WO2021233428A1 - 含氮饱和杂环化合物及其制备方法、药物组合物和应用 - Google Patents

含氮饱和杂环化合物及其制备方法、药物组合物和应用 Download PDF

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WO2021233428A1
WO2021233428A1 PCT/CN2021/095192 CN2021095192W WO2021233428A1 WO 2021233428 A1 WO2021233428 A1 WO 2021233428A1 CN 2021095192 W CN2021095192 W CN 2021095192W WO 2021233428 A1 WO2021233428 A1 WO 2021233428A1
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alkyl
group
alkenyl
alkynyl
pharmaceutically acceptable
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French (fr)
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邱关鹏
王永钢
邓代国
雷曾荣
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广州费米子科技有限责任公司
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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
    • A61K31/4355—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 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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
    • A61K31/437—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 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
    • C07D471/04—Ortho-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to organic compounds, especially nitrogen-containing saturated heterocyclic compounds, and preparation methods, pharmaceutical compositions and applications thereof.
  • the somatostatin receptor family (somatostatin receptors, SSTRs) is a family of G protein-coupled receptors that mediate somatostatin and its analogues, and have a variety of biological effects. focus on. Studies have shown that the specific membrane receptors on these cell membranes include SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, which can regulate growth hormone (GH) secretion, induce cell apoptosis, and inhibit tumors through cAMP, PTP, and MAPK signaling pathways. Biological processes such as cell proliferation, inhibition of insulin and cell growth play an important role, and at the same time exhibit kinetic characteristics similar to those of other G protein-coupled receptors.
  • GH growth hormone
  • Somatostatin is a cyclic polypeptide widely distributed in the central nervous system and surrounding tissues. It exists in two forms, 14 peptides (SST-14) and 28 peptides (SST-28). Research results have shown that SST as a signal molecule is mediated by the SST receptor family on the cell membrane, and there are only two forms of SST. The complexity of the physiological function of SST is reflected by the complexity of the receptor. Therefore, the biological significance of SSTR is more important than SST to some extent. SSTRs are similar in structure to other G protein-coupled receptors, with 7 transmembrane (TM) alpha helix structures, and N-glycosylation sites and palmitoylation sites in the N-terminal region (except SSTR3). In addition, there is a highly conserved amino acid sequence unique to SSTR in TM7.
  • TM transmembrane
  • SSTRs are coupled to a variety of cellular effector systems through G protein, which mainly involve the following four important signal transduction pathways: one is the cyclic adenosine monophosphate (cAMP) pathway; the other is the voltage-dependent Ca 2+ pathway; the third is the mitogen Activated protein kinase (mitogen-activated protein kinases, MAPK) pathway; fourth is the protein tyrosine phosphatase (protein tyrosine phosphatase, PTP) pathway.
  • cAMP cyclic adenosine monophosphate
  • MAPK mitogen Activated protein kinases
  • PTP protein tyrosine phosphatase
  • SSTR1 is related to the inhibition of cell growth; in addition to inducing cell apoptosis, SSTR3 is also involved in inhibiting the release of GH and insulin, as well as processing and regulating sensory signals, as well as the integration of sensory and visceral functions, smell and other sensory functions; SSTR4 also inhibits GH and insulin SSTR2 and SSTR5 play a major role in regulating the growth of animals, mainly inhibiting the release of GH and insulin, participating in central integration, and mediating tumor anti-proliferation and induction Apoptosis is the dominant subtype that mediates anti-tumor effects.
  • SSTR4 has come to the forefront as a potential mediator of central nervous system pathology, inflammation and even pain mechanisms.
  • Targeting SSTR4 has the additional advantage that it limits the secretion of the pituitary gland but does not inhibit the secretion of glucagon, growth hormone or insulin.
  • the expression level of SSTR4 is relatively high in the hippocampus and neocortex, memory and learning areas, and the pathology of Alzheimer's disease. Recent studies have indeed shown that SSTR4 agonists can improve learning and memory in rodent models of Alzheimer’s disease, which corresponds to a decrease in ⁇ -amyloid protein levels.
  • SSTR4 receptor stimulation can enhance cue memory in a dose-dependent manner, which may have direct cognitive enhancement activity.
  • Other studies have shown that the combination of SSTR4 and K + ion channels can regulate the excitability of the hippocampus, which has guiding significance for the treatment of certain forms of epilepsy with SSTR4 agonists.
  • the effects of SSTR4 agonists are effective in acute and chronic related anti-peripheral injury and anti-inflammatory activity related rodent pain models.
  • Recent research data shows that SRIF released by the nociceptor expressed by the capsaicin-sensitive receptor TRPV1 acts on SSTR4 and SSTR2 to produce an anti-noxious effect.
  • Pain is the most common clinical symptom that bothers patients, and it is also one of the main reasons for patients to see a doctor. According to the duration of pain, pain can be divided into acute pain and chronic pain. Acute pain includes pain caused by tissue damage and postoperative inflammation; chronic pain includes nociceptive pain, neuropathic pain, visceral pain, and mixed pain.
  • the current burden of pain treatment is still well-known analgesics, including narcotic analgesics (lidocaine, etc.), opioids, and non-steroidal anti-inflammatory drugs (NSAIDs). Drugs with new mechanisms of action have also joined the ranks of analgesics, such as antidepressants and anticonvulsants.
  • CN105473574A discloses the following compound of formula (I), which is an agonist of SSTR4 and is suitable for the prevention or treatment of medical conditions related to SSTR4.
  • SSTR4 agonists with good drug efficacy, high bioavailability and good solubility.
  • A is selected from C 6-14 aryl group, 5 to 14 membered heteroaryl group, 5 to 14 membered heterocyclic group and 5 to 14 membered cycloalkyl group, and the aryl group, heteroaryl group and heterocyclic group in A
  • the group and the cycloalkyl group are optionally further substituted with 0 to 5 R 3 ; wherein the heteroaryl group and the heterocyclic group each contain 1 to 4 heteroatoms selected from N, O and S;
  • R 3 is each independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy Group C 1-4 alkyl, -(CH 2 ) m -alkenyl, -(CH 2 ) m -alkynyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m- (3 to 10-membered heterocyclic group), -O-(CH 2 ) m -C 3-10 carbocyclic group and -O-(CH 2 ) m -(3 to 10-membered heterocyclic group), the hetero The ring contains 1 to 4 heteroatoms selected from N, O and S, and the alkyl, alkoxy, carbocyclic or heterocyclic ring described in R 3 is each independently optionally further selected from 0 to 4 -H , -F,
  • L 1 is selected from a single bond or -(CR a R b ) m -, wherein each of Ra and R b is independently selected from -H and C 1-6 alkyl;
  • L 2 is selected from -NH- and -O-;
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and C 3-6 cycloalkyl, wherein R 1 and R 2 are not simultaneously -H;
  • R 1 and R 2 together form a 3- to 6-membered saturated cyclic group containing 0 to 1 groups selected from -O-, -NR 16 -, -SO- and -SO 2 -;
  • R 16 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl, halogen, hydroxy, cyano and C 3-6 cycloalkyl;
  • M is selected from a single bond, -(CR c R d ) m -and -(CR c R d ) m O-, wherein R c and Rd are each independently selected from -H and C 1-6 alkyl;
  • X 1 , X 2 , and X 3 are each independently selected from a single bond and -(CR e R f ) n -;
  • X 4 is selected from -CH 2 -, -CH 2 CH 2 -and -CH 2 CH 2 CH 2 -;
  • R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R e , R f are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkoxy C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3-10 carbocyclic group, -(CH 2 ) m -O- (3 to 10 membered heterocyclic group), phenyl and 5 to 6 membered heteroaryl groups, the heterocyclic ring and heteroaryl group each contain 1 to 4 heteroatoms selected from N, O and S, hetero atoms, and R 4, R 5, R 6 , R 7, R 9, R 10, R e, R f in said alkyl, alkoxy, carbocycle Group, phenyl, heteroaryl and heterocycle are each independently
  • R 8 , R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected from -H, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • n, p, and q are independently selected from 0, 1, 2 or 3 each time they appear;
  • R 4 , R 5 , R 6 , and R 7 are not -H at the same time.
  • the present invention also provides a pharmaceutical composition containing a therapeutically effective amount of the compound or its stereoisomers, N-oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable Salts, polymorphs or prodrugs of, and pharmaceutically acceptable carriers or excipients.
  • the present invention also provides the compound as described above or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs or drug combinations as described above It is used in the preparation of medicines for treating and/or preventing diseases or symptoms affected by SSTR4 activation.
  • the present invention also provides the compound as described above or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs or drug combinations as described above And its application in the preparation of medicines for the treatment and/or prevention of pain.
  • the present invention has one or more of the following beneficial effects:
  • the compound provided by the present invention by introducing specific substituents at specific positions of the core structure, or adopting a core structure containing specific fused, spiro or bridged rings, the novel compounds thus obtained have excellent SSTR4 agonistic effects , Can be used as SSTR4 agonist to prevent and/or treat diseases or symptoms affected by SSTR4 activation, such as Alzheimer's disease and other CNS disorders, such as epilepsy and depression, and can be used to treat pain and/or inflammation from various sources .
  • experimental studies have shown that the compound of the present invention has high metabolic stability and excellent pharmacokinetic properties.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group, specifically a saturated hydrocarbon containing primary (normal) carbon atoms, secondary carbon atoms, tertiary carbon atoms, quaternary carbon atoms or a combination thereof. Phrases containing this term, for example, "C 1-6 alkyl” refers to an alkyl group containing 1 to 6 carbon atoms. Each occurrence can be C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl.
  • it may include an alkyl group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 10 carbon atoms, and more preferably a lower alkyl group containing 1 to 4 carbon atoms.
  • Non-limiting examples include: methyl, ethyl, 1-propyl, 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n -Butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-prop-1-yl (i-Bu, isobutyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl ( s-Bu, sec-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-prop-2-yl (t-Bu, tert-butyl, -C(CH 3 ) 3 ), 1- Pentyl (n-pentyl, -CH 2 CH 2 CH 2
  • the alkyl group may be substituted or unsubstituted. When substituted, it is substituted
  • Alkoxy refers to -O-alkyl, where alkyl is as defined herein above and is preferably an alkyl having 1 to 12 carbon atoms.
  • a phrase containing this term, for example, "C 1-4 alkoxy” refers to an -O-alkyl group having 1 to 4 carbon atoms in the alkyl moiety.
  • C 1-4 alkoxy groups can be C 1 alkoxy groups, C 2 alkoxy groups, C 3 alkoxy groups, C 4 alkoxy groups independently of each other.
  • the alkoxy group may be substituted or unsubstituted.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy or hexyl.
  • Alkoxyalkyl refers to an alkyl group substituted with an alkoxy group as described above. Examples include “C 1-4 alkoxy C 1-4 alkyl” or “C 1-6 alkoxy C 1-6 alkyl”. For example, “C 1-4 alkoxy C 1-4 alkyl” refers to C 1-4 alkyl substituted by C 1-4 alkoxy, and each time it appears, it can be C 1 alkane independently of each other. Oxygen C 1-4 alkyl, C 2 alkoxy C 1-4 alkyl, C 3 alkoxy C 1-4 alkyl, C 4 alkoxy C 1-4 alkyl. Alkoxyalkyl can be substituted or unsubstituted.
  • Alkenyl is an alkyl group defined in the present invention, which contains at least one carbon-carbon double bond.
  • the alkenyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, still more preferably 2 to 6 carbon atoms.
  • Alkynyl is an alkyl group defined in the present invention, which contains at least one carbon-carbon triple bond.
  • the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, still more preferably 2 to 6 carbon atoms.
  • Carbocyclyl or “cycloalkyl” refers to a saturated or partially unsaturated cyclic carbon-containing group.
  • the carbocyclic group is a 3 to 6 membered monocyclic ring, a 3 to 8 membered monocyclic ring, a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring, or a 10 to 15 membered tricyclic ring system.
  • the carbocyclic ring includes a bridged ring or a spiro ring.
  • Non-limiting examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, Benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl or spiro[3.3]heptane Base and so on.
  • the carbocyclic group may be optionally substituted.
  • Heterocyclic group or “heterocyclic ring” refers to a substituted or unsubstituted saturated or partially unsaturated heteroatom-containing cyclic group, and the heteroatom is selected from N, O, and S.
  • the heterocyclic group may be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, preferably a 3- to 10-membered heterocyclic group, and contains at least one, Preferably 1 to 4 heteroatoms selected from N, O or S.
  • the heteroatoms N or S in the heterocyclic ring can be oxidized to various oxidation states to form, for example, N-oxides.
  • the heterocyclic ring can be connected to other parts of the molecule through a heteroatom or a carbon atom.
  • the heterocyclic ring includes a bridged ring or a spiro ring.
  • heterocycles include, ethylene oxide, aziridinyl, oxetanyl, azetidine, 1,3-dioxolane, 1,4-dioxa Hexane, 1,3-dioxane, azepanyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiane, dihydrofuran, dihydropyran , Dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, chroman, dihydropyridyl, tetrahydrothienyl, sulfur oxide
  • Aryl refers to a substituted or unsubstituted all-carbon monocyclic or fused polycyclic unsaturated group with a conjugated ⁇ -electron system.
  • the aryl group is a 6 to 14 membered aromatic ring, preferably a 6 to 10 membered aromatic ring.
  • Non-limiting examples thereof include phenyl or naphthyl; the aryl group may be fused with a heteroaryl group, a heterocyclic group or a cycloalkyl group, and the part where the molecule is connected to the moiety is on the aryl group.
  • Non-limiting examples of aryl groups include benzofuran, benzocyclopentyl or benzothiazole, and the like.
  • Heteroaryl refers to a substituted or unsubstituted monocyclic or fused polycyclic unsaturated group containing at least one, preferably 1 to 4 heteroatoms selected from N, O and S.
  • the heteroaryl group is a 5 to 15 membered heteroaryl ring, a 5 to 14 membered heteroaryl group, or preferably a 5 to 10 membered heteroaryl ring, or more preferably a 5 to 6 membered heteroaryl group, wherein The number of heteroatoms is 1 to 4, preferably 1 to 3, and more preferably 1 to 2.
  • heteroaryl groups include pyridyl, furyl, thienyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzofuran, benzimidazole, benzopyridine Or pyrrolopyridine and so on.
  • Heteroalkyl refers to a group produced by replacing at least one carbon atom with a non-carbon atom on the basis of an alkyl group.
  • the non-carbon atom may be a N atom, an O atom, and/or an S atom.
  • the resulting heteroalkyl group is an alkoxy group (e.g., -OCH 3, etc.), an alkylamino group (e.g., -NHCH 3 , -N(CH 3 ) 2 etc.) or alkylthio (for example, -SCH 3 ).
  • the resulting heteroalkyl group is an alkyloxyalkyl group (for example, -CH 2 CH 2 -O-CH 3 etc.), alkylaminoalkyl (for example, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 etc.) or alkylthioalkyl (for example, -CH 2 -S-CH 3 ).
  • the resulting heteroalkyl group is a hydroxyalkyl group (for example, -CH 2 CH 2 -OH), an aminoalkyl group (for example, -CH 2 NH 2 ), or Mercaptoalkyl (e.g., -CH 2 CH 2 -SH).
  • Ammonio refers to a derivative of ammonia with the structural features of formula -N(X) 2 or formula -NR'R", wherein each "X", R'and R" is independently H, substituted or Unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • Non-limiting types of amino groups include -NH 2 , -N (alkyl) 2 , -NH (alkyl), -N (cycloalkyl) 2 , -NH (cycloalkyl), -N (heterocyclyl) 2.
  • Halogen refers to F, Cl, Br or I.
  • Halo refers to the replacement of one or more hydrogen atoms in a molecule or group with a halogen selected from F, Cl, Br, or I.
  • “Pharmaceutically acceptable salt” refers to a salt of a pharmaceutically acceptable non-toxic acid or base, and includes a salt formed with an inorganic acid or an inorganic base or a salt formed with an organic acid and an organic base.
  • Salts derived from inorganic bases include, but are not limited to, metal salts formed with Al, Ca, Li, Mg, K, Na, and Zn; salts derived from organic bases include, but are not limited to, those formed with primary, secondary, or tertiary amines Salt.
  • the primary, secondary or tertiary amines include naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, and triethylamine , Tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, Benminicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine or polyamine resin; derived from inorganic
  • the salts of acids and organic acids include, but are not limited to, salts formed with the following acids: sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid
  • Stepoisomers refer to isomers produced by the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • “Pharmaceutical composition” means a mixture of one or more of the compounds described in the text or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components. Other components are for example physiologically/pharmaceutically acceptable carriers or excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • Prodrug refers to a substance that can be converted into a compound of the present invention with biological activity under physiological conditions or through degradation.
  • the prodrug of the present invention is prepared by modifying the functional group in the compound, and the modification can be removed by conventional operations or removed in vivo to obtain the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl, amino or sulfhydryl group to any group in the compound of the present invention. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form a free hydroxyl group, a free amino group or a free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, compounds formed by hydroxyl or amino functional groups in the compounds of the present invention and formic acid, acetic acid or benzoic acid.
  • aryl group is optionally substituted by alkyl group means that alkyl group may but need not be present, and the term includes the case where the aryl group is substituted by the alkyl group and the case where the aryl group is not substituted by the alkyl group.
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • pharmaceutically acceptable carrier includes buffers compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption Retardants and the like. Each carrier must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient.
  • Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted ⁇ -cyclodextrin; (3) cellulose And its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients Excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polybasic Alcohols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (1
  • solvate refers to a compound that is combined with a solvent or a salt form thereof usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether and the like.
  • the compounds described herein can be prepared, for example, in crystalline form, and can be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • “Solvate” includes a solvate in a solution state and an isolatable solvate. Representative solvates include hydrates, ethanolates and methanolates.
  • metabolite refers to substances including products produced by the compound of the present invention in the body's metabolism, including intermediate metabolites and final metabolites.
  • polymorph refers to a crystalline form (or a salt, hydrate, or solvate thereof) of a compound in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to dominate. Various polymorphs of the compound can be prepared by crystallization under different conditions.
  • the dosage form and mode of administration of the compound of the present invention or its pharmaceutical composition are not particularly limited.
  • Representative administration methods include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intraperitoneal, intramuscular, or subcutaneous) injection and/or topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrant, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, complex silicate, and sodium carbonate; (e) solvent, such as paraffin; (f) absorption accelerator , For example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents (such as water or other solvents), solubilizers, and emulsifiers conventionally used in the art. Specific examples are, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil Oil, castor oil and sesame oil or mixtures of these substances.
  • the composition may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain a suspending agent.
  • ethoxylated isostearyl alcohol polyoxyethylene sorbitol and sorbitan esters
  • microcrystalline cellulose aluminum methoxide and agar, or mixtures thereof.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients are selected from water, ethanol and polyols, or suitable mixtures thereof.
  • Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. It is prepared by mixing the active ingredient with a pharmaceutically acceptable carrier, preservatives, buffers and/or propellants if necessary under aseptic conditions.
  • Embodiments of the present invention provide a compound having the structure of formula (I), or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or precursors thereof medicine:
  • A is selected from a C 6-14 aryl group, a 5- to 14-membered heteroaryl group, a 5- to 14-membered heterocyclic group, and a 5- to 14-membered cycloalkyl group, and the aryl group in A , Heteroaryl, heterocyclyl and cycloalkyl are optionally further substituted with 0 to 5 R 3 ; wherein the heteroaryl and heterocyclic group each contain 1 to 4 heteroatoms selected from N, O and S ;
  • R 3 is each independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 Alkoxy C 1-4 alkyl, -(CH 2 ) m -alkenyl, -(CH 2 ) m -alkynyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -O-(CH 2 ) m -C 3-10 carbocyclic group and -O-(CH 2 ) m -(3 to 10-membered heterocyclic group), the The heterocyclic ring contains 1 to 4 heteroatoms selected from N, O and S, and the alkyl, alkoxy, carbocyclic or heterocyclic ring described in R 3 is each independently optionally further selected from 0 to 4 -H,
  • L 1 is selected from a single bond and -(CR a R b ) m -, wherein R a and R b are each independently selected from -H and C 1-6 alkyl; m each time Each occurrence is independently selected from 0, 1, 2 or 3.
