WO2024251073A1 - 并哒嗪类化合物及其用途 - Google Patents

并哒嗪类化合物及其用途 Download PDF

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WO2024251073A1
WO2024251073A1 PCT/CN2024/097003 CN2024097003W WO2024251073A1 WO 2024251073 A1 WO2024251073 A1 WO 2024251073A1 CN 2024097003 W CN2024097003 W CN 2024097003W WO 2024251073 A1 WO2024251073 A1 WO 2024251073A1
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alkyl
membered
deuterium
substituents
hydrogen
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French (fr)
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陈俐娟
贾涛
王太津
李钢
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Chengdu Zenitar Biomedical Technology Co Ltd
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Chengdu Zenitar Biomedical Technology Co Ltd
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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
    • A61K31/4985—Pyrazines or piperazines 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
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the invention relates to a pyridazine compound and application thereof, belonging to the technical field of chemical 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 NF- ⁇ B nuclear entry, induces the production of precursors such as IL-1 ⁇ and IL-18, and induces post-translational modification of NLRP3.
  • TLR4 Toll-like receptor 4
  • the second signal promotes the formation of the NLRP3/ASC/pro-caspase-1 complex, that is, when activated, it aggregates with apoptosis-associated specklike protein (ASC) containing a caspase activation and recruitment domain. ASC then interacts with cysteine protease caspase-1 to form a complex called inflammasome.
  • ASC apoptosis-associated specklike protein
  • the pro-caspase (pro-caspase-1) is self-cleaved into an activated form. 2
  • the activated caspase-1 cleaves the pro-inflammatory cytokines IL-1 ⁇ and IL-18, converting them into active forms of IL-1 ⁇ and IL-18 and releasing them into the extracellular space, recruiting inflammatory cells to aggregate and amplifying the inflammatory response.
  • ASC speck-like protein can also recruit and activate caspase-8, cleaving the pro-forms of IL- ⁇ and IL-18 to convert them into mature forms and trigger cell pyroptosis.
  • Non-classical NLRP3 inflammasome activation is independent of TLR4 signaling pathway activation. It is initiated by caspase-11 directly recognizing intracellular LPS, initiating NLRP3 inflammasome activation, promoting the activation and release of Gasdermin D, and thus mediating cell death.
  • Abnormal activation of NLRP3 is associated with many diseases, including inflammasome-related diseases, immunological diseases, inflammatory diseases, nervous system diseases, autoimmune diseases and/or autoinflammatory diseases, cancer, chronic metabolic diseases, etc. diseases and neurological related diseases.
  • cryptopyrin-associated periodic syndrome CACS
  • Muckle-Wells syndrome MFS
  • familial cold autoinflammatory syndrome FCAS
  • NOMID neonatal-onset multisystem inflammatory disease
  • FMF familial Mediterranean fever
  • non-alcoholic steatohepatitis alcoholic liver disease
  • graft-versus-host disease multiple sclerosis (MS), rheumatoid arthritis, type I/type II diabetes and related complications (such as nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial
  • the present invention creatively develops a class of pyridazine compounds, which can act as NLRP3 inhibitors with high activity and excellent pharmacokinetic properties, and provides a new approach for treating NLRP3-related diseases.
  • the present invention first provides a compound represented by formula I or a pharmaceutically acceptable form thereof, wherein the structure of formula I is as follows:
  • X and Y are independently selected from C or N, and at most one of X and Y is selected from N;
  • Ring A is the following group optionally substituted by 0-6 R 8 : 5-6 membered alkyl ring (the 5-6 membered alkyl ring must be a double bond), 5- to 6-membered alkyl heterocycle (the 5- to 6-membered alkyl heterocycle According to the above X and Y, it is determined to be a single bond or a double bond), a benzene ring (the must be a double bond), a 5- to 6-membered heteroaromatic ring (the 5- to 6-membered heteroaromatic ring According to the above X and Y, it is determined to be a single bond or a double bond),
  • the connection direction remains unchanged from the general formula, that is, from left to right: X is connected to R 7 on the left, Y is connected to pyridazine N in the middle, and L is connected on the right); in ring A, the 5-6 membered alkyl heterocyclic ring and the 5-6 membered heteroaromatic ring
  • R2 and R3 , R3 and R4 , or R4 and R5 together with the atoms to which they are attached, form a 5- to 6-membered alkane ring, a benzene ring, a 5- to 6-membered alkane heterocycle, a 5- to 6-membered heteroaromatic ring
  • the substituent is selected from the group consisting of deuterium, halogen, -OH, -NH 2 , -CN, oxo, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 deuterated alkyl, -OC 1-6 alkyl, -OC 1-6 fluoroalkyl, -OC 1-6 deuterated alkyl, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-6 membered alkyl ring; when R 2 and R 3 , R 3 and R 4 or R
  • L is selected from -(CH 2 ) n1 -, -CH(CH 3 )(CH 2 ) n1 -, -(CH 2 ) n1 -CH(CH 3 )-, -(CH 2 ) n1 O-, -O(CH 2 ) n1 -, -OCH(CH 3 )(CH 2 ) n1 -, -(CH 2 ) n1 -NH-, -NH-(CH 2 ) n1 -, -NH-CH(CH 3 )(CH 2 ) n1 - or -NHC(CH 3 ) 2 (CH 2 ) n1 -, n1 is an integer selected from 0-3 (the left end is connected to ring A, and the right end is connected to R 6 ) (it can be seen from the embodiments of the present invention that when C in L is connected to ring A, it is connected to N on ring A; when N or O in L is connected to ring
  • R 6 is selected from hydrogen, deuterium, halogen, -CN, -OR 9a , -SR 9a , -NR 9b R 9c , -C( ⁇ O)R 9a , -OC( ⁇ O)R 9a , -C( ⁇ O)OR 9a , -C( ⁇ O)NR 9b R 9c , -NR 9b C( ⁇ O)R 9c , -SO 2 R 9a , -SO 2 NR 9b R 9c , -NR 9b SO 2 R 9c , or 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, C 1-6 alkyl substituted with
  • R 9a , R 9b and R 9c are independently selected from hydrogen, deuterium or the following groups substituted by 0-6 substituents: 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, C 1-6 alkyl; in R 9a , R 9b and R 9c , the substituents are selected from deuterium, halogen, -N(R 10a R 10b ), -C(O)N(R 10a R 10b ), -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 deuterated alkyl, C 1-4- fluoroalkyl, 3-6-membered cycloal
  • R 9b and R 9c and the atoms to which they are connected form a 3- to 6-membered alkyl heterocyclic ring substituted with 0-6 substituents; when R 9b and R 9c and the atoms to which they are connected are connected to form a ring, the substituents are selected from: deuterium, halogen, -N(R 10a R 10b ), -C(O)N(R 10a R 10b ), -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocycloalkyl; when R 9b and R 9c and the atoms to which they are connected are connected to form a ring, the 3- to 6-membered heterocycloalkyl contains 1 to 3 heteroatoms selected from at least one of N, S and O, and the 4- to 6-membered heterocycloalkyl in the substituent contains 1 to 3 heteroatoms selected from at least one
  • R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , and R 10g are independently selected from hydrogen, C 1-4 alkyl, N,N-dimethyl-substituted C 1-4 alkyl, and 3-6-membered cycloalkyl;
  • R 8 is selected from hydrogen, deuterium, halogen, -NH 2 , -OH, -CN, -CONH 2 or the following groups optionally substituted with 0-6 substituents: C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)NH-C 1-6 alkyl, 3-6 membered cycloalkyl, -C(O)-3-6 membered cycloalkyl, -C(O)NH-3-6 membered cycloalkyl; in R 8 , the substituent is selected from: deuterium, halogen, -OH, -NH 2 or -CN;
  • the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotopically labeled substances, metabolites or prodrugs.
  • R 1 is selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-6 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, wherein the substituents are selected from: deuterium, halogen, -OH, -NH 2 or -CN.
  • R 1 is 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 is selected from hydrogen, deuterium, F, Cl, -OH, -CN, -CH 3 , fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.
  • R 2 and R 4 are independently selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-6 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, wherein the substituents are selected from: deuterium, halogen, -OH, -NH 2 or -CN.
  • R 2 and R 4 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 2 and R 4 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 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, 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 1-3 heteroatoms selected from at least one of N, S and O.
  • R 3 is selected from hydrogen, deuterium, F, Cl, Br, -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 1-2 heteroatoms selected from at least one of N, S and O.
  • R3 is selected from hydrogen, deuterium, F, Cl, Br, CN, methyl, fluoromethyl, deuterated methyl, methylthio, fluoromethylthio, deuterated methylthio, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl, vinyl, ethynyl, phenyl, fluorophenyl, deuterated phenyl.
  • R 5 is selected from hydrogen, deuterium, halogen, -OH, -NH 2 , -CN or the following groups optionally substituted with 0-6 substituents: C 1-4 alkyl, -OC 1-4 alkyl, -SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl, wherein the substituents are selected from: deuterium, halogen, -OH, -NH 2 or -CN.
  • R 5 is selected from hydrogen, deuterium, F, Cl, -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 5 is selected from hydrogen, deuterium, F, Cl, -OH, -CN, -CH 3 , fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl, fluorocyclopropyl.
  • R2 and R3 , R3 and R4, or R4 and R5 can form, together with the atoms to which they are connected, a 5-6-membered alkane ring, a benzene ring, a 5-6-membered alkane heterocycle, a 5-6-membered heteroaromatic ring, or
  • the substituent is selected from: deuterium, halogen, -OH, -NH2 , -CN, oxo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 deuterated alkyl, -OC1-4 alkyl, -O-fluoro C1-4 alkyl, -O-deuterated C1-4 alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl; when R2 and R3 , R3 and R4,
  • 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, Br, Cl, -OH, -NH2 , -CN, oxo, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 deuterated alkyl, -OC1-4 alkyl, -O-fluoro C1-4 alkyl, -O-deuterated C1-4 alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.
  • R2 and R3 or R3 and R4 together with the atoms to which they are attached form a group substituted with 0-3 substituents.
  • the substituent is selected from: deuterium, F, Br, Cl, -OH, -NH2 , -CN, oxo, methyl, fluoromethyl, deuterated methyl, methoxy, fluoromethoxy, deuterated methoxy, cyclopropyl or fluorocyclopropyl, or two of the substituents connected to the same carbon atom form a 3-4 membered cycloalkyl.
  • L is selected from a bond or -CH2- , -CH2CH2- , -CH2-CH( CH3 )-, -CH2 - C( CH3 ) 2- , -CH(CH3) CH2- , -O- , -O- CH2- , -O- CH2CH2- , -O-CH( CH3 )-, -NH-, -NH-CH2-, -NH- CH2CH2- , -NH-CH (CH3 ) - or -NHC( CH3 ) 2- (the left end is connected to ring A and the right end is connected to R6 ) (it can be seen from the embodiments of the present invention that when the C in L is connected to ring A, it is connected to N on ring A; when the N or O in L is connected to ring A, it is connected to C on ring A).
  • R7 is selected from hydrogen, deuterium, fluorine, chlorine , -OH, -NH2, -CN, methyl, fluoromethyl, deuterated methyl, ethyl, fluoroethyl, methoxy, fluoromethoxy, cyclopropyl, fluorocyclopropyl, -CONH2 , -CONHCH3 , -CONHCD3 or -CONH-cyclopropyl.
  • R 8 is selected from hydrogen, deuterium, fluorine, -NH 2 , -CONH 2 , -CN or the following groups optionally substituted with 0-3 substituents: C 1-4 alkyl, -C(O)-C 1-4 alkyl, -C(O)-3-4 membered cycloalkyl, -C(O)NH-C 1-4 alkyl, -C(O)NH-3-4 membered cycloalkyl3-4 membered cycloalkyl; in R 8 , the substituents are selected from: deuterium, halogen, -OH, -NH 2 or -CN.
  • R8 is selected from hydrogen, deuterium, fluorine or a The following groups: C 1-4 alkyl, -C(O)-C 1-4 alkyl, -C(O)-3-4 membered cycloalkyl, 3-4 membered cycloalkyl; in R 8 , the substituent is selected from: deuterium, fluorine or -OH.
  • R 8 is selected from hydrogen, fluorine, methyl, fluoromethyl, deuterated methyl, ethyl, fluoroethyl, cyclopropyl, fluorocyclopropyl, -C(O)CH 3 , -C(O)CD 3 or -C(O)-cyclopropyl.
  • Ring A is the following group optionally substituted by 0-3 R 8 : 5-6 membered alkyl ring (the 5-6 membered alkyl ring must be a double bond), 5- to 6-membered alkyl heterocycle (the 5- to 6-membered alkyl heterocycle According to the above X and Y, it is determined to be a single bond or a double bond), a benzene ring (the must be a double bond), a 5- to 6-membered heteroaromatic ring (the 5- to 6-membered heteroaromatic ring According to the above X and Y, it is determined to be a single bond or a double bond),
  • the connection direction remains unchanged from the general formula, that is, from left to right: X is connected to R 7 on the left, Y is connected to pyridazine N in the middle, and L is connected on the right); in ring A, the 5-6 membered alkyl heterocyclic ring and the 5-6 membered
  • ring A The following groups optionally substituted by 0-2 R 8 :
  • connection direction remains unchanged from the general formula, that is, from left to right: X is connected to R7 on the left, Y is connected to pyridazine N in the middle, and L is connected to the right).
  • n2 is selected from an integer of 0-2.
  • R 6 is selected from the following structures:
  • R 11b is selected from hydrogen, deuterium, halogen, -CN, -OR 12a , -NR 12d R 12e , -C( ⁇ O)R 12a , -C( ⁇ O)OR 12a , -C( ⁇ O)NR 12d R 12e , -NR 12d C( ⁇ O)R 12e , -SO 2 R 12a , -SO 2 NR 12d R 12e , -NR 12d SO 2 R 12e , or a 6-10 membered aryl group, a 5-10 membered heteroaryl group, a 3-6 membered heterocycloalkyl group, a 3-6 membered cycloalkyl group, or a C 1-6 alkyl group substituted with 0-3 substituents; in R 11a , the substituent is selected from deuterium, fluorine, chlorine, -OH, -NR 12b R 12c , or -C( ⁇ O)NR 12b R 12c , CN
  • R 11c and R 11d are independently selected from hydrogen, deuterium or C 1-4 alkyl substituted with 0-3 substituents; in R 11c and R 11d , The substituent is selected from deuterium, fluorine and chlorine.
  • R 11a is selected from H, deuterium, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 hydroxy-substituted alkyl, 3-6-membered cycloalkyl, 3-6-membered fluorocycloalkyl, 3-6-membered cycloalkyl substituted with hydroxy, C 1-4 alkanoyl, 3-6-membered cycloalkanoyl, C 1-4 alkoxyacyl, 3-6-membered cycloalkoxyacyl, C 1-4 alkanesulfonyl, 3-6 - membered cycloalkanesulfonyl,
  • R 11b is selected from H, deuterium, fluorine, chlorine, amino, hydroxyl, cyano, oxo, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 deuterated alkyl, C 1-4 hydroxy-substituted alkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy, C 1-4 deuterated alkoxy, 3-6 membered cycloalkyl, 3-6 membered fluorocycloalkyl, 3-6 membered cycloalkyl substituted with hydroxyl, C 1-4 alkanoyl, 3-6 membered cycloalkanoyl, C 1-4 alkoxyacyl, 3-6 membered cycloalkoxyacyl, C 1-4 alkylsulfonyl, 3-6 membered cycloalkanesulfonyl, methylamino, dimethylamino,
  • R 11c and R 11d are independently selected from hydrogen, deuterium, methyl, deuterated methyl and fluoromethyl.
  • R 6 is selected from the following structures:
  • the present invention also provides some specific compounds, which are selected from:
  • the present invention also provides some specific compounds, which are selected from:
  • the present invention also provides some compounds, which are selected from:
  • the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula I or its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope-labeled substance, metabolite or prodrug as an active ingredient, supplemented with a pharmaceutically acceptable carrier.
  • a further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining a compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.
  • the pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention is a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (2005).
  • the pharmaceutical composition can be administered in any form as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient.
  • it can be prepared into various suitable dosage forms according to the administration route.
  • the administration of the compounds or pharmaceutical compositions of the present invention may be combined with another therapeutic method.
  • the other therapeutic method may be selected from, but not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.
  • the present invention also relates to a pharmaceutical preparation, which uses the above-mentioned compound of formula I or its pharmaceutically acceptable form, or a mixture thereof, or a pharmaceutical composition of the present invention as an active ingredient.
  • the preparation is in the form of a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • a further object of the present invention is to provide a preparation, for example, in the form of a kit.
  • the articles of manufacture of the present invention include, but are not limited to, kits and packaging.
  • the articles of manufacture of the present invention comprise: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent, the first therapeutic agent comprising: a compound of Formula I or a pharmaceutically acceptable form thereof, or a mixture thereof; (c) an optional package insert indicating that the pharmaceutical composition can be used to treat a neoplastic condition (as defined below); and (d) a second container.
  • the first container is a container for holding a pharmaceutical composition. This container can be used for preparation, storage, transportation and/or individual/batch sales.
  • the first container is intended to cover bottles, jars, vials, flasks, syringes, tubes (e.g., for cream products), or any other container for preparing, holding, storing or dispensing pharmaceutical products.
  • the second container is a container for accommodating the first container and optional package instructions.
  • the second container include, but are not limited to, boxes (e.g., paper or plastic boxes), boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.
  • the package instructions may be physically adhered to the outside of the first container via a cable tie, glue, staples, or other adhesion means, or they may be placed inside the second container without any physical tool for adhesion to the first container.
  • the package instructions are located outside the second container. When located outside the second container, it is preferred that the package instructions are physically adhered via a cable tie, glue, staples, or other adhesion means. Alternatively, it may abut or contact the outside of the second container without physical adhesion.
  • the present invention provides the use of the aforementioned compound of formula I, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating NLRP3-related diseases.
  • the present invention provides a method for preventing or treating NLRP3-related diseases, comprising administering the compound of formula I or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of the present invention to an individual in need thereof.
  • the present invention provides a method for preventing or treating NLRP3-related diseases in combination with the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention and another treatment method, wherein the other treatment method includes but is not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof.
  • the NLRP3-related disease includes: inflammatory disease, autoimmune disease, cardiovascular disease, cancer, renal disease, gastrointestinal disease, respiratory disease, endocrine disease or central nervous system disease.
  • the NLRP3-related diseases include: cryptopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), non-alcoholic steatohepatitis, alcoholic liver disease, graft-versus-host disease, multiple sclerosis (MS), rheumatoid arthritis, type I/type II diabetes and related complications (e.g., nephropathy, retinopathy), psoriasis, Alzheimer's disease, atherosclerosis, gout, chronic kidney disease, sepsis, liver fibrosis, idiopathic pulmonary fibrosis, epilepsy, neuropathic pain, depression, Parkinson's disease, asthma, acute myocardial infarction, lupus erythematosus, rheumatoid arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, Rhe
  • CAPS
  • the compounds of the present invention can be used in combination with chemoradiotherapy or immunotherapy to prevent or treat NLRP3-related diseases.
  • the present invention provides a class of pyridazine compounds and uses thereof.
  • the compounds and compositions can be used to prepare NLRP3 inflammasome inhibitors, providing a new approach for treating NLRP3-related diseases.
  • compositions comprising "a” pharmaceutically acceptable excipient can be interpreted as indicating that the composition includes “one or more” pharmaceutically acceptable excipients.
  • C 1-6 should be understood to include any sub-ranges and each point value therein, such as C 2-5 , C 1-4 , C 1-5 , etc., as well as C 1 , C 3 , 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 7-10 , C 7-9 , C 8-9 , etc., as well as C 3 , C 4 , C 8 , C 10 , etc.
  • the expression "3-10 yuan” should be understood to include any sub-ranges and each point value therein, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 4-5 yuan, 4-6 yuan, 5-8 yuan, 6-7 yuan, etc., as well as 3, 6, 7, 10 yuan, etc.
  • 5-10 yuan should also be understood in a similar manner, for example, it can cover any sub-ranges and point values contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 6-10 yuan, 7-8 yuan, etc. as well as 5, 6, 7, 8, 9, 10 yuan, etc.
  • halogen means fluorine, chlorine, bromine or iodine.
  • alkyl includes a linear or branched monovalent saturated hydrocarbon group.
  • alkyl includes methyl, isopropyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, neopentyl, n-hexyl, 2-methylpentyl, etc.
  • C 1-4 in “C 1-4 alkyl” refers to a group containing 1, 2, 3 or 4 carbon atoms 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, cyclohexyl, cycloheptyl, cyclononyl, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings or spiro rings, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decalinyl, etc.
  • monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclononyl, cyclopentene, cyclohexene, etc.
  • bicyclic cycloalkyl groups including fused rings, bridge
  • C3-12 cycloalkyl refers to a cycloalkyl group having 3-12 ring carbon atoms (such as 3, 6, 7, 10 or 12).
  • the cycloalkyl or cycloalkylene group in the present invention is optionally substituted by one or more substituents described in the present invention.
  • heterocycloalkyl refers to a saturated or partially saturated, monocyclic or polycyclic (such as a bicyclic, for example: a cyclic, bridged or spirocyclic) non-aromatic group, whose ring atoms are composed of carbon atoms and at least one (for example, 1, 2, 3 or 4) heteroatoms 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 one of the ring atoms.
  • heterocycloalkyl refers to a heterocycloalkyl group having 3 to 8 ring atoms.
  • Common heterocycloalkyl groups include (but are not limited to) oxirane, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, cyclopentane, etc.
  • the heterocycloalkyl, heterocycloalkylene or heterocycle in the present invention are optionally substituted by one or more substituents (such as oxo) described in the present invention.
  • 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 should be understood 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 are -CH 2 F, -CHF 2 , -CCl 3 , -C 2 Cl 5 , -CH 2 CF 3 , -CH 2 Cl, 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 substituent, 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, -CHF 2 , -CF 3 , -C 2 F 5 , -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.
