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WO2023078461A1 - Heterocyclic compound, and preparation method therefor and use thereof - Google Patents

Heterocyclic compound, and preparation method therefor and use thereof Download PDF

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Publication number
WO2023078461A1
WO2023078461A1 PCT/CN2022/130676 CN2022130676W WO2023078461A1 WO 2023078461 A1 WO2023078461 A1 WO 2023078461A1 CN 2022130676 W CN2022130676 W CN 2022130676W WO 2023078461 A1 WO2023078461 A1 WO 2023078461A1
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Prior art keywords
alkyl
halogenated
heteroatoms
group
alkoxy
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PCT/CN2022/130676
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French (fr)
Chinese (zh)
Inventor
张学军
李学强
王洪强
李超
刘礼飞
钱丽娜
赵心
李莉娥
杨俊�
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Publication of WO2023078461A1 publication Critical patent/WO2023078461A1/en
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
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    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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    • 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
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    • 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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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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    • C07F5/025—Boronic and borinic acid compounds
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the invention belongs to the field of medicine, in particular, the invention relates to a heterocyclic compound and its preparation method and application.
  • the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) gene is located on chromosome 4 4q34 ⁇ q35, with a span of about 31kb, a total of 7 exons, and a molecular weight of 29kD.
  • 15-PGDH is composed of 266 amino acids and belongs to the family of short-chain dehydrogenases (SDR). It consists of two identical subunits to form a dimer, but some people think that it only has enzymatic activity when it exists as a monomer. .
  • 15-PGDH is the key enzyme for the degradation and inactivation of prostaglandins (PGs) and related eicosane bioactive substances, and is widely present in the lungs, kidneys, gastrointestinal tract, thyroid, prostate and placenta of humans and mammals In normal tissues, on the one hand, it can catalyze the oxidation of active 15-hydroxy prostaglandins into 15-keto prostaglandins with greatly weakened activity; on the other hand, it can degrade some other non-prostaglandins in the presence of NAD + coenzyme factors
  • the polycyclic aromatic hydrocarbons can reduce the carcinogens and pre-carcinogens produced under physiological or pathological conditions through oxidation reactions.
  • the object of the present invention is to provide a heterocyclic compound used as a 15-PGDH inhibitor.
  • heterocyclic compounds represented by formula I their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently N, O, S, CH 2 , CH or C;
  • heteroatoms is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", “the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or “the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;
  • R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
  • R 1 and R 2 together with the N atom they are connected to form a 3-11 membered heterocycloalkyl group; wherein, the 3-11 membered heterocycloalkyl group is further replaced by 0, 1 or more R 1- 1 ; when there are multiple substituents, the substituents are the same or different;
  • n 0, 1, 2 or 3 respectively;
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, O, S, CH 2 , CH or C;
  • R 4 and R 5 are absent, or together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by 1 or more R 4-1 , or together forms an unsubstituted or substituted by 1 A 3-8-membered heterocycloalkyl group substituted by one or more R 4-1 , said R 4-1 being a C 1 -C 6 alkyl or a halogenated C 1 -C 6 alkyl; said when the substituent is When multiple, the substituents are the same or different.
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently N, O, S, CH 2 , CH or C;
  • heteroatoms is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", “the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or “the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;
  • R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
  • R 1 and R 2 together with the N atom they are connected to form a 3-11 membered heterocycloalkyl group; wherein, the 3-11 membered heterocycloalkyl group is further replaced by 0, 1 or more R 1- 1 ; when there are multiple substituents, the substituents are the same or different;
  • n 0, 1, 2 or 3 respectively;
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, O, S, CH 2 , CH or C;
  • R 4 and R 5 together form a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by 1 or more R 4-1 , or together forms an unsubstituted or substituted by 1 or more 3-8 membered heterocycloalkyl substituted by R 4-1 , said R 4-1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl; when there are multiple substituents, The substituents are the same or different.
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently N, O, S, CH 2 , CH or C;
  • heteroatoms is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", “the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or “the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;
  • R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
  • R 1 and R 2 together with the N atom they are connected to form a 3-11 membered heterocycloalkyl group; wherein, the 3-11 membered heterocycloalkyl group is further replaced by 0, 1 or more R 1- 1 ; when there are multiple substituents, the substituents are the same or different;
  • n 0, 1, 2 or 3 respectively;
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, O, S, CH 2 , CH or C;
  • R 4 and R 5 are absent, or together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by 1 or more R 4-1 , or together forms an unsubstituted or substituted by 1 A 3-8-membered heterocycloalkyl group substituted by one or more R 4-1 , said R 4-1 being a C 1 -C 6 alkyl or a halogenated C 1 -C 6 alkyl; said when the substituent is When multiple, the substituents are the same or different.
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom
  • Z 1 , Z 2 and Z 3 are each independently N or C;
  • heteroatoms is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are 6-membered heteroalkane rings selected from one or more of N, O, and S", “the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or “the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;
  • R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
  • R 1 and R 2 together with the N atom they are connected to form a C 3 -C 8 cycloalkyl or a 3-11 membered heterocycloalkyl; wherein, the C 3 -C 8 cycloalkyl or 3-11 Member heterocycloalkyl is further substituted by R 1-1 ;
  • n 0, 1, 2 or 3 respectively;
  • X 1 , X 2 and X 3 are each independently N or C;
  • R 4 and R 5 together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by R 4-1 , or together forms a 3-8 membered unsubstituted or substituted by R 4-1 Heterocycloalkyl, the R 4-1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom
  • Z1 is CH or N
  • Z 2 is CH
  • Z 3 is CH
  • Z 4 is C or N
  • Z 5 is CH or CH 2 ;
  • Z 6 is CH or CH 2 ;
  • Z7 is N, O or CH
  • heteroalkene ring is phenyl, "6-membered heteroaromatic ring with 1 or 2 heteroatoms and N as heteroatom", or 6-membered heteroaryl ring with 1 or 2 heteroatoms and N and/or O as heteroatom Heteroalkene ring";
  • R 1 , R 2 together with the N atom they are connected to form a 3-8 membered heterocycloalkyl group; wherein, the 3-8 membered heterocycloalkyl group is further replaced by 0, 1 or 2 R 1-1 Substitution; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the 3-8 membered heterocycloalkane are selected from one or more of N, O and S, and the heteroatoms are The number of atoms is 1, 2 or 3;
  • Each R 1-1 is independently halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
  • R a and R b are C 1 -C 6 alkyl
  • n 0, 1, 2 or 3 respectively;
  • X1 is CH
  • X2 is CH
  • X3 is CH
  • X 4 is C
  • X 5 is C or N
  • X 6 is C
  • R 3 is C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl
  • R 6 is hydrogen or halogen
  • R 4 and R 5 together form an unsubstituted C 3 -C 6 cycloalkyl group with the C atom they are connected to, or together form an unsubstituted 3-8 membered heterocycloalkyl group; the 3-8 membered heterocycloalkane
  • the heteroatoms in are selected from one or more of N, O and S, and the number of said heteroatoms is 1, 2 or 3.
  • the solvate may be a hydrate.
  • the 6-membered heteroalkene ring contains one double bond.
  • the 3-8 membered heterocycloalkyl group is a 4-membered monoheterocycloalkane base, 5-membered monoheterocycloalkyl group, 6-membered monoheterocycloalkyl group, 3-membered spiro 6-membered heterocycloalkyl group, 5-membered and 5-membered heterocycloalkyl group or 3-membered and 5-membered heterocycloalkyl group
  • the 3-8 membered heterocycloalkyl has 1 heteroatom selected from N, O, S (eg N and/or O); for example, piperidine, azetidine, tetrahydropyrrole, 4-oxa- 7-Azaspiro[2.5]octane, morpholine, 6-azaspiro[2.5]octane, 3-azabic
  • said halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine.
  • the C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl, also eg methyl or ethyl.
  • the halogen in the halogenated C 1 -C 6 alkyl is independently fluorine, chlorine, bromine or iodine, such as fluorine.
  • the C 1 -C 6 alkyl in the halogenated C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also eg methyl or ethyl.
  • the halogenated C 1 -C 6 alkyl is independently a halogenated C 1 -C 4 alkyl, for example, replaced by 1, 2 or 3 F-substituted C 1 -C 4 alkyl, also for example, monofluoromethyl, difluoromethyl or trifluoromethyl.
  • the C 1 -C 6 alkyl in the halogenated C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also eg methyl or ethyl.
  • the C 1 -C 6 alkyl in the halogenated C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also eg methyl or ethyl.
  • the halogenated C 1 -C 6 alkyl is C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl radical, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl.
  • the C 1 -C 6 alkyl group in the C 1 -C 6 deuterated alkyl group is a C 1-4 alkyl group, such as methyl, ethyl, n-propyl radical, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl.
  • the C 1 -C 6 deuterated alkyl is a C 1 -C 4 deuterated alkyl, such as C 1 substituted by 1, 2 or 3 deuteriums -C 4 alkyl. Also for example,
  • said halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • the C 3 -C 6 cycloalkyl is propyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropyl or cyclobutyl.
  • the heteroatom in the 3-8 membered heterocycloalkyl is N, O or S (such as N).
  • the present invention when R 4 and R 5 together form a 3-8 membered heterocycloalkyl group that is unsubstituted or substituted by 1 or more R 4-1 with the C atom it is connected to, the The 3-8 membered heterocycloalkyl group is a 3-6 membered heterocycloalkyl group, such as a 4-membered heterocycloalkyl group, or an oxygen-containing 4-membered heterocycloalkyl group.
  • R6 is hydrogen
  • Z 1 is CH or N.
  • Z2 is CH.
  • Z3 is CH.
  • Z 4 is C or N.
  • Z 5 is CH or CH 2 .
  • Z 6 is CH or CH 2 .
  • Z7 is N, O or CH.
  • X 1 is CH.
  • X2 is CH.
  • X3 is CH.
  • X4 is C.
  • X 5 is C or N.
  • X6 is C.
  • R 4 and R 5 form an unsubstituted C 3 -C 6 cycloalkyl group together with the C atom they are connected to, or together form an unsubstituted 3-6 membered heterocycloalkyl group;
  • the heteroatoms in the 3-6 membered heterocycloalkane are selected from one or more of N, O and S (such as N or O), and the number of heteroatoms is 1, 2 or 3 ( eg 1).
  • R 4 and R 5 together form a C 3 -C 6 cycloalkyl group unsubstituted or substituted by 1 or more R 4- 1 with the C atom to which they are attached, or together form A 3-6-membered heterocycloalkyl group that is unsubstituted or substituted by 1 or more R 4-1 ; the number of heteroatoms in the 3-6-membered heterocycloalkyl group is 1, and the heteroatom is N, O or S (such as N or O).
  • R 3 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl, such as C 1 -C 3 alkyl or C 1 -C 3 deuterated alkyl , also for example methyl or
  • R a is C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halo Substituted C 1 -C 6 alkoxy; such as C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl or halogenated C 1 -C 4 alkyl; also such as methyl or ethyl.
  • heterocyclic compounds shown in formula I' their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom
  • Z 1 , Z 2 and Z 3 are each independently N or C;
  • heteroatoms is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", “the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or “the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;
  • R 1 and R 2 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl; or, R 1 and R 2 together form a 3-11 membered hetero Cycloalkyl; wherein, the 3-11 membered heterocycloalkyl is further substituted by R 1-1 ;
  • n 0, 1, 2 or 3 respectively;
  • X 1 , X 2 and X 3 are each independently N or C;
  • R 4 and R 5 together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by R 4-1 , or together forms a 3-8 membered unsubstituted or substituted by R 4-1 Heterocycloalkyl, the R 4-1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.
  • said R 1 and R 2 together with the N atom to which they are connected form a 3-8 membered heterocycloalkyl group.
  • the 3-8 membered heterocycloalkyl is monocyclic, fused bicyclic, or bicyclic optionally including bridged rings or spiro rings.
  • the 3-8 membered heterocycloalkyl group further has 1 to 3 heteroatoms that are N, O or S.
  • R 1 and R 2 form a 3-8 membered heterocycloalkyl group together with the N atom they are connected to; wherein, the 3-8 membered heterocycloalkyl group is further replaced by 0, 1 One or two R 1-1 are substituted; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the 3-8 membered heterocycloalkane are selected from N, O and S One or more (such as N and/or O), the number of heteroatoms is 1, 2 or 3.
  • R 1-1 is halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy, for example halogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; also for example F, methyl, ethyl, C 1 -substituted by 1, 2 or 3 F C 4 alkyl, such as F, monofluoromethyl, difluoromethyl or trifluoromethyl.
  • R 1 , R 2 together with the N atom they are connected to form the following group:
  • R 1 , R 2 together with the N atom they are connected to form the following group:
  • the heterocyclic compound shown in formula I has a structure shown in formula II-1:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are as defined in the first aspect of the present invention;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I has a structure shown in formula II-2:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are as defined in the first aspect of the present invention;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, R is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl,
  • Oxo ( O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;
  • R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as defined in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as defined in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • the heterocyclic compound shown in formula I is selected from the following structures: Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.
  • heterocyclic compound represented by formula I is selected from any of the following compounds:
  • a heterocyclic compound represented by formula I as described in the first aspect of the present invention its tautomers, stereoisomers, solvates, and pharmaceutically acceptable salts
  • the preparation method of prodrug, described method comprises the steps:
  • Y 1 is halogen
  • Y 3 is halogen or boronic acid group
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n are as defined in the first aspect of the present invention.
  • the fourth aspect of the present invention provides another heterocyclic compound as shown in formula I, its tautomers, stereoisomers, solvates, pharmaceutically acceptable
  • a method for the preparation of a salt or a prodrug, said method comprising the steps of:
  • Y 1 is a halogen
  • Y 2 is hydrogen or trimethylsulfoxide
  • Y 3 is a halogen or boronic acid group
  • R 4 and R 5 form a cyclobutane or oxetane together with the C atom they are connected to group
  • R 1 , R 2 , R 3 , R 6 , X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n are as defined in the first aspect of the invention.
  • the present invention provides intermediates as shown in formula A-1, formula A-2-1, formula A-2, formula B-1, said formula A-1, formula A-2-1,
  • the intermediates shown in formula A-2 and formula B-1 are used to prepare heterocyclic compounds shown in formula I as described in the first aspect of the present invention, their tautomers, stereoisomers, solvates, pharmaceutical acceptable salts or prodrugs.
  • the intermediate shown in formula A-1 has the structure:
  • Y 1 is halogen
  • R 3 , R 4 , R 5 , R 6 , X 1 , X 2 and X 3 are as defined in the first aspect of the present invention.
  • the intermediate shown in formula A-2-1 has the structure:
  • the definitions of X2 and X3 are as defined in the first aspect of the invention.
  • the intermediate shown in formula A-2 has the structure:
  • Y 1 is a halogen
  • R 4 and R 5 form a cyclobutanyl group or an oxetanyl group together with the C atom they are connected to
  • R 6 , X 1 , X 2 and X 3 are as defined in Clause 1 of the present invention on the one hand.
  • the intermediate shown in formula B-1 has the structure:
  • Y 3 is halogen or boronic acid group; R 1 , R 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n are as defined in this paper described in the first aspect of the invention.
  • the intermediate represented by the formula A-1 is selected from any of the following compounds:
  • the intermediate is selected from the following compounds:
  • the intermediate represented by the formula A-2-1 is selected from any of the following compounds:
  • the intermediate represented by the formula A-2 is selected from any of the following compounds:
  • the intermediate represented by the formula B-1 is selected from any of the following compounds:
  • the intermediate is selected from the following compounds:
  • the intermediate is selected from the following compounds:
  • the sixth aspect of the present invention provides a pharmaceutical composition, which includes: the heterocyclic compound represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers body, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier.
  • the seventh aspect of the present invention provides the heterocyclic compound represented by the formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or precursors
  • the use of medicine, or the use of the pharmaceutical composition described in the fifth aspect of the present invention includes: inhibiting 15-PGDH; and/or, preventing and/or treating 15-PGDH-related diseases; and/or, preparing Drugs, pharmaceutical compositions or preparations for inhibiting 15-PGDH, and/or preventing and/or treating 15-PGDH-related diseases.
  • the 15-PGDH-related diseases include but are not limited to: fibrosis, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host disease, hair growth, osteoporosis, ear disease, eye disease, neutropenia, diabetes, underactive bladder, or, in the promotion of stem cell or implants in bone marrow transplantation or organ transplantation, neurogenesis and nerve cell death, blood cell reconstitution, tissue regeneration, and cervical ripening one, two or more.
  • the 15-PGDH-related diseases include but are not limited to: fibrosis (such as pulmonary fibrosis, including idiopathic pulmonary fibrosis, etc., liver fibrosis, renal fibrosis, myocardial fibrosis, scleroderma and myelofibrosis), inflammatory diseases [such as chronic obstructive pulmonary disease (COPD), acute lung injury, sepsis, exacerbation of asthma and lung disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), Peptic ulcer (eg, NSAID-induced ulcer), autoinflammatory disease (eg, Behcet's disease), vasculitic syndrome, acute liver injury, acute kidney injury, nonalcoholic fatty liver disease (NASH), atopic dermatitis , psoriasis, interstitial cystitis, prostatitis syndrome (eg, chronic prostatitis/chronic pelvic pain syndrome)], cardiovascular disease (eg, pulmonary hypertension, an pulmonary hyper
  • the 15-PGDH-related diseases include but not limited to: idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the 15-PGDH-related diseases include but not limited to: liver regeneration.
  • a method for inhibiting 15-PGDH, or preventing and/or treating 15-PGDH-related diseases comprising the steps of: administering the formula I described in the first aspect of the present invention to a subject in need Heterocycles, tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs thereof.
  • a method for preventing and/or treating diseases which includes administering to patients an effective amount of the aforementioned heterocyclic compound represented by formula I, its tautomer, stereo Isomers, solvates, pharmaceutically acceptable salts or prodrugs, the disease is a fibrotic disease and/or an inflammatory disease.
  • Both the fibrotic disease and the inflammatory disease can be the same as above.
  • reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein.
  • the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 .
  • R 1 ", “R1” and “R 1 " have the same meaning and can be substituted for each other. For other symbols such as R 2 , similar definitions have the same meanings.
  • a number from 1 to 10 should be understood as not only recording each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • halogen alone or as part of another substituent, means fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.
  • alkyl means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and attached to the rest of the molecule by a single bond straight-chain or branched hydrocarbon chain groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.
  • An alkyl group can be unsubstituted or substituted with one or more suitable substituents.
  • alkenyl means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds.
  • alkynyl refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.
  • C 1 -C 6 alkyl alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3
  • cycloalkyl by itself or as part of another substituent means a cyclic alkyl group.
  • mn-membered cycloalkyl or " Cm - Cncycloalkyl” is understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms.
  • 3-15 membered cycloalkyl or "C 3 -C 15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which May contain 1 to 4 rings.
  • 3-10 membered cycloalkyl contains 3-10 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as a decahydronaphthalene ring. Cycloalkyl groups may be substituted with one or more substituents.
  • cycloalkyl is used interchangeably with the term "carbocyclyl”.
  • heterocycloalkyl refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by a heteroatom, which Atoms are such as, but not limited to, N, O, S, and P.
  • mn membered heterocycloalkyl or "C m -C n heterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms, wherein the hetero ring atoms are selected from N, O, S, P are preferably selected from N, O or S.
  • heterocycloalkyl or “C 4 -C 8 heterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 8 atoms, wherein 1, 2 , 3, or 4 ring atoms are selected from N, O, S, P, preferably selected from N, O or S.
  • "4-10 membered heterocyclic group” means a saturated, unsaturated or partially saturated ring having 4 to 10 atoms.
  • a heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl ring group or a heteroaryl ring group.
  • heterocycloalkyl When a prefix such as 4-8 membered or 4-10 membered is used to indicate heterocycloalkyl, the number of carbons is also meant to include heteroatoms. Including monocyclic, bicyclic, tricyclic, spiro or bridged rings.
  • heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc.
  • heterocycloalkyl is used interchangeably with the term “heteroalkane”.
  • alkenyl by itself or as part of another substituent refers to a straight or branched chain monovalent hydrocarbon group of two to forty carbon atoms having at least one carbon-carbon sp2 double bond (for example C2- C 6 alkenyl, another example is C 2 -C 4 alkenyl), and includes groups with "cis” and “trans” orientations or "E” and “Z” orientations.
  • alkenyl groups include, but are not limited to, vinyl and allyl.
  • alkynyl by itself or as part of another substituent refers to a straight or branched chain monovalent hydrocarbon radical (e.g. C2 - C6 ) of two to forty carbon atoms having at least one carbon-carbon sp triple bond.
  • alkynyl another example is C 2 -C 4 alkynyl).
  • alkynyl include, but are not limited to, ethynyl and propynyl.
  • alkoxy by itself or as part of another substituent, refers to the group -ORx , wherein Rx is "alkyl" as defined above.
  • oxo by itself or as part of another substituent, means that two hydrogens on a methylene group are replaced by oxygen, ie a methylene group is replaced by a carbonyl group.
  • aryl by itself or as part of another substituent means a monocyclic or polycyclic carbocyclic ring having from 6 to 20 carbon atoms, at least one of which is aromatic. When one of the rings is a non-aromatic ring, the group can be attached through an aromatic ring or through a non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthyl.
  • heteromatic ring means a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is aromatic.
  • the group may be a carbon group or a heteroatom group (ie it may be C-attached or N-attached, wherever this is possible).
  • the group can be attached through an aromatic ring or through a non-aromatic ring.
  • heteroaryl groups include, but are not limited to: imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, Benzothienyl, benzofuryl, quinolinyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N - methylpyrrolyl and tetrahydroquinoline.
  • heteroaryl may be used interchangeably with the terms “heteroaromatic", “heteroaryl” or "heteroaryl”.
  • heteroalkene ring refers to a monocyclic group with heteroatoms (the monocyclic group has a double bond, but is not aromatic), preferably containing 1, 2 or a monocyclic ring of 3 ring heteroatoms independently selected from N, O and S.
  • heterocycloalkenyl groups are: dihydrofuryl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroiso Thiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, 3,4-dihydro-2H-pyran, pyranyl, Thipyryl, dihydropyridyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl, dihydrotetrazolyl and the like.
  • heteroalkenyl may be used interchangeably with the term “heterocycloalkenyl”.
  • the term "spiro" refers to a polycyclic group in which the single rings share one carbon atom (called the spiro atom), which may contain one or more double bonds, but none of the rings has A fully conjugated ⁇ -electron system.
  • the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • Non-limiting examples of spirocycloalkyl groups include:
  • spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, non-limiting examples include:
  • bridged ring refers to a cyclic hydrocarbon in which any two rings in a compound share two carbon atoms that are not directly connected, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc.
  • Non-limiting examples include:
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • the compounds provided herein, including intermediates useful in the preparation of the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof.
  • "Protected derivatives” are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as protecting groups).
  • Suitable protecting groups for the carboxyl moiety include benzyl, tert-butyl, etc., and isotopes, etc.
  • Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable hydroxy protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
  • amine salt refers to the product obtained by neutralizing an alkyl primary, secondary or tertiary amine with an acid.
  • the acid includes an inorganic acid or an organic acid as described in this application.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
  • the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
  • the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
  • treatment refers to therapeutic therapy.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • patient refers to any animal, preferably a mammal, that is about to or has received the administration of the compound or composition according to the embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.
  • terapéuticaally effective amount refers to an amount of a compound which, when administered to a patient, is sufficient to effectively treat a disease or condition described herein.
  • the “therapeutically effective amount” will vary depending on the compound, the disorder and its severity, and the age of the patient to be treated, and can be adjusted as necessary by those skilled in the art.
  • inflammatory bowel disease refers to IBD and is used to describe diseases involving chronic inflammation of the digestive tract.
  • the main types include: ulcerative colitis and Crohn's disease. Ulcerative colitis. Causes inflammation and ulcers in the superficial lining of the large intestine (colon) and rectum. Crohn's disease, on the other hand, is characterized by inflammation of the lining of the digestive tract, often involving the deeper layers of the digestive tract.
  • the reaction temperature can be appropriately selected according to the solvent, starting material, reagent, etc.
  • the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc.
  • the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification.
  • the present invention provides heterocyclic compounds shown in formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, the compound of formula I is effective for 15-PGDH has a significant inhibitory effect. Can significantly increase the production of PGE2. And it has a significant effect on IPF and liver regeneration. Combined with the pharmacokinetic data of mice, it can be known that the compounds of the present invention respectively exhibit excellent pharmacokinetic properties in mice, and have relatively high safety and drug-making properties.
  • the present invention provides methods and intermediates for preparing heterocyclic compounds shown in I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, and the operation of the method
  • the method is simple, high in yield and high in purity, and can be used in the industrialized production of medicines.
  • IC 50 half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56mL, 29.1mmol, 2.5M n-hexane solution
  • the first step Synthesis of 6'-bromospiro[cyclopropa-1,1'-isoindoline]-3'-one (A1-2)
  • reaction solution was cooled to 0°C, slowly poured into 1N HCl (10 mL), neutralized with saturated sodium bicarbonate (20 mL), extracted with ethyl acetate (60 mL), combined organic phases, washed with saturated brine (30 mL), Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product.
  • reaction solution was diluted with water (5 mL), quenched with ammonia water (20 mL), extracted with ethyl acetate (60 mL), combined organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure
  • A1 6'-bromo-2'-methylspiro[cyclopropa-1,1'-isoindoline]-3'-one (A1) (114 mg, yield 99.1%) was obtained.
  • intermediate A2 refers to the synthesis of intermediate A1, and methyl iodide is replaced by deuterated methyl iodide.
  • intermediate A3 refers to the synthesis of intermediate A1, and A1-1 is replaced by A3-1.
  • the first step the synthesis of methyl 5-bromo-3-(bromomethyl)picolinate (A4-2)
  • 5-Bromo-3-methylpicolinate (A4-1) (5g, 21.73mmol) was dissolved in carbon tetrachloride (50mL), and azobisisobutyronitrile (0.71g, 4.35mmol) was added and NBS (4.64g, 26.1mmol) was reacted at 80°C for 5h. Dilute with water (100 mL), extract with ethyl acetate (100 mL), combine organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product.
  • the second step the synthesis of methyl 5-bromo-3-(cyanomethyl)picolinate (A4-3)
  • the third step the synthesis of methyl 5-bromo-3-(1-cyanocyclopropyl)picolinate (A4-4)
  • Methyl 5-bromo-3-(cyanomethyl)picolinate (A4-3) (2 g, 7.84 mmol) was dissolved in DMF (30 mL), cesium carbonate (7.66 g, 23.52 mmol) and 1,2- Dibromoethane (1.77g, 9.41mmol) was reacted at 60°C for 3h.
  • the first step the synthesis of 4-bromo-2-hydrazinopyridine (A5-2)
  • the synthetic route of target compound 1 is as follows:
  • Step 1 Synthesis of (8-bromoquinolin-3-yl)(4,4-difluoropiperidin-1-yl)methanone (B1-2)
  • the second step the synthesis of (3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)boronic acid (B1-3)
  • the synthetic route of target compound 2 is as follows:
  • Step 1 Synthesis of (8-bromoquinolin-3-yl)(3,3-difluoropyrrolidin-1-yl)methanone (B2-1)
  • the second step the synthesis of (3-(3,3-difluoropyrrolidine-1-carbonyl)quinolin-8-yl)boronic acid (B2-2)
  • the synthetic route of target compound 3 is as follows:
  • the first step the synthesis of (8-bromoquinolin-3-yl)(3-fluoropiperidin-1-yl)methanone (B3-1)
  • the second step the synthesis of (3-(3-fluoropiperidine-1-carbonyl)quinolin-8-yl)boronic acid (B3-2)
  • Step 1 Synthesis of (4-chloroquinolin-7-yl)(4,4-difluoropiperidin-1-yl)methanone (B5-2)
  • the second step the synthesis of (7-(4,4-difluoropiperidine-1-carbonyl)quinolin-4-yl)boronic acid (B5-3)
  • Example 6 2'-methyl-6'-(3-(morpholine-4-carbonyl)quinolin-8-yl)spiro[cyclopropane-1,1'-isoindoline]-3' -
  • the synthetic route of the preparation target compound 6 of ketone (compound 6) is as follows:
  • the first step the synthesis of (8-bromoquinolin-3-yl)(morpholine)methanone (B6-1)
  • the second step the synthesis of (3-(morpholine-4-carbonyl)quinolin-8-yl)boronic acid (B6-2)
  • the synthetic route of target compound 8 is as follows:
  • the synthesis of compound 8 refers to the synthesis of compound 1, and 3-fluoro-3-methylazetidine hydrochloride was used instead of 4,4-difluoropiperidine.
  • the synthetic route of target compound 9 is as follows:
  • the synthesis of compound 9 refers to the synthesis of compound 1, with 4-oxa-7-azaspiro[2.5]octane instead of 4,4-difluoropiperidine, LC-MS, M/Z (ESI): 440.2 [M +H] + .
  • Example 10 2'-methyl-6'-(3-((3aR, 6As)-octahydrocyclopentane[c]pyrrole-2-carbonyl)quinolin-8-yl)spiro[cyclopropane- Preparation of 1,1'-isoindoline]-3'-one (compound 10)
  • the synthetic route of target compound 10 is as follows:
  • the synthesis of compound 10 refers to the synthesis of compound 1, using (3aR,6aS)-octahydrocyclopentane[c]pyrrole instead of 4,4-difluoropiperidine.
  • the synthetic route of target compound 12 is as follows:
  • the synthetic route of target compound 13 is as follows:
  • the first step the synthesis of N-cyclobutene-2-methylpropane-2-sulfoxide amide (B13-2)
  • the third step the synthesis of 2-(1-aminocyclobutyl)-4-bromobenzoic acid methyl ester hydrochloride (B13-4)
  • Step 5 Synthesis of 6'-bromo-2'-methylspiro[cyclobutane-1,1'-isoindoline]-3'-one (B13-6)
  • Step 6 6'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclobutane-1,1'-isobis Synthesis of Indoline]-3'-one (Compound 13)
  • the synthetic route of target compound 15 is as follows:
  • the first step 2,2-dimethyl-4-(2'-methyl-3'-oxyspiro[cyclopropane-1,1'-isoindoline]-6'-yl)-3, 4-Dihydro-2H-pyridine[3,2-b][1,4]oxazine-7-carboxylic acid ethyl ester (B15-2)
  • reaction solution was directly concentrated, diluted with water (10 mL), adjusted to pH 5 with 1N hydrochloric acid (5 mL), extracted three times with ethyl acetate (60 mL), combined the organic phases, and concentrated to obtain compound 2,2-dimethyl- 4-(2'-Methyl-3'-oxyspiro[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-dihydro-2H-pyridin[3,2 -b] [1,4]oxazine-7-carboxylic acid (B15-3) (66 mg, yield 98%).
  • the third step 6'-(7-(4,4-difluoropiperidine-1-carbonyl)-2,2-dimethyl-2,3-dihydro-4H-pyridine[3,2-b] [1,4]oxazin-4-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (compound 15)
  • the synthetic route of target compound 16 is as follows:
  • Step 5 Methyl 4-ethyl-1-(2-methyl-3-oxyl-2,3-dihydro-[1,2,4]triazolyl[4,3-a]pyridine- 7-yl)-3-oxyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (B16-6)
  • the sixth step 4-ethyl-1-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7- Base)-3-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (B16-7)
  • reaction solution was directly concentrated, diluted with water (10mL), adjusted to pH 5 with 1N hydrochloric acid (5mL), extracted with ethyl acetate (20mL ⁇ 3), combined the organic phases, and concentrated to obtain the compound 4-ethyl-1- (2-Methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-oxo-1,2 , 3,4-Tetrahydroquinoline-6-carboxylic acid (B16-7) (18 mg, yield 97%).
  • the seventh step 7-(4,4-difluoropiperidine-1-carbonyl)-1-ethyl-4-(2-methyl-3-oxyl-2,3-dihydro-[1,2 ,4] Triazol[4,3-a]pyridin-7-yl)-3,4-dihydroquinolin-2(1H)-one (compound 16)
  • Example 17 6'-(7-(3-fluoro-3-methylazetidine-1-carbonyl)-2,2-dimethyl-2,3-dihydro-4H-pyridine[3 ,2-b][1,4]oxazin-4-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (compound 17)
  • the synthetic route of target compound 17 is as follows:
  • Test Example 1 Compound Inhibition Test on 15-PGDH Enzyme
  • Assay Buffer 50 mM Tris-HCl, pH 7.5, 0.01 vol% Tween 20 was used to prepare 15-PGDH (R&D Systems, Cat. No. 5660-DH-010) to double the final concentration, ie 30 nM. Then, 8 ⁇ l/well was added to a 384 white plate (Cisbio Bioassays, Cat. No. 66PL384025). Set negative control wells, add only Assay Buffer without enzyme. Then use Assay Buffer to configure the compound to 4 times the final concentration, that is, start at 4000nM, dilute 3 times, and have 10 concentrations.
  • the compound of table 1 is to 15-PGDH inhibitory test result
  • Test Example 2 Effects of Compounds on PGE 2 Levels in A549 Cell Supernatant
  • A549 cells (Wuhan Punuosai) were cultured in F12K+10% FBS, and the cells in good logarithmic phase were taken for experiments, the cells were digested, counted, and the cells were seeded into 24-well plates, 8000 cells/well. The cells were cultured overnight in a 37°C, 5% CO 2 incubator. After the cells adhere to the wall, change the medium containing 0.5% FBS for about 10 hours, add IL-1 ⁇ to each well (final concentration 20ng/mL, 1mL/well), and set up a control group (the control group does not add IL-1 ⁇ ) .
  • mice Male mice were adaptively fed for 1-2 weeks, and after reaching the standard body weight (25g), a certain dose of bleomycin was used to induce the IPF model (idiopathic pulmonary fibrosis model). On the day of modeling, the animals were randomly divided into models according to their weight. The drug group and the drug group were given daily oral gavage administration, and the vehicle control group was given blank vehicle for 21 consecutive days. During the administration period, body weight was measured every 3 days.
  • the animals were euthanized, and the lungs were removed from the thyroid cartilage (without perfusion), and 10% formalin was slowly perfused into the lungs until the bilateral lungs were filled, and the main trachea was ligated and placed 5-10 times
  • the tissue volume was fixed in 10% formalin, and the left lung was made into paraffin tissue sections, HE stained and Masson Trichrome stained, and a Hamamatsu NanoZoomer Digital Pathology (S210) slice scanner was used for panoramic scanning of the slices for pathological analysis.
  • S210 Hamamatsu NanoZoomer Digital Pathology
  • Test Example 4 Drug effect experiment of mouse liver resection regeneration
  • mice pharmacokinetic properties of the compounds of the present invention were determined according to the following experimental methods.