  • L 2 is selected from -NH- and -O-.
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and C 3-6 cycloalkyl, wherein R 1 and R 2 are not both -H at the same time; or R 1 and R 2 together can form a 3- to 6-membered saturated cyclic group containing 0 to 1 groups selected from -O-, -NR 16 -, -SO- and -SO 2 -;
  • R 16 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl, halogen, hydroxy, cyano and C 3-6 cycloalkyl.
  • R 1 and R 2 may each independently be selected from other cycloalkyl, alkyl, amino, alkoxy, aryl, heteroaryl, heteroalkyl, and heterocyclic groups.
  • M is selected from a single bond, -(CR c R d ) m -and -(CR c R d ) m O-, wherein R c and R d are independently selected from -H and C 1-6 alkyl; each occurrence of m is independently selected from 0, 1, 2 and 3.
  • Q is selected from one of the following structures:
  • X 1 , X 2 , and X 3 are each independently selected from a single bond and -(CR e R f ) n -;
  • X 4 is selected from -CH 2 -, -CH 2 CH 2 -and -CH 2 CH 2 CH 2 -;
  • R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R e , R f are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkoxy C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3-10 carbocyclic group, -(CH 2 ) m -O- (3 to 10-membered heterocyclic group), phenyl and 5 to 6-membered heteroaryl groups, the heterocyclic and heteroaryl groups each contain 1 to 4 heteroatoms selected from N, O and S, hetero atoms, and R 4, R 5, R 6 , R 7, R 9, R 10, R e, R f in said alkyl, alkoxy, carbocycle Group, phenyl, heteroaryl and heterocycle are each independently optionally
  • R 8 , R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected from -H, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • Each occurrence of m, n, p, and q is independently selected from 0, 1, 2, and 3.
  • R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R e , R f , R 8 , R 11 , R 12 , R 13 , R 14 , R 15 Each can also be independently selected from other cycloalkyl, alkyl, heterocyclyl, heteroaryl, alkoxy, or amino, aryl, and heteroalkyl.
  • A is selected from C 6-10 aryl groups and 5- to 10-membered heteroaryl groups, and the aryl or heteroaryl group in A is optionally further substituted with 0 to 5 R 3 .
  • A is a 5- to 10-membered heteroaryl group and is optionally further substituted with 0 to 5 R 3 .
  • A is selected from phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, indolyl, indazolyl, imidazo[1,2-a]pyridyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl and imidazolyl, and A is unsubstituted or optionally further substituted with 1 to 5 R 3 .
  • A is selected from naphthyl, indolyl, indazolyl and imidazo[1,2-a]pyridyl, and the naphthyl, indolyl, indazolyl or imidazo[1,2- a] Pyridyl is unsubstituted or optionally further substituted with 1 to 5 R 3 .
  • A is selected from one of the following structures:
  • A is optionally further substituted with 0 to 5 R 3 .
  • A is unsubstituted or optionally further substituted with 1 to 3 R 3 .
  • A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A is: In one of the specific embodiments, A
  • A is optionally selected from other aryl, heteroaryl, or amino, alkoxy, cycloalkyl, alkyl, heteroalkyl, and heterocyclic groups.
  • R 3 is each independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-4 alkane Oxy, C 1-4 alkoxy, C 1-4 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -O-(CH 2 ) m -C 3-10 carbocyclic group and- O-(CH 2 ) m -(3 to 10-membered heterocyclic group), the heterocyclic ring contains 1 to 4 heteroatoms selected from N, O and S, and the alkyl group and alkane mentioned in R 3
  • the oxy, carbocyclic or heterocyclic groups are each independently optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, hydroxyl, mercapto, cyano, amino, C 1-4 alkyl and C 1-4 Alkoxy substituents are substituted.
  • R 3 is each independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, cyano, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1- 4 Alkoxy C 1-4 alkyl, cyclopropyl, cyclobutyl and cyclopropylmethyl.
  • R 3 is methyl.
  • R 3 is -Cl.
  • R 3 is methoxy.
  • R 3 is CF 3 .
  • R 3 can also be selected from other alkyl groups, alkoxy groups, heterocyclic groups, cycloalkyl groups, heteroalkyl groups, or amino, aryl and heteroaryl groups.
  • R 1 and R 2 are each independently selected from C 1-6 alkyl and C 3-6 cycloalkyl; or R 1 and R 2 together form a group consisting of 0 to 1 selected from -O-, -SO- and -SO 2 -saturated cyclic groups with 3 to 6 members.
  • R 1 and R 2 are each independently selected from methyl, ethyl, propyl, cyclopropyl and cyclobutyl; or R 1 and R 2 can form a 3-membered saturated carbocyclic group together.
  • R 1 and R 2 can also be independently selected from other alkyl groups, cycloalkyl groups, or amino, alkoxy, aryl, heteroaryl, heteroalkyl and heterocyclyl groups. .
  • Q is selected from one of the following structures:
  • Q may also be independently selected from other heterocyclic groups, cycloalkyl groups, amino groups, alkoxy groups, aryl groups, heteroaryl groups, heteroalkyl groups, and alkyl groups.
  • X 4 is selected from -CH 2 -, -CH 2 CH 2 -and -CH 2 CH 2 CH 2 -.
  • R 12 , R 13 , R 14 , and R 15 are selected from -H.
  • the compound has a structure of formula (II):
  • L 2 is -NH-.
  • L 1 is selected from a single bond and -(CR a R b ) m -, wherein R a and R b are each independently selected from -H and C 1 -6 alkyl.
  • L 1 is selected from a single bond, -CH 2 -and -CH 2 CH 2 -. More preferably, L 1 is selected from a single bond and -CH 2 -. Most preferably, L 1 is a single bond.
  • X 1 and X 2 are each independently selected from a single bond and -(CR e R f ) n -.
  • X 1 and X 2 are each independently selected from a single bond, -CH 2 -and -CH 2 CH 2 -. More preferably, X 1 and X 2 are each independently selected from a single bond and -CH 2 -.
  • R e and R f are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3-10 carbocyclic group, -(CH 2 ) m -O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6-membered heteroaryl group, a heterocyclyl, heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S, and R e and
  • the alkyl group, alkoxy group, carbocyclic group, phenyl group, heteroaryl group or heterocyclic ring described in R f are each independently optionally further selected from 0 to 4 selected from -H, -F, -Cl, -Br, -I,
  • R e and R f are each independently selected from -H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R e and R f are each independently selected from -H and methyl. Most preferably, R e and R f are each -H.
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3-10 carbocyclic group, -(CH 2 ) m -O- (3 to 10-membered heterocyclic group), phenyl and 5 to 6-membered heteroaryl groups, the heterocyclic group, heteroaryl group Containing 1 to 4 heteroatoms selected from N, O and S, alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or hetero as described in R 4 , R 5 , R 6 , R 7
  • the rings are each independently and optionally further 0 to 4 selected from -H
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from -H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R 4 , R 5 , R 6 , and R 7 are each independently selected from -H and methyl. In one of the specific embodiments, R 4 , R 5 , R 6 , and R 7 are each independently -H.
  • R 8 is selected from -H, C 1-6 alkyl and C 3-6 cycloalkyl.
  • R 8 is selected from -H, methyl, ethyl and cyclopropyl. More preferably, R 8 is -H.
  • M is selected from a single bond, -(CR c R d ) m -and -(CR c R d ) m O-, wherein R c and R d Each is independently selected from -H and C 1-6 alkyl.
  • M is selected from a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 O- and CH 2 CH 2 O-. More preferably, M is selected from a single bond and -CH 2 O-.
  • M is a single bond. In one of the specific embodiments, M is -CH 2 O-.
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl, C 3-6 cycloalkyl, wherein R 1 and R 2 is not -H at the same time; or, R 1 and R 2 together form a saturated cyclic group containing 0 to 1 selected from -O-, -NR 16 -, -SO- and SO 2- ; R 16 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl, halogen, hydroxy, cyano and C 3-6 cycloalkyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R 1 and R 2 are each independently a methyl group.
  • R 1 and R 2 together form a 3 to 6-membered saturated cyclic group containing 0 to 1 selected from -O-, -SO- and SO 2 -. More preferably, R 1 and R 2 can form a cyclopropyl group together.
  • the compound has a structure of formula (III):
  • X 1 is selected from a single bond and -CH 2 -.
  • L 1 is selected from a single bond and - (CR a R b) m -, wherein R a, R b is independently selected from -H and C 1- 6 alkyl.
  • L 1 is selected from a single bond, -CH 2 -and -CH 2 CH 2 -. More preferably, L 1 is selected from a single bond and -CH 2 -. Most preferably, L 1 is a single bond.
  • R 6 and R 7 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkane Oxygen C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3 -10 carbocyclic group, -(CH 2 ) m -O- (3 to 10-membered heterocyclic group), phenyl and 5 to 6-membered heteroaryl groups, each of which contains 1 to 4 A heteroatom selected from N, O and S, the alkyl, alkoxy, carbocyclic, phenyl, heteroaryl or heterocyclic group described in R 4 , R 5 , R 6 , and R 7 are each independently Optionally selected further by 0 to 4 substituents selected from -H, -F, -Cl, -
  • R 6 and R 7 are each independently selected from -H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R 6 and R 7 are each independently selected from -H and methyl. Most preferably, R 6 and R 7 are each independently -H.
  • R 8 is selected from -H, C 1-6 alkyl and C 3-6 cycloalkyl.
  • R 8 is selected from -H, methyl, ethyl and cyclopropyl. More preferably, R 8 is -H.
  • the compound has a structure of formula (IV):
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkoxy C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3-10 carbocyclic group, -(CH 2 ) m -O- (3 to 10 membered heterocyclic group), phenyl and 5 to 6 membered heteroaryl groups, the heterocyclic and heteroaromatic groups
  • Each group contains 1 to 4 heteroatoms selected from N, O and S, and the alkyl group, alkoxy group, carbocyclic group, phenyl group, heteroaryl group described in R 4 , R 5 , R 6 , and R 7 Group or heterocyclic ring each independently optionally further selected
  • R 4 , R 5 , and R 6 are -H;
  • R 7 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkoxy C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3-10 carbocyclic group, -(CH 2 ) m -O- (3 to 10-membered heterocyclic group), phenyl and 5 to 6-membered heteroaryl groups, the heterocyclic and heteroaryl groups each contain 1 to 4 heteroatoms selected from N, O and S, and the alkyl group, alkoxy group, carbocyclic group, phenyl group, heteroaryl group or heterocyclic group described in R 7 are each independently optionally further 0 to 4 substituents selected from -H, -F, -Cl,
  • R 7 or the R 7 -containing group substituted by the substituent is selected from C 1-6 alkyl, C 1-6 alkoxy, methoxymethyl, hydroxymethyl, monofluoro Methyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, furyl, imidazolyl and thiazolyl; and R 7 is independently optionally further selected from 0 to 4 -H, -F, -Cl, -Br, -I, hydroxyl, mercapto, cyano, amino, C 1-4 alkyl, and C 1-4 alkoxy substituents.
  • R 5 , R 6 , and R 7 are -H;
  • R 4 is selected from C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkoxy C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3-10 carbocyclic group, -(CH 2 ) m -O- (3 to 10-membered heterocyclic group), phenyl and 5 to 6-membered heteroaryl groups, the heterocyclic and heteroaryl groups each contain 1 to 4 heteroatoms selected from N, O and S, and the alkyl group, alkoxy group, carbocyclyl group, phenyl group, heteroaryl group or heterocyclic group described in R 4 are each independently optionally further 0 to 4 substituents selected from -H, -F, -Cl
  • R 4 or the R 4 containing group substituted by the substituent is selected from C 1-6 alkyl, methoxymethyl, hydroxymethyl, monofluoromethyl, difluoromethyl, Trifluoromethyl, cyclopropyl, cyclobutyl, cyclobutoxy, cyclopentyl, tetrahydrofuranyl, phenyl, pyridyl, furyl, imidazolyl and thiazolyl, the phenyl, pyridyl, furan Group, imidazolyl, thiazolyl each independently optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, hydroxyl, cyano, amino, C 1-4 alkyl and C 1-4 alkoxy The substituents are substituted.
  • L 1 is selected from a single bond and -(CR a R b ) m -, wherein R a and R b are each independently selected from -H and C 1 -6 alkyl.
  • L 1 is selected from a single bond, -CH 2 -and -CH 2 CH 2 -. More preferably, L 1 is selected from a single bond and -CH 2 -. Most preferably, L 1 is a single bond.
  • M is selected from a single bond, -(CR c R d ) m -and -(CR c R d ) m O-, wherein R c , R d Each is independently selected from -H and C 1-6 alkyl.
  • M is selected from a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 O- and CH 2 CH 2 O-. More preferably, M is selected from a single bond and -CH 2 O-. Most preferably, M is a single bond.
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and C 3-6 cycloalkyl, wherein R 1 and R 2 is not -H at the same time; or, R 1 and R 2 together form a 3 to 6-membered saturated ring containing 0 to 1 groups selected from -O-, -NR 16 -, -SO- and SO 2- R 16 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkyl, halogen, hydroxy, cyano and C 3-6 cycloalkyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R 1 and R 2 are each independently selected from methyl.
  • R 1 and R 2 together form a 3- to 6-membered saturated cyclic group containing 0 to 1 -O-, -SO- and SO 2 -. More preferably, R 1 and R 2 can form a cyclopropyl group together.
  • R 8 is selected from -H, C 1-6 alkyl, and C 3-6 cycloalkyl.
  • R 8 is selected from -H, methyl, ethyl and cyclopropyl. More preferably, R 8 is -H.
  • the compound has a structure of formula (V):
  • X 3 is selected from a single bond, -CH 2 -, -CH 2 CH 2 -and -CH 2 CH 2 CH 2 -.
  • p and q are independently selected from 0, 1, 2 and 3 each time they appear.
  • R 9 and R 10 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy Group C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3- 10- carbocyclic group, -(CH 2 ) m -O- (3 to 10-membered heterocyclic group), phenyl and 5 to 6-membered heteroaryl groups, each of said heterocyclic groups and heteroaryl groups contains 1 to 4 Heteroatoms selected from N, O and S, the alkyl group, alkoxy group, carbocyclic group, phenyl group, heteroaryl group or heterocyclic group described in R 9 and R 10 are each independently optionally further substituted by 0 to 4 Substituted by a substituent selected from -H,
  • R 9 and R 10 are each independently selected from -H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R 9 and R 10 are each independently selected from -H and methyl. In one of the specific embodiments, R 9 and R 10 are each independently -H.
  • R 8 is selected from -H, C 1-6 alkyl and C 3-6 cycloalkyl.
  • R 8 is selected from -H, methyl, ethyl and cyclopropyl. More preferably, R 8 is -H.
  • p and q are independently selected from 0, 1, 2 and 3 each time they appear.
  • each time p and q appear each is independently selected from 0, 1, and 2.
  • L 2 is -NH-.
  • L 1 is selected from a single bond and - (CR a R b) m -, wherein R a, R b is independently selected from -H and C 1-6 alkyl.
  • L 1 is selected from a single bond, -CH 2 -and -CH 2 CH 2 -. More preferably, L 1 is selected from a single bond and -CH 2 -. Most preferably, L 1 is a single bond.
  • M is selected from a single bond, -(CR c R d ) m -and -(CR c R d ) m O-, wherein R c and R d are independent Ground is selected from -H and C 1-6 alkyl.
  • M is selected from a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 O- and CH 2 CH 2 O-. More preferably, M is selected from a single bond and -CH 2 O-. Most preferably, M is a single bond.
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and C 3-6 cycloalkyl, wherein R 1 and R 2 is not -H at the same time; or, R 1 and R 2 together form a 3 to 6-membered saturated ring containing 0 to 1 groups selected from -O-, -NR 16 -, -SO- and SO 2- R 16 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkyl, halogen, hydroxy, cyano and C 3-6 cycloalkyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R 1 and R 2 are each independently a methyl group.
  • R 1 and R 2 together form a 3 to 6-membered saturated cyclic group containing 0 to 1 selected from -O-, -SO- and SO 2 -. More preferably, R 1 and R 2 can form a cyclopropyl group together.
  • p and q are each 1; X 3 is -CH 2 -; R 9 , R 10 , and R 11 are each -H; L 1 is a single bond; L 2 is -NH-; M is a single bond.
  • the compound has a structure of formula (VI):
  • L 2 is -NH-.
  • R 9 and R 10 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkoxy C 1-6 alkyl, -(CH 2 ) m -C 3-10 carbocyclic group, -(CH 2 ) m -(3 to 10-membered heterocyclic group), -(CH 2 ) m -OC 3-10 carbocyclic group, -(CH 2 ) m -O- (3 to 10-membered heterocyclic group), phenyl and 5 to 6-membered heteroaryl groups, the heterocyclic groups and heteroaryl groups each contain 1 to 4 heteroatoms selected from N, O and S, the alkyl group, alkoxy group, carbocyclyl group, phenyl group, heteroaryl group or heterocyclic group described in R 9 and R 10 are each independently optionally further 0 to 4 substituents selected from -H, -F, -Cl, -
  • R 9 and R 10 are each independently selected from -H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R 9 and R 10 are each independently selected from -H and methyl. In one of the specific embodiments, R 9 and R 10 are each independently -H.
  • R 8 is selected from -H, C 1-6 alkyl and C 3-6 cycloalkyl.
  • R 8 is selected from -H, methyl, ethyl and cyclopropyl. More preferably, R 8 is -H.
  • L 1 is selected from a single bond and -(CR a R b ) m -, wherein R a and R b are each independently selected from -H and C 1 -6 alkyl.
  • L 1 is selected from a single bond, -CH 2 -and -CH 2 CH 2 -. More preferably, L 1 is selected from a single bond and -CH 2 -. Most preferably, L 1 is a single bond.
  • M is selected from a single bond, -(CR c R d ) m -and -(CR c R d ) m O-, wherein R c , R d Independently selected from -H and C 1-6 alkyl.
  • M is selected from a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 O- and CH 2 CH 2 O-. More preferably, M is selected from a single bond and -CH 2 O-. Most preferably, M is a single bond.
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and C 3-6 cycloalkyl, wherein R 1 and R 2 is not -H at the same time; or, R 1 and R 2 together can form a 3- to 6-membered saturated cyclic group containing 0 to 1 -O-, -NR 16 -, -SO- and SO 2-groups Group; R 16 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl, halogen, hydroxy, cyano and C 3-6 cycloalkyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R 1 and R 2 are each independently a methyl group.
  • R 1 and R 2 together form a 3 to 6-membered saturated cyclic group containing 0 to 1 group selected from -O-, -SO- and SO 2 -. More preferably, R 1 and R 2 can form a cyclopropyl group together.
  • R 9 , R 10 , and R 11 are each -H; L 1 is a single bond; and M is a single bond.
  • the present invention relates to compounds of formula (a), or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof,
  • X 1 is CR 3 'or NR 3;
  • X 2 is CR 3 'or NR 3;
  • X 1 and substituents with the adjacent carbon atoms and the substituent group R 3 ' together form a benzene ring or a 5- to 6-membered heteroaromatic ring, a benzene ring or a 5- to 6-membered heteroaromatic ring Optionally substituted by 1-4 R 3' ;
  • R 3 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -( CH 2 ) n -(5 to 6-membered heteroaryl) and -SR x ;
  • R 4 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl); Wherein the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are optionally halogen, cyano, -OR, -NR'R", C 1-6 alkyl , Halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl substitution;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3;
  • s 0, 1 or 2;
  • r 0, 1, or 2.
  • the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof ,in,
  • X 1 is CR 3 'or NR 3;
  • X 2 is CR 3' ;
  • X 1 and its substituents form a benzene ring or 5- to 6-membered heteroaromatic ring together with the adjacent carbon atom and its substituent R 3' , and the benzene ring or 5- to 6-membered heteroaromatic ring is 1 -4 R 3 'substituent;
  • R 3 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -( CH 2 ) n -(5 to 6-membered heteroaryl) and -SR x ;
  • R 4 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are optionally halogen, cyano, -OR, -NR'R", C 1-6 alkyl, Halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl substitutions;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3;
  • s is 0 or 1;
  • r is 0 or 1.
