WO2022237903A1 - 一种喹唑啉类化合物、其制备方法及其应用 - Google Patents

一种喹唑啉类化合物、其制备方法及其应用 Download PDF

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WO2022237903A1
WO2022237903A1 PCT/CN2022/092860 CN2022092860W WO2022237903A1 WO 2022237903 A1 WO2022237903 A1 WO 2022237903A1 CN 2022092860 W CN2022092860 W CN 2022092860W WO 2022237903 A1 WO2022237903 A1 WO 2022237903A1
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substituted
membered
ring
solvate
pharmaceutically acceptable
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PCT/CN2022/092860
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English (en)
French (fr)
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王余吉
杜丽莎
夏广新
赵菲
李供省
郝利军
吴伊晨
柯樱
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上海医药集团股份有限公司
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Priority to EP22806865.6A priority Critical patent/EP4339188A1/en
Priority to US18/560,102 priority patent/US20240262793A1/en
Priority to JP2023570410A priority patent/JP2024517974A/ja
Publication of WO2022237903A1 publication Critical patent/WO2022237903A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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    • A61P31/14—Antivirals for RNA viruses
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    • A61P31/20—Antivirals for DNA viruses
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
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    • 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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to a quinazoline compound, its preparation method and application.
  • Inflammatory diseases have become an important threat to the health of the global population. Inflammation is closely related to the pathological process of many diseases, including many infectious and immune diseases, malignant tumors, cardiovascular diseases, diabetes and other chronic non-communicable major diseases. Autoimmune diseases refer to a class of diseases induced by the body's immune system attacking its own organs, tissues or cells, causing damage, mainly including psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Multiple sclerosis (MS), etc.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • MS Multiple sclerosis
  • HCQ Hydroxychloroquine
  • the technical problem to be solved by the present invention is to provide a quinazoline compound with novel structure and anti-inflammatory effect.
  • the compound of the present invention has good inhibitory effect on cytokines TNF- ⁇ , IL-6 and IL-1 ⁇ .
  • the present invention provides a quinazoline compound as shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof:
  • X is a halogen
  • Y is CH or N
  • L is -(CH 2 ) m - or -(CH 2 ) m - substituted by 1, 2 or 3 C 1-4 alkyl groups; m is 4, 5 or 6;
  • R 1 is H or
  • R 2 is C 1-4 alkyl or C 1-4 alkyl substituted by 1, 2 or 3 R 2-1 ;
  • R 2-1 is 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 6-12 aryl, 3-7 membered heterocycle substituted by 1, 2 or 3 R 2-1-1 Alkyl, 5-6-membered heteroaryl substituted by 1, 2 or 3 R 2-1-2 or C 6-12 aryl substituted by 1, 2 or 3 R 2-1-3 ;
  • the heteroatom of the 5-6 membered heteroaryl group The number is 1, 2 or 3, and the heteroatoms of the 5-6 membered heteroaryl group are selected from one or more of oxygen, sulfur and nitrogen;
  • R 2-1-1 is independently C 1-4 alkyl
  • R 2-1-2 is independently C 1-4 alkyl or C 1-4 alkoxy
  • R 2-1-3 is independently halogen, cyano, C 1-4 alkoxy, C 1-4 alkyl substituted by 1, 2 or 3 halogens, C substituted by 1, 2 or 3 halogens 1-4 alkoxy, C 6-12 aryl, 5-6 membered heteroaryl,
  • the number of heteroatoms in the 5-6 membered heteroaryl group is 1, 2 or 3, and the heteroatoms in the 5-6 membered heteroaryl group are selected from one or more of oxygen, sulfur and nitrogen;
  • R 2-1-3-1 is independently C 1-4 alkyl
  • R 2-1-3-2 is independently C 1-4 alkyl
  • R 1 , R 2 and the N atoms between them together form ring A, and said ring A is a 4-12 membered heterocycloalkyl or 4-12 substituted by 1, 2 or 3 R 2-2 Member heterocycloalkyl; said ring A is a 4-12 member heterocycloalkyl or 4-12 member heterocycloalkyl substituted by 1, 2 or 3 R 2-2 , said 4-12
  • the number of heteroatoms in the heterocycloalkyl group is 1, 2 or 3, and the heteroatoms in the 4-12-membered heterocycloalkyl group are selected from one or more of oxygen, sulfur and nitrogen;
  • R 2-2 is independently oxo, C 1-4 alkyl or halogen.
  • R 2 is C 1-4 alkyl substituted by 1, 2 or 3 R 2-1
  • R 2-1 is 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, substituted by 1, A 3-7 membered heterocycloalkyl group substituted by 2 or 3 R 2-1-1 or a 5-6 membered heteroaryl group substituted by 1, 2 or 3 R 2-1-2 ;
  • ring A is a single ring
  • ring A is a 4-12 membered heterocycloalkyl group substituted by 2 or 3 R 2-2
  • R 2-2 is independently oxo, C 1-4 alkyl or halogen
  • the substituent of the 4-12 membered heterocycloalkyl group contains oxo, the number of oxo is 2 or 3.
  • X is halogen
  • Y is CH or N
  • L is -(CH 2 ) m - or -(CH 2 ) m - substituted by 1, 2 or 3 C 1-4 alkyl groups; m is 4 or 5;
  • R 1 is H or
  • R 2 is C 1-4 alkyl substituted by 1, 2 or 3 R 2-1 ;
  • R 2-1 is 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 6-12 aryl, 3-7 membered heterocycle substituted by 1, 2 or 3 R 2-1-1 Alkyl, 5-6-membered heteroaryl substituted by 1, 2 or 3 R 2-1-2 or C 6-12 aryl substituted by 1, 2 or 3 R 2-1-3 ;
  • the heteroatom of the 5-6 membered heteroaryl group The number is 1, 2 or 3, and the heteroatoms of the 5-6 membered heteroaryl group are selected from one or more of oxygen, sulfur and nitrogen;
  • R 2-1-1 is independently C 1-4 alkyl
  • R 2-1-2 is independently C 1-4 alkyl or C 1-4 alkoxy
  • R 2-1-3 is independently halogen, cyano, C 1-4 alkoxy, C 1-4 alkyl substituted by 1, 2 or 3 halogens, C substituted by 1, 2 or 3 halogens 1-4 alkoxy, 5-6 membered heteroaryl,
  • the number of heteroatoms in the 5-6 membered heteroaryl group is 1, 2 or 3, and the heteroatoms in the 5-6 membered heteroaryl group are selected from one or more of oxygen, sulfur and nitrogen;
  • R 2-1-3-1 is independently C 1-4 alkyl
  • R 2-1-3-2 is independently C 1-4 alkyl
  • R 2-2-1 is independently oxo, C 1-4 alkyl or halogen
  • R 2-2-2 is independently oxo, C 1-4 alkyl or halogen
  • R 2 is C 1-4 alkyl substituted by 1, 2 or 3 R 2-1
  • R 2-1 is 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, substituted by 1, A 3-7 membered heterocycloalkyl group substituted by 2 or 3 R 2-1-1 or a 5-6 membered heteroaryl group substituted by 1, 2 or 3 R 2-1-2 ;
  • the ring A is a 5-12 membered heterocycloalkyl A 1
  • the heterocycloalkyl A 1 is a bridged ring
  • said ring A is a 5-10 membered heterocycloalkyl A 2 substituted by 2 or 3 R 2-2-1
  • said heterocycloalkyl A 2 is a monocyclic ring
  • R 2- 2-1 is independently oxo, C 1-4 alkyl or halogen, and when the substituent of the 5-10 membered heterocycloalkyl group contains oxo, the number of oxo is 2 or 3.
  • L is Among them, the side marked with * indicates that it is connected to the N on the NH in the mother core structure.
  • X is F or Cl.
  • R 2 is C 1-4 alkyl substituted by 1, 2 or 3 R 2-1 .
  • R 2-1-3 is independently halogen, cyano, C 1-4 alkoxy, C 1-4 alkyl substituted by 1, 2 or 3 halogens, substituted by 1, 2 or 3 halogen substituted C 1-4 alkoxy, 5-6 membered heteroaryl,
  • the number of heteroatoms in the 5-6 membered heteroaryl group is 1, 2 or 3, and the heteroatoms in the 5-6 membered heteroaryl group are selected from one or more of oxygen, sulfur and nitrogen.
  • the ring A is a 5-12 membered heterocycloalkyl A 1
  • the heterocycloalkyl A 1 is Bridged ring
  • the heterocycloalkyl A 3 is a spiro ring.
  • R 2-2-1 is independently oxo, C 1-4 alkyl or halogen
  • R 2-2-2 is independently oxo, C 1-4 alkyl or halogen.
  • R 2-2-1 is independently oxo, C 1-4 alkyl or halogen
  • R 2-2-2 is independently oxo, C 1-4 alkyl or halogen
  • R 1 , R 2 and the N atoms between them together form a ring A, and the ring A can be
  • Z is CH or N
  • R a , R b and R c are each independently H or C 1-4 alkyl; or R b , R c and the atoms connected to them together form a C 3-6 aliphatic carbocyclic ring or a 3-6 membered aliphatic heterocyclic ring;
  • the number of heteroatoms in the 3-6 membered aliphatic heterocyclic ring is 1 or 2, and the heteroatoms in the 3-6 membered aliphatic heterocyclic ring are selected from one or more of oxygen, sulfur and nitrogen;
  • Structural Fragment represents a 3-6 membered nitrogen-containing heterocycloalkyl group substituted by 2 or 3 R d ; the number of heteroatoms in the heterocycloalkyl group is 1, 2 or 3, and the heterocycloalkyl group in In addition to nitrogen, the other heteroatoms are selected from one or more of oxygen, sulfur and nitrogen;
  • the R d is H, oxo or halogen; or two adjacent R d and the atoms connected to it form a C 3-6 aliphatic carbocyclic ring, a 3-6 membered aliphatic heterocyclic ring, surrounded by 1, 2 or C 3-6 aliphatic carbon ring substituted by 3 R d-1 or 3-6 membered aliphatic heterocyclic ring substituted by 1, 2 or 3 R d- 1 ; or two R d on the same atom are connected to it
  • the atoms together form a C 3-6 aliphatic carbon ring, a 3-6 membered aliphatic heterocyclic ring, a C 3-6 aliphatic carbon ring substituted by 1, 2 or 3 R d-1 or a C 3-6 aliphatic carbon ring substituted by 1, 2 or A 3-6-membered aliphatic heterocyclic ring substituted by 3 R d-1 ; the number of heteroatoms in the aliphatic heterocyclic ring
  • R d-1 is independently C 1-4 alkyl.
  • R a is H
  • R b and R c are each independently C 1-4 alkyl.
  • R 2 is methyl or ethyl substituted by 1 or 2 R 2-1 .
  • R2 is
  • the C 1-4 alkyl in R 2 , among the C 1-4 alkyl and the C 1-4 alkyl substituted by 1, 2 or 3 R 2-1 , the C 1-4 alkyl May independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl or ethyl.
  • the number of heteroatoms can be independently 1, and the type of heteroatoms can be independently N or O.
  • the The 3-7 membered heterocycloalkyl group can be independently a 4-5 membered heterocycloalkyl group, such as tetrahydropyrrolyl or oxetanyl, more for example
  • the type of heteroatom can be selected from one or both of N and O.
  • the said The 5-6 membered heteroaryl group of can be independently oxazolyl, triazolyl, pyridyl or pyrazinyl, for example
  • Aryl in the C 6-12 aryl group and the C 6-12 aryl group substituted by 1, 2 or 3 R 2-1-3 , in the C 6-12 aryl group -12 Aryl can be independently phenyl or naphthyl, such as
  • the C 1-4 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl Or sec-butyl, for example methyl.
  • the C 1-4 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl Or sec-butyl, for example methyl.
  • the C 1-4 alkoxy is independently methoxy, ethoxy or propoxy, for example, ethoxy.
  • the halogen is independently F, Cl, Br or I, such as F or Cl.
  • the C 1-4 alkoxy group is independently methoxy, ethoxy or propoxy, for example, methoxy.
  • the C 1-4 alkyl substituted by 1, 2 or 3 halogens is independently trifluoromethyl, trifluoroethyl or trifluoropropyl, For example trifluoromethyl.
  • the C 1-4 alkoxy group substituted by 1, 2 or 3 halogens is independently trifluoromethoxy, trifluoroethoxy or trifluoro Propoxy is, for example, trifluoromethoxy.
  • the C 6-12 aryl is phenyl or naphthyl.
  • the 5-6 membered heteroaryl can be pyrazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl or pyrrolyl, such as pyrazole base, for example
  • the C 1-4 alkyl groups can be independently methyl, ethyl, n-propyl, isopropyl radical, n-butyl, tert-butyl, isobutyl or sec-butyl, for example methyl.
  • the C 1-4 alkyl groups can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl Or sec-butyl, for example methyl or ethyl.
  • the halogens can be independently F, Cl, Br or I, such as F.
  • the C 1-4 alkyl groups can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl , isobutyl or sec-butyl, for example methyl.
  • R b , R c and the atoms connected to them jointly form a C 3-6 aliphatic carbon ring
  • the C 3-6 aliphatic carbon ring can be cyclopropane, cyclobutane, cyclopentane or cyclopropane Hexane such as cyclopropane, cyclobutane or cyclopentane.
  • R b , R c and the atoms connected to them together form a 3-6 membered aliphatic heterocyclic ring.
  • the number of heteroatoms can be 1, and the number of heteroatoms
  • the species can be N.