  • C2-4 alkenyl refers to an alkenyl group having 2 to 4 carbon atoms.
  • Common alkenyl groups include (but are not limited to) vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, etc.
  • the alkenyl group in the present invention is optionally substituted by one or more substituents described in the present invention.
  • alkynyl refers to a straight or branched aliphatic hydrocarbon group having at least one C ⁇ C triple bond.
  • C 2-4 alkynyl refers to an alkynyl group having 2 to 4 carbon atoms.
  • Common alkynyl groups include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group in the present invention is optionally substituted by one or more substituents described in the present invention.
  • aryl or aromatic ring refers to an all-carbon monocyclic or fused polycyclic (such as bicyclic) aromatic group or aromatic ring with a conjugated ⁇ electron system.
  • C6-10 aryl refers to an aromatic group containing 6-10 carbon atoms. Examples thereof include, but are not limited to, phenyl and naphthyl.
  • the aryl or aromatic ring in the present invention is optionally substituted by one or more substituents described in the present invention.
  • heteroaryl or “heteroaromatic ring” refers to an aromatic ring with a conjugated ⁇ electron system, wherein one or more (e.g., 1, 2 or 3) ring atoms are heteroatoms selected from N, O, P and S, and the remaining ring atoms are C.
  • a heteroaryl or heteroaromatic ring can be characterized by the number of ring atoms.
  • a 5-12 membered heteroaryl can contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, in particular 5, 6, 9, 10 ring atoms.
  • heteroaryl examples include thienyl, furanyl, oxazolyl, pyrazolyl, pyridyl, pyrazinyl, isoxazolyl, triazolyl, thiadiazolyl, etc.; the term also encompasses the case where the heteroaryl or heteroaromatic ring may be optionally further fused to an aryl or heteroaryl ring to form a fused ring.
  • the heteroaryl or heteroaromatic ring in the present invention is optionally substituted by one or more substituents described herein.
  • 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 isotopic 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 in the compounds of the present invention include, but are not limited to, hydrogen isotopes (e.g., deuterium ( 2H ), tritium ( 3H )); carbon isotopes (e.g., 13C and 14C ); chlorine isotopes (e.g., 37Cl ); iodine isotopes (e.g., 125I ); nitrogen isotopes (e.g., 13N and 15N ); oxygen isotopes (e.g., 17O and 18O ); phosphorus isotopes (e.g., 32P ); and sulfur isotopes (e.g., 34S ).
  • hydrogen isotopes e.g., deuterium ( 2H ), tritium ( 3H )
  • carbon isotopes e.g., 13C and 14C
  • chlorine isotopes e.g., 37Cl
  • polymorph refers to different solid crystalline phases produced by the presence of two or more different molecular arrangements in the solid state of certain compounds of the present invention.
  • Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.
  • crystallization will produce a solvate of the compound of the present invention.
  • solvate used in the present invention refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules.
  • the solvent may be water, in which case the solvate is a hydrate.
  • the solvent may be an organic solvent.
  • the compound of the present invention may exist as a hydrate, including a single hydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, etc., and corresponding solvated forms.
  • the compound of the present invention may form a true solvate, but in some cases, it may also retain only adventitious water or a mixture of water plus a portion of an adventitious solvent.
  • the compound of the present invention may react in a solvent or precipitate or crystallize from a solvent. Solvates of the compound of the present invention are also included within the scope of the present invention.
  • the present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • stereoisomer means an isomer formed due to at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three, or four) asymmetric centers it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It is to be understood that the scope of the present invention encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
  • pharmaceutically acceptable salts include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts.
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts.
  • 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 free bases without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, decanoate, undecylenate, glycolate, gluconate, oxalate, maleate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, 4-aminosalicylate, naphthalene disulfonate, etc.
  • “Pharmaceutically acceptable base addition salts” refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, lithium salts, ammonium salts, Calcium salt, magnesium salt, iron salt, zinc salt, copper salt, aluminum salt etc. Preferred inorganic salt is ammonium salt, sodium salt, calcium salt and magnesium salt.
  • Salt derived from organic base includes but is not limited to the following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, N-ethylpiperidine, polyamine resin etc.
  • Preferred organic base includes isopropylamine, diethylamine, ethanolamine, choline hexacaffeine.
  • esters refers to esters derived from the compounds described herein, including physiologically hydrolyzable esters.
  • the compounds of the present invention may themselves also be esters.
  • nitrogen-containing heterocycles are capable of forming nitrogen oxides.
  • nitrogen-containing heterocycles that are capable of forming nitrogen oxides.
  • tertiary amines are capable of forming nitrogen oxides.
  • the synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane.
  • peroxyacids such as peracetic acid and metachloroperbenzoic acid (mCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane such as dimethyl dioxirane.
  • 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, enzymolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by a method of 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 means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously in the form of a single entity or a single dosage form.
  • non-fixed combination means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously, in combination or sequentially at variable intervals in the form of separate entities. This also applies to cocktail therapy, for example the administration of three or more active ingredients.
  • tumor includes but is not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the lung, adenocarcinoma of the lung, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, rhinitis cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.
  • treating means reversing, alleviating, inhibiting the progression of, 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 structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the solvent, tetramethylsilane (TMS) as the internal standard, and chemical shifts are given in units of 10 -6 (ppm).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, signal: 6110).
  • HPLC determination used Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5wn, chromatographic column) and 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 Weigh int-1a (21.7 g, 90.8 mmol), LiOH.H 2 O (11.4 g, 272 mmol), Pd 2 (dba) 3 (1.7 g, 1.82 mmol) and BippyPhos (1.8 g, 3.63 mmol) into a flask, then add dioxane (220 mL) and water (22 mL), replace with N 2 three times, and reflux at 100°C for overnight. The reaction mixture was cooled to room temperature, filtered through a layer of celite, and then rinsed with EtOAc (100 mL).
  • Step 2 Dissolve the compound int-1b (14.0 g, 79.5 mmol) in toluene (280 mL), cool to 0°C, then add NaH (6.36 g, 159 mmol, 60%) in batches, and stir at 0°C for 1 h. Then add I2 (20.2 g, 79.5 mmol) in batches to the above suspension, and stir at 0°C for 1 h. After the reaction is complete, quench with water, adjust pH to 5 with 2M hydrochloric acid, extract with EtOAc, dry with anhydrous Na 2 SO 4 , filter, and swirl the filtrate under reduced pressure.
  • Step 3 Add compound int-1c (20.7 g, 68.5 mmol) and K 2 CO 3 (18.9 g, 137 mmol) to acetone (200 mL), then add MeI (14.6 g, 103 mmol), and stir overnight at 25°C.
  • Step 4 Add compound int-1d (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) into anhydrous dioxane (60 mL), and then add pinacol borane (4.94 g, 38.6 mmol), and reflux at 110° C. under nitrogen protection for overnight reaction.
  • Step 3 Compound int-3c (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 4 Compound int-3d (13.7 g, 56.4 mmol), bis-pinacol borate (17.2 g, 67.7 mmol), KOAc (11.1 g, 113 mmol) and Pd(PPh 3 )Cl 2 (2.00 g, 2.82 mmol) were added to dioxane (137 mL) and reacted at 90° C. for 12 h under nitrogen protection.
  • Step 1 Dissolve the compound 3-bromo-2-hydroxybenzaldehyde (25.0 g, 104.65 mmol), CH 3 I (60.63 g, 373.14 mmol), and K 2 CO 3 (34.38 g, 248.76 mmol) in DMF (200 mL), and heat to 50°C for 3 hours. Add water to the reaction solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent from the filtrate under reduced pressure to obtain the target compound int-4b (yellow oily liquid, 22.5 g, yield: 84%), without further purification, MS/ESI [M+H] + : 215.1.
  • Step 2 At 0°C, Et 3 N (12.71 g, 125.58 mmol) was added dropwise to HOOH (14.45 g, 313.95 mmol), followed by reaction at room temperature for 30 minutes, and then a DMF (200 mL) solution containing compound int-4b (22.5 g, 104.65 mmol) and cycloisopropyl malonate (15.08 g, 104.65 mmol) was added, and the mixture was heated to 100°C for overnight reaction. A NaOH aqueous solution was added to the reaction solution to adjust the pH to 9, and the mixture was extracted with ethyl acetate.
  • Step 4 Compound int-4d (4.7 g, 19.50 mmol) and 2-(difluoromethanesulfonyl)pyridine (5.65 g, 29.25 mmol) were dissolved in DMF (30 mL), cooled to -50 °C, and a DMF solution of potassium tert-butoxide was added under nitrogen protection, and the temperature was raised to -40 °C. After reacting for 3 hours, a saturated aqueous ammonium chloride solution (26 ml) was added to quench the reaction, and then 3N HCl (26 ml) was added. The temperature was raised to room temperature, and the reaction was extracted with ethyl acetate.
  • Step 5 Under nitrogen protection, compound int-4e (1.92 g, 6.98 mmol), pinacol diboron (2.66 g, 10.47 mmol), PdCl 2 (dppf) (0.57 g, 0.7 mmol), potassium acetate (2.05 g, 20.94 mmol) were dissolved in 1,4-dioxane solution and refluxed at 100°C overnight. After the reaction was 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 solvent was removed from the filtrate under reduced pressure.
  • Step 1 Weigh the starting material compound 1 (1eq, 25g), trimethylsilyl acetylene (1.2eq), triethylamine (2.5eq), cuprous bromide (0.1eq), (PPh 3 ) 2 PdCl 2 (0.05eq), transfer all the materials into a 2L three-necked flask, add toluene (500mL) and ventilate with nitrogen three times, then place at room temperature for reaction. After 1h, LC/MS detected that the reaction was complete. Add ethyl acetate (100mL) to the reaction suspension, then filter through diatomaceous earth, and filter the filter cake with 100mL of ethyl acetate. The concentrated solid was dispersed in 100 mL of ether, stirred for 15 min, and filtered. The filter cake was drained to obtain compound 2, which was directly used in the next step without further purification.
  • Step 2 Transfer the crude product obtained in the previous step to a 1L flask, then add 400mL of methanol to stir and dissolve. Heat to 65°C, then add potassium carbonate solid (1eq) in batches. After 1h of reaction, LC/MS is performed to detect the complete reaction. Filter the reaction suspension through diatomaceous earth, and the filtrate is not further processed.
  • Step 3 Heat the filtrate from the previous step to 65°C, then add 6N hydrochloric acid dropwise until the hydrochloric acid concentration of the system reaches 1N. Stir at room temperature for 4 hours and then perform LC/MS detection to show that the reaction is complete. Concentrate the reaction solution, adjust the pH to a weak base, and extract with ethyl acetate. Concentrate the combined organic phase, then slurry with ether, filter, and drain the filter cake to obtain compound 4 (15.4 g).
  • Step 4 Compound 4 (15.4 g, 1 eq) and potassium carbonate (2 eq) were transferred to a 1 L flask, 400 mL of dioxane was added, and the mixture was heated to 80 ° C. Then a dioxane solution of TsCl (1.1 eq) was added dropwise, and the mixture was reacted for 6 h before LC/MS detection. The suspension was filtered through diatomaceous earth, and the filtrate was concentrated. The concentrate was dispersed in ether (100 mL), stirred for 15 min, and then filtered to obtain compound 5.
  • Step 6 Dissolve compound 6 in 100 mL of methanol/water (suspension system), add potassium hydroxide to adjust the pH to about 14. Transfer the system to a 50°C oil bath for reaction for 1 hour. After the reaction temperature drops to room temperature, add 300 mL of dichloromethane to the reaction system for extraction. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Disperse the solid in 50 mL of ether, continue stirring for 0.5 hours, and then filter. The filter cake is rinsed with a small amount of ether and dried to obtain compound 7.
  • Step 7 Add compound 7 (308 mg, 1 mmol), cesium carbonate (650 mg, 2 mmol), and compound 8 (1.2 mmol) to 20 mL of acetonitrile and heat to 80°C for 1 h. After the reaction is complete, cool to room temperature, concentrate to remove the solvent, extract with dichloromethane, combine the organic phases and spin dry, and purify by column chromatography to obtain compound 8.
  • Example 2 to 35 The synthesis methods of Examples 2 to 35, Examples 628 to 673 and Examples 686 to 689 were prepared by referring to Example 1 to obtain target compounds A2 to A85.
  • Example 37 to 85 The synthesis methods of Examples 37 to 85, Examples 674 to 683 and Example 690 were prepared by referring to Example 36 to obtain target compounds B2 to B61.
  • Example 87 to 135 and Example 684 were prepared by referring to Example 86 to obtain target compounds C2 to C51.
  • Example 90 Compound C5: 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 10.18 (s, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 5.28-5.15 (m, 1H), 3.17-3.08 (m, 1H), 2.91-2.81 (m, 1H), 2.50-2.45 (m, 2H), 2.27 (s, 3H), 2.20-1.96 (m, 5H), 1.93-1.85 (m, 1H), 1.85-1.72 (m, 1H).
  • Step 3 Under nitrogen atmosphere, anhydrous dichloromethane (20 mL) and oxalyl chloride (1.0 mL, 11.25 mmol) were added to a 100 mL round-bottom flask. The mixture was cooled to -78 °C. Anhydrous DMSO (1.1 mL, 15 mmol) was slowly added. The reactants were stirred for 30 minutes. A dichloromethane solution (5 mL) of compound 28 (1.2 g, 7.5 mmol) was slowly added. The reaction was stirred for about 3 hours until the reaction was complete as monitored by TLC (1:1 ethyl acetate/n-hexane).
  • Example 137 to 200 The synthesis methods of Examples 137 to 200 were carried out by referring to Example 136 to obtain target compounds D2 to D65.
  • Step 1 Weigh compound 1 (5.0 g, 24.0 mmol), compound 33 (4.41 g, 26.4 mmol) and DIEA (6.20 g, 1.82 mmol) into a flask, then add 25 mL of dimethyl sulfoxide, heat to 110 ° C and react overnight. The reaction was cooled to room temperature and slowly added dropwise to 125 mL of water. A large amount of solid precipitated and filtered. The filter cake was slurried with ethyl acetate (15 mL) for 0.5 h and filtered.
  • Step 2 Add HCl/EtOAc (2.5 mL, 4.0 M) to compound 34 (500 mg, 1.70 mmol) and stir at room temperature for 1 h. A large amount of solid was generated, which was filtered, and the filter cake was rinsed with EtOAc and dried under reduced pressure to obtain the target compound 35 (440 mg, 2.43 mmol, gray solid).
  • Step 3 Weigh compound 35 (340 mg, 1.56 mmol), DIEA (972 mg, 7.52 mmol) and trimethyl orthoformate (998 mg, 9.40 mmol) into DMF (3 mL), heat to 110°C and stir for 3 h. After the reaction is complete, filter and collect the filtrate to obtain the target compound 36, which is directly used in the next step.
  • Examples 202 to 245 were prepared by referring to Example 201 to obtain target compounds E2 to E45.
  • Example 247 to 295 The synthesis methods of Examples 247 to 295 were carried out by referring to Example 246 to obtain target compounds F2 to F50.
  • Example 296 The synthesis methods of Examples 297 to 310 refer to Example 296 to obtain target compounds G2 to G15.
  • Example 312 to 325 The synthesis methods of Examples 312 to 325 refer to Example 311 to obtain target compounds H2 to H15.
  • Example 327-340 The synthesis methods of Examples 327-340 refer to Example 326 to obtain target compounds I2 ⁇ I15.
  • Example 342-360 The synthesis methods of Examples 342-360 refer to Example 341 to obtain target compounds J2 ⁇ J20.
  • Example 361 1-((6-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazolo[4,3-c] Pyridazin-3-yl)amino)propan-2-ol
  • Examples 363 to 440 were prepared by referring to Examples 361 and 362 to obtain target compounds K3 to K80.
  • Examples 444 to 530 refer to Examples 441, 442 and 443 to obtain target compounds L4 to L90.
  • Example 531 3-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-(2-hydroxypropyl)-5,5-dimethyl -5,7-Dihydro-6-pyrrolo[2,3-c]pyridazin-6-one
  • Step 1 Compound 62 (10 g, 54.6 mmol), compound 33 (9.1 g, 54.6 mmol), DIEA (21.1 g, 163.9 mmol) and isopropanol (150 mL) were placed in a reaction bottle and stirred at 70° C. for 2 h. After the reaction was completed, the mixture was cooled to room temperature, and 200 mL of ethyl acetate and 200 mL of saturated aqueous ammonium chloride solution were added.
  • Step 2 Compound 84 (2.5 g, 8.0 mmol), triethylamine (4.0 g, 40.0 mmol) and dichloromethane (50 mL) were placed in a reaction bottle, and isobutyryl chloride (2.1 g, 20.0 mmol) was added. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was completed, 50 mL of saturated ammonium chloride and 30 mL of dichloromethane were added to the system, and the aqueous phase was further extracted with 20 mL of dichloromethane.
  • Step 4 Compound 86 (400 mg, 1.1 mmol), intermediate int-1 (544.8 mg, 1.7 mmol), Pd(dppf)Cl 2 (84.0 mg, 0.1 mmol), cesium carbonate (1120.6 mg, 3.4 mmol), dioxane (15 mL) and water (3 mL) were placed in a reaction flask, protected by nitrogen, and stirred at 100°C for 12 h.
  • Example 533 to 550 and Example 685 were prepared by referring to Example 531 and Example 532 to obtain target compounds M3 to M21.
  • Example 685 Compound M21: 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 10.36 (br s, 1H), 7.83 (s, 1H), 7.17 (s, 1H), 7.11 (s, 1H), 4.83 (s, 2H), 2.30 (s, 3H), 2.12 (s, 3H), 1.42 (s, 6H).
  • Step 1 Dissolve compound 90 (50.0 mg, 0.427 mmol) in 1 mL of 6M hydrochloric acid, cool to 0°C, add solid sodium nitrite (32.0 mg, 0.470 mmol), stir at 0°C for 0.5 h after addition.
  • Step 2 Compound 92 (71 mg, 0.323 mmol) was dissolved in 4 mL of acetic acid and stirred at 110°C for 3 h. After the reaction was completed, the solvent was directly dried to obtain compound 93 (60 mg, 92.3%, khaki solid), which was directly used in the next step without further purification;
  • Example 552 to 625 The synthesis methods of Examples 552 to 625 refer to Example 551 to obtain target compounds N2 to N75.
  • 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 in RPMI medium containing PMA (10 ⁇ M) and placed in an incubator at 37°C and 5% CO 2 for overnight induction. The next day, the medium was replaced with Opti-MEM medium containing 1 ⁇ g/mL LPS; 3 hours later, drugs were added for 40 minutes; Nigericin (10 ⁇ M) was added for 40 minutes; cell supernatants were collected for ELISA analysis.
  • the compounds of the present invention have good inhibitory activity against NLRP3 inflammasome.
  • the compounds of the present invention have an IC 50 of NLRP3 inhibitory activity less than or equal to 500 nM, preferably less than or equal to
  • the IC 50 of the compound shown in the present invention is most preferably 250 nM, more preferably 100 nM or less, more preferably 50 nM or less, and the IC 50 of the compound shown in the present invention is most preferably 5 nM or less.
  • CHO cells stably expressing hERG were cultured in a cell culture flask and placed in an incubator at 37°C and 5% CO 2. When the cell density grew to 60-80%, the cell culture medium was removed, and the cells were washed once with PBS and digested with Detachin. After complete digestion, the cells were neutralized with culture medium, centrifuged, the supernatant was removed, and the cells were resuspended with culture medium. The cell density was adjusted to 2-5 ⁇ 10 6 /mL for later use.
  • Compound preparation Dilute the compound stock solution with 100% DMSO, that is, take 10 ⁇ L of the compound stock solution and add it to 20 ⁇ L DMSO, and dilute it 3 times continuously to 6 concentrations. Take 4 ⁇ L of the 6 concentrations of the compound respectively and add it to 396 ⁇ L of extracellular fluid, that is, dilute it 100 times to get 6 intermediate concentrations. Then take 80 ⁇ L of the 6 intermediate concentration compounds respectively and add them to 320 ⁇ L of extracellular fluid, that is, dilute it 5 times to the final concentration to be tested. The highest test concentration is 40 ⁇ M, and there are 6 concentrations of 40, 13.33, 4.44, 1.48, 0.49 and 0.16 ⁇ M respectively. The DMSO content in the final test concentration does not exceed 0.2%, and this concentration of DMSO has no effect on the hERG potassium channel.
  • the compound preparation is completed by the Bravo instrument throughout the dilution process.
  • Electrophysiological recording process The single-cell high-impedance sealing and whole-cell pattern formation process are all automatically completed by the Qpatch instrument. After obtaining the whole-cell recording mode, the cell is clamped at -80 mV. Before giving a 5-second +40 mV depolarizing stimulus, a 50-millisecond -50 mV pre-voltage is given, and then repolarizes to -50 mV for 5 seconds, and then returns to -80 mV. This voltage stimulus is applied every 15 seconds. After recording for 2 minutes, the extracellular solution is given for 5 minutes, 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 detection concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • the compounds of the present invention have a weak inhibitory effect on hERG potassium ion channels.
  • the compounds of the present invention have an IC 50 greater than 10uM for hERG inhibition, preferably greater than 20uM for compounds, more preferably greater than 30uM for compounds, and the most preferred compound hERG inhibition IC 50 among the compounds shown in the present invention is greater than 40uM.
  • Sample preparation Weigh the compound and add DMSO to dissolve it, then add sodium chloride solution for injection to prepare the compound solution for administration.
  • Sample collection 6 Balb/c mice (Chengdu Dashuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030), male, 3 intravenous administration (IV), 3 gavage administration (PO), about 0.05mL of blood was collected at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h and 48h after administration, the collected blood was centrifuged at 3500rpm for 15min, the supernatant plasma was collected, and it was frozen at -40°C for testing.
  • the blood concentration was quantitatively analyzed by LC-MS/MS analysis method, and pharmacokinetic parameters such as peak time (Cmax), area under the drug-time curve (AUC (0-t)), half-life (T 1/2 ), clearance (CL), tissue distribution (Vdss), bioavailability (F), etc.
  • Cmax peak time
  • AUC (0-t) area under the drug-time curve
  • T 1/2 half-life
  • CL clearance
  • Vdss tissue distribution
  • F bioavailability
  • Compounds A3, A69 and A82 of the present invention have good pharmacokinetic properties in Balb/c mice, including good oral bioavailability, exposure, half-life and clearance.
  • 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)].