  • the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof ,in,
  • X 1 is CR 3 'or NR 3;
  • X 2 is NR 3 ;
  • X 1 and its substituents form a benzene ring or 5- to 6-membered heteroaromatic ring together with the adjacent carbon atom and its substituent R 3' , and the benzene ring or 5- to 6-membered heteroaromatic ring is 1 -4 R 3 'substituent;
  • R 3 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -( CH 2 ) n -(5 to 6-membered heteroaryl) and -SR x ;
  • R 4 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are optionally halogen, cyano, -OR, -NR'R", C 1-6 alkyl, Halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl substitutions;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3;
  • s is 0 or 1;
  • r is 0 or 1.
  • the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof ,in,
  • X 1 is CR 3' ;
  • X 2 is NR 3 ;
  • X 1 and its substituents form a benzene ring together with the adjacent carbon atom and its substituent R 3' , and the benzene ring is substituted by 1-4 R 3' ;
  • R 3 is selected from -H and C 1-6 alkyl
  • R 3 ' is C 1-6 alkyl
  • R 4 is selected from -H and C 1-6 alkyl
  • R 5 is selected from -H and C 1-6 alkyl
  • R 1 and R 2 are each independently a methyl group
  • s 1;
  • the present invention relates to compounds of formula (b), or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof,
  • X 1 is CR 3 'or NR 3;
  • X 2 is CR 3 'or NR 3;
  • X 1 and substituents with the adjacent carbon atoms and the substituent group R 3 ' together form a benzene ring or a 5- to 6-membered heteroaromatic ring, a benzene ring or a 5- to 6-membered heteroaromatic ring Optionally substituted by 1-4 R 3' ;
  • R 3 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -( CH 2 ) n -(5 to 6-membered heteroaryl) and -SR x ;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic group,- (CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl); wherein Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl substituted;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3.
  • the present invention relates to the compound of formula (b) above, or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof ,
  • X 1 is CR 3 'or NR 3;
  • X 2 is CR 3' ;
  • X 1 and its substituents form a benzene ring or 5- to 6-membered heteroaromatic ring together with the adjacent carbon atom and its substituent R 3' , and the benzene ring or 5- to 6-membered heteroaromatic ring is 1 -4 R 3 'substituent;
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -( CH 2 ) n -(5 to 6-membered heteroaryl) and -SR x ;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic group,- (CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl); the alkane Group, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl substitution;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3.
  • the present invention relates to the compound of formula (b) above, or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof ,in,
  • X 1 is CR 3 'or NR 3;
  • X 2 is NR 3 ;
  • X 1 and its substituents form a benzene ring or 5- to 6-membered heteroaromatic ring together with the adjacent carbon atom and its substituent R 3' , and the benzene ring or 5- to 6-membered heteroaromatic ring is 1 -4 R 3 'substituent;
  • R 3 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -( CH 2 ) n -(5 to 6-membered heteroaryl) and -SR x ;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic group,- (CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl); the alkane Group, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl substitution;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3.
  • the present invention relates to compounds of formula (c), or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof,
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -( CH 2 ) n -(5 to 6-membered heteroaryl) and -SR x ;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic group,- (CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl); wherein Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl substituted;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3;
  • t 0, 1, 2, 3, 4, or 5.
  • the present invention relates to the compound of formula (c) above, or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof ,in,
  • R 3' is selected from halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl and -SR x ;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R x is selected from C 1-6 alkyl, halogenated C 1-6 alkyl and -(CH 2 ) n -C 3-6 carbocyclic group;
  • n 0, 1, 2 or 3;
  • t 0, 1, or 2.
  • the present invention relates to the compound of formula (c) above, or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof ,in,
  • R 3 ' is selected from C 1-4 alkyl and -SR x;
  • R 4 is C 1-4 alkyl
  • R 5 is selected from -H and C 1-4 alkyl
  • R 1 and R 2 are each independently selected from -H and C 1-4 alkyl
  • R x is selected from C 1-4 alkyl and halo C 1-4 alkyl
  • t 1 or 2.
  • the present invention relates to the compound of formula (c) above, or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof ,
  • R 3' is C 1-4 alkyl
  • R 4 is C 1-4 alkyl
  • R 5 is -H
  • R 1 and R 2 are each independently a methyl group
  • the present invention relates to compounds of formula (c-1), or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro medicine,
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl ⁇ -SR x ;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3.
  • the present invention relates to the above-mentioned compound of formula (c-1), or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or Prodrugs, of which,
  • R 3' is selected from halogen, C 1-4 alkyl, halo C 1-4 alkyl and -SR x ;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R x is selected from C 1-6 alkyl, halogenated C 1-6 alkyl and -(CH 2 ) n -C 3-6 carbocyclic group;
  • n 0, 1, 2 or 3.
  • the present invention relates to the above-mentioned compound of formula (c-1), or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or Prodrug,
  • R 3 ' is selected from C 1-4 alkyl and -SR x;
  • R 4 is C 1-4 alkyl and halo C 1-4 alkyl
  • R 5 is selected from -H and C 1-4 alkyl
  • R x is selected from C 1-4 alkyl and halogenated C 1-4 alkyl.
  • the present invention relates to the above-mentioned compound of formula (c-1), or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or Prodrug,
  • R 3' is C 1-4 alkyl
  • R 4 is C 1-4 alkyl
  • R 5 is -H.
  • the present invention relates to compounds of formula (d), or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof,
  • R 3 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl Group, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -( CH 2 ) n -(5 to 6-membered heteroaryl) and -SR x ;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic group,- (CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl); wherein Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted by halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl substituted;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic ring -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3;
  • t 0, 1, 2, 3, or 4.
  • the present invention relates to the compound of formula (d) above, or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs ,in,
  • R 3 is selected from C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 3 ' is selected from -H, halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl group, and -SR x;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 1 and R 2 are each independently selected from -H, C 1-6 alkyl and halo C 1-6 alkyl;
  • R x is selected from C 1-6 alkyl, halogenated C 1-6 alkyl and -(CH 2 ) n -C 3-6 carbocyclic group;
  • n 0, 1, 2 or 3;
  • t 0, 1, or 2.
  • the present invention relates to the compound of formula (d) above, or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs ,in,
  • R 3 is C 1-4 alkyl
  • R 3 ' is selected from -H, C 1-4 alkyl, and -SR x;
  • R 4 is C 1-4 alkyl
  • R 5 is selected from -H and C 1-4 alkyl
  • R 1 and R 2 are each independently selected from -H and C 1-4 alkyl
  • R x is selected from C 1-4 alkyl and halo C 1-4 alkyl
  • t 0 or 1.
  • the present invention relates to the compound of formula (d) above, or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs ,
  • R 3 is C 1-4 alkyl
  • R 3 ' is selected from -H and C 1-4 alkyl
  • R 4 is C 1-4 alkyl
  • R 5 is -H
  • R 1 and R 2 are each independently a methyl group
  • t 0 or 1.
  • the present invention relates to a compound of formula (d-1), or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro medicine,
  • R 3 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 3 ' is selected from -H, halogen, cyano, -OR, -NR'R ", C 1-6 alkyl, halo C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl ⁇ -SR x ;
  • R 4 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 5 is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
  • R is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R'and R" are each selected from -H, C 1-6 alkyl and halo C 1-6 alkyl, or R'and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl , -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3 to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl and -(CH 2 ) n -(5 to 6-membered heteroaryl);
  • n 0, 1, 2 or 3.
  • the present invention relates to the above-mentioned compound of formula (d-1), or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or Prodrugs, of which,
  • R 3 is selected from C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 3 ' is selected from -H, halogen, cyano, C 1-6 alkyl and C 1- alkyl and haloalkyl -SR x;
  • R 4 is selected from C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 5 is selected from -H, C 1-6 alkyl and halo C 1-6 alkyl
  • R x is selected from C 1-6 alkyl, halogenated C 1-6 alkyl and -(CH 2 ) n -C 3-6 carbocyclic group;
  • n 0, 1, 2 or 3.
  • the present invention relates to the above-mentioned compound of formula (d-1), or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or Prodrugs, of which,
  • R 3 is C 1-4 alkyl
  • R 3 ' is selected from -H, C 1-4 alkyl, and -SR x;
  • R 4 is C 1-4 alkyl
  • R 5 is selected from -H and C 1-4 alkyl
  • R x is selected from C 1-4 alkyl and halogenated C 1-4 alkyl.
  • the present invention relates to the above-mentioned compound of formula (d-1), or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or Prodrugs, of which,
  • R 3 is C 1-4 alkyl
  • R 3 ' is selected from -H and C 1-4 alkyl
  • R 4 is C 1-4 alkyl
  • R 5 is -H.
  • the compound is selected from one of the following structures:
  • the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, Mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronate, galacturonate, Citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate and three Fluoromethanesulfonate, or a combination thereof.
  • the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, acetate, maleate, succinate, fumarate, malate, oxalate, tartaric acid Salt, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, and triflate, or combinations thereof.
  • the embodiment of the present invention also provides a preparation method of the compound, which includes the following steps:
  • Embodiments of the present invention also provide a pharmaceutical composition containing a therapeutically effective amount of the above-mentioned compound or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceuticals Acceptable salts, polymorphs or prodrugs, and pharmaceutically acceptable carriers or excipients.
  • Embodiments of the present invention also provide the compound as described above or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, or, as above
  • the pharmaceutical composition is used in the preparation of a medicine for treating and/or preventing diseases or symptoms affected by SSTR4 activation.
  • the disease or symptom affected by SSTR4 activation is pain.
  • Embodiments of the present invention also provide the compound as described above or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, or, as above The application of the pharmaceutical composition in preparing a medicine for treating and/or preventing pain.
  • the present invention provides the compound of the present invention or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs or the present invention.
  • the pharmaceutical composition of the invention is used for the treatment and/or prevention of diseases or symptoms affected by SSTR4 activation. In one embodiment, the compound or composition is used to treat and/or prevent pain.
  • the present invention provides a method for treating diseases or symptoms affected by SSTR4 activation, which comprises administering the compound of the present invention or its stereoisomers, N-oxides, hydrates, solvates, Metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs or the pharmaceutical composition of the present invention.
  • the present invention provides a method of treating pain, which comprises administering the compound or pharmaceutical composition of the present invention.
  • the pain is neuralgia.
  • the pain is back pain, chronic back pain, trigeminal neuralgia, type I complex regional pain syndrome, type II complex regional pain syndrome, irritable bowel syndrome, diabetic neuropathy , Pain caused by osteoarthritis, tumor pain, muscle fiber pain.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR is measured with (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • HPLC measurement uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology Waiting for the company.
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature.
  • Room temperature is the most suitable reaction temperature, which is 20°C to 30°C.
  • DIPEA Diisopropylethylamine
  • HATU 2-(7-Aza 1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • LiHMDS Lithium hexamethyldisilazide
  • Raney-Ni Raney Nickel
  • Raney-Ni Raney Nickel
  • Burgess’reagent Burgess reagent, CAS No.: 29684-56-8
  • the 10.1 g of the racemate compound 3f obtained above was subjected to chiral resolution to obtain 4.5 g each of 3f-P1 (compound with shorter retention time) and 3f-P2 (compound with longer retention time).
  • the seventh step 3-(tert-butoxycarbonyl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (Intermediate 3-P1 and Intermediate 3-P2)
  • Step 2 N-(2-(8-Methylimidazo[1,5-a]pyridin-3-yl)prop-2-yl)-5-azaspiro[2.4]heptane-1-carboxy Amide hydrochloride (Compound 1)
  • the first step 5-((2-(8-Methylimidazo[1,5-a]pyridin-3-yl)prop-2-yl)carbamoyl)tert-butyl-2-azabicyclo[ 2.2.1]Heptane-2-carboxylic acid tert-butyl ester (6B)
  • the first step 7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbonitrile (7B)
  • Cerium trichloride (320 mg, 1.3 mmol) was stirred in dry tetrahydrofuran (5 mL) for 1 hour, the temperature was lowered to -78° C., methyl lithium (1 mL, 1.3 mmol, 1.3M) was added dropwise, and the mixture was stirred for 1 hour. Then drip 7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbonitrile 7B (100mg, 0.32mmol) in tetrahydrofuran (1mL ) The solution was slowly warmed to room temperature and stirred for 16 hours.
  • Dissolve 8F (100mg, 0.44mmol) in acetonitrile (1mL), add 2,2,6,6-tetramethylpiperidine nitroxide (3.4mg, 0.022mmol) and 10% sodium chlorite aqueous solution at room temperature (79.2mg, 0.88mmol), stirred for 30 minutes. Then 10% aqueous sodium hypochlorite solution (65 mg, 0.88 mmol) was added. Stir at room temperature overnight, and extract with ethyl acetate (10 mL x 2). The filtrate was dried over anhydrous sodium sulfate and spin-dried in vacuo to obtain an oil 8G, which was directly thrown into the next reaction without purification (80mg, yield: 75%).
  • the seventh step 1-methyl-6-((2-(8-methylimidazo[1,5-a]pyridin-3-yl)prop-2-yl)carbamoyl)-3-aza Bicyclo[3.1.0] hexane-3-carboxylic acid tert-butyl ester (8H)
  • reaction solution was poured into water, extracted with ethyl acetate, and the combined organic phase was washed with saturated brine and dried with anhydrous sodium sulfate.
  • the solvent was spin-dried in vacuo, and the crude product was purified by preparative HPLC to obtain 9B-P1 (140 mg) and 9B-P2 (150 mg).
  • 9B-P1 was then chirally resolved to obtain 9B-P1-1 (70 mg, a compound with a shorter retention time) and 9B-P1-2 (65 mg, a compound with a longer retention time).
  • the conditions for chiral splitting are shown in the following table:
  • 9B-P2 was then chirally resolved to obtain 9B-P2-1 (65 mg, a compound with a shorter retention time) and 9B-P2-2 (80 mg, a compound with a longer retention time).
  • the conditions for chiral splitting are shown in the following table:
  • the excess boron tribromide is removed by vacuum spin-drying at a water bath temperature not exceeding 20°C, and the residue is adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution, and then spin-dried in vacuo to obtain a crude product.
  • the crude product was purified by preparative HPLC to obtain compound 12 (19 mg, yield: 34.0%) as a white solid.
  • 15A-P1 60 mg, compound with shorter retention time
  • 15A-P2 60 mg, compound with longer retention time
  • reaction solution was spin-dried to remove the solvent and trifluoroacetic acid, the residue was adjusted to weakly alkaline with ammonia water, and the crude product was spin-dried to obtain a crude product.
  • the crude product was purified by prep-TLC to obtain the product compound 15 (21.4 mg, yield: 44.5%).
  • the organic phase was dried with anhydrous sodium sulfate and spin-dried in vacuo to obtain a crude oil.
  • the reaction solution was poured into water, the organic phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and spin-dried in vacuo to obtain a crude product.
  • the reaction solution was poured into water, the organic phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and spin-dried in vacuo to obtain a crude product.
  • the first step (1-(((3-chloropyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl) tert-butyl carbamate (20B)
  • the reaction solution was poured into water, the organic phase was extracted with ethyl acetate, the combined organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and spin-dried in vacuo to obtain a crude yellow oil.
  • reaction solution was poured into water, the organic phase was extracted with dichloromethane, the combined organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was spin-dried under vacuum to obtain (2-(8-chloroimidazo[1,5- a] tert-butyl pyridin-3-yl)prop-2-yl)carbamate 20C (100 mg, crude).
  • reaction solution was spin-dried in vacuo to obtain a crude product (100 mg), which was added to methanol solution (10 mL), hydrochloric acid-dioxane solution (2 mL) was added dropwise, stirred overnight at room temperature, and then spin-dried in vacuo to further obtain the crude product (Compound 20).
  • the crude product was purified by preparative HPLC to obtain a pale yellow oil (2.27 mg, yield: 4.59%).
  • the first step (3-methoxypyridin-2-yl)methylamine (21B)
  • the organic phase was washed once with 50 mL saturated NaCl aqueous solution, the organic phase was dried with anhydrous sodium sulfate, filtered with suction, and the organic phase was spin-dried. Obtain a residue.
  • the organic phase was washed once with 20 mL of saturated NaCl aqueous solution and dried with anhydrous sodium sulfate. Filter with suction and spin dry the organic phase to obtain a residue.
  • the first step 4-(2-((2-(8-methylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)amino)-2-oxoethyl)piper Tert-butyl pyridine-1-carboxylate (22A)
  • Test purpose To determine the agonistic effect of the test compound on the SSTR4 receptor using the Cell-based human SSTR4 cAMP assay.
  • Cell culture and reagent preparation cell strain: Flp-In-CHO-SSTR4 stable pool; complete medium: Ham's F-12K+10% FBS+1x penicillin-streptomycin (PS)+600 ⁇ g/ml Hygromycin B; cell seeding medium: Ham's F-12K+10% FBS; experiment buffer: 1X HBSS+20mM HEPES+0.1%BSA+500uM IBMX.
  • the Flp-In-CHO-SSTR4 stable pool cell line is cultured in complete medium at 37°C, 5% CO 2 to 70% to 90% confluence.
  • the cells were resuspended in seeding medium, seeded on a 384-well cell culture plate (384 PE culture plate), seeded with 7,000 cells per well, and cultured overnight at 37°C, 5% CO 2.
  • step 3 Add 2.5 ⁇ l of the 8X compound working solution diluted in step 3 to the corresponding test well, centrifuge at 200g at room temperature for 5 seconds, and incubate at 37°C for 10 min.
  • the compound of the present invention has obvious human auxin type IV receptor SSTR4 agonistic activity.
  • the pooled human liver microsomes and male rat liver microsomes were used to analyze the metabolic degradation of the test compounds at 37°C.
  • the final incubation reaction system solution contains phosphate buffer (pH 7.4), positive control compound (dextromethorphan) or test compound (200 ⁇ M, 1.5 ⁇ L) and liver microsomes (0.5mg/mL, 238.5 ⁇ L).
  • NADPH 5mM, 60 ⁇ L
  • a fixed volume of the reaction mixture (30 ⁇ L) was sampled into the solution at a fixed time point (0, 5, 15, 30, 60 min) to quench the reaction. After centrifugation (4000 rpm, 15 min), the supernatant (100 ⁇ L) was mixed with distilled water (100 ⁇ L), and then subjected to LC-MS/MS analysis to test the amount of the compound.
  • the compound of the present invention has good metabolic stability in liver microsomes.
  • the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the rats were orally and intravenously administered the test compound. To study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.
  • test compound was administered to rats orally and intravenously.
  • 0.2 mL of blood was collected from the submandibular vein or other suitable blood vessel, placed in a K2-EDTA test tube, and then stored on ice.
  • the plasma was separated by centrifugation at 6800g for 6 minutes at a temperature of 2-8°C, and stored at -80°C for LC/MS/MS analysis.
  • the rats were given food 4 hours after the administration.