  • R b , R c and the atoms connected to them together form a 3-6 membered aliphatic heterocyclic ring
  • the 3-6 membered aliphatic heterocyclic ring can be a 6-membered aliphatic heterocyclic ring, such as a piperidine ring, more E.g
  • the number of heteroatoms can be 1 or 2 independently, and the types of heteroatoms can be N, N and S independently.
  • the 3-6 membered nitrogen-containing heterocycloalkyl group can be independently thiomorpholinyl, tetrahydropyrrolyl or N-heterocyclobutanyl, for example
  • the C 3-6 aliphatic carbon ring can be independently cyclopropane, cyclobutane, cyclopentane or cyclohexane, such as cyclopentane.
  • the number of heteroatoms can be independently 1, and the type of heteroatoms can be independently N or O.
  • the 3-6-membered aliphatic ring can be independently oxetane, tetrahydropyrrole ring or tetrahydropyran ring, for example, two R d on the same atom and the atoms connected to it form together
  • a 3-6 membered aliphatic heterocyclic ring or a 3-6 membered aliphatic heterocyclic ring substituted by 1, 2 or 3 R d-1 the 3-6 membered aliphatic heterocyclic ring can be
  • the C 1-4 alkyl group in R d-1 , can be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec Butyl is, for example, methyl.
  • X is halogen; Y is CH or N; R is R 2 is C 1-4 alkyl substituted by 1 , 2 or 3 R 2-1; R 2-1 is or C 6-12 aryl substituted by 1, 2 or 3 R 2-1-3 ; L is preferably
  • X is Cl
  • Y is CH
  • L is -(CH 2 ) m - when substituted by 1 methyl group, R 1 , R 2 and the N atoms between them form ring A together, so The ring A described is Wherein R a is C 1-4 alkyl, R b and R c are both H.
  • the R d is oxo or halogen; or two adjacent R d and the atoms connected to them form a C 3-6 aliphatic carbon ring, or two R d on the same atom and the atoms connected to them form a 3-6 6-membered aliphatic heterocyclic ring or 3-6 membered aliphatic heterocyclic ring substituted by 1, 2 or 3 R d-1 ; the number of heteroatoms in the aliphatic heterocyclic ring is 1, 2 or 3, so
  • the heteroatoms in the aliphatic ring are selected from one or more of oxygen, sulfur and nitrogen.
  • R1 is
  • R 2 is C 1-4 alkyl substituted by 1, 2 or 3 R 2-1
  • R 2-1 is 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl
  • R 1 , R 2 and the N atoms between them together form a ring A
  • the ring A is a 5-12 membered heterocycloalkyl A 1
  • the heterocycloalkyl A 1 is bridged ring
  • the heterocycloalkyl A 3 is a spiro ring
  • the number of heteroatoms is 1, 2 or 3, and the number of heteroatoms is selected from one or more of oxygen, sulfur and nitrogen.
  • ring A is a 5-10 membered heterocyclic ring substituted by 2 or 3 R 2-2-1 Alkyl A 2 , the heterocycloalkyl A 2 is monocyclic; R 2-2-1 is independently oxo, C 1-4 alkyl or halogen, and when the 5-10 membered heterocycloalkane
  • the substituent of the group contains oxo
  • the number of said oxo is 2 or 3
  • the heterocycloalkyl group the number of heteroatoms is 1, 2 or 3, and the number of heteroatoms is selected from One or more of oxygen, sulfur and nitrogen.
  • the quinazoline compound shown in formula I can be a compound as described in formula I-1 or I-1':
  • the quinazoline compound as described in formula I may be a compound as described in formula 1-2:
  • the quinazoline compound as described in formula I may be a compound as described in formula 1-2:
  • the quinazoline compound as shown in formula I is any of the following compounds:
  • the present invention also provides a kind of preparation method of above-mentioned quinazoline compound shown in formula I, it is any one in the following method:
  • Method 1 which comprises the following steps: in a solvent, under the action of alkali and iodine salt, the compound shown in formula II-1 is reacted with the compound shown in formula II-2;
  • X is a halogen, such as F, Cl, Br or I, preferably Cl;
  • Y is CH; the definitions of all the other substituents in the above formulas are as described above;
  • the solvent can be a common solvent for this type of reaction in the art, such as a nitrile solvent, preferably acetonitrile;
  • Described alkali can be the common alkali of this type of reaction in this field, for example the carbonate of alkali metal, preferably potassium carbonate;
  • the iodized salt can be an iodized salt commonly used in this type of reaction in the art, such as KI;
  • Method 2 In a solvent, under the action of a base and a quaternary ammonium salt, react the compound shown in formula II-1 with the compound shown in formula II-2;
  • X is a halogen, such as F, Cl, Br or I, preferably Cl;
  • Y is N; the definitions of all the other substituents in the above formulas are as described above;
  • the solvent can be a common solvent for this type of reaction in the art, such as a nitrile solvent, preferably acetonitrile;
  • Described alkali can be the common alkali of this type of reaction in this field, for example the carbonate of alkali metal, preferably potassium carbonate;
  • the quaternary ammonium salt can be a quaternary ammonium salt commonly used in this type of reaction in the art, such as n-Bu 4 NBr;
  • Method 3 which comprises the following steps: in a solvent, under the action of a base, the compound shown in formula II-3 and the compound shown in formula II-4 are reacted;
  • X 2 is halogen, such as F, Cl, Br or I, preferably Cl; in formula I, R 1 is The definitions of all the other substituents in the above formulas are as described above;
  • the solvent can be a common solvent for this type of reaction in the art, such as a nitrile solvent, preferably acetonitrile;
  • the base may be a base commonly used in this type of reaction in the art, such as alkali metal carbonate, preferably potassium carbonate.
  • the present invention also provides a pharmaceutical composition, which includes substance X and pharmaceutical excipients; said substance X is the above-mentioned quinazoline compound shown in formula I, its pharmaceutically acceptable salt, its solvate or a solvate of a pharmaceutically acceptable salt thereof.
  • the present invention also provides an application of substance Y in the preparation of medicine; said substance Y is the quinazoline compound shown in formula I as above, its pharmaceutically acceptable salt, its solvate, The solvate of its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition, the drug has inhibitory effect on 1, 2 or 3 of cytokines TNF- ⁇ , IL-6, IL-1 ⁇ medicine.
  • the present invention also provides an application of substance Y in the preparation of inhibitors; said substance Y is the quinazoline compound shown in formula I as above, its pharmaceutically acceptable salt, and its solvate , a solvate of a pharmaceutically acceptable salt thereof or the pharmaceutical composition as described above, wherein the inhibitor is 1 of cytokine TNF- ⁇ inhibitor, IL-6 inhibitor and IL-1 ⁇ inhibitor, 2 or 3 types.
  • the inhibitor is an inhibitor that can inhibit 1, 2 or 3 of TNF- ⁇ , IL-6 and IL-1 ⁇ in vitro.
  • the present invention also provides an application of substance Y in the preparation of medicine; said substance Y is the quinazoline compound shown in formula I as above, its pharmaceutically acceptable salt, its solvate, A solvate of its pharmaceutically acceptable salt or a pharmaceutical composition as described above; the drug is used for prevention and/or treatment with 1, 2 or 3 of TNF- ⁇ , IL-6 and IL-1 ⁇ Drugs for related diseases.
  • the present invention also provides an application of substance Y in the preparation of medicine; said substance Y is the quinazoline compound shown in formula I as above, its pharmaceutically acceptable salt, its solvate, A solvate of its pharmaceutically acceptable salt or a pharmaceutical composition as described above; the drug is used for the prevention and/or treatment of autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, cutaneous Lupus erythematosus, diabetes, Sjogren's syndrome, multiple sclerosis, etc.), malaria, infectious diseases (such as AIDS, viral hepatitis, coronavirus, etc.), allergic diseases (such as asthma, etc.), cardiovascular system diseases, post-organ transplantation Drugs for anti-rejection reactions, chronic obstructive pulmonary disease, tumors and other diseases related to the abnormal function and response state of the body's immune system.
  • autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, cutaneous Lup
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight-chain or branched-chain alkyl group having a specified number of carbon atoms (eg, C 1 -C 4 ).
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl, and the like.
  • alkoxy refers to the group Rx- O-, wherein Rx is alkyl as defined above.
  • aliphatic carbocycle refers to a cyclic, saturated monocyclic ring with a specified number of carbon atoms (such as C 3-6 ). Examples of aliphatic carbocycles include but are not limited to cyclopropane, cyclobutane, cyclopentane , Cyclohexane.
  • heterocycloalkyl refers to a specified number of ring atoms (such as 5 to 10 members), a specified number of heteroatoms (such as 1, 2 or 3), a specified heteroatom type (N, O and S) One or more) cyclic groups, which are monocyclic, bridged or spiro, and each ring is saturated.
  • Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
  • heteroalicyclic ring refers to a specified number of ring atoms (such as 3 to 6 members), a specified number of heteroatoms (such as 1, 2 or 3), and a specified type of heteroatom (one of N, O and S).
  • rings which are monocyclic, and examples of aliphatic rings include, but are not limited to, oxetane, tetrahydropyrrole rings, and tetrahydropyran rings.
  • aryl refers to a cyclic group consisting only of carbon atoms with a specified number of carbon atoms (such as C 6 to C 10 ), which is monocyclic or polycyclic, and at least one ring is aromatic ( in accordance with Huckel's rule).
  • the aryl group is connected to other segments in the molecule through an aromatic ring or a non-aromatic ring.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
  • heteroaryl refers to a group having a specified number of ring atoms (such as 5-10 members), a specified number of heteroatoms (such as 1, 2 or 3), and a specified heteroatom type (one of N, O and S). one or more) cyclic groups, which are monocyclic or polycyclic, and at least one ring is aromatic (according to Huckel's rule). Heteroaryl groups are linked to other moieties in the molecule through aromatic rings or non-aromatic rings.
  • Heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.
  • the heteroaryl is monocyclic.
  • a "-" at the end of a group means that the group is attached to other fragments in the molecule through this site.
  • fragment means that the structural fragment is connected to other fragments in the molecule through this site.
  • E.g, means cyclohexyl.
  • any variable (such as the group R 1-1 ) appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other.
  • a C 6 ⁇ C 10 aryl group substituted by 3 R 1-1 means that the C 6 ⁇ C 10 aryl group will be substituted by 3 R 1-1 , and the definitions of the 3 R 1-1 are mutually independent and mutually does not affect.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base.
  • base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like.
  • acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, and the like. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.
  • solvate refers to a substance formed after crystallization of a compound with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • solvate of a pharmaceutically acceptable salt refers to a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, solvent (including but not limited to: water, methanol, ethanol etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term “pharmaceutically acceptable salt” above, and the solvent is stoichiometric or non-stoichiometric.
  • solvent including but not limited to: water, methanol, ethanol etc.
  • Solvates of pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.
  • therapeutically effective amount refers to the amount of a compound administered to a patient sufficient to effectively treat the disease.
  • the therapeutically effective dose will vary according to the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
  • pharmaceutical excipients refers to the excipients and additives used in the production of drugs and the preparation of prescriptions, and refers to all substances contained in pharmaceutical preparations except for active ingredients. For details, see Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).
  • treating refers to any of the following: (1) amelioration of one or more biological manifestations of disease; (2) interference with one or more points in the biological cascade leading to disease; (3) slowing of disease The development of one or more biological manifestations.
  • prevention refers to reducing the risk of developing a disease.
  • patient refers to any animal, preferably a mammal, most preferably a human, who has been or is about to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention lies in that the quinazoline compound of the present invention has a novel structure and has good inhibitory effect on cytokines TNF- ⁇ , IL-6 and IL-1 ⁇ .
  • Step 1 prepares 4-amino-1-pentanol (compound 1-2)
  • Step 4 prepares 4-((7-chloroquinolin-4-yl)amino)pentan-1-ol (compound 1-5)
  • Step 5 prepares 7-chloro-N-(5-chloropentan-2-yl) quinoline-4-amine (compound 1-6)
  • the raw material 7-chloro-N-(5-chloropentan-2-yl)quinolin-4-amine (80 mg, 0.28 mmol) was dissolved in 20 mL of acetonitrile, and KI (10 mg), K 2 CO 3 (100 mg , 0.73mmol) and thiomorpholine-1,1-dioxide (150mg, 1.11mmol), the reaction mixture was heated to 60-70°C under the protection of argon, and reacted for 48 hours. After the reaction was complete, it was concentrated, and the residue was separated by column chromatography to obtain 15 mg of the product with a yield of 13.89%.
  • Step 2 prepares 4-((7-chloroquinazolin-4-yl)amino)pentan-1-ol (compound 2-3)
  • Step 3 prepares 7-chloro-N-(5-chloropentan-2-yl)quinazolin-4-amine (compound 2-4)
  • the raw material 7-chloro-N-(5-chloropentan-2-yl)quinazolin-4-amine (100mg, 0.35mmol) was dissolved in 20mL of acetonitrile, and n-Bu 4 NBr (10mg), K 2 CO 3 (100mg, 0.73mmol) and imidazolidine-2,4-dione (100mg, 1.00mmol), the reaction mixture was heated to 60-70°C under argon protection, and reacted for 48 hours. After the reaction was complete, it was concentrated, and the residue was separated by column chromatography to obtain 54 mg of the product, with a yield of 44.12%.
  • Example 14 According to the same method as in Example 13, the compound of Example 14 was prepared, and the specific experimental data are shown in Table 2.