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Abstract

本发明公开了一类并哒嗪类化合物及其用途，属于化学医药技术领域。本发明提供的式I所示并哒嗪类化合物，其能够作为NLRP3抑制剂，具有高活性和优异的药物代谢动力学性质，为治疗NLRP3相关疾病提供了新途径。

Description

并哒嗪类化合物及其用途 技术领域
本发明涉及一种并哒嗪类化合物及其用途，属于化学医药技术领域。
背景技术
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。
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。
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。
发明内容
本发明创造性的开发了一类并哒嗪类化合物，其能够作为NLRP3抑制剂，具有高活性和优异的药物代谢动力学性质，为治疗NLRP3相关疾病提供了新途径。
本发明首先提供了式Ⅰ所示化合物或其药学上可接受的形式，所述式Ⅰ结构如下：
其中，
X和Y独立地选自C或N，且X和Y中至多一个选自N；
当X或Y选自N时，为单键；当X和Y选自C时，为双键；
环A为任选被0-6个R8取代的以下基团：5～6元烷基环(该5～6元烷基环的必然为双键)、5～6元烷基杂环(该5～6元烷基杂环的根据上述X和Y的情况，确定为单键或双键)、苯环(该苯环的必然为双键)、5～6元杂芳环(该5～6元杂芳环的根据上述X和Y的情况，确定为单键或双键)、 与通式的连接方向不变，即从左到右依次为：左为X与R7方向相连，中间为Y与哒嗪N相连，右为与L相连)；环A中，所述5～6元烷基杂环、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；
R1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中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
R2和R4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；R2和R4中，所述取代基选自：氘、卤素、-OH、-NH2或-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；
R5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；R5中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
或者，R2与R3、R3与R4或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、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、3～6元环烷基、3～6元氟代环烷基，或同一碳原子连接的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；
L选自-(CH2)n1-、-CH(CH3)(CH2)n1-、-(CH2)n1-CH(CH3)-、-(CH2)n1O-、-O(CH2)n1-、-OCH(CH3)(CH2)n1-、-(CH2)n1-NH-、-NH-(CH2)n1-、-NH-CH(CH3)(CH2)n1-或-NHC(CH3)2(CH2)n1-，n1为选自0-3的整数(左端与环A相连，右端与R6相连)(由本发明实施例可知，当L中的C与环A相连时，其与环A上的N相连；当L中的N或O与环A相连时，其与环A上的C相连)；
R6选自氢、氘、卤素、-CN、-OR9a、-SR9a、-NR9bR9c、-C(＝O)R9a、-OC(＝O)R9a、-C(＝O)OR9a、-C(＝O)NR9bR9c、-NR9bC(＝O)R9c、-SO2R9a、-SO2NR9bR9c、-NR9bSO2R9c或被0-6个R9d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；
R9a、R9b和R9c独立地选自氢、氘或者被0-6个取代基取代的以下基团：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；R9a、R9b和R9c中，所述取代基选自：氘、卤素、-N(R10aR10b)、-C(O)N(R10aR10b)、-OH、-CN、C1-4烷基、C1-4烷氧基、C1-4氘代烷基、C1-4氟代烷基、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；R9a、R9b和R9c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，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；
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；R9b与R9c与它们所连接的原子相连成环时，所述取代基选自：氘、卤素、-N(R10aR10b)、-C(O)N(R10aR10b)、-OH、-CN、C1-4烷基、C1-4烷氧基、3～6元环烷基、4～6元杂环烷基；R9b与R9c与它们所连接的原子相连成环时，所述3～6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子，所述取代基中4～6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；
R9d选自氢、氘、卤素、-CN、-OR10c、-SR10c、-NR10dR10e、-C(＝O)R10c、-OC(＝O)R10c、-C(＝O)OR10c、-C(＝O)NR10dR10e、-NR10dC(＝O)R10e、-SO2R10c、-SO2NR10dR10e、-NR10dSO2R10e或者被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、C1-6烷基；R9d中，所述取代基选自氘、卤素、-OH、-NR10fR10g、-C(＝O)NR10fR10g、 CN、C1-4烷基、C1-4烷氧基或者3～6元环烷基；R9d中，所述5～10元杂芳基、3～8元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；
R10a、R10b、R10c、R10d、R10e、R10f、R10g独立地选自氢、C1-4烷基、N,N-二甲基取代的C1-4烷基、3～6元环烷基；
R7选自氢、氘、卤素、-OH、-NH2、-CN、-CONH2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、-NH-C1-6烷基、-NHC(＝O)-C1-6烷基、-NHC(＝O)-3～6元环烷基、-(C＝O)NH-C1-6烷基、-(C＝O)NH-3～6元环烷基、C2-6烯基、C2-6炔基、3～6元环烷基；R7中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
R8选自氢、氘、卤素、-NH2、-OH、-CN、-CONH2或任选被0-6个取代基取代的以下基团：C1-6烷基、-C(O)-C1-6烷基、-C(O)NH-C1-6烷基、3～6元环烷基、-C(O)-3～6元环烷基、-C(O)NH-3～6元环烷基；R8中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
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。
在本发明的一些实施例中，R1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。
在本发明的一些优选实施例中，R1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。
在本发明的一些更优选实施例中，R1选自氢、氘、F、Cl、-OH、-CN、-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。
在本发明的一些实施例中，R2和R4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。
在本发明的一些优选实施例中，R2和R4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。
在本发明的一些更优选实施例中，R2和R4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。
在本发明的一些实施例中，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。
在本发明的一些优选实施例中，R3选自氢、氘、F、Cl、Br、-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。
在本发明的一些更优选实施例中，R3选自氢、氘、F、Cl、Br、CN、甲基、氟代甲基、氘代甲基、甲硫基、氟代甲硫基、氘代甲硫基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基、氟代环丙基、乙烯基、乙炔基、苯基、氟代苯基、氘代苯基。
在本发明的一些实施例中，R5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。
在本发明的一些优选实施例中，R5选自氢、氘、F、Cl、-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。
在本发明的一些更优选实施例中，R5选自氢、氘、F、Cl、-OH、-CN、-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。
在本发明的一些实施例中，R2与R3、R3与R4或者R4与R5可以与它们所连接的原子一起形成被0-6个取代基取代的5～6元烷烃环、苯环、5～6元烷烃杂环、5～6元杂芳环或所述取代基选自：氘、卤素、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-氟代C1-4烷基、-O-氘代C1-4烷基、3～6元环烷基或3～6元氟代环烷基，或者同一碳原子连接的2个所述取代基形成3～4元环烷基；R2与R3、R3与R4或者R4与R5与它们所连接的原子相连成环时，所述5～6元烷烃杂环、5～6元杂芳环含有1～2个选自N、S、O中至少一个的杂原子。
在本发明的一些优选实施例中，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、Br、Cl、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-氟代C1-4烷基、-O-氘代C1-4烷基、3～6元环烷基或3～6元氟代环烷基，或者同一碳原子连接的2个所述取代基形成3～4元环烷基。
在本发明的一些更优选实施例中，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、Br、Cl、-OH、-NH2、-CN、氧代基、甲基、氟代甲基、氘代甲基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基或氟代环丙基，或者同一碳原子连接的2个所述取代基形成3～4元环烷基。
在本发明的一些实施例中，结构单元选自：

在本发明的一些实施例中，L选自键或者-CH2-、-CH2CH2-、-CH2-CH(CH3)-、-CH2-C(CH3)2-、-CH(CH3)CH2-、-O-、-O-CH2-、-O-CH2CH2-、-O-CH(CH3)-、-NH-、-NH-CH2-、-NH-CH2CH2-、-NH-CH(CH3)-或-NHC(CH3)2-(左端与环A相连，右端与R6相连)(由本发明实施例可知，当L中的C与环A相连时，其与环A上的N相连；当L中的N或O与环A相连时，其与环A上的C相连)。
在本发明的一些实施例中，R7选自氢、氘、卤素、-OH、-NH2、-CN或任选被0-3个取代基取代的以下基团：C1-3烷基、-O-C1-3烷基、-S-C1-3烷基、-CONH2、-NH-C1-3烷基、-NHC(＝O)-C1-3烷基、-NHC(＝O)-3～6元环烷基、-(C＝O)NH-C1-3烷基、-(C＝O)NH-3～6元环烷基、C2-4烯基、C2-4炔基、3～6元环烷基；R7中，所述取代基选自：氘、卤素、-OH、-NH2或-CN。
在本发明的一些优选实施例中，R7选自氢、氘、卤素、-OH、-NH2、-CN或者被0-3个取代基取代的以下基团：C1-3烷基、-O-C1-3烷基、-CONH2、-(C＝O)NH-C1-3烷基、-(C＝O)NH-3～4元环烷基或者3～4元环烷基；R7中，所述取代基选自：氘、氟或-OH。
在本发明的一些更优选实施例中，R7选自氢、氘、氟、氯、-OH、-NH2、-CN、甲基、氟代甲基、氘代甲基、乙基、氟代乙基、甲氧基、氟代甲氧基、环丙基、氟代环丙基、-CONH2、-CONHCH3、-CONHCD3或-CONH-环丙基。
在本发明的一些实施例中，R8选自氢、氘、氟、-NH2、-CONH2、-CN或任选被0-3个取代基取代的以下基团：C1-4烷基、-C(O)-C1-4烷基、-C(O)-3～4元环烷基、-C(O)NH-C1-4烷基、-C(O)NH-3～4元环烷基3～4元环烷基；R8中，所述取代基选自：氘、卤素、-OH、-NH2或-CN。
在本发明的一些优选实施例中，R8选自氢、氘、氟或任选被0-3个取代基取代的以 下基团：C1-4烷基、-C(O)-C1-4烷基、-C(O)-3～4元环烷基、3～4元环烷基；R8中，所述取代基选自：氘、氟或-OH。
在本发明的一些实施例中，更优选的，R8选自氢、氟、甲基、氟代甲基、氘代甲基、乙基、氟代乙基、环丙基、氟代环丙基、-C(O)CH3、-C(O)CD3或-C(O)-环丙基。
在本发明的一些实施例中，环A为任选被0-3个R8取代的以下基团：5～6元烷基环(该5～6元烷基环的必然为双键)、5～6元烷基杂环(该5～6元烷基杂环的根据上述X和Y的情况，确定为单键或双键)、苯环(该苯环的必然为双键)、5～6元杂芳环(该5～6元杂芳环的根据上述X和Y的情况，确定为单键或双键)、 与通式的连接方向不变，即从左到右依次为：左为X与R7方向相连，中间为Y与哒嗪N相连，右为与L相连)；环A中，所述5～6元烷基杂环、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。
在本发明的一些优选实施例中，环A任选被0-2个R8取代的以下基团：

(环A与通式的连接方向不变，即从左到右依次为：左为X与R7方向相连，中间为Y与哒嗪N相连，右为与L相连)。
在本发明的一些实施例中，结构单元选自：
n2选自0-2的整数。
在本发明的一些优选实施例中，结构单元选自：
在本发明的一些优选实施例中，结构单元选自：
在本发明的一些实施例中，R6选自以下结构：

R11a选自氢、氘、-C(＝O)R12a、-C(＝O)OR12a、-SO2R12a或者被0-3个取代基取代的6～10元芳基、5～10元杂芳基、3～6元环烷基、3～6元杂环烷基、C1-6烷基；R11a中，所述取代基选自氘、氟、氯、-OH、-NR12bR12c、-C(＝O)NR12bR12c、CN、C1-4烷基、C1-4烷氧基或者3～6元环烷基；R11a中，所述5～10元杂芳基、3～6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；R12a、R12b和R12c独立地选自氢、C1-4烷基、N,N-二甲基取代的C1-4烷基、3～6元环烷基；
R11b选自氢、氘、卤素、-CN、-OR12a、-NR12dR12e、-C(＝O)R12a、-C(＝O)OR12a、-C(＝O)NR12dR12e、-NR12dC(＝O)R12e、-SO2R12a、-SO2NR12dR12e、-NR12dSO2R12e或者被0-3个取代基取代的6～10元芳基、5～10元杂芳基、3～6元杂环烷基、3～6元环烷基、C1-6烷基；R11a中，所述取代基选自氘、氟、氯、-OH、-NR12bR12c、-C(＝O)NR12bR12c、CN、C1-4烷基、C1-4烷氧基或者3～6元环烷基；R11a中，所述5～10元杂芳基、3～6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；R12a、R12b、R12c、R12d和R12e独立地选自氢、C1-4烷基、N,N-二甲基取代的C1-4烷基、3～6元环烷基；
R11c、R11d独立地选自氢、氘或者被0-3个取代基取代的C1-4烷基；R11c、R11d中， 所述取代基选自氘、氟、氯。
在本发明的一些优选实施例中，R11a选自H、氘、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4羟基取代的烷基、3～6元环烷基、3～6元氟代环烷基、羟基取代的3～6元环烷基、C1-4烷酰基、3～6元环烷酰基、C1-4烷氧酰基、3～6元环烷氧酰基、C1-4烷磺酰基、3～6元环烷磺酰基、
R11b选自H、氘、氟、氯、氨基、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羟基取代的烷基、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、羟基取代的3～6元环烷基、C1-4烷酰基、3～6元环烷酰基、C1-4烷氧酰基、3～6元环烷氧酰基、C1-4烷磺酰基、3～6元环烷磺酰基、甲氨基、二甲基氨基、
R11c、R11d独立地选自氢、氘、甲基、氘代甲基、氟代甲基。
在本发明的一些实施例中，R6选自以下结构：