Abstract

一种具有式(I)结构的含氮饱和杂环化合物及其制备方法、药物组合物和应用。该含氮饱和杂环化合物是一类结构新颖、药效更好、生物利用度高和溶解性更好的生长抑素受体亚型4(SSTR4)激动剂类化合物。

Description

含氮饱和杂环化合物及其制备方法、药物组合物和应用 技术领域
本发明涉及有机化合物，特别是含氮饱和杂环化合物及其制备方法、药物组合物和应用。
背景技术
生长抑素受体家族(somatostatin receptors，SSTRs)是一类介导生长抑素及其类似物，具有多种生物学效应的G蛋白偶联受体家族，其生理功能和作用机制长期以来倍受关注。研究表明，这些细胞膜上存在的特定膜受体包括SSTR1、SSTR2、SSTR3、SSTR4以及SSTR5，它们可以通过cAMP、PTP和MAPK信号通路，在调控生长激素(GH)分泌、诱导细胞凋亡、抑制肿瘤细胞增生、抑制胰岛素作用和抑制细胞生长等生物学过程发挥重要的作用，同时表现出与其它G蛋白偶联受体性质相似的动力学特征。
生长抑素(somatostatin，SST)是一种广泛分布于中枢神经系统和周围组织的环状多肽，在体内以14肽(SST-14)和28肽(SST-28)两种形式存在。已有研究结果表明，SST作为信号分子由细胞膜上的SST受体家族介导，SST只有2种形式。SST生理功能的复杂性是通过受体的复杂性来体现的。因此，SSTR的生物学意义从某种程度上比SST还重要。SSTRs与其它G蛋白偶联的受体结构相似，有7个跨膜(transmembrane，TM)α螺旋结构，N端区域有N-糖基化位点和棕榈酰基化位点(SSTR3除外)。另外，在TM7还存在SSTR特有的高度保守的氨基酸序列。
SSTRs通过G蛋白与多种细胞效应系统相偶联，主要涉及以下4条重要的信号传导途径：一是环腺苷酸(cAMP)途径；二是电压依赖的Ca 2+途径；三是有丝分裂原激活的蛋白激酶(mitogen-activated protein kinases，MAPK)途径；四是蛋白酪氨酸磷酸酶(protein tyrosine phosphatase，PTP)途径。
SSTR1与抑制细胞生长有关；SSTR3除了诱导细胞凋亡，还参与抑制GH、胰岛素的释放，以及处理和调节感觉信号以及感觉功能与内脏功能，嗅觉与其他感觉功能的整合；SSTR4也抑制GH和胰岛素的释放，并协调锥体外系运动与感觉功能；SSTR2与SSTR5在调控动物的生长过程中起主要作用，主要抑制GH、胰岛素释放，参与中枢整合作用，还参与介导肿瘤的抗增殖作用及诱导细胞凋亡，是介导抗肿瘤作用的主导亚型，这些结果均揭示内分泌和免疫之间存在着密切的关系。
在这五种受体中，SSTR4作为中枢神经系统病理、炎症甚至疼痛机制的潜在介质已经走到了最前沿。靶向SSTR4具有额外的优势，它限制了垂体的分泌，但没有抑制胰高血糖素、生长激素或胰岛素的分泌。在中枢神经系统中，SSTR4在海马体和新皮质、记忆和学习区域以及阿尔茨海默病病理中的表达水平相对较高。最近的研究确实表明，SSTR4激动剂能改善阿尔茨海默病啮齿动物模型的学习和记忆，这与β-淀粉样蛋白水平降低相对应。此外，研究还发现SSTR4受体刺激可以剂量依赖性地增强线索记忆，从而可能具有直接的认知增强活性。其他研究表明，SSTR4与K +离子通道结合能够调节海马体的兴奋性，这对SSTR4激动剂治疗某些形式的癫痫具有指导意义。另外，SSTR4激动剂的作用在急性和慢性相关的抗外周伤害和抗炎活性有关啮齿动物的疼痛模型中有效。最近的研究数据 显示，辣椒素敏感受体TRPV1表达的伤害感受器释放的SRIF作用于SSTR4和SSTR2，产生抗伤害作用。
疼痛是临床上最常见、最困扰患者的症状，也是患者就诊的主要原因之一。依据疼痛持续时间，疼痛可分为急性疼痛和慢性疼痛。急性疼痛包括组织损伤引起的疼痛和术后炎症引起的疼痛；慢性疼痛则包括伤害感受性疼痛、神经性疼痛、内脏疼痛和混合性疼痛。目前担负疼痛治疗重担的仍然是人们熟知的镇痛药，包括麻醉镇痛药(利多卡因等)、阿片类药物、非甾体抗炎药(NSAIDs)。而具有新作用机制的药物也加入到了镇痛药的行列，比如抗抑郁药、抗惊厥药。尽管很多患者可以从现有的镇痛药中获益，但是这些药物也只能使1/4患者的症状得到充分缓解。再加上现有药物通常存在着耐受性低、毒副反应大、长期安全性差、潜在药物滥用和使用不方便等问题，使得患者迫切需要更加安全有效的镇痛药物。而SSTR4激动剂用于镇痛领域受到了越来越多的关注，新型SSTR4激动剂的研发具有广阔应用前景并且也是迫切需要的。
CN105473574A公开了以下的式(I)化合物，其为SSTR4的激动剂，适用于预防或治疗与SSTR4相关的医学病症。然而，本领域对于药效好、生物利用度高和溶解性好的SSTR4激动剂仍存在广泛需求。
Figure PCTCN2021095192-appb-000001
发明内容
基于此，有必要提供一种含氮饱和杂环化合物，其是一类结构新颖、药效更好、生物利用度高和溶解性更好的生长抑素受体亚型4(SSTR4)激动剂类化合物。
具体技术方案如下：
一种具有式(I)结构的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药：
Figure PCTCN2021095192-appb-000002
其中，A选自C 6-14芳基、5至14元杂芳基、5至14元杂环基和5至14元环烷基，且A中所述芳基、杂芳基、杂环基和环烷基任选进一步被0至5个R 3取代；其中所述杂芳基和杂环基各自包含1至4个选自N、O和S的杂原子；
R 3各自独立地选自-H、-F、-Cl、-Br、-I、羟基、氰基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧 基C 1-4烷基、-(CH 2) m-烯基、-(CH 2) m-炔基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-O-(CH 2) m-C 3-10碳环基和-O-(CH 2) m-(3至10元杂环基)，所述的杂环含有1至4个选自N、O和S的杂原子，且R 3中所述的烷基、烷氧基、碳环或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；
L 1选自单键或-(CR aR b) m-，其中R a和R b各自独立地选自-H和C 1-6烷基；
L 2选自-NH-和-O-；
R 1和R 2各自独立地选自-H、C 1-6烷基和C 3-6环烷基，其中R 1和R 2不同时为-H；
或R 1和R 2一起形成包含0至1个选自-O-、-NR 16-、-SO-和-SO 2-的基团的3至6元饱和环状基团；
R 16选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、卤素、羟基、氰基和C 3-6环烷基；
M选自单键、-(CR cR d) m-和-(CR cR d) mO-，其中R c和R d各自独立地选自-H和C 1-6烷基；
Q选自如下结构之一：
Figure PCTCN2021095192-appb-000003
其中，X 1，X 2，X 3各自独立地选自单键和-(CR eR f) n-；
X 4选自-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-；
R 4、R 5、R 6、R 7、R 9、R 10、R e、R f各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环和杂芳基各自含有1至4个选自N、O和S的杂原子，且R 4、R 5、R 6、R 7、R 9、R 10、R e、R f中所述的烷基、烷氧基、碳环基、苯基、杂芳基和杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；
R 8、R 11、R 12、R 13、R 14、R 15各自独立地选自-H、C 1-6烷基和C 3-6环烷基；
m、n、p、q每次出现时各自独立地选自0、1、2或3；
当X 1和X 2同时为单键时，R 4、R 5、R 6、R 7不同时为-H。
本发明还提供一种药物组合物，所述药物组合物含有治疗有效量的如上所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，以及药学上可接受的载体或者赋形剂。
本发明还提供如上所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或如上所述的药物组合物，在制备具有治疗和/或预防受SSTR4活化影响的疾病或症状的药物中的应用。
本发明还提供如上所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或如上所述的药物组合物，在制备具有治疗和/或预防疼痛的药物中的应用。
与现有技术相比较，本发明具有如下有益效果中的一种或多种：
本发明提供的化合物，通过在母核结构的特定位点引入特定的取代基，或采用含特定并环、螺环或桥环的母核结构，由此获得的新型化合物具有优异的SSTR4激动作用，能够作为SSTR4激动剂预防和/或治疗受SSTR4活化影响的疾病或症状，例如阿尔茨海默病及其他CNS病症，如癫痫和抑郁症，同时可用于治疗各种来源的疼痛和/或炎症。此外，经试验研究表明，本发明化合物具有高代谢稳定性和优异的药代动力学特性。
具体实施方式
以下结合具体实施例对本发明的化合物及其制备方法、药物组合物和应用作进一步详细的说明。本发明可以以许多不同的形式来实现，并不限于本文所描述的实施方式。相反地，提供这些实施方式的目的是使人们对本发明公开内容理解更加透彻全面。
除非另有定义，本文使用的所有技术和科学术语具有本领域技术人员通常理解的含义。本文在说明书中所使用的术语只是为了描述具体的实施方案的目的，不旨在于限制本发明。本文所使用的术语“和/或”意指一个或多个相关的所列项目中的任意一种和所有项目的组合。
术语“烷基”是指饱和的直链或支链脂肪族烃基团，具体为包含伯(正)碳原子、仲碳原子、叔碳原子、季碳原子或其组合的饱和烃。包含该术语的短语，例如，“C 1-6烷基”是指包含1～6个碳原子的烷基，每次出现时，可以互相独立地为C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基、C 6烷基。在其中一个实施方案中，可以包括含有1至20个碳原子的烷基，优选含有1至10个碳原子的烷基，更优选的是含有1至4个碳原子的低级烷基。非限制性实例包括：甲基、乙基、1-丙基、2-丙基(i-Pr、i-丙基、-CH(CH 3) 2)、1-丁基(n-Bu、n-丁基、-CH 2CH 2CH 2CH 3)、2-甲基-丙-1-基(i-Bu、异丁基、-CH 2CH(CH 3) 2)、2-丁基(s-Bu、仲丁基、-CH(CH 3)CH 2CH 3)、2-甲基-丙-2-基(t-Bu、叔丁基、-C(CH 3) 3)、1-戊基(n-戊基、-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-丁-2-基(-C(CH 3) 2CH 2CH 3)、3-甲基-丁-2-基(-CH(CH 3)CH(CH 3) 2)、3-甲基-丁-1-基(-CH 2CH 2CH(CH 3) 2)、2-甲基-丁-1-基(-CH 2CH(CH 3)CH 2CH 3)、己-1-基(-CH 2CH 2CH 2CH 2CH 2CH 3)、己-2-基(-CH(CH 3)CH 2CH 2CH 2CH 3)、己-3-基(-CH(CH 2CH 3)(CH 2CH 2CH 3))、2-甲基-戊-2-基(-C(CH 3) 2CH 2CH 2CH 3)、3-甲基-戊-2-基(-CH(CH 3)CH(CH 3)CH 2CH 3)、4-甲基-戊-2-基(-CH(CH 3)CH 2CH(CH 3) 2)、3-甲基-戊-3-基(-C(CH 3)(CH 2CH 3) 2)、2-甲基-戊-3-基(-CH(CH 2CH 3)CH(CH 3) 2)、2,3-二甲基-丁-2-基(-C(CH 3) 2CH(CH 3) 2)、3,3-二甲基-丁-2-基(-CH(CH 3)C(CH 3) 3、辛基(-(CH 2) 7CH 3)和正壬基，及其各种支链异构体。所述烷基可以是取代的或未取代的，当被取代时，取代基优选为1至5个，并且取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“烷氧基”是指-O-烷基，其中烷基如本文上面所定义并且优选为具有1至12个碳原子的烷基。包含该术语的短语，例如，“C 1-4烷氧基”是指烷基部分包含1～4个碳原子的-O-烷基。每次出现时，C 1-4烷氧基可以互相独立地为C 1烷氧基、C 2烷氧基、C 3烷氧基、C 4烷氧基。烷氧基可以是取代的或未取代的，其非限制性实例包括，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基或己 氧基。当被取代时，取代基优选为1至5个，并且取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“烷氧基烷基”指与被如上所述烷氧基取代的烷基。实例包括“C 1-4烷氧基C 1-4烷基”或“C 1-6烷氧基C 1-6烷基”。例如，“C 1-4烷氧基C 1-4烷基”是指被C 1-4烷氧基取代的C 1-4烷基，每次出现时，其可以互相独立地为C 1烷氧基C 1-4烷基、C 2烷氧基C 1-4烷基、C 3烷氧基C 1-4烷基、C 4烷氧基C 1-4烷基。烷氧基烷基可以是取代的或未取代的。烷氧基烷基的非限制性实例包括，甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、丙氧基甲基、丙氧基乙基、异丙氧基甲基、丁氧基丙基、叔丁氧基乙基、戊氧基乙基、己氧基乙基、环丙氧基甲基、环丙氧基乙基、环丙氧基丙基或环己氧基甲基；当被取代时，取代基优选为1至5个，并且取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“烯基”是本发明定义的烷基中，包含至少一个碳-碳双键。在其中一个实施方案中，所述烯基含有2至20个碳原子，优选2至12个碳原子，进一步优选2至8个碳原子，更进一步优选为2至6个碳原子。烯基的非限定实例包括取代或未取代的乙烯基、2-丙烯基、3-丁烯基、2-丁烯基、4-戊烯基、3-戊烯基、2-己烯基、3-己烯基、2-庚烯基、3-庚烯基、4-庚烯基、3-辛烯基、3-壬烯基或4-癸烯基等，当被取代时，取代基优选为1至5个，并且取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“炔基”是本发明定义的烷基中，包含至少一个碳-碳叁键。在其中一个实施方案中，所述炔基含有2至20个碳原子，优选2至12个碳原子，进一步优选2至8个碳原子,更进一步优选2-6个碳原子。炔基的非限定实例包括取代或未取代的乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、4-戊炔基、3-戊炔基、2-己炔基、3-己炔基、3-丁炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基或4-癸炔基等，当被取代时，取代基优选为1至5个，并且取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“碳环基”或“环烷基”是指饱和或者部分不饱和的环状含碳基团。在其中一个实施方案中，碳环基是3至6元的单环、3至8元的单环、3至10元的单环、4至12元双环或者10至15元三环系统。碳环包括桥环或者螺环。碳环基的非限制性实例包括环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环戊烯基、环己二烯基、环庚三烯基、苯并环戊基、二环[3.2.1]辛烷基、二环[5.2.0]壬烷基、三环[5.3.1.1]十二烷基、金刚烷基或螺[3.3]庚烷基等。碳环基可以任选被取代。当被取代时，取代基优选为1至5个，并且所述取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“杂环基”或“杂环”是指取代的或未取代的饱和或者部分不饱和的含杂原子的环状基团，所述杂原子选自N、O和S。在其中一个实施方案中，所述杂环基可以是3至8元的单环、4至12元双环或者10至15元三环系统，优选3至10元杂环基，且包含至少一个，优选1至4个选自N、O或S的杂原子。杂环中的杂原子N或S可被氧化成各种氧化态形成例如N-氧化物。杂环可以通过杂原子或者碳原子与分子的其它部分相连。杂环包括桥环或者螺环。杂环的非限制性实例包括，环氧乙烷、氮杂环丙基、氧杂环丁烷基、氮杂环丁烷基、1,3-二氧戊环、1,4-二氧杂己环、1,3-二噁烷、氮杂环庚基、 吡喃基、哌啶基、吗啉基、硫吗啉基、1,3-二噻烷、二氢呋喃、二氢吡喃、二硫杂戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并二氢呋喃、二氢吡啶基、四氢噻吩基、硫氧化的四氢噻吩基、四氢喹啉基、四氢异喹啉基、二氢吲哚基等；当被取代时，取代基优选为1至5个并且独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“芳基”是指取代的或未取代全碳单环或稠和多环不饱和基团，具有共轭的π电子体系。在其中一个实施方案中，芳基为6至14元芳香环，优选6至10元芳香环。其非限定性实例包括苯基或萘基；所述芳基可以杂芳基、杂环基或环烷基稠和，且与分子其与部分连接的部位在芳基上。芳基的非限定性实例包括苯并呋喃、苯并环戊烷基或苯并噻唑等。当芳基被取代时，取代基优选为1至5个，并且取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“杂芳基”是指取代或未取代的且含有至少一个，优选1至4个选自N、O和S杂原子的单环或稠和多环不饱和基团。在其中一个实施方案中，杂芳基为5至15元杂芳环、5至14元杂芳基，或优选5至10元杂芳环，或更优选为5至6元杂芳基，其中杂原子的数量为1至4个，优选为1至3个，更优选为1至2个。杂芳基的非限制性实例包括吡啶基、呋喃基、噻吩基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并呋喃、苯并咪唑、苯并吡啶或吡咯并吡啶等。当杂芳基被取代时，取代基优选为1至5个，并且取代基独立地选自F、Cl、Br、I、＝O、烷基、烯基、炔基、烷氧基、羟基、硝基、氰基和氨基。
“杂烷基”是指在烷基的基础上至少一个碳原子被非碳原子替代所产生的基团，非碳原子可以为N原子、O原子和/或S原子等。例如，如果烷基中连接至母核结构的碳原子被非碳原子代替，则所得到的杂烷基分别是烷氧基(例如，-OCH 3等)、烷基氨基(例如，-NHCH 3、-N(CH 3) 2等)或烷基硫基(例如，-SCH 3)。如果烷基中连接至母核结构的碳原子没有被非碳原子代替并且杂原子嵌在基团内部，则所得到的杂烷基分别是烷基氧基烷基(例如，-CH 2CH 2-O-CH 3等)、烷基氨基烷基(例如，-CH 2NHCH 3、-CH 2N(CH 3) 2等)或烷基硫基烷基(例如、-CH 2-S-CH 3)。如果烷基的末端碳原子被非碳原子代替，则所得到的杂烷基分别是羟基烷基(例如，-CH 2CH 2-OH)、氨基烷基(例如，-CH 2NH 2)或巯基烷基(例如，-CH 2CH 2-SH)。
“氨基”是指氨的衍生物，具有式-N(X) 2或式-NR’R”的结构特征，其中每个“X”、R’和R”各自独立地是H、取代的或未被取代的烷基、取代的或未被取代的环烷基、取代的或未被取代的杂环基、取代的或未取代的芳基或取代的或未取代的杂芳基。氨基的非限制性类型包括-NH 2、-N(烷基) 2、-NH(烷基)、-N(环烷基) 2、-NH(环烷基)、-N(杂环基) 2、-NH(杂环基)、-N(芳基) 2、-NH(芳基)、-N(烷基)(芳基)、-N(烷基)(杂环基)、-N(环烷基)(杂环基)、-N(芳基)(杂芳基)、-N(烷基)(杂芳基)等。
“卤素”是指F、Cl、Br或I。“卤代”是指用选自F、Cl、Br或I的卤素替换分子或基团中的一个或多个氢原子。
“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括与无机酸或无机碱形成的盐或与有机酸和有机碱形成的盐。衍生自无机碱的盐包括但不限于与Al、Ca、Li、Mg、K、Na和Zn形成的金属盐；衍生自有机碱的盐包括但不限于与伯胺、仲胺或叔胺形成的盐。所述伯胺、仲胺或叔胺包括天然存在的取代或未取代的胺、环胺和碱性离子交换树脂，例如氨、异丙基胺、三甲基胺、二乙胺、 三乙胺、三丙基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶或聚胺树脂；衍生自无机酸和有机酸的盐包括但不限于与以下酸形成的盐：硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸等。
“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、对映异构体和构象异构体。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前药与其它化学组分形成的混合物。其它组分例如生理学/药学上可接受的载体或赋形剂。药物组合物的目的是促进化合物对生物体的给药。
“前药”是指可以在生理条件下或者通过降解转化为具有生物活性的本发明化合物的物质。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被除去或者在体内被除去，从而得到母体化合物。前药包括本发明化合物中的一个羟基、氨基或者巯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、游离的氨基或者游离的疏基。前药的例子包括但不限于，本发明化合物中的羟基或氨基功能基团与甲酸、乙酸或苯甲酸所形成的化合物。
"任选的"或"任选地"意味着随后所描述的事件或环境可以但不必发生，包括该事件或环境发生或不发生的场合。例如，“芳基任选被烷基取代”意味着烷基可以但不必须存在，该术语包括芳基被烷基取代的情形和芳基不被烷基取代的情形。
“药学上可接受的载体”指药学上可接受的材料、组合物或媒剂，例如液体或固体填充剂、稀释剂、赋形剂、溶剂或囊封材料。如本文所用，术语“药学上可接受的载体”包括与药物施用相容的缓冲剂、注射用无菌水、溶剂、分散介质、包衣、抗细菌剂及抗真菌剂、等渗剂及吸收延迟剂及诸如此类。在与配制物中其他成分兼容且对患者无害的意义上，每种载体必须为“药学上可接受的”。合适的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉、马铃薯淀粉及经取代或未经取代的β-环糊精；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素；(4)粉状黄蓍胶；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油类，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯类，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液；(19)乙醇；(20)磷酸盐缓冲液；及(21)药物配制物中所采用的其他无毒兼容物质。
术语“溶剂化物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理 缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂化物包括药学上可接受的溶剂化物且进一步包括化学计量的溶剂化物和非化学计量的溶剂化物。在一些情况下，所述溶剂化物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂化物”包括溶液状态的溶剂化物和可分离的溶剂化物。代表性的溶剂化物包括水合物、乙醇合物和甲醇合物。
术语“代谢产物”是指物质包括本发明化合物在体内新陈代谢中产生的产物，包括中间代谢产物和最终代谢产物。
术语“多晶型”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂化物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明的化合物或其药物组合物的剂型和施用方式没有特别限制。
代表性的施用方式包括但并不限于：口服、瘤内、直肠、肠胃外(静脉内、腹膜内、肌内或皮下)注射和/或局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、复合硅酸盐、和碳酸钠；(e)溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇和十二烷基硫酸钠，或其混合物。