  • the raw material 4-((7-chloroquinazolin-4-yl)amino)pentan-1-ol (50 mg, 0.19 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and PPh 3 (280 mg, 1.07 mmol), DIAD ( 240mg, 1.19mmol) and pyrrolidine-2,5-dione (100mg, 1.01mmol), the reaction mixture was reacted at room temperature under the protection of argon for 48 hours. After the reaction was complete, it was concentrated, and the residue was separated by column chromatography to obtain 57 mg of the product, with a yield of 87.10%.
  • Step 1 prepares 5-(benzyl(2-hydroxyethyl)amino)pentan-2-one (compound 4-3)
  • Step 2 prepares 2-[4-aminopentyl (benzyl) amino] ethanol (compound 4-4)
  • Step 3 prepares 2-(benzyl(4-((7-chloroquinazolin-4-yl)amino)pentyl)amino)ethanol (compound 4-5)
  • Step 5 prepares 2-((4-((7-chloroquinazolin-4-yl)amino)pentyl)amino)ethanol (compound 4-7)
  • LC-MS m/z 377.2[M+H] + .
  • Step 4 prepares tert-butyl (5-aminopentyl) (2-hydroxyethyl) carbonate (compound 5-6)
  • reaction mixture was concentrated by a rotary evaporator and 1M NaOH solution was added to the residue, extracted with dichloromethane (20mLx3), the organic phases were combined, dried over anhydrous Na 2 SO 4 , concentrated to dryness to obtain tert-butyl (5-aminopentyl base) (2-hydroxyethyl) carbonate (1.1 g, 4.453 mmol, yield 55.96%) as a yellow oil.
  • LC-MS m/z 247.3[M+H] + .
  • Step 1 prepares 5-((7-fluoroquinazolin-4-yl)amino)pentan-1-ol (compound 6-3)
  • Step 2 prepares N-(5-chloropentyl)-7-fluoroquinazolin-4-amine (compound 6-4)
  • the starting material 5-((7-fluoroquinazolin-4-yl)amino)pentan-1-ol (0.6 g, 2.4 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and thionyl chloride (1.2 g, 10 mmol) and a catalytic amount of N,N-dimethylformamide (0.3 mL), the reaction mixture was reacted at room temperature for 4 hours under the protection of argon. After the reaction was complete, it was concentrated, and the pH of the residue was adjusted to 8 with aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic phase was dried, filtered and concentrated, and the residue was separated by column chromatography to obtain 493 mg of the product with a yield of 76.5%.
  • the raw material N-(5-chloropentyl)-7-fluoroquinazolin-4-amine (80mg, 0.3mmol) was dissolved in 5mL of dry tetrahydrofuran, and imidazolidine-2,4-dione (60mg, 0.6 mmol), potassium carbonate (130mg, 0.9mmol) and tetrabutylammonium bisulfate (20mg, 0.06mmol), the reaction mixture was heated to 60°C under the protection of argon, and reacted overnight. After the reaction was complete, it was concentrated, and the residue was separated on a silica gel preparation plate to obtain 42 mg of the product, with a yield of 42.4%.
  • LPS LPS was added to the complete medium and the final concentration of LPS was adjusted to 100 ng/mL, and the compound was prepared with the medium containing LPS.
  • the compounds were added to the corresponding cell wells according to the prepared concentration gradient drugs.
  • Positive control group (LPS+) is the culture medium solution that does not contain drug but contains LPS and 0.1% DMSO that final concentration is 100ng/mL
  • negative control group (LPS-) is the culture medium solution that does not add LPS and contains 0.1% DMSO.
  • the volume of each well is 100 ⁇ L.
  • Detection sample collection centrifuge at 1000 rpm for 5 minutes, and collect the cell supernatant and cell pellet respectively.
  • Cell supernatants were used to detect TNF- ⁇ and IL-6; cell pellets were collected for detection of IL-1 ⁇ . After the cell supernatant was collected, the remaining liquid in the well was discarded, and 100 ⁇ L of cell lysate (20mM Tris 8.0; 2mM EDTA; 0.5% Triton X-100) was added to each well to fully lyse.
  • ELISA Enzyme-linked immunosorbent assay
  • Inhibition rate (%) [1-(OD450 drug addition -OD450 LPS-)/(OD450 LPS+ -OD450 LPS - )] ⁇ 100%.
  • Compounds of the invention have an IC50 of less than 2000 [mu]M in this assay. Certain compounds have IC50s below 10 ⁇ M. Tables 7 and 8 provide specific IC50 values for compounds of the invention tested in this assay.

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Abstract

提供了一种喹唑啉类化合物及其应用，具体提供了一种如式I所示的喹唑啉类化合物，所述化合物结构新颖，对细胞因子TNF-α，IL-6，IL-1β具有良好的抑制效果。

Description

一种喹唑啉类化合物、其制备方法及其应用
本申请要求申请日为2021年5月14日的中国专利申请2021105302760的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种喹唑啉类化合物、其制备方法及其应用。
背景技术
炎症性疾病已成为影响全球人群健康的重要威胁，炎症和多种疾病的病理进程密切相关，包括许多传染性疾病和免疫性疾病、恶性肿瘤、心血管疾病、糖尿病等慢性非传染性重大疾病。自身免疫性疾病是指机体免疫系统攻击自身的器官、组织或细胞，引起损伤而诱发的一类疾病，主要包括银屑病、类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、多发性硬化(MS)等。
炎症细胞因子TNF-α、IL-6和IL-1β在自身免疫性疾病患者血清、局部病灶组织中表达丰富，抑制以上三个因子的形成能有效降低炎症反应，减少炎症对机体组织的破坏。羟氯喹(HCQ)问世于1944年，最初作为抗疟疾药物而引人注意。后来发现HCQ还具有消炎特性，因而被作为消炎剂来治疗某些炎性疾病，广泛用于治疗系统性红斑狼疮、类风湿性关节炎、肖格伦综合征和迟发性皮肤卟啉症等病症。
对HCQ进行改造，研究出活性更好的更新换代药物一直是药物化学领域的研究热点。
发明内容
本发明要解决的技术问题是提供一种结构新颖的具有抗炎作用的喹唑啉类化合物。本发明的化合物对细胞因子TNF-α，IL-6，IL-1β具有良好的抑制效果。
本发明提供了一种如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物：
Figure PCTCN2022092860-appb-000001
其中，X为卤素；
Y为CH或N；
L为-(CH 2) m-或被1、2或3个C 1-4烷基取代的-(CH 2) m-；m为4、5或6；
R 1为H或
Figure PCTCN2022092860-appb-000002
R 2为C 1-4烷基或被1、2或3个R 2-1取代的C 1-4烷基；
R 2-1为3-7元杂环烷基、5-6元杂芳基、C 6-12芳基、被1、2或3个R 2-1-1取代的3-7元杂环烷基、被1、2或3个R 2-1-2取代的5-6元的杂芳基或被1、2或3个R 2-1-3取代的C 6-12芳基；所述的5-6元杂芳基和所述的被1、2或3个R 2-1-2取代的5-6元杂芳基里，所述的5-6元杂芳基的杂原子数量为1、2或3个，所述的5-6元杂芳基的杂原子选自氧、硫和氮中的一种或多种；所述3-7元杂环烷基和被1、2或3个R 2-1-1取代的3-7元杂环烷基里，所述3-7元杂环烷基的杂原子数量为1、2或3个，所述3-7元杂环烷基的杂原子选自氧、硫和氮中的一种或多种；
R 2-1-1独立地为C 1-4烷基；
R 2-1-2独立地为C 1-4烷基或C 1-4烷氧基；
R 2-1-3独立地为卤素、氰基、C 1-4烷氧基、被1、2或3个卤素取代的C 1-4烷基、被1、2或3个卤素取代的C 1-4烷氧基、C 6-12芳基、5-6元杂芳基、
Figure PCTCN2022092860-appb-000003
所述的5-6元杂芳基的杂原子数量为1、2或3个，所述的5-6元杂芳基的杂原子选自氧、硫和氮中的一种或多种；
R 2-1-3-1独立地为C 1-4烷基；
R 2-1-3-2独立地为C 1-4烷基；
或者，R 1、R 2及它们之间的N原子一起形成环A，所述的环A为4-12元杂环烷基或被1、2或3个R 2-2取代的4-12元杂环烷基；所述的环A为4-12元杂环烷基或被1、2或3个R 2-2取代的4-12元杂环烷基里，所述的4-12元杂环烷基的杂原子数量为1、2 或3个，所述的4-12元杂环烷基的杂原子选自氧、硫和氮中的一种或多种；
R 2-2独立地为氧代、C 1-4烷基或卤素。
在某一方案中，所述的如式I所示的喹唑啉类化合物满足下列条件中的1个、2个或3个：
i：R 1为
Figure PCTCN2022092860-appb-000004
ii：R 2为被1、2或3个R 2-1取代的C 1-4烷基，R 2-1为3-7元杂环烷基、5-6元杂芳基、被1、2或3个R 2-1-1取代的3-7元杂环烷基或被1、2或3个R 2-1-2取代的5-6元的杂芳基；
iii：R 1、R 2及它们之间的N原子一起形成环A，所述的环A为螺环或桥环；或者R 1、R 2及它们之间的N原子一起形成环A，所述的环A为单环，环A为被2或3个R 2-2取代的4-12元杂环烷基，R 2-2独立地为氧代、C 1-4烷基或卤素，且当所述的4-12元杂环烷基的取代基包含氧代时，所述氧代的个数为2个或3个。
在某一方案中，X为卤素；
Y为CH或N；
L为-(CH 2) m-或被1、2或3个C 1-4烷基取代的-(CH 2) m-；m为4或5；
R 1为H或
Figure PCTCN2022092860-appb-000005
R 2为被1、2或3个R 2-1取代的C 1-4烷基；
R 2-1为3-7元杂环烷基、5-6元杂芳基、C 6-12芳基、被1、2或3个R 2-1-1取代的3-7元杂环烷基、被1、2或3个R 2-1-2取代的5-6元的杂芳基或被1、2或3个R 2-1-3取代的C 6-12芳基；所述的5-6元杂芳基和所述的被1、2或3个R 2-1-2取代的5-6元杂芳基里，所述的5-6元杂芳基的杂原子数量为1、2或3个，所述的5-6元杂芳基的杂原子选自氧、硫和氮中的一种或多种；所述3-7元杂环烷基和被1、2或3个R 2-1-1取代的3-7元杂环烷基里，所述3-7元杂环烷基的杂原子数量为1、2或3个，所述3-7元杂环烷基的杂原子选自氧、硫和氮中的一种或多种；
R 2-1-1独立地为C 1-4烷基；
R 2-1-2独立地为C 1-4烷基或C 1-4烷氧基；
R 2-1-3独立地为卤素、氰基、C 1-4烷氧基、被1、2或3个卤素取代的C 1-4烷基、被1、2或3个卤素取代的C 1-4烷氧基、5-6元杂芳基、
Figure PCTCN2022092860-appb-000006
所述的5-6元杂 芳基的杂原子数量为1、2或3个，所述的5-6元杂芳基的杂原子选自氧、硫和氮中的一种或多种；