在本发明的一些实施例中，结构单元选自：

本发明还提供了一些具体化合物，所述化合物选自：
A系列：

B系列：
C系列：
D系列：

E系列：

F系列：

G系列：
H系列：
I系列：

J系列：
K系列：

L系列：


M系列：
N系列：
本发明还提供了一些具体化合物，所述化合物选自：
A系列：

B系列：
C系列：
D系列：
E系列：
F系列：

G系列：
H系列：
I系列：
J系列：
K系列：

L系列：
M系列：
N系列：

在本发明的一些实施例中，结构单元选自：
在本发明的一些实施例中，结构单元选自：
在本发明的一些实施例中，结构单元选自：


本发明还提供了一些化合物，所述化合物选自：
A系列：

B系列：

C系列：M系列：
其他：
第二方面，本发明提供了一种药物组合物，其以前述式I化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药为活性成分，辅以药学上可接受的载体。
本发明的进一步的目的在于提供一种制备本发明的药物组合物的方法，所述方法包括将含式I化合物或其药学上可接受的形式、或者它们的混合物、与一种或多种药学上可接受的载体组合。
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。
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。
在另一些实施方案中，本发明的化合物或药物组合物的施用可以与另外的治疗方法组合。所述另外的治疗方法可以选自，但不限于：放射疗法、化疗疗法、免疫疗法，或其组合。
本发明还涉及一种药物制剂，其以上述式I化合物或其药学上可接受的形式、或它们的混合物、或者本发明的药物组合物作为活性成分。在一些实施方案中，所述制剂的形式为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明的进一步的目的在于提供一种制品，例如以试剂盒形式提供。本文所用的制 品意图包括但不限于药盒和包装。本发明的制品包含：(a)第一容器；(b)位于第一容器中的药物组合物，其中所述组合物包含：第一治疗剂，所述第一治疗剂包括：含式I化合物或其药学上可接受的形式、或者它们的混合物；(c)任选存在的包装说明书，其说明所述药物组合物可用于治疗肿瘤病症(如下文所定义)；和(d)第二容器。
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。
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。
第三方面，本发明提供前述式I化合物，及相关具体化合物或其药学上可接受的形式、或者本发明的药物组合物在制备用于预防或治疗NLRP3相关疾病的药物中的用途。
本发明提供一种用于预防或治疗NLRP3相关疾病的方法，所述方法包括向有此需要的个体施用上述式I化合物或其药学上可接受的形式、或者本发明的药物组合物。
本发明提供上述式I化合物或其药学上可接受的形式或者本发明的药物组合物与另外的治疗方法组合用于预防或治疗NLRP3相关疾病的方法，所述另外的治疗方法包括但不限于：放射疗法、化疗疗法，免疫疗法、或其组合。
在一些实施方案中，所述NLRP3相关疾病包括：炎性疾病、自身免疫疾病、心血管系统疾病、癌症、肾系统疾病、胃肠道疾病、呼吸系统疾病、内分泌系统疾病或者中枢神经系统疾病。
在一些实施方案中，所述NLRP3相关疾病包括：隐热蛋白相关周期综合征(CAPS)、穆克尔-韦尔斯综合征(MWS)、家族性寒冷性自身炎性综合征(FCAS)、新生儿发病多系统炎性疾病(NOMID)、家族性地中海热(FMF)、非酒精性脂肪性肝炎、酒精性肝病、移植物抗宿主病、多发性硬化(MS)、类风湿性关节炎、I型/II型糖尿病及相关并发症(例如肾病、视网膜病)、牛皮癣、阿尔茨海默氏病、动脉粥样硬化、痛风、慢性肾疾病、脓毒症、肝纤维化、特发性肺纤维化、癫痫、神经病理性疼痛、抑郁症、帕金森病、哮喘、急性心肌梗塞、红斑狼疮、类风湿关节炎、克罗恩氏病、溃疡性结肠炎、炎症性肠病、 类风湿性关节炎、强制性脊髓炎、支气管哮喘、急性呼吸窘迫综合征、慢性阻塞性肺部疾病或者缺血性中风。
在进一步优选的实施方案中，本发明的化合物可以与放化疗或免疫疗法联用以预防或治NLRP3相关疾病。
本发明的有益效果：
本发明提供了一类并哒嗪类化合物及其用途，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。
术语定义：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。
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。
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。
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、C1-4、C1-5等，以及C1、C3、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、C7-10、C7-9、C8-9等以及C3、C4、C8、C10等。又例如，表述“3-10元”应理解为涵盖其中的任意亚范围以及的每个点值，例如3-4元、3-5元、3-6元、3-7元、4-5元、4-6元、5-8元、6-7元等以及3、6、7、10元等。还例如，表述“5-10元”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5-6元、5-7元、5-8元、5-9元、6-10元、7-8元等以及5、6、7、8、9、10元等。
本文中使用，除非另有说明，表示单键或者双键。
在本发明中，除非另有说明，卤素是指氟、氯、溴或碘。
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、异丙基、异丁基、叔丁基、正戊基、2-戊基、新戊基、正己基、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。
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、环己基、环庚基、环壬基、环戊烯、环己烯等；或双环环烷基，包括稠环、桥环或螺环，诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基、双环[5.2.0]壬基、十氢化萘基等。例如，“C3-12环烷基”指具有3-12个环碳原子(如3、6、7、10或12个)的环烷基。本发明中的环烷基或亚环烷基任选地被一个或多个本发明所描述的取代基取代。
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。例如，“3-8元杂环烷基”是指具有3至8个环原子的杂环烷基。常见的杂环烷基包括(但不限于)环氧乙烷基、氧代环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、四氢吡喃基、环丁砜等。本发明中的杂环烷基、亚杂环烷基或杂环任选地被一个或多个本发明所描述的取代基(例如氧代基)取代。
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。卤代烷基的实例如-CH2F、-CHF2、-CCl3、-C2Cl5、-CH2CF3、-CH2Cl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。
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-CHF2、-CF3、-C2F5、-CH2CF3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。
在本发明中，除非另有说明，“烯基”是指具有至少一个C＝C双键的、直链或支链的脂肪族烃基。例如，“C2-4烯基”是指具有2至4个碳原子的烯基。常见的烯基包括(但不限于)乙烯基、丙烯基、正丁烯基、3-甲基丁-2-烯基、正戊烯基、正辛烯基、正癸烯基等。本发明中的烯基任选地被一个或多个本发明所描述的取代基取代。
在本发明中，除非另有说明，“炔基”是指具有至少一个C≡C三键的、直链或支链的脂肪族烃基。例如，“C2-4炔基”是指具有2至4个碳原子的炔基。常见的炔基包括(但不限于)乙炔基、2-丙炔基、2-丁炔基、1,3-丁二炔基等。本发明中的炔基任选地被一个或多个本发明所描述的取代基取代。
在本发明中，除非另有说明，“芳基”或“芳环”指具有共轭π电子系统的全碳单环或稠合多环(如双环)芳族基团或芳族环。如本文中所使用，术语“C6-10芳基”指含有6-10个碳原子的芳族基团。其实例包括但不限于苯基和萘基等。本发明中的芳基或芳环任选地被一个或多个本发明所描述的取代基取代。
在本发明中，除非另有说明，“杂芳基”或“杂芳环”指具有共轭π电子系统的芳族环，其中一个或多个(例如1、2或3个)环原子是选自N、O、P和S的杂原子，其余的环原子为C。杂芳基或杂芳环可以用环原子的数目表征。例如，5-12元杂芳基可以含有5-12个(例如5、6、7、8、9、10、11或12个)环原子，特别是含有5、6、9、10个环原子。杂芳基的实例为例如，噻吩基、呋喃基、噁唑基、吡唑基、吡啶基、吡嗪基、异噁唑基、三唑基、噻二唑基等；该术语还涵盖杂芳基或杂芳环可任选地进一步稠合于芳基、或杂芳基环上，形成稠环的情况。本发明中的杂芳基或杂芳环任选地被一个或多个本发明所描述的取代基取代。
在本发明中，除非另有说明，“氧代基”是指其与其相连的碳原子一起形成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。
本发明还包括所有药学上可接受的同位素化合物，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。本发明的化合物中的同位素的实例包括(但不限于)氢同位素(例如氘(2H)、氚(3H))；碳同位素(例如13C及14C)；氯同位素(例如37Cl)；碘同位素(例如125I)；氮同位素(例如13N及15N)；氧同位素(例如17O及18O)；磷同位素(例如32P)；及硫同位素(例如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。
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。
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。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、草酸盐、马来酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、4-胺基水杨酸盐、萘二磺酸盐等。这些盐可通过本专利已知的方法制备。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、锂盐、铵盐、 钙盐、镁盐、铁盐、锌盐、铜盐、铝盐等。优选的无机盐为铵盐、钠盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、胆碱己咖啡因。
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。本发明的化合物本身也可以是酯。
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。
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。
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。
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。
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。
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。
在本发明中，除非另有说明，“肿瘤”包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻炎癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
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。
不违背本领域常识基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
具体实施方式
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。
本发明实施例中所用试剂和原料均市售可得。
表1本发明中字母缩写及其含义

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。
MS的测定用Agilent SQD(ESI)质谱仪(生产商：Agilent，信号：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)。
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。
柱层析一般使用青岛海洋100-200、200-300目硅胶为载体。
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。
中间体int-1：2-(2-甲氧基-6-甲基-4-三氟甲基苯基)-4，4，5，5-四甲基-1，3，2-二氧杂硼烷
第一步：称取int-1a(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int-1b(14.1g,80.0mmol，淡黄色液体，产率88％),MS:[M-H]+＝175.0。
第二步：将化合物int-1b(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int-1c(20.7g,68.5mmol，淡黄色固体，产率86％)，MS:[M-H]-＝301。
第三步：将化合物int-1c(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int-1d(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)。
第四步：将化合物int-1d(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int-1(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)。
中间体int-2：(2-羟基-6-甲基-4-(三氟甲基)苯基)硼酸
将化合物int-1(3.16g，10mmol)溶于DCM(100mL),氮气保护下加入BBr3(1M,20mL),-10℃反应一小时,MeOH淬灭，减压除去溶剂，残留物柱层析分离(DCM:MeOH＝10:1)得到目标化合物int-2(1.19g，54％收率)。
中间体int-3：2-(4-甲氧基苯并[b]噻吩-5-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
第一步：将CuBr2(146.5g,656mmol)加入到EtOAc(250mL)中，80℃搅拌10分钟。然后将化合物INT1a(25.0g,164mmol)溶于氯仿(250mL)中再加入到上述悬浮液中，80℃回流反应过夜。反应完全后减压浓缩，残余物用EtOAc(500mL)打浆0.5h，过滤，滤液浓缩至干得到目标化合物int-3b(46.0g,148mmol，浅棕色固体，产率90％),MS:[M+H]+＝309.0,311.0,313.0。
第二步：将化合物int-3b(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int-3c(31.0g,135mmol，浅棕色固体，产率93％)，MS:[M-H]-＝227.0,229.0。
第三步：将化合物int-3c(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int-3d(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)。
第四步：将化合物int-3d(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int-3(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)。
中间体int-4：2-(1-(二氟亚甲基)-4-甲氧基-2,3-二氢-1H-茚-5-基)-4,4,5,5-四甲 基-1,3,2-二氧杂硼烷
第一步：将化合物3-溴-2-羟基苯甲醛(25.0g,104.65mmol),CH3I(60.63g,373.14mmol),K2CO3(34.38g,248.76mmol)溶于DMF(200mL)中,加热到50℃反应3小时。反应液中加入水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，得到目标化合物int-4b(黄色油状液体,22.5g,产率：84％)，无需进一步纯化，MS/ESI[M+H]+:215.1。
第二步：在0℃下，将Et3N(12.71g,125.58mmol)滴加到HOOH(14.45g,313.95mmol)中，随后室温反应30分钟，然后加入溶有化合物int-4b(22.5g,104.65mmol)和丙二酸环(亚)异丙酯(15.08g,104.65mmol)的DMF(200mL)溶液,加热到100℃反应过夜。反应液中加入NaOH水溶液,调节PH＝9,乙酸乙酯萃取,水相加入HCl(3M),调节PH＝5,乙酸乙酯萃取,合并有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，残留物柱层析分离(PE:EA＝5:1)得到目标化合物int-4c(白色固体，20.3g,产率：75％),MS/ESI[M+H]+:259.1。
第三步：将多聚磷酸(200g)加热到90℃，加入化合物int-4c(20.3g,78.34mmol),反应一小时后停止加热，加入水溶液，待溶液冷却至室温，二氯甲烷萃取，饱和NaCl水溶液洗涤有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，残留物柱层析分离(PE:EA＝5:1)得到目标化合物int-4d(黄色固体，9.7g,产率：51.3％)，MS/ESI[M+H]+:241.1。
第四步：将化合物int-4d(4.7g,19.50mmol),2-(二氟甲烷磺酰基)吡啶(5.65g,29.25mmol)溶于DMF(30mL)中，冷却至-50℃，氮气保护下加入叔丁醇钾的DMF溶液,升温至-40℃，反应3小时后，加入饱和氯化铵水溶液(26ml)淬灭，随后加入3N HCl(26ml),升温至室温，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，残留物柱层析分离(PE:EA＝20:1)得到目标化合物int-4e(黄色油状液体，1.92g,产率：35.8％)1H NMR(400MHz,CDCl3)δ7.53(d,J＝7.7Hz,1H),7.11(d,J＝7.7Hz,1H),3.75(s,3H),3.01–2.95(m,2H),2.76–2.65(m,2H)。
第五步：氮气保护下，将化合物int-4e(1.92g,6.98mmol)联硼酸频那醇酯(2.66g,10.47mmol),PdCl2(dppf)(0.57g,0.7mmol),乙酸钾(2.05g,20.94mmol)溶于1,4-二氧六环溶液中，100℃回流过夜，反应完全后，恢复至室温，加水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压除去溶剂，残留物柱层析分离(PE:EA＝10:1)得到目标化合物int-4(黄色固体，1.02g,产率：45.4％)。1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),3.81(s,3H),2.97–2.82(m,2H),2.62–2.51(m,2H),1.30(s,12H)。
中间体int-5：2-(4-甲氧基苯并呋喃-5-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷
2-(4-甲氧基苯并呋喃-5-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷的制备参照中间体int-3。MS/ESI[M+H]+:275.1。
实施例1：2-(7-(2-羟丙基)-7H-吡咯并[2,3-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚
第一步：称量起始原料化合物1(1eq,25g)，三甲基硅乙炔(1.2eq)，三乙胺(2.5eq)，溴化亚铜(0.1eq)，(PPh3)2PdCl2(0.05eq)，将所有物料转至2L的三颈瓶内，加入甲苯(500mL)进行氮气换气三次，然后置于室温下进行反应，1h后LC/MS检测反应完全。加入乙酸乙酯(100mL)到反应混悬液中，然后通过硅藻土过滤，滤饼再用100mL的乙 酸乙酯进行淋洗，合并有机相后进行浓缩。将浓缩后的固体分散在100mL的乙醚中，搅拌15min后进行过滤，滤饼抽干以后得化合物2，不需要进一步纯化直接用于下一步反应。
第二步：将上一步得到的粗品转至1L烧瓶中，然后加入400mL的甲醇进行搅拌溶解。加热至65℃，然后分批多次加入碳酸钾固体(1eq)。反应1h后进行LC/MS检测反应完全。将反应混悬液通过硅藻土进行过滤，滤液不做进一步处理。
第三步：将上一步的滤液加热至65℃，然后滴加6N的盐酸至体系的盐酸浓度达到1N。室温下搅拌4h后进行LC/MS检测显示反应完全。将反应液进行浓缩，然后调节pH为弱碱性，用乙酸乙酯进行萃取。合并的有机相进行浓缩，然后用乙醚进行打浆，之后进行过滤，滤饼抽干即可得到化合物4(15.4g)。
第四步：将化合物4(15.4g，1eq)和碳酸钾(2eq)转至1L的烧瓶内，加入400mL的二氧六环，加热至80℃。然后滴加TsCl(1.1eq)的二氧六环溶液，滴毕后反应6h后进行LC/MS检测。将混悬液通过硅藻土过滤，滤液进行浓缩。将浓缩物分散在乙醚(100mL)中,搅拌15min后进行过滤，得化合物5。
第五步：将化合物5(15.4g,50mmol)，int-1(17.4g,55mmol,1.1equiv),碳酸钾(13.8g,100mmol,2equiv)和(dppf)PdCl2(1.8g,2.5mmol,0.05equiv)加入到500mL三颈瓶内，加入二氧六环/乙醇/水＝7:3:4(共计200mL)作为溶剂，置换氮气三次后转入80℃的油浴内反应2h后进行LC/MS检测。将反应液进行浓缩后用乙酸乙酯进行萃取，合并有机相后进行浓缩，粗产品通过柱层析纯化得化合物6。
第六步：将化合物6溶在100mL甲醇/水中(混悬体系)，加入氢氧化钾调节pH至14左右.将体系转至50℃油浴中反应1h。反应降至室温后将二氯甲烷300mL加入反应体系内进行萃取，有机相经无水硫酸钠干燥后减压浓缩得到粗品。将固体分散在50mL乙醚中，并持续搅拌0.5h后过滤，滤饼用少量乙醚淋洗，干燥后得到化合物7。
第七步：将化合物7(308mg,1mmol)，碳酸铯(650mg,2mmol)，化合物8(1.2mmol)加入到20mL乙腈中，加热至80℃反应1h。反应完全后降至室温，浓缩除去溶剂后用二氯甲烷萃取，有机相合并旋干后柱层析纯化得化合物8。
第八步：将上一步所得化合物8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A1。MS/ESI:[M+H]+＝352.2。1H NMR(400MHz,DMSO)δ14.13(s,1H),8.78(s,1H),8.28(s,1H),8.08(s,1H),7.30(d,J＝2.4Hz,2H),6.73(d,J＝2.4Hz,1H),5.03(d,J＝5.0Hz,1H),4.45(dd,J＝13.8,4.3Hz,1H), 4.33(dd,J＝13.8,7.4Hz,1H),4.16(p,J＝5.9Hz,1H),2.35(s,3H),1.12(d,J＝6.2Hz,3H)。
实施例2～35、实施例628～673和实施例686～689的合成方法参照实施例1，得到目标化合物A2～A85。
表2本发明化合物A2～A85