用于口服给药的液体剂型包括药学上可接受的乳液剂、溶液剂、悬浮剂、糖浆剂或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂(如水或其它溶剂)、增溶剂和乳化剂。具体实例为例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油类，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物。除了惰性稀释剂外，组合物也可包含助剂，如润湿剂、悬浮剂、甜味剂、矫味剂和香料。例如，悬浮液可包含悬浮剂。具体实例为例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或它们的混合物。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散剂、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液或分散剂的无菌粉末。适宜的含水或非水载体、稀释剂、溶剂或赋形剂选自水、乙醇和多元醇，或者它们适宜的混合物。
用于局部给药的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。由活性成分在无菌条件下与药学上可接受的载体及防腐剂、缓冲剂和/或必要时可能需要的推进剂一起混合而成。
以下为本发明的实施方案。
本发明的实施方案提供一种具有式(I)结构的化合物，或其立体异构体、N-氧化物、水合物、溶剂 化物、代谢产物、药学上可以接受的盐、多晶型或前药：
Figure PCTCN2021095192-appb-000004
具体地，式(I)中，A选自C 6-14芳基、5至14元杂芳基、5至14元杂环基和5至14元环烷基，且A中所述芳基、杂芳基、杂环基和环烷基任选进一步被0至5个R 3取代；其中所述杂芳基和杂环基各自包含1至4个选自N、O和S的杂原子；
其中，R 3各自独立地选自-H、-F、-Cl、-Br、-I、羟基、氰基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、-(CH 2) m-烯基、-(CH 2) m-炔基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-O-(CH 2) m-C 3-10碳环基和-O-(CH 2) m-(3至10元杂环基)，所述的杂环含有1至4个选自N、O和S的杂原子，且R 3中所述的烷基、烷氧基、碳环或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；m每次出现时各自独立地选自0、1、2和3。
具体地，式(I)中，L 1选自单键和-(CR aR b) m-，其中R a和R b各自独立地选自-H和C 1-6烷基；m每次出现时各自独立地选自0、1、2或3。
具体地，式(I)中，L 2选自-NH-和-O-。
具体地，式(I)中，R 1和R 2各自独立地选自-H、C 1-6烷基和C 3-6环烷基，其中R 1和R 2不同时为-H；或R 1可以和R 2一起形成包含0至1个选自-O-、-NR 16-、-SO-和-SO 2-的基团的3至6元饱和环状基团；
其中，R 16选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、卤素、羟基、氰基和C 3-6环烷基。
在另外一个具体的实施方案中，R 1和R 2还可以各自独立地选自其它环烷基、烷基、氨基、烷氧基、芳基、杂芳基、杂烷基和杂环基。
具体地，式(I)中，M选自单键、-(CR cR d) m-和-(CR cR d) mO-，其中R c和R d独立地选自-H和C 1-6烷基；m每次出现时各自独立地选自0、1、2和3。
具体地，式(I)中，Q选自如下结构之一：
Figure PCTCN2021095192-appb-000005
其中，X 1，X 2，X 3各自独立地选自单键和-(CR eR f) n-；
X 4选自-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-；
R 4、R 5、R 6、R 7、R 9、R 10、R e、R f各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环和杂芳基各自含有1至4个选自N、O和S的杂原子，且R 4、R 5、R 6、R 7、R 9、R 10、R e、R f中所述的烷基、烷氧基、碳环基、苯基、杂芳基和杂环各 自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基、C 1-4烷氧基的取代基所取代；
R 8、R 11、R 12、R 13、R 14、R 15各自独立地选自-H、C 1-6烷基和C 3-6环烷基；
m、n、p、q每次出现时各自独立地选自0、1、2和3。
在另外一个具体的实施方案中，R 4、R 5、R 6、R 7、R 9、R 10、R e、R f、R 8、R 11、R 12、R 13、R 14、R 15还可以各自独立地选自其它环烷基、烷基、杂环基、杂芳基、烷氧基，或氨基、芳基和杂烷基。
具体地，式(I)中，当X 1和X 2同时为单键时，R 4、R 5、R 6、R 7不同时为-H。
在其中一个具体的实施方案中，A选自C 6-10芳基和5至10元杂芳基，且A中所述芳基或杂芳基任选进一步被0至5个R 3取代。优选地，A为5至10元杂芳基且任选进一步被0至5个R 3取代。
在其中一个具体的实施方案中，A选自苯基、萘基、吡啶基、呋喃基、噻吩基、吡咯基、吲哚基、吲唑基、咪唑并[1,2-a]吡啶基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基和咪唑基，且A为未取代的或任选进一步被1至5个R 3取代。选地，A选自萘基、吲哚基、吲唑基和咪唑并[1,2-a]吡啶基，且所述萘基、吲哚基、吲唑基或咪唑并[1,2-a]吡啶基为未取代的或任选进一步被1至5个R 3取代。
在其中一个具体的实施方案中，A选自如下结构之一：
Figure PCTCN2021095192-appb-000006
优选为：
Figure PCTCN2021095192-appb-000007
A任选进一步被0至5个R 3取代。优选地，A为未取代的或任选进一步被1至3个R 3取代。
在其中一个具体的实施方案中，A为：
Figure PCTCN2021095192-appb-000008
在其中一个具体的实施方案中，A为：
Figure PCTCN2021095192-appb-000009
在其中一个具体的实施方案中，A为：
Figure PCTCN2021095192-appb-000010
在其中一个具体的实施方案中，A为：
Figure PCTCN2021095192-appb-000011
在其中一个具体的实施方案中，A为：
Figure PCTCN2021095192-appb-000012
在其中一个具体的实施方案中，A为：
Figure PCTCN2021095192-appb-000013
在其中一个具体的实施方案中，A为：
Figure PCTCN2021095192-appb-000014
在其中一个具体的实施方案中，A为：
Figure PCTCN2021095192-appb-000015
在其中一个具体的实施方案中，A为：
Figure PCTCN2021095192-appb-000016
在另外一个具体的实施方案中，A任选地选自其它芳基、杂芳基，或氨基、烷氧基、环烷基、烷基、杂烷基和杂环基。
在其中一个具体的实施方案中，R 3各自独立地选自-H、-F、-Cl、-Br、-I、羟基、氰基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、-(CH 2) m-C 3-10碳环基、-O-(CH 2) m-C 3-10碳环基和-O-(CH 2) m-(3至10元杂环基)，所述的杂环含有1至4个选自N、O和S的杂原子，且R 3中所述的烷基、烷氧基、碳环或杂环各自独立任选进一步被0至4个选自H、F、Cl、Br、I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。优选地，R 3各自独立地选自-H、-F、-Cl、-Br、-I、羟基、氰基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、环丙基、环丁基和环丙基甲基。在其中一个具体的实施方案中，R 3为甲基。在其中一个具体的实施方案中，R 3为-Cl。在其中一个具体的实施方案中，R 3为甲氧基。在其中一个具体的实施方案中，R 3为CF 3。
在另外一个具体的实施方案中，R 3还可以选自其它烷基、烷氧基、杂环基、环烷基、杂烷基，或氨基、芳基和杂芳基。
在其中一个具体的实施方案中，R 1和R 2各自独立地选自C 1-6烷基和C 3-6环烷基；或R 1可以和R 2一起形成包含0至1个选自-O-、-SO-和-SO 2-的3至6元饱和环状基团。优选地，R 1和R 2各自独立地选自甲基、乙基、丙基、环丙基和环丁基；或R 1可以和R 2一起形成3元饱和碳环基。
在另外一个具体的实施方案中，R 1和R 2还可以各自独立地选自其它烷基、环烷基，或氨基、烷氧基、芳基、杂芳基、杂烷基和杂环基。
在其中一个具体的实施方案中，Q选自如下结构之一：
Figure PCTCN2021095192-appb-000017
在另外一个具体的实施方案中，Q还可以各自独立地选自其它杂环基、环烷基、氨基、烷氧基、芳基、杂芳基、杂烷基和烷基。
在其中一个具体的实施方案中，X 4选自-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-。
在其中一个具体的实施方案中，R 12、R 13、R 14、R 15选自-H。
具体地，所述的化合物具有式(II)结构：
Figure PCTCN2021095192-appb-000018
在其中一个具体的实施方案中，在通式(II)中，L 2为-NH-。
在其中一个具体的实施方案中，在通式(II)中，L 1选自单键和-(CR aR b) m-，其中R a和R b各自独立地选自-H和C 1-6烷基。优选地，L 1选自单键、-CH 2-和-CH 2CH 2-。更为优选地，L 1选自单键和-CH 2-。最为优选地，L 1为单键。
在其中一个具体的实施方案中，在通式(II)中，X 1和X 2各自独立地选自单键和-(CR eR f) n-。优选地，X 1和X 2各自独立地选自单键、-CH 2-和-CH 2CH 2-。更为优选地，X 1和X 2各自独立地选自单键和-CH 2-。
其中，R e和R f各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环、杂芳基含有1至4个选自N、O和S的杂原子，且R e和R f中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。优选地，R e、R f各自独立地选自-H、甲基、乙基、甲氧基、乙氧基、环丙基和环丁基。更为优选地，R e和R f各自独立地选自-H和甲基。最为优选地，R e和R f各自为-H。
在其中一个具体的实施方案中，通式(II)中，R 4、R 5、R 6、R 7各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环、杂芳基含有1至4个选自N、O和S的杂原子，R 4、R 5、R 6、R 7中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。优选地，R 4、R 5、R 6、R 7各自独立地选自-H、甲基、乙基、甲氧基、乙氧基、环丙基和环丁基。更为优选地，R 4、R 5、R 6、R 7各自独立地选自-H和甲基。在其中一个具体的实施方案中，R 4、R 5、R 6、R 7各自独立地为-H。
在其中一个具体的实施方案中，在通式(II)中，R 8选自-H、C 1-6烷基和C 3-6环烷基。优选地，R 8选自-H、甲基、乙基和环丙基。更为优选地，R 8为-H。
在其中一个具体的实施方案中，在通式(II)中，M选自单键、-(CR cR d) m-和-(CR cR d) mO-，其中R c和R d各自独立地选自-H和C 1-6烷基。优选地，M选自单键、-CH 2-、-CH 2CH 2-、-CH 2O-和CH 2CH 2O-。更为优选地，M选自单键和-CH 2O-。在其中一个具体的实施方案中，M为单键。在其中一个具体的实施方案中，M为-CH 2O-。
在其中一个具体的实施方案中，在通式(II)中，R 1和R 2各自独立地选自-H、C 1-6烷基、C 3-6环烷基，其中R 1和R 2不同时为-H；或，R 1可以和R 2一起形成包含0至1个选自-O-、-NR 16-、-SO-和SO 2- 的3至6元饱和环状基团；R 16选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、卤素、羟基、氰基和C 3-6环烷基。
优选地，R 1、R 2各自独立地选自甲基、乙基、异丙基和环丙基。更为优选地，R 1、R 2各自独立地为甲基。
优选地，R 1可以和R 2一起形成包含0至1个选自-O-、-SO-和SO 2-的3至6元饱和环状基团。更为优选地，R 1可以和R 2一起形成环丙基。
优选地，所述化合物具有式(III)结构：
Figure PCTCN2021095192-appb-000019
在其中一个具体的实施方案中，在通式(III)中，X 1选自单键和-CH 2-。
在其中一个具体的实施方案中，在通式(III)中，L 1选自单键和-(CR aR b) m-，其中R a，R b独立地选自-H和C 1-6烷基。优选地，L 1选自单键、-CH 2-和-CH 2CH 2-。更为优选地，L 1选自单键和-CH 2-。最为优选地，L 1为单键。
在其中一个具体的实施方案中，在通式(III)中，R 6、R 7各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环和杂芳基各自含有1至4个选自N、O和S的杂原子，R 4、R 5、R 6、R 7中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。优选地，R 6、R 7各自独立地选自-H、甲基、乙基、甲氧基、乙氧基、环丙基和环丁基。更为优选地，R 6、R 7各自独立地选自-H和甲基。最为优选地，R 6、R 7各自独立地为-H。
在其中一个具体的实施方案中，在通式(III)中，R 8选自-H、C 1-6烷基和C 3-6环烷基。优选地，R 8选自-H、甲基、乙基和环丙基。更为优选地，R 8为-H。
优选地，所述的化合物具有式(IV)结构：
Figure PCTCN2021095192-appb-000020
在其中一个具体的实施方案中，在通式(IV)中，R 4、R 5、R 6、R 7各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环、杂芳基各自含有1至4个选自N、O和S的杂原子，且R 4、R 5、R 6、R 7中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基 和C 1-4烷氧基的取代基所取代；R 4、R 5、R 6、R 7不同时为-H。
在其中一个具体的实施方案中，在通式(IV)中，R 4、R 5、R 6为-H；R 7选自C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环、杂芳基各自含有1至4个选自N、O和S的杂原子，且R 7中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。更为具体地，R 7或被所述取代基取代后的含R 7基团选自C 1-6烷基、C 1-6烷氧基、甲氧基甲基、羟甲基、一氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、苯基、吡啶基、呋喃基、咪唑基和噻唑基；且R 7独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基、C 1-4烷氧基的取代基所取代。
在其中一个具体的实施方案中，在通式(IV)中，R 5、R 6、R 7为-H；R 4选自C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环、杂芳基各自含有1至4个选自N、O和S的杂原子，且R 4中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。更为具体地，R 4或被所述取代基取代后的含R 4基团选自C 1-6烷基、甲氧基甲基、羟甲基、一氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环丁氧基、环戊基、四氢呋喃基、苯基、吡啶基、呋喃基、咪唑基和噻唑基，所述的苯基、吡啶基、呋喃基、咪唑基、噻唑基各自独立任选进一步被0至4个选自H、F、Cl、Br、I、羟基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。
在其中一个具体的实施方案中，在通式(IV)中，L 1选自单键和-(CR aR b) m-，其中R a，R b各自独立地选自-H和C 1-6烷基。优选地，L 1选自单键、-CH 2-和-CH 2CH 2-。更为优选地，L 1选自单键和-CH 2-。最为优选地，L 1为单键。
在其中一个具体的实施方案中，在通式(IV)中，M选自单键、-(CR cR d) m-和-(CR cR d) mO-，其中R c、R d各自独立地选自-H和C 1-6烷基。优选地，M选自单键、-CH 2-、-CH 2CH 2-、-CH 2O-和CH 2CH 2O-。更为优选地，M选自单键和-CH 2O-。最为优选地M为单键。
在其中一个具体的实施方案中，在通式(IV)中，R 1、R 2各自独立地选自-H、C 1-6烷基和C 3-6环烷基，其中R 1和R 2不同时为-H；或，R 1可以和R 2一起形成包含0至1个选自-O-、-NR 16-、-SO-和SO 2-的基团的3至6元饱和环状基团；R 16选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、卤素、羟基、氰基和C 3-6环烷基。
优选地，R 1、R 2各自独立地选自甲基、乙基、异丙基和环丙基。更为优选地，R 1、R 2各自独立地选自甲基。
优选地，R 1可以和R 2一起形成包含0至1个-O-、-SO-和SO 2-的3至6元饱和环状基团。更为优选地，R 1可以和R 2一起形成环丙基。
在其中一个具体的实施方案中，在通式(IV)中，R 8选自-H、C 1-6烷基和C 3-6环烷基。优选地，R 8选自-H、甲基、乙基和环丙基。更为优选地，R 8为-H。
具体地，所述的化合物具有式(V)结构：
Figure PCTCN2021095192-appb-000021
在其中一个具体的实施方案中，在通式(V)中，X 3选自单键、-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-。
在其中一个具体的实施方案中，通式(V)中，p、q每次出现时各自独立地选自0、1、2和3。
在其中一个具体的实施方案中，通式(V)中，R 9、R 10各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环、杂芳基各自含有1至4个选自N、O和S的杂原子，R 9、R 10中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。优选地，R 9、R 10各自独立地选自-H、甲基、乙基、甲氧基、乙氧基、环丙基和环丁基。更为优选地，R 9、R 10各自独立地选自-H和甲基。在其中一个具体的实施方案中，R 9、R 10各自独立地为-H。
在其中一个具体的实施方案中，在通式(V)中，R 8选自-H、C 1-6烷基和C 3-6环烷基。优选地，R 8选自-H、甲基、乙基和环丙基。更为优选地，R 8为-H。
在其中一个具体的实施方案中，在通式(V)中，p、q每次出现时各自独立地选自0、1、2和3。优选地，p、q每次出现时，各自独立地选自0、1和2。
在其中一个具体的实施方案中，通式(V)中，L 2为-NH-。
在其中一个具体的实施方案中，通式(V)中，L 1选自单键和-(CR aR b) m-，其中R a，R b独立地选自-H和C 1-6烷基。优选地，L 1选自单键、-CH 2-和-CH 2CH 2-。更为优选地，L 1选自单键和-CH 2-。最为优选地，L 1为单键。
在其中一个具体的实施方案中，通式(V)中，M选自单键、-(CR cR d) m-和-(CR cR d) mO-，其中R c、R d独立地选自-H和C 1-6烷基。优选地，M选自单键、-CH 2-、-CH 2CH 2-、-CH 2O-和CH 2CH 2O-。更为优选地，M选自单键和-CH 2O-。最为优选地M为单键。
在其中一个具体的实施方案中，在通式(V)中，R 1、R 2各自独立地选自-H、C 1-6烷基和C 3-6环烷基，其中R 1和R 2不同时为-H；或，R 1可以和R 2一起形成包含0至1个选自-O-、-NR 16-、-SO-和SO 2-的基团的3至6元饱和环状基团；R 16选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、卤素、羟基、氰基和C 3-6环烷基。
优选地，R 1、R 2各自独立地选自甲基、乙基、异丙基和环丙基。更为优选地，R 1、R 2各自独立地为甲基。
优选地，R 1可以和R 2一起形成包含0至1个选自-O-、-SO-和SO 2-的3至6元饱和环状基团。更为优选地，R 1可以和R 2一起形成环丙基。
在其中一个具体实施方案中，在通式(V)中，p、q各自为1；X 3为-CH 2-；R 9、R 10、R 11各自为-H；L 1为单键；L 2为-NH-；M为单键。
优选地，所述的化合物具有式(VI)结构：
Figure PCTCN2021095192-appb-000022
在其中一个具体实施方案中，在通式(VI)中，L 2为-NH-。
在其中一个具体的实施方案中，在在通式(VI)中，R 9、R 10各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环、杂芳基各自含有1至4个选自N、O和S的杂原子，R 9、R 10中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。优选地，R 9、R 10各自独立地选自-H、甲基、乙基、甲氧基、乙氧基、环丙基和环丁基。更为优选地，R 9、R 10各自独立地选自-H和甲基。在其中一个具体的实施方案中，R 9、R 10各自独立地为-H。
在其中一个具体的实施方案中，在通式(VI)中，R 8选自-H、C 1-6烷基和C 3-6环烷基。优选地，R 8选自-H、甲基、乙基和环丙基。更为优选地，R 8为-H。
在其中一个具体的实施方案中，在通式(VI)中，L 1选自单键和-(CR aR b) m-，其中R a，R b各自独立地选自-H和C 1-6烷基。优选地，L 1选自单键、-CH 2-和-CH 2CH 2-。更为优选地，L 1选自单键和-CH 2-。最为优选地，L 1为单键。
在其中一个具体的实施方案中，在通式(VI)中，M选自单键、-(CR cR d) m-和-(CR cR d) mO-，其中R c、R d独立地选自-H和C 1-6烷基。优选地，M选自单键、-CH 2-、-CH 2CH 2-、-CH 2O-和CH 2CH 2O-。更为优选地，M选自单键和-CH 2O-。最为优选地M为单键。
在其中一个具体的实施方案中，在通式(VI)中，R 1、R 2各自独立地选自-H、C 1-6烷基和C 3-6环烷基，其中R 1和R 2不同时为-H；或，R 1可以和R 2一起形成包含0至1个-O-、-NR 16-、-SO-和SO 2-的基团的3至6元饱和环状基团；R 16选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、卤素、羟基、氰基和C 3-6环烷基。
优选地，R 1、R 2各自独立地选自甲基、乙基、异丙基和环丙基。更为优选地，R 1、R 2各自独立地为甲基。
优选地，R 1可以和R 2一起形成包含0至1个选自-O-、-SO-和SO 2-的基团的3至6元饱和环状基团。更为优选地，R 1可以和R 2一起形成环丙基。
在其中一个具体的实施方案中，通式(VI)中，R 9、R 10、R 11各自为-H；L 1为单键；M为单键。
进一步，本发明涉及如下实施方案。
在一个实施方案中，本发明涉及式(a)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、 代谢产物、药学上可以接受的盐、多晶型或前药，
Figure PCTCN2021095192-appb-000023
其中，
Figure PCTCN2021095192-appb-000024
表示单键或双键，条件是两个
Figure PCTCN2021095192-appb-000025
中有且仅有一个表示双键；
X 1为CR 3’或NR 3；
X 2为CR 3’或NR 3；