R 2-1-3-1独立地为C 1-4烷基；
R 2-1-3-2独立地为C 1-4烷基；
或者，R 1、R 2及它们之间的N原子一起形成环A，所述的环A为5-12元杂环烷基A 1，所述的杂环烷基A 1为桥环；或被2或3个R 2-2-1取代的5-10元杂环烷基A 2，所述杂环烷基A 2为单环；或被1、2或3个R 2-2-2取代8-12元杂环烷基A 3，所述杂环烷基A 3为螺环；所述的杂环烷基里，杂原子数量为1、2或3个，杂原子的个数选自氧、硫和氮的一种或多种；
R 2-2-1独立地为氧代、C 1-4烷基或卤素；
R 2-2-2独立地为氧代、C 1-4烷基或卤素；
且其满足下列条件中的1个、2个或3个：
i：R 1为
Figure PCTCN2022092860-appb-000007
ii：R 2为被1、2或3个R 2-1取代的C 1-4烷基，R 2-1为3-7元杂环烷基、5-6元杂芳基、被1、2或3个R 2-1-1取代的3-7元杂环烷基或被1、2或3个R 2-1-2取代的5-6元的杂芳基；
iii：R 1、R 2及它们之间的N原子一起形成环A，所述的环A为5-12元杂环烷基A 1，所述的杂环烷基A 1为桥环；或被1、2或3个R 2-2-2取代8-12元杂环烷基A 3，所述杂环烷基A 3为螺环；或者R 1、R 2及它们之间的N原子一起形成环A，所述的环A为被2或3个R 2-2-1取代的5-10元杂环烷基A 2，所述杂环烷基A 2为单环；R 2-2-1独立地为氧代、C 1-4烷基或卤素，且当所述的5-10元杂环烷基的取代基包含氧代时，所述氧代的个数为2个或3个。
在某一方案中，如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物里，某些基团的定义可如下所述，其他基团的定义可如其他任一方案所述(以下简称“在某一方案中”)：L为-(CH 2) m-；被1个甲基取代的-(CH 2) m-；m为4或5；例如为
Figure PCTCN2022092860-appb-000008
在某一方案中，L为
Figure PCTCN2022092860-appb-000009
Figure PCTCN2022092860-appb-000010
其中，标*的一侧表示与母核结构中NH上的N相连。
在某一方案中，X为F或Cl。
在某一方案中，R 2为被1、2或3个R 2-1取代的C 1-4烷基。
在某一方案中，R 2-1-3独立地为卤素、氰基、C 1-4烷氧基、被1、2或3个卤素取代的C 1-4烷基、被1、2或3个卤素取代的C 1-4烷氧基、5-6元杂芳基、
Figure PCTCN2022092860-appb-000011
所述的5-6元杂芳基的杂原子数量为1、2或3个，所述的5-6元杂芳基的杂原子选自氧、硫和氮中的一种或多种。
在某一方案中，R 1、R 2及它们之间的N原子一起形成环A，所述的环A为5-12元杂环烷基A 1，所述的杂环烷基A 1为桥环；或被2或3个R 2-2-1取代的5-10元杂环烷基A 2，所述杂环烷基A 2为单环；或被1、2或3个R 2-2-2取代8-12元杂环烷基A 3，所述杂环烷基A 3为螺环。
R 2-2-1独立地为氧代、C 1-4烷基或卤素；
R 2-2-2独立地为氧代、C 1-4烷基或卤素。
在某一方案中，R 1、R 2及它们之间的N原子一起形成环A，所述的环A为5-12元杂环烷基A 1，所述的杂环烷基A 1为桥环；或被2或3个R 2-2-1取代的5-10元杂环烷基A 2，所述杂环烷基A 2为单环；或被1、2或3个R 2-2-2取代8-12元杂环烷基A 3，所述杂环烷基A 3为螺环；
R 2-2-1独立地为氧代、C 1-4烷基或卤素；
R 2-2-2独立地为氧代、C 1-4烷基或卤素；
A 2中，当所述的5-10元杂环烷基的取代基包含氧代时，所述氧代的个数为2个或3个。
在某一方案中，R 1、R 2及它们之间的N原子一起形成环A，所述的环A可为
Figure PCTCN2022092860-appb-000012
其中，Z为CH或N；
R a、R b和R c各自独立地为H或C 1-4烷基；或者R b、R c和与其相连的原子共同形成C 3-6脂碳环或3～6元脂杂环；所述的3～6元脂杂环的杂原子数量为1个或2个，所述的3～6元脂杂环的杂原子选自氧、硫和氮中的一种或多种；
结构片段
Figure PCTCN2022092860-appb-000013
表示被2个或3个R d取代的3～6元含氮杂环烷基；所述的杂环 烷基的杂原子数量为1个、2个或3个，所述的杂环烷基的中除含氮外，其余杂原子选自氧、硫和氮中的一种或多种；
所述的R d为H、氧代或卤素；或相邻的两个R d与其相连的原子共同形成C 3-6脂碳环、3～6元脂杂环、被1个、2个或3个R d-1取代的C 3-6脂碳环或被1个、2个或3个R d- 1取代的3～6元脂杂环；或者同一原子上的两个R d与其相连的原子共同形成C 3-6脂碳环、3～6元脂杂环、被1个、2个或3个R d-1取代的C 3-6脂碳环或被1个、2个或3个R d-1取代的3～6元脂杂环；所述的脂杂环的杂原子数量为1个、2个或3个，所述的脂杂环中杂原子选自氧、硫和氮中的一种或多种；
R d-1独立地为C 1-4烷基。
在某一方案中，R a为H，R b和R c各自独立地为C 1-4烷基。
在某一方案中，R 2为被1或2个R 2-1取代的甲基或乙基。
在某一方案中，环A为
Figure PCTCN2022092860-appb-000014
Figure PCTCN2022092860-appb-000015
在某一方案中，R 2为
Figure PCTCN2022092860-appb-000016
Figure PCTCN2022092860-appb-000017
在某一方案中，R 2中，所述的C 1-4烷基和被1、2或3个R 2-1取代的C 1-4烷基里，所述的C 1-4烷基可独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基或乙基。
在某一方案中，R 2-1中，所述的3-7元杂环烷基和被1、2或3个R 2-1-1取代的3-7元杂环烷基里，所述的3-7元杂环烷基中，杂原子的数量可独立地为1个，杂原子的种类可独立地为N或O。
在某一方案中，R 2-1中，所述的3-7元杂环烷基和被1、2或3个R 2-1-1取代的3-7元 杂环烷基里，所述的3-7元杂环烷基可独立地为4-5元杂环烷基，例如四氢吡咯基或氧杂环丁烷基，更例如为
Figure PCTCN2022092860-appb-000018
在某一方案中，R 2-1中，所述的5-6元杂芳基和被1、2或3个R 2-1-2取代的5-6元的杂芳基里，所述的5-6元杂芳基中，杂原子的种类可选自N和O的一种或两种。
在某一方案中，R 2-1中，所述的5-6元杂芳基和被1、2或3个R 2-1-2取代的5-6元的杂芳基里，所述的5-6元杂芳基可独立地为噁唑基、三唑基、吡啶基或吡嗪基，例如
Figure PCTCN2022092860-appb-000019
Figure PCTCN2022092860-appb-000020
在某一方案中，R 2-1中，所述的C 6-12芳基和被1、2或3个R 2-1-3取代的C 6-12芳基里，所述的C 6-12芳基可独立地为苯基或萘基，例如为
Figure PCTCN2022092860-appb-000021
在某一方案中，R 2-1-1中，所述C 1-4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基。
在某一方案中，R 2-1-2中，所述C 1-4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基。
在某一方案中，R 2-1-2中，所述C 1-4烷氧基独立地为甲氧基、乙氧基或丙氧基，例如为乙氧基。
在某一方案中，R 2-1-3中，所述卤素独立地为F、Cl、Br或I，例如为F或Cl。
在某一方案中，R 2-1-3中，所述C 1-4烷氧基独立地为甲氧基、乙氧基或丙氧基，例如为甲氧基。
在某一方案中，R 2-1-3中，所述被1、2或3个卤素取代的C 1-4烷基独立地为三氟甲基、三氟乙基或三氟丙基，例如为三氟甲基。
在某一方案中，R 2-1-3中，所述被1、2或3个卤素取代的C 1-4烷氧基独立地为三氟甲氧基、三氟乙氧基或三氟丙氧基，例如为三氟甲氧基。
在某一方案中，R 2-1-3中，所述C 6-12芳基为苯基或萘基。
在某一方案中，R 2-1-3中，所述5-6元杂芳基可为吡唑基、吡嗪基、哒嗪基、吡啶基、 嘧啶基或吡咯基，例如为吡唑基，再例如为
Figure PCTCN2022092860-appb-000022
在某一方案中，R 2-1-3-1和R 2-1-3-2中，所述的C 1-4烷基可独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基。
在某一方案中，R 2-2中，所述的C 1-4烷基可独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基或乙基。
在某一方案中，R 2-2中，所述卤素可独立地为F、Cl、Br或I，例如为F。
在某一方案中，R a、R b和R c中，所述的C 1-4烷基可独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基。
在某一方案中，R b、R c和与其相连的原子共同形成C 3-6脂碳环，所述的C 3-6脂碳环可为环丙烷、环丁烷、环戊烷或环己烷，例如环丙烷、环丁烷或环戊烷。
在某一方案中，R b、R c和与其相连的原子共同形成3～6元脂杂环，所述的3～6元脂杂环中，杂原子的数量可为1个，杂原子的种类可为N。
在某一方案中，R b、R c和与其相连的原子共同形成3～6元脂杂环，所述的3～6元脂杂环可为6元脂杂环，例如哌啶环，更例如
Figure PCTCN2022092860-appb-000023
在某一方案中，
Figure PCTCN2022092860-appb-000024
的定义中，所述的3～6元含氮杂环烷基中，杂原子的数量可独立地为1个或2个，杂原子的种类可独立地为N、N和S。
在某一方案中，
Figure PCTCN2022092860-appb-000025
的定义中，所述的3～6元含氮杂环烷基可独立地为硫代吗啉基、四氢吡咯基或N杂环丁烷基，例如
Figure PCTCN2022092860-appb-000026
在某一方案中，
Figure PCTCN2022092860-appb-000027
的定义中，所述的C 3-6脂碳环可独立地为环丙烷、环丁烷、环戊烷或环己烷，例如环戊烷。
在某一方案中，
Figure PCTCN2022092860-appb-000028
的定义中，所述的3～6元脂杂环中，杂原子的数目可独立地为1个，杂原子的种类可独立地为N或O。
在某一方案中，
Figure PCTCN2022092860-appb-000029
的定义中，所述的3～6元脂杂环可独立地为氧杂环丁烷、四氢吡咯环或四氢吡喃环，例如同一原子上的两个R d与其相连的原子共同形成3～6 元脂杂环或被1个、2个或3个R d-1取代的3～6元脂杂环时，所述的3～6元脂杂环可为
Figure PCTCN2022092860-appb-000030
在某一方案中，R d-1中，所述的C 1-4烷基可为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基。
在某一方案中，X为卤素；Y为CH或N；R 1为
Figure PCTCN2022092860-appb-000031
R 2为被1、2或3个R 2- 1取代的C 1-4烷基；R 2-1为或被1、2或3个R 2-1-3取代的C 6-12芳基；L较佳地为
Figure PCTCN2022092860-appb-000032
在某一方案中，X为卤素；Y为N；R 1为
Figure PCTCN2022092860-appb-000033
R 2为
Figure PCTCN2022092860-appb-000034
L为-(CH 2) m-，m为4或5。
在某一方案中，X为Cl；Y为CH；L为当被1个甲基取代的-(CH 2) m-，R 1、R 2及它们之间的N原子一起形成环A，所述的环A为
Figure PCTCN2022092860-appb-000035
其中R a为C 1-4烷基，R b和R c均为H。
在某一方案中，X为Cl；Y为N；L为当被1个甲基取代的-(CH 2) m-，m为4或5；R 1、R 2及它们之间的N原子一起形成环A，所述的环A为
Figure PCTCN2022092860-appb-000036
在某一方案中，X为Cl；Y为CH；L为被1个甲基取代的-(CH 2) m-，m为4或5；R 1、R 2及它们之间的N原子一起形成环A，所述的环A为
Figure PCTCN2022092860-appb-000037
所述的R d为氧代或卤素；或相邻的两个R d与其相连的原子共同形成C 3-6脂碳环，或者同一原子上的两个R d与其相连的原子共同形成3～6元脂杂环或被1个、2个或3个R d-1取代的3～6元脂杂环；所述的脂杂环的杂原子数量为1个、2个或3个，所述的脂杂环中杂原子选自氧、硫和氮中的一种或多种。
在某一方案中，X为Cl；Y为CH；L为被1个甲基取代的-(CH 2) m-，m为4或5；R 1为H；R 2为被1、2或3个R 2-1取代的C 1-4烷基，R 2-1为被1、2或3个R 2-1-1取代的3-7元杂环烷基。
在某一方案中，R 1为
Figure PCTCN2022092860-appb-000038
在某一方案中，R 2为被1、2或3个R 2-1取代的C 1-4烷基，R 2-1为3-7元杂环烷基、5-6元杂芳基、被1、2或3个R 2-1-1取代的3-7元杂环烷基或被1、2或3个R 2-1-2取代的5-6元的杂芳基。
在某一方案中，R 1、R 2及它们之间的N原子一起形成环A，所述的环A为5-12元杂环烷基A 1，所述的杂环烷基A 1为桥环；或被1、2或3个R 2-2-2取代8-12元杂环烷基A 3，所述杂环烷基A 3为螺环，所述的杂环烷基里，杂原子数量为1、2或3个，杂原子的个数选自氧、硫和氮的一种或多种。
在某一方案中，当R 1、R 2及它们之间的N原子一起形成环A时，所述的环A为被2或3个R 2-2-1取代的5-10元杂环烷基A 2，所述杂环烷基A 2为单环；R 2-2-1独立地为氧代、C 1-4烷基或卤素，且当所述的5-10元杂环烷基的取代基包含氧代时，所述氧代的个数为2个或3个，所述的杂环烷基里，杂原子数量为1、2或3个，杂原子的个数选自氧、硫和氮的一种或多种。
在某一方案中，所述如式I所示的喹唑啉类化合物可为如式I-1或I-1’所述的化合物：
Figure PCTCN2022092860-appb-000039
其中各取代基的定义均如前所述。
在某一方案中，所述如式I所述的喹唑啉类化合物可为如式I-2所述的化合物：
Figure PCTCN2022092860-appb-000040
其中各取代基的定义均如前所述。
在某一方案中，所述如式I所述的喹唑啉类化合物可为如式I-2所述的化合物：
Figure PCTCN2022092860-appb-000041
其中各取代基的定义均如前所述。
在某一方案中，所述如式I所示的喹唑啉类化合物为以下任一化合物：
Figure PCTCN2022092860-appb-000042
Figure PCTCN2022092860-appb-000043
Figure PCTCN2022092860-appb-000044
Figure PCTCN2022092860-appb-000045
Figure PCTCN2022092860-appb-000046
本发明还提供一种上述如式I所示的喹唑啉类化合物的制备方法，其为以下方法中的任一种：