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Abstract

A heterocyclic compound as shown in formula I, a tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug thereof, a preparation method therefor, and the use thereof. The heterocyclic compound has a better 15-PGDH inhibitory effect.

Description

杂环类化合物及其制备方法和用途Heterocyclic compound and its preparation method and use

本申请要求申请日为2021年11月8日的中国专利申请2021113164349的优先权。本申请要求申请日为2022年7月15日的中国专利申请2022108377941的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 2021113164349 with a filing date of November 8, 2021. This application claims the priority of Chinese patent application 2022108377941 with a filing date of July 15, 2022. This application cites the full text of the above-mentioned Chinese patent application.

技术领域technical field

本发明属于医药领域，具体地，本发明涉及到一种杂环类化合物及其制备方法和用途。The invention belongs to the field of medicine, in particular, the invention relates to a heterocyclic compound and its preparation method and application.

背景技术Background technique

15-羟基前列腺素脱氢酶(15-PGDH)基因位于4号染色体4q34～q35上，大约跨度为31kb，共有7个外显子，分子量为29kD。15-PGDH由266个氨基酸组成，属于短链脱氢酶(short-chain dehydrogenases，SDR)家族，由两个相同亚单位构成二聚体，但也有人认为它以单体存在时才有酶活性。15-PGDH是前列腺素(Prostaglandins，PGs)和相关二十烷类生物活性物质降解、灭活的关键酶，广泛存在于人和哺乳动物的肺、肾、胃肠道、甲状腺、前列腺和胎盘等正常组织中，它一方面可催化有活性的15-羟基前列腺素氧化成为活性大大减弱的15-酮基前列腺素，另一方面能在NAD +辅酶因子存在的情况下，降解其他一些非前列腺素的多环芳香烃，通过氧化反应减少生理或病理情况下产生的致癌物和前致癌物。 The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) gene is located on chromosome 4 4q34~q35, with a span of about 31kb, a total of 7 exons, and a molecular weight of 29kD. 15-PGDH is composed of 266 amino acids and belongs to the family of short-chain dehydrogenases (SDR). It consists of two identical subunits to form a dimer, but some people think that it only has enzymatic activity when it exists as a monomer. . 15-PGDH is the key enzyme for the degradation and inactivation of prostaglandins (PGs) and related eicosane bioactive substances, and is widely present in the lungs, kidneys, gastrointestinal tract, thyroid, prostate and placenta of humans and mammals In normal tissues, on the one hand, it can catalyze the oxidation of active 15-hydroxy prostaglandins into 15-keto prostaglandins with greatly weakened activity; on the other hand, it can degrade some other non-prostaglandins in the presence of NAD + coenzyme factors The polycyclic aromatic hydrocarbons can reduce the carcinogens and pre-carcinogens produced under physiological or pathological conditions through oxidation reactions.

目前尚无15-PGDH抑制途径治疗包括纤维化在内的众多病症的药物上市。因此，开发新的可抑制15-PGDH活性的化合物对于疾病的治疗具有积极意义。There are currently no drugs on the market that inhibit the 15-PGDH pathway for the treatment of many conditions, including fibrosis. Therefore, the development of new compounds that can inhibit the activity of 15-PGDH has positive significance for the treatment of diseases.

发明内容Contents of the invention

本发明的目的是提供一种杂环类化合物，用作15-PGDH抑制剂。The object of the present invention is to provide a heterocyclic compound used as a 15-PGDH inhibitor.

在本发明的第一方面，提供了式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药：In the first aspect of the present invention, there are provided heterocyclic compounds represented by formula I, their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs:

Figure PCTCN2022130676-appb-000001
Figure PCTCN2022130676-appb-000001

其中，in,

Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom;

Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地为N、O、S、CH 2、CH或C； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently N, O, S, CH 2 , CH or C;

Figure PCTCN2022130676-appb-000002
为苯基、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”，或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烯环”；
Figure PCTCN2022130676-appb-000002
is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", "the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;

R 1和R 2各自独立地为氢、C 1-C 6烷基或C 3-C 8环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;

或者，R 1、R 2与其所连接到的N原子一起形成3-11元杂环烷基；其中，所述3-11元杂环烷基进一步被0个、1个或多个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同； Alternatively, R 1 and R 2 together with the N atom they are connected to form a 3-11 membered heterocycloalkyl group; wherein, the 3-11 membered heterocycloalkyl group is further replaced by 0, 1 or more R 1- 1 ; when there are multiple substituents, the substituents are the same or different;

R 1-1为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷氧羰基、C 1-C 6烷基羰氧基、C 1-C 6烷氧基C 1-C 6烷基、C 1-C 6烷氧羰基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基羰基、C 3-C 8环烷氧基，任选具有1或2个C 1-C 6烷基基团的氨基羰基基团，C 1-C 6烷基磺酰基基团，任选具有1或2个C 1-C 6烷基基团的氨基磺酰基，C 1-C 6烷基磺酰基氨基基团和任选具有1或2个C 1-C 6烷基基团的氨基； R 1-1 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkoxy, optionally aminocarbonyl with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 Alkylsulfonyl groups, optionally aminosulfonyl groups with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 alkylsulfonylamino groups and optionally 1 or 2 C 1 -Amino group of C 6 alkyl group;

R a和R b为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R a and R b are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 - C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkane Oxygen;

m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively;

X 1、X 2、X 3、X 4、X 5和X 6各自独立地为N、O、S、CH 2、CH或C； X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, O, S, CH 2 , CH or C;

R 3和R 6各自独立地为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷 基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 3 and R 6 are each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkanes radical, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;

R 4和R 5不存在，或者与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基，所述R 4-1为C 1-C 6烷基或卤代C 1-C 6烷基；所述当取代基为多个时，所述的取代基相同或不同。 R 4 and R 5 are absent, or together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by 1 or more R 4-1 , or together forms an unsubstituted or substituted by 1 A 3-8-membered heterocycloalkyl group substituted by one or more R 4-1 , said R 4-1 being a C 1 -C 6 alkyl or a halogenated C 1 -C 6 alkyl; said when the substituent is When multiple, the substituents are the same or different.

在本发明中，所述的如式I所示的杂环类化合物中某些取代基的定义可如下所述，未提及的取代基的定义均如上任一方案所述。In the present invention, the definitions of certain substituents in the heterocyclic compound shown in formula I can be as follows, and the definitions of unmentioned substituents are as described in any scheme above.

在本发明一优选实施方案中，其中，In a preferred embodiment of the present invention, wherein,

Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom;

Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地为N、O、S、CH 2、CH或C； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently N, O, S, CH 2 , CH or C;

Figure PCTCN2022130676-appb-000003
为苯基、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”，或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烯环”；
Figure PCTCN2022130676-appb-000003
is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", "the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;

R 1和R 2各自独立地为氢、C 1-C 6烷基或C 3-C 8环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;

或者，R 1、R 2与其所连接到的N原子一起形成3-11元杂环烷基；其中，所述3-11元杂环烷基进一步被0个、1个或多个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同； Alternatively, R 1 and R 2 together with the N atom they are connected to form a 3-11 membered heterocycloalkyl group; wherein, the 3-11 membered heterocycloalkyl group is further replaced by 0, 1 or more R 1- 1 ; when there are multiple substituents, the substituents are the same or different;

R 1-1为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷氧羰基、C 1-C 6烷基羰氧基、C 1-C 6烷氧基C 1-C 6烷基、C 1-C 6烷氧羰基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基羰基或C 3-C 8环烷氧基，任选具有1或2个C 1-C 6烷基基团的氨基羰基基团，C 1-C 6烷基磺酰基基团，任选具有1或2个C 1-C 6烷基基团的氨基磺酰基，C 1-C 6烷基磺酰基氨基基团和任选具有1或2个C 1-C 6烷基基团的氨基； R 1-1 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 3 -C 8 cycloalkylcarbonyl or C 3 -C 8 cycloalkoxy, optionally an aminocarbonyl group with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 Alkylsulfonyl groups, optionally aminosulfonyl groups with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 alkylsulfonylamino groups and optionally 1 or 2 C 1 -Amino group of C 6 alkyl group;

R a和R b为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R a and R b are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 - C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkane Oxygen;

m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively;

X 1、X 2、X 3、X 4、X 5和X 6各自独立地为N、O、S、CH 2、CH或C； X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, O, S, CH 2 , CH or C;

R 3和R 6各自独立地为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 3 and R 6 are each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkanes radical, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy;

R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基，所述R 4-1为C 1-C 6烷基或卤代C 1-C 6烷 基；所述当取代基为多个时，所述的取代基相同或不同。 R 4 and R 5 together form a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by 1 or more R 4-1 , or together forms an unsubstituted or substituted by 1 or more 3-8 membered heterocycloalkyl substituted by R 4-1 , said R 4-1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl; when there are multiple substituents, The substituents are the same or different.

在本发明一优选实施方案中，Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； In a preferred embodiment of the present invention, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom;

Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地为N、O、S、CH 2、CH或C； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently N, O, S, CH 2 , CH or C;

Figure PCTCN2022130676-appb-000004
为苯基、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”，或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烯环”；
Figure PCTCN2022130676-appb-000004
is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", "the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;

R 1和R 2各自独立地为氢、C 1-C 6烷基或C 3-C 8环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;

或者，R 1、R 2与其所连接到的N原子一起形成3-11元杂环烷基；其中，所述3-11元杂环烷基进一步被0个、1个或多个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同； Alternatively, R 1 and R 2 together with the N atom they are connected to form a 3-11 membered heterocycloalkyl group; wherein, the 3-11 membered heterocycloalkyl group is further replaced by 0, 1 or more R 1- 1 ; when there are multiple substituents, the substituents are the same or different;

R 1-1为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷氧羰基、C 1-C 6烷基羰氧基、C 1-C 6烷氧基C 1-C 6烷基、C 1-C 6烷氧羰基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基羰基或C 3-C 8环烷氧基，任选具有1或2个C 1-C 6烷基基团的氨基羰基基团，C 1-C 6烷基磺酰基基团，任选具有1或2个C 1-C 6烷基基团的氨基磺酰基，C 1-C 6烷基磺酰基氨基基团和任选具有1或2个C 1-C 6烷基基团的氨基； R 1-1 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 3 -C 8 cycloalkylcarbonyl or C 3 -C 8 cycloalkoxy, optionally an aminocarbonyl group with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 Alkylsulfonyl groups, optionally aminosulfonyl groups with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 alkylsulfonylamino groups and optionally 1 or 2 C 1 -Amino group of C 6 alkyl group;

R a和R b为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R a and R b are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 - C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkane Oxygen;

m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively;

X 1、X 2、X 3、X 4、X 5和X 6各自独立地为N、O、S、CH 2、CH或C； X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, O, S, CH 2 , CH or C;

R 3和R 6各自独立地为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 3 and R 6 are each independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 - C 6 alkoxy;

R 4和R 5不存在，或者与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基，所述R 4-1为C 1-C 6烷基或卤代C 1-C 6烷基；所述当取代基为多个时，所述的取代基相同或不同。 R 4 and R 5 are absent, or together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by 1 or more R 4-1 , or together forms an unsubstituted or substituted by 1 A 3-8-membered heterocycloalkyl group substituted by one or more R 4-1 , said R 4-1 being a C 1 -C 6 alkyl or a halogenated C 1 -C 6 alkyl; said when the substituent is When multiple, the substituents are the same or different.

在本发明一优选实施方案中，In a preferred embodiment of the present invention,

Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom;

Z 1、Z 2和Z 3各自独立地为N或C； Z 1 , Z 2 and Z 3 are each independently N or C;

Figure PCTCN2022130676-appb-000005
为苯基、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6 元杂烷环”、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”，或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烯环”；
Figure PCTCN2022130676-appb-000005
is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are 6-membered heteroalkane rings selected from one or more of N, O, and S", "the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;

R 1和R 2各自独立地为氢、C 1-C 6烷基或C 3-C 8环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;

或者，R 1、R 2与其所连接到的N原子一起形成C 3-C 8环烷基或3-11元杂环烷基；其中，所述C 3-C 8环烷基或3-11元杂环烷基进一步被R 1-1所取代； Alternatively, R 1 and R 2 together with the N atom they are connected to form a C 3 -C 8 cycloalkyl or a 3-11 membered heterocycloalkyl; wherein, the C 3 -C 8 cycloalkyl or 3-11 Member heterocycloalkyl is further substituted by R 1-1 ;

R 1-1为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷氧羰基、C 1-C 6烷氧基C 1-C 6烷基、C 1-C 6烷氧羰基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基羰基或C 3-C 8环烷氧基，任选具有1或2个C 1-C 6烷基基团的氨基羰基基团，C 1-C 6烷基磺酰基基团，任选具有1或2个C 1-C 6烷基基团的氨基磺酰基，C 1-C 6烷基磺酰基氨基基团和任选具有1或2个C 1-C 6烷基基团的氨基； R 1-1 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl Carbonyl or C 3 -C 8 cycloalkoxy, optionally an aminocarbonyl group with 1 or 2 C 1 -C 6 alkyl groups, a C 1 -C 6 alkylsulfonyl group, optionally with 1 or aminosulfonyl with 2 C 1 -C 6 alkyl groups, C 1 -C 6 alkylsulfonylamino groups and amino groups optionally with 1 or 2 C 1 -C 6 alkyl groups;

R a和R b为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R a and R b are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 - C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkane Oxygen;

m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively;

X 1、X 2和X 3各自独立地为N或C； X 1 , X 2 and X 3 are each independently N or C;

R 3和R 6各自独立地为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 3 and R 6 are each independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 - C 6 alkoxy;

R 4和R 5与其所连接到的C原子一起形成未取代或被R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被R 4-1取代的3-8元杂环烷基，所述R 4-1为C 1-C 6烷基或卤代C 1-C 6烷基。 R 4 and R 5 together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by R 4-1 , or together forms a 3-8 membered unsubstituted or substituted by R 4-1 Heterocycloalkyl, the R 4-1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.

在本发明一优选实施方案中，Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； In a preferred embodiment of the present invention, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom;

Z 1为CH或N； Z1 is CH or N;

Z 2为CH； Z 2 is CH;

Z 3为CH； Z 3 is CH;

Z 4为C或N； Z 4 is C or N;

Z 5为CH或CH 2； Z 5 is CH or CH 2 ;

Z 6为CH或CH 2； Z 6 is CH or CH 2 ;

Z 7为N、O或CH； Z7 is N, O or CH;

Figure PCTCN2022130676-appb-000006
为苯基、“杂原子数为1个或2个，杂原子为N的6元杂芳环”，或“杂原子数为1个或2个，杂原子为N和/或O”的6元杂烯环”；
Figure PCTCN2022130676-appb-000006
is phenyl, "6-membered heteroaromatic ring with 1 or 2 heteroatoms and N as heteroatom", or 6-membered heteroaryl ring with 1 or 2 heteroatoms and N and/or O as heteroatom Heteroalkene ring";

R 1、R 2与其所连接到的N原子一起形成3-8元杂环烷基；其中，所述3-8元杂环烷基进一步被0 个、1个或2个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同；所述3-8元杂环烷中的杂原子选自N、O和S中的一种或多种，所述杂原子个数为1个、2个或3个； R 1 , R 2 together with the N atom they are connected to form a 3-8 membered heterocycloalkyl group; wherein, the 3-8 membered heterocycloalkyl group is further replaced by 0, 1 or 2 R 1-1 Substitution; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the 3-8 membered heterocycloalkane are selected from one or more of N, O and S, and the heteroatoms are The number of atoms is 1, 2 or 3;

各个R 1-1独立地为卤素、C 1-C 6烷基或卤代C 1-C 6烷基； Each R 1-1 is independently halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;

R a和R b为C 1-C 6烷基； R a and R b are C 1 -C 6 alkyl;

m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively;

X 1为CH； X1 is CH;

X 2为CH； X2 is CH;

X 3为CH； X3 is CH;

X 4为C； X 4 is C;

X 5为C或N； X 5 is C or N;

X 6为C； X 6 is C;

R 3为C 1-C 6烷基或C 1-C 6氘代烷基； R 3 is C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl;

R 6为氢或卤素； R 6 is hydrogen or halogen;

R 4和R 5与其所连接到的C原子一起形成未取代的C 3-C 6环烷基，或者一起形成未取代的3-8元杂环烷基；所述3-8元杂环烷中的杂原子选自N、O和S中的一种或多种，所述杂原子个数为1个、2个或3个。 R 4 and R 5 together form an unsubstituted C 3 -C 6 cycloalkyl group with the C atom they are connected to, or together form an unsubstituted 3-8 membered heterocycloalkyl group; the 3-8 membered heterocycloalkane The heteroatoms in are selected from one or more of N, O and S, and the number of said heteroatoms is 1, 2 or 3.

在本发明一优选实施方案中，所述溶剂化物可为水合物。In a preferred embodiment of the present invention, the solvate may be a hydrate.

在本发明一优选实施方案中，所述6元杂烯环含有一个双键。In a preferred embodiment of the invention, the 6-membered heteroalkene ring contains one double bond.

在本发明一优选实施方案中，当R 1、R 2与其所连接到的N原子一起形成3-8元杂环烷基，所述3-8元杂环烷基为4元单杂环烷基、5元单杂环烷基、6元单杂环烷基、3元螺6元杂环烷基、5元并5元杂环烷基或3元并5元杂环烷基，所述3-8元杂环烷基具有1个选自N、O、S的杂原子(例如N和/或O)；例如，哌啶、氮杂环丁烷、四氢吡咯、4-氧杂-7-氮杂螺环[2.5]辛烷、吗啉、6-氮杂螺环[2.5]辛烷、3-氮杂双环[3.1.0]己烷或八氢环戊[c]吡咯；还例如

Figure PCTCN2022130676-appb-000007
Figure PCTCN2022130676-appb-000008
In a preferred embodiment of the present invention, when R 1 and R 2 together form a 3-8 membered heterocycloalkyl group with the N atom they are connected to, the 3-8 membered heterocycloalkyl group is a 4-membered monoheterocycloalkane base, 5-membered monoheterocycloalkyl group, 6-membered monoheterocycloalkyl group, 3-membered spiro 6-membered heterocycloalkyl group, 5-membered and 5-membered heterocycloalkyl group or 3-membered and 5-membered heterocycloalkyl group, the 3-8 membered heterocycloalkyl has 1 heteroatom selected from N, O, S (eg N and/or O); for example, piperidine, azetidine, tetrahydropyrrole, 4-oxa- 7-Azaspiro[2.5]octane, morpholine, 6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane or octahydrocyclopenta[c]pyrrole; also For example
Figure PCTCN2022130676-appb-000007
Figure PCTCN2022130676-appb-000008

在本发明一优选实施方案中，各个R 1-1中，所述卤素独立地为氟、氯、溴或碘，例如氟。在本发明一优选实施方案中，各个R 1-1中，所述C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基。 In a preferred embodiment of the present invention, in each R 1-1 , said halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine. In a preferred embodiment of the present invention, in each R 1-1 , the C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl, also eg methyl or ethyl.

在本发明一优选实施方案中，各个R 1-1中，所述卤代C 1-C 6烷基中卤素独立地为氟、氯、溴或碘，例如氟。 In a preferred embodiment of the present invention, in each R 1-1 , the halogen in the halogenated C 1 -C 6 alkyl is independently fluorine, chlorine, bromine or iodine, such as fluorine.

在本发明一优选实施方案中，各个R 1-1中，所述卤代C 1-C 6烷基中C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基。 In a preferred embodiment of the present invention, in each R 1-1 , the C 1 -C 6 alkyl in the halogenated C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also eg methyl or ethyl.

在本发明一优选实施方案中，各个R 1-1中，所述卤代C 1-C 6烷基独立地为卤代C 1-C 4烷基，例如被1个、2个或3个F取代的C 1-C 4烷基，还例如，一氟甲基、二氟甲基或三氟甲基。 In a preferred embodiment of the present invention, in each R 1-1 , the halogenated C 1 -C 6 alkyl is independently a halogenated C 1 -C 4 alkyl, for example, replaced by 1, 2 or 3 F-substituted C 1 -C 4 alkyl, also for example, monofluoromethyl, difluoromethyl or trifluoromethyl.

在本发明一优选实施方案中，各个R a中，所述卤代C 1-C 6烷基中C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基。 In a preferred embodiment of the present invention, in each R a , the C 1 -C 6 alkyl in the halogenated C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also eg methyl or ethyl.

在本发明一优选实施方案中，各个R b中，所述卤代C 1-C 6烷基中C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基。 In a preferred embodiment of the present invention, in each R b , the C 1 -C 6 alkyl in the halogenated C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also eg methyl or ethyl.

在本发明一优选实施方案中，R 3中，所述卤代C 1-C 6烷基为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基。 In a preferred embodiment of the present invention, in R 3 , the halogenated C 1 -C 6 alkyl is C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl radical, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl.

在本发明一优选实施方案中，R 3中，所述C 1-C 6氘代烷基中C 1-C 6烷基为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基。 In a preferred embodiment of the present invention, in R 3 , the C 1 -C 6 alkyl group in the C 1 -C 6 deuterated alkyl group is a C 1-4 alkyl group, such as methyl, ethyl, n-propyl radical, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl.

在本发明一优选实施方案中，R 3中，所述C 1-C 6氘代烷基为C 1-C 4氘代烷基，例如被1个、2个或3个氘取代的C 1-C 4烷基。还例如

Figure PCTCN2022130676-appb-000009
In a preferred embodiment of the present invention, in R 3 , the C 1 -C 6 deuterated alkyl is a C 1 -C 4 deuterated alkyl, such as C 1 substituted by 1, 2 or 3 deuteriums -C 4 alkyl. Also for example
Figure PCTCN2022130676-appb-000009

在本发明一优选实施方案中，R 6中，所述卤素为氟、氯、溴或碘，例如氟。 In a preferred embodiment of the present invention, in R 6 , said halogen is fluorine, chlorine, bromine or iodine, such as fluorine.

在本发明一优选实施方案中，当R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的C 3-C 6环烷基时，所述的C 3-C 6环烷基为丙基、环丁基、环戊基或环己基，例如环丙基或环丁基。 In a preferred embodiment of the present invention, when R 4 and R 5 form a C 3 -C 6 cycloalkyl group unsubstituted or substituted by one or more R 4-1 together with the C atom to which they are attached, the The C 3 -C 6 cycloalkyl is propyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropyl or cyclobutyl.

在本发明一优选实施方案中，当R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基时，所述的3-8元杂环烷基中的杂原子为N、O或S(例如N)。 In a preferred embodiment of the present invention, when R 4 and R 5 together form a 3-8 membered heterocycloalkyl group that is unsubstituted or substituted by 1 or more R 4-1 with the C atom it is connected to, the The heteroatom in the 3-8 membered heterocycloalkyl is N, O or S (such as N).

在本发明一优选实施方案中，当R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基时，所述的3-8元杂环烷基中的杂原子为1个。 In a preferred embodiment of the present invention, when R 4 and R 5 together form a 3-8 membered heterocycloalkyl group that is unsubstituted or substituted by 1 or more R 4-1 with the C atom it is connected to, the The heteroatom in the 3-8 membered heterocycloalkyl group is 1.

在本发明一优选实施方案中，当R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基时，所述的3-8元杂环烷基为3-6元杂环烷基，例如4元杂环烷基，还例如含氧4元杂环烷基。 In a preferred embodiment of the present invention, when R 4 and R 5 together form a 3-8 membered heterocycloalkyl group that is unsubstituted or substituted by 1 or more R 4-1 with the C atom it is connected to, the The 3-8 membered heterocycloalkyl group is a 3-6 membered heterocycloalkyl group, such as a 4-membered heterocycloalkyl group, or an oxygen-containing 4-membered heterocycloalkyl group.

在本发明一优选实施方案中，R 6为氢。 In a preferred embodiment of the invention R6 is hydrogen.

在本发明一优选实施方案中，Z 1为CH或N。 In a preferred embodiment of the invention Z 1 is CH or N.

在本发明一优选实施方案中，Z 2为CH。 In a preferred embodiment of the invention, Z2 is CH.

在本发明一优选实施方案中，Z 3为CH。 In a preferred embodiment of the invention, Z3 is CH.

在本发明一优选实施方案中，Z 4为C或N。 In a preferred embodiment of the invention, Z 4 is C or N.

在本发明一优选实施方案中，Z 5为CH或CH 2。 In a preferred embodiment of the invention, Z 5 is CH or CH 2 .

在本发明一优选实施方案中，Z 6为CH或CH 2。 In a preferred embodiment of the invention, Z 6 is CH or CH 2 .

在本发明一优选实施方案中，Z 7为N、O或CH。 In a preferred embodiment of the invention, Z7 is N, O or CH.

在本发明一优选实施方案中，X 1为CH。 In a preferred embodiment of the invention, X 1 is CH.

在本发明一优选实施方案中，X 2为CH。 In a preferred embodiment of the invention, X2 is CH.

在本发明一优选实施方案中，X 3为CH。 In a preferred embodiment of the invention, X3 is CH.

在本发明一优选实施方案中，X 4为C。 In a preferred embodiment of the invention, X4 is C.

在本发明一优选实施方案中，X 5为C或N。 In a preferred embodiment of the invention, X 5 is C or N.

在本发明一优选实施方案中，X 6为C。 In a preferred embodiment of the invention, X6 is C.

在本发明一优选实施方案中，R 4和R 5与其所连接到的C原子一起形成未取代的C 3-C 6环烷基，或者一起形成未取代的3-6元杂环烷基；所述3-6元杂环烷中的杂原子选自N、O和S中的一种或多种(例如N或O)，所述杂原子个数为1个、2个或3个(例如1个)。 In a preferred embodiment of the present invention, R 4 and R 5 form an unsubstituted C 3 -C 6 cycloalkyl group together with the C atom they are connected to, or together form an unsubstituted 3-6 membered heterocycloalkyl group; The heteroatoms in the 3-6 membered heterocycloalkane are selected from one or more of N, O and S (such as N or O), and the number of heteroatoms is 1, 2 or 3 ( eg 1).

在本发明一优选实施方案中，R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4- 1取代的C 3-C 6环烷基，或者一起形成未取代或被1个或多个R 4-1取代的3-6元杂环烷基；所述3-6元杂环烷基中的杂原子数为1个，杂原子为N、O或S(例如N或O)。 In a preferred embodiment of the present invention, R 4 and R 5 together form a C 3 -C 6 cycloalkyl group unsubstituted or substituted by 1 or more R 4- 1 with the C atom to which they are attached, or together form A 3-6-membered heterocycloalkyl group that is unsubstituted or substituted by 1 or more R 4-1 ; the number of heteroatoms in the 3-6-membered heterocycloalkyl group is 1, and the heteroatom is N, O or S (such as N or O).

在本发明一优选实施方案中，R 3为氢、C 1-C 6烷基或C 1-C 6氘代烷基，例如C 1-C 3烷基或C 1-C 3氘代烷基，还例如甲基或

Figure PCTCN2022130676-appb-000010
In a preferred embodiment of the present invention, R 3 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl, such as C 1 -C 3 alkyl or C 1 -C 3 deuterated alkyl , also for example methyl or
Figure PCTCN2022130676-appb-000010

在本发明一优选实施方案中，R b为氧代(＝O)、C 1-C 6烷基、C 1-C 6氘代烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；例如氧代(＝O)、C 1-C 4烷基、C 1-C 4氘代烷基或卤代C 1-C 4烷基；还例如氧代(＝O)、甲基或乙基。 In a preferred embodiment of the present invention, R b is oxo (=O), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 - C 6 alkoxy or halogenated C 1 -C 6 alkoxy; for example oxo (=O), C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl or halogenated C 1 -C 4 Alkyl; also eg oxo (=O), methyl or ethyl.

在本发明一优选实施方案中，R a为C 1-C 6烷基、C 1-C 6氘代烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；例如C 1-C 4烷基、C 1-C 4氘代烷基或卤代C 1-C 4烷基；还例如甲基或乙基。 In a preferred embodiment of the present invention, R a is C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halo Substituted C 1 -C 6 alkoxy; such as C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl or halogenated C 1 -C 4 alkyl; also such as methyl or ethyl.

在本发明的第二方面，提供了式I’所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药：In the second aspect of the present invention, there are provided heterocyclic compounds shown in formula I', their tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs:

Figure PCTCN2022130676-appb-000011
Figure PCTCN2022130676-appb-000011

其中，Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； Wherein, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom;

Z 1、Z 2和Z 3各自独立地为N或C； Z 1 , Z 2 and Z 3 are each independently N or C;

Figure PCTCN2022130676-appb-000012
为苯基、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”，或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烯环”；
Figure PCTCN2022130676-appb-000012
is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", "the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”;

R 1和R 2各自独立地选自氢、C 1-C 6烷基、C 3-C 8环烷基；或者，R 1、R 2与其所连接到的N原子一起形成3-11元杂环烷基；其中，所述3-11元杂环烷基进一步被R 1-1所取代； R 1 and R 2 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl; or, R 1 and R 2 together form a 3-11 membered hetero Cycloalkyl; wherein, the 3-11 membered heterocycloalkyl is further substituted by R 1-1 ;

R 1-1为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷氧羰基、C 1-C 6烷氧基C 1-C 6烷基、C 1-C 6烷氧羰基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基羰基、C 3-C 8环烷氧基，任选具有1或2个C 1-C 6烷基基团的氨基羰基基团，C 1-C 6烷基磺酰基基团，任选具有1或2个C 1-C 6烷基基团的氨基磺酰基，C 1-C 6烷基磺酰基氨基基团和任选具有1或2个C 1-C 6烷基基团的氨基； R 1-1 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl Carbonyl, C 3 -C 8 cycloalkoxy, optionally an aminocarbonyl group with 1 or 2 C 1 -C 6 alkyl groups, a C 1 -C 6 alkylsulfonyl group, optionally with 1 or aminosulfonyl with 2 C 1 -C 6 alkyl groups, C 1 -C 6 alkylsulfonylamino groups and amino groups optionally with 1 or 2 C 1 -C 6 alkyl groups;

R a和R b为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基； R a and R b are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 - C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkane Oxygen;

m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively;

X 1、X 2和X 3各自独立地为N或C； X 1 , X 2 and X 3 are each independently N or C;

R 3和R 6各自独立地为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基； R 3 and R 6 are each independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkoxy;

R 4和R 5与其所连接到的C原子一起形成未取代或被R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被R 4-1取代的3-8元杂环烷基，所述R 4-1为C 1-C 6烷基或卤代C 1-C 6烷基。 R 4 and R 5 together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by R 4-1 , or together forms a 3-8 membered unsubstituted or substituted by R 4-1 Heterocycloalkyl, the R 4-1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl.

在本发明一优选实施方案中，

Figure PCTCN2022130676-appb-000013
为苯基或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”。 In a preferred embodiment of the present invention,
Figure PCTCN2022130676-appb-000013
is phenyl or "a 6-membered heteroaryl ring with 1, 2 or 3 heteroatoms selected from one or more of N, O and S".

在本发明一优选实施方案中，

Figure PCTCN2022130676-appb-000014
为苯基。 In a preferred embodiment of the present invention,
Figure PCTCN2022130676-appb-000014
For phenyl.

在本发明一优选实施方案中，

Figure PCTCN2022130676-appb-000015
为“杂原子数为1个、2个或3个，杂原子为N的6元杂芳环”。 In a preferred embodiment of the present invention,
Figure PCTCN2022130676-appb-000015
It is "a 6-membered heteroaromatic ring with 1, 2 or 3 heteroatoms, and the heteroatom is N".

在本发明一优选实施方案中，

Figure PCTCN2022130676-appb-000016
为“杂原子数为1个、2个或3个，杂原子为N和O的6 元杂烷环”。 In a preferred embodiment of the present invention,
Figure PCTCN2022130676-appb-000016
It is "a 6-membered heteroalkane ring having 1, 2 or 3 heteroatoms, and the heteroatoms are N and O".

在本发明一优选实施方案中，

Figure PCTCN2022130676-appb-000017
为
Figure PCTCN2022130676-appb-000018
Figure PCTCN2022130676-appb-000019
In a preferred embodiment of the present invention,
Figure PCTCN2022130676-appb-000017
for
Figure PCTCN2022130676-appb-000018
Figure PCTCN2022130676-appb-000019

在本发明一优选实施方案中，

Figure PCTCN2022130676-appb-000020
为
Figure PCTCN2022130676-appb-000021
Figure PCTCN2022130676-appb-000022
In a preferred embodiment of the present invention,
Figure PCTCN2022130676-appb-000020
for
Figure PCTCN2022130676-appb-000021
Figure PCTCN2022130676-appb-000022

在本发明一优选实施方案中，

Figure PCTCN2022130676-appb-000023
为
Figure PCTCN2022130676-appb-000024
较佳地，
Figure PCTCN2022130676-appb-000025
Figure PCTCN2022130676-appb-000026
所在环连接形成
Figure PCTCN2022130676-appb-000027
In a preferred embodiment of the present invention,
Figure PCTCN2022130676-appb-000023
for
Figure PCTCN2022130676-appb-000024
Preferably,
Figure PCTCN2022130676-appb-000025
Figure PCTCN2022130676-appb-000026
Where the ring joins to form
Figure PCTCN2022130676-appb-000027

在本发明一优选实施方案中，

Figure PCTCN2022130676-appb-000028
为
Figure PCTCN2022130676-appb-000029
In a preferred embodiment of the present invention,
Figure PCTCN2022130676-appb-000028
for
Figure PCTCN2022130676-appb-000029

较佳地，

Figure PCTCN2022130676-appb-000030
为
Figure PCTCN2022130676-appb-000031
Preferably,
Figure PCTCN2022130676-appb-000030
for
Figure PCTCN2022130676-appb-000031

在本发明一优选实施方案中，

Figure PCTCN2022130676-appb-000032
为
Figure PCTCN2022130676-appb-000033
Figure PCTCN2022130676-appb-000034
In a preferred embodiment of the present invention,
Figure PCTCN2022130676-appb-000032
for
Figure PCTCN2022130676-appb-000033
Figure PCTCN2022130676-appb-000034

在本发明一优选实施方案中，所述R 1、R 2与其所连接到的N原子一起形成3-8元杂环烷基。较佳地，所述3-8元杂环烷基是单环的、稠和二环的，或者任选包括桥环或螺环的二环的。较佳地，所述3-8元杂环烷基进一步具有1至3个为N、O或S的杂原子。 In a preferred embodiment of the present invention, said R 1 and R 2 together with the N atom to which they are connected form a 3-8 membered heterocycloalkyl group. Preferably, the 3-8 membered heterocycloalkyl is monocyclic, fused bicyclic, or bicyclic optionally including bridged rings or spiro rings. Preferably, the 3-8 membered heterocycloalkyl group further has 1 to 3 heteroatoms that are N, O or S.