或者，X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环任选被1-4个R 3’取代；
R 3选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
R 4选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；其中所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3；
s为0、1或2；
r为0、1或2。
在一个实施方案中，本发明涉及上述式(a)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
Figure PCTCN2021095192-appb-000026
表示单键或双键，条件是两个
Figure PCTCN2021095192-appb-000027
中有且仅有一个表示双键；
X 1为CR 3’或NR 3；
X 2为CR 3’；
X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环被1-4个R 3’取代；
R 3选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
R 4选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3；
s为0或1；
r为0或1。
在一个实施方案中，本发明涉及上述式(a)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
Figure PCTCN2021095192-appb-000028
表示单键或双键，条件是两个
Figure PCTCN2021095192-appb-000029
中有且仅有一个表示双键；
X 1为CR 3’或NR 3；
X 2为NR 3；
X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环被1-4个R 3’取代；
R 3选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
R 4选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3；
s为0或1；
r为0或1。
在一个实施方案中，本发明涉及上述式(a)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
Figure PCTCN2021095192-appb-000030
表示单键或双键，条件是两个
Figure PCTCN2021095192-appb-000031
中有且仅有一个表示双键；
X 1为CR 3’；
X 2为NR 3；
X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环，所述苯环被1-4个R 3’取代；
R 3选自-H和C 1-6烷基；
R 3’为C 1-6烷基；
R 4选自-H和C 1-6烷基；
R 5选自-H和C 1-6烷基；
R 1和R 2各自独立地为甲基；
s为1；
r为1。
在一个实施方案中，本发明涉及式(b)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
Figure PCTCN2021095192-appb-000032
其中，
Figure PCTCN2021095192-appb-000033
表示单键或双键，条件是两个
Figure PCTCN2021095192-appb-000034
中有且仅有一个表示双键；
X 1为CR 3’或NR 3；
X 2为CR 3’或NR 3；
或者，X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环任选被1-4个R 3’取代；
R 3选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；其中所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3。
在一个实施方案中，本发明涉及上述式(b)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
其中，
Figure PCTCN2021095192-appb-000035
表示单键或双键，条件是两个
Figure PCTCN2021095192-appb-000036
中有且仅有一个表示双键；
X 1为CR 3’或NR 3；
X 2为CR 3’；
X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环被1-4个R 3’取代；
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3。
在一个实施方案中，本发明涉及上述式(b)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
Figure PCTCN2021095192-appb-000037
表示单键或双键，条件是两个
Figure PCTCN2021095192-appb-000038
中有且仅有一个表示双键；
X 1为CR 3’或NR 3；
X 2为NR 3；
X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环被1-4个R 3’取代；
R 3选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3。
在一个实施方案中，本发明涉及式(c)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
Figure PCTCN2021095192-appb-000039
其中，
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；其中所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3；
t为0、1、2、3、4或5。
在一个实施方案中，本发明涉及上述式(c)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
R 3’选自卤素、氰基、C 1-6烷基、卤代C 1-6烷基和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R x选自C 1-6烷基、卤代C 1-6烷基和-(CH 2) n-C 3-6碳环基；
n为0、1、2或3；
t为0、1或2。
在一个实施方案中，本发明涉及上述式(c)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
R 3’选自C 1-4烷基和-SR x；
R 4为C 1-4烷基；
R 5选自-H和C 1-4烷基；
R 1和R 2各自独立地选自-H和C 1-4烷基；
R x选自C 1-4烷基和卤代C 1-4烷基；
t为1或2。
在一个实施方案中，本发明涉及上述式(c)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
其中，
R 3’为C 1-4烷基；
R 4为C 1-4烷基；
R 5为-H；
R 1和R 2各自独立地为甲基；
t为1。
在一个实施方案中，本发明涉及式(c-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
Figure PCTCN2021095192-appb-000040
其中，
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3。
在一个实施方案中，本发明涉及上述式(c-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂 化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
R 3’选自卤素、C 1-4烷基、卤代C 1-4烷基和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R x选自C 1-6烷基、卤代C 1-6烷基和-(CH 2) n-C 3-6碳环基；
n为0、1、2或3。
在一个实施方案中，本发明涉及上述式(c-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
其中，
R 3’选自C 1-4烷基和-SR x；
R 4为C 1-4烷基和卤代C 1-4烷基；
R 5选自-H和C 1-4烷基；
R x选自C 1-4烷基和卤代C 1-4烷基。
在一个实施方案中，本发明涉及上述式(c-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
其中，
R 3’为C 1-4烷基；
R 4为C 1-4烷基；
R 5为-H。
在一个实施方案中，本发明涉及式(d)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
Figure PCTCN2021095192-appb-000041
其中，
R 3选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；其中所述烷基、烯基、炔基、碳环基、杂环 基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3；
t为0、1、2、3或4。
在一个实施方案中，本发明涉及上述式(d)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
R 3选自C 1-6烷基和卤代C 1-6烷基；
R 3’选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
R x选自C 1-6烷基、卤代C 1-6烷基和-(CH 2) n-C 3-6碳环基；
n为0、1、2或3；
t为0、1或2。
在一个实施方案中，本发明涉及上述式(d)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
R 3为C 1-4烷基；
R 3’选自-H、C 1-4烷基和-SR x；
R 4为C 1-4烷基；
R 5选自-H和C 1-4烷基；
R 1和R 2各自独立地选自-H和C 1-4烷基；
R x选自C 1-4烷基和卤代C 1-4烷基；
t为0或1。
在一个实施方案中，本发明涉及上述式(d)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
其中，
R 3为C 1-4烷基；
R 3’选自-H和C 1-4烷基；
R 4为C 1-4烷基；
R 5为-H；
R 1和R 2各自独立地为甲基；
t为0或1。
在一个实施方案中，本发明涉及式(d-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
Figure PCTCN2021095192-appb-000042
其中，
R 3选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基和-SR x；
R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
R选自-H、C 1-6烷基和卤代C 1-6烷基；
R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
n为0、1、2或3。
在一个实施方案中，本发明涉及上述式(d-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
R 3选自C 1-6烷基和卤代C 1-6烷基；
R 3’选自-H、卤素、氰基、C 1-6烷基和卤代C 1-烷基和-SR x；
R 4选自C 1-6烷基和卤代C 1-6烷基；
R 5选自-H、C 1-6烷基和卤代C 1-6烷基；
R x选自C 1-6烷基、卤代C 1-6烷基和-(CH 2) n-C 3-6碳环基；
n为0、1、2或3。
在一个实施方案中，本发明涉及上述式(d-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
R 3为C 1-4烷基；
R 3’选自-H、C 1-4烷基和-SR x；
R 4为C 1-4烷基；
R 5选自-H和C 1-4烷基；
R x选自C 1-4烷基和卤代C 1-4烷基。
在一个实施方案中，本发明涉及上述式(d-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
R 3为C 1-4烷基；
R 3’选自-H和C 1-4烷基；
R 4为C 1-4烷基；
R 5为-H。
在其中一个具体的实施方案中，所述的化合物选自如下结构之一：
Figure PCTCN2021095192-appb-000043
在其中一个具体的实施方案中，所述药学上可以接受的盐选自盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐和三氟甲磺酸盐，或它们的组合。
优选地，所述药学上可以接受的盐选自盐酸盐、硫酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、富马酸盐、苹果酸盐、草酸盐、酒石酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐和三氟甲磺酸盐，或它们的组合。
本发明的实施方案还提供所述化合物的制备方法，包括如下步骤：
Figure PCTCN2021095192-appb-000044
以化合物1和化合物2进行缩合反应，其中G表示氮保护基；
脱除所述缩合反应的产物中的氮保护基。本发明的实施方案还提供一种药物组合物，所述药物组合物含有治疗有效量的如上所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，以及药学上可接受的载体或者赋形剂。
本发明的实施方案还提供如上所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，或，如上所述的药物组合物，在制备具有治疗和/或预防受SSTR4活化影响的疾病或症状的药物中的应用。
在其中一个具体的实施方案中，所述受SSTR4活化影响的疾病或症状为疼痛。
本发明的实施方案还提供如上所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，或，如上所述的药物组合物，在制备具有治疗和/或预防疼痛的药物中的应用。
在一个实施方案中，本发明提供本发明所述化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或本发明的药物组合物，其用于治疗和/或预防受SSTR4活化影响的疾病或症状。在一个实施方案中，所述化合物或组合物用于治疗和/或预防疼痛。
在一个实施方案中，本发明提供一种治疗受SSTR4活化影响的疾病或症状的方法，其包括给予本发明所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或本发明所述的药物组合物。在一个实施方案中，本发明提供一种治疗疼痛的方法，其包括给予本发明所述的化合物或药物组合物。
在其中一个具体的实施方案中，所述疼痛为神经痛。
在其中一个具体的实施方案中，所述疼痛为背痛、慢性背痛、三叉神经痛、I型复杂区域疼痛综合征、II型复杂区域疼痛综合征、肠激惹综合征、糖尿病性神经病变、骨关节炎所引起的疼痛、肿瘤疼痛、肌肉纤维疼痛。
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
实施例中无特殊说明，反应在氮气氛下进行。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温。
室温为最适宜的反应温度，为20℃～30℃。
化学合成相关缩写：
Ac：乙酰基
AcOH：乙酸
Bn：苄基
Boc：叔丁氧羰基
Bz：苯甲酰基
DIPEA：二异丙基乙胺
DMF：N,N-二甲基甲酰胺
DCM：二氯甲烷
DIEA：N,N-二异丙基乙胺
EA：乙酸乙酯
Et：乙基
EtOAc：乙酸乙酯
Et 3N:三乙胺
HATU：2-(7-氮杂1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐
HPLC：高效液相色谱
LiHMDS：六甲基二硅基氨基锂
Me：甲基
MeLi：甲基锂
NMP：N-甲基吡咯烷酮
Raney-Ni：雷尼镍
NEt 3：三乙胺
overnight：过夜
Raney-Ni：雷尼镍
SEM：(三甲基硅)乙氧基甲基
SEMCl：2-(三甲基甲硅烷基)乙氧基甲基氯化物
SFC：超临界流体色谱法
TBTU：2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐
TEA：三乙胺
TEMPO：2,2,6,6-四甲基哌啶氧化物
THF：四氢呋喃
TLC：薄层色谱
TFA：三氟乙酸
TBAF：四正丁基氟化铵
Burgess’reagent：伯吉斯试剂，CAS No.：29684-56-8
rt：室温
h：小时
合成内容：
中间体1：
2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-胺盐酸盐(中间体1)
Figure PCTCN2021095192-appb-000045
第一步：(3-甲基吡啶-2-基)甲胺(1b)
Figure PCTCN2021095192-appb-000046
将化合物1a(10.0g，84.6mmol，1eq)加入到500mL高压反应釜中，在氩气保护下加入EtOH(200mL)和Raney镍(Raney Ni)(4.00g)，并将反应釜密封。用氢气置换高压反应釜中的气体3至4次，继续通入氢气，使反应釜中压力保持在50Psi左右，在35℃下搅拌反应32h。停止反应，将混合物通过硅藻土过滤，用50mL EtOH洗涤，滤液用无水硫酸钠干燥，过滤并在减压下浓缩，以得到呈深紫色液体的化合物1b(6.85g，收率：66.2％)，其未经纯化直接用于下步反应。
1H NMR(400MHz,CDCl 3)δ8.52-8.40(m,1H),7.50-7.39(m,1H),7.20-6.93(m,1H),3.96(s,2H),2.92(s,3H).
MS(ESI):m/z＝123.0[M+H] +.
第二步：(2-甲基-1-(((3-甲基吡啶-2-基)甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁基酯(1c)
Figure PCTCN2021095192-appb-000047
将化合物1b(5.50g，45.0mmol，1eq)、N-叔丁氧羰基-2-甲基丙氨酸(9.13g，45.0mmol，1eq)、TBTU(14.4g，45.0mmol，1eq)和Et 3N(13.7g，135mmol，3eq)分别加入到反应瓶中，并加入THF(400mL)，在20℃搅拌12小时。蒸发溶剂，并将残余物用300mL二氯甲烷稀释，用1M NaOH(150mL×2)和盐水(150mL)洗涤。有机层用无水硫酸钠干燥，过滤并减压浓缩，得到残余物。残余物通过快速硅胶色谱纯化(石油醚：乙酸乙酯＝1：1)，得到浅黄色固体化合物1c(4.35g，收率：31.1％)。
MS(ESI):m/z＝308.2[M+H] +.
第三步：(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酸叔丁酯(1d)
Figure PCTCN2021095192-appb-000048
将化合物1c(3.80g，12.4mmol，1eq)溶解在二氯甲烷(30mL)中，冷却至0℃，然后加入伯格斯试剂(Burgess’reagent)(3.55g，14.9mmol，1.2eq)。将混合物在20℃下搅拌4天。将混合物在减压下浓缩以得到残余物。残余物通过快速硅胶色谱法纯化(石油醚：乙酸乙酯＝1∶1)，得到浅黄色固体1d(1.76g，收率：47.5％)。
MS(ESI):m/z＝290.2[M+H] +.
第四步：2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-胺盐酸盐(中间体1)
Figure PCTCN2021095192-appb-000049
将化合物1d(900mg，3.12mmol，1eq)在甲醇(4mL)中的溶液冷却至0℃，并加入HCl/甲醇(4M，16mL)，并在0℃下搅拌2h。将混合物减压浓缩，得到白色固体的中间体1(850mg，粗品)，直接用于下一步反应。
MS(ESI):m/z＝190.2[M+H] +.
中间体2：
2-(1-甲基-1H-吲唑-3-基)丙-2-胺(中间体2)
Figure PCTCN2021095192-appb-000050
第一步：1-甲基-1H-吲唑-3-甲腈(2b)
Figure PCTCN2021095192-appb-000051
将1H-吲唑-3-甲腈2a(3g，20.9mmol)溶解在干燥的DMF(50mL)中，降温至0℃，然后向其中缓慢分批加入钠氢60％(1.2g,30mmol)，搅拌30分钟。再滴入碘甲烷(4.26g,30mmol)，缓慢升至室温并搅拌16小时。反应液用饱和氯化铵水溶液(100mL)淬灭、用乙酸乙酯(50mL×2)萃取。有机相用无水硫酸钠干燥，真空旋干得到油状物粗品。将该粗品经硅胶柱纯化(石油醚：乙酸乙酯＝5：1)得到1-甲基-1H-吲唑-3-甲腈2b(2.5g，收率：75.7％)。
MS(ESI):m/z＝158.1[M+H] +.
第二步：2-(1-甲基-1H-吲唑-3-基)丙-2-胺(中间体2)
Figure PCTCN2021095192-appb-000052
将三氯化铈(3.13g，12.7mmol)在干燥的四氢呋喃(30mL)中搅拌1小时。降温至-78℃，向其中滴入甲基锂(9.8mL,12.7mmol,1.3M)，继续搅拌1小时。再滴入1-甲基-1H-吲唑-3-甲腈2b(500mg,3.18mmol)的四氢呋喃(5mL)溶液，然后缓慢升至室温并搅拌16小时。反应液用10％氢氧化钠水溶液6mL淬灭，过滤。滤液用无水硫酸钠干燥，真空旋干得到黄色油状物粗品。粗品经硅胶柱纯化(石油醚：乙酸乙酯＝1：1)得到2-(1-甲基-1H-吲唑-3-基)丙-2-胺(中间体2)(250mg,收率：48％)。
MS(ESI):m/z＝190.1[M+H] +.
中间体3-P1和中间体3-P2：
3-(叔丁氧羰基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酸(中间体3-P1和中间体3-P2)
Figure PCTCN2021095192-appb-000053
Figure PCTCN2021095192-appb-000054
将3-甲基呋喃-2,5-二酮(20g,0.179mol)及苄胺(19.1g,0.179mol)在冰乙酸(80mL)中于100℃搅拌4小时，真空除去溶剂。残留物通过硅胶柱纯化(石油醚：乙酸乙酯＝10：1)得到白色固体1-苄基-3-甲基-1H-吡咯-2,5-二酮3b(28g，收率：80％)。
MS(ESI):m/z＝202.1[M+H] +.
第二步：(5-苄基-6a-甲基-4,6-二氧代-1,3a,4,5,6,6a-六氢吡咯并[3,4-c]吡唑-3-羧酸乙酯(3c)
Figure PCTCN2021095192-appb-000055
将1-苄基-3-甲基-1H-吡咯-2,5-二酮3b(28g,0.139mol)及重氮乙酸乙酯(48g,0.418mol)在甲苯(100mL)中于50℃搅拌3天。真空除去溶剂。残留物通过硅胶柱纯化(石油醚：乙酸乙酯＝8：1)得到白色固体(5-苄基-6a-甲基-4,6-二氧代-1,3a,4,5,6,6a-六氢吡咯并[3,4-c]吡唑-3-羧酸乙酯3c(42g,收率：95％)。
MS(ESI):m/z＝316.1[M+H] +.
第三步:3-苄基-1-甲基-2,4-二氧代-3-氮杂双环[3.1.0]己烷-6-羧酸乙酯(3d)
Figure PCTCN2021095192-appb-000056
将5-苄基-6a-甲基-4,6-二氧代-1,3a，4,5,6,6a-六氢吡咯并[3,4-c]吡唑-3-羧酸乙酯3c(14g,44.4mmol)悬浮在甲苯(50mL)中，升温至200℃(油浴的温度)，搅拌1小时。薄层色谱法监测，显示原料转化完全。平行投3锅反应。将得到的黑色粘稠状残留物合并起来经硅胶柱纯化(石油醚：乙酸乙酯＝30：1)得到白色固体产品3-苄基-1-甲基-2,4-二氧代-3-氮杂双环[3.1.0]己烷-6-羧酸乙酯3d(22g，收率： 57.4％)。
MS(ESI):m/z＝288.1[M+H] +.
