN(100mL)中，然后加入氘代溴乙烷(6.83g,59.9mmol),室温搅拌过夜。反应完全后过滤，滤液旋干，滤饼用EtOAc(100mL)溶解，用水(30mL×3)洗涤，收集有机相，用无水Na2SO4干燥，过滤，滤液浓缩至干得到目标化合物79a(10.1g，43.3mmol，浅棕色固体，收率87％)。1H NMR(400MHz,CDCl3)δ4.99(s,1H),3.73(s,1H),2.54–2.21(m,4H),1.74–1.52(m,4H),1.45(s,9H)。Step 1: Compound 29c (10.0 g, 49.9 mmol) and K 2 CO 3 (13.8 g, 99.8 mmol) were added to MeCN (100 mL), and then deuterated bromoethane (6.83 g, 59.9 mmol) was added and stirred at room temperature overnight. After the reaction was complete, the mixture was filtered and the filtrate was dried by rotary evaporation. The filter cake was dissolved in EtOAc (100 mL), washed with water (30 mL×3), and the organic phase was collected and dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated to dryness to obtain the target compound 79a (10.1 g, 43.3 mmol, light brown solid, yield 87%). 1 H NMR (400 MHz, CDCl 3 ) δ4.99 (s, 1H), 3.73 (s, 1H), 2.54–2.21 (m, 4H), 1.74–1.52 (m, 4H), 1.45 (s, 9H).
第二步：将化合物79a(10.1g,43.3mmol)溶入到二氧六环(50mL)中，然后慢慢加入HCl/二氧六环(65mL,4.0M)，室温搅拌1h。然后减压浓缩旋干得到目标化合物79b(9.20g,44.6mmol，白色固体，收率100％)。Step 2: Compound 79a (10.1 g, 43.3 mmol) was dissolved in dioxane (50 mL), and then HCl/dioxane (65 mL, 4.0 M) was slowly added, and stirred at room temperature for 1 h. Then, the mixture was concentrated under reduced pressure and dried to obtain the target compound 79b (9.20 g, 44.6 mmol, white solid, yield 100%).
(R)-5-(4-((1-(乙基-d5)哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例38。MS/ESI[M+H]+＝424.2。1H NMR(400MHz,MeOD)δ8.39(s,1H),7.61(d,J＝2.0Hz,1H),7.08(q,J＝8.4Hz,2H),6.93(d,J＝1.6Hz,1H),4.42(td,J＝10.1,5.0Hz,1H),3.76(s,1H),3.26(s,1H),2.90–2.59(m,3H),2.12–1.95(m,2H),1.76(ddd,J＝39.6,16.8,5.3Hz,6H),1.27(t,J＝12.2Hz,5H)。Preparation of (R)-5-(4-((1-(ethyl-d 5 )piperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol Reference Example 38. MS/ESI [M+H] + = 424.2. 1 H NMR (400 MHz, MeOD) δ 8.39 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.08 (q, J = 8.4 Hz, 2H), 6.93 (d, J = 1.6 Hz, 1H), 4.42 (td, J = 10.1, 5.0 Hz, 1H), 3.76 (s, 1H), 3.26 (s, 1H), 2.90–2.59 (m, 3H), 2.12–1.95 (m, 2H), 1.76 (ddd, J = 39.6, 16.8, 5.3 Hz, 6H), 1.27 (t, J = 12.2 Hz, 5H).
实施例80：(R)-5-(4-(((4-甲基吗啉-2-基)甲基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 80: (R)-5-(4-(((4-methylmorpholin-2-yl)methyl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
第一步：反应瓶中加入化合物18g(1.33g，5.8mmol)，化合物80a(1.14g，5.3mmol)，Pd(OAc)2(119mg，0.53mmol)，BINAP(660mg，1.06mmol)，Cs2CO3(5.2g，15.9mmol)和甲苯(25ml)。置换氮气，110℃反应过夜。过滤，加硅胶拌样，柱层析即得目标化合物80b(560mg)，MS/ESI[M+H]+＝409.2。Step 1: Add compound 18g (1.33g, 5.8mmol), compound 80a (1.14g, 5.3mmol), Pd(OAc) 2 (119mg, 0.53mmol), BINAP (660mg, 1.06mmol), Cs 2 CO 3 (5.2g, 15.9mmol) and toluene (25ml) into a reaction flask. Replace nitrogen and react at 110°C overnight. Filter, add silica gel to mix, and perform column chromatography to obtain the target compound 80b (560mg), MS/ESI [M+H] + = 409.2.