实施例3化合物A3：1H NMR(400MHz,Chloroform-d)δ8.02–7.95(m,1H),7.89(s,1H),7.20(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.57(d,J＝3.5Hz,1H),5.27–5.17(m,1H),3.07(dd,J＝11.5,3.8Hz,1H),2.76–2.63(m,2H),2.51(s,3H),2.36(s,3H),2.36–2.30(m,1H),2.17–1.99(m,2H),1.92–1.75(m,2H)。
实施例5化合物A5：1H NMR(400MHz,Chloroform-d)δ7.87(s,1H),7.66(d,J＝3.5Hz,1H),7.19(d,J＝1.9Hz,1H),7.11(d,J＝1.8Hz,1H),6.61(d,J＝3.4Hz,1H),4.74(ddd,J＝12.3,10.0,4.2Hz,1H),4.06(td,J＝10.0,4.3Hz,1H),2.46(s,3H),2.28–2.12(m,2H),2.04(qd,J＝12.4,3.8Hz,1H),1.96–1.84(m,2H),1.61–1.44(m,3H)。
实施例11化合物A11：1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.08(d,J＝3.5Hz,1H),7.80(s,1H),7.16(d,J＝1.8Hz,1H),7.12(d,J＝1.8Hz,1H),6.62(d,J＝3.5Hz,1H),5.75–5.67(m,1H),3.06(td,J＝8.6,4.2Hz,1H),2.92(dd,J＝9.9,3.7Hz,1H),2.85 (dd,J＝9.9,6.8Hz,1H),2.63–2.54(m,1H),2.49–2.43(m,1H),2.39(s,3H),2.11–2.02(m,4H)。
实施例12化合物A12：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.75(d,J＝3.4Hz,1H),7.21(d,J＝1.9Hz,1H),7.15–7.10(m,1H),6.57(d,J＝3.4Hz,1H),4.72(dd,J＝14.1,4.8Hz,1H),4.33(dd,J＝14.1,5.5Hz,1H),3.14–3.06(m,1H),2.90–2.83(m,1H),2.53(s,3H),2.38(s,3H),2.32–2.25(m,1H),1.72–1.52(m,4H).19F NMR(376MHz,Chloroform-d)δ-63.06。
实施例21化合物A21：1H NMR(400MHz,DMSO)：δ13.85(s,1H),8.78(s,1H),8.26,8.8.26(d,J＝8.4Hz,1H),7.98(s,1H),7.30(d,J＝3.2Hz,1H),6.78(d,J＝3.2Hz,1H),5.50(s,2H),2.30(s,3H)。
实施例22化合物A22：1H NMR(400MHz,DMSO)：δ9.44(s,1H),8.09(s,1H),8.05(d,J＝2.5Hz,1H),6.72(d,J＝2.6Hz,1H),6.59(d,J＝15.4Hz,2H),5.02(d,J＝5.1Hz,1H),4.42(dd,J＝13.6,4.7Hz,1H),4.31(dd,J＝13.6,4.8Hz,1H),4.12-4.02(m,1H),2.31(s,3H),2.27(s,3H),1.19(s,3H)。
实施例31化合物A31：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.71(d,J＝3.4Hz,1H),7.22–7.18(m,1H),7.13–7.10(m,1H),6.59(d,J＝3.4Hz,1H),4.65(dd,J＝14.5,3.4Hz,1H),4.48(dd,J＝14.6,7.1Hz,1H),4.05–3.98(m,1H),3.91(ddd,J＝11.5,3.3,1.6Hz,1H),3.65(td,J＝11.5,2.5Hz,1H),2.88(dt,J＝11.3,1.9Hz,1H),2.66(dq,J＝11.4,1.9Hz,1H),2.50(s,3H),2.27(s,3H),2.13(td,J＝11.5,3.4Hz,1H),1.85(t,J＝10.7Hz,1H).19F NMR(376MHz,Chloroform-d)δ-63.05。
实施例33化合物A33：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.81(d,J＝3.4Hz,1H),7.21(d,J＝1.9Hz,1H),7.15–7.10(m,1H),6.60(d,J＝3.5Hz,1H),5.22(tt,J＝9.7,4.0Hz,1H),3.73–3.63(m,2H),3.24(dd,J＝11.0,3.9Hz,1H),2.97–2.88(m,1H),2.73(t,J＝10.2Hz,1H),2.65(q,J＝5.2Hz,2H),2.52(s,3H),2.38(t,J＝10.4Hz,1H),2.27–2.18(m,1H),2.14–2.01(m,1H),1.98–1.81(m,2H)。
实施例628化合物A36：1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.57(d,J＝3.4Hz,1H),7.20(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.59(d,J＝3.4Hz,1H),4.47–4.35(m,2H),2.75(d,J＝11.1Hz,1H),2.67(d,J＝11.2Hz,1H),2.50(s,3H),2.47–2.35(m,1H),2.26(s,3H),2.10(t,J＝11.2Hz,1H),1.96(t,J＝10.4Hz,1H),1.80–1.57(m,3H),1.23–1.11(m,1H)。
实施例629化合物A37：1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.70(d,J＝ 3.5Hz,1H),7.22(d,J＝1.8Hz,1H),7.13(d,J＝1.8Hz,1H),6.61(d,J＝3.4Hz,1H),4.65(dd,J＝14.6,3.4Hz,1H),4.42(dd,J＝14.6,7.4Hz,1H),4.12–4.04(m,1H),3.93(dd,J＝11.5,2.6Hz,1H),3.83(dd,J＝11.3,2.7Hz,1H),3.76–3.68(m,2H),3.63–3.55(m,1H),3.33(dd,J＝11.5,10.0Hz,1H),2.52(s,3H)。
实施例630化合物A38：1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.88(t,J＝2.9Hz,1H),7.21(d,J＝1.9Hz,1H),7.13(d,J＝1.9Hz,1H),6.62(d,J＝3.5Hz,1H),5.65–5.51(m,1H),5.18–5.00(m,1H),3.00(dd,J＝10.5,4.7Hz,1H),2.85(t,J＝11.3Hz,1H),2.77(dt,J＝11.7,3.8Hz,2H),2.52(s,3H),2.42(s,3H),2.26–2.13(m,2H)。
实施例631化合物A39：1H NMR(400MHz,Chloroform-d)δ7.95(d,J＝3.5Hz,1H),7.90(s,1H),7.21(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.54(d,J＝3.5Hz,1H),6.26–6.21(m,1H),5.96–5.91(m,1H),5.85–5.81(m,1H),3.39–3.30(m,1H),2.93–2.83(m,3H),2.51(s,3H),2.33(s,3H)。
实施例632化合物A40：1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.71(d,J＝3.4Hz,1H),7.21(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.58(d,J＝3.4Hz,1H),4.64(t,J＝6.5Hz,2H),3.04(t,J＝6.5Hz,2H),2.66–2.60(m,4H),2.52(s,3H),1.83–1.77(m,4H)。
实施例633化合物A41：1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.70(d,J＝3.4Hz,1H),7.22(d,J＝1.9Hz,1H),7.12(d,J＝1.8Hz,1H),6.59(d,J＝3.4Hz,1H),4.62(t,J＝6.2Hz,2H),2.92(t,J＝6.2Hz,2H),2.84(p,J＝6.4Hz,1H),2.79–2.60(m,8H),2.51(s,3H),1.13(d,J＝6.5Hz,6H)。
实施例634化合物A42：1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.71(d,J＝3.4Hz,1H),7.20(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.58(d,J＝3.4Hz,1H),4.61(t,J＝6.3Hz,2H),2.89(t,J＝6.3Hz,2H),2.71–2.41(m,13H),1.10(t,J＝7.2Hz,3H)。
实施例635化合物A43：1H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.71(d,J＝3.5Hz,1H),7.19(d,J＝1.9Hz,1H),7.11(d,J＝1.9Hz,1H),6.58(d,J＝3.4Hz,1H),4.60(t,J＝6.2Hz,2H),2.88(t,J＝6.2Hz,2H),2.71–2.34(m,11H),2.29(s,3H)。
实施例636化合物A44：1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.69(d,J＝3.5Hz,1H),7.19(d,J＝1.9Hz,1H),7.10(d,J＝1.9Hz,1H),6.57(d,J＝3.4Hz,1H),4.60(t,J＝6.3Hz,2H),3.68–3.56(m,2H),2.84(t,J＝6.3Hz,2H),2.77(dt,J＝10.2,1.8Hz,2H),2.48(s,3H),1.88(dd,J＝11.3,10.0Hz,2H),1.15(d,J＝6.3Hz,6H)。
实施例637化合物A45：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.71(d,J＝ 3.4Hz,1H),7.21(d,J＝1.9Hz,1H),7.12(d,J＝2.0Hz,1H),6.58(d,J＝3.4Hz,1H),4.67–4.48(m,2H),3.82–3.72(m,1H),3.67–3.55(m,2H),3.30–3.11(m,2H),2.83(dt,J＝11.6,2.9Hz,1H),2.70(dt,J＝13.8,5.5Hz,1H),2.54–2.44(m,5H),0.82(d,J＝6.3Hz,3H)。
实施例638化合物A46：1H NMR(400MHz,DMSO-d6)δ7.98(d,J＝3.4Hz,1H),7.81(s,1H),7.24(d,J＝1.8Hz,1H),7.13(d,J＝1.7Hz,1H),6.61(d,J＝3.4Hz,1H),4.47–4.33(m,2H),3.04–2.86(m,3H),2.68–2.53(m,2H),2.35(tt,J＝7.1,3.7Hz,1H),2.06(s,3H),1.76–1.64(m,2H),1.57–1.44(m,1H)。
实施例639化合物A47：1H NMR(400MHz,DMSO-d6)δ8.11(d,J＝3.5Hz,1H),7.80(s,1H),7.18(d,J＝1.9Hz,1H),7.15(s,1H),6.62(d,J＝3.5Hz,1H),5.66–5.56(m,1H),3.28–3.22(m,2H),3.15(dd,J＝11.6,4.9Hz,1H),3.07–3.02(m,1H),2.47–2.37(m,1H),2.17–2.09(m,1H),2.07(s,3H)。
实施例640化合物A48：1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.08(d,J＝3.5Hz,1H),7.80(s,1H),7.16(d,J＝1.8Hz,1H),7.12(d,J＝1.8Hz,1H),6.62(d,J＝3.5Hz,1H),5.75–5.67(m,1H),3.06(td,J＝8.6,4.2Hz,1H),2.92(dd,J＝9.9,3.7Hz,1H),2.85(dd,J＝9.9,6.8Hz,1H),2.63–2.54(m,1H),2.49–2.43(m,1H),2.39(s,3H),2.11–2.02(m,4H)。
实施例641化合物A49：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.67(d,J＝3.5Hz,1H),7.21(d,J＝1.9Hz,1H),7.13(d,J＝1.9Hz,1H),6.60(d,J＝3.4Hz,1H),4.75(t,J＝5.1Hz,1H),4.61(d,J＝5.1Hz,2H),3.46(s,6H),2.52(s,3H)。
实施例642化合物A50：1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),7.94(d,J＝3.3Hz,1H),7.81(s,1H),7.16(s,2H),6.59(d,J＝3.2Hz,1H),4.64(t,J＝5.2Hz,2H),3.83(t,J＝5.2Hz,2H),3.28(s,3H),2.07(s,3H)。
实施例643化合物A51：1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),7.82(d,J＝3.5Hz,1H),7.80(s,1H),7.14(d,J＝1.8Hz,1H),7.11(d,J＝1.8Hz,1H),6.59(d,J＝3.4Hz,1H),5.43(s,2H),3.17(s,3H),2.88(s,3H),2.05(s,3H)。
实施例644化合物A52：1H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.68(d,J＝3.5Hz,1H),7.22–7.19(m,1H),7.13(d,J＝1.8Hz,1H),6.61(d,J＝3.4Hz,1H),4.67–4.62(m,2H),4.17–4.12(m,2H),2.50(s,3H)。
实施例645化合物A53：1H NMR(400MHz,Chloroform-d)δ8.70(d,J＝4.9Hz,2H),7.95(s,1H),7.75(d,J＝3.5Hz,1H),7.24(t,J＝4.9Hz,1H),7.20(d,J＝1.9Hz,1H),7.12 (s,1H),6.70(d,J＝3.5Hz,1H),5.96(s,2H),2.53(s,3H)。
实施例646化合物A54：1H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.71(d,J＝3.4Hz,1H),7.21(d,J＝1.9Hz,1H),7.12(d,J＝2.0Hz,1H),6.58(d,J＝3.4Hz,1H),4.60(t,J＝6.3Hz,2H),2.84(t,J＝6.3Hz,2H),2.51(s,3H),2.33(s,6H)。
实施例647化合物A55：1H NMR(400MHz,Chloroform-d)δ10.96(s,1H),7.94(s,1H),7.62(d,J＝3.5Hz,1H),7.22(d,J＝1.9Hz,1H),7.14(s,1H),6.69(d,J＝3.5Hz,1H),5.30(s,2H),3.83(s,3H),2.53(s,3H)。
实施例648化合物A56：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.77(d,J＝3.4Hz,1H),7.21(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.59(d,J＝3.4Hz,1H),4.75(dd,J＝14.1,2.8Hz,1H),4.44(dd,J＝14.1,7.1Hz,1H),4.36(qd,J＝7.0,2.8Hz,1H),3.95–3.87(m,1H),3.84–3.76(m,1H),2.51(s,3H),2.17–2.08(m,1H),1.97–1.76(m,2H),1.69–1.58(m,1H)。
实施例649化合物A57：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.71(d,J＝3.4Hz,1H),7.22–7.18(m,1H),7.13–7.10(m,1H),6.59(d,J＝3.4Hz,1H),4.65(dd,J＝14.5,3.4Hz,1H),4.48(dd,J＝14.6,7.1Hz,1H),4.05–3.98(m,1H),3.91(ddd,J＝11.5,3.3,1.6Hz,1H),3.65(td,J＝11.5,2.5Hz,1H),2.88(dt,J＝11.3,1.9Hz,1H),2.66(dq,J＝11.4,1.9Hz,1H),2.50(s,3H),2.27(s,3H),2.13(td,J＝11.5,3.4Hz,1H),1.85(t,J＝10.7Hz,1H).19F NMR(376MHz,Chloroform-d)δ-63.05。
实施例650化合物A58：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.75(d,J＝3.4Hz,1H),7.21(d,J＝1.9Hz,1H),7.15–7.10(m,1H),6.57(d,J＝3.4Hz,1H),4.72(dd,J＝14.1,4.8Hz,1H),4.33(dd,J＝14.1,5.5Hz,1H),3.14–3.06(m,1H),2.90–2.83(m,1H),2.53(s,3H),2.38(s,3H),2.32–2.25(m,1H),1.72–1.52(m,4H).19F NMR(376MHz,Chloroform-d)δ-63.06。
实施例651化合物A59：1H NMR(400MHz,Chloroform-d)δ7.82(s,1H),7.56(d,J＝3.5Hz,1H),7.28(s,1H),7.16(d,J＝1.8Hz,1H),7.09(d,J＝1.8Hz,1H),6.53(d,J＝3.4Hz,1H),4.50(d,J＝5.5Hz,2H),4.23(dt,J＝11.2,5.4Hz,1H),2.35(s,3H),2.29–2.08(m,3H),1.96–1.86(m,1H).19F NMR(376MHz,Chloroform-d)δ-62.92。
实施例652化合物A60：1H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.57(d,J＝3.4Hz,1H),7.17(d,J＝1.9Hz,1H),7.14(s,1H),7.10(d,J＝1.2Hz,1H),6.56(d,J＝3.4Hz,1H),4.59–4.45(m,2H),4.26(dt,J＝10.9,5.5Hz,1H),2.39(s,3H),2.35–2.19(m,3H),2.21–2.09(m,1H),1.99–1.88(m,1H)。
实施例653化合物A61：1H NMR(400MHz,Chloroform-d)δ7.90(d,J＝0.8Hz,1H),7.71(dd,J＝14.9,3.5Hz,1H),7.22(d,J＝2.2Hz,1H),7.12(s,1H),6.59(t,J＝3.6Hz,1H),5.16–4.91(m,1H),3.92–3.77(m,2H),3.35–3.21(m,1H),3.15–3.08(m,1H),2.94–2.69(m,2H),2.51(s,3H),2.33–2.17(m,2H),2.01–1.87(m,2H),1.05(dd,J＝6.7,1.8Hz,3H)。
实施例654化合物A62：1H NMR(400MHz,Chloroform-d)δ8.05(d,J＝3.4Hz,1H),7.90(s,1H),7.21(d,J＝1.8Hz,1H),7.14–7.09(m,1H),6.57(d,J＝3.5Hz,1H),5.29–5.19(m,1H),3.17(dd,J＝11.1,3.8Hz,1H),2.97–2.84(m,2H),2.87–2.76(m,1H),2.61–2.52(m,1H),2.51(s,3H),2.19–2.05(m,2H),1.92–1.77(m,2H),1.10(d,J＝6.6Hz,6H)。
实施例655化合物A63：1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.90(s,1H),7.21(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.58(d,J＝3.5Hz,1H),5.22(tt,J＝8.4,4.2Hz,1H),2.99(d,J＝11.1Hz,1H),2.82(p,J＝7.8Hz,1H),2.69–2.56(m,2H),2.52(s,3H),2.32–2.19(m,1H),2.17–1.99(m,4H),1.97–1.87(m,2H),1.85–1.64(m,4H)。
实施例656化合物A64：1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.91(s,1H),7.21(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.60(d,J＝3.5Hz,1H),5.27(tt,J＝8.4,4.1Hz,1H),4.68(p,J＝6.5Hz,4H),3.60(p,J＝6.5Hz,1H),2.96(dd,J＝11.0,3.7Hz,1H),2.68–2.55(m,2H),2.51(s,3H),2.35–2.29(m,1H),2.21–2.07(m,2H),1.94–1.79(m,2H)。
实施例657化合物A65：1H NMR(400MHz,Chloroform-d)δ8.00(d,J＝12.0Hz,1H),7.91(s,1H),7.21(d,J＝1.9Hz,1H),7.13(d,J＝1.8Hz,1H),6.59(d,J＝3.5Hz,1H),5.24(tt,J＝8.7,3.7Hz,1H),4.00–3.93(m,1H),3.92–3.83(m,1H),3.81–3.69(m,2H),3.25–3.00(m,2H),2.82(t,J＝9.7Hz,1H),2.69(q,J＝8.3,6.4Hz,1H),2.52(s,3H),2.21–1.98(m,4H),1.95–1.80(m,3H)。
实施例658化合物A66：1H NMR(400MHz,Chloroform-d)δ8.02(d,J＝3.6Hz,1H),7.91(s,1H),7.22(d,J＝1.9Hz,1H),7.13(d,J＝1.9Hz,1H),6.58(d,J＝3.4Hz,1H),5.28–5.19(m,1H),4.04(dd,J＝11.1,4.3Hz,2H),3.38(tt,J＝12.0,2.3Hz,2H),3.26–3.20(m,1H),2.92–2.80(m,2H),2.68–2.56(m,2H),2.53(s,3H),2.19–2.06(m,2H),1.91–1.81(m,2H),1.79–1.75(m,2H),1.70–1.63(m,2H)。
实施例659化合物A67：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.70(d,J＝3.4Hz,1H),7.21(d,J＝1.9Hz,1H),7.12(dd,J＝1.9,1.1Hz,1H),6.60(d,J＝3.4Hz,1H), 4.64(dd,J＝14.6,3.4Hz,1H),4.42(dd,J＝14.6,7.3Hz,1H),4.11–4.04(m,1H),3.93(dd,J＝11.5,2.6Hz,1H),3.83(dd,J＝11.4,2.7Hz,1H),3.75–3.68(m,2H),3.59(td,J＝11.8,2.8Hz,1H),3.33(dd,J＝11.5,10.0Hz,1H),2.51(s,3H)。
实施例660化合物A68：1H NMR(400MHz,Chloroform-d)δ7.88(d,J＝10.8Hz,1H),7.63–7.50(m,1H),7.18(d,J＝2.1Hz,1H),7.09(d,J＝2.1Hz,1H),6.59(dd,J＝14.2,3.4Hz,1H),4.47(dd,J＝14.1,6.7Hz,1H),4.36–3.99(m,2H),3.69–3.54(m,1H),3.29–2.68(m,2H),2.44(d,J＝4.3Hz,3H),2.33–2.21(m,1H),2.01(d,J＝53.8Hz,3H),1.84–1.70(m,2H),1.55–1.30(m,2H)。
实施例661化合物A69：1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.72(d,J＝3.4Hz,1H),7.21(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.60(d,J＝3.4Hz,1H),4.66(dd,J＝14.5,3.5Hz,1H),4.49(dd,J＝14.5,7.1Hz,1H),4.06–3.99(m,1H),3.94–3.88(m,1H),3.66(td,J＝11.4,2.5Hz,1H),2.88(dt,J＝11.2,2.0Hz,1H),2.71–2.64(m,1H),2.52(s,3H),2.28(s,3H),2.13(td,J＝11.5,3.4Hz,1H),1.86(t,J＝10.7Hz,1H)。
实施例662化合物A70：1H NMR(400MHz,Chloroform-d)δ10.94(s,1H),7.88(s,1H),7.75(d,J＝3.5Hz,1H),7.17(d,J＝1.9Hz,1H),7.10(d,J＝2.0Hz,1H),6.60(d,J＝3.5Hz,1H),5.08–4.96(m,1H),4.00(dd,J＝12.0,4.1Hz,1H),3.75–3.66(m,2H),3.23–3.13(m,1H),3.03(q,J＝7.4Hz,2H),2.51–2.39(m,4H),2.27–2.19(m,1H),2.02–1.81(m,2H),1.39(t,J＝7.4Hz,3H)。
实施例663化合物A71：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.77(d,J＝3.5Hz,1H),7.20(d,J＝1.9Hz,1H),7.14–7.11(m,1H),6.61(d,J＝3.5Hz,1H),5.07–4.96(m,1H),3.99(dd,J＝12.0,4.2Hz,1H),3.80–3.67(m,2H),3.24–3.14(m,1H),3.04–2.91(m,2H),2.56–2.45(m,4H),2.29–2.20(m,1H),2.04–1.95(m,1H),1.94–1.82(m,3H),1.07(t,J＝7.4Hz,3H)。
实施例664化合物A72：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.73(d,J＝3.5Hz,1H),7.22–7.19(m,1H),7.14–7.11(m,1H),6.62(d,J＝3.5Hz,1H),5.18–5.07(m,1H),3.99–3.91(m,1H),3.73–3.64(m,1H),3.54(dd,J＝12.1,9.7Hz,1H),3.17–3.08(m,1H),2.87(s,6H),2.50(s,3H),2.36–2.22(m,2H),2.02–1.84(m,2H)。
实施例665化合物A73：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.69(d,J＝3.5Hz,1H),7.21(d,J＝1.9Hz,1H),7.12(d,J＝1.9Hz,1H),6.61(d,J＝3.5Hz,1H),5.19–5.10(m,1H),4.04–3.98(m,1H),3.67(dt,J＝13.2,4.0Hz,1H),3.29(dd,J＝12.6,10.4Hz,1H),3.01–2.93(m,1H),2.89(s,6H),2.51(s,3H),2.37–2.30(m,1H),2.28–2.19(m, 1H),1.99–1.83(m,2H)。
实施例666化合物A74：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.69(d,J＝3.5Hz,1H),7.20(d,J＝2.0Hz,1H),7.12(d,J＝1.9Hz,1H),6.60(d,J＝3.5Hz,1H),5.03–4.92(m,1H),4.77(d,J＝7.3Hz,1H),4.24(dd,J＝13.3,3.9Hz,1H),4.03–3.89(m,2H),3.46(dd,J＝13.2,9.6Hz,1H),3.12–3.01(m,1H),2.49(s,3H),2.36–2.29(m,2H),1.95–1.77(m,2H)。
实施例667化合物A75：1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),7.99(d,J＝3.4Hz,1H),7.76(s,1H),7.15–7.03(m,3H),6.76(dd,J＝2.6,1.5Hz,1H),6.63–6.51(m,3H),5.56(s,2H),2.80(s,6H),2.01(s,3H)。
实施例668化合物A76：1H NMR(400MHz,Methanol-d4)δ8.64(s,1H),8.46(d,J＝4.4Hz,1H),7.97(d,J＝3.3Hz,1H),7.92–7.81(m,2H),7.40(dd,J＝7.9,4.7Hz,1H),7.12(s,1H),7.06(s,1H),6.71(d,J＝3.2Hz,1H),5.77(s,2H),2.10(s,3H)。
实施例669化合物A77：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.72(d,J＝3.5Hz,1H),7.21(d,J＝1.9Hz,1H),7.15–7.09(m,1H),6.59(d,J＝3.4Hz,1H),4.66(dd,J＝14.5,3.2Hz,1H),4.46(dd,J＝14.5,7.4Hz,1H),3.97–3.83(m,2H),3.54(td,J＝11.4,2.5Hz,1H),3.03(dt,J＝11.2,2.0Hz,1H),2.83–2.73(m,1H),2.52(s,3H),2.37(td,J＝11.5,3.4Hz,1H),2.10(t,J＝10.7Hz,1H),1.61(tt,J＝6.5,3.8Hz,1H),0.49–0.34(m,4H)。
实施例670化合物A78：1H NMR(400MHz,Methanol-d4)δ7.89(d,J＝3.5Hz,1H),7.86(s,1H),7.12(d,J＝1.8Hz,1H),7.06(d,J＝1.7Hz,1H),6.65(d,J＝3.5Hz,1H),4.50(s,2H),2.11(s,3H),1.24(s,6H)。
实施例671化合物A79：1H NMR(400MHz,Chloroform-d)δ8.52(s,1H),7.88(s,1H),7.69(d,J＝3.5Hz,1H),7.20(d,J＝1.9Hz,1H),7.11(d,J＝1.9Hz,1H),6.57(d,J＝3.5Hz,1H),4.64(dd,J＝14.5,3.3Hz,1H),4.45(dd,J＝14.5,7.5Hz,1H),4.14–4.06(m,1H),3.95–3.88(m,1H),3.75–3.65(m,1H),3.08(dt,J＝11.4,2.1Hz,1H),2.89–2.76(m,2H),2.45(s,3H),2.40(dd,J＝11.5,3.5Hz,1H),2.16(t,J＝10.8Hz,1H),1.08(dd,J＝6.6,1.7Hz,6H)。
实施例672化合物A80：1H NMR(400MHz,Chloroform-d)δ7.87–7.78(m,2H),7.09(d,J＝15.0Hz,2H),6.60(d,J＝3.5Hz,1H),4.60(dd,J＝14.4,3.9Hz,1H),4.54–4.45(m,1H),4.08–4.00(m,1H),3.90–3.82(m,1H),3.65–3.55(m,2H),3.31–3.27(m,1H),2.99(d,J＝11.3Hz,1H),2.80–2.74(m,1H),2.52(t,J＝5.8Hz,2H),2.23(td,J＝11.5,3.4Hz, 1H),2.10(s,3H),2.02(t,J＝10.8Hz,1H)。
实施例673化合物A81：1H NMR(400MHz,Methanol-d4)δ7.97(d,J＝3.6Hz,1H),7.84(d,J＝2.1Hz,1H),7.11(d,J＝1.7Hz,1H),7.05(d,J＝1.8Hz,1H),6.67(d,J＝3.5Hz,1H),4.40–4.30(m,1H),3.20–3.14(m,1H),3.01–2.94(m,1H),2.82(t,J＝11.2Hz,1H),2.42(s,1H),2.38(s,3H),2.36–2.32(m,1H),2.21–2.13(m,1H),2.11(s,3H),1.92–1.83(m,1H)。
实施例686化合物A82：1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.80(d,J＝3.5Hz,1H),7.22(d,J＝1.8Hz,1H),7.13(d,J＝1.9Hz,1H),6.62(d,J＝3.5Hz,1H),5.15-4.98(m,1H),3.96(dd,J＝11.8,4.2Hz,1H),3.80-3.71(m,2H),3.23-3.14(m,1H),2.89(s,3H),2.51(s,3H),2.28-2.20(m,1H),2.07-1.86(m,3H)。
实施例687化合物A83：1H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.66(d,J＝3.5Hz,1H),7.20(d,J＝1.9Hz,1H),7.11(d,J＝1.9Hz,1H),6.59(d,J＝3.5Hz,1H),5.48(dd,J＝8.5,4.4Hz,1H),3.51(s,1H),2.96-2.89(m,1H),2.69-2.63(m,1H),2.60(s,3H),2.49(s,3H),2.43(d,J＝9.1Hz,1H),2.34-2.27(m,1H),2.10-2.04(m,1H),1.92-1.86(m,1H),1.79(d,J＝10.6Hz,1H)。
实施例688化合物A84：1H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.57(d,J＝3.4Hz,1H),7.21(s,1H),7.12(s,1H),6.60(d,J＝3.4Hz,1H),4.46–4.39(m,2H),2.75(d,J＝11.3Hz,1H),2.70–2.63(m,1H),2.50(s,3H),2.46–2.36(m,1H),2.26(s,3H),2.10(t,J＝11.0Hz,1H),1.97(t,J＝10.4Hz,1H),1.81–1.69(m,2H),1.65–1.55(m,1H),1.23–1.11(m,1H)。
实施例689化合物A85：1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),7.99(d,J＝3.6Hz,1H),7.73(s,1H),7.07(d,J＝1.8Hz,1H),7.04(d,J＝1.8Hz,1H),6.56(d,J＝3.5Hz,1H),5.33–5.16(m,1H),3.50–3.39(m,1H),3.25–3.14(m,2H),2.78–2.63(m,1H),2.57(s,3H),2.16–1.99(m,2H),1.96(s,3H),1.93–1.84(m,2H)。
实施例36：2-(7-(2-羟丙基)-4-甲基-7H-吡咯并[2,3-c]哒嗪-3-基)-5-(三氟甲基)苯酚
第一步：在圆底烧瓶中加入化合物9(1.45g，10mmol)，NaHCO3(2.1g，25mmol)和MeOH(20mL)中，然后滴加Br2(0.57mL，11mmol)。将该混合物在室温下搅拌 4小时，然后过滤。将滤液在真空中浓缩，所得残留物中加入EtOAc(100mL)，并依次用饱和NaHCO3水溶液(2×20mL)和NaCl水溶液(1×20mL)洗涤。有机相用MgSO4干燥，过滤，浓缩。粗产物用柱层析纯化得化合物10(1.0g，收率45.5％)。MS/ESI:[M+H]+＝222.1。
2-(7-(2-羟丙基)-4-甲基-7H-吡咯并[2,3-c]哒嗪-3-基)-5-(三氟甲基)苯酚的制备参照实施例1。MS/ESI:[M+H]+＝222.1。
实施例37～85、实施例674～683和实施例690的合成方法参照实施例36，得到目标化合物B2～B61。
表3本发明化合物B2～B61