第四步：3-苄基-1-甲基-3-氮杂双环[3.1.0]己烷-6-甲醛(3e)
Figure PCTCN2021095192-appb-000057
将3-苄基-1-甲基-2,4-二氧代-3-氮杂双环[3.1.0]己烷-6-羧酸乙酯3d(22g，76.6mmol)分为2批次(即11g×2)分别溶解在干燥的THF(190mL×2)中，于冰水浴下分批加入四氢铝锂(5.8g×2,153.2mmol)，室温搅拌18小时。反应液于冰水浴下用十水合硫酸钠(59.2g×2,183.8mmol)淬灭。过滤掉固体，真空旋干滤液得到淡黄色油状物粗品，其为3-苄基-1-甲基-3-氮杂双环[3.1.0]己烷-6-甲醛3e(15g，收率：91％)收率：。不用纯化，直接投下一步。
MS(ESI):m/z＝216.1[M+H] +.
第五步：(3-苄基-1-甲基-3-氮杂双环[3.1.0]己-6-基)甲醇(3f)
Figure PCTCN2021095192-appb-000058
将3-苄基-1-甲基-3-氮杂双环[3.1.0]己烷-6-甲醛(15g,69.8mmol)溶于甲醇(240mL)中，于冰水浴下分批加入硼氢化钠(660mg,17.4mmol)，室温搅拌2小时。于冰水浴下缓慢滴加丙酮(30mL)以淬灭反应，搅拌30分钟。真空旋干得到油状物粗品。粗品经硅胶柱纯化(二氯甲烷：甲醇＝60：1)得到外消旋体(3-苄基-1-甲基-3-氮杂双环[3.1.0]己-6-基)甲醇3f(10.1g，淡黄色油状物，收率：66.7％)。
MS(ESI):m/z＝218.1[M+H] +.
将上述得到的10.1克外消旋体化合物3f进行手性拆分，分别得到3f-P1(保留时间较短的化合物)和3f-P2(保留时间较长的化合物)各4.5g。
手性拆分的具体条件如下表所示：
Figure PCTCN2021095192-appb-000059
Figure PCTCN2021095192-appb-000060
第六步：6-(羟甲基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(3g)
Figure PCTCN2021095192-appb-000061
将3-苄基-1-甲基-3-氮杂双环[3.1.0]己-6-基)甲醇3f-P1(4.5，20.7mmol)溶于甲醇(60mL)中，加入钯炭(0.45g)、三乙胺(6.3g,62.2mmol)和一缩二碳酸二叔丁酯(6.8g,31.1mmol)。插入氢气球，置换三次氢气，然后于室温搅拌过夜。反应完毕，过滤掉钯炭，旋干滤液，得到粗品。粗品经硅胶柱纯化(石油醚：乙酸乙酯＝6：1)得到6-(羟甲基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯3g-P1(3.1g，淡黄色油状物，收率：65.9％)。
MS(ESI):m/z＝228.1[M+H] +.
将3-苄基-1-甲基-3-氮杂双环[3.1.0]己-6-基)甲醇3f-P2(4.5g，20.7mmol)溶于甲醇(60mL)中，加入钯炭(0.45g)、三乙胺(6.3g,62.2mmol)和一缩二碳酸二叔丁酯(6.8g,31.1mmol)。插入氢气球，置换三次氢气，然后于室温搅拌过夜。反应完毕，过滤掉钯炭，旋干滤液，得到粗品。粗品经硅胶柱纯化(石油醚：乙酸乙酯＝6：1)得到6-(羟甲基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯3g-P2(3.5g，淡黄色油状物，收率：74.4％)。
MS(ESI):m/z＝228.1[M+H] +.
第七步：3-(叔丁氧羰基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酸(中间体3-P1和中间体3-P2)
Figure PCTCN2021095192-appb-000062
将6-(羟甲基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯3g-P1(3.1g,13.7mmol)溶于乙腈(30mL)中，室温下加入2,2,6,6-四甲基哌啶氮氧化物(TEMPO)(0.13g,0.819mmol)和18％亚氯酸钠水溶液(18mL)。搅拌5分钟后，滴加10％次氯酸钠水溶液(2mL溶于20mL水中，取12mL)，室温搅拌过夜。用乙酸乙酯(40mL×2)萃取，有机相用无水硫酸钠干燥，真空旋干得到油状物，其为3-(叔丁氧羰基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酸中间体3-P1(3.0g,收率：90％)：。不用纯化直接投到下一步。
MS(ESI):m/z＝242.1[M+H] +.
1HNMR(400MHz,DMSO-d 6)δ12.20(brs,1H),3.56-3.44(m,2H),3.38-3.12(m,2H),1.81(t,1H),1.37(s,9H),1.32-1.27(m,4H).
将6-(羟甲基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯3g-P2(3.5g,15.4mmol)溶于乙腈(35mL)中，室温下加入2,2,6,6-四甲基哌啶氮氧化物(0.144g,0.925mmol)和18％亚氯酸钠水溶液(21mL)。搅拌5分钟后，滴加10％次氯酸钠水溶液(2mL溶于20mL水中，取14mL)，室温搅拌过夜。用乙酸乙酯(40mL×2)萃取，有机相用无水硫酸钠干燥，真空旋干得到油状物，其为3-(叔丁氧羰基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酸中间体3-P2(3.3g,收率：81％)，不用纯化直接投到下一步。
MS(ESI):m/z＝242.1[M+H] +.
1HNMR(400MHz,DMSO-d 6)δ12.22(brs,1H),3.56-3.44(m,2H),3.38-3.12(m,2H),1.81(t,1H),1.37(s,9H),1.32-1.27(m,4H).
中间体4：
7-甲基-1H-吲唑-3-腈(中间体4)
Figure PCTCN2021095192-appb-000063
将7-甲基-1H-吲唑-3-腈4a(1.0g，6.39mmol)溶解在干燥DMF(10mL)中，降温至0℃，然后缓慢加入钠氢60％(0.40g,10mmol,),搅拌30min，再滴入碘甲烷(1.42g,10mmol)，缓慢升至室温并搅拌16小时。10％氯化铵水溶液25mL淬灭，用乙酸乙酯(50mL×2)萃取，滤液无水硫酸钠干燥，真空旋干得到粗品，硅胶柱纯化(石油醚：乙酸乙酯＝5：1)得到7-甲基-1H-吲唑-3-腈中间体4(1.0g，收率：91.8％)。
MS(ESI):m/z＝172.1[M+1] +.
实施例1
N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-5-氮杂螺[2.4]庚烷-1-羧酰胺盐酸盐(化合物1)
Figure PCTCN2021095192-appb-000064
第一步：1-((2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)-5-氮杂螺[2.4]庚烷-5-羧酸叔丁酯(1B)
Figure PCTCN2021095192-appb-000065
将中间体1(80mg，0.354mmol，1eq)、5-Boc-5-氮杂螺[2.4]庚烷-1-羧酸1A(94mg，0.389mmol，1.1eq)、HATU(162mg，0.424mmol，1.2eq)和DIPEA(184mg，1.42mmol，4eq)溶解在DMF(1.5mL)中，在25℃下搅拌12小时。将混合物用10mL水稀释，并用乙酸乙酯(8mL×3)萃取。合并的有机层用盐水(15mL)洗涤，用无水硫酸钠干燥，过滤并在减压下浓缩以得到残余物。残余物通过快速硅胶色谱法纯化(石油醚：乙酸乙酯＝1：1)，得到浅黄色固体1B(110mg，收率：63.1％)。
MS(ESI):m/z＝413.2[M+H] +.
第二步：N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-5-氮杂螺[2.4]庚烷-1-羧酰胺盐酸盐(化合物1)
Figure PCTCN2021095192-appb-000066
将化合物1B(110mg，0.36mmol，1eq)溶解在乙酸乙酯(2mL)中，冷却至0℃，加入HCl/乙酸乙酯(4M，6mL)，并在0℃下搅拌1小时。将混合物在减压下浓缩以得到残余物。向残余物中加入30mL纯净水和1mL MeCN，然后冻干，得到为灰色固体化合物1(70mg，收率：75.2％)。
1H NMR(400MHz,CD 3OD)δ8.53-8.43(dd,1H),8.08(s,1H),7.09-7.21(m,1H),7.05(d,1H),3.36-3.47(m,1H),3.27-3.30(m,1H),3.17-3.25(m,1H),3.06-3.14(m,1H),2.54(s,3H),2.09-2.18(m,1H),1.95(m,6H),1.77-1.90(m,2H),1.60-1.70(m,1H),1.03(m,1H).
MS(ESI):m/z＝313.1[M+H] +.
实施例2
(3aR,5r,6aS)-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺盐酸盐(化合物2)
Figure PCTCN2021095192-appb-000067
第一步：(3aR,5r,6aS)-5-((2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基酯(2B)
Figure PCTCN2021095192-appb-000068
将中间体1(40mg，0.177mmol，1eq)，化合物2A(CAS No.:442877-23-8)(45mg，0.177mmol，1.1eq)，HATU(81mg，0.212mmol，1.2eq)和DIPEA(92mg，0.718mmol，4eq)溶解在DMF(1mL)中并将该溶液在25℃下搅拌12小时。将混合物用10mL水稀释，并用乙酸乙酯(8mL×3)萃取。合并的有机层用盐水(15mL)洗涤，用无水硫酸钠干燥，过滤并在减压下浓缩以得到残余物。残余物通过快速硅胶色谱纯化(石油醚：乙酸乙酯＝1∶1)，得到浅黄色固体2B(60mg，收率：66.5％)。
1H NMR(400MHz,CDCl 3)δ7.94-7.92(m,1H),7.34(s,1H),6.91(s,1H),6.51-6.48(m,2H),3.48-3.43(m,2H),3.17-3.37(m,2H),2.71-2.85(m,1H),2.55-2.69(m,2H),2.41(s,3H),2.14(m,2H),1.91(s,6H),1.74-1.70(m,2H),1.44(s,9H).
MS(ESI):m/z＝427.2[M+H] +.
第二步：(3aR,5r,6aS)-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺盐酸盐(化合物2)
Figure PCTCN2021095192-appb-000069
将化合物2B(60mg，0.14mmol，1eq)的乙酸乙酯(2mL)溶液冷却至0℃，加入HCl/乙酸乙酯(4M，6mL)并在0℃搅拌1h。将混合物减压浓缩，得到残余物。向残余物中加入30mL水和1mL MeCN，然后冻干，得到橙色油状物化合物2(50mg，收率：97.9％)。
1H NMR(400MHz,CD 3OD)δ8.37(d,1H),8.08(s,1H),7.13-7.05(m,1H),7.05-6.98(m,1H),3.28-3.23(m,2H),3.08(d,2H),2.81-2.97(m,3H),2.52(s,3H),2.16-2.28(m,2H),1.90(s,6H),1.39-1.50(m,2H).
MS(ESI):m/z＝327.1[M+H] +.
实施例3
(3aR,5s,6aS)-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺盐酸盐(化合物3)
Figure PCTCN2021095192-appb-000070
第一步：(3aR,5s,6aS)-5-((2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基酯(3B)
Figure PCTCN2021095192-appb-000071
将中间体1(40mg，0.177mmol，1eq)、化合物3A(CAS:1401464-09-2)(45mg，0.177mmol，1.1eq)、HATU(81mg，0.212mmol，1.2eq)和DIPEA(92mg，1.42mmol，4eq)溶解在DMF(1mL)中并将该溶液在25℃下搅拌1小时。将混合物用10mL水稀释，并用乙酸乙酯(8mL×3)萃取。合并的有机层用盐水(15mL)洗涤，用无水硫酸钠干燥，过滤并在减压下浓缩以得到残余物。残余物通过快速硅胶色谱纯化(石油醚：乙酸乙酯＝1∶1)，得到浅黄色固体3B(60mg，收率：66.5％)。
1H NMR(400MHz,CDCl 3)δ7.95(br s,1H),7.37(s,1H),6.86(s,1H),6.49(m,2H),3.54(m,2H),3.15(m,2H),2.84-2.91(m,1H),2.80(m,2H),2.43(s,3H),2.07-2.12(m,2H),1.92(s,6H),1.78(m,2H),1.48(s,9H).
MS(ESI):m/z＝427.2[M+H] +.
第二步：(3aR,5s,6aS)-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺盐酸盐(化合物3)
Figure PCTCN2021095192-appb-000072
将化合物3B(60mg，0.14mmol，1eq)溶解在乙酸乙酯(2mL)中，冷却至0℃，添加HCl/乙酸乙酯(4M，6mL)，并在0℃搅拌2h。将混合物在减压下浓缩以得到残余物。向残余物中加入30mL纯净水，1mL MeCN，然后冻干，得到浅黄色油状的化合物3(33mg，收率：64.7％)。
1H NMR(400MHz,CD 3OD)δ8.40(d,1H),8.07(s,1H),7.12-7.05(m,1H),7.04-6.98(m,1H),3.44-3.55(m,2H),3.00-3.14(m,1H),2.80-2.96(m,4H),2.52(s,3H),1.90(s,6H),1.72-1.83(m,4H).
MS(ESI):m/z＝327.1[M+H] +.
实施例4
(3aR,5s,6aS)-N-(2-(1,7-二甲基-1H-吲唑-3-基)丙-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺盐酸盐(化合物4)
Figure PCTCN2021095192-appb-000073
第一步：2-(1,7-二甲基-1H-吲唑-3-基)丙-2-胺(4B)
Figure PCTCN2021095192-appb-000074
将三氯化铈(1.15g，4.67mmol)在干燥四氢呋喃(10mL)中搅拌1小时，降温至-78℃,滴入甲基锂(2.35mL,4.67mmol,2M),搅拌1小时。再滴入1,7-二甲基-1H-吲唑-3-甲腈(中间体4)(200mg,1.17mmol)的四氢呋喃(5mL)溶液，缓慢升至室温并搅拌16小时。用20％氢氧化钠水溶液1mL淬灭，过滤，滤液用无水硫酸钠干燥，真空旋干得到黄色油状物4B(180mg，粗品，未纯化)。
第二步：(3aR,5s,6aS)-N-(2-(1,7-二甲基-1H-吲唑-3-基)丙-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺盐酸盐(化合物4)
Figure PCTCN2021095192-appb-000075
将2-(1,7-二甲基-1H-吲唑-3-基)丙-2-胺4B(60mg,0.3mmol)，化合物3A(75mg,0.3mmol)，HATU(170mg,0.45mmoL)和二异丙基乙胺(78mg,0.6mmol)溶于N,N-二甲基甲酰胺(1mL)中，室温搅拌16小时，反应液经制备型HPLC纯化得到白色固体(75mg)。将该产品加入3M盐酸乙酸乙酯溶液(4mL)中,搅拌2小时，真空除去溶剂得到白色固体化合物4(45mg，收率：36.8％)。
1H NMR(400MHz,CD 3OD)δ7.82(d,1H),7.28(d,1H),7.08(t,1H),4.35(s,3H),3.51-3.49(m,2H),3.11-3.01(m,1H),3.04-2.90(m,4H),2.78(s,3H),1.83-1.76(m,10H).
MS(ESI):m/z＝341.1[M+H] +.
实施例5
(1R,3r,5S)-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-8-氮杂双环[3.2.1]辛烷-3-羧酰胺盐酸盐(化合物5)
Figure PCTCN2021095192-appb-000076
将中间体1(50mg,0.26mmol)、化合物5A(CAS:1222996-05-5)(66mg,0.26mmol)、HATU(148mg,0.39mmoL)和二异丙基乙胺(101mg,0.78mmol)溶于N,N-二甲基甲酰胺(2mL)中，室温搅拌16小时。加入乙酸乙酯(60mL)，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，真空旋干得到黄色粗品(75mg)。将该粗品加入4M盐酸的二噁烷(dioxane)溶液(4mL)中,室温搅拌2小时，真空除去溶剂。残余物经 制备型HPLC纯化得到白色固体(1R,3r,5S)-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-8-氮杂双环[3.2.1]辛烷-3-羧酰胺盐酸盐(34mg，收率：39.3％)。
1H NMR(400MHz,CD 3OD)δ8.78(s,1H),8.42(d,1H),8.10(s,1H),7.09-7.05(m,2H),3.94-3.75(m,2H),2.88-2.85(m,1H),2.54(s,3H),2.28-2.24(m,4H),1.94(s,6H),1.88-1.85(m,4H).
MS(ESI):m/z＝327.2[M+H] +.
实施例6
N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-2-氮杂双环[2.2.1]庚烷-5-羧酰胺盐酸盐(化合物6)
Figure PCTCN2021095192-appb-000077
第一步：5-((2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)叔丁基-2-氮杂双环[2.2.1]庚烷-2-羧酸叔丁基酯(6B)
Figure PCTCN2021095192-appb-000078
将中间体1(50mg g,0.26mmol)溶于DMF(0.5mL)中，室温下加入2-(叔丁氧羰基)-2-氮杂双环[2.2.1]庚烷-5-羧酸(127.51mg,0.53mmol)、N,N-二异丙基乙胺(68.25mg,0.53mmol)和HATU(150.79mg,0.40mmol)，维持室温搅拌反应8小时。向反应液中加入乙酸乙酯(3mL)，用饱和食盐水(10mL×3)洗涤，浓缩。残留物用硅胶柱色谱分离纯化(石油醚：乙酸乙酯＝1:1～1:3)得到白色固体状的化合物6B(50mg,收率：45.9％)。
MS(ESI):m/z＝413.0[M+H] +
第二步：N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-2-氮杂双环[2.2.1]庚烷-5-羧酰胺盐酸盐(化合物6)
Figure PCTCN2021095192-appb-000079
将6B(50mg,0.12mmol)溶于盐酸二噁烷溶液(1mL)中，室温反应1小时。浓缩反应液，加入乙酸乙酯(3mL)，浆化并过滤。冻干得白色固体状的化合物，其为N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-2-氮杂双环[2.2.1]庚烷-5-羧酰胺盐酸盐化合物6(25mg，收率：67.7％)。
1H NMR(400MHz,CD 3OD)δ9.07(s,1H),8.39(d,1H),8.09(s,1H),7.17–6.95(m,2H),3.98(m,1H),3.11(m,1H),3.01(m,1H),2.89(m,1H),2.78(m,1H),2.52(s,3H),1.95–1.81(m,10H).
MS(ESI):m/z＝313.0[M+H] +.
实施例7
(3aR,5s,6aS)-N-(2-(7-甲基-1H-吲唑-3-基)丙烷-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺(化合物7)
Figure PCTCN2021095192-appb-000080
第一步：7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-甲腈(7B)
Figure PCTCN2021095192-appb-000081
将7-甲基-1H-吲唑-3-甲腈7A(1g，6.36mmol)溶解在干燥DMF(5mL)中，降温至0℃，然后缓慢加入NaH(370mg，9.54mmol)，搅拌30分钟。再滴入(2-(氯甲氧基)乙基)三甲基硅烷(1.60g,9.54mmol)，缓慢升至室温并搅拌16小时。用10％氯化铵水溶液5mL淬灭，用乙酸乙酯(100mLX2)萃取。滤液用无水硫酸钠干燥，真空旋干得到油状物。将所述油状物经硅胶柱纯化(石油醚：乙酸乙酯＝5：1)得到7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-甲腈7B(1.2g，收率：65.9％)。
第二步：2-(7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙-2-胺(7C)
Figure PCTCN2021095192-appb-000082
将三氯化铈(320mg，1.3mmol)在干燥四氢呋喃(5mL)中搅拌1小时，降温至-78℃，滴入甲基锂(1mL,1.3mmol,1.3M)，搅拌1小时。再滴入7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-甲腈7B(100mg，0.32mmol)的四氢呋喃(1mL)溶液，缓慢升至室温并搅拌16小时。用10％氢氧化钠水溶液1mL淬灭，过滤，滤液用无水硫酸钠干燥，真空旋干得到黄色油状物，其为2-(7-甲基-1-((2-(三 甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙-2-胺7C(80mg，粗品，未纯化)。
第三步：(3aR,5s,6aS)-5-((2-(7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基酯(7D)
Figure PCTCN2021095192-appb-000083
将2-(7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙-2-胺7C(60mg，0.18mmol)，化合物(3aR,5s,6aS)-2-(叔丁氧羰基)八氢环戊二烯并[c]吡咯-5-羧酸(75mg,0.18mmol)，HATU(64mg,0.25mmoL)和二异丙基乙胺(78mg,0.6mmol)溶于N,N-二甲基甲酰胺(1mL)中，室温搅拌16小时。反应液经制备型HPLC纯化得到白色固体7D(75mg，收率：75％)。
MS(ESI):m/z＝501.0[M-55] +.