方法1，其包含以下步骤：在溶剂中，在碱和碘盐的作用下，如式II-1所示的化合物与如式II-2所示的化合物进行反应，即可；
Figure PCTCN2022092860-appb-000047
其中，X 1为卤素，例如F、Cl、Br或I，优选为Cl；Y为CH；上述各式中其余各取代基的定义均如前所述；
所述的溶剂可为本领域此类反应常用溶剂，例如腈类溶剂，优选为乙腈；
所述的碱可为本领域此类反应常用碱，例如碱金属的碳酸盐，优选为碳酸钾；
所述的碘盐可为本领域此类反应常用碘盐，例如KI；
方法2：在溶剂中，在碱和季铵盐的作用下，如式II-1所示的化合物与如式II-2所示的化合物进行反应，即可；
Figure PCTCN2022092860-appb-000048
其中，X 1为卤素，例如F、Cl、Br或I，优选为Cl；Y为N；上述各式中其余各取代基的定义均如前所述；
所述的溶剂可为本领域此类反应常用溶剂，例如腈类溶剂，优选为乙腈；
所述的碱可为本领域此类反应常用碱，例如碱金属的碳酸盐，优选为碳酸钾；
所述的季铵盐可为本领域此类反应常用季铵盐，例如n-Bu 4NBr；
方法3，其包含以下步骤：在溶剂中，在碱的作用下，如式II-3所示的化合物和如式II-4所示的化合物进行反应，即可；
Figure PCTCN2022092860-appb-000049
其中，式II-4中，X 2为卤素，例如F、Cl、Br或I，优选为Cl；式I中，R 1为
Figure PCTCN2022092860-appb-000050
上述各式中其余各取代基的定义均如前所述；
所述的溶剂可为本领域此类反应常用溶剂，例如腈类溶剂，优选为乙腈；
所述的碱可为本领域此类反应常用碱，例如碱金属的碳酸盐，优选为碳酸钾。
本发明还提供一种药物组合物，其包括物质X和药用辅料；所述的物质X为上述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
本发明还提供一种物质Y在制备药物中的应用；所述的物质Y为如上所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或如上所述的药物组合物，所述的药物为对细胞因子TNF-α、IL-6、IL-1β中的1、2或3种有抑制作用的药物。
本发明还提供一种物质Y在制备抑制剂中的应用；所述的物质Y为如上所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶 剂合物或如上所述的药物组合物，所述的抑制剂为细胞因子TNF-α抑制剂、IL-6抑制剂和IL-1β抑制剂中的1、2或3种。
某一方案中，所述的抑制剂为在体外对TNF-α、IL-6和IL-1β中的1、2或3种有抑制作用的抑制剂。
本发明还提供一种物质Y在制备药物中的应用；所述的物质Y为如上所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或如上所述的药物组合物；所述药物为用于预防和/或治疗与TNF-α、IL-6和IL-1β中的1、2或3种相关的疾病的药物。
本发明还提供一种物质Y在制备药物中的应用；所述的物质Y为如上所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或如上所述的药物组合物；所述药物为用于预防和/或治疗自身免疫性疾病(例如类风湿性关节炎、系统性红斑狼疮、皮肤性红斑狼疮、糖尿病、干燥综合征、多发性硬化等)，疟疾，感染性疾病(例如艾滋病、病毒性肝炎、冠状病毒等)，过敏性疾病(例如哮喘等)，心血管系统疾病，器官移植后的抗排异反应，慢性阻塞性肺疾病、肿瘤等与机体免疫系统的功能及反应状态异常有关的疾病的药物。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数(例如C 1～C 4)的直链或支链烷基。烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基等。
术语“烷氧基”是指基团R X-O-，其中，R X为上文所定义的烷基。
术语“氧代”是指基团
Figure PCTCN2022092860-appb-000051
术语“脂碳环”是指具有指定碳原子数(例如C 3-6)的、环状的、饱和的单环，脂碳环的例子包括但不限于环丙烷、环丁烷、环戊烷、环己烷。
术语“杂环烷基”是指具有指定环原子数(例如5～10元)的、指定杂原子数(例如1、2或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团，其为单环、桥环或螺环，且每一个环均为饱和的。杂环烷基包括但不限于氮杂环丁烷基、四氢吡咯基、四氢呋喃基、吗啉基、哌啶基等。
术语“脂杂环”是指具有指定环原子数(例如3～6元)的、指定杂原子数(例如1、2或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环，其为单环，脂杂环的例子包括但不限于氧杂环丁烷、四氢吡咯环、四氢吡喃环。
术语“芳基”是指具有指定的碳原子数(例如C 6～C 10)的、仅由碳原子组成的环状基团，其为单环或多环，且至少一个环具有芳香性(符合休克尔规则)。芳基通过具有芳香 性的环或不具有芳香性的环与分子中的其他片段连接。芳基包括但不限于苯基、萘基等。
术语“杂芳基”是指具有指定环原子数(例如5～10元)的、指定杂原子数(例如1、2或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团，其为单环或多环，且至少一个环具有芳香性(符合休克尔规则)。杂芳基通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。杂芳基包括但不限于呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、噁唑基、噻唑基、吡啶基、嘧啶基、吲哚基等。在某一方案中，所述的杂芳基为单环。
基团末端的“-”是指该基团通过该位点与分子中的其他片段连接。例如，CH 3-C(＝O)-是指乙酰基。
结构片段中的
Figure PCTCN2022092860-appb-000052
是指该结构片段通过该位点与分子中的其他片段连接。例如，
Figure PCTCN2022092860-appb-000053
是指环己基。
当任意变量(例如基团R 1-1)在化合物的定义中多次出现时，它们的定义互相独立、互不影响。例如，被3个R 1-1取代的C 6～C 10芳基是指C 6～C 10芳基会被3个R 1-1取代，3个R 1-1的定义互相独立的、互不影响。
术语“药学上可接受的盐”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱反应得到的盐。当化合物中含有相对酸性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物的游离形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于钠盐、钾盐、钙盐、铝盐、镁盐、铋盐、铵盐等。当化合物中含有相对碱性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物的游离形式接触的方式获得酸加成盐。药学上可接受的酸加成盐包括但不限于盐酸盐、硫酸盐、甲磺酸盐等。具体参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,2002)。
术语“溶剂合物”是指化合物与溶剂(包括但不限于：水、甲醇、乙醇等)结晶后形成的物质。溶剂合物分为化学计量类溶剂合物和非化学计量类溶剂合物。
术语“药学上可接受的盐的溶剂合物”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱、溶剂(包括但不限于：水、甲醇、乙醇等)结合形成的物质，其中，药学上可接受的盐与上文术语“药学上可接受的盐”的含义相同，溶剂为化学计量的或非化学计量的。药学上可接受的盐的溶剂合物包括但不限于盐酸盐一水合物。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将 根据化合物、疾病种类、疾病的严重度、患者的年龄等变化，但可由本领域技术人员视情况调整。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。具体参见中华人民共和国药典(2020年版)或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009)。
术语“治疗”是指下述任一情形：(1)缓解疾病的一种或多种生物学表现；(2)干扰引发疾病的生物级联中的一个或多个点；(3)减缓疾病的一种或多种生物学表现发展。
术语“预防”是指降低发生疾病的风险。
术语“患者”是指已经或即将接受治疗的任何动物，优选哺乳动物，最优选人类。哺乳动物包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人类等。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的喹唑啉类化合物结构新颖，对细胞因子TNF-α，IL-6，IL-1β具有良好的抑制效果。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1:4-(4-((7-氯喹啉-4-基)氨基)戊基)硫代吗啉-1,1-二氧化物(化合物1)
Figure PCTCN2022092860-appb-000054
步骤1制备4-氨基-1-戊醇(化合物1-2)
在室温并有氢气保护下，将5-羟基-2-戊酮(5.0g,48.96mmol)和甲酸铵(10.0g,158.58mmol)加入到含钯/炭(1g)的甲醇(200mL)的溶液中，室温搅拌48小时。将反 应混合物减压浓缩，剩余液体加入乙酸乙酯(200mL)打浆。过滤，减压浓缩至干，得到粗品4-氨基-1-戊醇(4g,收率79.22％)。LC-MS:m/z 104.1[M+H] +.
步骤2制备5-((叔丁基二苯基甲硅烷基)氧基)戊-2-胺(化合物1-3)
在室温并有氩气保护的情况下，将4-氨基-1-戊醇(4.0g,38.83mmol)、咪唑(5.28g,77.67mmol)和叔丁基二苯基氯硅烷(16.02g,58.25mmol)加入到二氯甲烷(200mL)的溶液中，室温搅拌18小时。反应完全，浓缩后加入水和乙酸乙酯，乙酸乙酯萃取三次，有机相经干燥、过滤，浓缩，再经柱层析分离得到产物5-((叔丁基二苯基甲硅烷基)氧基)戊-2-胺(5.4g,收率40.79％)。LC-MS:m/z 342.2[M+H] +.
步骤3制备N-(5-((叔丁基二苯基甲硅烷基)氧基)戊基-2-基)-7-氯喹啉-4-胺(化合物1-4)
将原料5-((叔丁基二苯基甲硅烷基)氧基)戊-2-胺(3.8g，11.14mmol)溶于40mL 1,4-二氧六环中，分别加入Pd 2(dba) 3(50mg)、BINAP(40mg)、Cs 2CO 3(7.25g，22.25mmol)和4,7-二氯喹啉(2.0g，10.1mmol)，该反应混合物在氩气保护下加热至110℃，反应18小时。反应完全，浓缩，剩余物经柱层析分离得到产品4g，收率78.72％。LC-MS:m/z 503.2[M+H] +.
步骤4制备4-((7-氯喹啉-4-基)氨基)戊-1-醇(化合物1-5)
将原料N-(5-((叔丁基二苯基甲硅烷基)氧基)戊基-2-基)-7-氯喹啉-4-胺(4.0g，7.95mmol)溶于40mL甲醇中，加入氟化铵(2.0g，54.05mmol)，该反应混合物在氩气保护下加热回流，反应2小时。反应完全，浓缩，剩余物经液相制备分离得到产品1.6g，收率76.19％。LC-MS:m/z 265.1[M+H] +.
步骤5制备7-氯-N-(5-氯戊烷-2-基)喹啉-4-胺(化合物1-6)
将原料4-((7-氯喹啉-4-基)氨基)戊-1-醇(2.0g，7.58mmol)溶于40mL二氯甲烷中，加入氯化亚砜(2.0g，16.81mmol)和催化量的N，N-二甲基甲酰胺(0.1mL)，该反应混合物在氩气保护下室温反应2小时。反应完全，浓缩，剩余物经碳酸氢钠溶液淬灭，经乙酸乙酯萃取。有机相干燥、过滤、浓缩得到初产品2.1g，收率97.95％，直接用于下一步反应。LC-MS:m/z 283.1[M+H] +.
步骤6制备4-(4-((7-氯喹啉-4-基)氨基)戊基)硫代吗啉-1,1-二氧化物(化合物1)
将原料7-氯-N-(5-氯戊烷-2-基)喹啉-4-胺(80mg，0.28mmol)溶于20mL乙腈中，分别加入KI(10mg)、K 2CO 3(100mg，0.73mmol)和硫吗啉-1,1-二氧化物(150mg，1.11mmol)，该反应混合物在氩气保护下加热至60-70℃，反应48小时。反应完全，浓缩，剩余物经柱层析分离得到产品15mg，收率13.89％。 1H NMR(400MHz,CDCl 3)δ8.47(d,J＝5.6Hz,1H),7.98(d,J＝1.8Hz,1H),7.87(d,J＝9.0Hz,1H),7.35(dd,J＝8.9,2.0Hz,1H),6.45(d,J＝5.7Hz,1H),5.57(s,1H),3.78(dd,J＝13.4,6.8Hz,1H),3.05(d,J＝6.1Hz,4H),2.99(d,J＝5.9Hz,4H),2.56(t,J＝6.9Hz,2H),1.86–1.76(m,1H),1.76–1.56(m,4H),1.39(d,J＝6.3Hz,3H).LC-MS:m/z 382.1[M+H] +.
实施例2-12
按照实施例1的相同方法，制备实施例2-12的化合物，具体实验数据见表1。
表1化合物1-12的实验数据表
Figure PCTCN2022092860-appb-000055
Figure PCTCN2022092860-appb-000056
Figure PCTCN2022092860-appb-000057
Figure PCTCN2022092860-appb-000058
Figure PCTCN2022092860-appb-000059
实施例13:3-(4-((7-氯喹唑啉-4-基)氨基)戊基)咪唑烷-2,4-二酮(化合物13)
Figure PCTCN2022092860-appb-000060
步骤1制备N-(5-((叔丁基二苯基甲硅烷基)氧基)戊烷-2-基)-7-氯喹唑啉-4-胺(化合物2-2)
将原料5-((叔丁基二苯基甲硅烷基)氧基)戊-2-胺(2.8g，8.20mmol)溶于40mL异丙醇中，分别加入DIPEA(3.5g，27.08mmol)和4,7-二氯喹唑啉(2.0g，10.05mmol)，该反应混合物在氩气保护下加热至90℃，反应18小时。反应完全，浓缩，剩余物经制备分离得到产品3.1g，收率75.01％。LC-MS:m/z 504.2[M+H] +.
步骤2制备4-((7-氯喹唑啉-4-基)氨基)戊-1-醇(化合物2-3)
将原料N-(5-((叔丁基二苯基甲硅烷基)氧基)戊基-2-基)-7-氯喹唑啉-4-胺(3.1g，6.15mmol)溶于40mL甲醇中，加入氟化铵(2.0g，54.05mmol)，该反应混合物在氩气保护下加热回流，反应2小时。反应完全，浓缩，剩余物经液相制备分离得到产品1.3g，收率79.75％。LC-MS:m/z 266.1[M+H] +.
步骤3制备7-氯-N-(5-氯戊烷-2-基)喹唑啉-4-胺(化合物2-4)
将原料4-((7-氯喹啉-4-基)氨基)戊-1-醇(1.0g，3.76mmol)溶于20mL二氯甲烷中，加入氯化亚砜(1.0g，8.40mmol)和催化量的N，N-二甲基甲酰胺(0.1 mL)，该反应混合物在氩气保护下室温反应2小时。反应完全，浓缩，剩余物经碳酸氢钠溶液淬灭，经乙酸乙酯萃取。有机相干燥、过滤、浓缩得到初产品1.0g，收率93.66％，直接用于下一步反应。LC-MS:m/z 284.1[M+H] +.