第二步：反应瓶中加入化合物80b(367mg，0.9mmol)，化合物38e(500mg，1.8mmol)， Pd(PPh3)4(104mg，0.09mmol)，Na2CO3(286mg，2.7mmol)，二氧六环(10ml)，脱氧水(2ml)。将体系置换为氮气氛围，100℃反应过夜。反应液过硅藻土垫，滤液减压浓缩，加硅胶拌样，柱层析即得目标产物80c(500mg)，MS/ESI[M+H]+＝521.3。Step 2: Compound 80b (367 mg, 0.9 mmol) and compound 38e (500 mg, 1.8 mmol) were added to the reaction flask. Pd(PPh 3 ) 4 (104 mg, 0.09 mmol), Na 2 CO 3 (286 mg, 2.7 mmol), dioxane (10 ml), deoxygenated water (2 ml). The system was replaced with nitrogen atmosphere and reacted at 100°C overnight. The reaction solution was passed through a celite pad, the filtrate was concentrated under reduced pressure, and silica gel was added to stir the sample. The target product 80c (500 mg) was obtained by column chromatography, MS/ESI [M+H] + = 521.3.
第三步：化合物80c(726mg，1.4mmol)溶于无水DCM(5ml)中，加入盐酸二氧六环(4M，10ml)，室温反应2h。LCMS监测反应完全，旋干溶剂，DCM溶解，用饱和碳酸钾水溶液调节溶液至碱性。水相用DCM萃取三次，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液旋干，柱层析即得目标化合物80d(314mg)，MS/ESI[M+H]+＝421.2。Step 3: Compound 80c (726 mg, 1.4 mmol) was dissolved in anhydrous DCM (5 ml), and dioxane hydrochloride (4 M, 10 ml) was added, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by LCMS, the solvent was dried, dissolved in DCM, and the solution was adjusted to alkalinity with saturated aqueous potassium carbonate solution. The aqueous phase was extracted three times with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying. The target compound 80d (314 mg) was obtained by column chromatography, MS/ESI [M+H] + = 421.2.
第四步：化合物80d(126mg，0.3mmol)，多聚甲醛(10.8mg，0.36mmol)，催化量的乙酸溶解于甲醇(3ml)中，室温搅拌0.5h。后加入NaBH3CN(56.7mg，0.9mmol)，室温反应过夜。加入饱和碳酸氢钠淬灭反应，水相用DCM萃取三次，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液旋干，柱层析即得目标化合物80e(122mg)，MS/ESI[M+H]+＝435.2。Step 4: Compound 80d (126 mg, 0.3 mmol), paraformaldehyde (10.8 mg, 0.36 mmol), and a catalytic amount of acetic acid were dissolved in methanol (3 ml) and stirred at room temperature for 0.5 h. NaBH 3 CN (56.7 mg, 0.9 mmol) was then added and reacted overnight at room temperature. Saturated sodium bicarbonate was added to quench the reaction, and the aqueous phase was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The target compound 80e (122 mg) was obtained by column chromatography, MS/ESI [M+H] + = 435.2.