在本发明一优选实施方案中，R 1、R 2与其所连接到的N原子一起形成3-8元杂环烷基；其中，所述3-8元杂环烷基进一步被0个、1个或2个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同；所述3-8元杂环烷中的杂原子选自N、O和S中的一种或多种(例如N和/或O)，所述杂原子个数为1个、2个或3个。 In a preferred embodiment of the present invention, R 1 and R 2 form a 3-8 membered heterocycloalkyl group together with the N atom they are connected to; wherein, the 3-8 membered heterocycloalkyl group is further replaced by 0, 1 One or two R 1-1 are substituted; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the 3-8 membered heterocycloalkane are selected from N, O and S One or more (such as N and/or O), the number of heteroatoms is 1, 2 or 3.

在本发明一优选实施方案中，R 1-1为卤素、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基，例如卤素、C 1-C 4烷基或卤代C 1-C 4烷基；还例如F、甲基、乙基、被1个、2个或3个F取代的C 1-C 4烷基，又例如F、一氟甲基、二氟甲基或三氟甲基。 In a preferred embodiment of the present invention, R 1-1 is halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy, for example halogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; also for example F, methyl, ethyl, C 1 -substituted by 1, 2 or 3 F C 4 alkyl, such as F, monofluoromethyl, difluoromethyl or trifluoromethyl.

在本发明一优选实施方案中，R 1、R 2与其所连接到的N原子一起形成如下基团： In a preferred embodiment of the present invention, R 1 , R 2 together with the N atom they are connected to form the following group:

Figure PCTCN2022130676-appb-000035
Figure PCTCN2022130676-appb-000035

在本发明一优选实施方案中，R 1、R 2与其所连接到的N原子一起形成如下基团： In a preferred embodiment of the present invention, R 1 , R 2 together with the N atom they are connected to form the following group:

Figure PCTCN2022130676-appb-000036
Figure PCTCN2022130676-appb-000036

本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，

Figure PCTCN2022130676-appb-000037
用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。在本发明一优选实施方案中，所述的如式I所示的杂环类化合物具有式II-1所示结构： Those skilled in the art can understand that, according to the convention used in this field, in the structural formula of the present application,
Figure PCTCN2022130676-appb-000037
Used to depict a chemical bond, which is the point at which a moiety or substituent is attached to a core or backbone structure. In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I has a structure shown in formula II-1:

Figure PCTCN2022130676-appb-000038
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7的定义如本发明第一方面中所述；R 1、R 2、R 3、R 4、R 5、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。
Figure PCTCN2022130676-appb-000038
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are as defined in the first aspect of the present invention; R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物具有式II-2所示结构：In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I has a structure shown in formula II-2:

Figure PCTCN2022130676-appb-000039
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7的定义如本发明第一方面中所述；R 1、R 2、R 3、R 4、R 5、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。
Figure PCTCN2022130676-appb-000039
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are as defined in the first aspect of the present invention; R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000040
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、 C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000040
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000041
其中，R 7氢、为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000041
Wherein, R 7 hydrogen, is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000042
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000042
Wherein, R is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl,

氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 Oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000043
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000043
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000044
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000044
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000045
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000045
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000046
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000046
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000047
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000047
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000048
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000048
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 Alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000049
其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000049
Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 Alkoxy; R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000050
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000050
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000051
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000051
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000052
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000052
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000053
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000053
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000054
其中R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000054
Wherein R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000055
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000055
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000056
其中R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000056
Wherein R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000057
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第 一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000057
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000058
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000058
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000059
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000059
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000060
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000060
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000061
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000061
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000062
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000062
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000063
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000063
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000064
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000064
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000065
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000065
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000066
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000066
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000067
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000067
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自如下结构：

Figure PCTCN2022130676-appb-000068
其中，R 1、R 2、R 3、R 7、R a、R b、m和n的定义如本发明第 一方面中所述。 In a preferred embodiment of the present invention, the heterocyclic compound shown in formula I is selected from the following structures:
Figure PCTCN2022130676-appb-000068
Wherein, the definitions of R 1 , R 2 , R 3 , R 7 , R a , R b , m and n are as described in the first aspect of the present invention.

在本发明一优选实施方案中，所述的如式I所示的杂环类化合物选自下列任一化合物：In a preferred embodiment of the present invention, the heterocyclic compound represented by formula I is selected from any of the following compounds:

Figure PCTCN2022130676-appb-000069
Figure PCTCN2022130676-appb-000069

Figure PCTCN2022130676-appb-000070
Figure PCTCN2022130676-appb-000070

本发明第三方面，提供了一种如本发明第一方面所述的如式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药的制备方法，所述方法包括步骤：In the third aspect of the present invention, there is provided a heterocyclic compound represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, solvates, and pharmaceutically acceptable salts Or the preparation method of prodrug, described method comprises the steps:

(1a)中间体A-1-1与格氏试剂接触并反应，得到中间体A-1，(1a) Intermediate A-1-1 contacts and reacts with Grignard reagent to obtain Intermediate A-1,

Figure PCTCN2022130676-appb-000071
Figure PCTCN2022130676-appb-000071

(1b)中间体A-1与中间体B-1接触并反应，得到式I所示化合物，(1b) Intermediate A-1 contacts and reacts with Intermediate B-1 to obtain the compound shown in formula I,

Figure PCTCN2022130676-appb-000072
Figure PCTCN2022130676-appb-000072

其中，Y 1为卤素；Y 3为卤素或硼酸基；R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、Z 5、Z 6、Z 7、R a、R b、m和n的定义如本发明第一方面中所述。 Among them, Y 1 is halogen; Y 3 is halogen or boronic acid group; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n are as defined in the first aspect of the present invention.

本发明第四方面，提供了另一种如本发明第一方面所述的如式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药的制备方法，所述方法包括步骤：The fourth aspect of the present invention provides another heterocyclic compound as shown in formula I, its tautomers, stereoisomers, solvates, pharmaceutically acceptable A method for the preparation of a salt or a prodrug, said method comprising the steps of:

(2a)中间体A-2-1与格氏试剂接触并反应，得到中间体A-2；(2a) Intermediate A-2-1 is contacted and reacted with a Grignard reagent to obtain Intermediate A-2;

Figure PCTCN2022130676-appb-000073
Figure PCTCN2022130676-appb-000073

(2b)中间体A-2与中间体B-1接触，得到式I所示化合物，(2b) intermediate A-2 is contacted with intermediate B-1 to obtain the compound shown in formula I,

Figure PCTCN2022130676-appb-000074
Figure PCTCN2022130676-appb-000074

其中，Y 1为卤素；Y 2为氢或三甲基亚砜；Y 3为卤素或硼酸基；R 4、R 5与其所连接到的C原子一起形成环丁烷基或氧杂环丁烷基；R 1、R 2、R 3、R 6、X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、Z 5、Z 6、Z 7、R a、R b、m和n的定义如本发明第一方面中所述。 Among them, Y 1 is a halogen; Y 2 is hydrogen or trimethylsulfoxide; Y 3 is a halogen or boronic acid group; R 4 and R 5 form a cyclobutane or oxetane together with the C atom they are connected to group; R 1 , R 2 , R 3 , R 6 , X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n are as defined in the first aspect of the invention.

本发明第五方面，提供了如式A-1、式A-2-1、式A-2、式B-1所示的中间体，所述式A-1、式A-2-1、式A-2、式B-1所示的中间体用于制备如本发明第一方面所述式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药。In the fifth aspect, the present invention provides intermediates as shown in formula A-1, formula A-2-1, formula A-2, formula B-1, said formula A-1, formula A-2-1, The intermediates shown in formula A-2 and formula B-1 are used to prepare heterocyclic compounds shown in formula I as described in the first aspect of the present invention, their tautomers, stereoisomers, solvates, pharmaceutical acceptable salts or prodrugs.

在本发明一优选实施方案中，式A-1所示中间体具有结构：In a preferred embodiment of the present invention, the intermediate shown in formula A-1 has the structure:

Figure PCTCN2022130676-appb-000075
其中，Y 1为卤素；R 3、R 4、R 5、R 6、X 1、X 2和X 3的定义如本发明第一方面中所述。
Figure PCTCN2022130676-appb-000075
Wherein, Y 1 is halogen; R 3 , R 4 , R 5 , R 6 , X 1 , X 2 and X 3 are as defined in the first aspect of the present invention.

在本发明一优选实施方案中，式A-2-1所示中间体具有结构：In a preferred embodiment of the present invention, the intermediate shown in formula A-2-1 has the structure:

Figure PCTCN2022130676-appb-000076
其中，Y 1为卤素；Y 2为氢或三甲基亚砜；R 4、R 5与其所连接到的C原子一起形成环丁烷基或氧杂环丁烷基；R 6、X 1、X 2和X 3的定义的定义如本发明第一方面中所述。
Figure PCTCN2022130676-appb-000076
Among them, Y 1 is halogen; Y 2 is hydrogen or trimethylsulfoxide; R 4 and R 5 form cyclobutanyl or oxetanyl together with the C atom they are connected to; R 6 , X 1 , The definitions of X2 and X3 are as defined in the first aspect of the invention.

在本发明一优选实施方案中，式A-2所示中间体具有结构：In a preferred embodiment of the present invention, the intermediate shown in formula A-2 has the structure:

Figure PCTCN2022130676-appb-000077
其中，Y 1为卤素；R 4、R 5与其所连接到的C原子一起形成环丁烷基或氧杂环丁烷基；R 6、X 1、X 2和X 3的定义如本发明第一方面中所述。
Figure PCTCN2022130676-appb-000077
Wherein, Y 1 is a halogen; R 4 and R 5 form a cyclobutanyl group or an oxetanyl group together with the C atom they are connected to; R 6 , X 1 , X 2 and X 3 are as defined in Clause 1 of the present invention on the one hand.

在本发明一优选实施方案中，式B-1所示中间体具有结构：In a preferred embodiment of the present invention, the intermediate shown in formula B-1 has the structure:

Figure PCTCN2022130676-appb-000078
其中，Y 3为卤素或硼酸基；R 1、R 2、Z 1、Z 2、Z 3、Z 4、Z 5、Z 6、Z 7、R a、R b、m和n的定义如本发明第一方面中所述。
Figure PCTCN2022130676-appb-000078
Among them, Y 3 is halogen or boronic acid group; R 1 , R 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n are as defined in this paper described in the first aspect of the invention.

在本发明一优选实施方案中，所述的式A-1所示中间体选自下列任一化合物：In a preferred embodiment of the present invention, the intermediate represented by the formula A-1 is selected from any of the following compounds:

Figure PCTCN2022130676-appb-000079
Figure PCTCN2022130676-appb-000079

在本发明一优选实施方案中，所述中间体选自下列化合物：In a preferred embodiment of the present invention, the intermediate is selected from the following compounds:

Figure PCTCN2022130676-appb-000080
Figure PCTCN2022130676-appb-000080

在本发明一优选实施方案中，所述的式A-2-1所示中间体选自下列任一化合物：In a preferred embodiment of the present invention, the intermediate represented by the formula A-2-1 is selected from any of the following compounds:

Figure PCTCN2022130676-appb-000081
Figure PCTCN2022130676-appb-000081

在本发明一优选实施方案中，所述的式A-2所示中间体选自下列任一化合物：In a preferred embodiment of the present invention, the intermediate represented by the formula A-2 is selected from any of the following compounds:

Figure PCTCN2022130676-appb-000082
Figure PCTCN2022130676-appb-000082

在本发明一优选实施方案中，所述的式B-1所示中间体选自下列任一化合物：In a preferred embodiment of the present invention, the intermediate represented by the formula B-1 is selected from any of the following compounds:

Figure PCTCN2022130676-appb-000083
Figure PCTCN2022130676-appb-000083

Figure PCTCN2022130676-appb-000084
Figure PCTCN2022130676-appb-000084

在本发明一优选实施方案中，所述中间体选自下列化合物：In a preferred embodiment of the present invention, the intermediate is selected from the following compounds:

Figure PCTCN2022130676-appb-000085
Figure PCTCN2022130676-appb-000085

在本发明一优选实施方案中，所述中间体选自下列化合物：In a preferred embodiment of the present invention, the intermediate is selected from the following compounds:

Figure PCTCN2022130676-appb-000086
Figure PCTCN2022130676-appb-000086

本发明第六方面，提供一种药物组合物，所述的药物组合物包括：如本发明第一方面中所述的式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药；和药学上可接受的载体。The sixth aspect of the present invention provides a pharmaceutical composition, which includes: the heterocyclic compound represented by formula I as described in the first aspect of the present invention, its tautomers, stereoisomers body, solvate, pharmaceutically acceptable salt or prodrug; and a pharmaceutically acceptable carrier.

本发明第七方面，提供了如本发明第一方面中所述的式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药的用途，或本发明第五方面所述的药物组合物的用途，所述用途包括：抑制15-PGDH；和/或，预防和/或治疗15-PGDH相关的疾病；和/或，制备用于抑制15-PGDH，和/或预防和/或治疗15-PGDH相关的疾病的药物、药物组合物或制剂。The seventh aspect of the present invention provides the heterocyclic compound represented by the formula I as described in the first aspect of the present invention, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or precursors The use of medicine, or the use of the pharmaceutical composition described in the fifth aspect of the present invention, said use includes: inhibiting 15-PGDH; and/or, preventing and/or treating 15-PGDH-related diseases; and/or, preparing Drugs, pharmaceutical compositions or preparations for inhibiting 15-PGDH, and/or preventing and/or treating 15-PGDH-related diseases.

较佳的，所述15-PGDH相关的疾病包括但不限于：纤维化、炎性疾病、心血管疾病、创伤、自身免疫性疾病、移植物抗宿主疾病、毛发生长、骨质疏松症、耳病、眼病、中性白细胞减少、糖尿病、膀胱活动低下症，或者，在干细胞或骨髓移植或器官移植中的植入物中促进，神经发生和神经细胞死亡、血细胞重建、组织再生和宫颈成熟中的一种、两种或更多种。Preferably, the 15-PGDH-related diseases include but are not limited to: fibrosis, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host disease, hair growth, osteoporosis, ear disease, eye disease, neutropenia, diabetes, underactive bladder, or, in the promotion of stem cell or implants in bone marrow transplantation or organ transplantation, neurogenesis and nerve cell death, blood cell reconstitution, tissue regeneration, and cervical ripening one, two or more.

较佳地，所述15-PGDH相关的疾病包括但不限于：纤维化(如肺纤维化，包括特发性肺纤维化等，肝纤维化，肾纤维化，心肌纤维化，硬皮病和骨髓纤维化)，炎性疾病[如慢性阻塞性肺病(COPD)，急性肺损伤，脓毒症，哮喘和肺病的恶化，炎症性肠病(如溃疡性结肠炎和克罗恩氏病)，消化性溃疡(如NSAID诱导的溃疡)，自身炎性疾病(如贝切特氏病)，血管炎综合征，急性肝损伤，急性肾损伤，非酒精性脂肪肝(NASH)，特应性皮炎，牛皮癣，间质性膀胱炎，前列腺炎综合征(如慢性前列腺炎/慢性骨盆疼痛综合征)]，心血管疾病(如肺动脉高压，心绞痛，心肌梗死，心力衰竭，缺血性心脏病，慢性肾病，肾衰竭，脑卒中和周围循环紊乱)，创伤(如糖尿病性溃疡，烧伤，压迫性溃疡，急性粘膜损伤，包括斯-约二氏综合征，粘膜损伤(如粘膜炎或口腔炎)与抗癌化疗剂有关的，主要地如烷化剂，DNA合成抑制剂，DNA回旋酶抑制剂或抗代谢物，细胞或体液免疫疗法或放射线，或移植物抗宿主疾病)，自身免疫性疾病(如多发性硬化或类风湿性关节炎)，移植物抗宿主疾病(GVHD)，毛发生长，骨质疏松症，耳病(如听力损失，耳鸣，眩晕和平衡失调)，眼病(如青光眼和干眼)，中性白细胞减少，糖尿病，膀胱活动低下症，在干细胞或骨髓移植或器官移植中的植入物促进，神经发生和神经细胞死亡(如精神神经疾病，神经病，神经毒性疾病，神经性疼痛和神经变性疾病)，肝脏再生，肌肉再生(如肌肉萎缩，肌营养不良和肌肉损伤)，和宫颈成熟中的一种、两种或更多种。Preferably, the 15-PGDH-related diseases include but are not limited to: fibrosis (such as pulmonary fibrosis, including idiopathic pulmonary fibrosis, etc., liver fibrosis, renal fibrosis, myocardial fibrosis, scleroderma and myelofibrosis), inflammatory diseases [such as chronic obstructive pulmonary disease (COPD), acute lung injury, sepsis, exacerbation of asthma and lung disease, inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), Peptic ulcer (eg, NSAID-induced ulcer), autoinflammatory disease (eg, Behcet's disease), vasculitic syndrome, acute liver injury, acute kidney injury, nonalcoholic fatty liver disease (NASH), atopic dermatitis , psoriasis, interstitial cystitis, prostatitis syndrome (eg, chronic prostatitis/chronic pelvic pain syndrome)], cardiovascular disease (eg, pulmonary hypertension, angina, myocardial infarction, heart failure, ischemic heart disease, chronic renal disease, renal failure, stroke and peripheral circulatory disorders), trauma (such as diabetic ulcers, burns, pressure ulcers, acute mucosal injury, including Stevens-Johnson syndrome, mucosal injury (such as mucositis or stomatitis) and Related to anticancer chemotherapeutic agents, mainly such as alkylating agents, DNA synthesis inhibitors, DNA gyrase inhibitors or antimetabolites, cellular or humoral immunotherapy or radiation, or graft-versus-host disease), autoimmune diseases ( such as multiple sclerosis or rheumatoid arthritis), graft-versus-host disease (GVHD), hair growth, osteoporosis, ear disorders (such as hearing loss, tinnitus, vertigo, and balance disorders), eye disorders (such as glaucoma and dryness eye), neutropenia, diabetes mellitus, hypoactive bladder, implant promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and nerve cell death (eg, psychoneurological disease, neuropathy, neurotoxic disease, neuropathic Pain and neurodegenerative diseases), liver regeneration, muscle regeneration (such as muscle atrophy, muscular dystrophy, and muscle damage), and one, two, or more of cervical ripening.

较佳地，所述15-PGDH相关的疾病包括但不限于：特发性肺纤维化(IPF)。Preferably, the 15-PGDH-related diseases include but not limited to: idiopathic pulmonary fibrosis (IPF).

较佳地，所述15-PGDH相关的疾病包括但不限于：肝脏再生。Preferably, the 15-PGDH-related diseases include but not limited to: liver regeneration.

在本发明第八方面，提供一种抑制15-PGDH，或预防和/或治疗15-PGDH相关的疾病的方法，包括步骤：给需要的对象施用本发明第一方面所述的式I所示杂环类、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药。In the eighth aspect of the present invention, there is provided a method for inhibiting 15-PGDH, or preventing and/or treating 15-PGDH-related diseases, comprising the steps of: administering the formula I described in the first aspect of the present invention to a subject in need Heterocycles, tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs thereof.

在本发明第九方面，提供一种如前所述的式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，所述的用途为用于制备预防和/或治疗疾病的药物；所述的疾病为纤维化疾病和/或炎性疾病。In the ninth aspect of the present invention, there is provided a heterocyclic compound represented by formula I as described above, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, so Said application is for the preparation of medicines for preventing and/or treating diseases; said diseases are fibrotic diseases and/or inflammatory diseases.

在本发明第九方面，提供一种预防和/或治疗疾病的药物的方法，其包括向患者实施有效量如前所述的式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，所述的疾病为纤维化疾病和/或炎性疾病。In the ninth aspect of the present invention, there is provided a method for preventing and/or treating diseases, which includes administering to patients an effective amount of the aforementioned heterocyclic compound represented by formula I, its tautomer, stereo Isomers, solvates, pharmaceutically acceptable salts or prodrugs, the disease is a fibrotic disease and/or an inflammatory disease.

所述的纤维化疾病和所述的炎性疾病均可同前所述。Both the fibrotic disease and the inflammatory disease can be the same as above.

本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

术语和定义Terms and Definitions

除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。Unless otherwise stated, the definitions of groups and terms recorded in the specification and claims of this application include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations and combined group definitions and compound structures should fall within the scope of the description of the present application.

除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited in their entirety herein are hereby incorporated by reference in their entirety unless otherwise indicated. If there is more than one definition of a term herein, the definition in this chapter shall prevail.

应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that, unless the context clearly dictates otherwise, as used in the specification and claims, the singular includes the plural of the referents. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "comprises" as well as other forms, such as "comprises", "comprises" and "comprises" is not limiting.

可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构 部分和化合物。Definitions of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectroscopy, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are set forth, terms employed herein in the relevant descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those that are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.

当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH 2O等同于OCH 2。如本文所用，

Figure PCTCN2022130676-appb-000087
表示基团的连接位点。如本文所用，“R 1”、“R1”和“R 1”的含义相同，可相互替换。对于R 2等其它其他符号，类似定义的含义相同。 When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2 . As used herein,
Figure PCTCN2022130676-appb-000087
Indicates the attachment site of the group. As used herein, "R 1 ", "R1" and "R 1 " have the same meaning and can be substituted for each other. For other symbols such as R 2 , similar definitions have the same meanings.

本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。The section headings used herein are for the purpose of organizing the article only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.

除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings shown below unless otherwise specified.

本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“1～6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。当该数值范围被理解为“数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如，“1～10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。For the numerical ranges described in the specification and claims of this application, when the numerical range is understood as an "integer", it should be understood as describing the two endpoints of the range and each integer within the range. For example, "an integer of 1 to 6" should be understood as describing every integer of 0, 1, 2, 3, 4, 5, and 6. When this numerical range is understood to be a "number," it should be understood to recite both endpoints of the range as well as each integer within the range and each decimal within the range. For example, "a number from 1 to 10" should be understood as not only recording each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers with Sum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘；优选氟或氯。In the present application, the term "halogen", alone or as part of another substituent, means fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.

在单独或作为其他取代基一部分时，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、异戊基、新戊基和己基。烷基可以是未取代的或被一个或多个合适的取代基取代。如本文所用，术语“烯基”表示无支链或支链的单价烃链，其含有一个或多个碳-碳双键。如本文所用，术语“炔基”是指无支链或支链的一价烃链，其含有一个或多个碳-碳三键。By itself or as part of another substituent, the term "alkyl" means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and attached to the rest of the molecule by a single bond straight-chain or branched hydrocarbon chain groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl. An alkyl group can be unsubstituted or substituted with one or more suitable substituents. As used herein, the term "alkenyl" means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, the term "alkynyl" refers to an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon triple bonds.

在单独或作为其他取代基一部分时，术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。 The term "C 1 -C 6 alkyl" alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, said groups have 1, 2 or 3 carbon atoms (“C 1 -C 3 alkyl”), for example methyl, ethyl, n-propyl or isopropyl.

在单独或作为其他取代基一部分时，术语“环烷基”是指一种环状烷基。术语“m-n元环烷基”或者“C m-C n环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如，“3-15元 环烷基”或者“C 3-C 15环烷基”是指含有3至15，3至9，3至6或3至5个碳原子的环状烷基，它可能包含1至4个环。“3-10元环烷基”则含有3-10个碳原子。包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基和金刚烷基，或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。术语“环烷基”可以和术语“碳环基”交换使用。 The term "cycloalkyl" by itself or as part of another substituent means a cyclic alkyl group. The term "mn-membered cycloalkyl" or " Cm - Cncycloalkyl " is understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms. For example, "3-15 membered cycloalkyl" or "C 3 -C 15 cycloalkyl" refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which May contain 1 to 4 rings. "3-10 membered cycloalkyl" contains 3-10 carbon atoms. Including monocyclic, bicyclic, tricyclic, spiro or bridged rings. Examples of unsubstituted cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as a decahydronaphthalene ring. Cycloalkyl groups may be substituted with one or more substituents. The term "cycloalkyl" is used interchangeably with the term "carbocyclyl".

在单独或作为其他取代基一部分时，术语“杂环烷基”是指其中一个或多个(在一些实施方案中为1至3个)碳原子被杂原子取代的环烷基，所述杂原子例如但不限于N、O、S和P。术语“m-n元杂环烷基”或者“C m-C n杂环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的环，其中杂环原子选自N、O、S、P，优选地选自N、O或S。例如，术语“4-8元杂环烷基”或者“C 4-C 8杂环烷基”应理解为表示具有4至8个原子的饱和、不饱和或部分饱和的环，其中1、2、3、或4个环原子选自N、O、S、P，优选地选自N、O或S。“4-10元杂环基”则是表示具有4至10个原子的饱和、不饱和或部分饱和的环。在一些实施方案中，杂环烷基可以是与芳环基或杂芳环基稠合的杂环烷基。当诸如4-8元或4-10元的前缀用于表示杂环烷基时，碳的数目也意味着包括杂原子。包括单环、二环、三环、螺环或桥环。杂环烷基的示例为：吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢吡啶基、四氢吡咯基、氮杂环丁烷基、噻唑烷基、唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、氮杂环庚烷基、二氮杂环庚烷基、氧氮杂环庚烷基等。术语“杂环烷基”可以和术语“杂烷环”交换使用。 The term "heterocycloalkyl", by itself or as part of another substituent, refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by a heteroatom, which Atoms are such as, but not limited to, N, O, S, and P. The term "mn membered heterocycloalkyl" or "C m -C n heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having m to n atoms, wherein the hetero ring atoms are selected from N, O, S, P are preferably selected from N, O or S. For example, the term "4-8 membered heterocycloalkyl" or "C 4 -C 8 heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated ring having 4 to 8 atoms, wherein 1, 2 , 3, or 4 ring atoms are selected from N, O, S, P, preferably selected from N, O or S. "4-10 membered heterocyclic group" means a saturated, unsaturated or partially saturated ring having 4 to 10 atoms. In some embodiments, a heterocycloalkyl group can be a heterocycloalkyl group fused to an aryl ring group or a heteroaryl ring group. When a prefix such as 4-8 membered or 4-10 membered is used to indicate heterocycloalkyl, the number of carbons is also meant to include heteroatoms. Including monocyclic, bicyclic, tricyclic, spiro or bridged rings. Examples of heterocycloalkyl groups are: pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl , piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc. The term "heterocycloalkyl" is used interchangeably with the term "heteroalkane".

在单独或作为其他取代基一部分时，术语“烯基”是指指具有至少一个碳-碳sp2双键的二到四十个碳原子的直链或支链的一价烃基(例如C 2-C 6烯基，又例如C 2-C 4烯基)，并且包括具有“顺式”和“反式”取向或者“E”和“Z”取向的基团。烯基的实例包括但不限于乙烯基和烯丙基。 The term "alkenyl" by itself or as part of another substituent refers to a straight or branched chain monovalent hydrocarbon group of two to forty carbon atoms having at least one carbon-carbon sp2 double bond (for example C2- C 6 alkenyl, another example is C 2 -C 4 alkenyl), and includes groups with "cis" and "trans" orientations or "E" and "Z" orientations. Examples of alkenyl groups include, but are not limited to, vinyl and allyl.

在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳sp三键的二到四十个碳原子的直链或支链的单价烃基(例如C 2-C 6炔基，又例如C 2-C 4炔基)。炔基的实例包括但不限于乙炔基和丙炔基。 The term "alkynyl" by itself or as part of another substituent refers to a straight or branched chain monovalent hydrocarbon radical (e.g. C2 - C6 ) of two to forty carbon atoms having at least one carbon-carbon sp triple bond. Alkynyl, another example is C 2 -C 4 alkynyl). Examples of alkynyl include, but are not limited to, ethynyl and propynyl.

在单独或作为其他取代基一部分时，术语“烷氧基”是指基团-O-R X，其中，R X为如上文所定义的“烷基”。 The term "alkoxy", by itself or as part of another substituent, refers to the group -ORx , wherein Rx is "alkyl" as defined above.

在单独或作为其他取代基一部分时，术语“氧代”是指亚甲基上的两个氢被氧取代，也即亚甲基被羰基替代。The term "oxo", by itself or as part of another substituent, means that two hydrogens on a methylene group are replaced by oxygen, ie a methylene group is replaced by a carbonyl group.

在单独或作为其他取代基一部分时，术语“芳基”是指具有6到20个碳原子的单环或多环碳环，其中至少一个环是芳香环。当其中一个环是非芳香环时，该基团可通过芳香环连接，也可通过非芳香环连接。芳基的实例包括但不限于：苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基和苊基。The term "aryl" by itself or as part of another substituent means a monocyclic or polycyclic carbocyclic ring having from 6 to 20 carbon atoms, at least one of which is aromatic. When one of the rings is a non-aromatic ring, the group can be attached through an aromatic ring or through a non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthyl.

在单独或作为其他取代基一部分时，术语“杂芳环”是指单环或多环碳环，其中至少一个环原子为独立地选自氧、硫和氮的杂原子，其余的环原子为C，其中至少一个环是芳香环。该基团可为碳基团或杂原子基团(也即其可为C-连接的或N-连接的，只要其是可能的即可)。当其中一个环是非芳香环时，该基团可通过芳香环连接，也可通过非芳香环连接。杂芳基的实例包括但不限于：咪唑 基、吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、N-甲基吡咯基和四氢喹啉。术语“杂芳环”可以和术语“杂芳香环”、“杂芳基”或“杂芳环基”交换使用。By itself or as part of another substituent, the term "heteroaromatic ring" means a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is aromatic. The group may be a carbon group or a heteroatom group (ie it may be C-attached or N-attached, wherever this is possible). When one of the rings is a non-aromatic ring, the group can be attached through an aromatic ring or through a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, Benzothienyl, benzofuryl, quinolinyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N - methylpyrrolyl and tetrahydroquinoline. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic", "heteroaryl" or "heteroaryl".

在单独或作为其他取代基一部分时，术语“杂烯环”是指具有杂原子的单环基团(该单环基团具有双键、但不具有芳香性)，优选含有1个、2个或3个独立选自N、O和S的环杂原子的单环。杂环烯基的示例为：二氢呋喃基、二氢噻吩基、二氢吡咯基、二氧杂环戊烯基、二氢咪唑基、二氢吡唑基、二氢噻唑基、二氢异噻唑基、二氢噁二唑基、二氢噻二唑基、二氢三唑基、二氢四唑基、四氢吡啶基、3,4-二氢-2H-吡喃、吡喃基、噻喃基、二氢吡啶基、二氢吡嗪基、二氢嘧啶基、噁嗪基、二氢四唑基等。术语“杂烯环”可以和术语“杂环烯基”交换使用。By itself or as part of other substituents, the term "heteroalkene ring" refers to a monocyclic group with heteroatoms (the monocyclic group has a double bond, but is not aromatic), preferably containing 1, 2 or a monocyclic ring of 3 ring heteroatoms independently selected from N, O and S. Examples of heterocycloalkenyl groups are: dihydrofuryl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroiso Thiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridyl, 3,4-dihydro-2H-pyran, pyranyl, Thipyryl, dihydropyridyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl, dihydrotetrazolyl and the like. The term "heteroalkenyl" may be used interchangeably with the term "heterocycloalkenyl".

在单独或作为其他取代基一部分时，术语“螺环”指单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。螺环烷基的非限制性实例包括：By itself or as part of other substituents, the term "spiro" refers to a polycyclic group in which the single rings share one carbon atom (called the spiro atom), which may contain one or more double bonds, but none of the rings has A fully conjugated π-electron system. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

Figure PCTCN2022130676-appb-000088
Figure PCTCN2022130676-appb-000088

也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：Also included are spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, non-limiting examples include:

Figure PCTCN2022130676-appb-000089
Figure PCTCN2022130676-appb-000089

术语“桥环”是指化合物中的任意两个环共用两不直接相连的碳原子的环烃,根据组成环的数目分为二环烃、三环烃、四环烃等。非限制性实例包括：The term "bridged ring" refers to a cyclic hydrocarbon in which any two rings in a compound share two carbon atoms that are not directly connected, and can be divided into bicyclic hydrocarbons, tricyclic hydrocarbons, tetracyclic hydrocarbons, etc. Non-limiting examples include:

Figure PCTCN2022130676-appb-000090
Figure PCTCN2022130676-appb-000090

在单独或作为其他取代基一部分时，“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。By itself or as part of another substituent, "haloalkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens (such as -CvFw, where v=1 to 3, w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

本文提供的化合物，包括可用于制备本文提供的化合物的中间体，其含有反应性官能团(例如但不限于羧基，羟基和氨基部分)，还包括其保护的衍生物。“受保护的衍生物”是其中一个或多个反应性位点被一个或多个保护基团(也称为保护基团)封闭的那些化合物。合适的羧基部分保护基包括苄基，叔丁基等，以及同位素等。合适的氨基和酰氨基保护基包括乙酰基，三氟乙酰基，叔丁氧基羰基，苄氧 基羰基等。合适的羟基保护基包括苄基等。其他合适的保护基团是本领域普通技术人员所熟知的。The compounds provided herein, including intermediates useful in the preparation of the compounds provided herein, contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof. "Protected derivatives" are those compounds in which one or more reactive sites are blocked by one or more protecting groups (also known as protecting groups). Suitable protecting groups for the carboxyl moiety include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable hydroxy protecting groups include benzyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art.

在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or circumstance. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl.

在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。In this application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. "Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.

术语“胺盐”是指用酸中和烷基伯胺、仲胺或叔胺得到的产物。所述酸包括本申请中所述的无机酸或有机酸。The term "amine salt" refers to the product obtained by neutralizing an alkyl primary, secondary or tertiary amine with an acid. The acid includes an inorganic acid or an organic acid as described in this application.

术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。The term "stereoisomer" refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.

依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。Depending on the choice of starting materials and processes, the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。When the bond with the chiral carbon in the formula of the present invention is described as a straight line, it should be understood that the (R) and (S) two configurations of the chiral carbon and the resulting enantiomerically pure compounds and Mixtures of both are included within the scope of the general formula. Graphical representations of racemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of a stereocenter is indicated by wedge-shaped bonds and dashed-line bonds.

术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。The term "solvate" means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.

术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound. Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.

在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In this application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.

术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of categories of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.

术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。The term "treatment" refers to therapeutic therapy. In relation to a specific condition, treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.

术语“预防”是指获得或发生疾病或障碍的风险降低。The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为优。The term "patient" refers to any animal, preferably a mammal, that is about to or has received the administration of the compound or composition according to the embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.

术语“治疗有效量”是指在给予患者时，足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，可由本领域技术人员根据需要进行调整。The term "therapeutically effective amount" refers to an amount of a compound which, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the disorder and its severity, and the age of the patient to be treated, and can be adjusted as necessary by those skilled in the art.