实施例39化合物B4：1HNMR(DMSO-d6):δ10.42(s,1H),7.85(d,J＝3.4Hz,1H),7.47(d,J＝7.7Hz,1H),7.26-7.30(m,2H),6.68(d,J＝3.4Hz,1H),4.90(s,1H),4.39(s,2H),2.36(s,3H),1.12(s,6H)。
实施例42化合物B7：1H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.56(d,J＝8.1Hz,1H),7.40(d,J＝1.9Hz,1H),7.21(dd,J＝8.2,1.9Hz,1H),6.62(d,J＝3.5Hz,1H),5.26–5.16(m,1H),3.18–3.09(m,1H),2.78(t,J＝10.0Hz,2H),2.71(s,3H),2.43–2.35(m,4H),2.18–2.08(m,2H),1.91–1.82(m,2H)。
实施例674化合物B51：1H NMR(400MHz,Chloroform-d)δ7.39(d,J＝3.6Hz,1H),7.01(s,1H),6.97(s,1H),6.57(d,J＝3.4Hz,1H),5.20–4.96(m,2H),2.29(s,3H),2.18(s,3H),1.94(s,3H)。
实施例675化合物B52：1H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.70(d,J＝5.5Hz,1H),7.47(s,2H),7.36(d,J＝5.5Hz,1H),6.58(d,J＝3.5Hz,1H),5.22–5.13(m,1H),3.11–3.03(m,1H),2.74(s,3H),2.65(t,J＝9.8Hz,1H),2.36(s,3H),2.34–2.28(m,1H),2.17–2.09(m,1H),2.08–1.93(m,2H),1.89–1.78(m,2H)。
实施例676化合物B53：1H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.56(d,J＝8.1Hz,1H),7.40(d,J＝1.9Hz,1H),7.21(dd,J＝8.2,1.9Hz,1H),6.62(d,J＝3.5Hz,1H),5.26–5.16(m,1H),3.18–3.09(m,1H),2.78(t,J＝10.0Hz,2H),2.71(s,3H),2.43–2.35(m,4H),2.18–2.08(m,2H),1.91–1.82(m,2H)。
实施例677化合物B54：1H NMR(400MHz,Chloroform-d)δ7.63(d,J＝3.5Hz,1H), 7.55(d,J＝8.1Hz,1H),7.40–7.36(m,1H),7.20(dt,J＝8.1,1.2Hz,1H),6.61(d,J＝3.5Hz,1H),4.60(dd,J＝14.5,3.4Hz,1H),4.38(dd,J＝14.5,7.3Hz,1H),3.96–3.84(m,2H),3.55(td,J＝10.9,3.6Hz,1H),3.07–3.00(m,1H),2.88–2.75(m,2H),2.70(s,3H),2.56(dd,J＝12.1,10.3Hz,1H)。
实施例678化合物B55：1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝3.5Hz,1H),7.59–7.54(m,1H),7.38(d,J＝1.9Hz,1H),7.23–7.18(m,1H),6.62(d,J＝3.4Hz,1H),4.60(dd,J＝14.5,3.6Hz,1H),4.46(dd,J＝14.5,6.9Hz,1H),4.02–3.92(m,1H),3.92–3.85(m,1H),3.62(td,J＝11.4,2.5Hz,1H),2.82(dt,J＝11.1,1.9Hz,1H),2.72(s,3H),2.62(dq,J＝11.5,1.9Hz,1H),2.24(s,3H),2.08(td,J＝11.5,3.3Hz,1H),1.85–1.74(m,1H)。
实施例679化合物B56：1H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.63(d,J＝2.2Hz,1H),7.36–7.27(m,2H),6.98(d,J＝2.3Hz,1H),6.53(d,J＝3.4Hz,1H),5.33–5.20(m,1H),3.83(s,3H),3.24(d,J＝10.3Hz,1H),2.92–2.83(m,2H),2.46–2.40(m,1H),2.38(d,J＝6.5Hz,6H),2.21–2.13(m,2H),1.93–1.86(m,2H)。
实施例680化合物B57：1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝5.5Hz,1H),7.61(d,J＝3.4Hz,1H),7.46(s,2H),7.35(d,J＝5.4Hz,1H),6.59(d,J＝3.5Hz,1H),4.61(dd,J＝14.5,3.6Hz,1H),4.47(dd,J＝14.5,6.8Hz,1H),4.04–3.96(m,1H),3.90(ddd,J＝11.5,3.4,1.6Hz,1H),3.65(td,J＝11.4,2.4Hz,1H),2.84(dt,J＝11.2,1.9Hz,1H),2.74(s,3H),2.66–2.59(m,1H),2.25(s,3H),2.10(td,J＝11.4,3.3Hz,1H),1.81(t,J＝10.7Hz,1H)。
实施例681化合物B58：1H NMR(400MHz,Chloroform-d)δ7.80(s,1H),7.71(d,J＝8.7Hz,1H),7.56(d,J＝2.2Hz,1H),7.11(dd,J＝8.7,0.9Hz,1H),7.05(dd,J＝2.2,0.9Hz,1H),6.60(d,J＝3.5Hz,1H),5.15(tt,J＝8.7,4.1Hz,1H),3.13–3.03(m,1H),2.70(dt,J＝19.8,10.3Hz,2H),2.41(ddd,J＝8.6,5.5,3.1Hz,1H),2.36(s,3H),2.36–2.26(m,1H),2.15–1.95(m,2H),1.83(dq,J＝11.1,4.7Hz,2H),1.13–1.03(m,2H),0.87–0.79(m,2H)。
实施例682化合物B59：1H NMR(400MHz,Chloroform-d)δ9.81(s,1H),7.76(d,J＝3.4Hz,1H),7.66(d,J＝8.1Hz,1H),7.62(s,1H),7.24(t,J＝2.7Hz,1H),7.18(dd,J＝8.1,1.5Hz,1H),6.54(d,J＝3.5Hz,1H),6.49(t,J＝2.6Hz,1H),5.50–5.36(m,1H),3.32(d,J＝11.0Hz,1H),2.93–2.84(m,1H),2.78(d,J＝9.8Hz,1H),2.48(s,3H),2.45–2.37(m,1H),2.22(s,3H),2.17–2.07(m,2H),1.95–1.80(m,2H)。
实施例683化合物B60：1H NMR(400MHz,Methanol-d4)δ8.53(d,J＝3.6Hz,1H),7.60(d,J＝7.9Hz,1H),7.44(dd,J＝7.9,1.5Hz,1H),7.37(d,J＝1.4Hz,1H),7.21(d,J＝3.6Hz,1H),5.40–5.29(m,1H),3.96–3.81(m,1H),3.69–3.54(m,2H),3.20–3.07(m,1H),2.98(s,3H),2.60(s,3H),2.43–2.32(m,2H),2.30–2.21(m,1H),2.17–2.04(m,1H)。
实施例690化合物B61：1H NMR(400MHz,Methanol-d4)δ7.94(d,J＝3.6Hz,1H),7.71(d,J＝2.3Hz,1H),7.23–7.13(m,2H),7.03(dd,J＝2.4,0.9Hz,1H),6.69(d,J＝3.5Hz,1H),5.20–5.10(m,1H),3.23(dd,J＝10.9,3.9Hz,1H),2.92(d,J＝11.5Hz,1H),2.63(t,J＝10.7Hz,1H),2.44(s,3H),2.39(s,3H),2.31–2.22(m,1H),2.21–2.13(m,1H),2.13–2.02(m,1H),1.99–1.80(m,2H)。
实施例86：2-(1-(2-羟丙基)-1H-吡唑并[3,4-c]哒嗪-5-基)-3-甲基-5-(三氟甲基)苯酚
第一步：将化合物19(2g,1eq.)，水合肼(4eq.)和甲醇加入反应瓶中，升温至60℃反应2h。待反应完成后，降温至室温，过滤。将滤饼干燥即得化合物20(1.6g，收率82.1％)。MS/ESI:[M+H]+＝170.1。
第二步：在0℃下，将亚硝酸钠(814mg，2eq.)的5ml水溶液逐滴加入到化合物20(1.6g)的10mL乙酸溶液中，升温至室温并反应过夜。反应完全后，降温至0℃，过滤，滤饼用冷水洗涤即得化合物21(1g，收率44.2％，黄色固体)。MS/ESI:[M+H]+＝241.1。
第三步：将化合物21(1g，1.0eq.)，0.1M盐酸水溶液(60ml)和DME(10ml)加入到反应瓶中，升温至80℃反应2h。反应完全后降至室温。加入乙酸乙酯萃取三次，有机相合并后饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩。粗产物柱层析(PE:EA＝5:1)纯化即得化合物22(260mg，黄色固体)。MS/ESI:[M+H]+＝155.1；1HNMR(400MHz,DMSO-d6):δ14.70(s,1H),8.53-8.29(m,2H)。
第四步：将化合物22(200mg，1eq.)，化合物8(1.5eq.)，碳酸钾(3eq.)和乙 腈(8mL)加入反应瓶中，室温反应过夜。反应完全后过滤，所得滤液减压浓缩，残留物柱层析纯化即得化合物23(210mg，白色固体)。MS/ESI:[M+H]+＝213.1。
第五步：将化合物23(200mg，1eq.)，中间体int-1(2eq.)，Pd(dppf)Cl2(0.1eq.)，碳酸铯(3eq.)，二氧六环和水加入反应瓶中，氮气保护下100℃反应过夜。反应完全后垫硅藻土过滤，滤液减压浓缩，残留物柱层析即得化合物24(90mg，白色固体)。MS/ESI:[M+H]+＝367.1。
第六步：将化合物24(50mg，1eq.)加入反应管中，置换氮气，加入无水DCM，降温至-30℃，滴加1M三溴化硼DCM溶液0.4mL，-30℃反应3h。加甲醇淬灭反应，减压浓缩，残留物柱层析即得化合物C1(30mg)。MS/ESI:[M+H]+＝353.1。1H NMR(400MHz,CD3OD)δ8.84(s,1H),8.71(s,1H),7.26(s,1H),7.15(s,1H),4.76–4.73(m,1H),4.50–4.43(m,1H),3.66(s,2H),2.24(s,3H),1.35(d,J＝6.4Hz,3H)。
实施例87～135和实施例684的合成方法参照实施例86，得到目标化合物C2～C51。
表4本发明化合物C2～C51






实施例90化合物C5：1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.42(s,1H),8.18(s,1H),7.20(s,1H),7.14(s,1H),5.28-5.15(m,1H),3.17-3.08(m,1H),2.91-2.81(m,1H),2.50-2.45(m,2H),2.27(s,3H),2.20-1.96(m,5H),1.93-1.85(m,1H),1.85-1.72(m,1H)。
实施例99化合物C14：1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.32(s,1H),8.23(s,1H),7.22(d,J＝11.2Hz,2H),4.79-4.56(m,2H),2.70-2.59(m,2H),2.47-2.35(m,1H),2.18(s,3H),2.12(s,3H),2.08-1.91(m,2H),1.78-1.61(m,2H),1.58-1.46(m,1H),1.18-1.06(m,1H)。
实施例103化合物C18：1H NMR(400MHz,CD3OD)δ8.22(s,1H),8.05(s,1H),7.03(s,1H),6.97(s,1H),4.85(d,J＝7.1Hz,2H),3.46-3.40(m,2H),3.22-3.19(m,2H),2.26(s,3H),2.12(s,1H),2.02(s,3H)。
实施例104化合物C19：1HNMR(400MHz,Chloroform-d)：δ9.79(s,1H),8.22(s,1H),8.03(s,1H),6.80(s,1H),6.75(s,1H),4.85(dd,J＝14.2,3.0Hz,1H),4.69(dd,J＝14.2,7.8Hz,1H),4.53–4.41(m,1H),3.15(s,1H),2.39(s,3H),2.34(s,3H),1.37(d,J＝6.4Hz,3H)。
实施例684化合物C51：1H NMR(400MHz,DMSO-d6)δ10.20(br s,1H),8.41(s,1H),8.16(s,1H),7.17(dd,J＝22.8,1.6Hz,2H),4.81(d,J＝6.4Hz,2H),2.89(d,J＝6.4Hz,2H),2.21(s,6H),2.08(s,3H)。
实施例136：2-(1-(2-羟丙基)-4-甲基-1H-吡唑并[3,4-c]哒嗪-5-基)-5-(三氟甲基)苯酚
第一步：将化合物25(5g,1eq.)，2-丁炔酸甲酯(1.1eq.)和二甲苯加入封管中，160℃反应过夜。减压浓缩除去二甲苯，残留物柱层析纯化即得化合物27(2g,)。MS/ESI:[M+H]+＝211.0。
第二步：将化合物27(2g)溶于无水甲苯中，降温至0℃，滴加DIBAL-H甲苯溶液(1.5M，18mL)，0℃反应1h。加饱和氯化铵溶液淬灭反应乙酸乙酯萃取三次，饱和食盐水洗涤，无水硫酸钠干燥，过滤，残留物柱层析纯化得化合物28(610mg)。MS/ESI:[M+H]+＝193.0。
第三步：在氮气氛围下，向100mL圆底烧瓶中加入无水二氯甲烷(20mL)和草酰氯(1.0mL，11.25mmol)。将混合物冷却至-78℃。缓慢加入无水DMSO(1.1mL，15mmol)。将反应物搅拌30分钟。缓慢加入化合物28(1.2g，7.5mmol)的二氯甲烷溶液(5mL)。将反应搅拌约3小时，直到TLC(1∶1乙酸乙酯/正己烷)监测反应完全。加入三乙胺(4.3mL，30mmol)猝灭反应并搅拌10分钟，然后升温至室温。在反应也中加入水(50mL)，然后用二氯甲烷(2×25mL)萃取。有机相用饱和NaHCO3溶液(25mL)和盐水(25mL)洗涤，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物29(0.8g)。MS/ESI:[M+H]+＝191.1。
第四步：将化合物29(1.9g，10mmol)和一水合肼(60％水溶液，10mL)加入140mL水中，反应升温至100℃搅拌72小时。将反应混合物冷却至室温，并用20mL乙酸乙酯萃取。将水层分离并用乙酸乙酯(3x20mL)萃取。有机相合并后无水硫酸钠干燥，过滤，浓缩。柱层析纯化得化合物30(1.2g，收率71％)MS/ESI:[M+H]+＝169.1。
第五步：将化合物30(169mg，1eq.)，化合物8(1.5eq.)，碳酸钾(3eq.)和乙 腈(8mL)加入反应瓶中，室温反应过夜。反应完全后过滤，所得滤液减压浓缩，残留物柱层析纯化即得化合物31(158mg)。MS/ESI:[M+H]+＝227.1。
第六步：将化合物31(114mg，1eq.)，化合物32(2eq.)，Pd(dppf)Cl2(0.1eq.)，碳酸铯(3eq.)，二氧六环和水加入反应瓶中，氮气保护下100℃反应过夜。反应完全后垫硅藻土过滤，滤液减压浓缩，残留物柱层析即得化合物D1(52mg，白色固体)。MS/ESI:[M+H]+＝353.1。
实施例137～200的合成方法参照实施例136，得到目标化合物D2～D65。
表5本发明化合物D2～D65







实施例201：2-(7-(2-羟丙基)-7H-咪唑并[4,5-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚
第一步：称取化合物1(5.0g,24.0mmol)，化合物33(4.41g，26.4mmol)和DIEA(6.20g,1.82mmol)加入到烧瓶中，然后加入25mL二甲亚砜，加热至110℃反应过夜。反应冷却至室温，慢慢滴加到125mL水中，有大量固体析出，过滤，滤饼用乙酸乙酯(15mL)打浆0.5h过滤，滤饼干燥得到目标化合物34(5.5g,18.7mmol，灰色固体，产率78％),1H NMR(400MHz,DMSO)δ7.13(d,J＝8.4Hz,1H),6.60(d,J＝2.3Hz,1H),6.56-6.50(m, 1H),6.26(s,1H),6.14(s,2H),4.20(d,J＝5.2Hz,2H),3.82(s,3H),3.75(s,3H)；MS/ESI:[M+H]+＝295.0。
第二步：向化合物34(500mg,1.70mmol)中加入HCl/EtOAc(2.5mL,4.0M),室温搅拌反应1h。有大量固体生成，过滤，滤饼用EtOAc淋洗，减压干燥得到目标化合物35(440mg,2.43mmol，灰色固体)。
第三步：称取化合物35(340mg,1.56mmol)，DIEA(972mg,7.52mmol)和原甲酸三甲酯(998mg,9.40mmol)加入到DMF(3mL)中，加热至110℃下搅拌3h。反应完全后过滤，收集滤液得到目标化合物36，直接用于下一步反应。
第四步：向化合物36的DMF溶液中加入K2CO3(672mg,4.86mmol)和溴丙酮(400mg,2.92mmol),室温反应过夜。反应完全后，将反应液倒入到水中(15mL)，用DCM/MeOH(15mL×3,v:v＝5:1)萃取，收集有机相，用无水Na2SO4干燥，减压浓缩旋干，用柱层析分离(DCM:MeOH＝10:1)得到目标化合物37(100mg,0.475mmol，淡黄色固体，产率20％),MS/ESI:[M+H]+＝211.0。
第五步：将化合物37(200mg，1eq.)，中间体int-1(2eq.)，Pd(dppf)Cl2(0.1eq.)，碳酸铯(3eq.)，二氧六环和水加入反应瓶中，氮气保护下100℃反应过夜。反应完全后垫硅藻土过滤，滤液减压浓缩，残留物柱层析即得化合物38(85mg，白色固体)。MS/ESI:[M+H]+＝367.1。
第六步：将化合物38(50mg，1eq.)加入反应管中，置换氮气，加入无水DCM，降温至-30℃，滴加1M三溴化硼DCM溶液0.4mL，-30℃反应3h。加甲醇淬灭反应，减压浓缩，残留物柱层析即得化合物E1(28mg)。MS/ESI:[M+H]+＝353.1。
实施例202～245的合成方法参照实施例201，得到目标化合物E2～E45。
表6本发明化合物E2～E45