第五步：反应瓶中加入化合物80e(122mg，0.28mmol)，DCM(2ml)，降温至-5℃，滴加1M BBr3(0.2ml，2mmol)，-5℃反应2h，滴加甲醇淬灭反应。加硅胶拌样，柱层析即得目标产物80(39mg)，MS/ESI[M+H]+＝421.2，1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝2.2Hz,1H),7.22(d,J＝8.6Hz,1H),7.09(d,J＝8.5Hz,1H),7.04(d,J＝2.2Hz,1H),4.91(m,1H),4.02–3.82(m,3H),3.75(td,J＝11.4,2.4Hz,1H),3.64(t,J＝2.6Hz,1H),3.56–3.42(m,1H),3.07(t,J＝2.5Hz,1H),2.84(d,J＝11.3Hz,1H),2.70(d,J＝11.5Hz,1H),2.32(s,3H),2.17(td,J＝11.5,3.4Hz,1H),1.99(d,J＝11.4Hz,1H),1.95–1.77(m,4H),1.51–1.34(m,4H)。Step 5: Compound 80e (122 mg, 0.28 mmol) and DCM (2 ml) were added to the reaction flask, cooled to -5°C, 1M BBr 3 (0.2 ml, 2 mmol) was added dropwise, reacted at -5°C for 2 h, and methanol was added dropwise to quench the reaction. Silica gel was added to mix the sample, and the target product 80 (39 mg) was obtained by column chromatography, MS/ESI [M+H] + = 421.2, 1 H NMR (400 MHz, Chloroform-d) δ7.55 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 4.91 (m, 1H), 4.02–3.82 (m, 3H), 3.75 (td, J = 11.4, 2.4 Hz, 1H), 3.64 (t, J = 2.6 Hz ,1H),3.56–3.42(m,1H),3.07(t,J＝2.5Hz,1H),2.84(d,J＝11.3Hz,1H),2.70(d,J＝11.5Hz,1H),2.32(s,3H),2.17(td,J＝11.5,3.4Hz,1H),1.99(d,J＝11.4Hz,1H),1.95–1.77(m,4H),1.51–1.34(m,4H).
实施例81：(R)-5-(4-(((5,5-二氟-1-甲基哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 81: (R)-5-(4-(((5,5-difluoro-1-methylpiperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
(R)-5-(4-(((5,5-二氟-1-甲基哌啶-3-基)氨基)-5,6,7-8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例80。MS/ESI[M+H]+＝441.4，1H NMR(400MHz,Chloroform-d)δ7.56(d,J＝2.2Hz,1H),7.23(d,J＝8.5Hz,1H),7.09(dd,J＝8.6,0.9Hz, 1H),7.04(dd,J＝2.2,0.9Hz,1H),5.30(d,J＝9.6Hz,1H),4.86–4.68(m,1H),3.69–3.57(m,1H),3.13–3.02(m,2H),2.98(d,J＝11.8Hz,1H),2.62–2.49(m,1H),2.45–2.39(m,4H),2.39–2.25(m,1H),2.04–1.75(m,5H),1.53–1.33(m,3H)。Preparation of (R)-5-(4-(((5,5-difluoro-1-methylpiperidin-3-yl)amino)-5,6,7-8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol Reference Example 80. MS/ESI [M+H] + = 441.4, 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.09 (dd, J = 8.6, 0.9 Hz, 1H), 7.04 (dd, J = 2.2, 0.9 Hz, 1H), 5.30 (d, J = 9.6 Hz, 1H), 4.86–4.68 (m, 1H), 3.69–3.57 (m, 1H), 3.13–3.02 (m, 2H), 2.98 (d, J = 11.8 Hz, 1H), 2.62–2.49 (m, 1H), 2.45–2.39 (m, 4H), 2.39–2.25 (m, 1H), 2.04–1.75 (m, 5H), 1.53–1.33 (m, 3H).