步骤4制备3-(4-((7-氯喹唑啉-4-基)氨基)戊基)咪唑烷-2,4-二酮(化合物13)
将原料7-氯-N-(5-氯戊烷-2-基)喹唑啉-4-胺(100mg，0.35mmol)溶于20mL乙腈中，分别加入n-Bu 4NBr(10mg)、K 2CO 3(100mg，0.73mmol)和咪唑烷-2,4-二酮(100mg，1.00mmol)，该反应混合物在氩气保护下加热至60-70℃，反应48小时。反应完全，浓缩，剩余物经柱层析分离得到产品54mg，收率44.12％。 1H NMR(400MHz,CDCl 3)δ8.62(s,1H),7.81(t,J＝5.5Hz,2H),7.41(dd,J＝8.8,2.1Hz,1H),6.13(d,J＝8.0Hz,1H),5.74(s,1H),4.66–4.52(m,1H),4.01(d,J＝0.9Hz,2H),3.68–3.56(m,2H),1.90–1.80(m,2H),1.72–1.60(m,2H),1.32(d,J＝6.5Hz,3H).LC-MS:m/z 348.1[M+H] +.
实施例14
按照实施例13的相同方法，制备实施例14的化合物，具体实验数据见表2。
表2化合物13、14的实验数据表
Figure PCTCN2022092860-appb-000061
实施例15:1-(4-((7-氯喹唑啉-4-基)氨基)戊基)吡咯烷-2,5-二酮(化合物15)
Figure PCTCN2022092860-appb-000062
步骤1制备1-(4-((7-氯喹唑啉-4-基)氨基)戊基)吡咯烷-2,5-二酮(化合物15)
将原料4-((7-氯喹唑啉-4-基)氨基)戊-1-醇(50mg，0.19mmol)溶于20mL无水四氢呋喃中，分别加入PPh 3(280mg，1.07mmol)、DIAD(240mg，1.19mmol)和吡咯烷-2,5-二酮(100mg，1.01mmol)，该反应混合物在氩气保护下室温反应48小时。反应完全，浓缩，剩余物经柱层析分离得到产品57mg，收率87.10％。 1H NMR(400MHz,CDCl 3)δ8.63(s,1H),7.82(d,J＝2.0Hz,1H),7.78(d,J＝8.8Hz,1H),7.42(dd,J＝8.8,2.1Hz,1H),5.97(d,J＝7.9Hz,1H),4.63–4.51(m,1H),3.67–3.52(m,2H),2.74(s,4H),1.76–1.60(m,4H),1.32(d,J＝6.5Hz,3H).LC-MS:m/z 348[M+H] +.
表3化合物15的实验数据表
Figure PCTCN2022092860-appb-000063
实施例16:2-((4-((7-氯喹唑啉-4-基)氨基)戊基)(噁唑-2-基甲基)氨基)乙-1-醇(化合物16)
Figure PCTCN2022092860-appb-000064
步骤1制备5-(苄基(2-羟乙基)氨基)戊-2-酮(化合物4-3)
室温下将原料2-(苄基氨基)乙醇(17.5g，116mmol)，5-氯戊-2-酮(28g，232mmol)，碳酸钾(24g，174mmol)和碘化钾(1.9g，12mmol)加于N，N-二甲基甲酰胺(300mL)中，氩气保护下120℃反应过夜。蒸干N,N-二甲基甲酰胺后，加水并用二氯甲烷萃取三次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋蒸至干。残留物用柱层析纯化得到黄色油状物5-(苄基(2-羟乙基)氨基)戊-2-酮(23g,98mmol，收率84.5％)。LC-MS:m/z 236[M+H] +.
步骤2制备2-[4-氨基戊基(苄基)氨基]乙醇(化合物4-4)
原料5-(苄基(2-羟乙基)氨基)戊-2-酮(9g，38mmol)溶于甲醇((200mL)中，室温下加入醋酸铵(17.7g，230mmol)搅拌30分钟。然后加入氰基硼氢化钠(5g，80mmol)，室温搅拌过夜。蒸干甲醇后，加入40％氢氧化钠水溶液(200mL)，二氯甲烷萃取三次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋蒸至干。残留物用柱层析纯化得到黄色油状物2-[4-氨基戊基(苄基)氨基]乙醇(2.45g，10.4mmol，收率27.1％)。LC-MS:m/z 237[M+H] +.
步骤3制备2-(苄基(4-((7-氯喹唑啉-4-基)氨基)戊基)氨基)乙醇(化合物4-5)
原料2-[4-氨基戊基(苄基)氨基]乙醇(2.4g，10mmol)和4,7-二氯喹唑啉(2.26g，11.4mmol)加入到N,N-二异丙基乙胺(7.5g)中，90℃搅拌过夜。蒸干N,N-二异丙基乙胺，加水并用二氯甲烷萃取三次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋蒸至干。残留物用柱层析纯化得到黄色油状物2-(苄基(4-((7-氯喹唑啉-4-基)氨基)戊基)氨基)乙醇(2.2g，5.5mmol，收率54％)。LC-MS:m/z 399[M+H] +.
步骤4制备N 1-苄基-N 1-(2-((叔丁基二甲基硅基)氧)乙基)-N 4-(7-氯喹唑啉-4-基)戊烷-1,4-二胺(化合物4-6)
原料2-(苄基(4-((7-氯喹唑啉-4-基)氨基)戊基)氨基)乙醇(2.2g,5.5mmol)和咪唑(0.752g,11.0mmol)溶于无水二氯甲烷(30mL)中，冰浴下滴入叔丁基二甲基氯硅烷(1g，6.6mmol)，反应液室温搅拌过夜。反应液水洗三次，无水硫酸钠干燥，过滤后旋蒸至干。残留物用柱层析纯化得到白色固体N1-苄基-N1-(2-((叔丁基二甲基硅基)氧)乙基)-N4-(7-氯喹唑啉-4-基)戊烷-1,4-二胺(1.4g,2.7mmol，收率50％)。LC-MS:m/z 513[M+H] +.
步骤5制备2-((4-((7-氯喹唑啉-4-基)氨基)戊基)氨基)乙醇(化合物4-7)
原料N1-苄基-N1-(2-((叔丁基二甲基硅基)氧)乙基)-N4-(7-氯喹唑啉-4-基)戊烷-1,4-二胺(1.4g，2.7mmol)溶于无水二氯甲烷(30mL)中，冰浴下滴入1-氯乙基氯甲酸酯(0.51g，3.6mmol)，反应液室温下搅拌2小时。蒸去二氯甲烷，加入甲醇回流2小时。蒸去甲醇，残留物用柱层析纯化得到黄色油状物2-((4-((7-氯喹唑啉-4-基)氨基)戊基)氨基)乙醇(0.388g，1.26mmol，收率46％)。LC-MS:m/z 309[M+H] +.
步骤6制备2-((4-((7-氯喹唑啉-4-基)氨基)戊基)(噁唑-2-基甲基)氨基)乙-1-醇(化合物16)
原料2-((4-((7-氯喹唑啉-4-基)氨基)戊基)氨基)乙醇(65mg,0.21mmol)，2-(氯甲基)噁唑(30mg，0.26mmol)和碳酸钾(44mg，0.32mmol)加入乙腈(5mL)中，反应液80℃搅拌过夜。蒸干溶剂后，加水并用二氯甲烷萃取三次，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤后旋蒸至干。残留物用硅胶制备板纯化得到黄色油状物2-((4-((7-氯喹唑啉-4-基)氨基)戊基)(噁唑-2-基甲基)氨基)乙-1-醇(39mg,0.10mmol，收率47.52％)。 1H NMR(400MHz,CDCl 3)δ8.62(s,1H),7.85(d,J＝2.0Hz,1H),7.82(d,J＝8.9Hz,1H),7.63(s,1H),7.42(dd,J＝8.8,2.0Hz,1H),7.08(s,1H),6.00(d,J＝6.4Hz,1H),4.58–4.47(m,1H),3.90(s,2H),3.65(t,J＝5.1Hz,2H),2.79(t,J＝4.4Hz,2H),2.73-2.64(m,2H),1.85- 1.80(m,2H),1.71–1.62(m,3H),1.34(d,J＝6.5Hz,3H)。LC-MS:m/z 390[M+H] +.
实施例17-43
按照实施例16的相同方法，制备实施例17-43的化合物，具体实验数据见表4
表4化合物16-43的实验数据表
Figure PCTCN2022092860-appb-000065
Figure PCTCN2022092860-appb-000066
Figure PCTCN2022092860-appb-000067
Figure PCTCN2022092860-appb-000068
Figure PCTCN2022092860-appb-000069
Figure PCTCN2022092860-appb-000070
Figure PCTCN2022092860-appb-000071
Figure PCTCN2022092860-appb-000072
Figure PCTCN2022092860-appb-000073
Figure PCTCN2022092860-appb-000074
实施例44:甲基4-(((5-((7-氯喹唑啉-4-基)氨基)戊基)(2-羟乙基)氨基)甲基)苯甲酸酯(化合物44)
Figure PCTCN2022092860-appb-000075
步骤1制备2-(5-(苄基(2-羟乙基)氨基)戊基)异吲哚-1，3-二酮(化合物5-3)
在室温下，将碳酸钾(2.07g,15mmol)、2-(5-溴戊基)异吲哚-1，3-二酮(2.96g,10mmol)加入到2-(苄氨基)乙-1-醇(1.51g,10mmol)在乙腈(30mL)的溶液中。升温至80℃并搅拌16小时。然后冷却至室温，过滤，滤液浓缩干得到淡黄色液体2-(5-(苄基(2-羟乙基)氨基)戊基)异吲哚-1，3-二酮(3.66g,10mmol,收率100％)。LC-MS:m/z 367.2[M+H] +.
步骤2制备2-(5-((2-羟乙基)氨基)戊基)异吲哚-1,3-二酮(化合物5-4)
将2-(5-(苄基(2-羟乙基)氨基)戊基)异吲哚-1，3-二酮(3.66g,10mmol)溶于甲醇(40mL),然后加入10％Pd/C(0.9g)。1atom H 2压力,30℃反应48小时。LCMS显示反应完 全，过滤去除Pd/C，母液浓缩干得到淡黄色液体2-(5-((2-羟乙基)氨基)戊基)异吲哚-1,3-二酮(2.76g,10mmol,收率99％)，直接用于下一步反应。LC-MS:m/z 277.2[M+H] +.
步骤3制备叔丁基(5-(1,3-二氧异吲哚-2-基)戊基)(2-羟乙基)碳酸酯(化合物5-5)
将2-(5-((2-羟乙基)氨基)戊基)异吲哚-1,3-二酮(2.76g，10mmol)溶于二氯甲烷(30mL)中，然后加入二碳酸二叔丁酯(2.62g，12mmol)，三乙胺(1.5g，15mmol)。在室温下搅拌16小时后，LCMS显示反应完成。将反应混合物通过旋转蒸发仪浓缩并将残余物通过biotage制备色谱柱纯化(25g硅胶，MeOH/DCM＝0～5％，v/v)，得叔丁基(5-(1,3-二氧异吲哚-2-基)戊基)(2-羟乙基)碳酸酯(3.0g，7.958mmol，收率79.58％)，为黄色油状物。LC-MS:m/z 377.2[M+H] +.
步骤4制备叔丁基(5-氨基戊基)(2-羟乙基)碳酸酯(化合物5-6)
将叔丁基(5-(1,3-二氧异吲哚-2-基)戊基)(2-羟乙基)碳酸酯(3.0g，7.958mmol)溶于甲醇(20mL)中，然后加入水合肼(10mL，50％)。在30℃下搅拌6小时后，LCMS显示反应完成。将反应混合物通过旋转蒸发仪浓缩并于残余物中加入1M NaOH溶液，用二氯甲烷(20mLx3)萃取，合并有机相，无水Na 2SO 4干燥，浓缩干得到叔丁基(5-氨基戊基)(2-羟乙基)碳酸酯(1.1g，4.453mmol，收率55.96％)，为黄色油状物。LC-MS:m/z 247.3[M+H] +.
步骤5制备叔丁基(5-((7-氯喹唑啉-4-基)氨基)戊基)(2-羟乙基)碳酸酯(化合物5-7)
在室温下，向4,7-二氯喹唑啉(0.88g，4.453mmol)在异丙醇(10mL)的溶液中加入得到叔丁基(5-氨基戊基)(2-羟乙基)碳酸酯(1.1g，4.453mmol)，DIPEA(1.29g，10.00mmol)。80℃下搅拌搅拌16小时后，将反应浓缩干。加入饱和碳酸氢钠水溶液(100mL)，用二氯甲烷(100mL×2)萃取。合并有机相，无水硫酸钠干燥，浓缩干过硅胶柱纯化(洗脱剂：石油醚：乙酸乙酯＝10：1)得到产物叔丁基(5-((7-氯喹唑啉-4-基)氨基)戊基)(2-羟乙基)碳酸酯(1.2g，2.934mmol，收率65.89％)，为黄色油状物。LC-MS:m/z 409.2[M+H] +.
步骤6制备2-((5-((7-氯喹唑啉-4-基)氨基)戊基)氨基)乙-1-醇(化合物5-8)
在室温下，向叔丁基(5-((7-氯喹唑啉-4-基)氨基)戊基)(2-羟乙基)碳酸酯(1.2g，2.94mmol)在甲醇(5mL)的溶液中加入氯化氢/1,4-二氧六环溶液(10mL)。室温搅拌1.5 小时后，将反应浓缩干得到2-((5-((7-氯喹唑啉-4-基)氨基)戊基)氨基)乙-1-醇(0.905g，2.94mmol，收率100％)，为黄色固体。LC-MS:m/z 309.2[M+H] +.