实施例205化合物E5：1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.24(s,1H),7.26(s,1H),7.13(s,1H),5.78–5.62(m,1H),3.09(dd,J＝10.8,3.2Hz,1H),2.84–2.72(m,2H),2.34(s,3H),2.31(s,3H),2.21(dd,J＝11.0,6.0Hz,2H),2.09–1.94(m,2H),1.93–1.78(m,2H)。
实施例246：2-(7-(2-羟丙基)-4-甲基-7H-咪唑并[4,5-c]哒嗪-3-基)-5-(三氟甲基)苯酚
2-(7-(2-羟丙基)-4-甲基-7H-咪唑并[4,5-c]哒嗪-3-基)-5-(三氟甲基)苯酚的制备参照实施例201。MS/ESI:[M+H]+＝353.2。
实施例247～295的合成方法参照实施例246，得到目标化合物F2～F50。
表7本发明化合物F2～F50






实施例296：2-(7-(2-羟丙基)-6,7-二氢-5H-吡咯并[2,3-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚
第一步：将化合物25(5g,1eq.)，化合物44(1.1eq.)和二甲苯加入封管中，160℃反应过夜。减压浓缩除去二甲苯，残留物柱层析纯化即得化合物45(2.3g,)。MS/ESI:[M+H]+＝292.1。
第二步：在圆底烧瓶中加入化合物45(2.9g，10mmol)，叔丁醇钾(1.23g，11mmol)和DMSO(20mL)，反应升温至50℃搅拌6小时。反应完全后降至室温，加入水和乙酸乙酯萃取。有机相合并后依次用水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物46(1.8g，收率70.6％)。MS/ESI:[M+H]+＝256.1。
第三步：将化合物46(256mg，1eq.)，中间体int-1(2eq.)，Pd(dppf)Cl2(0.1eq.)，碳酸铯(3eq.)，二氧六环和水加入反应瓶中，氮气保护下100℃反应过夜。反应完全后垫硅藻土过滤，滤液减压浓缩，残留物柱层析即得化合物47(178mg，白色固体)。MS/ESI:[M+H]+＝410.2。
第四步：将化合物47(205mg，1eq.)，化合物8(1.5eq.)，碳酸钾(3eq.)和乙腈(8mL)加入反应瓶中，室温反应过夜。反应完全后过滤，所得滤液减压浓缩，残留物柱层析纯化即得化合物48(154mg，白色固体)。MS/ESI:[M+H]+＝310.1。
第五步：将化合物48(100mg，1eq.)加入反应管中，置换氮气，加入无水DCM，降温至-30℃，滴加1M三溴化硼DCM溶液0.4mL，-30℃反应3h。加甲醇淬灭反应，减压浓缩，残留物柱层析即得化合物G1(42mg)。MS/ESI:[M+H]+＝354.1。
实施例297～310的合成方法参照实施例296，得到目标化合物G2～G15。
表8本发明化合物G2～G15

实施例311：2-(7-(2-羟丙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-c]哒嗪-3-基)-5- (三氟甲基)苯酚
2-(7-(2-羟丙基)-4-甲基-6,7-二氢-5H-吡咯并[2,3-c]哒嗪-3-基)-5-(三氟甲基)苯酚的制备参照实施例296。MS/ESI:[M+H]+＝354.1。
实施例312～325的合成方法参照实施例311，得到目标化合物H2～H15。
表9本发明化合物H2～H15


实施例326：2-(8-(2-羟丙基)-5,6,7,8-四氢吡啶并[2,3-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚
2-(8-(2-羟丙基)-5,6,7,8-四氢吡啶并[2,3-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚的制备参照实施例296。MS/ESI:[M+H]+＝368.2。
实施例327-340的合成方法参照实施例326，得到目标化合物I2～I15。
表10本发明化合物I2～I15


实施例341：2-(8-(2-羟丙基)-7,8-二氢-6H-哒嗪并[4,3-b][1,4]恶嗪-3-基)-3-甲基-5-(三氟甲基)苯酚
第一步：在圆底烧瓶中加入化合物62(1.82g，10mmol)，化合物63(1.93g，12mmol)，NaH(60％，0.48g，12mmol)和DMF(20mL)，室温搅拌2小时。加入水和乙酸乙酯萃取，有机相合并后依次水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物64(1.2g)。MS/ESI:[M+H]+＝308.0。
2-(8-(2-羟丙基)-7,8-二氢-6H-哒嗪并[4,3-b][1,4]恶嗪-3-基)-3-甲基-5-(三氟甲基)苯酚的制备参照实施例296。MS/ESI:[M+H]+＝370.1。
实施例342-360的合成方法参照实施例341，得到目标化合物J2～J20。
表11本发明化合物J2～J20


实施例361：1-((6-(2-甲氧基-6-甲基-4-(三氟甲基)苯基)-1-甲基-1H-吡唑并[4,3-c] 哒嗪-3-基)氨基)丙-2-醇
第一步：化合物69(3.0g，1.0eq.)溶解于35mL乙醇中，加入水合肼(1.4g,3.0eq)，20℃反应2小时。TLC监测原料反应完全。减压浓缩除去溶剂后，得到化合物70(1.2g)，直接用于下一步反应。MS/ESI:[M+H]+＝203.5。
第二步：将化合物70(2.4g，1.0eq.)溶解于H2O:MeOH:THF＝1:1:1(24mL)中，0℃下将LiOH(2.4g，5.3eq.)加入反应瓶中，0℃反应6小时。TLC监测原料反应完全。减压浓缩除去溶剂后，加入30mL水，用1N稀盐酸调PH为2，乙酸乙酯萃取3次。合并有机相后饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物71(2.0g)。MS/ESI:[M+H]+＝171.0。
第三步：将化合物71(2.0g，1.0eq.)，DIEA(1.3g，1.1eq.)溶解于DMF(20mL)中，0℃下加入碘甲烷(1.4g，1.0eq.)。室温反应过夜。TLC监测原料反应完。反应液用乙酸乙酯和水萃取3次，合并有机相后饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物72(1.2g)。MS/ESI:[M+H]+＝185.0。
第四步：将化合物72(0.5g，1.0eq.)，中间体int-1(1.5eq.)，Pd(dppf)Cl2(0.1eq.)，Cs2CO3(2.0eq.)溶解于1,4-二氧六环(10mL)和水(1mL)中，置换氮气后，100℃反应12小时。TLC监测原料反应完全。反应液用乙酸乙酯和水萃取，合并有机相后饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物73(0.3g)。MS/ESI:[M+H]+＝339.1。
第五步：将化合物73(350mg)溶解于POCl3中(3mL)，110℃反应12小时。LCMS监测目标产物生成且原料反应完全。将反应液加入冰水中淬灭后，再加入饱和碳酸氢钠水溶液，用二氯甲烷萃取，合并有机相后饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物74(245mg)。MS/ESI:[M+H]+＝357.1。
第六步：将化合物74(357mg，1eq.)，化合物75(1.5eq.)，碳酸钾(3eq.)和乙腈(8mL)加入反应瓶中，室温反应过夜。反应完全后过滤，所得滤液减压浓缩，残留物柱层析纯化即得化合物76(231mg，白色固体)。MS/ESI:[M+H]+＝396.2。
第七步：将化合物76(0.1g，1eq.)加入反应管中，置换氮气，加入无水DCM， 降温至-30℃，滴加1M三溴化硼DCM溶液0.4mL，-30℃反应3h。加甲醇淬灭反应，减压浓缩，残留物柱层析即得化合物K1(68mg)。MS/ESI:[M+H]+＝382.2。
实施例362：2-(3-((2-羟丙基)氨基)-1,7-二甲基-1H-吡唑并[4,3-c]哒嗪-6-基)-5-(三氟甲基)苯酚
2-(3-((2-羟丙基)氨基)-1,7-二甲基-1H-吡唑并[4,3-c]哒嗪-6-基)-5-(三氟甲基)苯酚的制备参照实施例361。MS/ESI:[M+H]+＝382.2。
实施例363～440的合成方法参照实施例361和实施例362，得到目标化合物K3～K80。
表12本发明化合物K3～K80










实施例436化合物K76：1H NMR(400MHz,)δ8.34(s,1H),7.11(d,J＝8.0Hz,2H),4.65(s,1H),3.18(s,3H),2.22-2.15(m,2H),2.15(s,3H),2.03-1.99(m,2H),1.78-1.73(m,2H),1.49-1.43(m,2H),1.12(s,3H)。
实施例441：2-(8-((2-羟丙基)氨基)嘧啶并[5,4-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚
第一步：将化合物69(2.06g，10mmol)，化合物33(2.0g，12mmol)，DIEA(15mmol)和DMSO(20mL)加入圆底烧瓶中，反应升温至110℃搅拌6小时。反应完全后降至室温，加水稀释后乙酸乙酯萃取。合并有机相后依次水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物77(2.2g)。MS/ESI:[M+H]+＝306.1。
第二步：在圆底烧瓶中加入化合物77(3.05g，10mmol)，三氟乙酸(3mL)和二氯甲烷(20mL)，反应室温搅拌16小时。反应完全后加入饱和碳酸钠溶液将pH调至8-9，二氯甲烷萃取。合并有机相后依次水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物78(1.6g)。MS/ESI:[M+H]+＝188.1。
第三步：在圆底烧瓶中加入化合物78(5.0g)，乙酸铵(4.1g)和原甲酸三乙酯(30mL)，反应升温至100℃搅拌16小时。反应完全后降至室温，加入水和乙酸乙酯萃取。合并有机相后依次水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物80(1.7g)。MS/ESI:[M+H]+＝182.1。
第四步：将化合物80(0.5g，1.0eq.)，中间体int-1(1.5eq.)，Pd(dppf)Cl2(0.1eq.)，Cs2CO3(2.0eq.)溶解于1,4-二氧六环(10mL)和水(1mL)中，置换氮气后，100℃反应12小时。TLC监测原料反应完全。反应液用乙酸乙酯和水萃取，合并有机相后饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物81(0.3g)。MS/ESI:[M+H]+＝337.1。
第五步：将化合物81(350mg)溶解于POCl3中(3mL)，110℃反应12小时。LCMS监测目标产物生成且原料反应完全。将反应液加入冰水中淬灭后，再加入饱和碳酸氢钠水溶液，用二氯甲烷萃取，合并有机相后饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物82(187mg)。MS/ESI:[M+H]+＝355.1。
第六步：将化合物82(357mg，1eq.)，化合物75(1.5eq.)，碳酸钾(3eq.)和乙 腈(8mL)加入反应瓶中，室温反应过夜。反应完全后过滤，所得滤液减压浓缩，残留物柱层析纯化即得化合物83(231mg，白色固体)。MS/ESI:[M+H]+＝394.2。
第七步：将化合物83(0.1g，1eq.)加入反应管中，置换氮气，加入无水DCM，降温至-30℃，滴加1M三溴化硼DCM溶液0.4mL，-30℃反应3h。加甲醇淬灭反应，减压浓缩，残留物柱层析即得化合物L1(42mg)。MS/ESI:[M+H]+＝380.2。
实施例442：2-(8-((2-羟丙基)氨基)-4-甲基嘧啶并[5,4-c]哒嗪-3-基)-5-(三氟甲基)苯酚
2-(8-((2-羟丙基)氨基)-4-甲基嘧啶并[5,4-c]哒嗪-3-基)-5-(三氟甲基)苯酚的制备参照实施例441。MS/ESI:[M+H]+＝380.2。
实施例443：3-(2-羟基-6-甲基-4-(三氟甲基)苯基)-8-((2-羟丙基)氨基)-5-甲基嘧啶并[5，4-c]哒嗪-6(5H)-酮
第一步：在圆底烧瓶中加入化合物98(1.87g，10mmol)和7N的NH3甲醇溶液20mL。反应在室温下搅拌小时，反应完全后浓缩除去溶剂，加入水和乙酸乙酯萃取。合并有机相后饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物103(1.2g)。MS/ESI:[M+H]+＝173.1。
第二步：将化合物103(1.72g，10mmol)，CDI(1.62g，10mmol)和四氢呋喃(20mL)加入圆底烧瓶中，反应升温至60℃搅拌12小时。反应完全后降至室温，浓 缩除去溶剂，加入水和乙酸乙酯萃取。合并有机相后饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物104(1.32g)。MS/ESI:[M+H]+＝199.0。
第三步：将化合物104(2.0g，1.0eq.)，DIEA(1.3g，1.1eq.)溶解于DMF(20mL)中，0℃下加入碘甲烷(1.4g，1.0eq.)。室温反应过夜。TLC监测原料反应完。反应液用乙酸乙酯和水萃取3次，合并有机相后饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物105(1.8g)。MS/ESI:[M+H]+＝213.0。
2-(8-((2-羟丙基)氨基)-4-甲基嘧啶并[5,4-c]哒嗪-3-基)-5-(三氟甲基)苯酚的制备以化合物104为原料参照实施例441。MS/ESI:[M+H]+＝410.2。
实施例444～530的合成方法参照实施例441、442和443，得到目标化合物L4～L90。
表13本发明化合物L4～L90











实施例512化合物L72：1H NMR(400MHz,MeOD)δ7.68(s,1H),7.18(s,1H),7.11(s,1H),4.53(dq,J＝12.2,3.9Hz,1H),3.54(s,3H),3.04–2.87(m,1H),2.71–2.59(m,1H),2.57–2.40(m,2H),2.38(s,3H),2.20(s,3H),2.03–1.83(m,2H),1.82–1.66(m,2H)。
实施例531：3-(2-羟基-6-甲基-4-(三氟甲基)苯基)-7-(2-羟丙基)-5,5-二甲基 -5,7-二氢-6-吡咯并[2,3-c]哒嗪-6-酮
第一步：将化合物62(10g，54.6mmol)，化合物33(9.1g，54.6mmol)，DIEA(21.1g，163.9mmol)和异丙醇(150mL)置于反应瓶中，70℃搅拌2h。反应完成，降温至室温，加入200mL乙酸乙酯和200mL饱和氯化铵水溶液，乙酸乙酯相继续用200mL饱和氯化铵洗涤两次，无水硫酸钠干燥、过滤、旋干得化合物84(17.0g，99.4％，橘红色固体)；1H NMR(400MHz,Chloroform-d)δ7.13(d,J＝8.4Hz,1H),6.62(s,1H),6.54-6.45(m,2H),5.55(t,1H),4.32(d,J＝5.6Hz,2H),3.86(s,3H),3.82(s,3H)。
第二步：将化合物84(2.5g，8.0mmol)，三乙胺(4.0g，40.0mmol)和二氯甲烷(50mL)置于反应瓶中，加入异丁酰氯(2.1g，20.0mmol)，加毕，室温搅拌过夜。反应完成，体系加入50mL饱和氯化铵和30mL二氯甲烷，水相继续用20mL二氯甲烷萃取，合并有机相，无水硫酸钠干燥、过滤、旋干得化合物85(4.1g，粗品)，直接用于下一步，未做进一步纯化；1H NMR(400MHz,Chloroform-d)δ7.19(d,J＝8.4Hz,1H),6.46(dd,J＝8.4,2.4Hz,1H),6.41(d,J＝2.4Hz,1H),5.30(s,1H),4.72(s,1H),4.61(d,J＝14.4Hz,1H),4.22(d,J＝14.4Hz,1H),3.81(s,3H),3.73(s,3H),1.26-1.22(m,6H),1.17-1.09(m,6H)。
第三步：将化合物85(4.1g，粗品)，碳酸铯(5.8g，17.7mmol)和无水DMF(50mL)置于反应瓶中，80℃搅拌2h。反应完成，过滤收集滤液旋干，经硅胶柱层析(石油醚：乙酸乙酯＝5：1-0：1)纯化得化合物86(2.7g，97.5％，白色固体)；LC-MS:ESI[M+H]+＝316.1。
第四步：将化合物86(400mg，1.1mmol)，中间体int-1(544.8mg，1.7mmol)，Pd(dppf)Cl2(84.0mg，0.1mmol)，碳酸铯(1120.6mg，3.4mmol)，二氧六环(15mL) 和水(3mL)置于反应瓶中，氮气保护，100℃搅拌12h。反应完成，降温至室温，直接硅胶拌样，经硅胶柱层析(石油醚：乙酸乙酯＝3：1)纯化得化合物87(475mg，产率82.6％)；LC-MS:ESI[M+H]+＝470.2。
第五步：在圆底烧瓶中加入化合物87(4.7g，10mmol)，三氟乙酸(5mL)和二氯甲烷(40mL)，反应室温搅拌16小时。反应完全后加入饱和碳酸钠溶液将pH调至8-9，二氯甲烷萃取。合并有机相后依次水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物88(2.6g)。MS/ESI:[M+H]+＝352.1。
第六步：将化合物88(352mg，1eq.)，化合物8(1.5eq.)，碳酸钾(3eq.)和乙腈(8mL)加入反应瓶中，室温反应过夜。反应完全后过滤，所得滤液减压浓缩，残留物柱层析纯化即得化合物89(269mg，白色固体)。MS/ESI:[M+H]+＝410.1。
第七步：将化合物89(100mg，1eq.)加入反应管中，置换氮气，加入无水DCM，降温至-30℃，滴加1M三溴化硼DCM溶液0.4mL，-30℃反应3h。加甲醇淬灭反应，减压浓缩，残留物柱层析即得化合物M1(38mg)。MS/ESI:[M+H]+＝396.1。1H NMR(400MHz,DMSO)δ10.27(s,1H),7.71(s,1H),7.15(s,1H),7.09(s,1H),4.95(d,J＝5.2Hz,1H),4.29-4.13(m,1H),3.84(dd,J＝13.3,7.8Hz,1H),3.66(dd,J＝13.4,5.3Hz,1H),2.13(s,3H),1.37(d,J＝3.6Hz,6H),1.12(d,J＝6.2Hz,3H)。
实施例532：2-(7-(2-羟丙基)-5,5-二甲基-6,7-二氢-5H-吡咯并[2,3-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚
在圆底烧瓶中加入化合物M1(0.1g)和硼烷四氢呋喃溶液(1M/L，2mL)，升温至60℃反应2小时，反应完全后降至室温，加水淬灭，乙酸乙酯萃取。合并有机相后依次水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。粗产物柱层析纯化得化合物M2(26mg)。MS/ESI:[M+H]+＝382.2。
实施例533～550和实施例685的合成方法参照实施例531和实施例532，得到目标化合物M3～M21。
表14本发明化合物M3～M21