实施例82：5-(4-(((3R，5R)-5-氟-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇
Example 82: 5-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol
5-(4-(((3R，5R)-5-氟-1-甲基哌啶-3-基)氨基)-5,6,7,8-四氢-5,8-邻苯二甲嗪-1-基)苯并呋喃-4-醇的制备参考实施例80。MS/ESI[M+H]+＝423.5，1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝2.2Hz,1H),7.22(d,J＝8.6Hz,1H),7.09(dd,J＝8.6,0.9Hz,1H),7.04(dd,J＝2.2,0.9Hz,1H),4.93(d,J＝44.6Hz,1H),4.81–4.62(m,1H),3.64(t,J＝2.8Hz,1H),3.05(m,2H),2.70(m,1H),2.63–2.46(m,2H),2.40(s,3H),2.25(m,1H),1.96–1.68(m,5H),1.52–1.34(m,4H)。Preparation of 5-(4-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydro-5,8-phthalazin-1-yl)benzofuran-4-ol Reference Example 80. MS/ESI[M+H] + ＝423.5， 1 H NMR (400 MHz, Chloroform-d) δ7.55 (d, J＝2.2 Hz, 1H), 7.22 (d, J＝8.6 Hz, 1H), 7.09 (dd, J＝8.6, 0.9 Hz, 1H), 7.04 (dd, J＝2.2, 0.9 Hz, 1H), 4.93 (d, J＝44.6 Hz, 1H), 4.81–4.62 (m, 1H), 3.64 (t, J＝2.8 Hz, 1H), 3.05 (m, 2H), 2.70 (m, 1H), 2.63–2.46 (m, 2H), 2.40 (s, 3H), 2.25 (m, 1H), 1.96–1.68 (m, 5H), 1.52–1.34 (m, 4H).
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 Pronosai Life Science Technology Co., Ltd., PMA: Sigma-Aldrich, RPMI medium: Hyclone, LPS: Sigma-Aldrich, Opti-MEM medium: Gibco, Nigericin: Invivogen, Human IL-1β ELISA detection 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，Ref-1参照专利WO2021193897中实施例63合成方法合成获得。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 with RPMI medium containing PMA (10μM) and placed in a 37°C, 5% CO 2 incubator for induction overnight. The next day, the culture medium was replaced with Opti-MEM medium containing 1μg/mL LPS; after 3h, the drug was added for 40min; Nigericin (10μM) was added for 40min; the cell supernatant was collected for ELISA analysis. Compound MCC950 was purchased from MCE, and Ref-1 was synthesized according to the synthesis method of Example 63 in patent WO2021193897. The experimental results are shown in Table 2 below.
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，尤其是化合物38和39等对NLRP3炎症体抑制作用优于参照化合物MCC950和Ref-1。Conclusion: The compounds of the present invention have good inhibitory activity on NLRP3 inflammasome, especially compounds 38 and 39 have better inhibitory effects on NLRP3 inflammasome than reference compounds MCC950 and Ref-1.
2、化合物对hERG钾离子通道的抑制实验 2. 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 aspirated, and the cells were washed once with PBS and then digested with Detachin. After complete digestion, the cells were neutralized by adding culture medium, then centrifuged, the supernatant was aspirated, and the cells were resuspended in 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20μL DMSO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 10μL of the compound stock solution and add it to 20μL DMSO, and dilute it 3 times continuously to 6 concentrations. Take 4μL of the 6 concentrations of the compound respectively and add it to 396μL of extracellular fluid, that is, dilute it 100 times to get 6 intermediate concentrations. Then take 80μL of the 6 intermediate concentration compounds respectively and add them to 320μL of extracellular fluid, that is, dilute it 5 times to the final concentration to be tested. The highest test concentration is 40μM, and there are 6 concentrations of 40, 13.33, 4.44, 1.48, 0.49 and 0.16μM 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, 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. After all concentrations are given continuously, the positive control compound 3μM Cisapride is given. At least 3 cells (n≥3) are 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3。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 3.
表3 化合物对hERG钾离子通道抑制结果

Table 3 Inhibition results of compounds on hERG potassium ion channel

结论：本发明化合物29、33、35、38、39和76等对hERG钾离子通道抑制作用较弱，特别是化合物29、33、35和39对hERG钾离子通道抑制弱于参照化合物Ref-1。3、化合物在Balb/c小鼠体内的药代动力学评价Conclusion: Compounds 29, 33, 35, 38, 39 and 76 of the present invention have weak inhibitory effects on hERG potassium ion channels, especially compounds 29, 33, 35 and 39 have weaker inhibitory effects on hERG potassium ion channels than reference compound Ref-1. 3. Pharmacokinetic evaluation of compounds 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4。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 4.