步骤7制备甲基4-(((5-((7-氯喹唑啉-4-基)氨基)戊基)(2-羟乙基)氨基)甲基)苯甲酸酯(化合物44)
将2-((5-((7-氯喹唑啉-4-基)氨基)戊基)氨基)乙-1-醇(0.08g，0.2591mmol，)和甲基4-(溴甲基)苯甲酸酯(0.060g，0.2619mmol)溶于乙腈(3mL)中，加碳酸钾(0.04g，0.2899mmol)。混合物在80℃下搅拌16小时。将反应混合物冷却至室温，浓缩干，薄层制备硅胶板纯化(展开剂：二氯甲烷：甲烷＝10：1)得到黄色油状产物甲基4-(((5-((7-氯喹唑啉-4-基)氨基)戊基)(2-羟乙基)氨基)甲基)苯甲酸酯(23mg，0.05033mmol，收率19.43％)。 1H NMR(400MHz,d-DMSO)δ8.45(s,1H),8.32-8.39(t,J＝6.0Hz,1H),8.27(d,J＝8.9Hz,1H),7.85(d,J＝8.2Hz,2H),7.70(d,J＝2.2Hz,1H),7.55(dd,J＝8.8,2.2Hz,1H),7.43(d,J＝8.1Hz,2H),4.33(t,J＝5.2Hz,1H),3.84(s,3H),3.63(s,2H),3.51(q,J＝6.8Hz,2H),3.45(q,J＝6.4Hz,2H),2.44(m,4H),1.67–1.54(m,2H),1.53–1.40(m,2H),1.38–1.28(m,2H).LC-MS:m/z 457.2[M+H] +.
实施例45-49
按照实施例44的相同方法，制备实施例45-49的化合物，具体实验数据见表5
表5化合物44-49的实验数据表
Figure PCTCN2022092860-appb-000076
Figure PCTCN2022092860-appb-000077
Figure PCTCN2022092860-appb-000078
实施例50：3-(5-((7-氟喹唑啉-4-基)氨基)戊基)咪唑烷-2,4-二酮(化合物50)
Figure PCTCN2022092860-appb-000079
步骤1制备5-((7-氟喹唑啉-4-基)氨基)戊-1-醇(化合物6-3)
将原料4-氯-7-氟喹唑啉(0.9g，5mmol)和5-氨基戊-1-醇(0.5g，5mmol)溶于10mL异丙醇中，加入N,N-二异丙基乙胺(0.7g，5mmol)，该反应混合物在氩气保护下加热至90℃，反应6小时。反应完全，浓缩，剩余物经柱层析分离得到产品622mg，收率50％。LC-MS:m/z 250.1[M+H] +.
步骤2制备N-(5-氯戊基)-7-氟喹唑啉-4-胺(化合物6-4)
将原料5-((7-氟喹唑啉-4-基)氨基)戊-1-醇(0.6g，2.4mmol)溶于20mL无水二氯甲烷中，加入氯化亚砜(1.2g，10mmol)和催化量的N,N-二甲基甲酰胺(0.3mL)，该反应混合物在氩气保护下室温反应4小时。反应完全，浓缩，剩余物经碳酸氢钠水溶液调pH至8，二氯甲烷萃取。有机相干燥、过滤、浓缩，剩余物经柱层析分离得到产品493mg，收率76.5％。LC-MS:m/z 268.0[M+H] +.
步骤3制备3-(5-((7-氟喹唑啉-4-基)氨基)戊基)咪唑烷-2,4-二酮(化合物50)
将原料N-(5-氯戊基)-7-氟喹唑啉-4-胺(80mg，0.3mmol)溶于5mL干燥四氢呋喃中，分别加入咪唑烷-2,4-二酮(60mg，0.6mmol)，碳酸钾(130mg，0.9mmol)和四丁基硫酸氢铵(20mg，0.06mmol)，该反应混合物在氩气保护下加热至60℃，反应过夜。反应完全，浓缩，剩余物经硅胶制备板分离得到产品42mg，收率42.4％。 1H NMR(400MHz,MeOD)δ8.45(s,1H),8.23(dd,J＝9.9,5.8Hz,1H),7.37-7.32(m,2H),3.93(s,2H),3.64(t,J＝7.1Hz,2H),3.52(t,J＝7.1Hz,2H),1.83-1.75(m,2H),1.74-1.66(m,2H),1.50–1.41(m,2H).LC-MS:m/z 332.0[M+H] +.
实施例51-77
按照实施例50的相同方法，制备实施例51-77的化合物，具体实验数据见表6
表6化合物50-77的实验数据表
Figure PCTCN2022092860-appb-000080
Figure PCTCN2022092860-appb-000081
Figure PCTCN2022092860-appb-000082
Figure PCTCN2022092860-appb-000083
Figure PCTCN2022092860-appb-000084
Figure PCTCN2022092860-appb-000085
Figure PCTCN2022092860-appb-000086
效果实施例1：化合物对细胞因子抑制作用的IC 50值测定
实验方法与步骤
(1)细胞培养与接种：用无血清培养基RP1640将1mg/mL的PMA母液配制成100ng/mL的PMA溶液。取正常培养的THP-1细胞离心，用完全培养基(含有10％FBS的RP1640培养基)重悬计数，调整细胞密度为2×10 6cells/mL，然后加入等体积100ng/mL的PMA溶液，此时细胞密度为1×10 6cells/mL，PMA终浓度为50ng/mL。每孔100μL接种于96孔细胞培养板中，每孔细胞个数为1×10 5个。将96孔细胞培养板放置于37摄氏度，5％CO 2的条件下培养24小时。
(2)加药处理细胞：第二天在完全培养基中加入LPS并调整LPS终浓度为100ng/mL，并用该含有LPS的培养基配制化合物。化合物按照配制好的浓度梯度药物分别加入相应的细胞孔中。阳性对照组(LPS+)为不含药物但含有终浓度为100ng/mL的LPS和0.1％DMSO的培养基溶液，阴性对照组(LPS-)为不加LPS含0.1％DMSO的培养基溶液。每孔体积为100μL。
(3)检测样品收集：1000转离心5分钟，分别收集细胞上清液和细胞沉淀。细胞上清液用于检测TNF-α和IL-6；收集细胞沉淀用于检测IL-1β。细胞上清液收集完成后，吸弃孔内剩余液体，每孔加入100μL细胞裂解液(20mM Tris 8.0；2mM EDTA；0.5％Triton X-100)，充分裂解。
(4)样品检测：酶联免疫吸附测定法(ELISA)检测各个细胞因子的含量：具体步骤在对应试剂盒说明书的指导下操作。试剂盒货号如下：
Human TNF-alpha Quantikine ELISA Kit货号Catalog#STA00D
Human IL-1 beta/IL-1F2 Quantikine ELISA Kit货号Catalog#SLB50
Human IL-6 Quantikine ELISA Kit货号Catalog#S6050。
(5)数据分析：按下列公式对化合物的体外抑制活性进行计算：
抑制率(％)＝[1-(OD450 加药－OD450 LPS-)/(OD450 LPS+－OD450 LPS-)]×100％。
在该测定中，本发明的化合物具有低于2000μM的IC 50。某些化合物具有低于10μM的IC 50。表7和表8提供本发明的化合物在该测定中测试的具体IC 50值。
表7本发明的化合物在该测定中测试的具体IC 50值
Figure PCTCN2022092860-appb-000087
Figure PCTCN2022092860-appb-000088
表8本发明的化合物在该测定中测试的具体IC 50值
Figure PCTCN2022092860-appb-000089
Figure PCTCN2022092860-appb-000090
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (20)

  1. 一种如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，
    Figure PCTCN2022092860-appb-100001
    其中，X为卤素；
    Y为CH或N；
    L为-(CH 2) m-或被1、2或3个C 1-4烷基取代的-(CH 2) m-；m为4、5或6；
    R 1为H或
    Figure PCTCN2022092860-appb-100002
    R 2为C 1-4烷基或被1、2或3个R 2-1取代的C 1-4烷基；
    R 2-1为3-7元杂环烷基、5-6元杂芳基、C 6-12芳基、被1、2或3个R 2-1-1取代的3-7元杂环烷基、被1、2或3个R 2-1-2取代的5-6元的杂芳基或被1、2或3个R 2-1-3取代的C 6-12芳基；所述的5-6元杂芳基和所述的被1、2或3个R 2-1-2取代的5-6元杂芳基里，所述的5-6元杂芳基的杂原子数量为1、2或3个，所述的5-6元杂芳基的杂原子选自氧、硫和氮中的一种或多种；所述3-7元杂环烷基和被1、2或3个R 2-1-1取代的3-7元杂环烷基里，所述3-7元杂环烷基的杂原子数量为1、2或3个，所述3-7元杂环烷基的杂原子选自氧、硫和氮中的一种或多种；
    R 2-1-1独立地为C 1-4烷基；
    R 2-1-2独立地为C 1-4烷基或C 1-4烷氧基；
    R 2-1-3独立地为卤素、氰基、C 1-4烷氧基、被1、2或3个卤素取代的C 1-4烷基、被1、2或3个卤素取代的C 1-4烷氧基、C 6-12芳基、5-6元杂芳基、
    Figure PCTCN2022092860-appb-100003
    所述的5-6元杂芳基的杂原子数量为1、2或3个，所述的5-6元杂芳基的杂原子选自氧、硫和氮中的一种或多种；
    R 2-1-3-1独立地为C 1-4烷基；
    R 2-1-3-2独立地为C 1-4烷基；
    或者，R 1、R 2及它们之间的N原子一起形成环A，所述的环A为4-12元杂环烷基或被1、2或3个R 2-2取代的4-12元杂环烷基；所述的环A为4-12元杂环烷基或被1、2或3个R 2-2取代的4-12元杂环烷基里，所述的4-12元杂环烷基的杂原子数量为1、2或3个，所述的4-12元杂环烷基的杂原子选自氧、硫和氮中的一种或多种；
    R 2-2独立地为氧代、C 1-4烷基或卤素。
  2. 如权利要求1所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述的如式I所示的喹唑啉类化合物满足下列条件中的1个、2个或3个：
    i：R 1为
    Figure PCTCN2022092860-appb-100004
    ii：R 2为被1、2或3个R 2-1取代的C 1-4烷基，R 2-1为3-7元杂环烷基、5-6元杂芳基、被1、2或3个R 2-1-1取代的3-7元杂环烷基或被1、2或3个R 2-1-2取代的5-6元的杂芳基；
    iii：R 1、R 2及它们之间的N原子一起形成环A，所述的环A为螺环或桥环；或者
    R 1、R 2及它们之间的N原子一起形成环A，所述的环A为单环，环A为被2或3个R 2- 2取代的4-12元杂环烷基，R 2-2独立地为氧代、C 1-4烷基或卤素，且当所述的4-12元杂环烷基的取代基包含氧代时，所述氧代的个数为2个或3个。
  3. 如权利要求1所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种:
    (1)L为-(CH 2) m-或被1个甲基取代的-(CH 2) m-；m为4或5；
    (2)R 2为被1、2或3个R 2-1取代的C 1-4烷基，优选为被1或2个R 2-1取代的甲基或乙基；
    (3)R 2-1-3独立地为卤素、氰基、C 1-4烷氧基、被1、2或3个卤素取代的C 1-4烷基、被1、2或3个卤素取代的C 1-4烷氧基、5-6元杂芳基、
    Figure PCTCN2022092860-appb-100005
    所述的5-6元杂芳基的杂原子数量为1、2或3个，所述的5-6元杂芳基的杂原子选自氧、硫和氮中的一种或多种；
    (4)R 1、R 2及它们之间的N原子一起形成环A，所述的环A为5-12元杂环烷基A 1，所述的杂环烷基A 1为桥环；或被2或3个R 2-2-1取代的5-10元杂环烷基A 2，所述杂环烷基A 2为单环；或被1、2或3个R 2-2-2取代8-12元杂环烷基A 3，所述杂环烷基A 3为螺环；R 2-2-1独立地为氧代、C 1-4烷基或卤素；R 2-2-2独立地为氧代、C 1-4烷基或卤素；A 2 中，当所述的5-10元杂环烷基的取代基包含氧代时，所述氧代的个数为2个或3个。
  4. 如权利要求1所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，当R 1、R 2及它们之间的N原子一起形成环A时，所述的环A为
    Figure PCTCN2022092860-appb-100006
    其中，Z为CH或N；
    R a、R b和R c各自独立地为H或C 1-4烷基，较佳地，R a为H，R b和R c各自独立地为C 1-4烷基；或者R b、R c和与其相连的原子共同形成C 3-6脂碳环或3～6元脂杂环；所述的3～6元脂杂环的杂原子数量为1个或2个，所述的3～6元脂杂环的杂原子选自氧、硫和氮中的一种或多种；
    结构片段
    Figure PCTCN2022092860-appb-100007
    表示被2个或3个R d取代的3～6元含氮杂环烷基；所述的杂环烷基的杂原子数量为1个、2个或3个，所述的杂环烷基的中除含氮外，其余杂原子选自氧、硫和氮中的一种或多种；
    所述的R d为H、氧代或卤素；或相邻的两个R d与其相连的原子共同形成C 3-6脂碳环、3～6元脂杂环、被1个、2个或3个R d-1取代的C 3-6脂碳环或被1个、2个或3个R d- 1取代的3～6元脂杂环；或者同一原子上的两个R d与其相连的原子共同形成C 3-6脂碳环、3～6元脂杂环、被1个、2个或3个R d-1取代的C 3-6脂碳环或被1个、2个或3个R d-1取代的3～6元脂杂环；所述的脂杂环的杂原子数量为1个、2个或3个，所述的脂杂环中杂原子选自氧、硫和氮中的一种或多种；
    R d-1独立地为C 1-4烷基。
  5. 如权利要求1～4至少一项所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：
    (1)L为
    Figure PCTCN2022092860-appb-100008
    再例如为
    Figure PCTCN2022092860-appb-100009
    Figure PCTCN2022092860-appb-100010
    其中，标*的一侧表示与母核结构中NH上的N相连；
    (2)X为F或Cl；
    (3)R 2为
    Figure PCTCN2022092860-appb-100011
    Figure PCTCN2022092860-appb-100012
    (4)当R 1、R 2及它们之间的N原子一起形成环A时，所述的环A为
    Figure PCTCN2022092860-appb-100013
    Figure PCTCN2022092860-appb-100014
  6. 如权利要求1～3至少一项所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：