术语“炎症性肠病”是指IBD，用于描述涉及消化道慢性炎症的疾病。主要类型包括：溃疡性结肠炎和克罗恩氏病。溃疡性结肠炎。会在大肠(结肠)和直肠浅表层覆膜引起炎症和溃疡。而克罗恩氏病的特征是消化道内膜发炎，炎症通常会累及消化道的深层。The term "inflammatory bowel disease" refers to IBD and is used to describe diseases involving chronic inflammation of the digestive tract. The main types include: ulcerative colitis and Crohn's disease. Ulcerative colitis. Causes inflammation and ulcers in the superficial lining of the large intestine (colon) and rectum. Crohn's disease, on the other hand, is characterized by inflammation of the lining of the digestive tract, often involving the deeper layers of the digestive tract.

各步骤的反应，反应温度可因溶剂、起始原料、试剂等适宜选择，反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后，目标化合物可按常用方法自反应体系中进行分离、提纯等步骤，如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下，目标化合物也可不经过分离、纯化直接进入下一步反应。In the reaction of each step, the reaction temperature can be appropriately selected according to the solvent, starting material, reagent, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc. After the reaction of each step, the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification.

在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

有益效果Beneficial effect

本发明人经过广泛而深入地研究，意外地开发了一种杂环类化合物或其药学上可接受的盐及制备方法和用途。After extensive and in-depth research, the inventor unexpectedly developed a heterocyclic compound or a pharmaceutically acceptable salt thereof, a preparation method and use thereof.

本发明提供了式I所示杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，所述式I化合物对15-PGDH具有显著的抑制作用。可以显著增加PGE2的生成。并且对IPF和肝脏再生效果显著。结合小鼠的药代动力学数据，可知本发明化合物分别在小鼠体内表现出优良的药代动力学性质，具备较高的安全性和成药性质。The present invention provides heterocyclic compounds shown in formula I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, the compound of formula I is effective for 15-PGDH has a significant inhibitory effect. Can significantly increase the production of PGE2. And it has a significant effect on IPF and liver regeneration. Combined with the pharmacokinetic data of mice, it can be known that the compounds of the present invention respectively exhibit excellent pharmacokinetic properties in mice, and have relatively high safety and drug-making properties.

本发明提供了制备I所示杂环类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药的方法及中间体，所述方法操作简单、收率高、纯度高，可用于医药工业化生产。The present invention provides methods and intermediates for preparing heterocyclic compounds shown in I, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, and the operation of the method The method is simple, high in yield and high in purity, and can be used in the industrialized production of medicines.

具体实施方式Detailed ways

需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中的。It should be understood that the following description is only the most preferred embodiment of the present invention, and should not be considered as limiting the protection scope of the present invention. On the basis of fully understanding the present invention, the experimental methods that do not indicate specific conditions in the following examples usually follow conventional conditions, or according to the conditions suggested by the manufacturer, those skilled in the art can make unessential changes to the technical solution of the present invention Changes, such changes should be considered included in the protection scope of the present invention.

本申请具有如下定义：This application has the following definitions:

符号或单位：Symbol or unit:

IC 50：半数抑制浓度，指达到最大抑制效果一半时的浓度 IC 50 : half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

M：mol/L，例如正丁基锂(14.56mL，29.1mmol，2.5M的正己烷溶液)表示摩尔浓度为2.5mol/L的正丁基锂的正己烷溶液M: mol/L, such as n-butyllithium (14.56mL, 29.1mmol, 2.5M n-hexane solution) means n-hexane solution of n-butyllithium with a molar concentration of 2.5mol/L

N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液N: Equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution

试剂：Reagent:

NBS：N-溴代丁二酰亚胺NBS: N-Bromosuccinimide

DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide

中间体A1:6'-溴-2'-甲基螺[环丙并-1,1'-异二氢吲哚]-3'-酮的制备Intermediate A1: Preparation of 6'-bromo-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one

中间体A1的合成路线如下：The synthetic route of intermediate A1 is as follows:

Figure PCTCN2022130676-appb-000091
Figure PCTCN2022130676-appb-000091

第一步：6'-溴螺[环丙并-1,1'-异二氢吲哚]-3'-酮(A1-2)的合成The first step: Synthesis of 6'-bromospiro[cyclopropa-1,1'-isoindoline]-3'-one (A1-2)

Figure PCTCN2022130676-appb-000092
Figure PCTCN2022130676-appb-000092

将4-溴-2-氰基-苯甲酸甲酯(A1-1)(500mg，2.08mmol)和钛酸四异丙酯(651mg，2.29mmol，676μL)溶于乙醚(10mL)，在0℃氮气保护下缓慢滴加乙基溴化镁乙醚溶液(3M，2.08mL)，反应液在25℃反应1h。将反应液冷却至0℃，缓慢倒入1N HCl(10mL)中，饱和碳酸氢钠(20mL)中和，用乙酸乙酯(60mL)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)，得到化合物6'-溴螺[环丙并-1,1'-异二氢吲哚]-3'-酮(A1-2)(110mg，58.7mmol，收率19.1％)。4-Bromo-2-cyano-benzoic acid methyl ester (A1-1) (500mg, 2.08mmol) and tetraisopropyl titanate (651mg, 2.29mmol, 676μL) were dissolved in ether (10mL), at 0°C Ethylmagnesium bromide diethyl ether solution (3M, 2.08mL) was slowly added dropwise under nitrogen protection, and the reaction solution was reacted at 25°C for 1h. The reaction solution was cooled to 0°C, slowly poured into 1N HCl (10 mL), neutralized with saturated sodium bicarbonate (20 mL), extracted with ethyl acetate (60 mL), combined organic phases, washed with saturated brine (30 mL), Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product was separated and purified on a silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1-1:1) to obtain the compound 6'-bromospiro[cyclopropane-1,1'-isoindoline ]-3'-one (A1-2) (110 mg, 58.7 mmol, yield 19.1%).

LC-MS,M/Z(ESI):237.9[M+H] +。 LC-MS, M/Z (ESI): 237.9 [M+H] + .

第二步：6'-溴-2'-甲基-螺[环丙并-1,1'-异二氢吲哚]-3'-酮(A1)的合成The second step: Synthesis of 6'-bromo-2'-methyl-spiro[cyclopropane-1,1'-isoindoline]-3'-one (A1)

Figure PCTCN2022130676-appb-000093
Figure PCTCN2022130676-appb-000093

将6'-溴螺[环丙并-1,1'-异二氢吲哚]-3'-酮(A1-2)(110mg，398μmol)和碳酸钾(165.3mg，1.20mmol)溶于N,N-二甲基甲酰胺(5mL)，在0℃下滴加碘甲烷(113mg，797μmol，49.6μL)，反应液在25℃反应1h。将反应液用水(5mL)稀释，用氨水(20mL)淬灭，用乙酸乙酯(60mL)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物6'-溴-2'-甲基螺[环丙并-1,1'-异二氢吲哚]-3'-酮(A1)(114mg，收率99.1％)。6'-Bromospiro[cyclopropa-1,1'-isoindoline]-3'-one (A1-2) (110 mg, 398 μmol) and potassium carbonate (165.3 mg, 1.20 mmol) were dissolved in N , N-dimethylformamide (5 mL), iodomethane (113 mg, 797 μmol, 49.6 μL) was added dropwise at 0°C, and the reaction solution was reacted at 25°C for 1 h. The reaction solution was diluted with water (5 mL), quenched with ammonia water (20 mL), extracted with ethyl acetate (60 mL), combined organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure The compound 6'-bromo-2'-methylspiro[cyclopropa-1,1'-isoindoline]-3'-one (A1) (114 mg, yield 99.1%) was obtained.

LC-MS,M/Z(ESI):252.1[M+H] +。 LC-MS, M/Z (ESI): 252.1 [M+H] + .

中间体A2:6'-溴-2'-(氘代甲基)-螺[环丙并-1,1'-异二氢吲哚]-3'-酮的制备Intermediate A2: Preparation of 6'-bromo-2'-(deuteromethyl)-spiro[cyclopropane-1,1'-isoindoline]-3'-one

Figure PCTCN2022130676-appb-000094
Figure PCTCN2022130676-appb-000094

中间体A2的合成参考中间体A1的合成，用氘代碘甲烷替代碘甲烷。LC-MS,M/Z(ESI):255.1[M+H] +。 The synthesis of intermediate A2 refers to the synthesis of intermediate A1, and methyl iodide is replaced by deuterated methyl iodide. LC-MS, M/Z (ESI): 255.1 [M+H] + .

中间体A3:6'-溴-7'-氟-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮的制备Intermediate A3: Preparation of 6'-bromo-7'-fluoro-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one

中间体A3的合成路线如下：The synthetic route of intermediate A3 is as follows:

Figure PCTCN2022130676-appb-000095
Figure PCTCN2022130676-appb-000095

中间体A3的合成参考中间体A1的合成，用A3-1替代A1-1。LC-MS,M/Z(ESI):271.2[M+H] +。 The synthesis of intermediate A3 refers to the synthesis of intermediate A1, and A1-1 is replaced by A3-1. LC-MS, M/Z (ESI): 271.2 [M+H] + .

中间体A4:3'-溴-6'-甲基螺[环丙烷-1,5'-吡咯[3,4-b]吡啶]-7'(6'H)-酮的制备Intermediate A4: Preparation of 3'-bromo-6'-methylspiro[cyclopropane-1,5'-pyrrole[3,4-b]pyridin]-7'(6'H)-one

中间体A4的合成路线如下：The synthetic route of intermediate A4 is as follows:

Figure PCTCN2022130676-appb-000096
Figure PCTCN2022130676-appb-000096

第一步：5-溴-3-(溴甲基)吡啶甲酸甲酯(A4-2)的合成The first step: the synthesis of methyl 5-bromo-3-(bromomethyl)picolinate (A4-2)

Figure PCTCN2022130676-appb-000097
Figure PCTCN2022130676-appb-000097

将5-溴-3-甲基吡啶甲酸甲酯(A4-1)(5g，21.73mmol)溶解在四氯化碳(50mL)中，加入偶氮二异丁腈(0.71g，4.35mmol)和NBS(4.64g，26.1mmol)，80℃反应5h。用水(100mL)稀释，用乙酸乙酯(100mL)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)纯化得到化合物5-溴-3-(溴甲基)吡啶甲酸甲酯(A4-2)(4.5g，收率67％)。5-Bromo-3-methylpicolinate (A4-1) (5g, 21.73mmol) was dissolved in carbon tetrachloride (50mL), and azobisisobutyronitrile (0.71g, 4.35mmol) was added and NBS (4.64g, 26.1mmol) was reacted at 80°C for 5h. Dilute with water (100 mL), extract with ethyl acetate (100 mL), combine organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1) to obtain the compound 5-bromo-3-(bromomethyl)picolinate methyl ester (A4-2) (4.5 g, yield 67%).

LC-MS,M/Z(ESI):307.8[M+H] +。 LC-MS, M/Z (ESI): 307.8 [M+H] + .

第二步：5-溴-3-(氰甲基)吡啶甲酸甲酯(A4-3)的合成The second step: the synthesis of methyl 5-bromo-3-(cyanomethyl)picolinate (A4-3)

Figure PCTCN2022130676-appb-000098
Figure PCTCN2022130676-appb-000098

将5-溴-3-(溴甲基)吡啶甲酸甲酯(A4-2)(4g，12.95mmol)溶解在DMF(40mL)中，加入碳酸铯(12.66g，38.8mmol)和三甲基氰硅烷(1.54g，15.54mmol)，60℃反应12h。用水(100mL)稀释，用乙酸乙酯(100mL)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1-1:1)纯化得到化合物5-溴-3-(氰甲基)吡啶甲酸甲酯(A4-3)(2.5g，收率76％)。Dissolve methyl 5-bromo-3-(bromomethyl)picolinate (A4-2) (4 g, 12.95 mmol) in DMF (40 mL), add cesium carbonate (12.66 g, 38.8 mmol) and trimethylcyanide Silane (1.54g, 15.54mmol) was reacted at 60°C for 12h. Dilute with water (100 mL), extract with ethyl acetate (100 mL), combine organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 3:1-1:1) to obtain compound 5-bromo-3-(cyanomethyl)picolinate methyl ester (A4-3) (2.5 g, yield 76%).

LC-MS,M/Z(ESI):254.9[M+H] +。 LC-MS, M/Z (ESI): 254.9 [M+H] + .

第三步：5-溴-3-(1-氰基环丙基)吡啶甲酸甲酯(A4-4)的合成The third step: the synthesis of methyl 5-bromo-3-(1-cyanocyclopropyl)picolinate (A4-4)

Figure PCTCN2022130676-appb-000099
Figure PCTCN2022130676-appb-000099

将5-溴-3-(氰甲基)吡啶甲酸甲酯(A4-3)(2g，7.84mmol)溶解在DMF(30mL)中，加入碳酸铯(7.66g，23.52mmol)和1,2-二溴乙烷(1.77g，9.41mmol)，60℃反应3h。用水(50mL)稀释，用乙酸乙酯(50mL)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)纯化得到化合物5-溴-3-(1-氰基环丙基)吡啶甲酸甲酯(A4-4)(1.8g，收率82％)。Methyl 5-bromo-3-(cyanomethyl)picolinate (A4-3) (2 g, 7.84 mmol) was dissolved in DMF (30 mL), cesium carbonate (7.66 g, 23.52 mmol) and 1,2- Dibromoethane (1.77g, 9.41mmol) was reacted at 60°C for 3h. Dilute with water (50 mL), extract with ethyl acetate (50 mL), combine organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1) and purified to obtain the compound 5-bromo-3-(1-cyanocyclopropyl)picolinate methyl ester ( A4-4) (1.8 g, yield 82%).

LC-MS,M/Z(ESI):281.0[M+H] +。 LC-MS, M/Z (ESI): 281.0 [M+H] + .

第四步：3'-溴螺[环丙烷-1,5'-吡咯并[3,4-b]吡啶]-7'(6'H)-酮(A4-5)的合成The fourth step: Synthesis of 3'-bromospiro[cyclopropane-1,5'-pyrrolo[3,4-b]pyridine]-7'(6'H)-one (A4-5)

Figure PCTCN2022130676-appb-000100
Figure PCTCN2022130676-appb-000100

将5-溴-3-(1-氰基环丙基)吡啶甲酸甲酯(A4-4)(2g，7.84mmol)加入到20mL 20％乙醇KOH(53.4mmol)溶液中搅拌24h。在另一烧瓶中，将溴(0.5mL，9.7mmol)添加到H 2O(40mL)中的NaOH(1.9g，47.5mmol)溶液中以生成NaOBr。将该溶液缓慢添加到第一种溶液中，并搅拌过夜，用饱和亚硫酸钠溶液(10mL)使该反应停止，并搅拌20分钟。然后用硫酸氢钾溶液酸化该溶液，并用EtOAc(3×25mL)萃取。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1-1:1)纯化得到化合物3'-溴螺[环丙烷-1,5'-吡咯并[3,4-b]吡啶]-7'(6'H)-酮(A4-5)(0.6g，收率47.0％)。 Add methyl 5-bromo-3-(1-cyanocyclopropyl)picolinate (A4-4) (2 g, 7.84 mmol) into 20 mL of 20% ethanol KOH (53.4 mmol) and stir for 24 h. In another flask, bromine (0.5 mL, 9.7 mmol) was added to a solution of NaOH (1.9 g, 47.5 mmol) in H2O (40 mL) to generate NaOBr. This solution was slowly added to the first solution and stirred overnight, the reaction was quenched with saturated sodium sulfite solution (10 mL) and stirred for 20 minutes. The solution was then acidified with potassium bisulfate solution and extracted with EtOAc (3 x 25 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 3:1-1:1) to obtain the compound 3'-bromospiro[cyclopropane-1,5'-pyrrolo[3,4 -b] Pyridine]-7'(6'H)-one (A4-5) (0.6 g, yield 47.0%).

LC-MS,M/Z(ESI):239.0[M+H] +。 LC-MS, M/Z (ESI): 239.0 [M+H] + .

第五步：3'-溴-6'-甲基螺[1,5'-吡咯[3,4-b]吡啶]-7'(6'H)-酮(A4)的合成Step 5: Synthesis of 3'-bromo-6'-methylspiro[1,5'-pyrrole[3,4-b]pyridine]-7'(6'H)-one (A4)

Figure PCTCN2022130676-appb-000101
Figure PCTCN2022130676-appb-000101

将3'-溴螺[环丙烷-1,5'-吡咯并[3,4-b]吡啶]-7'(6'H)-酮(A4-5)(500mg，2.09mmol)溶解在DMF(5mL)中，加入碳酸钾(867mg，6.27mmol)和碘甲烷(356mg，2.51mmol)，室温反应3h。用水(20mL)稀释，用乙酸乙酯(20mL)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)纯化得到化合物3'-溴-6'-甲基螺[1,5'-吡咯[3,4-b]吡啶]-7'(6'H)-酮(A4)(450mg，收率85％)。3'-Bromospiro[cyclopropane-1,5'-pyrrolo[3,4-b]pyridin]-7'(6'H)-one (A4-5) (500mg, 2.09mmol) was dissolved in DMF (5mL), potassium carbonate (867mg, 6.27mmol) and iodomethane (356mg, 2.51mmol) were added, and reacted at room temperature for 3h. Dilute with water (20 mL), extract with ethyl acetate (20 mL), combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1-1:1) to obtain the compound 3'-bromo-6'-methylspiro[1,5'-pyrrole[3 ,4-b]pyridin]-7'(6'H)-one (A4) (450 mg, yield 85%).

LC-MS,M/Z(ESI):253.0[M+H] +。 LC-MS, M/Z (ESI): 253.0 [M+H] + .

中间体A5:7-溴-2-甲基-[1,2,4]三唑基[4,3-a]吡啶-3(2H)-酮的制备Intermediate A5: Preparation of 7-bromo-2-methyl-[1,2,4]triazolyl[4,3-a]pyridin-3(2H)-one

中间体A5的合成路线如下：The synthetic route of intermediate A5 is as follows:

Figure PCTCN2022130676-appb-000102
Figure PCTCN2022130676-appb-000102

第一步：4-溴-2-肼基吡啶(A5-2)的合成The first step: the synthesis of 4-bromo-2-hydrazinopyridine (A5-2)

Figure PCTCN2022130676-appb-000103
Figure PCTCN2022130676-appb-000103

将80％的水合肼溶液(17ml)加入到4-溴-2-氟吡啶(A5-1)(5g,28.4mmol)于乙醇(50mL)的溶液中，将反应混合物在室温条件下搅拌12小时，浓缩，将残留物用水(50mL)稀释，乙酸乙酯(50mL*3)萃取，合并有机相，经无水硫酸钠干燥，过滤旋干得到4-溴-2-肼基吡啶(A5-2)(3.7g，收率69.3％)。80% hydrazine hydrate solution (17ml) was added to a solution of 4-bromo-2-fluoropyridine (A5-1) (5g, 28.4mmol) in ethanol (50mL), and the reaction mixture was stirred at room temperature for 12 hours , concentrated, the residue was diluted with water (50mL), extracted with ethyl acetate (50mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain 4-bromo-2-hydrazinopyridine (A5-2 ) (3.7 g, yield 69.3%).

LC-MS,M/Z(ESI):187.9[M+H] +。 LC-MS, M/Z (ESI): 187.9 [M+H] + .

第二步：7-溴-[1,2,4]三唑基[4,3-a]吡啶-3(2H)-酮(A5-3)的合成The second step: Synthesis of 7-bromo-[1,2,4]triazolyl[4,3-a]pyridin-3(2H)-one (A5-3)

Figure PCTCN2022130676-appb-000104
Figure PCTCN2022130676-appb-000104

将4-溴-2-肼基吡啶(A5-2)(3.2g,17.02mmol)溶解在四氢呋喃(30mL)中，加入羰基二咪唑(5.52g,34.0mmol)，室温下搅拌12小时，用水(50mL)稀释，乙酸乙酯(50mL*3)萃取，合并有机相，经无水硫酸钠干燥，过滤旋干，用乙酸乙酯(10mL)打浆得到7-溴-[1,2,4]三唑基[4,3-a]吡啶-3(2H)-酮(A5-3)(2.2g，收率60.4％)。4-Bromo-2-hydrazinopyridine (A5-2) (3.2g, 17.02mmol) was dissolved in tetrahydrofuran (30mL), carbonyldiimidazole (5.52g, 34.0mmol) was added, stirred at room temperature for 12 hours, water ( 50mL), extracted with ethyl acetate (50mL*3), combined the organic phases, dried over anhydrous sodium sulfate, filtered and spin-dried, and slurried with ethyl acetate (10mL) to obtain 7-bromo-[1,2,4]tri Azolyl[4,3-a]pyridin-3(2H)-one (A5-3) (2.2 g, yield 60.4%).

LC-MS,M/Z(ESI):213.9[M+H] +。 LC-MS, M/Z (ESI): 213.9 [M+H] + .

第三步：7-溴-2-甲基-[1,2,4]三唑基[4,3-a]吡啶-3(2H)-酮(A5)的合成Step 3: Synthesis of 7-bromo-2-methyl-[1,2,4]triazolyl[4,3-a]pyridin-3(2H)-one (A5)

Figure PCTCN2022130676-appb-000105
Figure PCTCN2022130676-appb-000105

在室温下将碘甲烷(995mg,7.01mmol)滴加到7-溴-[1,2,4]三唑基[4,3-a]吡啶-3(2H)-酮(A5-3)(500mg,2.33mmol)和碳酸铯(1.14g,3.50mmol)于DMF(5mL)的混合物中，室温下搅拌3小时，用水(20mL)稀释，乙酸乙酯(20mL*3)萃取，合并有机相，经无水硫酸钠干燥，过滤旋干，粗品用硅胶柱分离纯化(石油醚：乙酸乙酯(V/V)＝5：1-1：1)纯化得到7-溴-2-甲基-[1,2,4]三唑基[4,3-a]吡啶-3(2H)-酮(A5)(400mg，收率75％)。Add methyl iodide (995 mg, 7.01 mmol) dropwise to 7-bromo-[1,2,4]triazolyl[4,3-a]pyridin-3(2H)-one (A5-3) at room temperature ( 500mg, 2.33mmol) and cesium carbonate (1.14g, 3.50mmol) in a mixture of DMF (5mL), stirred at room temperature for 3 hours, diluted with water (20mL), extracted with ethyl acetate (20mL*3), combined the organic phases, Dried over anhydrous sodium sulfate, filtered and spin-dried, the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1-1:1) to obtain 7-bromo-2-methyl-[ 1,2,4]Triazolyl[4,3-a]pyridin-3(2H)-one (A5) (400 mg, yield 75%).

LC-MS,M/Z(ESI):227.9[M+H] +。 LC-MS, M/Z (ESI): 227.9 [M+H] + .

中间体A6:(2-甲基-3-氧代-2,3-二氢-[1,2,4]三唑基[4,3-a]吡啶-7-基)硼酸的制备Intermediate A6: Preparation of (2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolyl[4,3-a]pyridin-7-yl)boronic acid

中间体A6的合成路线如下：The synthetic route of intermediate A6 is as follows:

Figure PCTCN2022130676-appb-000106
Figure PCTCN2022130676-appb-000106

第一步：(2-甲基-3-氧代-2,3-二氢-[1,2,4]三唑基[4,3-a]吡啶-7-基)硼酸(A6)的合成The first step: (2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolyl[4,3-a]pyridin-7-yl)boronic acid (A6) synthesis

Figure PCTCN2022130676-appb-000107
Figure PCTCN2022130676-appb-000107

将7-溴-2-甲基-[1,2,4]三唑基[4,3-a]吡啶-3(2H)-酮(A5)(0.58g，2.56mmol)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3,2-二噁硼戊环(974mg，3.84mmol)和醋酸钾(753mg，7.67mmol)溶于二氧六环(10mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(187mg，255μmol)，反应液在100℃反应2h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得粗品，用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-1:1)纯化得到到化合物(2-甲基-3-氧代-2,3-二氢-[1,2,4]三唑基[4,3-a]吡啶-7-基)硼酸(A6)(0.35g，收率70％)。7-Bromo-2-methyl-[1,2,4]triazolyl[4,3-a]pyridin-3(2H)-one (A5) (0.58g, 2.56mmol), 4,4, 5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan Dioxane (974mg, 3.84mmol) and potassium acetate (753mg, 7.67mmol) were dissolved in dioxane (10mL), nitrogen was replaced 3 times, and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride ( II) (187mg, 255μmol), the reaction solution was reacted at 100°C for 2h. After the reaction was completed, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, concentrate to obtain a crude product, and use Silica gel column separation and purification (petroleum ether: ethyl acetate (V/V) = 10:1-1:1) was purified to obtain the compound (2-methyl-3-oxo-2,3-dihydro-[1, 2,4]Triazolyl[4,3-a]pyridin-7-yl)boronic acid (A6) (0.35 g, yield 70%).

LC-MS,M/Z(ESI):194.1[M+H] +。 LC-MS, M/Z (ESI): 194.1 [M+H] + .

实施例1：6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物1)的制备Example 1: 6'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1'-isodihydro Preparation of indole]-3'-one (compound 1)

目标化合物1的合成路线如下：The synthetic route of target compound 1 is as follows:

Figure PCTCN2022130676-appb-000108
Figure PCTCN2022130676-appb-000108

第一步：(8-溴喹啉-3-基)(4,4-二氟哌啶-1-基)甲酮(B1-2)的合成Step 1: Synthesis of (8-bromoquinolin-3-yl)(4,4-difluoropiperidin-1-yl)methanone (B1-2)

Figure PCTCN2022130676-appb-000109
Figure PCTCN2022130676-appb-000109

将8-溴喹啉-3-羧酸(B1-1)(1.0g，3.97mmol)，4,4-二氟哌啶(480mg，3.97mmol)和N,N-二异丙基乙胺(1.03g，7.93mmol，1.38mL)溶于N,N-二甲基甲酰胺(10mL)，加入O-(7-氮杂苯并三唑-1-yl)-N,N,N,N-四甲基糖醛正离子六氟磷酸盐(1.81g，4.76mmol)，在25℃反应1h。反应结束后，加水(20mL)稀释，饱和碳酸氢钠(10mL)中和，用乙酸乙酯(90mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-5:1)纯化得到(8-溴喹啉-3-基)(4,4-二氟哌啶-1-基)甲酮(B1-2)(1.14g，收率66.8％)。8-bromoquinoline-3-carboxylic acid (B1-1) (1.0g, 3.97mmol), 4,4-difluoropiperidine (480mg, 3.97mmol) and N,N-diisopropylethylamine ( 1.03g, 7.93mmol, 1.38mL) was dissolved in N,N-dimethylformamide (10mL), adding O-(7-azabenzotriazole-1-yl)-N,N,N,N- Tetramethylfurfural positive ion hexafluorophosphate (1.81g, 4.76mmol) was reacted at 25°C for 1h. After the reaction, dilute with water (20 mL), neutralize with saturated sodium bicarbonate (10 mL), extract three times with ethyl acetate (90 mL), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-5:1) to obtain (8-bromoquinolin-3-yl)(4,4-difluoropiperidine- 1-yl)methanone (B1-2) (1.14 g, yield 66.8%).

LC-MS,M/Z(ESI):355.0[M+H] +。 LC-MS, M/Z (ESI): 355.0 [M+H] + .

第二步：(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)硼酸(B1-3)的合成The second step: the synthesis of (3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)boronic acid (B1-3)

Figure PCTCN2022130676-appb-000110
Figure PCTCN2022130676-appb-000110

将(8-溴喹啉-3-基)(4,4-二氟哌啶-1-基)甲酮(B1-2)(1.10g，2.56mmol)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3,2-二噁硼戊环(974mg，3.84mmol)和醋酸钾(753mg，7.67mmol)溶于二氧六环(10mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(187mg，255μmol)，反应液在100℃反应2h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)硼酸(B1-3)(1.3g，粗品)。(8-bromoquinolin-3-yl)(4,4-difluoropiperidin-1-yl)methanone (B1-2) (1.10g, 2.56mmol), 4,4,5,5-tetra Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (974mg, 3.84 mmol) and potassium acetate (753mg, 7.67mmol) were dissolved in dioxane (10mL), nitrogen replacement was performed 3 times, and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (II) (187mg, 255μmol), and the reaction solution was reacted at 100°C for 2h. After the reaction, cool to room temperature, dilute with water (30mL), extract three times with ethyl acetate (120mL), combine the organic phases, wash with saturated brine (40mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound (3 -(4,4-Difluoropiperidin-1-carbonyl)quinolin-8-yl)boronic acid (B1-3) (1.3 g, crude).

LC-MS,M/Z(ESI):321.0[M+H] +。 LC-MS, M/Z (ESI): 321.0 [M+H] + .

第三步：6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物1)的合成The third step: 6'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1'-isodihydro Synthesis of Indole]-3'-one (Compound 1)

Figure PCTCN2022130676-appb-000111
Figure PCTCN2022130676-appb-000111

将(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)硼酸(B1-3)(191mg，346μmol)，6'-溴-2'-甲基-螺[环丙并-1,1'-异二氢吲哚]-3'-酮(A1)(50mg，173μmol)和碳酸钾(59.8mg，433μmol)溶于二氧六环(5mL)和水(1mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(187mg，255μmol)，90℃反应1h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(色谱柱：Waters Xbridge 150×25mm×5μm；溶剂：A＝氨水，B＝乙腈；梯度：25％-55％，9分钟)，冻干，得到6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物1)(50mg，收率64.0％)。(3-(4,4-Difluoropiperidin-1-carbonyl)quinolin-8-yl)boronic acid (B1-3) (191 mg, 346 μmol), 6'-bromo-2'-methyl-spiro[ Cyclopropano-1,1'-isoindoline]-3'-one (A1) (50 mg, 173 μmol) and potassium carbonate (59.8 mg, 433 μmol) were dissolved in dioxane (5 mL) and water (1 mL ), replaced with nitrogen three times, added 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (187mg, 255μmol), and reacted at 90°C for 1h. After the reaction, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product is separated by reverse-phase high-performance liquid chromatography, and the separation method is (chromatographic column: Waters Xbridge 150 * 25mm * 5 μ m; Solvent: A=ammonia, B=acetonitrile; Gradient: 25%-55%, 9 minutes), Freeze-dry to obtain 6'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1'-isodihydro Indole]-3'-one (compound 1) (50 mg, yield 64.0%).

1H NMR(400MHz,DMSO-d 6):δ8.95(d,1H),8.60(d,1H),8.13(dd,1H),7.92(dd,1H),7.73-7.82(m,3H),7.55(s,1H),3.71-3.92(m,2H),3.46-3.60(m,2H),2.83(s,3H),2.03-2.17(m,4H),1.67-1.76(m,2H),1.41-1.52(m,2H). 1 H NMR(400MHz,DMSO-d 6 ):δ8.95(d,1H),8.60(d,1H),8.13(dd,1H),7.92(dd,1H),7.73-7.82(m,3H) ,7.55(s,1H),3.71-3.92(m,2H),3.46-3.60(m,2H),2.83(s,3H),2.03-2.17(m,4H),1.67-1.76(m,2H) ,1.41-1.52(m,2H).

LC-MS,M/Z(ESI):448.2[M+H] +。 LC-MS, M/Z (ESI): 448.2 [M+H] + .

实施例2：6'-(3-(3,3-二氟吡咯烷-1-羰基)喹啉-8-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物2)的制备Example 2: 6'-(3-(3,3-difluoropyrrolidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1'-isodihydro Preparation of indole]-3'-one (compound 2)

目标化合物2的合成路线如下：The synthetic route of target compound 2 is as follows:

Figure PCTCN2022130676-appb-000112
Figure PCTCN2022130676-appb-000112

第一步：(8-溴喹啉-3-基)(3,3-二氟吡咯烷-1-基)甲酮(B2-1)的合成Step 1: Synthesis of (8-bromoquinolin-3-yl)(3,3-difluoropyrrolidin-1-yl)methanone (B2-1)

Figure PCTCN2022130676-appb-000113
Figure PCTCN2022130676-appb-000113

将8-溴喹啉-3-羧酸(B1-1)(500mg，1.98mmol)，3,3-二氟吡咯烷盐酸盐(342mg，2.38mmol)和N,N-二异丙基乙胺(1.04mL，5.95mmol)溶于N,N-二甲基甲酰胺(10mL)，加入O-(7-氮杂苯并三唑-1-yl)-N,N,N,N-四甲基糖醛正离子六氟磷酸盐(905mg，2.38mmol)，在25℃反应12h。反应结束后，加水(20mL)稀释，饱和碳酸氢钠(10mL)中和，用乙酸乙酯(90mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-5:1)纯化得到(8-溴喹啉-3-基)(3,3-二氟吡咯烷-1-基)甲酮(B2-1)(500mg，收率73.9％)。8-bromoquinoline-3-carboxylic acid (B1-1) (500mg, 1.98mmol), 3,3-difluoropyrrolidine hydrochloride (342mg, 2.38mmol) and N,N-diisopropylethyl Amine (1.04 mL, 5.95 mmol) was dissolved in N,N-dimethylformamide (10 mL), O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetra Methylfurfural positive ion hexafluorophosphate (905mg, 2.38mmol) was reacted at 25°C for 12h. After the reaction, dilute with water (20 mL), neutralize with saturated sodium bicarbonate (10 mL), extract three times with ethyl acetate (90 mL), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-5:1) to obtain (8-bromoquinolin-3-yl)(3,3-difluoropyrrolidine- 1-yl)methanone (B2-1) (500 mg, yield 73.9%).

LC-MS,M/Z(ESI):341.0[M+H] +。 LC-MS, M/Z (ESI): 341.0 [M+H] + .

第二步：(3-(3,3-二氟吡咯烷-1-羰基)喹啉-8-基)硼酸(B2-2)的合成The second step: the synthesis of (3-(3,3-difluoropyrrolidine-1-carbonyl)quinolin-8-yl)boronic acid (B2-2)

Figure PCTCN2022130676-appb-000114
Figure PCTCN2022130676-appb-000114

将(8-溴喹啉-3-基)(3,3-二氟吡咯烷-1-基)甲酮(500mg，1.47mmol)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3,2-二噁硼戊环(744mg，2.93mmol)和醋酸钾(288mg，2.93mmol) 溶于二氧六环(10mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(107mg，0.147mmol)，反应液在100℃反应2h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物(3-(3,3-二氟吡咯烷-1-羰基)喹啉-8-基)硼酸(B2-2)(569mg，粗品)。(8-bromoquinolin-3-yl)(3,3-difluoropyrrolidin-1-yl)methanone (500mg, 1.47mmol), 4,4,5,5-tetramethyl-2-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (744mg, 2.93mmol) and potassium acetate ( 288mg, 2.93mmol) was dissolved in dioxane (10mL), replaced with nitrogen 3 times, added 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (107mg, 0.147mmol), the reaction solution React at 100°C for 2h. After the reaction, cool to room temperature, dilute with water (30mL), extract three times with ethyl acetate (120mL), combine the organic phases, wash with saturated brine (40mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound (3 -(3,3-Difluoropyrrolidine-1-carbonyl)quinolin-8-yl)boronic acid (B2-2) (569 mg, crude).