表4 化合物在Balb/c小鼠体内的药代动力学测试结果
Table 4 Pharmacokinetic test results of the compounds in Balb/c mice
结论：本发明化合物在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: The compounds of the present invention have good pharmacokinetic properties in Balb/c mice, including good oral Oral bioavailability, exposure, half-life and clearance, etc.
4、LPS诱导脓毒症小鼠模型评价4. Evaluation of LPS-induced sepsis mouse model
实验方法：7-8周Balb/c小鼠口服25mg/kg或50mg/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。实验结果如表5所示。Experimental method: 7-8 weeks old Balb/c mice were orally administered 25mg/kg or 50mg/kg of the compound or a solvent control (sterile 0.9% NaCl solution), and 1 hour later, 10mg/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. The experimental results are shown in Table 5.
表5 化合物对LPS诱导脓毒症小鼠的存活率
Table 5 Effect of compounds on the survival rate of mice with LPS-induced sepsis
结论：本发明化合物对LPS诱导脓毒症小鼠具有较好的体内疗效，能够增加LPS诱导脓毒症小鼠的存活率，尤其是同等剂量下化合物39对LPS诱导脓毒症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 septic mice and can increase the survival rate of LPS-induced septic mice. In particular, at the same dose, the survival rate of compound 39 on LPS-induced septic mice is better than that of the reference compound MCC950.
5、化合物体内脑血比评价5. 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，再入加注射用氯化钠溶液，配成1mg·mL-1的化合物溶液，待给药用。24只小鼠，雄鼠，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 make a 1mg·mL -1 compound solution for administration. 24 male mice were orally administered at 10mg·kg -1 . Whole blood and whole brain were collected at 1h and 6h after administration (n=3). Whole blood was centrifuged at 3500rpm for 15min, and the supernatant plasma was collected. The weight of the centrifuge tube was weighed as M1, the weight of the centrifuge tube containing the whole brain was weighed as M2, the weight of the centrifuge tube after adding water homogenate was weighed as M3, and the weight of the centrifuge tube after taking out 30μL of homogenate was weighed as M4. Take 30μL of plasma and 30μL of brain homogenate in a centrifuge tube, add 120μL of acetonitrile precipitate containing 20ng·ml -1 internal standard SAHA, 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6所示。 The results of the compound brain-to-blood ratios are shown in Table 6 below.
表6 化合物给药后小鼠脑血比测试结果
Table 6 Results of brain-to-blood ratio test in mice after compound administration
结论：本发明化合物29和38在1h的脑暴露量显著高于参考化合物Ref-1，脑血比优于参考化合物Ref-1，因此化合物29和38具有脑渗透的潜力。Conclusion: The brain exposure of compounds 29 and 38 of the present invention at 1 h was significantly higher than that of the reference compound Ref-1, and the brain-to-blood ratio was better than that of the reference compound Ref-1. Therefore, compounds 29 and 38 have the potential for brain penetration.
6、化合物对人PBMC细胞IL-1β产生抑制活性测定6. 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7。The experimental results are shown in Table 7 below.
表7 化合物对PBMC细胞IL-1β抑制结果
Table 7 Inhibition results of compounds on IL-1β in PBMC cells
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39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 39 has an inhibitory activity IC 50 on the production of IL-1β by human PBMC cells that is better than MCC950.