    (1)R 2中，所述的C 1-4烷基和被1、2或3个R 2-1取代的C 1-4烷基里，所述的C 1-4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基或乙基；
    (2)R 2-1中，所述的3-7元杂环烷基和被1、2或3个R 2-1-1取代的3-7元杂环烷基里，所述的3-7元杂环烷基中，杂原子的数量独立地为1个；
    (3)R 2-1中，所述的3-7元杂环烷基和被1、2或3个R 2-1-1取代的3-7元杂环烷基里，所述的3-7元杂环烷基中杂原子的种类独立地为N或O；
    (4)R 2-1中，所述的3-7元杂环烷基和被1、2或3个R 2-1-1取代的3-7元杂环烷基里，所述的3-7元杂环烷基独立地为4-5元杂环烷基；
    (5)R 2-1中，所述的5-6元杂芳基和被1、2或3个R 2-1-2取代的5-6元的杂芳基里，所述的5-6元杂芳基中，杂原子的种类选自N和O的一种或两种；
    (6)R 2-1-1和R 2-1-2中，所述C 1-4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基；
    (7)R 2-1-2中，所述C 1-4烷氧基独立地为甲氧基、乙氧基或丙氧基，例如为乙氧基；
    (8)R 2-1-3中，所述卤素独立地为F、Cl、Br或I，例如为F或Cl；
    (9)R 2-1-3中，所述C 1-4烷氧基独立地为甲氧基、乙氧基或丙氧基，例如为甲氧基；
    (10)R 2-1-3中，所述被1、2或3个卤素取代的C 1-4烷基独立地为三氟甲基、三氟乙基或三氟丙基，例如为三氟甲基；
    (11)R 2-1-3中，所述被1、2或3个卤素取代的C 1-4烷氧基独立地为三氟甲氧基、三氟乙氧基或三氟丙氧基，例如为三氟甲氧基；
    (12)R 2-1-3中，所述C 6-12芳基为苯基或萘基；
    (13)R 2-1-3中，所述5-6元杂芳基为吡唑基、吡嗪基、哒嗪基、吡啶基、嘧啶基或吡咯基，例如为吡唑基，再例如为
    Figure PCTCN2022092860-appb-100015
    (14)R 2-1-3-1和R 2-1-3-2中，所述的C 1-4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基；
    (15)R 2-2中，所述的C 1-4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基或乙基；
    (16)R 2-2中，所述卤素独立地为F、Cl、Br或I，例如为F。
  7. 如权利要求6所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：
    (1)R 2-1中，所述的3-7元杂环烷基和被1、2或3个R 2-1-1取代的3-7元杂环烷基里，所述的3-7元杂环烷基独立地为四氢吡咯基或氧杂环丁烷基，更例如为
    Figure PCTCN2022092860-appb-100016
    Figure PCTCN2022092860-appb-100017
    (2)R 2-1中，所述的5-6元杂芳基和被1、2或3个R 2-1-2取代的5-6元的杂芳基里，所述的5-6元杂芳基独立地为噁唑基、三唑基、吡啶基或吡嗪基，例如
    Figure PCTCN2022092860-appb-100018
    Figure PCTCN2022092860-appb-100019
    (3)R 2-1中，所述的C 6-12芳基和被1、2或3个R 2-1-3取代的C 6-12芳基里，所述的 C 6-12芳基独立地为苯基或萘基，例如为
    Figure PCTCN2022092860-appb-100020
  8. 如权利要求4所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：
    (1)R a、R b和R c中，所述的C 1-4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基；
    (2)当R b、R c和与其相连的原子共同形成C 3-6脂碳环时，所述的C 3-6脂碳环为环丙烷、环丁烷、环戊烷或环己烷，例如环丙烷、环丁烷或环戊烷；
    (3)当R b、R c和与其相连的原子共同形成3～6元脂杂环，所述的3～6元脂杂环中，杂原子的数量为1个；
    (4)当R b、R c和与其相连的原子共同形成3～6元脂杂环，所述的3～6元脂杂环中，杂原子的种类为N；
    (5)当R b、R c和与其相连的原子共同形成3～6元脂杂环，所述的3～6元脂杂环为6元脂杂环；
    (6)
    Figure PCTCN2022092860-appb-100021
    的定义中，所述的3～6元含氮杂环烷基中，杂原子的数量为1个或2个；
    (7)
    Figure PCTCN2022092860-appb-100022
    的定义中，所述的3～6元含氮杂环烷基中，杂原子的种类为N、N和S；
    (8)
    Figure PCTCN2022092860-appb-100023
    的定义中，所述的C 3-6脂碳环独立地为环丙烷、环丁烷、环戊烷或环己烷，例如环戊烷；
    (9)
    Figure PCTCN2022092860-appb-100024
    的定义中，所述的3～6元脂杂环中，杂原子的数目独立地为1个；
    (10)
    Figure PCTCN2022092860-appb-100025
    的定义中，所述的3～6元脂杂环中，杂原子的种类独立地为N或O；
    (11)R d-1中，所述的C 1-4烷基为甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基或仲丁基，例如为甲基。
  9. 如权利要求8所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶 剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其满足以下条件的一种或多种：
    (1)当R b、R c和与其相连的原子共同形成3～6元脂杂环，所述的3～6元脂杂环为哌啶环，例如
    Figure PCTCN2022092860-appb-100026
    (2)
    Figure PCTCN2022092860-appb-100027
    的定义中，所述的3～6元含氮杂环烷基独立地为硫代吗啉基、四氢吡咯基或N杂环丁烷基，例如
    Figure PCTCN2022092860-appb-100028
    (3)
    Figure PCTCN2022092860-appb-100029
    的定义中，所述的3～6元脂杂环独立地为氧杂环丁烷、四氢吡咯环或四氢吡喃环，例如同一原子上的两个R d与其相连的原子共同形成3～6元脂杂环或被1个、2个或3个R d-1取代的3～6元脂杂环时，所述的3～6元脂杂环为
    Figure PCTCN2022092860-appb-100030
    Figure PCTCN2022092860-appb-100031
  10. 如权利要求1所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，其为以下情况中的任一种：
    (1)X为卤素；Y为CH或N；R 1为
    Figure PCTCN2022092860-appb-100032
    R 2为被1、2或3个R 2-1取代的C 1- 4烷基；R 2-1为或被1、2或3个R 2-1-3取代的C 6-12芳基；L较佳地为
    Figure PCTCN2022092860-appb-100033
    (2)X为卤素；Y为N；R 1为
    Figure PCTCN2022092860-appb-100034
    R 2为
    Figure PCTCN2022092860-appb-100035
    L为-(CH 2) m-，m为4或5；
    (3)X为Cl；Y为CH；L为被1个甲基取代的-(CH 2) m-，R 1、R 2及它们之间的N原子一起形成环A，所述的环A为
    Figure PCTCN2022092860-appb-100036
    其中R a为C 1-4烷基，R b和R c均为H；
    (4)X为Cl；Y为N；L为当被1个甲基取代的-(CH 2) m-，R 1、R 2及它们之间的N 原子一起形成环A，所述的环A为
    Figure PCTCN2022092860-appb-100037
    (5)X为Cl；Y为CH；L为被1个甲基取代的-(CH 2) m-，R 1、R 2及它们之间的N原子一起形成环A，所述的环A为
    Figure PCTCN2022092860-appb-100038
    所述的R d为氧代或卤素；或相邻的两个R d与其相连的原子共同形成C 3-6脂碳环，或者同一原子上的两个R d与其相连的原子共同形成3～6元脂杂环或被1个、2个或3个R d-1取代的3～6元脂杂环；所述的脂杂环的杂原子数量为1个、2个或3个，所述的脂杂环中杂原子选自氧、硫和氮中的一种或多种；
    (6)X为Cl；Y为CH；L为被1个甲基取代的-(CH 2) m-，m为4或5；R 1为H；R 2为被1、2或3个R 2-1取代的C 1-4烷基，R 2-1为被1、2或3个R 2-1-1取代的3-7元杂环烷基。
  11. 如权利要求1所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述如式I所示的喹唑啉类化合物为如式I-1或I-1’所述的化合物：
    Figure PCTCN2022092860-appb-100039
  12. 如权利要求1所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述如式I所示的喹唑啉类化合物为如式I-2所示的化合物：
    Figure PCTCN2022092860-appb-100040
  13. 如权利要求1所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，所述如式I所示的喹唑啉类化合物为如式I-3所示的化合物：
    Figure PCTCN2022092860-appb-100041
  14. 如权利要求1～13至少一项所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，其特征在于，
    所述如式I所示的喹唑啉类化合物为以下任一化合物：
    Figure PCTCN2022092860-appb-100042
    Figure PCTCN2022092860-appb-100043
    Figure PCTCN2022092860-appb-100044
    Figure PCTCN2022092860-appb-100045
    Figure PCTCN2022092860-appb-100046
  15. 一种如权利要求1～14至少一项所述的式I所示的喹唑啉类化合物的制备方法，其为以下方法中的任一种：
    方法1，其包含以下步骤：在溶剂中，在碱和碘盐的作用下，如式II-1所示的化合物与如式II-2所示的化合物进行反应，即可；
    Figure PCTCN2022092860-appb-100047
    其中，X 1为卤素，例如F、Cl、Br或I，优选为Cl；Y为CH；
    所述的溶剂可为本领域此类反应常用溶剂，例如腈类溶剂，优选为乙腈；
    所述的碱可为本领域此类反应常用碱，例如碱金属的碳酸盐，优选为碳酸钾；
    所述的碘盐可为本领域此类反应常用碘盐，例如KI；
    方法2：在溶剂中，在碱和季铵盐的作用下，如式II-1所示的化合物与如式II-2所示的化合物进行反应，即可；
    Figure PCTCN2022092860-appb-100048
    其中，X 1为卤素，例如F、Cl、Br或I，优选为Cl；Y为N；
    所述的溶剂可为本领域此类反应常用溶剂，例如腈类溶剂，优选为乙腈；
    所述的碱可为本领域此类反应常用碱，例如碱金属的碳酸盐，优选为碳酸钾；
    所述的季铵盐可为本领域此类反应常用季铵盐，例如n-Bu 4NBr；
    方法3，其包含以下步骤：在溶剂中，在碱的作用下，如式II-3所示的化合物和如式II-4所示的化合物进行反应，即可；
    Figure PCTCN2022092860-appb-100049
    其中，式II-4中，X 2为卤素，例如F、Cl、Br或I，优选为Cl；式I中，R 1为
    Figure PCTCN2022092860-appb-100050
    所述的溶剂可为本领域此类反应常用溶剂，例如腈类溶剂，优选为乙腈；
    所述的碱可为本领域此类反应常用碱，例如碱金属的碳酸盐，优选为碳酸钾。
  16. 一种药物组合物，其特征在于，其包括物质X和药用辅料；所述的物质X为如权利要求1～14至少一项所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
  17. 一种物质Y在制备药物中的应用，其特征在于，所述的物质Y为如权利要求1～14至少一项所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或如权利要求16所述的药物组合物，所述的药物为对细胞因子TNF-α、IL-6、IL-1β中的1、2或3种有抑制作用的药物。
  18. 一种物质Y在制备抑制剂中的应用；所述的物质Y为如权利要求1～14至少一项所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或如权利要求16所述的药物组合物，所述的抑制剂为细胞因子TNF-α抑制剂、IL-6抑制剂和IL-1β抑制剂中的1、2或3种，较佳地，所述的抑制剂为在体外对TNF-α、IL-6和IL-1β中的1、2或3种有抑制作用的抑制剂。
  19. 一种物质Y在制备药物中的应用；所述的物质Y为如权利要求1～14至少一项所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或如权利要求16所述的药物组合物；所述药物为用于预防和/或治疗与TNF-α、IL-6和IL-1β中的1、2或3种相关的疾病的药物。
  20. 一种物质Y在制备药物中的应用，其特征在于，所述的物质Y为如权利要求1～14至少一项所述的如式I所示的喹唑啉类化合物、其药学上可接受的盐、其溶剂合物、其药学上可接受的盐的溶剂合物或如权利要求16所述的药物组合物；所述药物为用于预防和/或治疗自身免疫性疾病(例如类风湿性关节炎、系统性红斑狼疮、皮肤性红斑狼疮、糖尿病、干燥综合征、多发性硬化等)，疟疾，感染性疾病(例如艾滋病、病毒性肝炎、冠状病毒等)，过敏性疾病(例如哮喘等)，心血管系统疾病，器官移植后的抗排异反应，慢性阻塞性肺疾病、肿瘤等与机体免疫系统的功能及反应状态异常有关的疾病的药物。
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