实施例685化合物M21：1H NMR(400MHz,DMSO-d6)δ10.36(br s,1H),7.83(s,1H),7.17(s,1H),7.11(s,1H),4.83(s,2H),2.30(s,3H),2.12(s,3H),1.42(s,6H)。
实施例551：2-(8-((2-羟丙基)氨基)-4-甲基吡唑并[5,1-c][1,2,4]三嗪-3-基)-5-(三氟甲基)苯酚
第一步：将化合物90(50.0mg，0.427mmol)溶解于1mL 6M的盐酸中，降温至0℃，加入亚硝酸钠固体(32.0mg，0.470mmol)，加毕，0℃搅拌0.5h。将3-氯戊烷-2,4-二酮(57.2mg，0.427mmol)和醋酸钠(58.1mg，0.427mmol)分散于乙醇/水＝0.8mL/0.8mL中，降温至0℃，将上述反应液直接加入此反应液中，加毕，0℃搅拌2h。反应完成，过滤收集固体，滤饼用2mL乙醇/水＝1/2洗涤，真空干燥得化合物92(71mg，75.5％，淡黄色固体)；1H NMR(400MHz,DMSO-d6)δ12.94(br s,1H),10.67(s,1H),8.02(s,1H),2.47(s,3H)；LC-MS:ESI[M+H]+＝221.0。
第二步：将化合物92(71mg，0.323mmol)溶解于4mL乙酸中，110℃搅拌3h，反应完成，直接旋干溶剂得化合物93(60mg，92.3％，土黄色固体)，直接用于下一步，未做进一步纯化；1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),2.86(s,3H)；LC-MS:ESI[M+H]+＝203.0。
第三步：将化合物93(202mg，1eq.)，化合物75(1.5eq.)，碳酸钾(3eq.)和乙腈(8mL)加入反应瓶中，室温反应过夜。反应完全后过滤，所得滤液减压浓缩，残留物柱层析纯化即得化合物94(157mg，白色固体)。MS/ESI:[M+H]+＝242.1。
第四步：将化合物94(100mg，1eq.)，化合物32(2eq.)，Pd(dppf)Cl2(0.1eq.)，碳酸铯(3eq.)，二氧六环和水加入反应瓶中，氮气保护下100℃反应过夜。反应完全后垫硅藻土过滤，滤液减压浓缩，残留物柱层析纯化即得化合物N1(41mg)。MS/ESI:[M+H]+＝368.1。
实施例552～625的合成方法参照实施例551，得到目标化合物N2～N75。
表15本发明化合物N2～N75










实施例626：(R)-2-(5-氯-7-((4-甲基吗啉-2-基)甲基)-7H-吡咯并[2,3-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚
称量化合物A69(1eq,200mg)于100mL的两口瓶中，加入20mL超干二氯甲烷，氮气换气三次，冰浴下加入NCS(1.2eq,79mg)，然后升至室温进行反应，2h后LC/MS检测反应完全。加水淬灭反应，DCM(20mL)萃取3次，合并有机相，饱和食盐水洗1次，无水硫酸钠干燥，有机相进行浓缩，硅胶拌样。DCM/MeOH(100:1～97:3)进行柱层析，得到目标化合物O1。MS/ESI:[M+H]+＝368.1。1H NMR(400MHz,Methanol-d4)δ7.94(d,J＝9.2Hz,1H),7.86(d,J＝7.4Hz,1H),7.14(d,J＝1.7Hz,1H),7.08(d,J＝1.8Hz,1H),4.70–4.60(m,1H),4.59–4.48(m,1H),4.06–3.95(m,1H),3.95–3.87(m,1H),3.59(td,J ＝11.6,2.4Hz,1H),2.92(dt,J＝11.4,2.0Hz,1H),2.69(dq,J＝11.8,1.9Hz,1H),2.29(s,3H),2.17(dd,J＝11.6,3.4Hz,1H),2.12(s,3H),1.92(t,J＝10.9Hz,1H)。
实施例627：(R)-2-(5-氯-7-(1-甲基哌啶-3-基)-7H-吡咯并[2,3-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚
(R)-2-(5-氯-7-(1-甲基哌啶-3-基)-7H-吡咯并[2,3-c]哒嗪-3-基)-3-甲基-5-(三氟甲基)苯酚的制备参考实施例626，得到目标化合物O2。MS/ESI:[M+H]+＝425.1。1H NMR(400MHz,Chloroform-d)δ8.10(s,1H),7.90(s,1H),7.20(d,J＝1.9Hz,1H),7.15–7.11(m,1H),5.31–5.22(m,1H),3.08–2.92(m,1H),2.77(dd,J＝10.5,6.7Hz,1H),2.62(s,1H),2.51(s,3H),2.49–2.44(m,1H),2.37(s,3H),2.07(dq,J＝12.2,7.1,5.3Hz,2H),1.89–1.76(m,2H)。
生物活性测试：
1、人类单核细胞中的NLRP3炎症体抑制活性测定
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)。
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。
实验结果如下表16和17，其中在表16中，+++表示：1uM抑制率大于等于90％，++表示：1uM抑制率大于等于50％且小于90％，+表示:1uM抑制率小于50％。
表16化合物对NLRP3炎症体在1uM浓度下抑制率



表17化合物对NLRP3炎症体半数抑制率(IC50)
实验结果：本发明化合物对NLRP3炎症体具有较好的抑制活性。在一些实施方案中，本发明的化合物对于NLRP3抑制活性IC50小于等于500nM、优选化合物小于等于 250nM、进一步优选化合物小于等于100nM、更优选化合物小于等于50nM、本发明所示的化合物中最优选化合物IC50小于等于5nM。
2、化合物对hERG钾离子通道的抑制实验
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。
化合物准备：将化合物母液用100％ DMSO进行稀释，即取10μL化合物母液加入到20μLDMSO中，3倍连续稀释至6个浓度。分别取4μL的6个浓度的化合物，加入到396μL细胞外液中，即100倍稀释得到6个中间浓度。再分别取80μL的6个中间浓度化合物，加入到320μL细胞外液中，即5倍稀释至需要测试的最终浓度。最高测试浓度为40μM，依次分别为40，13.33，4.44，1.48，0.49和0.16μM共6个浓度。最终测试浓度中的DMSO含量不超过0.2％，此浓度的DMSO对hERG钾通道没有影响。化合物准备由Bravo仪器完成整个稀释过程。
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)。
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))
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：在一些实施方案中，本发明方案化合物对hERG钾离子通道具有较弱的抑制作用。在一些实施方案中，本发明的化合物对于hERG抑制IC50大于10uM、优选化合物大于20uM、进一步优选化合物大于30uM、本发明所示的化合物中最优选化合物hERG抑制IC50大于40uM。
表18化合物对hERG钾离子通道抑制结果
结论：本发明化合物A69等对hERG钾离子通道抑制作用较弱。
3、化合物在Balb/c小鼠体内的药代动力学评价
实验目的：了解化合物的药代动力学情况。
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。
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。
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。
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19。
表19化合物在Balb/c小鼠体内的药代动力学测试结果
结论：本发明化合物A3、A69和A82等在Balb/c小鼠体内具有良好的药代动力学性质，包括良好的口服生物利用度、暴露量、半衰期和清除率等。
4、化合物体内脑血比评价
实验目的：获得化合物的脑血比。
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。
实验步骤：称量化合物，加少量DMSO，再加入注射用氯化钠溶液，配成1mg·mL-1的化合物溶液，待给药用。按10mg·kg-1口服给药，给药后1h、6h分别采集全血和全脑(n＝3)。全血离心3500rpm 15min，收集上清血浆。称取离心管重量为M1，装入全脑的离心管重量为M2，加水匀浆后离心管重量为M3，取出30μL匀浆后离心管重量 为M4。取30μL血浆和30μL脑匀浆于离心管中，加入120μL含20ng·ml-1内标SAHA的乙腈沉淀，涡旋30s，于13000rpm离心15min，取上清装进样瓶待测。
标准曲线范围：10～10000ng·ml-1。
脑中药物含量＝实测值×0.03×(M3-M1)/[(M2-M1)×(M3-M4)]。
化合物脑血比结果如下表20所示。
表20化合物给药后小鼠脑血比测试结果
结论：本发明化合物A3、A69和B52等在1小时和6小时具有较高的脑血比，说明本发明化合物具有入脑的潜力。

Claims (25)

  1. 式Ⅰ所示化合物或其药学上可接受的形式，其特征在于：所述式Ⅰ结构如下：
    其中，
    X和Y独立地选自C或N，且X和Y中至多一个选自N；
    当X或Y选自N时，为单键；当X和Y选自C时，为双键；
    环A为任选被0-6个R8取代的以下基团：5～6元烷基环、5～6元烷基杂环、苯环、5～6元杂芳环、 环A中，所述5～6元烷基杂环、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；
    R1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中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
    R2和R4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；R2和R4中，所述取代基选自：氘、卤素、-OH、-NH2或-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；
    R5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；R5中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
    或者，R2与R3、R3与R4或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、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、3～6元环烷基、3～6元氟代环烷基，或同一碳原子连接的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；
    L选自-(CH2)n1-、-CH(CH3)(CH2)n1-、-(CH2)n1-CH(CH3)-、-(CH2)n1O-、-O(CH2)n1-、-OCH(CH3)(CH2)n1-、-(CH2)n1-NH-、-NH-(CH2)n1-、-NH-CH(CH3)(CH2)n1-或-NHC(CH3)2(CH2)n1-，n1为选自0-3的整数；
    R6选自氢、氘、卤素、-CN、-OR9a、-SR9a、-NR9bR9c、-C(＝O)R9a、-OC(＝O)R9a、-C(＝O)OR9a、-C(＝O)NR9bR9c、-NR9bC(＝O)R9c、-SO2R9a、-SO2NR9bR9c、-NR9bSO2R9c或被0-6个R9d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；
    R9a、R9b和R9c独立地选自氢、氘或者被0-6个取代基取代的以下基团：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；R9a、R9b和R9c中，所述取代基选自：氘、卤素、-N(R10aR10b)、-C(O)N(R10aR10b)、-OH、-CN、C1-4烷基、C1-4烷氧基、C1-4氘代烷基、C1-4氟代烷基、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；R9a、R9b和R9c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，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；
    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；R9b与R9c与它们所连接的原子相连成环时，所述取代基选自：氘、卤素、-N(R10aR10b)、-C(O)N(R10aR10b)、-OH、-CN、C1-4烷基、C1-4烷氧基、3～6元环烷基、4～6元杂环烷基；R9b与R9c与它们所连接的原子相连成环时，所述3～6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子，所述取代基中4～6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；
    R9d选自氢、氘、卤素、-CN、-OR10c、-SR10c、-NR10dR10e、-C(＝O)R10c、-OC(＝O)R10c、-C(＝O)OR10c、-C(＝O)NR10dR10e、-NR10dC(＝O)R10e、-SO2R10c、-SO2NR10dR10e、-NR10dSO2R10e或者被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、C1-6烷基；R9d中，所述取代基选自氘、卤素、-OH、-NR10fR10g、-C(＝O)NR10fR10g、CN、C1-4烷基、C1-4烷氧基或者3～6元环烷基；R9d中，所述5～10元杂芳基、3～8元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；
    R10a、R10b、R10c、R10d、R10e、R10f、R10g独立地选自氢、C1-4烷基、N,N-二甲基取代的C1-4烷基、3～6元环烷基；
    R7选自氢、氘、卤素、-OH、-NH2、-CN、-CONH2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、-NH-C1-6烷基、-NHC(＝O)-C1-6烷基、-NHC(＝O)-3～6元环烷基、-(C＝O)NH-C1-6烷基、-(C＝O)NH-3～6元环烷基、C2-6烯基、C2-6炔基、3～6元环烷基；R7中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
    R8选自氢、氘、卤素、-NH2、-OH、-CN、-CONH2或任选被0-6个取代基取代的以下基团：C1-6烷基、-C(O)-C1-6烷基、-C(O)NH-C1-6烷基、3～6元环烷基、-C(O)-3～6元环烷基、-C(O)NH-3～6元环烷基；R8中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
    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。
  2. 根据权利要求1任一项所述的化合物，其特征在于：
    R1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；
    优选的，R1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；
    更优选的，R1选自氢、氘、F、Cl、-OH、-CN、-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。
  3. 根据权利要求1～2任一项所述的化合物，其特征在于：
    R2和R4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；
    优选的，R2和R4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；
    更优选的，R2和R4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。
  4. 根据权利要求1～3任一项所述的化合物，其特征在于：
    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；
    优选的，R3选自氢、氘、F、Cl、Br、-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；
    更优选的，R3选自氢、氘、F、Cl、Br、CN、甲基、氟代甲基、氘代甲基、甲硫基、氟代甲硫基、氘代甲硫基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基、氟代环丙基、乙烯基、乙炔基、苯基、氟代苯基、氘代苯基。
  5. 根据权利要求1～4任一项所述的化合物，其特征在于：
    R5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；
    优选的，R5选自氢、氘、F、Cl、-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；
    更优选的，R5选自氢、氘、F、Cl、-OH、-CN、-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。
  6. 根据权利要求1～5任一项所述的化合物，其特征在于：
    R2与R3、R3与R4或者R4与R5可以与它们所连接的原子一起形成被0-6个取代基取代的5～6元烷烃环、苯环、5～6元烷烃杂环、5～6元杂芳环或所述取代基选自：氘、卤素、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-氟代C1-4烷基、-O-氘代C1-4烷基、3～6元环烷基或3～6元氟代环烷基，或者同一碳原子连接的2个所述取代基形成3～4元环烷基；R2与R3、R3与R4或者R4与R5与它们所连接的原子相连成环时，所述5～6元烷烃杂环、5～6元杂芳环含有1～2个选自N、S、O中至少一个的杂原子；
    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、Br、Cl、-OH、-NH2、-CN、氧代基、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、-O-C1-4烷基、-O-氟代C1-4烷基、-O-氘代C1-4烷基、3～6元环烷基或3～6元氟代环烷基，或者同一碳原子连接的2个所述取代基形成3～4元环烷基；
    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、Br、Cl、-OH、-NH2、-CN、氧代基、甲基、氟代甲基、氘代甲基、甲氧基、氟代甲氧基、氘代甲氧基、环丙基或氟代环丙基，或者同一碳原子连接的2个所述取代基形成3～4元环烷基。
  7. 根据权利要求1～6任一项所述的化合物，其特征在于：结构单元选自：

  8. 根据权利要求1～7任一项所述的化合物，其特征在于：L选自键或者-CH2-、-CH2CH2-、-CH2-CH(CH3)-、-CH2-C(CH3)2-、-CH(CH3)CH2-、-O-、-O-CH2-、-O-CH2CH2-、-O-CH(CH3)-、-NH-、-NH-CH2-、-NH-CH2CH2-、-NH-CH(CH3)-或-NHC(CH3)2-。
  9. 根据权利要求1～8任一项所述的化合物，其特征在于：
    R7选自氢、氘、卤素、-OH、-NH2、-CN或任选被0-3个取代基取代的以下基团：C1-3烷基、-O-C1-3烷基、-S-C1-3烷基、-CONH2、-NH-C1-3烷基、-NHC(＝O)-C1-3烷基、-NHC(＝O)-3～6元环烷基、-(C＝O)NH-C1-3烷基、-(C＝O)NH-3～6元环烷基、C2-4烯基、C2-4炔基、3～6元环烷基；R7中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
    优选的，R7选自氢、氘、卤素、-OH、-NH2、-CN或者被0-3个取代基取代的以下基团：C1-3烷基、-O-C1-3烷基、-CONH2、-(C＝O)NH-C1-3烷基、-(C＝O)NH-3～4元环烷基或者3～4元环烷基；R7中，所述取代基选自：氘、氟或-OH；
    更优选的，R7选自氢、氘、氟、氯、-OH、-NH2、-CN、甲基、氟代甲基、氘代甲基、乙基、氟代乙基、甲氧基、氟代甲氧基、环丙基、氟代环丙基、-CONH2、-CONHCH3、-CONHCD3或-CONH-环丙基。
  10. 根据权利要求1～9任一项所述的化合物，其特征在于：
    R8选自氢、氘、氟、-NH2、-CONH2、-CN或任选被0-3个取代基取代的以下基团：C1-4烷基、-C(O)-C1-4烷基、-C(O)-3～4元环烷基、-C(O)NH-C1-4烷基、-C(O)NH-3～4元环烷基3～4元环烷基；R8中，所述取代基选自：氘、卤素、-OH、-NH2或-CN；
    优选的，R8选自氢、氘、氟或任选被0-3个取代基取代的以下基团：C1-4烷基、-C(O)-C1-4烷基、-C(O)-3～4元环烷基、3～4元环烷基；R8中，所述取代基选自：氘、氟或-OH；
    更优选的，R8选自氢、氟、甲基、氟代甲基、氘代甲基、乙基、氟代乙基、 环丙基、氟代环丙基、-C(O)CH3、-C(O)CD3或-C(O)-环丙基。
  11. 根据权利要求1～10任一项所述的化合物，其特征在于：
    环A为任选被0-3个R8取代的以下基团：5～6元烷基环、5～6元烷基杂环、苯环、5～6元杂芳环、 环A中，所述5～6元烷基杂环、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；
    优选的，环A任选被0-2个R8取代的以下基团：
  12. 根据权利要求1～11任一项所述的化合物，其特征在于：结构单元选自：

    n2选自0-2的整数；
    优选的，结构单元选自：
  13. 根据权利要求1～12任一项所述的化合物，其特征在于：R6选自以下结构：


    R11a选自氢、氘、-C(＝O)R12a、-C(＝O)OR12a、-SO2R12a或者被0-3个取代基取代的6～10元芳基、5～10元杂芳基、3～6元环烷基、3～6元杂环烷基、C1-6烷基；R11a中，所述取代基选自氘、氟、氯、-OH、-NR12bR12c、-C(＝O)NR12bR12c、CN、C1-4烷基、C1-4烷氧基或者3～6元环烷基；R11a中，所述5～10元杂芳基、3～6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；R12a、R12b和R12c独立地选自氢、C1-4烷基、N,N-二甲基取代的C1-4烷基、3～6元环烷基；
    R11b选自氢、氘、卤素、-CN、-OR12a、-NR12dR12e、-C(＝O)R12a、-C(＝O)OR12a、-C(＝O)NR12dR12e、-NR12dC(＝O)R12e、-SO2R12a、-SO2NR12dR12e、-NR12dSO2R12e或者被0-3个取代基取代的6～10元芳基、5～10元杂芳基、3～6元杂环烷基、3～6元环烷基、C1-6烷基；R11a中，所述取代基选自氘、氟、氯、-OH、-NR12bR12c、-C(＝O)NR12bR12c、CN、C1-4烷基、C1-4烷氧基或者3～6元环烷基；R11a中，所述5～10元杂芳基、3～6元杂环烷基含有1～3个选自N、S、O中至少一个的杂原子；R12a、R12b、R12c、R12d和R12e独立地选自氢、C1-4烷基、N,N-二甲基取代的C1-4烷基、3～6元环烷基；
    R11c、R11d独立地选自氢、氘或者被0-3个取代基取代的C1-4烷基；R11c、R11d中，所述取代基选自氘、氟、氯；
    优选的，R11a选自H、氘、C1-4烷基、C1-4氟代烷基、C1-4氘代烷基、C1-4羟基取代的烷基、3～6元环烷基、3～6元氟代环烷基、羟基取代的3～6元环烷基、C1-4烷酰基、3～6元环烷酰基、C1-4烷氧酰基、3～6元环烷氧酰基、C1-4烷磺酰基、3～6元环烷磺酰基、
    R11b选自H、氘、氟、氯、氨基、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羟基取代的烷基、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、羟基取代的3～6元环烷基、C1-4烷酰基、3～6元环烷酰基、C1-4烷氧酰基、3～6元环烷氧酰基、C1-4烷磺酰基、3～6元环烷磺酰基、甲氨基、二甲基氨基、
    R11c、R11d独立地选自氢、氘、甲基、氘代甲基、氟代甲基。
  14. 根据权利要求1～13任一项所述的化合物，其特征在于：R6选自以下结构：

  15. 根据权利要求1～14任一项所述的化合物，其特征在于：结构单元 选自：

  16. 根据权利要求1～15任一项所述的化合物，其特征在于：所述化合物选自：
    A系列：

    B系列：
    C系列：

    D系列：

    E系列：

    F系列：

    G系列：
    H系列：
    I系列：
    J系列：
    K系列：

    L系列：

    M系列：
    N系列：
  17. 根据权利要求1～15任一项所述的化合物，其特征在于：所述化合物选自：
    A系列：
    B系列：
    C系列：
    D系列：
    E系列：
    F系列：
    G系列：
    H系列：
    I系列：
    J系列：
    K系列：

    L系列：
    M系列：
    N系列：

  18. 根据权利要求1所述的化合物，其特征在于：结构单元选自：
  19. 根据权利要求1所述的化合物，其特征在于：结构单元选自：

  20. 根据权利要求1所述的化合物，其特征在于：结构单元选自：


  21. 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：
    A系列：

    B系列：

  22. 药物组合物，其特征在于：其是以权利要求1～21任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药为活性成分，辅以药学上可接受的载体。
  23. 权利要求1～21任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、氮氧化物、同位素标记物、代谢物或前药，及权利要求22所述的药物组合物，在制备用于预防和/或治疗NLRP3相关疾病的药物中的用途。
  24. 根据权利要求23所述的用途，其特征在于：所述NLRP3相关疾病包括：炎性疾病、自身免疫疾病、心血管系统疾病、癌症、肾系统疾病、胃肠道疾病、呼吸系统疾病、内分泌系统疾病或者中枢神经系统疾病。
  25. 根据权利要求23所述的用途，其特征在于：所述NLRP3相关疾病包括：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。
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