Claims (22)

  1. 式Ⅰ的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 of formula I or a pharmaceutically acceptable form thereof, characterized in that: the structure of formula I is as follows:
    其中：in:
    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元烷基环；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 alkyl ring; ... 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;
    X选自O、-NR7a-、-C(R7bR7c)-、-CH2C(R7bR7c)-或者-C(R7bR7c)CH2-；X is selected from O, -NR 7a -, -C(R 7b R 7c )-, -CH 2 C(R 7b R 7c )- or -C(R 7b R 7c )CH 2 -;
    L选自-(CH2)n1-、O、-(CH2)n1-NH-、-NH-(CH2)n1-、-NH-CH(CH2)n1CH3-，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, 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 , and -CN; R 6 , the 5- to 10-membered heteroaromatic The alkyl, 3-8 membered heterocycloalkyl, 6-10 membered heterospirocycloalkyl, 6-10 membered heterobridged cycloalkyl contain 1-3 heteroatoms selected from at least one of N, S, and O;
    R7a选自氢、氘、-COR9a、-CONHR9a、-CON(R9bR9c)、-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、6元芳基、5-6元杂芳基；R7a中，所述取代基选自：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, deuterium, -COR 9a , -CONHR 9a , -CON(R 9b R 9c ), -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, 6 membered aryl, 5-6 membered heteroaryl; in R 7a , the substituent is selected from 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和R7c选自氢、氘、氟、-OH、-NH2、-CN或者C1-4烷基；R 7b and R 7c are selected from hydrogen, deuterium, fluorine, -OH, -NH 2 , -CN or C 1-4 alkyl;
    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(R12aR12b)、-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 12a R 12b ), -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，所述取代基选自选自：氘、卤素、-N(R12aR12b)、-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元烷基杂环含有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 heterocycle substituted by 0-6 substituents, wherein the substituents are selected from: deuterium, halogen, -N(R 12a R 12b ), -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 are connected to form a ring, the 3-6 membered alkyl heterocycle 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;
    R12a和R12b独立地选自氢或C1-4烷基；R 12a and R 12b are independently selected from hydrogen or C 1-4 alkyl;
    R9a、R9b和R9c独立地选自被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、6元芳基、5-6元杂芳基，所述取代基选自：氘、卤素、-OH、-NH2或-CN；R9a、R9b和R9c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 9a , R 9b and R 9c are independently selected from the following groups 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, 6-membered aryl, 5-6-membered heteroaryl, wherein 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 and 5-6-membered heteroaryl contain 1 to 3 heteroatoms selected from at least one of N, S and O;
    或者，R9b与R9c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，所述取代基选自：氘、卤素、-NH2、-OH、-CN、C1-4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；R9b与R9c与它们所连接的原子相连成环时，所述3-6元烷基杂环含有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；Alternatively, R 9b and R 9c and the atoms to which they are attached form a 3-6 membered alkyl heterocyclic ring substituted with 0-6 substituents, wherein the substituents are selected from: deuterium, halogen, -NH 2 , -OH, -CN, C 1-4 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylmethylene or 4-6 membered heterocycloalkylmethylene; when R 9b and R 9c and the atoms to which they are attached form a ring, the 3-6 membered alkyl heterocyclic ring 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 substituents contain 1 to 3 heteroatoms selected from at least one of N, S and O. There are 1 to 3 heteroatoms selected from at least one of N, S, and O;
    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.
  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所述的化合物，其特征在于：The compound according to claim 1, 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、-CH3、氟代甲基、氘代甲基、-SCH3、氟代甲硫基、氘代甲硫基、-OCH3、氟代甲氧基、氘代甲氧基、环丙基、氟代环丙基、F、Cl。More preferably, R 3 is selected from hydrogen, deuterium, -CH 3 , fluoromethyl, deuterated methyl, -SCH 3 , fluoromethylthio, deuterated methylthio, -OCH 3 , fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, F, and Cl.
  4. 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:
    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元环烷烃、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元烷基环；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, form a 5-6 membered cycloalkane, 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, C1-4 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 3-membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4-membered alkyl ring; 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 heterocyclic ring or 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元烷基环；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 alkyl ring;
    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元烷基环。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, -NH 2 , -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 alkyl ring.