LC-MS,M/Z(ESI):307.2[M+H] +。 LC-MS, M/Z (ESI): 307.2 [M+H] + .

第三步：6'-(3-(3,3-二氟吡咯烷-1-羰基)喹啉-8-基)-2'-甲基螺环[环丙烷-1,1'-异二氢吲哚]-3'-酮的合成The third step: 6'-(3-(3,3-difluoropyrrolidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1'-isobis Synthesis of indoline]-3'-one

Figure PCTCN2022130676-appb-000115
Figure PCTCN2022130676-appb-000115

将(3-(3,3-二氟吡咯烷-1-羰基)喹啉-8-基)硼酸(B2-2)(569mg，1.85mmol)，6'-溴-2'-甲基螺[环丙并-1,1'-异二氢吲哚]-3'-酮(369mg，1.47mol)和碳酸钠(311mg，2.93mmol)溶于二氧六环(5mL)和水(1mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(107mg，0.147mmol)，90℃反应1h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150×25mm×5μm；溶剂：A＝氨水，B＝乙腈；梯度：25％-55％，9分钟)，冻干，得到6'-(3-(3,3-二氟吡咯烷-1-羰基)喹啉-8-基)-2'-甲基螺环[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物2)(350mg，收率55.1％)。(3-(3,3-Difluoropyrrolidine-1-carbonyl)quinolin-8-yl)boronic acid (B2-2) (569 mg, 1.85 mmol), 6'-bromo-2'-methylspiro[ Cyclopropano-1,1'-isoindoline]-3'-one (369 mg, 1.47 mol) and sodium carbonate (311 mg, 2.93 mmol) were dissolved in dioxane (5 mL) and water (1 mL), Nitrogen was replaced 3 times, 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (107mg, 0.147mmol) was added and reacted at 90°C for 1h. After the reaction, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was separated by reverse-phase high-performance liquid chromatography, and the separation method was (column: Waters Xbridge 150×25mm×5 μm; solvent: A=ammonia, B=acetonitrile; gradient: 25%-55%, 9 minutes), freezing Dry to give 6'-(3-(3,3-difluoropyrrolidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1'-isodihydro Indole]-3'-one (compound 2) (350 mg, yield 55.1%).

1H NMR(400MHz,DMSO-d 6):δ8.98(S,1H),8.73(d,1H),8.13(d,1H),7.82(d,1H),7.71-7.79(m,3H),7.52(s,1H),3.93-4.11(m,2H),3.77-3.84(m,2H),2.81(s,3H),2.48(t,2H),1.69-1.72(m,2H),1.42-1.46(m,2H). 1 H NMR(400MHz,DMSO-d 6 ):δ8.98(S,1H),8.73(d,1H),8.13(d,1H),7.82(d,1H),7.71-7.79(m,3H) ,7.52(s,1H),3.93-4.11(m,2H),3.77-3.84(m,2H),2.81(s,3H),2.48(t,2H),1.69-1.72(m,2H),1.42 -1.46(m,2H).

LC-MS,M/Z(ESI):434.2[M+H] +。 LC-MS, M/Z (ESI): 434.2 [M+H] + .

实施例3：6'-(3-(3-氟哌啶-1-羰基)喹啉-8-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物3)的制备Example 3: 6'-(3-(3-fluoropiperidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline] Preparation of -3'-ketone (compound 3)

目标化合物3的合成路线如下：The synthetic route of target compound 3 is as follows:

Figure PCTCN2022130676-appb-000116
Figure PCTCN2022130676-appb-000116

第一步：(8-溴喹啉-3-基)(3-氟哌啶-1-基)甲酮(B3-1)的合成The first step: the synthesis of (8-bromoquinolin-3-yl)(3-fluoropiperidin-1-yl)methanone (B3-1)

Figure PCTCN2022130676-appb-000117
Figure PCTCN2022130676-appb-000117

将8-溴喹啉-3-羧酸(B1-1)(500mg，1.98mmol)，3-氟哌啶盐酸盐(332mg，2.38mmol)和N,N-二异丙基乙胺(1.04mL，5.95mmol)溶于N,N-二甲基甲酰胺(10mL)，加入O-(7-氮杂苯并三唑-1-yl)-N,N,N,N-四甲基糖醛正离子六氟磷酸盐(905mg，2.38mmol)，在25℃反应12h。反应结束后，加水(20mL)稀释，饱和碳酸氢钠(10mL)中和，用乙酸乙酯(90mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝10:1-5:1)纯化得到(8-溴喹啉-3-基)(3-氟哌啶-1-基)甲酮(B3-1)(500mg,收率74.8％)。8-bromoquinoline-3-carboxylic acid (B1-1) (500mg, 1.98mmol), 3-fluoropiperidine hydrochloride (332mg, 2.38mmol) and N,N-diisopropylethylamine (1.04 mL, 5.95mmol) was dissolved in N,N-dimethylformamide (10mL), and O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethylsugar Aldehydic cation hexafluorophosphate (905mg, 2.38mmol) was reacted at 25°C for 12h. After the reaction, dilute with water (20 mL), neutralize with saturated sodium bicarbonate (10 mL), extract three times with ethyl acetate (90 mL), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=10:1-5:1) to obtain (8-bromoquinolin-3-yl)(3-fluoropiperidin-1-yl ) Methanone (B3-1) (500 mg, yield 74.8%).

LC-MS,M/Z(ESI):337.1[M+H] +。 LC-MS, M/Z (ESI): 337.1 [M+H] + .

第二步：(3-(3-氟哌啶-1-羰基)喹啉-8-基)硼酸(B3-2)的合成The second step: the synthesis of (3-(3-fluoropiperidine-1-carbonyl)quinolin-8-yl)boronic acid (B3-2)

Figure PCTCN2022130676-appb-000118
Figure PCTCN2022130676-appb-000118

将(8-溴喹啉-3-基)(3-氟哌啶-1-基)甲酮(500mg，1.48mmol)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3,2-二噁硼戊环(755mg，2.97mmol)和醋酸钾(292mg，2.97mmol)溶于二氧六环(10mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(109mg，0.147mmol)， 反应液在100℃反应2h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物(3-(3-氟哌啶-1-羰基)喹啉-8-基)硼酸(B3-2)(571mg，粗品)。(8-Bromoquinolin-3-yl)(3-fluoropiperidin-1-yl)methanone (500mg, 1.48mmol), 4,4,5,5-tetramethyl-2-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (755mg, 2.97mmol) and potassium acetate (292mg, 2.97 mmol) was dissolved in dioxane (10mL), replaced with nitrogen for 3 times, added 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (109mg, 0.147mmol), and the reaction solution was heated at 100°C Reaction 2h. After the reaction, cool to room temperature, dilute with water (30mL), extract three times with ethyl acetate (120mL), combine the organic phases, wash with saturated brine (40mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound (3 -(3-fluoropiperidine-1-carbonyl)quinolin-8-yl)boronic acid (B3-2) (571 mg, crude product).

LC-MS,M/Z(ESI):303.2[M+H] +。 LC-MS, M/Z (ESI): 303.2 [M+H] + .

第三步：6'-(3-(3-氟哌啶-1-羰基)喹啉-8-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物3)的合成The third step: 6'-(3-(3-fluoropiperidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline] Synthesis of -3'-ketone (compound 3)

Figure PCTCN2022130676-appb-000119
Figure PCTCN2022130676-appb-000119

将(3-(3-氟哌啶-1-羰基)喹啉-8-基)硼酸(B3-2)(571mg，1.89mmol)，6'-溴-2'-甲基螺[环丙并-1,1'-异二氢吲哚]-3'-酮(369mg，1.47mol)和碳酸钠(375mg，1.48mmol)溶于二氧六环(5mL)和水(1mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(109mg，0.148mmol)，90℃反应1h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150×25mm×5μm；溶剂：A＝氨水，B＝乙腈；梯度：25％-55％，9分钟)，冻干，得到6'-(3-(3-氟哌啶-1-羰基)喹啉-8-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物3)(300mg，收率47.0％)。(3-(3-fluoropiperidine-1-carbonyl)quinolin-8-yl)boronic acid (B3-2) (571mg, 1.89mmol), 6'-bromo-2'-methylspiro[cyclopropane -1,1'-isoindoline]-3'-one (369mg, 1.47mol) and sodium carbonate (375mg, 1.48mmol) were dissolved in dioxane (5mL) and water (1mL), nitrogen replacement 3 Once, 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (109mg, 0.148mmol) was added and reacted at 90°C for 1h. After the reaction, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was separated by reverse-phase high-performance liquid chromatography, and the separation method was (column: Waters Xbridge 150×25mm×5 μm; solvent: A=ammonia, B=acetonitrile; gradient: 25%-55%, 9 minutes), freezing Dry to give 6'-(3-(3-fluoropiperidin-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]- 3'-Keto (Compound 3) (300 mg, yield 47.0%).

1H NMR(400MHz,DMSO-d 6):δ8.84(d,1H),8.48(s,1H),8.13(s,1H),7.90(d,1H),7.71-7.75(m,3H),7.53(s,1H),3.68(s,1H),3.11-3.22(m,2H),2.79(s,3H),2.48-2.51(m,2H),1.81-1.92(m,2H),1.61-1.75(m,3H),1.31-1.45(m,2H),1.21-1.26(m,1H). 1 H NMR(400MHz,DMSO-d 6 ):δ8.84(d,1H),8.48(s,1H),8.13(s,1H),7.90(d,1H),7.71-7.75(m,3H) ,7.53(s,1H),3.68(s,1H),3.11-3.22(m,2H),2.79(s,3H),2.48-2.51(m,2H),1.81-1.92(m,2H),1.61 -1.75(m,3H),1.31-1.45(m,2H),1.21-1.26(m,1H).

LC-MS,M/Z(ESI):430.2[M+H] +。 LC-MS, M/Z (ESI): 430.2 [M+H] + .

实施例4：6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-2'-(氘代甲基)螺环[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物4)的制备Example 4: 6'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-2'-(deuteromethyl)spiro[cyclopropane-1,1 Preparation of '-isoindoline]-3'-one (compound 4)

Figure PCTCN2022130676-appb-000120
Figure PCTCN2022130676-appb-000120

将(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)硼酸(B1-3)(90mg，282μmol)，6'-溴-2'-(氘代甲基)-螺[环丙并-1,1'-异二氢吲哚]-3'-酮(A2)(60mg，235μmol)和碳酸钾(81.1mg，587μmol)溶于二氧六环 (5mL)和水(1mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(17.2mg，23.5μmol)，90℃反应1h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150×25mm×5μm；溶剂：A＝氨水，B＝乙腈；梯度：25％-55％，9分钟)，冻干，得到6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-2'-(氘代甲基)螺环[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物4)(52.5mg，收率49.6％)。(3-(4,4-Difluoropiperidin-1-carbonyl)quinolin-8-yl)boronic acid (B1-3) (90 mg, 282 μmol), 6'-bromo-2'-(deuteromethyl )-spiro[cyclopropa-1,1'-isoindoline]-3'-one (A2) (60 mg, 235 μmol) and potassium carbonate (81.1 mg, 587 μmol) were dissolved in dioxane (5 mL) And water (1mL), nitrogen replacement 3 times, add 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (17.2mg, 23.5μmol), react at 90℃ for 1h. After the reaction, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was separated by reverse-phase high-performance liquid chromatography, and the separation method was (column: Waters Xbridge 150×25mm×5 μm; solvent: A=ammonia, B=acetonitrile; gradient: 25%-55%, 9 minutes), freezing Dry to give 6'-(3-(4,4-difluoropiperidin-1-carbonyl)quinolin-8-yl)-2'-(deuteromethyl)spiro[cyclopropane-1,1' -Isoindoline]-3'-one (compound 4) (52.5 mg, yield 49.6%).

1H NMR(400MHz,DMSO-d 6):δ8.94(d,1H),8.59(d,1H),8.13(dd,1H),7.92(dd,1H),7.73-7.82(m,3H),7.55(s,1H),3.78-3.80(m,2H),3.53-3.55(m,2H),2.10(s,4H),1.70-1.74(m,2H),1.44-1.47(m,2H). 1 H NMR(400MHz,DMSO-d 6 ):δ8.94(d,1H),8.59(d,1H),8.13(dd,1H),7.92(dd,1H),7.73-7.82(m,3H) ,7.55(s,1H),3.78-3.80(m,2H),3.53-3.55(m,2H),2.10(s,4H),1.70-1.74(m,2H),1.44-1.47(m,2H) .

LC-MS,M/Z(ESI):451.2[M+H] +。 LC-MS, M/Z (ESI): 451.2 [M+H] + .

实施例5：6'-(7-(4,4-二氟哌啶-1-羰基)喹啉-4-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物5)的制备Example 5: 6'-(7-(4,4-difluoropiperidine-1-carbonyl)quinolin-4-yl)-2'-methylspiro[cyclopropane-1,1'-isodihydro Preparation of indole]-3'-one (Compound 5)

Figure PCTCN2022130676-appb-000121
Figure PCTCN2022130676-appb-000121

第一步：(4-氯喹啉-7-基)(4,4-二氟哌啶-1-基)甲酮(B5-2)的合成Step 1: Synthesis of (4-chloroquinolin-7-yl)(4,4-difluoropiperidin-1-yl)methanone (B5-2)

Figure PCTCN2022130676-appb-000122
Figure PCTCN2022130676-appb-000122

将4-氯喹啉-7-羧酸(B5-1)(1g，4.82mmol)，4,4-二氟哌啶(584mg，4.82mmol)和N,N-二异丙基乙胺(1.25g，9.64mmol，1.68mL)溶于N,N-二甲基甲酰胺(10mL)，加入O-(7-氮杂苯并三唑-1-基)-N,N,N,N-四甲基糖醛正离子六氟磷酸盐(2.20g，5.78mmol)，在25℃反应1h。反应结束后，加水(20mL)稀释，饱和碳酸氢钠(10mL)中和，用乙酸乙酯(90mL)萃取三次，合并有机相，用 饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-2:1)纯化得到(4-氯喹啉-7-基)(4,4-二氟哌啶-1-基)甲酮(B5-2)(1.25g，收率83.5％)。4-Chloroquinoline-7-carboxylic acid (B5-1) (1g, 4.82mmol), 4,4-difluoropiperidine (584mg, 4.82mmol) and N,N-diisopropylethylamine (1.25g , 9.64mmol, 1.68mL) was dissolved in N,N-dimethylformamide (10mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl Urcuronium hexafluorophosphate (2.20g, 5.78mmol) was reacted at 25°C for 1h. After the reaction, dilute with water (20 mL), neutralize with saturated sodium bicarbonate (10 mL), extract three times with ethyl acetate (90 mL), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-2:1) to obtain (4-chloroquinolin-7-yl)(4,4-difluoropiperidine-1 -yl)methanone (B5-2) (1.25g, yield 83.5%).

LC-MS,M/Z(ESI):311.1[M+H] +。 LC-MS, M/Z (ESI): 311.1 [M+H] + .

第二步：(7-(4,4-二氟哌啶-1-羰基)喹啉-4-基)硼酸(B5-3)的合成The second step: the synthesis of (7-(4,4-difluoropiperidine-1-carbonyl)quinolin-4-yl)boronic acid (B5-3)

Figure PCTCN2022130676-appb-000123
Figure PCTCN2022130676-appb-000123

将(4-氯喹啉-7-基)(4,4-二氟哌啶-1-基)甲酮(B5-2)(1.25g，4.02mmol)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3,2-二噁硼戊环(1.53g，6.03mmol)和醋酸钾(1.18g，12.06mmol)溶于二氧六环(10mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(294mg，402μmol)，反应液在100℃反应2h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物(7-(4,4-二氟哌啶-1-羰基)喹啉-4-基)硼酸(B5-3)(1.1g，粗品)。(4-chloroquinolin-7-yl)(4,4-difluoropiperidin-1-yl)methanone (B5-2) (1.25g, 4.02mmol), 4,4,5,5-tetramethyl Base-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.53g, 6.03 mmol) and potassium acetate (1.18g, 12.06mmol) were dissolved in dioxane (10mL), nitrogen replacement was performed 3 times, and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (294mg , 402μmol), the reaction solution was reacted at 100°C for 2h. After the reaction, cool to room temperature, dilute with water (30mL), extract three times with ethyl acetate (120mL), combine the organic phases, wash with saturated brine (40mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound (7 -(4,4-Difluoropiperidin-1-carbonyl)quinolin-4-yl)boronic acid (B5-3) (1.1 g, crude).

LC-MS,M/Z(ESI):321.0[M+H] +。 LC-MS, M/Z (ESI): 321.0 [M+H] + .

第三步：6'-(7-(4,4-二氟哌啶-1-羰基)喹啉-4-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物5)的合成The third step: 6'-(7-(4,4-difluoropiperidine-1-carbonyl)quinolin-4-yl)-2'-methylspiro[cyclopropane-1,1'-isodihydro Synthesis of Indole]-3'-one (Compound 5)

Figure PCTCN2022130676-appb-000124
Figure PCTCN2022130676-appb-000124

将(7-(4,4-二氟哌啶-1-羰基)喹啉-4-基)硼酸(B5-3)(111mg，346μmol)，6'-溴-2'-甲基螺[环丙并-1,1'-异二氢吲哚]-3'-酮(A1)(50.0mg，173μmol)和碳酸钾(59.8mg，433μmol)溶于二氧六环(5mL)和水(1mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(18.6mg，25.5μmol)，90℃反应1h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150×25mm×5μm；溶剂：A＝氨水，B＝乙腈；梯度：25％-55％，9分钟)，冻干，得到6'-(7-(4,4-二氟哌啶-1-羰基)喹啉-4-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物5)(52.6mg，收率67.9％)。(7-(4,4-Difluoropiperidine-1-carbonyl)quinolin-4-yl)boronic acid (B5-3) (111 mg, 346 μmol), 6'-bromo-2'-methylspiro[cyclo Propano-1,1'-isoindoline]-3'-one (A1) (50.0 mg, 173 μmol) and potassium carbonate (59.8 mg, 433 μmol) were dissolved in dioxane (5 mL) and water (1 mL ), replaced with nitrogen three times, added 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (18.6mg, 25.5μmol), and reacted at 90°C for 1h. After the reaction, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was separated by reverse-phase high-performance liquid chromatography, and the separation method was (column: Waters Xbridge 150×25mm×5 μm; solvent: A=ammonia, B=acetonitrile; gradient: 25%-55%, 9 minutes), freezing Dry to give 6'-(7-(4,4-difluoropiperidine-1-carbonyl)quinolin-4-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline Indol]-3'-one (compound 5) (52.6 mg, yield 67.9%).

1H NMR(400MHz,CDCl 3):δ9.02(d,1H),8.19(d,1H),8.05(d,1H),7.89(d,1H),7.60–7.52(m,2H),7.41(d,1H),7.16(s,1H),3.94(s,2H),3.65(s,2H),2.93(s,3H),2.04(s,4H),1.67(d,2H),1.41(t,2H). 1 H NMR (400MHz, CDCl 3 ): δ9.02(d,1H),8.19(d,1H),8.05(d,1H),7.89(d,1H),7.60–7.52(m,2H),7.41 (d,1H),7.16(s,1H),3.94(s,2H),3.65(s,2H),2.93(s,3H),2.04(s,4H),1.67(d,2H),1.41( t,2H).

LC-MS,M/Z(ESI):448.2[M+H] +。 LC-MS, M/Z (ESI): 448.2 [M+H] + .

实施例6：2'-甲基-6'-(3-(吗啉-4-羰基)喹啉-8-基)螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物6)的制备目标化合物6的合成路线如下：Example 6: 2'-methyl-6'-(3-(morpholine-4-carbonyl)quinolin-8-yl)spiro[cyclopropane-1,1'-isoindoline]-3' -The synthetic route of the preparation target compound 6 of ketone (compound 6) is as follows:

Figure PCTCN2022130676-appb-000125
Figure PCTCN2022130676-appb-000125

第一步：(8-溴喹啉-3-基)(吗啉)甲酮(B6-1)的合成The first step: the synthesis of (8-bromoquinolin-3-yl)(morpholine)methanone (B6-1)

Figure PCTCN2022130676-appb-000126
Figure PCTCN2022130676-appb-000126

将8-溴喹啉-3-羧酸(B1-1)(1.00g，3.97mmol)，吗啉(345mg，3.97mmol)和N,N-二异丙基乙胺(1.03g，7.93mmol，1.38mL)溶于N,N-二甲基甲酰胺(10mL)，加入O-(7-氮杂苯并三唑-1-YL)-N,N,N,N-四甲基糖醛正离子六氟磷酸盐(1.81g，4.76mmol)，在25℃反应1h。反应结束后，加水(20mL)稀释，饱和碳酸氢钠(10mL)中和，用乙酸乙酯(90mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:2)纯化得到(8-溴喹啉-3-基)(吗啉)甲酮(B6-1)(1.20g，收率94.2％)。8-bromoquinoline-3-carboxylic acid (B1-1) (1.00g, 3.97mmol), morpholine (345mg, 3.97mmol) and N,N-diisopropylethylamine (1.03g, 7.93mmol, 1.38mL) was dissolved in N,N-dimethylformamide (10mL), and O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylfurfural was added Ionic hexafluorophosphate (1.81g, 4.76mmol) was reacted at 25°C for 1h. After the reaction, dilute with water (20 mL), neutralize with saturated sodium bicarbonate (10 mL), extract three times with ethyl acetate (90 mL), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, and filter , concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:2) to obtain (8-bromoquinolin-3-yl)(morpholine)methanone (B6-1) (1.20g , yield 94.2%).

LC-MS,M/Z(ESI):321.0[M+H] +。 LC-MS, M/Z (ESI): 321.0 [M+H] + .

第二步：(3-(吗啉-4-羰基)喹啉-8-基)硼酸(B6-2)的合成The second step: the synthesis of (3-(morpholine-4-carbonyl)quinolin-8-yl)boronic acid (B6-2)

Figure PCTCN2022130676-appb-000127
Figure PCTCN2022130676-appb-000127

将(8-溴喹啉-3-基)(吗啉)甲酮(B6-1)(1.20g，3.74mmol)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1,3,2-二噁硼戊环(1.90g，7.47mmol)和醋酸钾(1.47g，14.95mmol)溶于二氧六环(10mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(273mg，374μmol)，反应液在100℃反应2h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物(3-(吗啉-4-羰基)喹啉-8-基)硼酸(B6-2)(1.30g，粗品)。(8-bromoquinolin-3-yl)(morpholine)methanone (B6-1) (1.20g, 3.74mmol), 4,4,5,5-tetramethyl-2-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.90g, 7.47mmol) and potassium acetate (1.47g, 14.95mmol) was dissolved in dioxane (10mL), nitrogen was replaced 3 times, 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (273mg, 374μmol) was added, and the reaction solution was heated at 100°C Reaction 2h. After the reaction, cool to room temperature, dilute with water (30mL), extract three times with ethyl acetate (120mL), combine the organic phases, wash with saturated brine (40mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound (3 -(morpholine-4-carbonyl)quinolin-8-yl)boronic acid (B6-2) (1.30 g, crude product).

LC-MS,M/Z(ESI):287.0[M+H] +。 LC-MS, M/Z (ESI): 287.0 [M+H] + .

第三步：2'-甲基-6'-(3-(吗啉-4-羰基)喹啉-8-基)螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物6)的合成The third step: 2'-methyl-6'-(3-(morpholine-4-carbonyl)quinolin-8-yl)spiro[cyclopropane-1,1'-isoindoline]-3' -Synthesis of ketone (compound 6)

Figure PCTCN2022130676-appb-000128
Figure PCTCN2022130676-appb-000128

将(3-(吗啉-4-羰基)喹啉-8-基)硼酸(B6-2)(200mg，543μmol)，5'-溴-2'-甲基-螺[环丙并-1,3'-异二氢二氢吲哚]-1'-酮(A1)(50mg，173μmol)和碳酸钾(150mg，1.08mmol)溶于二氧六环(5mL)和水(1mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(197mg，270μmol)，90℃反应1h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品柱层析(EA)，冻干，得到2'-甲基-6'-(3-(吗啉-4-羰基)喹啉-8-基)螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物6)(52.0mg，收率63.5％)。(3-(morpholine-4-carbonyl)quinolin-8-yl)boronic acid (B6-2) (200mg, 543μmol), 5'-bromo-2'-methyl-spiro[cyclopropane-1, 3'-isoindoline]-1'-one (A1) (50mg, 173μmol) and potassium carbonate (150mg, 1.08mmol) were dissolved in dioxane (5mL) and water (1mL), nitrogen replacement Add 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (197mg, 270μmol) three times, and react at 90°C for 1h. After the reaction, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was chromatographed (EA) and lyophilized to give 2'-methyl-6'-(3-(morpholine-4-carbonyl)quinolin-8-yl)spiro[cyclopropane-1,1'- Isoindoline]-3'-one (compound 6) (52.0 mg, yield 63.5%).

1H NMR(400MHz,CDCl 3):δ8.94(d,1H),8.33(d,1H),8.01(d,1H),7.92(dd,1H),7.81(dd,1H),7.73–7.66(m,2H),7.37–7.35(m,1H),3.96–3.44(m,8H),2.91(s,3H),1.62–1.61(m,2H),1.44–1.38(m,2H). 1H NMR (400MHz, CDCl 3 ): δ8.94(d,1H),8.33(d,1H),8.01(d,1H),7.92(dd,1H),7.81(dd,1H),7.73–7.66( m,2H),7.37–7.35(m,1H),3.96–3.44(m,8H),2.91(s,3H),1.62–1.61(m,2H),1.44–1.38(m,2H).

LC-MS,M/Z(ESI):414.0[M+H] +。 LC-MS, M/Z (ESI): 414.0 [M+H] + .

实施例7：3’-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-6’-甲基螺环[1,5’-吡咯[3,4-b]吡啶]-7’(6'H)-酮(化合物7)的制备Example 7: 3'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-6'-methylspiro[1,5'-pyrrole[3,4 -b] the preparation of pyridine] -7'(6'H)-ketone (compound 7)

Figure PCTCN2022130676-appb-000129
Figure PCTCN2022130676-appb-000129

将(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)硼酸(B1-3)(191mg，346μmol)，3'-溴-6'-甲基-螺[环丙烷-1,5'-吡咯[3,4-b]吡啶]-7'(6'H)-酮(50mg，173μmol)和碳酸钾(59.8mg，433μmol)溶于二氧六环(5mL)和水(1mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(187mg，255μmol)，90℃反应1h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150×25mm×5μm；溶剂：A＝氨水，B＝乙腈；梯度：25％-55％，9分钟)，冻干，得到3’-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-6’-甲基螺环[1,5’-吡咯[3,4-b]吡啶]-7’(6'H)-酮(化合物7)(55mg，收率71％)。(3-(4,4-Difluoropiperidin-1-carbonyl)quinolin-8-yl)boronic acid (B1-3) (191 mg, 346 μmol), 3'-bromo-6'-methyl-spiro[ Cyclopropane-1,5'-pyrrole[3,4-b]pyridine]-7'(6'H)-one (50 mg, 173 μmol) and potassium carbonate (59.8 mg, 433 μmol) were dissolved in dioxane (5 mL ) and water (1 mL), replaced with nitrogen three times, added 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (187mg, 255μmol), and reacted at 90°C for 1h. After the reaction, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was separated by reverse-phase high-performance liquid chromatography, and the separation method was (column: Waters Xbridge 150×25mm×5 μm; solvent: A=ammonia, B=acetonitrile; gradient: 25%-55%, 9 minutes), freezing Dry to give 3'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-6'-methylspiro[1,5'-pyrrole[3,4- b] Pyridine]-7'(6'H)-one (compound 7) (55 mg, yield 71%).

LC-MS,M/Z(ESI):449.2[M+H] +。 LC-MS, M/Z (ESI): 449.2 [M+H] + .

实施例8：6'-(3-(3-氟-3-甲基氮杂环丁烷-1-羰基)喹啉-8-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物8)的制备Example 8: 6'-(3-(3-fluoro-3-methylazetidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1,1 Preparation of '-isoindoline]-3'-one (compound 8)

目标化合物8的合成路线如下：The synthetic route of target compound 8 is as follows:

Figure PCTCN2022130676-appb-000130
Figure PCTCN2022130676-appb-000130

化合物8的合成参考化合物1的合成，用3-氟-3-甲基氮杂环丁烷盐酸盐替代4,4-二氟哌啶。The synthesis of compound 8 refers to the synthesis of compound 1, and 3-fluoro-3-methylazetidine hydrochloride was used instead of 4,4-difluoropiperidine.

1H NMR(400MHz,CDCl 3):δ9.12(d,1H),8.55(d,1H),8.00(d,1H),7.94(d,1H),7.86–7.80(m,1H),7.69(t,2H),7.36(s,1H),4.48(d,2H),4.36–4.21(m,2H),2.91(s,3H),1.68(d,3H),1.61(t,2H),1.41 (t,2H). 1H NMR (400MHz, CDCl 3 ): δ9.12(d,1H),8.55(d,1H),8.00(d,1H),7.94(d,1H),7.86–7.80(m,1H),7.69( t,2H),7.36(s,1H),4.48(d,2H),4.36–4.21(m,2H),2.91(s,3H),1.68(d,3H),1.61(t,2H),1.41 (t,2H).

LC-MS,M/Z(ESI):416.2[M+H] +。 LC-MS, M/Z (ESI): 416.2 [M+H] + .

实施例9：6'-(3-(4-氧杂-7-氮杂螺[2.5]辛烷-7-羰基)喹啉-8-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物9)的制备Example 9: 6'-(3-(4-oxa-7-azaspiro[2.5]octane-7-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclopropane-1 , Preparation of 1'-isoindoline]-3'-one (compound 9)

目标化合物9的合成路线如下：The synthetic route of target compound 9 is as follows:

Figure PCTCN2022130676-appb-000131
Figure PCTCN2022130676-appb-000131

化合物9的合成参考化合物1的合成，用4-氧杂-7-氮杂螺[2.5]辛烷替代4,4-二氟哌啶，LC-MS,M/Z(ESI):440.2[M+H] +。 The synthesis of compound 9 refers to the synthesis of compound 1, with 4-oxa-7-azaspiro[2.5]octane instead of 4,4-difluoropiperidine, LC-MS, M/Z (ESI): 440.2 [M +H] + .

实施例10：2'-甲基-6'-(3-((3aR，6As)-八氢环戊烷[c]吡咯-2-羰基)喹啉-8-基)螺环[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物10)的制备Example 10: 2'-methyl-6'-(3-((3aR, 6As)-octahydrocyclopentane[c]pyrrole-2-carbonyl)quinolin-8-yl)spiro[cyclopropane- Preparation of 1,1'-isoindoline]-3'-one (compound 10)

目标化合物10的合成路线如下：The synthetic route of target compound 10 is as follows:

Figure PCTCN2022130676-appb-000132
Figure PCTCN2022130676-appb-000132

化合物10的合成参考化合物1的合成，用(3aR,6aS)-八氢环戊烷[c]吡咯替代4,4-二氟哌啶。LC-MS,M/Z(ESI):438.2[M+H] +。 The synthesis of compound 10 refers to the synthesis of compound 1, using (3aR,6aS)-octahydrocyclopentane[c]pyrrole instead of 4,4-difluoropiperidine. LC-MS, M/Z (ESI): 438.2 [M+H] + .

实施例11：6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-7'-氟-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物11)的制备Example 11: 6'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-7'-fluoro-2'-methylspiro[cyclopropane-1,1 Preparation of '-isoindoline]-3'-one (compound 11)

Figure PCTCN2022130676-appb-000133
Figure PCTCN2022130676-appb-000133

将(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)硼酸(B1-3)(90mg，282μmol)，6'-溴-7'-氟-2'-甲基螺环[环丙烷-1,1'-异二氢吲哚]-3'-酮(A3)(65.0mg，240μmol)和碳酸钾(81.1mg，587μmol)溶于二氧六环(5mL)和水(1mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(17.2mg，23.5μmol)，90℃反应1h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150×25mm×5μm；溶剂：A＝氨水，B＝乙腈；梯度：25％-55％，9分钟)，冻干，得到6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-7'-氟-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物11)(40mg，收率36.4％)。(3-(4,4-Difluoropiperidine-1-carbonyl)quinolin-8-yl)boronic acid (B1-3) (90 mg, 282 μmol), 6'-bromo-7'-fluoro-2'- Methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (A3) (65.0 mg, 240 μmol) and potassium carbonate (81.1 mg, 587 μmol) were dissolved in dioxane (5 mL ) and water (1 mL), replaced with nitrogen three times, added 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (17.2mg, 23.5μmol), and reacted at 90°C for 1h. After the reaction, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was separated by reverse-phase high-performance liquid chromatography, and the separation method was (column: Waters Xbridge 150×25mm×5 μm; solvent: A=ammonia, B=acetonitrile; gradient: 25%-55%, 9 minutes), freezing Dry to give 6'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-7'-fluoro-2'-methylspiro[cyclopropane-1,1' -Isoindoline]-3'-one (compound 11) (40 mg, yield 36.4%).

LC-MS,M/Z(ESI):466.2[M+H] +。 LC-MS, M/Z (ESI): 466.2 [M+H] + .

实施例12：6'-(7-(4,4-二氟哌啶-1-羰基)-2,3-二氢-4H-吡啶[3,2-b][1,4]恶嗪-4-基)-2'-甲基螺环[环丙烷- 1,1'-异二氢吲哚]-3'-酮(化合物12)的制备Example 12: 6'-(7-(4,4-difluoropiperidine-1-carbonyl)-2,3-dihydro-4H-pyridin[3,2-b][1,4]oxazine- Preparation of 4-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (compound 12)

目标化合物12的合成路线如下：The synthetic route of target compound 12 is as follows:

Figure PCTCN2022130676-appb-000134
Figure PCTCN2022130676-appb-000134

第一步：4-(2'-甲基-3'-氧代吡咯[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸甲酯(B12-2)的合成The first step: 4-(2'-methyl-3'-oxopyrrole[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-dihydro-2H- Synthesis of methyl pyridin[3,2-b][1,4]oxazine-7-carboxylate (B12-2)

Figure PCTCN2022130676-appb-000135
Figure PCTCN2022130676-appb-000135

将6'-溴-2'-甲基螺[环丙并-1,1'-异二氢吲哚]-3'-酮(A1)(200mg，766μmol)，3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸甲酯(B12-1)(235mg，1.07mmol)和碳酸铯(749mg，2.30mmol)溶于二氧六环(10mL)，氮气置换气3次，加入三(二亚苄基丙酮)钯(70.1mg，76.6μmol)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(88.6mg，153μmol)，在氮气保护下100℃反应2h。反应结束后，加水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150×25mm×5μm；溶剂：A＝氨水，B＝乙腈；梯度：23％-53％，9分钟)，冻干，得到纯化得到4-(2'-甲基-3'-氧代吡咯[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸甲酯(B12-2)(90mg，收率31.7％)。6'-Bromo-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (A1) (200mg, 766μmol), 3,4-dihydro-2H -pyridin[3,2-b][1,4]oxazine-7-carboxylate methyl ester (B12-1) (235 mg, 1.07 mmol) and cesium carbonate (749 mg, 2.30 mmol) dissolved in dioxane ( 10 mL), nitrogen replacement gas 3 times, added tris(dibenzylideneacetone) palladium (70.1 mg, 76.6 μmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene ( 88.6mg, 153μmol), reacted at 100°C for 2h under the protection of nitrogen. After the reaction was completed, it was diluted with water (30 mL), extracted three times with ethyl acetate (120 mL), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by reverse-phase high-performance liquid chromatography, and the separation method was (column: Waters Xbridge 150×25mm×5 μm; solvent: A=ammonia, B=acetonitrile; gradient: 23%-53%, 9 minutes), frozen Drying and purification afforded 4-(2'-methyl-3'-oxopyrrole[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-dihydro-2H - Methyl pyridin[3,2-b][1,4]oxazine-7-carboxylate (B12-2) (90 mg, yield 31.7%).

LC-MS,M/Z(ESI):366.2[M+H] +。 LC-MS, M/Z (ESI): 366.2 [M+H] + .

第二步：4-(2'-甲基-3'-氧代吡咯[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸(B12-3)的合成The second step: 4-(2'-methyl-3'-oxopyrrole[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-dihydro-2H- Synthesis of pyridin[3,2-b][1,4]oxazine-7-carboxylic acid (B12-3)

Figure PCTCN2022130676-appb-000136
Figure PCTCN2022130676-appb-000136

将4-(2'-甲基-3'-氧代吡咯[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸甲酯(B12-2)(80mg，215μmol)溶于甲醇(5mL)和水(3mL)，加入氢氧化锂(15.4mg，646μmol)，反应液在25℃反应1h。反应结束后，反应液直接浓缩，用水(10mL)稀释，1N盐酸(5mL)调节pH至5，用乙酸乙酯(60mL)萃取三次，合并有机相，浓缩得到化合物4-(2'-甲基-3'-氧代吡咯[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸(B12-3)(85mg，收率97.7％)。LC-MS,M/Z(ESI):352.1[M+H] +。 4-(2'-Methyl-3'-oxopyrrole[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-dihydro-2H-pyridin[3 ,2-b][1,4]Oxazine-7-carboxylic acid methyl ester (B12-2) (80 mg, 215 μmol) was dissolved in methanol (5 mL) and water (3 mL), and lithium hydroxide (15.4 mg, 646 μmol ), and the reaction solution was reacted at 25° C. for 1 h. After the reaction, the reaction solution was directly concentrated, diluted with water (10 mL), adjusted to pH 5 with 1N hydrochloric acid (5 mL), extracted three times with ethyl acetate (60 mL), combined the organic phases, and concentrated to obtain compound 4-(2'-methyl -3'-Oxopyrrole[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-dihydro-2H-pyridine[3,2-b][1,4 ] Oxazine-7-carboxylic acid (B12-3) (85 mg, yield 97.7%). LC-MS, M/Z (ESI): 352.1 [M+H] + .

第三步：6'-(7-(4,4-二氟哌啶-1-羰基)-2,3-二氢-4H-吡啶[3,2-b][1,4]恶嗪-4-基)-2'-甲基螺环[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物12)的合成The third step: 6'-(7-(4,4-difluoropiperidine-1-carbonyl)-2,3-dihydro-4H-pyridine[3,2-b][1,4]oxazine- Synthesis of 4-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (compound 12)

Figure PCTCN2022130676-appb-000137
Figure PCTCN2022130676-appb-000137

将4-(2'-甲基-3'-氧代吡咯[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸(B12-3)(80mg，198μmol)，4,4-二氟哌啶(3a)(36mg，297μmol)和N,N-二异丙基乙胺(51.2mg，396μmol，69μL)溶于N,N-二甲基甲酰胺(10mL)，加入O-(7-氮杂苯并三唑-1-基)-N,N,N,N-四甲基糖醛正离子六氟磷酸盐(90.4mg，237μmol)，反应液在25℃反应1h。反应结束后，用水(20mL)稀释，用乙酸乙酯(90mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Phenomenex C 18 75×30mm×3μm；溶剂：A＝水+1％体积甲酸(99％)+水，B＝乙腈；梯度：28％-58％，7分钟)，冻干，得到6'-(7-(4,4-二氟哌啶-1-羰基)-2,3-二氢-4H-吡啶[3,2-b][1,4]恶嗪-4-基)-2'-甲基螺环[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物12)(55mg，收率60.3％)。 4-(2'-Methyl-3'-oxopyrrole[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-dihydro-2H-pyridin[3 ,2-b][1,4]oxazine-7-carboxylic acid (B12-3) (80 mg, 198 μmol), 4,4-difluoropiperidine (3a) (36 mg, 297 μmol) and N,N-di Isopropylethylamine (51.2 mg, 396 μmol, 69 μL) was dissolved in N,N-dimethylformamide (10 mL), and O-(7-azabenzotriazol-1-yl)-N,N, N,N-Tetramethylfurfural positive ion hexafluorophosphate (90.4mg, 237μmol), the reaction solution was reacted at 25°C for 1h. After the reaction, it was diluted with water (20 mL), extracted three times with ethyl acetate (90 mL), combined the organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product is separated by reverse-phase high-performance liquid chromatography, and the separation method is (column: Phenomenex C 18 75 * 30mm * 3 μm; Solvent: A=water+1% volume formic acid (99%)+water, B=acetonitrile; Gradient : 28%-58%, 7 minutes), lyophilized to obtain 6'-(7-(4,4-difluoropiperidine-1-carbonyl)-2,3-dihydro-4H-pyridine[3,2 -b][1,4]oxazin-4-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (compound 12) (55mg, Yield 60.3%).

1H NMR(400MHz,DMSO-d 6):δ7.77(d,1H),7.67(d,1H),7.53-7.55(m,1H),7.31(d,1H),7.24(d,1H),4.35-4.38(m,2H),3.96-3.98(m,2H),3.59(br s,4H),2.78(s,3H),1.96-2.10(m,4H),1.66-1.73(m,2H),1.34-1.41(m,2H). 1 H NMR(400MHz,DMSO-d 6 ):δ7.77(d,1H),7.67(d,1H),7.53-7.55(m,1H),7.31(d,1H),7.24(d,1H) ,4.35-4.38(m,2H),3.96-3.98(m,2H),3.59(br s,4H),2.78(s,3H),1.96-2.10(m,4H),1.66-1.73(m,2H ),1.34-1.41(m,2H).

LC-MS,M/Z(ESI):455.2[M+H] +。 LC-MS, M/Z (ESI): 455.2 [M+H] + .

实施例13：6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-2'-甲基螺[环丁烷-1,1'-异二氢吲哚]-3'-酮(化合物 13)的制备Example 13: 6'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclobutane-1,1'-isobis Preparation of indoline]-3'-one (compound 13)

目标化合物13的合成路线如下：The synthetic route of target compound 13 is as follows:

Figure PCTCN2022130676-appb-000138
Figure PCTCN2022130676-appb-000138

第一步：N-环丁烯-2-甲基丙烷-2-亚砜酰胺(B13-2)的合成The first step: the synthesis of N-cyclobutene-2-methylpropane-2-sulfoxide amide (B13-2)

Figure PCTCN2022130676-appb-000139
Figure PCTCN2022130676-appb-000139

将环丁酮(B13-1)(20g，285mmol)溶解在四氢呋喃(200mL)中，加入2-甲基丙烷-2-亚砜酰胺(38g，314mmol)和钛酸四异丙酯(162g，571mmol)，80℃反应12h。用水(100mL)稀释，过滤，滤液用乙酸乙酯(200mL)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)纯化得到化合物N-环丁烯-2-甲基丙烷-2-亚砜酰胺(B13-2)(35g，收率70.8％)。Dissolve cyclobutanone (B13-1) (20 g, 285 mmol) in tetrahydrofuran (200 mL), add 2-methylpropane-2-sulfoxide amide (38 g, 314 mmol) and tetraisopropyl titanate (162 g, 571 mmol ), reacted at 80°C for 12h. Dilute with water (100 mL), filter, and extract the filtrate with ethyl acetate (200 mL), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=5:1-1:1) to obtain the compound N-cyclobutene-2-methylpropane-2-sulfoxide amide (B13- 2) (35 g, yield 70.8%).

LC-MS,M/Z(ESI):174.1[M+H] +。 LC-MS, M/Z (ESI): 174.1 [M+H] + .

第二步：4-溴-2-(1-((叔丁基亚砜基)氨基)环丁基)苯甲酸甲酯(B13-3)的合成The second step: Synthesis of methyl 4-bromo-2-(1-((tert-butylsulfoxide)amino)cyclobutyl)benzoate (B13-3)

Figure PCTCN2022130676-appb-000140
Figure PCTCN2022130676-appb-000140

将4-溴-2-碘苯甲酸甲酯(3g，8.8mmol)溶解在四氢呋喃(30mL)中，降温至-78℃，加入2.5M的正丁基锂(4.22ml，10.56mmol)，-78℃反应0.5h，加入N-环丁烯-2-甲基丙烷-2-亚砜酰胺(1.83g，10.56mmol)，-78℃反应3h。用水(50mL)稀释，乙酸乙酯(50mL)萃取，合并有机相，用饱和食盐 水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1-1:1)纯化得到化合物4-溴-2-(1-((叔丁基亚砜基)氨基)环丁基)苯甲酸甲酯(B13-3)(2.5g，收率73.2％)。Dissolve methyl 4-bromo-2-iodobenzoate (3g, 8.8mmol) in tetrahydrofuran (30mL), cool to -78°C, add 2.5M n-butyllithium (4.22ml, 10.56mmol), -78 After reacting at ℃ for 0.5h, add N-cyclobutene-2-methylpropane-2-sulfoxide amide (1.83g, 10.56mmol), and react at -78℃ for 3h. Dilute with water (50 mL), extract with ethyl acetate (50 mL), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=3:1-1:1) to obtain the compound 4-bromo-2-(1-((tert-butylsulfoxide)amino) Methyl cyclobutyl)benzoate (B13-3) (2.5 g, yield 73.2%).

LC-MS,M/Z(ESI):388.0[M+H] +。 LC-MS, M/Z (ESI): 388.0 [M+H] + .

第三步：2-(1-氨基环丁基)-4-溴苯甲酸甲酯盐酸盐(B13-4)的合成The third step: the synthesis of 2-(1-aminocyclobutyl)-4-bromobenzoic acid methyl ester hydrochloride (B13-4)

Figure PCTCN2022130676-appb-000141
Figure PCTCN2022130676-appb-000141

将4-溴-2-(1-((叔丁基亚砜基)氨基)环丁基)苯甲酸甲酯(2g，5.15mmol)溶解在二氧六环(20mL)中，加入4M的氯化氢二氧六环溶液(6.4ml)，室温反应1h，旋干得到化合物4-溴-2-(1-((叔丁基亚砜基)氨基)环丁基)苯甲酸甲酯盐酸盐(B13-4)(1.46g，收率100％)。Dissolve methyl 4-bromo-2-(1-((tert-butylsulfoxide)amino)cyclobutyl)benzoate (2 g, 5.15 mmol) in dioxane (20 mL) and add 4M hydrogen chloride Dioxane solution (6.4ml), reacted at room temperature for 1h, and spin-dried to obtain compound 4-bromo-2-(1-((tert-butylsulfoxide) amino)cyclobutyl)methyl benzoate hydrochloride ( B13-4) (1.46 g, yield 100%).

LC-MS,M/Z(ESI):284.0[M+H] +。 LC-MS, M/Z (ESI): 284.0 [M+H] + .

第四步：6'-溴代吡咯[环丁烷-1,1'-异二氢吲哚]-3'-酮(B13-5)的合成The fourth step: Synthesis of 6'-bromopyrrole[cyclobutane-1,1'-isoindoline]-3'-one (B13-5)

Figure PCTCN2022130676-appb-000142
Figure PCTCN2022130676-appb-000142

将4-溴-2-(1-((叔丁基亚砜基)氨基)环丁基)苯甲酸甲酯盐酸盐(1g，3.12mmol)溶解在DMF(10mL)中，加入碳酸钾(1.29g，9.36mmol)，60℃反应12h。用水(20mL)稀释，乙酸乙酯(20mL)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1-1:1)纯化得到化合物6'-溴代吡咯[环丁烷-1,1'-异二氢吲哚]-3'-酮(B13-5)(600mg，收率76％)。Dissolve methyl 4-bromo-2-(1-((tert-butylsulfoxide)amino)cyclobutyl)benzoate hydrochloride (1 g, 3.12 mmol) in DMF (10 mL) and add potassium carbonate ( 1.29g, 9.36mmol), reacted at 60°C for 12h. Dilute with water (20 mL), extract with ethyl acetate (20 mL), combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 3:1-1:1) to obtain the compound 6'-bromopyrrole[cyclobutane-1,1'-isoindoline Indole]-3'-one (B13-5) (600 mg, yield 76%).

LC-MS,M/Z(ESI):252.0[M+H] +。 LC-MS, M/Z (ESI): 252.0 [M+H] + .

第五步：6'-溴-2'-甲基螺环[环丁烷-1,1'-异二氢吲哚]-3'-酮(B13-6)的合成Step 5: Synthesis of 6'-bromo-2'-methylspiro[cyclobutane-1,1'-isoindoline]-3'-one (B13-6)

Figure PCTCN2022130676-appb-000143
Figure PCTCN2022130676-appb-000143

将6'-溴代吡咯[环丁烷-1,1'-异二氢吲哚]-3'-酮(500mg，1.98mmol)溶解在DMF(5mL)中，加入碳酸钾(822mg，5.95mmol)，室温反应1h。用水(20mL)稀释，乙酸乙酯(20mL)萃取，合并 有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)纯化得到化合物6'-溴-2'-甲基螺环[环丁烷-1,1'-异二氢吲哚]-3'-酮(B13-6)(400mg，收率76％)。Dissolve 6'-bromopyrrole[cyclobutane-1,1'-isoindoline]-3'-one (500mg, 1.98mmol) in DMF (5mL), add potassium carbonate (822mg, 5.95mmol ), react at room temperature for 1h. Dilute with water (20 mL), extract with ethyl acetate (20 mL), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1-1:1) to obtain the compound 6'-bromo-2'-methyl spiro[cyclobutane-1,1 '-Isoindoline]-3'-one (B13-6) (400 mg, yield 76%).

LC-MS,M/Z(ESI):266.0[M+H] +。 LC-MS, M/Z (ESI): 266.0 [M+H] + .

第六步：6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-2'-甲基螺[环丁烷-1,1'-异二氢吲哚]-3'-酮(化合物13)的合成Step 6: 6'-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-2'-methylspiro[cyclobutane-1,1'-isobis Synthesis of Indoline]-3'-one (Compound 13)

Figure PCTCN2022130676-appb-000144
Figure PCTCN2022130676-appb-000144

将[3-(4,4-二氟哌啶-1-羰基)-8-喹啉基]硼酸(160mg，0.497mmol)，6'-溴-2'-甲基螺环[环丁烷-1,1'-异二氢吲哚]-3'-酮(159mg，0.59mol)和碳酸钠(158mg，1.49mmol)溶于二氧六环(5mL)和水(1mL)，氮气置换3次，加入1,1-双(二苯基磷)二茂铁氯化钯(II)(72.8mg，0.099mmol)，90℃反应1h。反应结束后，冷却至室温，用水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-1:1)纯化得到化合物6'-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-2'-甲基螺[环丁烷-1,1'-异二氢吲哚]-3'-酮(化合物13)(80mg，收率34.9％)。[3-(4,4-Difluoropiperidine-1-carbonyl)-8-quinolyl]boronic acid (160mg, 0.497mmol), 6'-bromo-2'-methylspiro[cyclobutane- 1,1'-isoindoline]-3'-one (159mg, 0.59mol) and sodium carbonate (158mg, 1.49mmol) were dissolved in dioxane (5mL) and water (1mL), and replaced with nitrogen three times , added 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride (72.8mg, 0.099mmol), and reacted at 90°C for 1h. After the reaction, cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (120 mL), combine the organic phases, wash with saturated brine (40 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 5:1-1:1) to obtain the compound 6'-(3-(4,4-difluoropiperidine-1-carbonyl )quinolin-8-yl)-2'-methylspiro[cyclobutane-1,1'-isoindoline]-3'-one (compound 13) (80 mg, yield 34.9%).

LC-MS,M/Z(ESI):462.2[M+H] +。 LC-MS, M/Z (ESI): 462.2 [M+H] + .

实施例14：6-(3-(4,4-二氟哌啶-1-羰基)喹啉-8-基)-2-甲基螺[异二氢吲哚-1,3'-氧杂环丁烷]-3-酮(化合物14)的制备Example 14: 6-(3-(4,4-difluoropiperidine-1-carbonyl)quinolin-8-yl)-2-methylspiro[isoindoline-1,3'-oxa Preparation of cyclobutane]-3-one (compound 14)

Figure PCTCN2022130676-appb-000145
Figure PCTCN2022130676-appb-000145

化合物14的合成参考化合物13，起始原料用3-氧杂环丁酮替代环丁酮。LC-MS,M/Z(ESI):464.2[M+H] +。 Compound 14 was synthesized with reference to compound 13, and the starting material was replaced by cyclobutanone with 3-oxetanone. LC-MS, M/Z (ESI): 464.2 [M+H] + .

实施例15：6'-(7-(4,4-二氟哌啶-1-羰基)-2,2-二甲基-2,3-二氢-4H-吡啶[3,2-b][1,4]恶嗪-4-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物15)的制备Example 15: 6'-(7-(4,4-difluoropiperidine-1-carbonyl)-2,2-dimethyl-2,3-dihydro-4H-pyridine[3,2-b] Preparation of [1,4]oxazin-4-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (compound 15)

目标化合物15的合成路线如下：The synthetic route of target compound 15 is as follows:

Figure PCTCN2022130676-appb-000146
Figure PCTCN2022130676-appb-000146

第一步：2,2-二甲基-4-(2'-甲基-3'-氧化螺[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸乙酯(B15-2)The first step: 2,2-dimethyl-4-(2'-methyl-3'-oxyspiro[cyclopropane-1,1'-isoindoline]-6'-yl)-3, 4-Dihydro-2H-pyridine[3,2-b][1,4]oxazine-7-carboxylic acid ethyl ester (B15-2)

Figure PCTCN2022130676-appb-000147
Figure PCTCN2022130676-appb-000147

将6'-溴-2'-甲基螺[环丙烷-1,3'-异二氢吲哚]-3'-酮(A1)(200mg，766μmol)，2,2-二甲基-3,4-二氢-2H-吡啶[3,2-b][1,4]噁嗪-7-羧酸乙酯(B15-1)(253mg，1.07mmol)和碳酸铯(749mg，2.30mmol)溶于二氧六环(10mL)，氮气置换气3次，加入三(二亚苄基丙酮)钯(70.1mg，76.6μmol)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(88.6mg，153μmol)，在氮气保护下100℃反应2h。反应结束后，加水(30mL)稀释，用乙酸乙酯(120mL)萃取三次，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Waters Xbridge 150*25mm*5um；溶剂：A＝氨水，B＝乙腈；梯度：23％-53％，9分钟)，冻干，得到纯化得到2,2-二甲基-4-(2'-甲基-3'-氧化螺[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸乙酯(B15-2)(125mg，收率40％)。6'-Bromo-2'-methylspiro[cyclopropane-1,3'-isoindoline]-3'-one (A1) (200mg, 766μmol), 2,2-dimethyl-3 , ethyl 4-dihydro-2H-pyridine[3,2-b][1,4]oxazine-7-carboxylate (B15-1) (253mg, 1.07mmol) and cesium carbonate (749mg, 2.30mmol) Dissolve in dioxane (10 mL), replace the gas with nitrogen three times, add tris(dibenzylideneacetone) palladium (70.1 mg, 76.6 μmol) and 4,5-bis(diphenylphosphine)-9,9- Dimethylxanthene (88.6 mg, 153 μmol) was reacted at 100° C. for 2 h under the protection of nitrogen. After the reaction was completed, it was diluted with water (30 mL), extracted three times with ethyl acetate (120 mL), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is separated by reverse-phase high-performance liquid chromatography, and the separation method is (column: Waters Xbridge 150*25mm*5um; solvent: A=ammonia, B=acetonitrile; gradient: 23%-53%, 9 minutes), frozen Drying and purification afforded 2,2-dimethyl-4-(2'-methyl-3'-oxyspiro[cyclopropane-1,1'-isoindoline]-6'-yl)-3 , ethyl 4-dihydro-2H-pyridine[3,2-b][1,4]oxazine-7-carboxylate (B15-2) (125 mg, yield 40%).

LC-MS,M/Z(ESI):408.2[M+H] +。 LC-MS, M/Z (ESI): 408.2 [M+H] + .

第二步：2,2-二甲基-4-(2'-甲基-3'-氧化螺[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸(B15-3)The second step: 2,2-dimethyl-4-(2'-methyl-3'-oxidized spiro[cyclopropane-1,1'-isoindoline]-6'-yl)-3, 4-Dihydro-2H-pyridine[3,2-b][1,4]oxazine-7-carboxylic acid (B15-3)

Figure PCTCN2022130676-appb-000148
Figure PCTCN2022130676-appb-000148

将2,2-二甲基-4-(2'-甲基-3'-氧化螺[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸乙酯(B15-2)(90mg，220μmol)溶于甲醇(5mL)和水(3mL)，加入氢氧化锂(15.4mg,646μmol)，反应液在25℃反应过夜。反应结束后，反应液直接浓缩，用水(10mL)稀释，1N盐酸(5mL)调节pH至5，用乙酸乙酯(60mL)萃取三次，合并有机相，浓缩得到化合物2,2-二甲基-4-(2'-甲基-3'-氧化螺[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸(B15-3)(66mg，收率98％)。2,2-Dimethyl-4-(2'-methyl-3'-oxyspiro[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-di Hydrogen-2H-pyridine[3,2-b][1,4]oxazine-7-carboxylate ethyl ester (B15-2) (90 mg, 220 μmol) was dissolved in methanol (5 mL) and water (3 mL) and added hydrogen Lithium oxide (15.4mg, 646μmol), the reaction solution was reacted overnight at 25°C. After the reaction, the reaction solution was directly concentrated, diluted with water (10 mL), adjusted to pH 5 with 1N hydrochloric acid (5 mL), extracted three times with ethyl acetate (60 mL), combined the organic phases, and concentrated to obtain compound 2,2-dimethyl- 4-(2'-Methyl-3'-oxyspiro[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-dihydro-2H-pyridin[3,2 -b] [1,4]oxazine-7-carboxylic acid (B15-3) (66 mg, yield 98%).

LC-MS,M/Z(ESI):380.2[M+H] +。 LC-MS, M/Z (ESI): 380.2 [M+H] + .

第三步：6'-(7-(4,4-二氟哌啶-1-羰基)-2,2-二甲基-2,3-二氢-4H-吡啶[3,2-b][1,4]恶嗪-4-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物15)The third step: 6'-(7-(4,4-difluoropiperidine-1-carbonyl)-2,2-dimethyl-2,3-dihydro-4H-pyridine[3,2-b] [1,4]oxazin-4-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (compound 15)

Figure PCTCN2022130676-appb-000149
Figure PCTCN2022130676-appb-000149

将2,2-二甲基-4-(2'-甲基-3'-氧化螺[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸(B15-3)(75mg，198μmol)，4,4-二氟哌啶(36.0mg，297μmol)和N,N-二异丙基乙胺(51.2mg，396μmol，69μL)溶于N,N-二甲基甲酰胺(10mL)，加入O-(7-氮杂苯并三唑-1-YL)-N,N,N,N-四甲基糖醛正离子六氟磷酸盐(90.4mg，237μmol)，反应液在25℃反应1h。反应结束后，用水(20mL)稀释，用乙酸乙酯(90mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过反相高效液相色谱法进行分离，分离方法为(柱子：Phenomenex C 18 75*30mm*3um；溶剂：A＝水+1％体积甲酸(99％)+水，B＝乙腈；梯度：28％-58％，7分钟)，冻干，得到化合物15(62mg，收率65％)。 2,2-Dimethyl-4-(2'-methyl-3'-oxyspiro[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-di Hydrogen-2H-pyridine[3,2-b][1,4]oxazine-7-carboxylic acid (B15-3) (75 mg, 198 μmol), 4,4-difluoropiperidine (36.0 mg, 297 μmol) and N,N-Diisopropylethylamine (51.2 mg, 396 μmol, 69 μL) was dissolved in N,N-dimethylformamide (10 mL), O-(7-azabenzotriazole-1-YL) was added -N,N,N,N-Tetramethylfurfural positive ion hexafluorophosphate (90.4mg, 237μmol), the reaction solution was reacted at 25°C for 1h. After the reaction, it was diluted with water (20 mL), extracted three times with ethyl acetate (90 mL), combined the organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product is separated by reverse-phase high-performance liquid chromatography, and the separation method is (column: Phenomenex C 18 75*30mm*3um; solvent: A=water+1% volume formic acid (99%)+water, B=acetonitrile; gradient : 28%-58%, 7 minutes), lyophilized to obtain compound 15 (62 mg, yield 65%).

1H NMR(400MHz,CDCl 3):δ7.89(d,1H),7.84(d,1H),7.35(dd,1H),7.19(d,1H),7.08(d,1H),3.74(s,4H),3.67(s,2H),2.87(s,3H),2.07–1.93(m,4H),1.58–1.56(m,2H),1.41(s,6H),1.36–1.31(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ7.89(d,1H),7.84(d,1H),7.35(dd,1H),7.19(d,1H),7.08(d,1H),3.74(s ,4H),3.67(s,2H),2.87(s,3H),2.07–1.93(m,4H),1.58–1.56(m,2H),1.41(s,6H),1.36–1.31(m,2H ).

LC-MS,M/Z(ESI):483.2[M+H] +。 LC-MS, M/Z (ESI): 483.2 [M+H] + .

实施例16：7-(4,4-二氟哌啶-1-羰基)-1-乙基-4-(2-甲基-3-氧基-2,3-二氢-[1,2,4]三唑[4,3-a]吡啶-7-基)-3,4-二氢喹啉-2(1H)-酮(化合物16)的制备Example 16: 7-(4,4-difluoropiperidine-1-carbonyl)-1-ethyl-4-(2-methyl-3-oxyl-2,3-dihydro-[1,2 ,4] Preparation of triazol[4,3-a]pyridin-7-yl)-3,4-dihydroquinolin-2(1H)-one (compound 16)

目标化合物16的合成路线如下：The synthetic route of target compound 16 is as follows:

Figure PCTCN2022130676-appb-000150
Figure PCTCN2022130676-appb-000150

第一步：3-(乙基氨基)苯甲酸甲酯(B16-2)Step 1: Methyl 3-(ethylamino)benzoate (B16-2)

Figure PCTCN2022130676-appb-000151
Figure PCTCN2022130676-appb-000151

将3-氨基苯甲酸甲酯(B16-1)(5g，33.1mmol)加至厚壁耐压瓶，加N,N-二甲基甲酰胺(40mL)，再加入碳酸钾(5.94g，43.0mmol)与碘乙烷(6.19g,39.7mmol)，55℃反应15h。反应结束后，冷却至室温，加水(50mL)稀释，用乙酸乙酯(50mL×3)萃取，合并有机相，用水(30mL)洗涤，再用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝40:1-15:1)纯化得到化合物3-(乙基氨基)苯甲酸甲酯(B16-2)(3.66g，收 率61.7％)。Add methyl 3-aminobenzoate (B16-1) (5g, 33.1mmol) to a thick-walled pressure bottle, add N,N-dimethylformamide (40mL), and then add potassium carbonate (5.94g, 43.0 mmol) reacted with ethyl iodide (6.19g, 39.7mmol) at 55°C for 15h. After the reaction, cool to room temperature, dilute with water (50mL), extract with ethyl acetate (50mL×3), combine the organic phases, wash with water (30mL), then wash with saturated brine (30mL), and dry over anhydrous sodium sulfate , filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=40:1-15:1) to obtain the compound 3-(ethylamino)benzoic acid methyl ester (B16-2) (3.66g , yield 61.7%).

LC-MS,M/Z(ESI):180.1[M+H] +。 LC-MS, M/Z (ESI): 180.1 [M+H] + .

第二步：3-(2-氰基-N-乙基乙酰氨基)苯甲酸甲酯(B16-3)The second step: methyl 3-(2-cyano-N-ethylacetamido)benzoate (B16-3)

Figure PCTCN2022130676-appb-000152
Figure PCTCN2022130676-appb-000152

将3-(乙基氨基)苯甲酸甲酯(B16-2)(2g，11.2mmol)溶于二氯甲烷(14mL)，0℃搅拌，滴加二环己基碳二亚胺(2.6g,12.6mmol)与4-二甲氨基吡啶(71mg,0.58mmol)的二氯甲烷溶液(25mL)。0℃反应2小时，反应液过滤，滤饼用二氯甲烷(50mL)洗，滤液浓缩得到得到粗品。粗产品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1-3:2)纯化得到化合物3-(2-氰基-N-乙基乙酰氨基)苯甲酸甲酯(B16-3)(2.45g，收率89％)。Dissolve methyl 3-(ethylamino)benzoate (B16-2) (2g, 11.2mmol) in dichloromethane (14mL), stir at 0°C, add dicyclohexylcarbodiimide (2.6g, 12.6 mmol) and 4-dimethylaminopyridine (71 mg, 0.58 mmol) in dichloromethane (25 mL). React at 0°C for 2 hours, filter the reaction solution, wash the filter cake with dichloromethane (50 mL), and concentrate the filtrate to obtain a crude product. The crude product was purified by silica gel column separation and purification (petroleum ether: ethyl acetate (V/V) = 5:1-3:2) to obtain the compound 3-(2-cyano-N-ethylacetamido) methyl benzoate (B16-3) (2.45 g, yield 89%).

LC-MS,M/Z(ESI):247.2[M+H] +。 LC-MS, M/Z (ESI): 247.2 [M+H] + .

第三步：2-氰基-4-乙基-3-氧代-3,4-二氢喹喔啉-6-羧酸甲酯(B16-4)The third step: 2-cyano-4-ethyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester (B16-4)

Figure PCTCN2022130676-appb-000153
Figure PCTCN2022130676-appb-000153

将3-(2-氰基-N-乙基乙酰氨基)苯甲酸甲酯(B16-3)(1.97g，8.0mmol)溶于乙腈(60mL)，加亚硝酸叔丁酯(0.83g,8.0mmol)、碳酸铯(2.6g,8.0mmol)，再加入冰醋酸(0.48g,8.0mmol)与粉末分子筛(4g)，反应液在100℃反应6h，冷却至室温，缓慢滴加连二亚硫酸钠(4.8g,27.6mmol)的乙醇(40mL)与水(80mL)溶液，滴加完毕后，90℃反应2.5小时。反应结束后，冷却至室温，浓缩，用饱和碳酸氢钠溶液(400mL)调节pH至8，用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(100mL)洗涤，浓缩得到粗产品2-氰基-4-乙基-3-氧代-3,4-二氢喹喔啉-6-羧酸甲酯(B16-4)直接用于下一步反应。Dissolve methyl 3-(2-cyano-N-ethylacetamido)benzoate (B16-3) (1.97g, 8.0mmol) in acetonitrile (60mL), add tert-butyl nitrite (0.83g, 8.0 mmol), cesium carbonate (2.6g, 8.0mmol), then add glacial acetic acid (0.48g, 8.0mmol) and powder molecular sieve (4g), the reaction solution was reacted at 100°C for 6h, cooled to room temperature, slowly added dropwise sodium dithionite ( 4.8g, 27.6mmol) of ethanol (40mL) and water (80mL) solution, after the dropwise addition, react at 90°C for 2.5 hours. After the reaction, cool to room temperature, concentrate, adjust the pH to 8 with saturated sodium bicarbonate solution (400 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (100 mL), and concentrate to obtain The crude product 2-cyano-4-ethyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester (B16-4) was directly used in the next reaction.

LC-MS,M/Z(ESI):258.1[M+H] +。 LC-MS, M/Z (ESI): 258.1 [M+H] + .

第四步：4-乙基-3-氧代-1,2,3,4-四氢喹喔啉-6-羧酸甲酯(B16-5)The fourth step: methyl 4-ethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (B16-5)

Figure PCTCN2022130676-appb-000154
Figure PCTCN2022130676-appb-000154

将2-氰基-4-乙基-3-氧代-3,4-二氢喹喔啉-6-羧酸甲酯(B16-4)(1.85g，8.0mmol)溶于四氢呋喃(40mL)，加入硼氢化钠(1.51g,39.9mmol)，反应液在50℃反应1.5小时。反应结束后，冷却至室温，0℃滴加饱和氯化铵溶液(40mL)淬灭，用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，浓缩得到粗产品，粗产品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:1)纯化得到化合物4-乙基-3-氧代-1,2,3,4-四氢喹喔啉-6-羧酸甲酯(B16-5)(1.37g，收率73％)。Dissolve methyl 2-cyano-4-ethyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (B16-4) (1.85 g, 8.0 mmol) in tetrahydrofuran (40 mL) , sodium borohydride (1.51g, 39.9mmol) was added, and the reaction solution was reacted at 50°C for 1.5 hours. After the reaction, cool to room temperature, dropwise add saturated ammonium chloride solution (40mL) at 0°C to quench, extract with ethyl acetate (50mL×3), combine organic phases, wash with saturated brine (30mL), anhydrous sulfuric acid Sodium drying, concentration to obtain crude product, the crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V/V) = 2:1) and purified to obtain compound 4-ethyl-3-oxo-1,2,3 , Methyl 4-tetrahydroquinoxaline-6-carboxylate (B16-5) (1.37 g, yield 73%).

LC-MS,M/Z(ESI):235.2[M+H] +。 LC-MS, M/Z (ESI): 235.2 [M+H] + .