  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:
    R10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 10 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，R10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 10 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1～5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:
  8. 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:
    X选自O、-NR7a-、-C(R7bR7c)-、-CH2C(R7bR7c)-或者-C(R7bR7c)CH2-；R7a选自氢、氘或者任选被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、6元芳基、5-6元杂芳基；R7a中，所述取代基选自：氘、氟、-OH、-NH2或-CN；R7a中，所述4-6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；R7b和R7c选自氢、氘、氟、-OH、-NH2、-CN或者C1-4烷基；X is selected from O, -NR 7a -, -C(R 7b R 7c )-, -CH 2 C(R 7b R 7c )- or -C(R 7b R 7c )CH 2 -; R 7a is selected from hydrogen, deuterium or the following groups optionally substituted by 0-3 substituents: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6-membered cycloalkyl, 4-6-membered heterocycloalkyl, 6-membered aryl, 5-6-membered heteroaryl; in R 7a , the substituent is selected from deuterium, fluorine, -OH, -NH 2 or -CN; in R 7a , the 4-6-membered heterocycloalkyl and 5-6-membered heteroaryl contain 1 to 2 heteroatoms selected from at least one of N, S and O; R 7b and R 7c are selected from hydrogen, deuterium, fluorine, -OH, -NH 2 , -CN or C 1-4 alkyl;
    优选的，X选自O、NR7a、CH2、CH2CH2；R7a选自氢、氘、甲基、氟代甲基、氘代甲基。 Preferably, X is selected from O, NR 7a , CH 2 , CH 2 CH 2 ; and R 7a is selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl.
  9. 根据权利要求1所述的化合物，其特征在于：L选自O、-NH-、-NH-CH2-、-NH-CHCH3-。The compound according to claim 1, characterized in that L is selected from O, -NH-, -NH-CH 2 -, and -NH-CHCH 3 -.
  10. 根据权利要求1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 claim 1, 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所述的化合物，其特征在于：R6中，所述取代基选自 The compound according to claim 1, characterized in that: in R 6 , the substituent is selected from
  12. 根据权利要求1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 claim 1, characterized in that: R 6 is selected from the following structures:
    R11a和R11b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 11a and R 11b 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;
    优选的，R11a和R11b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 11a and R 11b 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，R11a和R11b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 11a and R 11b 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,
  13. 根据权利要求12所述的化合物，其特征在于：R11a和R11b独立地选自H、 The compound according to claim 12, characterized in that: R 11a and R 11b are independently selected from H,
  14. 根据权利要求1所述的化合物，其特征在于：R6选自以下结构：

    The compound according to claim 1, characterized in that: R 6 is selected from the following structures:

  15. 根据权利要求1所述的化合物，其特征在于：R6选自以下结构：
    The compound according to claim 1, characterized in that: R 6 is selected from the following structures:
  16. 根据权利要求1所述的化合物，其特征在于：所述化合物选自：

    The compound according to claim 1, characterized in that the compound is selected from:

  17. 根据权利要求1所述的化合物，其特征在于：所述化合物选自：

    The compound according to claim 1, characterized in that the compound is selected from:

  18. 根据权利要求1所述的化合物，其特征在于：所述化合物选自：
    The compound according to claim 1, characterized in that the compound is selected from:
  19. 药物组合物，其特征在于：其是以权利要求1～18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 18 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.
  20. 权利要求1～18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19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。The compound according to any one of claims 1 to 18 or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug, and the pharmaceutical composition according to claim 19, in the preparation of a pharmaceutical composition for preventing and/or treating NLRP3 Use in medicines for related diseases.
  21. 根据权利要求20所述的用途，用于预防和/或治疗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 20, for preventing and/or treating NLRP3-related diseases includes: inflammatory diseases, autoimmune diseases, cardiovascular diseases, cancer, renal diseases, gastrointestinal diseases, respiratory diseases, endocrine system diseases or central nervous system diseases.
  22. 根据权利要求21所述的用途，所述的疾病包括：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。 According to the use according to claim 21, the 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, 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.
PCT/CN2023/133933 2022-11-25 2023-11-24 Bridged ring pyridazine compound and use thereof WO2024109922A1 (en)

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