第五步：甲基4-乙基-1-(2-甲基-3-氧基-2,3-二氢-[1,2,4]三唑基[4,3-a]吡啶-7-基)-3-氧基-1,2,3,4-四氢喹啉-6-羧酸盐(B16-6)Step 5: Methyl 4-ethyl-1-(2-methyl-3-oxyl-2,3-dihydro-[1,2,4]triazolyl[4,3-a]pyridine- 7-yl)-3-oxyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (B16-6)

Figure PCTCN2022130676-appb-000155
Figure PCTCN2022130676-appb-000155

将7-溴-2-甲基-[1,2,4]三唑基[4,3-a]吡啶-3(2H)-酮(A5)(49mg，0.22mmol)，4-乙基-3-氧代-1,2,3,4-四氢喹喔啉-6-羧酸甲酯(B16-5)(50mg，0.21mmol)和碳酸铯(209mg，0.64mmol)溶于二氧六环(10mL)，氮气置换气3次，加入三(二亚苄基丙酮)钯(29.3mg，0.03mmol)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(37.1mg，0.06mmol)，在氮气保护下100℃反应12h。反应结束后，加水(20mL)稀释，用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗产品用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝1:1)纯化得到化合物甲基4-乙基-1-(2-甲基-3-氧基-2,3-二氢-[1,2,4]三唑基[4,3-a]吡啶-7-基)-3-氧基-1,2,3,4-四氢喹啉-6-羧酸盐(B16-6)(19mg，收率23.5％)。7-Bromo-2-methyl-[1,2,4]triazolyl[4,3-a]pyridin-3(2H)-one (A5) (49 mg, 0.22 mmol), 4-ethyl- Methyl 3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (B16-5) (50 mg, 0.21 mmol) and cesium carbonate (209 mg, 0.64 mmol) were dissolved in dioxane ring (10 mL), nitrogen purged 3 times, tris(dibenzylideneacetone)palladium (29.3 mg, 0.03 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxa Anthracene (37.1mg, 0.06mmol) was reacted at 100°C for 12h under the protection of nitrogen. After the reaction, it was diluted with water (20 mL), extracted with ethyl acetate (30 mL×3), combined organic phases, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether:ethyl acetate (V/V)=1:1) to obtain the compound methyl 4-ethyl-1-(2-methyl-3-oxyl-2,3 -Dihydro-[1,2,4]triazolyl[4,3-a]pyridin-7-yl)-3-oxyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid Salt (B16-6) (19 mg, yield 23.5%).

LC-MS,M/Z(ESI):382.3[M+H] +。 LC-MS, M/Z (ESI): 382.3 [M+H] + .

第六步：4-乙基-1-(2-甲基-3-氧代-2,3-二氢-[1,2,4]三唑并[4,3-a]吡啶-7-基)-3-氧代-1,2,3,4-四氢喹啉-6-羧酸(B16-7)The sixth step: 4-ethyl-1-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7- Base)-3-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (B16-7)

Figure PCTCN2022130676-appb-000156
Figure PCTCN2022130676-appb-000156

将甲基4-乙基-1-(2-甲基-3-氧基-2,3-二氢-[1,2,4]三唑基[4,3-a]吡啶-7-基)-3-氧基-1,2,3,4-四氢喹啉-6-羧酸盐(B16-6)(19mg，0.05mmol)溶于甲醇(1mL)和水(1mL)，加入氢氧化锂(10mg,0.4mmol)，反应液在25℃反应过夜。反应结束后，反应液直接浓缩，用水(10mL)稀释，1N盐酸(5mL)调节pH至5，用乙酸乙酯(20mL×3)萃取，合并有机相，浓缩得到化合物4-乙基-1-(2-甲基-3-氧代-2,3-二氢-[1,2,4]三唑并[4,3-a]吡啶-7-基)-3-氧代-1,2,3,4-四氢喹啉-6-羧酸(B16-7)(18mg，收率97％)。Methyl 4-ethyl-1-(2-methyl-3-oxyl-2,3-dihydro-[1,2,4]triazolyl[4,3-a]pyridin-7-yl )-3-Oxy-1,2,3,4-tetrahydroquinoline-6-carboxylate (B16-6) (19 mg, 0.05 mmol) was dissolved in methanol (1 mL) and water (1 mL), and hydrogen Lithium oxide (10mg, 0.4mmol), the reaction solution was reacted overnight at 25°C. After the reaction, the reaction solution was directly concentrated, diluted with water (10mL), adjusted to pH 5 with 1N hydrochloric acid (5mL), extracted with ethyl acetate (20mL×3), combined the organic phases, and concentrated to obtain the compound 4-ethyl-1- (2-Methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-oxo-1,2 , 3,4-Tetrahydroquinoline-6-carboxylic acid (B16-7) (18 mg, yield 97%).

LC-MS,M/Z(ESI):366.1[M-H] +。 LC-MS, M/Z (ESI): 366.1 [MH] + .

第七步：7-(4,4-二氟哌啶-1-羰基)-1-乙基-4-(2-甲基-3-氧基-2,3-二氢-[1,2,4]三唑[4,3-a]吡啶-7-基)-3,4-二氢喹啉-2(1H)-酮(化合物16)The seventh step: 7-(4,4-difluoropiperidine-1-carbonyl)-1-ethyl-4-(2-methyl-3-oxyl-2,3-dihydro-[1,2 ,4] Triazol[4,3-a]pyridin-7-yl)-3,4-dihydroquinolin-2(1H)-one (compound 16)

Figure PCTCN2022130676-appb-000157
Figure PCTCN2022130676-appb-000157

将4-乙基-1-(2-甲基-3-氧代-2,3-二氢-[1,2,4]三唑并[4,3-a]吡啶-7-基)-3-氧代-1,2,3,4-四氢喹啉-6-羧酸(B16-7)(18mg，0.05mmol)，4,4-二氟哌啶(9.3mg，0.08mmol)和N,N-二异丙基乙胺(26mg，0.2mol)溶于N,N-二甲基甲酰胺(5mL)，加入O-(7-氮杂苯并三唑-1-YL)-N,N,N,N-四甲基糖醛正离子六氟磷酸盐(23mg，0.06mmol)，反应液在25℃反应1h。反应结束后，用水(20mL)稀释，用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品用硅胶柱分离纯化(二氯甲烷:甲醇(V/V)＝4:1)纯化得到化合物7-(4,4-二氟哌啶-1-羰基)-1-乙基-4-(2-甲基-3-氧基-2,3-二氢-[1,2,4]三唑[4,3-a]吡啶-7-基)-3,4-二氢喹啉-2(1H)-酮(化合物16)(18mg，收率75％)。4-Ethyl-1-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)- 3-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (B16-7) (18mg, 0.05mmol), 4,4-difluoropiperidine (9.3mg, 0.08mmol) and N,N-diisopropylethylamine (26mg, 0.2mol) was dissolved in N,N-dimethylformamide (5mL), and O-(7-azabenzotriazole-1-YL)-N ,N,N,N-Tetramethylfurfural positive ion hexafluorophosphate (23mg, 0.06mmol), the reaction solution was reacted at 25°C for 1h. After the reaction, it was diluted with water (20 mL), extracted with ethyl acetate (30 mL×3), combined organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane:methanol (V/V)=4:1) to obtain compound 7-(4,4-difluoropiperidine-1-carbonyl)-1-ethyl-4- (2-Methyl-3-oxyl-2,3-dihydro-[1,2,4]triazol[4,3-a]pyridin-7-yl)-3,4-dihydroquinoline- 2(1H)-Kone (compound 16) (18 mg, yield 75%).

LC-MS,M/Z(ESI):471.5[M+H] +。 LC-MS, M/Z (ESI): 471.5 [M+H] + .

1H NMR(400MHz,CDCl 3):δ7.70–7.66(m,1H),7.25(s,1H),7.09–7.03(m,2H),6.45(dd,2H),4.28(s,2H),4.07(q,2H),3.77(s,4H),3.64(s,3H),2.04(s,4H),1.34(t,3H). 1 H NMR (400MHz, CDCl 3 ): δ7.70–7.66(m,1H),7.25(s,1H),7.09–7.03(m,2H),6.45(dd,2H),4.28(s,2H) ,4.07(q,2H),3.77(s,4H),3.64(s,3H),2.04(s,4H),1.34(t,3H).

实施例17：6'-(7-(3-氟-3-甲基氮杂环丁烷-1-羰基)-2,2-二甲基-2,3-二氢-4H-吡啶[3,2-b][1,4]恶嗪-4-基)-2'-甲基螺[环丙烷-1,1'-异二氢吲哚]-3'-酮(化合物17)的制备Example 17: 6'-(7-(3-fluoro-3-methylazetidine-1-carbonyl)-2,2-dimethyl-2,3-dihydro-4H-pyridine[3 ,2-b][1,4]oxazin-4-yl)-2'-methylspiro[cyclopropane-1,1'-isoindoline]-3'-one (compound 17)

目标化合物17的合成路线如下：The synthetic route of target compound 17 is as follows:

Figure PCTCN2022130676-appb-000158
Figure PCTCN2022130676-appb-000158

将2,2-二甲基-4-(2'-甲基-3'-氧化螺[环丙烷-1,1'-异二氢吲哚]-6'-基)-3,4-二氢-2H-吡啶[3,2-b][1,4]恶嗪-7-羧酸(1-3)(75mg，198μmol)，4,4-二氟哌啶(26.5mg，297μmol)和N,N-二异丙基乙胺(51.2mg，396μmol，69μL)溶于N,N-二甲基甲酰胺(10mL)，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(90.4mg，237μmol)，反应液在25℃反应1h。反应结束后，用水(20mL)稀释，用乙酸乙酯(90mL)萃取三次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品通过柱层析，DCM/MeOH(v/v)＝15/1,得到化合物17(60mg，收率67％)。2,2-Dimethyl-4-(2'-methyl-3'-oxyspiro[cyclopropane-1,1'-isoindoline]-6'-yl)-3,4-di Hydrogen-2H-pyridine[3,2-b][1,4]oxazine-7-carboxylic acid (1-3) (75 mg, 198 μmol), 4,4-difluoropiperidine (26.5 mg, 297 μmol) and N,N-Diisopropylethylamine (51.2 mg, 396 μmol, 69 μL) was dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole)-N, N,N',N'-Tetramethylurea hexafluorophosphate (90.4mg, 237μmol), the reaction solution was reacted at 25°C for 1h. After the reaction, it was diluted with water (20 mL), extracted three times with ethyl acetate (90 mL), combined the organic phases, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was subjected to column chromatography, DCM/MeOH (v/v)=15/1, to obtain compound 17 (60 mg, yield 67%).

LC-MS,M/Z(ESI):451.1[M+H] +。 LC-MS, M/Z (ESI): 451.1 [M+H] + .

1H NMR(400MHz,CDCl 3)δ8.01(d,1H),7.90(d,1H),7.42(d,1H),7.36(dd,1H),7.08(d,1H),4.53-4.28(m,2H),4.26-4.13(m,2H),3.67(s,2H),2.87(s,3H),1.66(s,1H),1.61(s,2H),1.60-1.58(m,2H),1.41(s,6H),1.37-1.32(m,2H). 1 H NMR (400MHz, CDCl 3 )δ8.01(d,1H),7.90(d,1H),7.42(d,1H),7.36(dd,1H),7.08(d,1H),4.53-4.28( m,2H),4.26-4.13(m,2H),3.67(s,2H),2.87(s,3H),1.66(s,1H),1.61(s,2H),1.60-1.58(m,2H) ,1.41(s,6H),1.37-1.32(m,2H).

测试例1：化合物对15-PGDH酶抑制试验Test Example 1: Compound Inhibition Test on 15-PGDH Enzyme

用Assay Buffer(50mM Tris-HCl，pH 7.5，0.01体积％Tween 20)将15-PGDH(R&D Systems，货号5660-DH-010)配置成终浓度的2倍，即30nM。然后按照8μl/孔，加入到384白板中(Cisbio Bioassays，货号66PL384025)。设定阴性对照孔，不加酶只加Assay Buffer。然后用Assay Buffer将化合物配置成终浓度的4倍，即4000nM起始，3倍稀释，10个浓度。按照4μl/孔加入上述的白板中，混匀后，1000rpm离心1min，25℃孵育10min。同时设定阳性对照孔(只加15-PGDH)和阴性对照孔(不加15-PGDH)。再用Assay Buffer配置NAD +(Sellect.货号S2518)和PGE 2(R&D Systems，货号2296/10)的混合液。用Assay Buffer分别将NAD +和PGE 2配置成终浓度的4倍，即2mM和0.12mM。然后按照4μl/孔加入到上述的白板中，混匀后，1000rpm离心1min，25℃孵育30min进行反应。采用仪器TECAN SPARK 20M在激发波长为340nm，发射波长为485nm处检测。用GraphPad Prism 8.0进行四参数拟合计算IC 50值。 Assay Buffer (50 mM Tris-HCl, pH 7.5, 0.01 vol% Tween 20) was used to prepare 15-PGDH (R&D Systems, Cat. No. 5660-DH-010) to double the final concentration, ie 30 nM. Then, 8 μl/well was added to a 384 white plate (Cisbio Bioassays, Cat. No. 66PL384025). Set negative control wells, add only Assay Buffer without enzyme. Then use Assay Buffer to configure the compound to 4 times the final concentration, that is, start at 4000nM, dilute 3 times, and have 10 concentrations. Add 4 μl/well to the above white plate, mix well, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min. At the same time, positive control wells (with only 15-PGDH added) and negative control wells (without 15-PGDH added) were set. Then use Assay Buffer to configure the mixture of NAD + (Sellect. Cat. No. S2518) and PGE 2 (R&D Systems, Cat. No. 2296/10). Use Assay Buffer to configure NAD + and PGE 2 to 4 times the final concentration, namely 2mM and 0.12mM. Then add 4 μl/well to the above white plate, mix well, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 30 min to react. The instrument TECAN SPARK 20M is used for detection at an excitation wavelength of 340nm and an emission wavelength of 485nm. IC50 values were calculated by four-parameter fitting with GraphPad Prism 8.0.

表1化合物对15-PGDH抑制试验结果The compound of table 1 is to 15-PGDH inhibitory test result

化合物编号Compound number IC 50(nM) IC 50 (nM) 化合物1Compound 1 0.7570.757 化合物2Compound 2 0.820.82 化合物3Compound 3 0.470.47 化合物4Compound 4 1.001.00 化合物5Compound 5 0.320.32 化合物6Compound 6 2.392.39 化合物8Compound 8 0.410.41 化合物12Compound 12 0.3220.322 化合物15Compound 15 2.262.26 化合物16Compound 16 23.3923.39 化合物17Compound 17 0.810.81

实验结果表明，本发明化合物对15-PGDH具有显著的抑制作用。Experimental results show that the compound of the present invention has significant inhibitory effect on 15-PGDH.

测试例2：化合物对A549细胞上清中PGE 2水平的影响 Test Example 2: Effects of Compounds on PGE 2 Levels in A549 Cell Supernatant

A549细胞(武汉普诺赛)在F12K+10％FBS进行培养，取对数期的细胞状态良好的细胞进行实验，将细胞消化、计数，将细胞接种到24孔板，8000个/孔。将细胞置37℃，5％CO 2培养箱进行培养过夜。待细胞贴壁后，换含0.5％FBS的培养基处理约10h，向各孔添加IL-1β(终浓度20ng/mL，1mL/孔)，同时设置对照组(对照组不添加IL-1β)。IL-1β刺激约24h后，吸弃各孔细胞培养液，并用新鲜含0.5％FBS培养基轻轻清洗各孔，然后向各孔添加含各浓度的化合物(20nM和2500nM)的培养基400μL处理约12h。收集上清，采用ELISA试剂盒(R&D Systems，货号KGE004B)检测PGE 2。 A549 cells (Wuhan Punuosai) were cultured in F12K+10% FBS, and the cells in good logarithmic phase were taken for experiments, the cells were digested, counted, and the cells were seeded into 24-well plates, 8000 cells/well. The cells were cultured overnight in a 37°C, 5% CO 2 incubator. After the cells adhere to the wall, change the medium containing 0.5% FBS for about 10 hours, add IL-1β to each well (final concentration 20ng/mL, 1mL/well), and set up a control group (the control group does not add IL-1β) . After IL-1β stimulation for about 24 hours, the cell culture fluid in each well was discarded, and each well was gently washed with fresh medium containing 0.5% FBS, and then 400 μL of medium containing various concentrations of compounds (20 nM and 2500 nM) was added to each well for treatment About 12h. The supernatant was collected, and PGE 2 was detected using an ELISA kit (R&D Systems, Cat. No. KGE004B).

表2化合物对A549细胞上清中PGE2增加倍数Table 2 compounds increase the folds of PGE2 in A549 cell supernatant

化合物编号/化合物浓度Compound number/compound concentration 20nM20nM 化合物1Compound 1 5.85.8 化合物2Compound 2 3.953.95 化合物3Compound 3 9.819.81 化合物4Compound 4 6.346.34 化合物5Compound 5 13.713.7 化合物6Compound 6 3.003.00 化合物12Compound 12 3.43.4 化合物15Compound 15 11.711.7

实验结果表明，本发明化合物可以显著增加PGE 2的生成。 Experimental results show that the compound of the present invention can significantly increase the generation of PGE 2 .

测试例3：小鼠IPF药效实验Test Example 3: Drug efficacy experiment of mouse IPF

雄性小鼠适应性饲养1-2周，并体重达标后(25g)，以一定剂量的博来霉素诱导IPF模型(特发性肺纤维化模型)，造模当天根据动物体重随机分为模型组和给药组，并开始每天口服灌胃给药，溶媒对照组给予空白溶媒，连续给药21天。给药期间，每3天称量一次体重。在最后一天给药结束对动物进行安乐死，自甲状软骨开始取下肺脏(无需灌注)，向肺内缓慢灌注10％福尔马林至双侧肺脏充盈，结扎主气管后置于5-10倍组织体积的10％福尔马林中固定，对左肺进行石蜡组织切片制作、HE染色、Masson Trichrome染色，使用Hamamatsu NanoZoomer Digital Pathology(S210)切片扫描仪进行切片全景扫描，进行病理分析。Male mice were adaptively fed for 1-2 weeks, and after reaching the standard body weight (25g), a certain dose of bleomycin was used to induce the IPF model (idiopathic pulmonary fibrosis model). On the day of modeling, the animals were randomly divided into models according to their weight. The drug group and the drug group were given daily oral gavage administration, and the vehicle control group was given blank vehicle for 21 consecutive days. During the administration period, body weight was measured every 3 days. At the end of the last day of administration, the animals were euthanized, and the lungs were removed from the thyroid cartilage (without perfusion), and 10% formalin was slowly perfused into the lungs until the bilateral lungs were filled, and the main trachea was ligated and placed 5-10 times The tissue volume was fixed in 10% formalin, and the left lung was made into paraffin tissue sections, HE stained and Masson Trichrome stained, and a Hamamatsu NanoZoomer Digital Pathology (S210) slice scanner was used for panoramic scanning of the slices for pathological analysis.

实验结果显示，本发明的化合物可以显著降低纤维化程度。Experimental results show that the compound of the present invention can significantly reduce the degree of fibrosis.

测试例4：小鼠肝切除再生药效实验Test Example 4: Drug effect experiment of mouse liver resection regeneration

8周龄雄性C57BL/6J小鼠(20-24g)，动物麻醉，腹部朝上固定，手术部位剃毛并碘伏消毒；腹部横切开口约1.5-2cm，以止血夹夹住两侧的腹壁动脉；打开腹腔后将各肝叶游离，以手术线结扎需要切除的肝叶的肝门部，在其颜色变深后行肝脏左外叶及中叶切除；术后清理完腹腔残留血液后逐层缝合肌层以及皮毛层；注意术后护理。造模当天开始给药，分别在给药1天和3天各处死8只动物，取完整肝组织称重，与模型组进行对比，评估药物促进肝再生的作用。8-week-old male C57BL/6J mice (20-24g), the animals were anesthetized, the abdomen was fixed upward, the surgical site was shaved and disinfected with iodophor; Abdominal wall artery; After opening the abdominal cavity, each liver lobe is freed, and the hilum of the liver lobe to be resected is ligated with a surgical thread, and the left outer and middle lobe of the liver is resected after the color becomes darker; after the operation, the residual blood in the abdominal cavity is cleaned up. Suture the muscle layer and fur layer layer by layer; pay attention to postoperative care. The drug was administered on the day of modeling, and 8 animals were sacrificed on the 1st day and 3rd day of drug administration, and the whole liver tissue was taken and weighed, and compared with the model group to evaluate the effect of the drug on promoting liver regeneration.

实验结果显示，本发明的化合物可以显著的促进肝再生。Experimental results show that the compound of the present invention can significantly promote liver regeneration.

测试例5：小鼠药代动力学Test Example 5: Mouse Pharmacokinetics

参照下述实验方法测定本发明化合物的小鼠药代动力学性质。The mouse pharmacokinetic properties of the compounds of the present invention were determined according to the following experimental methods.

采用雄性CD-1小鼠3只，剂量为10mg/kg，给药途径为灌胃，溶媒为5％DMSO+10％Solutol+85％Saline，禁食过夜，采血时间点为给药前和在给药后15、30分钟以及1、2、4、6、8、24小时。血液样品6800g 2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆10μL加入200μL含100ng/mL内标的甲醇，涡旋混匀后2-8℃18000g离心7分钟。取200μL转移至96孔进样板中，进行LC-MS/MS定量分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Three male CD-1 mice were used, the dose was 10 mg/kg, the route of administration was intragastric administration, the vehicle was 5% DMSO+10% Solutol+85% Saline, fasted overnight, and the time points of blood collection were before administration and at 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours after administration. Blood samples were centrifuged at 2-8°C for 6 minutes at 6800g to collect plasma and stored at -80°C. Take 10 μL of plasma at each time point and add 200 μL methanol containing 100 ng/mL internal standard, vortex and mix well, and then centrifuge at 18000 g for 7 minutes at 2-8 °C. Transfer 200 μL to a 96-well injection plate for LC-MS/MS quantitative analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.

表3小鼠灌胃给药的主要药代动力学参数(均值)The main pharmacokinetic parameter (average value) of table 3 mouse gavage administration

化合物编号Compound number C max(ng/mL) C max (ng/mL) AUC (0-t)(h·ng/mL) AUC (0-t) (h·ng/mL) 化合物1Compound 1 26032603 1095110951 化合物12Compound 12 4923.384923.38 27398.4427398.44

实验结果表明，本发明化合物在小鼠体内表现出优良的药代动力学性质。Experimental results show that the compound of the present invention exhibits excellent pharmacokinetic properties in mice.

尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

Claims (25)

一种如式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药：A heterocyclic compound as shown in formula I, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs:
Figure PCTCN2022130676-appb-100001
Figure PCTCN2022130676-appb-100001
 其中，in, Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom; Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地为N、O、S、CH 2、CH或C； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently N, O, S, CH 2 , CH or C;
Figure PCTCN2022130676-appb-100002
为苯基、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”，或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烯环”；
Figure PCTCN2022130676-appb-100002
is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", "the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”; R 1和R 2各自独立地为氢、C 1-C 6烷基或C 3-C 8环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; 或者，R 1、R 2与其所连接到的N原子一起形成3-11元杂环烷基；其中，所述3-11元杂环烷基进一步被0个、1个或多个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同； Alternatively, R 1 and R 2 together with the N atom they are connected to form a 3-11 membered heterocycloalkyl group; wherein, the 3-11 membered heterocycloalkyl group is further replaced by 0, 1 or more R 1- 1 ; when there are multiple substituents, the substituents are the same or different; R 1-1为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷氧羰基、C 1-C 6烷基羰氧基、C 1-C 6烷氧基C 1-C 6烷基、C 1-C 6烷氧羰基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基羰基或C 3-C 8环烷氧基，任选具有1或2个C 1-C 6烷基基团的氨基羰基基团，C 1-C 6烷基磺酰基基团，任选具有1或2个C 1-C 6烷基基团的氨基磺酰基，C 1-C 6烷基磺酰基氨基基团和任选具有1或2个C 1-C 6烷基基团的氨基； R 1-1 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 3 -C 8 cycloalkylcarbonyl or C 3 -C 8 cycloalkoxy, optionally an aminocarbonyl group with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 Alkylsulfonyl groups, optionally aminosulfonyl groups with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 alkylsulfonylamino groups and optionally 1 or 2 C 1 -Amino group of C 6 alkyl group; R a和R b为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R a and R b are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 - C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkane Oxygen; m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively; X 1、X 2、X 3、X 4、X 5、X 6和X 7各自独立地为N、O、S、CH 2、CH或C； X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are each independently N, O, S, CH 2 , CH or C; R 3和R 6各自独立地为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基； R 3 and R 6 are each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkanes radical, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy; R 4和R 5不存在，或者与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基，所述R 4-1为：C 1-C 6烷基或卤代C 1-C 6烷基；所述当取代基为多个时，所述的取代基相同或不同。 R 4 and R 5 are absent, or together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by 1 or more R 4-1 , or together forms an unsubstituted or substituted by 1 A 3-8 membered heterocycloalkyl group substituted by one or more R 4-1 , said R 4-1 is: C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl; said substituent When there are multiple substituents, the substituents are the same or different. 如权利要求1所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可受的盐或前药，其特征在于，The heterocyclic compound represented by formula I as claimed in claim 1, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that,
Figure PCTCN2022130676-appb-100003
为苯基或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”；
Figure PCTCN2022130676-appb-100003
It is phenyl or "6-membered heteroaromatic ring with 1, 2 or 3 heteroatoms selected from one or more of N, O and S"; 和/或，
Figure PCTCN2022130676-appb-100004
为苯基；或，
Figure PCTCN2022130676-appb-100005
为“杂原子数为1个、2个或3个，杂原子为N的6元杂芳环”；或，
Figure PCTCN2022130676-appb-100006
为“杂原子数为1个、2个或3个，杂原子选自N和O的6元杂烷环”。 and / or,
Figure PCTCN2022130676-appb-100004
is phenyl; or,
Figure PCTCN2022130676-appb-100005
is "a 6-membered heteroaromatic ring with 1, 2 or 3 heteroatoms and the heteroatom being N"; or,
Figure PCTCN2022130676-appb-100006
It is "a 6-membered heteroalkane ring with 1, 2 or 3 heteroatoms selected from N and O". 如权利要求1所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，The heterocyclic compound represented by formula I as claimed in claim 1, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that,
Figure PCTCN2022130676-appb-100007
为
Figure PCTCN2022130676-appb-100008
Figure PCTCN2022130676-appb-100007
for
Figure PCTCN2022130676-appb-100008
 较佳地，
Figure PCTCN2022130676-appb-100009
为
Figure PCTCN2022130676-appb-100010
Preferably,
Figure PCTCN2022130676-appb-100009
for
Figure PCTCN2022130676-appb-100010
 如权利要求1～3任一项所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，The heterocyclic compound represented by formula I according to any one of claims 1 to 3, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that , 所述R 1、R 2与其所连接到的N原子一起形成3-8元杂环烷基； The R 1 and R 2 together with the N atom they are connected to form a 3-8 membered heterocycloalkyl group; 较佳地，所述3-8元杂环烷基是单环的、稠和二环的，或者任选包括桥环或螺环的二环的；和/或，所述3-8元杂环烷基进一步具有1至3个为N、O或S的杂原子更佳地，R 1、R 2与其所连接到的N原 子一起形成如下基团： Preferably, the 3-8 membered heterocycloalkyl is monocyclic, fused bicyclic, or bicyclic optionally including bridged rings or spiro rings; and/or, the 3-8 membered heterocycloalkyl The cycloalkyl group further has 1 to 3 heteroatoms which are N, O or S. More preferably, R 1 , R 2 together with the N atom to which they are attached form the following group:
Figure PCTCN2022130676-appb-100011
Figure PCTCN2022130676-appb-100011
 如权利要求1所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，The heterocyclic compound represented by formula I as claimed in claim 1, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that, 其中，in, Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom; Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地为N、O、S、CH 2、CH或C； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently N, O, S, CH 2 , CH or C;
Figure PCTCN2022130676-appb-100012
为苯基、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”，或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烯环”；
Figure PCTCN2022130676-appb-100012
is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", "the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”; R 1和R 2各自独立地为氢、C 1-C 6烷基或C 3-C 8环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; 或者，R 1、R 2与其所连接到的N原子一起形成3-11元杂环烷基；其中，所述3-11元杂环烷基进一步被0个、1个或多个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同； Alternatively, R 1 and R 2 together with the N atom they are connected to form a 3-11 membered heterocycloalkyl group; wherein, the 3-11 membered heterocycloalkyl group is further replaced by 0, 1 or more R 1- 1 ; when there are multiple substituents, the substituents are the same or different; R 1-1为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷氧羰基、C 1-C 6烷基羰氧基、C 1-C 6烷氧基C 1-C 6烷基、C 1-C 6烷氧羰基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基羰基或C 3-C 8环烷氧基，任选具有1或2个C 1-C 6烷基基团的氨基羰基基团，C 1-C 6烷基磺酰基基团，任选具有1或2个C 1-C 6烷基基团的氨基磺酰基，C 1-C 6烷基磺酰基氨基基团和任选具有1或2个C 1-C 6烷基基团的氨基； R 1-1 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 3 -C 8 cycloalkylcarbonyl or C 3 -C 8 cycloalkoxy, optionally an aminocarbonyl group with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 Alkylsulfonyl groups, optionally aminosulfonyl groups with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 alkylsulfonylamino groups and optionally 1 or 2 C 1 -Amino group of C 6 alkyl group; R a和R b为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R a and R b are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 - C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkane Oxygen; m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively; X 1、X 2、X 3、X 4、X 5和X 6各自独立地为N、O、S、CH 2、CH或C； X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, O, S, CH 2 , CH or C; R 3和R 6各自独立地为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 3 and R 6 are each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkanes radical, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy; R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基，所述R 4-1为C 1-C 6烷基或卤代C 1-C 6烷基；所述当取代基为多个时，所述的取代基相同或不同。 R 4 and R 5 together form a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by 1 or more R 4-1 , or together forms an unsubstituted or substituted by 1 or more 3-8 membered heterocycloalkyl substituted by R 4-1 , said R 4-1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl; when there are multiple substituents, The substituents are the same or different. 如权利要求1或5所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述溶剂化物为水合物；The heterocyclic compound represented by formula I, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1 or 5, is characterized in that, The solvate is a hydrate; 和/或，所述6元杂烯环含有一个双键；And/or, the 6-membered heteroalkene ring contains a double bond; 和/或，当R 1、R 2与其所连接到的N原子一起形成3-8元杂环烷基，所述3-8元杂环烷基为4元单杂环烷基、5元单杂环烷基、6元单杂环烷基、3元螺6元杂环烷基、5元并5元杂环烷基或3元并3元杂环烷基，所述3-8元杂环烷基具有1个为N、O或S的杂原子(例如N和/或O)；例如，哌啶、氮杂环丁烷、四氢吡咯、4-氧杂-7-氮杂螺环[2.5]辛烷、吗啉、6-氮杂螺环[2.5]辛烷、3-氮杂双环[3.1.0]己烷或八氢环戊[c]吡咯；还例如
Figure PCTCN2022130676-appb-100013
Figure PCTCN2022130676-appb-100014
And/or, when R 1 and R 2 together form a 3-8 membered heterocycloalkyl group with the N atom to which they are connected, the 3-8 membered heterocycloalkyl group is a 4-membered monoheterocycloalkyl group, a 5-membered unit Heterocycloalkyl, 6-membered monoheterocycloalkyl, 3-membered spiro 6-membered heterocycloalkyl, 5-membered and 5-membered heterocycloalkyl or 3-membered and 3-membered heterocycloalkyl, the 3-8 membered heterocycloalkyl Cycloalkyl has 1 heteroatom that is N, O, or S (eg, N and/or O); eg, piperidine, azetidine, tetrahydropyrrole, 4-oxa-7-azaspiro [2.5]octane, morpholine, 6-azaspiro[2.5]octane, 3-azabicyclo[3.1.0]hexane or octahydrocyclopenta[c]pyrrole; also for example
Figure PCTCN2022130676-appb-100013
Figure PCTCN2022130676-appb-100014
 和/或，各个R 1-1中，所述卤素独立地为氟、氯、溴或碘，例如氟； And/or, in each R 1-1 , said halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine; 和/或，各个R 1-1中，所述C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基； And/or, in each R 1-1 , the C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl; 和/或，各个R 1-1中，所述卤代C 1-C 6烷基中卤素独立地为氟、氯、溴或碘，例如氟； And/or, in each R 1-1 , the halogen in the halogenated C 1 -C 6 alkyl is independently fluorine, chlorine, bromine or iodine, such as fluorine; 和/或，各个R 1-1中，所述卤代C 1-C 6烷基中C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基； And/or, in each R 1-1 , the C 1 -C 6 alkyl in the halogenated C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl; 和/或，各个R 1-1中，所述卤代C 1-C 6烷基独立地为卤代C 1-C 4烷基，例如被1个、2个或3个F取代的C 1-C 4烷基，还例如，一氟甲基、二氟甲基或三氟甲基； And/or, in each R 1-1 , the halogenated C 1 -C 6 alkyl is independently a halogenated C 1 -C 4 alkyl, such as C 1 substituted by 1, 2 or 3 F -C Alkyl, also for example, monofluoromethyl, difluoromethyl or trifluoromethyl; 和/或，各个R a中，所述卤代C 1-C 6烷基中C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基； And/or, in each R a , the C 1 -C 6 alkyl in the halogenated C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl; 和/或，各个R b中，所述卤代C 1-C 6烷基中C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基； And/or, in each R b , the C 1 -C 6 alkyl in the halogenated C 1 -C 6 alkyl is independently a C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl; 和/或，R 3中，所述卤代C 1-C 6烷基为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基； And/or, in R 3 , the halogenated C 1 -C 6 alkyl is C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl or tert-butyl, also for example methyl or ethyl; 和/或，R 3中，所述C 1-C 6氘代烷基中C 1-C 6烷基为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如甲基或乙基； And/or, in R 3 , the C 1 -C 6 alkyl group in the C 1 -C 6 deuterated alkyl group is a C 1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl or tert-butyl, also for example methyl or ethyl; R 3中，所述C 1-C 6氘代烷基为C 1-C 4氘代烷基，例如被1个、2个或3个氘取代的C 1-C 4烷基，还例如
Figure PCTCN2022130676-appb-100015
In R 3 , the C 1 -C 6 deuterated alkyl is a C 1 -C 4 deuterated alkyl, such as a C 1 -C 4 alkyl substituted by 1, 2 or 3 deuteriums, also such as
Figure PCTCN2022130676-appb-100015
 和/或，R 6中，所述卤素为氟、氯、溴或碘，例如氟； And/or, in R 6 , the halogen is fluorine, chlorine, bromine or iodine, such as fluorine; 和/或，当R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的C 3-C 6环烷基时，所述的C 3-C 6环烷基为丙基、环丁基、环戊基或环己基，例如环丙基或环丁基； And/or, when R 4 and R 5 together form a C 3 -C 6 cycloalkyl group unsubstituted or substituted by 1 or more R 4-1 with the C atom to which they are connected, said C 3 - C Cycloalkyl is propyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl; 和/或，当R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基时，所述的3-8元杂环烷基中的杂原子为N、O或S(例如N)； And/or, when R 4 and R 5 form a 3-8 membered heterocycloalkyl group that is unsubstituted or substituted by 1 or more R 4-1 together with the C atom to which they are attached, said 3-8 The heteroatom in the membered heterocycloalkyl is N, O or S (eg N); 和/或，当R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基时，所述的3-8元杂环烷基中的杂原子为1个； And/or, when R 4 and R 5 form a 3-8 membered heterocycloalkyl group that is unsubstituted or substituted by 1 or more R 4-1 together with the C atom to which they are attached, said 3-8 The heteroatom in the membered heterocycloalkyl group is 1; 和/或，当R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基时，所述的3-8元杂环烷基为3-6元杂环烷基，例如4元杂环烷基，还例如含氧4元杂环烷基。 And/or, when R 4 and R 5 form a 3-8 membered heterocycloalkyl group that is unsubstituted or substituted by 1 or more R 4-1 together with the C atom to which they are attached, said 3-8 The membered heterocycloalkyl is 3-6 membered heterocycloalkyl, such as 4-membered heterocycloalkyl, and also such as oxygen-containing 4-membered heterocycloalkyl. 如权利要求1或5所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，The heterocyclic compound represented by formula I, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1 or 5, is characterized in that, R 6为氢； R6 is hydrogen; 和/或，Z 1为CH或N； And/or, Z 1 is CH or N; 和/或，Z 2为CH； And/or, Z 2 is CH; 和/或，Z 3为CH； And/or, Z 3 is CH; 和/或，Z 4为C或N； And/or, Z 4 is C or N; 和/或，Z 5为CH或CH 2； And/or, Z 5 is CH or CH 2 ; 和/或，Z 6为CH或CH 2； And/or, Z 6 is CH or CH 2 ; 和/或，Z 7为N、O或CH； And/or, Z 7 is N, O or CH; 和/或，X 1为CH； And/or, X 1 is CH; 和/或，X 2为CH； And/or, X 2 is CH; 和/或，X 3为CH； And/or, X 3 is CH; 和/或，X 4为C； And/or, X 4 is C; 和/或，X 5为C或N； And/or, X 5 is C or N; 和/或，X 6为C； And/or, X 6 is C; 和/或，R 4和R 5与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被1个或多个R 4-1取代的3-6元杂环烷基；所述3-6元杂环烷基中的杂原子数为1个，杂原子为N、O或S(例如N或O)；较佳地，R 4和R 5与其所连接到的C原子一起形成 未取代的C 3-C 6环烷基，或者一起形成未取代的3-6元杂环烷基；所述3-6元杂环烷中的杂原子选自N、O和S中的一种或多种(例如N或O)，所述杂原子个数为1个、2个或3个(例如1个)； And/or, R 4 and R 5 together form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by 1 or more R 4-1 with the C atom to which it is connected, or together forms an unsubstituted or substituted by 1 One or more R 4-1 substituted 3-6 membered heterocycloalkyl groups; the number of heteroatoms in the 3-6 membered heterocycloalkyl groups is 1, and the heteroatoms are N, O or S (such as N or O); preferably, R 4 and R 5 together form an unsubstituted C 3 -C 6 cycloalkyl group with the C atom they are connected to, or together form an unsubstituted 3-6 membered heterocycloalkyl group; said The heteroatoms in the 3-6 membered heterocycloalkane are selected from one or more of N, O and S (such as N or O), and the number of said heteroatoms is 1, 2 or 3 (such as 1 indivual); 和/或，R 3为氢、C 1-C 6烷基或C 1-C 6氘代烷基，例如C 1-C 3烷基或C 1-C 3氘代烷基，还例如甲基或
Figure PCTCN2022130676-appb-100016
And/or, R 3 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl, such as C 1 -C 3 alkyl or C 1 -C 3 deuterated alkyl, also such as methyl or
Figure PCTCN2022130676-appb-100016
 和/或，R b为氧代(＝O)、C 1-C 6烷基、C 1-C 6氘代烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；例如氧代(＝O)、C 1-C 4烷基、C 1-C 4氘代烷基或卤代C 1-C 4烷基；还例如氧代(＝O)、甲基或乙基； And/or, R b is oxo (=O), C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy Or halogenated C 1 -C 6 alkoxy; for example oxo (=O), C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl or halogenated C 1 -C 4 alkyl; also for example Oxo (=O), methyl or ethyl; 和/或，R a为C 1-C 6烷基、C 1-C 6氘代烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基；例如C 1-C 4烷基、C 1-C 4氘代烷基或卤代C 1-C 4烷基；还例如甲基或乙基； And/or, R a is C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy; for example C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl or halogenated C 1 -C 4 alkyl; also for example methyl or ethyl; 和/或，R 1、R 2与其所连接到的N原子一起形成3-8元杂环烷基；其中，所述3-8元杂环烷基进一步被0个、1个或2个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同；所述3-8元杂环烷中的杂原子选自N、O和S中的一种或多种(例如N和/或O)，所述杂原子个数为1个、2个或3个； And/or, R 1 , R 2 form a 3-8 membered heterocycloalkyl group together with the N atom they are connected to; wherein, the 3-8 membered heterocycloalkyl group is further replaced by 0, 1 or 2 R 1-1 substituted; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the 3-8 membered heterocycloalkane are selected from one or more of N, O and S (such as N and/or O), the number of heteroatoms is 1, 2 or 3; 和/或，R 1-1为卤素、C 1-C 6烷基、卤代C 1-C 6烷基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基，例如卤素、C 1-C 4烷基或卤代C 1-C 4烷基；还例如F、甲基、乙基、被1个、2个或3个F取代的C 1-C 4烷基，又例如F、一氟甲基、二氟甲基或三氟甲基。 And/or, R 1-1 is halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy, for example Halogen, C 1 -C 4 alkyl or halogenated C 1 -C 4 alkyl; also for example F, methyl, ethyl, C 1 -C 4 alkyl substituted by 1, 2 or 3 F, Another example is F, monofluoromethyl, difluoromethyl or trifluoromethyl. 如权利要求1或5所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，The heterocyclic compound represented by formula I, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 1 or 5, is characterized in that,
Figure PCTCN2022130676-appb-100017
为
Figure PCTCN2022130676-appb-100018
Figure PCTCN2022130676-appb-100019
Figure PCTCN2022130676-appb-100017
for
Figure PCTCN2022130676-appb-100018
Figure PCTCN2022130676-appb-100019
 和/或，
Figure PCTCN2022130676-appb-100020
为
Figure PCTCN2022130676-appb-100021
较佳地，
Figure PCTCN2022130676-appb-100022
为
Figure PCTCN2022130676-appb-100023
Figure PCTCN2022130676-appb-100024
and / or,
Figure PCTCN2022130676-appb-100020
for
Figure PCTCN2022130676-appb-100021
Preferably,
Figure PCTCN2022130676-appb-100022
for
Figure PCTCN2022130676-appb-100023
Figure PCTCN2022130676-appb-100024
 如权利要求1或5所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其具有式II所示结构：The heterocyclic compound represented by formula I as claimed in claim 1 or 5, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, is characterized in that it has Structure shown in formula II:
Figure PCTCN2022130676-appb-100025
Figure PCTCN2022130676-appb-100025
 其中，R 7为氢、卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； Wherein, R 7 is hydrogen, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy; Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7具有权利要求1或5所述的定义； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 have the definitions described in claim 1 or 5; R 1、R 2、R 3、R 4、R 5、X 1、X 2、X 3、R a、R b、m和n具有权利要求1或5所述的定义。 R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , X 3 , R a , R b , m and n have the definitions described in claim 1 or 5. 如权利要求9所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述杂环类化合物选自如下结构：The heterocyclic compound represented by formula I, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 9, it is characterized in that the heterocyclic Compounds are selected from the following structures:
Figure PCTCN2022130676-appb-100026
Figure PCTCN2022130676-appb-100026
Figure PCTCN2022130676-appb-100027
Figure PCTCN2022130676-appb-100027
 其中，in, R 7为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 7 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxy, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkyne Base, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkoxy; R 1、R 2、R 3、X 1、X 2、X 3、R a、R b、m和n具有权利要求9所述的定义。 R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , R a , R b , m and n have the definitions set forth in claim 9 . 如权利要求10所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述杂环类化合物选自如下结构：The heterocyclic compound represented by formula I, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug as claimed in claim 10, is characterized in that, the heterocyclic Compounds are selected from the following structures:
Figure PCTCN2022130676-appb-100028
Figure PCTCN2022130676-appb-100028
Figure PCTCN2022130676-appb-100029
Figure PCTCN2022130676-appb-100029
 其中，R 1、R 2、R 3、R 7、R a、R b、m和n具有权利要求9所述的定义。 Wherein, R 1 , R 2 , R 3 , R 7 , R a , R b , m and n have the definitions described in claim 9 . 如权利要求1所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述的式I所示的杂环类化合物满足如下任一方案：The heterocyclic compound represented by formula I according to claim 1, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that the formula The heterocyclic compound shown in I satisfies any of the following schemes: 方案1、Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； Scheme 1, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom; Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地为N、O、S、CH 2、CH或C； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently N, O, S, CH 2 , CH or C;
Figure PCTCN2022130676-appb-100030
为苯基、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”，或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烯环”；
Figure PCTCN2022130676-appb-100030
is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", "the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”; R 1和R 2各自独立地为氢、C 1-C 6烷基或C 3-C 8环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; 或者，R 1、R 2与其所连接到的N原子一起形成3-11元杂环烷基；其中，所述3-11元杂环烷基进一步被0个、1个或多个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同； Alternatively, R 1 and R 2 together with the N atom they are connected to form a 3-11 membered heterocycloalkyl group; wherein, the 3-11 membered heterocycloalkyl group is further replaced by 0, 1 or more R 1- 1 ; when there are multiple substituents, the substituents are the same or different; R 1-1为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷氧羰基、C 1-C 6烷基羰氧基、C 1-C 6烷氧基C 1-C 6烷基、C 1-C 6烷氧羰基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基羰基或C 3-C 8环烷氧基，任选具有1或2个C 1-C 6烷基基团的氨基羰基基团，C 1-C 6烷基磺酰基基团，任选具有1或2个C 1-C 6烷基基团的氨基磺酰基，C 1-C 6烷基磺酰基氨基基团和任选具有1或2个C 1-C 6烷基基团的氨基； R 1-1 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 3 -C 8 ring Alkyl, C 3 -C 8 cycloalkylcarbonyl or C 3 -C 8 cycloalkoxy, optionally an aminocarbonyl group with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 Alkylsulfonyl groups, optionally aminosulfonyl groups with 1 or 2 C 1 -C 6 alkyl groups, C 1 -C 6 alkylsulfonylamino groups and optionally 1 or 2 C 1 -Amino group of C 6 alkyl group; R a和R b为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R a and R b are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 - C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkane Oxygen; m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively; X 1、X 2、X 3、X 4、X 5和X 6各自独立地为N、O、S、CH 2、CH或C； X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently N, O, S, CH 2 , CH or C; R 3和R 6各自独立地为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 3 and R 6 are each independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 - C 6 alkoxy; R 4和R 5不存在，或者与其所连接到的C原子一起形成未取代或被1个或多个R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被1个或多个R 4-1取代的3-8元杂环烷基，所述R 4-1为C 1-C 6烷基或卤代C 1-C 6烷基；所述当取代基为多个时，所述的取代基相同或不同； R 4 and R 5 are absent, or together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl group which is unsubstituted or substituted by 1 or more R 4-1 , or together forms an unsubstituted or substituted by 1 A 3-8-membered heterocycloalkyl group substituted by one or more R 4-1 , said R 4-1 being a C 1 -C 6 alkyl or a halogenated C 1 -C 6 alkyl; said when the substituent is When multiple, the substituents are the same or different; 方案2、Scenario 2, Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom; Z 1、Z 2和Z 3各自独立地为N或C； Z 1 , Z 2 and Z 3 are each independently N or C;
Figure PCTCN2022130676-appb-100031
为苯基、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烷环”、“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂芳环”， 或“杂原子数为1个、2个或3个，杂原子选自N、O、S中的一种或多种的6元杂烯环”；
Figure PCTCN2022130676-appb-100031
is phenyl, "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O, and S, a 6-membered heteroalkane ring", "the number of heteroatoms is 1, 2 or 3, heteroatoms are selected from one or more of N, O, S 6-membered heteroaryl ring", or "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N , O, S in one or more 6-membered heteroalkene rings”; R 1和R 2各自独立地为氢、C 1-C 6烷基或C 3-C 8环烷基； R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; 或者，R 1、R 2与其所连接到的N原子一起形成C 3-C 8环烷基或3-11元杂环烷基；其中，所述C 3-C 8环烷基或3-11元杂环烷基进一步被R 1-1所取代； Alternatively, R 1 and R 2 together with the N atom they are connected to form a C 3 -C 8 cycloalkyl or a 3-11 membered heterocycloalkyl; wherein, the C 3 -C 8 cycloalkyl or 3-11 Member heterocycloalkyl is further substituted by R 1-1 ; R 1-1为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基、卤代C 1-C 6烷氧基、C 1-C 6烷氧羰基、C 1-C 6烷氧基C 1-C 6烷基、C 1-C 6烷氧羰基C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基羰基或C 3-C 8环烷氧基，任选具有1或2个C 1-C 6烷基基团的氨基羰基基团，C 1-C 6烷基磺酰基基团，任选具有1或2个C 1-C 6烷基基团的氨基磺酰基，C 1-C 6烷基磺酰基氨基基团和任选具有1或2个C 1-C 6烷基基团的氨基； R 1-1 is halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl Carbonyl or C 3 -C 8 cycloalkoxy, optionally an aminocarbonyl group with 1 or 2 C 1 -C 6 alkyl groups, a C 1 -C 6 alkylsulfonyl group, optionally with 1 or aminosulfonyl with 2 C 1 -C 6 alkyl groups, C 1 -C 6 alkylsulfonylamino groups and amino groups optionally with 1 or 2 C 1 -C 6 alkyl groups; R a和R b为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R a and R b are halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 - C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 -C 6 alkane Oxygen; m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively; X 1、X 2和X 3各自独立地为N或C； X 1 , X 2 and X 3 are each independently N or C; R 3和R 6各自独立地为卤素、羟基、氨基、硝基、氰基、羰基、氧代(＝O)、羧基、C 1-C 6烷基、C 1-C 6氘代烷基、C 2-C 6炔基、卤代C 1-C 6烷基、羟基C 1-C 6烷基、C 1-C 6烷基羰基、C 1-C 6烷氧基或卤代C 1-C 6烷氧基； R 3 and R 6 are each independently halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo (=O), carboxyl, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy or halogenated C 1 - C 6 alkoxy; R 4和R 5与其所连接到的C原子一起形成未取代或被R 4-1取代的C 3-C 6环烷基，或者一起形成未取代或被R 4-1取代的3-8元杂环烷基，所述R 4-1为C 1-C 6烷基或卤代C 1-C 6烷基； R 4 and R 5 together with the C atom to which they are attached form a C 3 -C 6 cycloalkyl which is unsubstituted or substituted by R 4-1 , or together forms a 3-8 membered unsubstituted or substituted by R 4-1 Heterocycloalkyl, said R 4-1 is C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl; 方案3、Z 1、Z 2、Z 3、Z 4、Z 5、Z 6和Z 7各自独立地表示环原子； Scheme 3, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 each independently represent a ring atom; Z 1为CH或N； Z1 is CH or N; Z 2为CH； Z 2 is CH; Z 3为CH； Z 3 is CH; Z 4为C或N； Z 4 is C or N; Z 5为CH或CH 2； Z 5 is CH or CH 2 ; Z 6为CH或CH 2； Z 6 is CH or CH 2 ; Z 7为N、O或CH； Z7 is N, O or CH;
Figure PCTCN2022130676-appb-100032
为苯基、“杂原子数为1个或2个，杂原子为N的6元杂芳环”，或“杂原子数为1个或2个，杂原子为N和/或O”的6元杂烯环”；
Figure PCTCN2022130676-appb-100032
is phenyl, "6-membered heteroaromatic ring with 1 or 2 heteroatoms and N as heteroatom", or 6-membered heteroaryl ring with 1 or 2 heteroatoms and N and/or O as heteroatom Heteroalkene ring"; R 1、R 2与其所连接到的N原子一起形成3-8元杂环烷基；其中，所述3-8元杂环烷基进一步被0个、1个或2个R 1-1所取代；当取代基为多个时，所述的取代基相同或不同；所述3-8元杂环烷中的 杂原子选自N、O和S中的一种或多种，所述杂原子个数为1个、2个或3个； R 1 , R 2 together with the N atom they are connected to form a 3-8 membered heterocycloalkyl group; wherein, the 3-8 membered heterocycloalkyl group is further replaced by 0, 1 or 2 R 1-1 Substitution; when there are multiple substituents, the substituents are the same or different; the heteroatoms in the 3-8 membered heterocycloalkane are selected from one or more of N, O and S, and the heteroatoms are The number of atoms is 1, 2 or 3; 各个R 1-1独立地为卤素、C 1-C 6烷基或卤代C 1-C 6烷基； Each R 1-1 is independently halogen, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl; R a和R b为C 1-C 6烷基； R a and R b are C 1 -C 6 alkyl; m、n分别为0、1、2或3；m and n are 0, 1, 2 or 3 respectively; X 1为CH； X1 is CH; X 2为CH； X2 is CH; X 3为CH； X3 is CH; X 4为C； X 4 is C; X 5为C或N； X 5 is C or N; X 6为C； X 6 is C; R 3为C 1-C 6烷基或C 1-C 6氘代烷基； R 3 is C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl; R 6为氢或卤素； R 6 is hydrogen or halogen; R 4和R 5与其所连接到的C原子一起形成未取代的C 3-C 6环烷基，或者一起形成未取代的3-8元杂环烷基；所述3-8元杂环烷中的杂原子选自N、O和S中的一种或多种，所述杂原子个数为1个、2个或3个。 R 4 and R 5 together form an unsubstituted C 3 -C 6 cycloalkyl group with the C atom they are connected to, or together form an unsubstituted 3-8 membered heterocycloalkyl group; the 3-8 membered heterocycloalkane The heteroatoms in are selected from one or more of N, O and S, and the number of said heteroatoms is 1, 2 or 3. 如权利要求1所述的式I所示的杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，所述杂环类化合物包括：The heterocyclic compound represented by formula I as claimed in claim 1, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, it is characterized in that the heterocyclic Class compounds include:
Figure PCTCN2022130676-appb-100033
Figure PCTCN2022130676-appb-100033
Figure PCTCN2022130676-appb-100034
Figure PCTCN2022130676-appb-100034
 一种如权利要求1～13任一项所述的式I所示的杂环类化合物的制备方法，其特征在于，其 为方案一或方案二，其中，A preparation method of a heterocyclic compound shown in formula I according to any one of claims 1 to 13, characterized in that it is scheme one or scheme two, wherein, 方案一包括如下步骤：Option 1 includes the following steps: (1a)中间体A-1-1与格氏试剂接触并反应，得到中间体A-1，(1a) Intermediate A-1-1 contacts and reacts with Grignard reagent to obtain Intermediate A-1,
Figure PCTCN2022130676-appb-100035
Figure PCTCN2022130676-appb-100035
 (1b)中间体A-1与中间体B-1接触并反应，得到式I所示化合物，(1b) Intermediate A-1 contacts and reacts with Intermediate B-1 to obtain the compound shown in formula I,
Figure PCTCN2022130676-appb-100036
Figure PCTCN2022130676-appb-100036
 其中，方案一中的Y 1为卤素；Y 3为卤素或硼酸基；R 1、R 2、R 3、R 4、R 5、R 6、X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、Z 5、Z 6、Z 7、R a、R b、m和n具有权利要求1所述的定义； Among them, Y 1 in Scheme 1 is halogen; Y 3 is halogen or boronic acid group; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n have the definitions described in claim 1; 方案二包括如下步骤：Option 2 includes the following steps: (2a)中间体A-2-1与格氏试剂接触并反应，得到中间体A-2；(2a) Intermediate A-2-1 is contacted and reacted with a Grignard reagent to obtain Intermediate A-2;
Figure PCTCN2022130676-appb-100037
Figure PCTCN2022130676-appb-100037
 (2b)中间体A-2与中间体B-1接触，得到式I所示化合物，(2b) intermediate A-2 is contacted with intermediate B-1 to obtain the compound shown in formula I,
Figure PCTCN2022130676-appb-100038
Figure PCTCN2022130676-appb-100038
 其中，方案二中的Y 1为卤素；Y 2为氢或三甲基亚砜；Y 3为卤素或硼酸基；R 4、R 5与其所连接到的C原子一起形成环丁烷基或氧杂环丁烷基；R 1、R 2、R 3、R 6、X 1、X 2、X 3、Z 1、Z 2、Z 3、Z 4、Z 5、Z 6、Z 7、R a、R b、m和n具有权利要求1-13所述的定义。 Among them, Y 1 in Scheme 2 is halogen; Y 2 is hydrogen or trimethylsulfoxide; Y 3 is halogen or boronic acid group; R 4 and R 5 form cyclobutanyl or oxygen together with the C atoms they are connected to Heterocyclobutanyl; R 1 , R 2 , R 3 , R 6 , X 1 , X 2 , X 3 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n have the definitions stated in claims 1-13. 式A-1、A-2-1、A-2或B-1所示中间体，其特征在于，所述中间体具有结构：The intermediate shown in formula A-1, A-2-1, A-2 or B-1 is characterized in that the intermediate has the structure:
Figure PCTCN2022130676-appb-100039
Figure PCTCN2022130676-appb-100039
 其中，Y 1选自卤素； Wherein, Y 1 is selected from halogen; R 3、R 4、R 5、R 6、X 1、X 2和X 3具有权利要求1-13任一项所述的定义； R 3 , R 4 , R 5 , R 6 , X 1 , X 2 and X 3 have the definitions described in any one of claims 1-13;
Figure PCTCN2022130676-appb-100040
Figure PCTCN2022130676-appb-100040
 其中，Y 1选自卤素； Wherein, Y 1 is selected from halogen; Y 2为氢或三甲基亚砜； Y 2 is hydrogen or trimethylsulfoxide; R 4、R 5与其所连接到的C原子一起形成环丁烷基或氧杂环丁烷基； R 4 , R 5 together with the C atom they are connected to form a cyclobutanyl group or an oxetanyl group; R 6、X 1、X 2和X 3具有权利要求1-13任一项所述的定义； R 6 , X 1 , X 2 and X 3 have the definitions described in any one of claims 1-13;
Figure PCTCN2022130676-appb-100041
Figure PCTCN2022130676-appb-100041
 其中，Y 1为卤素； Wherein, Y 1 is a halogen; R 4、R 5与其所连接到的C原子一起形成环丁烷基或氧杂环丁烷基； R 4 , R 5 together with the C atom they are connected to form a cyclobutanyl group or an oxetanyl group; R 6、X 1、X 2和X 3具有权利要求1-13任一项所述的定义；其中，Y 3为卤素或硼酸基； R 6 , X 1 , X 2 and X 3 have the definition described in any one of claims 1-13; wherein, Y 3 is halogen or boronic acid group; R 1、R 2、Z 1、Z 2、Z 3、Z 4、Z 5、Z 6、Z 7、R a、R b、m和n具有权利要求1-13任一项所述的定义。 R 1 , R 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n have the definitions described in any one of claims 1-13. 如下所示的化合物：Compounds shown below:
Figure PCTCN2022130676-appb-100042
Figure PCTCN2022130676-appb-100042
Figure PCTCN2022130676-appb-100043
Figure PCTCN2022130676-appb-100043
Figure PCTCN2022130676-appb-100044
Figure PCTCN2022130676-appb-100044
 一种药物组合物，其特征在于，所述药物组合物包括：如权利要求1-13中任一所述的式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药；和药学上可接受的载体。A pharmaceutical composition, characterized in that the pharmaceutical composition comprises: the heterocyclic compound shown in formula I according to any one of claims 1-13, its tautomers, stereoisomers, a solvate, a pharmaceutically acceptable salt or a prodrug; and a pharmaceutically acceptable carrier. 一种如权利要求1-13中任一所述的式I所示杂环类、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药的用途，或权利要求17所述的药物组合物的用途，所述用途包括：A use of heterocycles represented by formula I, tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs thereof as described in any one of claims 1-13, or The purposes of the pharmaceutical composition described in claim 17, described purposes comprises: 抑制15-PGDH；Inhibit 15-PGDH; 和/或，预防和/或治疗15-PGDH相关的疾病；And/or, prevention and/or treatment of 15-PGDH related diseases; 和/或，制备用于抑制15-PGDH，和/或预防和/或治疗15-PGDH相关的疾病的药物、药物组合物或制剂。And/or, preparing medicines, pharmaceutical compositions or preparations for inhibiting 15-PGDH, and/or preventing and/or treating diseases related to 15-PGDH. 如权利要求18所述的用途，其特征在于，所述15-PGDH相关的疾病包括：纤维化、炎性疾病、心血管疾病、创伤、自身免疫性疾病、移植物抗宿主疾病、毛发生长、骨质疏松症、耳病、眼病、中性白细胞减少、糖尿病、膀胱活动低下症，或者，在干细胞或骨髓移植或器官移植中的植入物中促进，神经发生和神经细胞死亡、血细胞重建、组织再生和宫颈成熟中的一种、两种或更多种。The use according to claim 18, wherein the 15-PGDH-related diseases include: fibrosis, inflammatory disease, cardiovascular disease, trauma, autoimmune disease, graft-versus-host disease, hair growth, Osteoporosis, ear disease, eye disease, neutropenia, diabetes mellitus, underactive bladder, or, in stem cell or implants in bone marrow transplantation or organ transplantation, promotion of neurogenesis and nerve cell death, blood cell reconstitution, One, two, or more of tissue regeneration and cervical ripening. 如权利要求19所述的用途，其特征在于，所述15-PGDH相关的疾病包括：肺纤维化，肝纤维化，肾纤维化，心肌纤维化，硬皮病和骨髓纤维化，慢性阻塞性肺病，急性肺损伤，脓毒症，哮喘和肺病的恶化，炎症性肠病，消化性溃疡，自身炎性疾病，血管炎综合征，急性肝损伤，急性肾损伤，非酒精性脂肪肝，特应性皮炎，牛皮癣，间质性膀胱炎，前列腺炎综合征，肺动脉高压，心绞痛，心肌梗死，心力衰竭，缺血性心脏病，慢性肾病，肾衰竭，脑卒中和周围循环紊乱，糖尿病性溃疡，烧伤，压迫性溃疡，急性粘膜损伤，包括斯-约二氏综合征，粘膜损伤与抗癌化疗剂有关的，多发性硬化，类风湿性关节炎，听力损失，耳鸣，眩晕，平衡失调，青光眼，干眼，精神神经疾病，神经病，神经毒性疾病，神经性疼痛和神经变性疾病，肌肉萎缩，肌营养不良和肌肉损伤。The use according to claim 19, characterized in that the 15-PGDH-related diseases include: pulmonary fibrosis, liver fibrosis, renal fibrosis, myocardial fibrosis, scleroderma and myelofibrosis, chronic obstructive Pulmonary disease, acute lung injury, sepsis, exacerbation of asthma and lung disease, inflammatory bowel disease, peptic ulcer, autoinflammatory disease, vasculitis syndrome, acute liver injury, acute kidney injury, nonalcoholic fatty liver disease, special Atopic dermatitis, psoriasis, interstitial cystitis, prostatitis syndrome, pulmonary hypertension, angina, myocardial infarction, heart failure, ischemic heart disease, chronic kidney disease, renal failure, stroke and peripheral circulatory disturbance, diabetic ulcer , burns, pressure ulcers, acute mucosal injury, including Stevens-Joe syndrome, mucosal injury associated with anticancer chemotherapy agents, multiple sclerosis, rheumatoid arthritis, hearing loss, tinnitus, vertigo, balance disorders, Glaucoma, dry eye, psychoneurological disease, neuropathy, neurotoxic disease, neuropathic pain and neurodegenerative disease, muscle atrophy, muscular dystrophy and muscle damage. 如权利要求19所述的用途，其特征在于，所述15-PGDH相关的疾病包括：溃疡性结肠炎，克罗恩氏病，NSAID诱导的溃疡，贝切特氏病，慢性前列腺炎，慢性骨盆疼痛综合征，粘膜炎，口腔炎。The use according to claim 19, wherein the 15-PGDH-related diseases include: ulcerative colitis, Crohn's disease, NSAID-induced ulcers, Behcet's disease, chronic prostatitis, chronic Pelvic pain syndrome, mucositis, stomatitis. 如权利要求19所述的用途，其特征在于，所述15-PGDH相关的疾病包括：特发性肺纤维化 或肝脏再生。The use according to claim 19, wherein the 15-PGDH-related diseases include: idiopathic pulmonary fibrosis or liver regeneration. 如权利要求19所述的用途，其特征在于，所述的炎性疾病为慢性阻塞性肺病、急性肺损伤、脓毒症、哮喘和肺病的恶化、炎症性肠病、消化性溃疡、自身炎性疾病、血管炎综合征、急性肝损伤、急性肾损伤、非酒精性脂肪肝、特应性皮炎、牛皮癣、间质性膀胱炎或前列腺炎综合征中的一种或多种，优选为炎症性肠病；The use according to claim 19, characterized in that the inflammatory disease is chronic obstructive pulmonary disease, acute lung injury, sepsis, exacerbation of asthma and lung disease, inflammatory bowel disease, peptic ulcer, autoinflammatory one or more of disease, vasculitis syndrome, acute liver injury, acute kidney injury, non-alcoholic fatty liver disease, atopic dermatitis, psoriasis, interstitial cystitis or prostatitis syndrome, preferably inflammation venereal enteropathy; 所述的炎症性肠病优选为溃疡性结肠炎和/或克罗恩氏病；The inflammatory bowel disease is preferably ulcerative colitis and/or Crohn's disease; 所述的消化性溃疡优选为NSAID诱导的溃疡；The peptic ulcer is preferably NSAID-induced ulcer; 所述的自身炎性疾病优选为NSAID诱导的溃疡；The autoinflammatory disease is preferably NSAID-induced ulcer; 所述的前列腺炎综合征优选为慢性前列腺炎；The prostatitis syndrome is preferably chronic prostatitis; 和/或，所述的心血管疾病为肺动脉高压、心绞痛、心肌梗死、心力衰竭、缺血性心脏病、脑卒中或周围循环紊乱中的一种或多种；And/or, the cardiovascular disease is one or more of pulmonary hypertension, angina pectoris, myocardial infarction, heart failure, ischemic heart disease, stroke or peripheral circulation disorder; 和/或，所述的创伤为糖尿病性溃疡、烧伤、压迫性溃疡、急性粘膜损伤、包括斯-约二氏综合征、粘膜损伤与抗癌化疗剂有关的中的一种或多种；And/or, the trauma is one or more of diabetic ulcers, burns, pressure ulcers, acute mucosal injuries, including Stevens-Johnson syndrome, mucosal injuries related to anticancer chemotherapy agents; 和/或，所述的自身免疫性疾病为多发性硬化和/或类风湿性关节炎；And/or, the autoimmune disease is multiple sclerosis and/or rheumatoid arthritis; 和/或，所述的耳病为听力损失、耳鸣、眩晕或平衡失调中的一种或多种；And/or, the ear disease is one or more of hearing loss, tinnitus, vertigo or imbalance; 和/或，所述的眼病为青光眼和/或干眼；And/or, the eye disease is glaucoma and/or dry eye; 和/或，所述的神经发生和神经细胞死亡为精神神经疾病、神经病、神经毒性疾病、神经性疼痛或神经变性疾病中的一种或多种。And/or, the neurogenesis and nerve cell death are one or more of psychoneuropathy, neuropathy, neurotoxic disease, neuropathic pain or neurodegenerative disease. 一种如权利要求1-13中所述的式I所示杂环类化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药或权利要求17所述的药物组合物的用途，所述的用途为用于制备预防和/或治疗疾病的药物；所述的疾病为纤维化疾病和/或炎性疾病；A heterocyclic compound represented by formula I as described in claims 1-13, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs or claimed in claim 17 The use of the pharmaceutical composition, the use is for the preparation of medicines for preventing and/or treating diseases; the diseases are fibrotic diseases and/or inflammatory diseases; 优选，所述的纤维化疾病和所述的炎性疾病均如权利要求23所述。Preferably, both the fibrotic disease and the inflammatory disease are as described in claim 23. 式A-1、A-2-1、A-2或B-1所示化合物，其特征在于，所述化合物具有结构：The compound represented by formula A-1, A-2-1, A-2 or B-1 is characterized in that the compound has the structure:
Figure PCTCN2022130676-appb-100045
Figure PCTCN2022130676-appb-100045
 其中，Y 1选自卤素； Wherein, Y 1 is selected from halogen; R 3、R 4、R 5、R 6、X 1、X 2和X 3具有权利要求1-13任一项所述的定义； R 3 , R 4 , R 5 , R 6 , X 1 , X 2 and X 3 have the definitions described in any one of claims 1-13;
Figure PCTCN2022130676-appb-100046
Figure PCTCN2022130676-appb-100046
 其中，Y 1选自卤素； Wherein, Y 1 is selected from halogen; Y 2为氢或三甲基亚砜； Y 2 is hydrogen or trimethylsulfoxide; R 4、R 5与其所连接到的C原子一起形成环丁烷基或氧杂环丁烷基； R 4 , R 5 together with the C atom they are connected to form a cyclobutanyl group or an oxetanyl group; R 6、X 1、X 2和X 3具有权利要求1-13任一项所述的定义； R 6 , X 1 , X 2 and X 3 have the definitions described in any one of claims 1-13;
Figure PCTCN2022130676-appb-100047
Figure PCTCN2022130676-appb-100047
 其中，Y 1为卤素； Wherein, Y 1 is a halogen; R 4、R 5与其所连接到的C原子一起形成环丁烷基或氧杂环丁烷基； R 4 , R 5 together with the C atom they are connected to form a cyclobutanyl group or an oxetanyl group; R 6、X 1、X 2和X 3具有权利要求1-13任一项所述的定义；其中，Y 3为卤素或硼酸基； R 6 , X 1 , X 2 and X 3 have the definition described in any one of claims 1-13; wherein, Y 3 is halogen or boronic acid group; R 1、R 2、Z 1、Z 2、Z 3、Z 4、Z 5、Z 6、Z 7、R a、R b、m和n具有权利要求1-13任一项所述的定义。 R 1 , R 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , R a , R b , m and n have the definitions described in any one of claims 1-13.
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