第四步：(3aR,5s,6aS)-N-(2-(7-甲基-1H-吲唑-3-基)丙烷-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺(化合物7)
Figure PCTCN2021095192-appb-000084
将(3aR,5s,6aS)-5-((2-(7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基酯7D(75mg,0.13mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.5mL)并在室温搅拌3小时。旋干溶剂，所得残余物经制备型HPLC纯化得到白色固体，其为化合物7(20mg，收率：45％)。
1H NMR(400MHz,CDCl 3)δ7.64(d,1H),7.14(m,2H),7.07(d,1H),3.19(m,1H),2.75(m,3H),2.57(m,1H),2.52(s,3H),2.00(m,4H),1.91(s,6H),1.75(m,2H).
MS(ESI):m/z＝327.2[M+H] +.
实施例8
1-甲基-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物8)
Figure PCTCN2021095192-appb-000085
第一步：1-苄基-3-甲基-1H-吡咯-2,5-二酮(8B)
Figure PCTCN2021095192-appb-000086
将3-甲基呋喃-2,5-二酮8A(5.0g,44.61mmol)及苯甲胺(4.78g,44.61mmol)在冰乙酸(20mL)中于100℃搅拌4小时。真空除去溶剂，残留物经硅胶柱纯化(石油醚：乙酸乙酯＝3：1)得到白色固体，其为1-苄基-3-甲基-1H-吡咯-2,5-二酮8B(8.3g，收率：92.4％)。
第二步：5-苄基-6a-甲基-4,6-二氧代-1,3a，4,5,6,6a-六氢吡咯并[3,4-c]吡唑-3-羧酸乙酯(8C)
Figure PCTCN2021095192-appb-000087
将1-苄基-3-甲基-1H-吡咯-2,5-二酮8B(4.0g,19.88mmol)及重氮乙酸乙酯(9.07g,79.51mmol)在甲苯(30mL)中于50℃搅拌4天。真空除去溶剂，残留物经硅胶柱纯化(石油醚：乙酸乙酯＝2：1)得到白色固体8C(5.7g,收率：95.1％)。
第三步:3-苄基-1-甲基-2,4-二氧代-3-氮杂双环[3.1.0]己烷-6-羧酸乙酯(8D)
Figure PCTCN2021095192-appb-000088
将8C(3.0g,9.96mmol)于200℃下搅拌1小时。残留物经硅胶柱纯化(石油醚：乙酸乙酯＝4：1)得到白色固体8D(1.9g，收率：66.4％)。
第四步：(3-苄基-1-甲基-3-氮杂双环[3.1.0]己-6-基)甲醇(8E)
Figure PCTCN2021095192-appb-000089
将8D(1.7g，5.92mmol)溶解在干燥THF(30mL)中，于水浴下分批加入四氢铝锂(0.829g,29.60mmol)并室温搅拌18小时。用10％氯化铵水溶液30mL淬灭，用乙酸乙酯(100mL x 3)萃取。滤液用无水硫酸钠干燥，真空旋干得到油状物。所述油状物经硅胶柱纯化(二氯甲烷：甲醇＝20：1)得到淡黄色油状物8E(0.8g，收率：62.5％)。
MS(ESI):m/z＝218.1[M+H] +.
第五步：6-(羟甲基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(8F)
Figure PCTCN2021095192-appb-000090
将8E(700mg，3.22mmol)溶于甲醇(10mL)中，加入钯炭(50mg)，三乙胺(966mg,9.66mmol)和一缩二碳酸二叔丁酯(1.05g,4.83mmol)。插入氢气球，置换三次氢气，然后于室温搅拌过夜。反应完毕后，过滤掉钯炭，旋干滤液，得到粗品。粗品经硅胶柱纯化(二氯甲烷：甲醇＝10：1)得到淡黄色油状物8F(350mg，收率：47.8％)。
MS(ESI):m/z＝172.1[M-55] +.
第六步：3-(叔丁氧羰基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酸(8G)
Figure PCTCN2021095192-appb-000091
将8F(100mg,0.44mmol)溶于乙腈(1mL)中，室温下加入2,2,6,6-四甲基哌啶氮氧化物(3.4mg,0.022mmol)和10％亚氯酸钠水溶液(79.2mg,0.88mmol)，搅拌30分钟。然后加入10％次氯酸钠水溶液(65mg,0.88mmol)。室温搅拌过夜，用乙酸乙酯(10mL x 2)萃取。滤液经无水硫酸钠干燥，真空旋干得到油状物8G，没有纯化直接将其投到下一步反应中(80mg,收率：75％)。
MS(ESI):m/z＝186.1[M-55] +.
第七步：1-甲基-6-((2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯(8H)
Figure PCTCN2021095192-appb-000092
将8G(80mg,0.33mmol),中间体1(62.7mg,0.33mmol),HATU(190mg,0.5mmoL)和三乙胺(99mg,0.99mmol)溶于N,N-二甲基甲酰胺(1mL)中，室温搅拌16小时。反应液用乙酸乙酯(10mL x 2) 萃取，滤液用无水硫酸钠干燥，真空旋干得到油状物。所述油状物经柱色谱纯化(石油醚：乙酸乙酯＝2：1)得到产物8H(70mg，收率：75％)。
MS(ESI):m/z＝413.1[M+H] +.
第八步：1-甲基-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物8)
Figure PCTCN2021095192-appb-000093
将8H(70mg,0.169mmol)溶于4M氯化氢的甲醇溶液中(2mL，8mmol)，室温搅拌18小时。旋干溶剂，残留物经制备型HPLC纯化得到白色固体化合物8(20mg，收率：37.7％)。
1H NMR(400MHz,CDCl 3)δ8.04-7.97(m,1H),7.34(s,1H),6.47(d,2H),3.07(m,3H),2.88(d,1H),2.40(s,3H),1.90(s,6H),1.87(m,1H),1.62(d,1H),1.22(s,3H).
MS(ESI):m/z＝313.1[M+H] +.
参照实施例8的合成方法，使用中间体3-P1与中间体1合成得到化合物8-P1。使用中间体3-P2与中间体1合成得到化合物8-P2。化合物8-P1与化合物8-P2为化合物8的光学纯异构体。
1-甲基-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物8-P1)
MS(ESI):m/z＝313.1[M+H] +.
1H NMR(400MHz,DMSO-d6)：δ8.37(s,1H),8.12(d,1H),7.22(s,1H),6.53–6.47(m,2H),2.92-2.77(m,3H),2.67–2.61(m,1H),2.33(s,3H),2.03–1.91(m,2H),1.67(s,3H),1.63(s,3H),0.98(s,3H).
1-甲基-N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物8-P2)
MS(ESI):m/z＝313.1[M+H] +.
1H NMR(400MHz,DMSO-d6)：δ8.45(s,1H),8.12(d,1H),7.22(s,1H),6.54–6.47(m,2H),3.02–2.90(m,3H),2.75(d,1H),2.33(s,3H),2.03–1.97(m,1H),1.72(d,1H),1.68(s,3H),1.63(s,3H),0.96(s,3H).
实施例9
N-(2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)-5-氮杂螺[2.4]庚烷-1-甲酰胺(化合物9)
Figure PCTCN2021095192-appb-000094
第一步：1-((2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)-5-氮杂螺[2.4]庚烷-5-羧酸苄基酯(9B)
Figure PCTCN2021095192-appb-000095
将5-((苯氧基)羰基)-5-氮杂螺[2.4]庚烷-1-羧酸9A(500mg,1.82mmol)和HATU(760mg,1.99mmol)在干燥N,N-二甲基甲酰胺(10mL)中并在室温下搅拌半小时。然后加入2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-胺中间体1(344mg,1.82mmol)和三乙胺(0.5mL)，室温下搅拌反应过夜。反应液倒入水中，用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥。真空旋干溶剂，粗品经制备型HPLC纯化后得到9B-P1(140mg)和9B-P2(150mg)。
MS(ESI):m/z＝447.1[M+H] +.
9B-P1再经手性拆分后得到9B-P1-1(70mg，保留时间较短的化合物)和9B-P1-2(65mg，保留时间较长的化合物)。手性拆分的条件如下表所示：
Figure PCTCN2021095192-appb-000096
Figure PCTCN2021095192-appb-000097
9B-P2再经手性拆分后得到9B-P2-1(65mg，保留时间较短的化合物)和9B-P2-2(80mg，保留时间较长的化合物)。手性拆分的条件如下表所示：
Figure PCTCN2021095192-appb-000098
第二步：N-(2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)-5-氮杂螺[2.4]庚烷-1-甲酰胺(化合物9)
Figure PCTCN2021095192-appb-000099
将1-((2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)-5-氮杂螺[2.4]庚烷-5-羧酸苄基酯9B-P1-1(70mg,0.157mmol)溶解在二氯甲烷(3mL)中，然后加入三溴化硼(197mg,0.786mmol)，反应在室温下搅拌半小时。在不超过20℃的水浴温度下真空旋干以除去过量的三溴化硼。残留物再用饱和碳酸氢钠水溶液调pH至7～8，然后真空旋干得到粗品。所述粗品经制备型HPLC纯化后得到化合物9(14mg，收率：28.6％)，白色固体。
MS(ESI):m/z＝313.0[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.15–8.07(m,1H),7.22(s,1H),6.57–6.42(m,2H),2.87–2.75(m,2H),2.44–2.27(m,5H),1.89–1.78(m,1H),1.75–1.54(m,8H),0.90–0.79(m,2H).
实施例10
N-(2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)-5-氮杂螺[2.4]庚烷-1-甲酰胺(化合物10)
Figure PCTCN2021095192-appb-000100
将1-((2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)-5-氮杂螺[2.4]庚烷-5-羧酸苄基酯9B-P1-2(65mg,0.146mmol)溶解在二氯甲烷(3mL)中，然后加入三溴化硼(183mg,0.73mmol)，反应在室温下搅拌半小时。在不超过20℃的水浴温度下真空旋干除去过量的三溴化硼。残留物再用饱和碳酸氢钠水溶液调pH至7～8，然后真空旋干得到粗品。所述粗品经制备型HPLC纯化后得到化合物10(6mg，收率：13.2％)，白色固体。
MS(ESI):M/Z＝313.0[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.15–8.07(m,1H),7.22(s,1H),6.57–6.42(m,2H),3.02–2.80(m,3H),2.33(m,1H),1.91–1.70(m,3H),1.68(s,3H),1.62(s,3H)0.92–0.79(m,2H).
实施例11
N-(2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)-5-氮杂螺[2.4]庚烷-1-甲酰胺(化合物11)
Figure PCTCN2021095192-appb-000101
将1-((2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)-5-氮杂螺[2.4]庚烷-5-羧酸苄基酯9B-P2-1(65mg,0.146mmol)溶解在二氯甲烷(3mL)中，然后加入三溴化硼(183mg,0.73mmol)，反应在室温下搅拌半小时。在不超过20℃的水浴温度下真空旋干除去过量的三溴化硼，残留物再用饱和碳酸氢钠水溶液调pH至7～8，然后真空旋干得到粗品。所述粗品经制备型HPLC纯化后得到化合物11(10mg，收率：22.0％)，其为白色固体。
MS(ESI):M/Z＝313.0[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.14(d,1H),7.30(s,1H),6.62–6.51(m,2H),3.02–2.77(m,4H),2.39(s,3H),1.87–1.72(m,7H),1.62–1.45(m,2H),1.07–0.93(m,2H).
实施例12
N-(2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)-5-氮杂螺[2.4]庚烷-1-甲酰胺(化合物12)
Figure PCTCN2021095192-appb-000102
将1-((2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)-5-氮杂螺[2.4]庚烷-5-羧酸苄基酯9B-P2-2(80mg,0.179mmol)溶解在二氯甲烷(3mL)中，然后加入三溴化硼(224mg,0.894mmol)，反应在室温下搅拌半小时。在不超过20℃的水浴温度下真空旋干除去过量的三溴化硼，残留物再用饱和碳酸氢钠水溶液调pH至7～8，然后真空旋干得到粗品。该粗品经制备型HPLC纯化后得到化合物12(19mg，收率：34.0％)，白色固体。
MS(ESI):M/Z＝313.0[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.14(d,1H),7.30(s,1H),6.62–6.51(m,2H),3.07–2.84(m,4H),2.39(s,3H),1.89–1.72(m,7H),1.66–1.52(m,2H),1.09–0.96(m,2H).
实施例13
N-(2-(1,7-二甲基-1H-吲唑-3-基)丙烷-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺甲酸盐(化合物13)
Figure PCTCN2021095192-appb-000103
第一步：2-(1,7-二甲基-1H-吲唑-3-基)丙-2-胺(13B)
Figure PCTCN2021095192-appb-000104
将三氯化铈(1.71g，6.97mmol)在无水四氢呋喃(20mL)中搅拌1小时。降温至-78℃，向其中滴入甲基锂(5.4mL,6.97mmol，1.3M)，搅拌1小时。再向其中滴入7-甲基-1H-吲唑-3-甲腈(中间体4)(300mg,1.74mmol)的无水四氢呋喃(3mL)溶液，缓慢升至室温并搅拌16小时。用10％氢氧化钠水溶液8mL淬灭，过滤，滤液用无水硫酸钠干燥，真空旋干得到黄色油状物粗品。所述粗品经硅胶柱纯化(石油醚：乙酸乙酯＝1：1)得到2-(1,7-二甲基-1H-吲唑-3-基)丙-2-胺13B(180mg,收率：50.5％)。
MS(ESI):m/z＝204.1[M+H] +.
第二步：6-((2-(1,7-二甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯(13C)
Figure PCTCN2021095192-appb-000105
将2-(1,7-二甲基-1H-吲唑-3-基)丙-2-胺13B(180mg，0.96mmol)，化合物3-(叔丁氧羰基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酸(232mg,0.96mmol),HATU(547mg,1.44mmoL)和三乙胺(303mg,3.0mmol)溶于N,N-二甲基甲酰胺(3mL)中，室温搅拌16小时。反应液加水淬灭，用乙酸乙酯萃取。有机相用无水硫酸钠干燥，真空旋干得到油状物。硅胶柱纯化(石油醚：乙酸乙酯＝1：1)得到6-((2-(1,7-二甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯13C(200mg，收率：48.6％)。
手性拆分得到13C-P1(80mg，保留时间较短的化合物)和13C-P2(80mg，保留时间较长的化合物)。
手性拆分的条件如下表所示：
Figure PCTCN2021095192-appb-000106
MS(ESI):m/z＝427.1[M+H] +.
第三步：N-(2-(1,7-二甲基-1H-吲唑-3-基)丙烷-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺甲酸盐(化合物13)
Figure PCTCN2021095192-appb-000107
将6-((2-(1,7-二甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯13C-P1(75mg,0.17mmol)溶于3N盐酸二噁烷(2mL)中，室温搅拌3小时。反应液旋干溶剂得到粗品。该粗品经制备型HPLC纯化后得到N-(2-(1,7-二甲基-1H-吲唑-3-基)丙烷-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺甲酸盐(化合物13)(13.6mg，收率：23.8％)。
MS(ESI):m/z＝327.1[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.49(s,1H),7.65(d,1H),7.05(d,1H),6.96–6.85(m,1H),4.24(s,3H),3.45-3.33(m,3H),3.23(d,1H),2.74(s,3H),1.94(t,1H),1.85-1.72(m,7H),1.12(s,3H).
实施例14
N-(2-(1,7-二甲基-1H-吲唑-3-基)丙烷-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物14)
Figure PCTCN2021095192-appb-000108
将6-((2-(1,7-二甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯13C-P2(75mg,0.17mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.5mL)，室温搅拌3小时。旋干反应液以除去溶剂和三氟乙酸。残留物用氨水调节pH至弱碱性，旋干得到粗品。该粗品经制备型薄层色谱法(prep-TLC)纯化得到N-(2-(1,7-二甲基-1H-吲唑-3-基)丙烷-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物14)(19.8mg，收率：34.7％)。
MS(ESI):m/z＝327.2[M+H] +.
1H NMR(400MHz,CD 3OD)δ7.66(d,1H),7.05(d,1H),6.91(t,1H),4.24(s,3H),3.04–2.90(m,3H),2.73–2.71(m,4H),1.77(s,3H),1.75(s,3H),1.64(m,1H),1.57(d,1H),1.06(s,3H).
实施例15
1-甲基-N-(2-(7-甲基-1H-吲唑-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物15)
Figure PCTCN2021095192-appb-000109
(7C合成方法参考实施例7)
第一步：1-甲基-6-((2-(7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯(15A)
Figure PCTCN2021095192-appb-000110
将2-(7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙-2-胺7C(140mg,0.43mmol)、化合物3-(叔丁氧羰基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酸8G(106mg,0.43mmol)、HATU(190mg,0.5mmol)和三乙胺(150mg,1.5mmol)溶于N,N-二甲基甲酰胺(2mL)中，室温搅拌16小时。反应液加水淬灭，用乙酸乙酯萃取。有机相用无水硫酸钠干燥，真空旋干得到油状物粗品。所述粗品经硅胶柱纯化(石油醚：乙酸乙酯＝1：1)得到1-甲基-6-((2-(7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯化合物15A(150mg，收率：47.3％)。
手性拆分后得到15A-P1(60mg，保留时间较短的化合物)和15A-P2(60mg，保留时间较长的化合物)。
手性拆分的条件如下表所示：
Figure PCTCN2021095192-appb-000111
Figure PCTCN2021095192-appb-000112
MS(ESI):m/z＝543.2[M+H] +.
第二步：1-甲基-N-(2-(7-甲基-1H-吲唑-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物15)
Figure PCTCN2021095192-appb-000113
将(1R,5R,6R)-1-甲基-6-((2-(7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯15A-P1(60mg,0.11mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.5mL)，室温搅拌3小时。反应液旋干除去溶剂和三氟乙酸，残留物用氨水调节pH至弱碱性，旋干得到粗品。该粗品经制备型薄层色谱法(prep-TLC)纯化得到产品化合物15(21.4mg，收率：44.5％)。
MS(ESI):m/z＝313.1[M+H] +.
1H NMR(400MHz,CD 3OD)δ7.67(d,1H),7.08(s,1H),6.97(t,1H),3.42-3.33(m,2H),3.17(s,2H),2.51(s,3H),1.91(s,1H),1.81(d,6H),1.71(d,1H),1.13(s,3H).
实施例16
1-甲基-N-(2-(7-甲基-1H-吲唑-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物16)
Figure PCTCN2021095192-appb-000114
将1-甲基-6-((2-(7-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯15A-P2(60mg,0.11mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.5mL)，室温搅拌3小时。反应液旋干除去溶剂和三氟乙酸。残留物用氨水调节pH至弱碱性，旋干得到粗品。该粗品经制备型薄层色谱法(prep-TLC)纯化得到产品(化合物16)(10.4mg，收率：20.4％)。
MS(ESI):m/z＝313.1[M+H] +.
1H NMR(400MHz,CD 3OD)δ7.67(d,1H),7.09(d,1H),6.97(t,1H),3.45-3.33(m,3H),3.18(d,1H),2.51(s,3H),1.91(s,1H),1.81(d,6H),1.74(s,1H),1.13(s,3H).
实施例17
(3aR,5s,6aS)-N-(2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺甲酸盐(化合物17)
Figure PCTCN2021095192-appb-000115
第一步：(3aR,5s,6aS)-5-((2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基酯(17A)
Figure PCTCN2021095192-appb-000116
将2-(1-甲基-1H-吲唑-3-基)丙-2-胺(中间体2)(80mg,0.42mmol)、化合物(3aR,5s,6aS)-2-(叔丁氧羰基)八氢环戊二烯并[c]吡咯-5-羧酸3A(108mg,0.42mmol)、HATU(239mg,0.63mmol)和三乙胺(202mg,2.0mmol)溶于N,N-二甲基甲酰胺(2mL)中，室温搅拌16小时。反应液加水淬灭，用乙酸乙酯萃取。有机相用无水硫酸钠干燥，真空旋干得到油状物粗品。该粗品经硅胶柱纯化(石油醚：乙酸乙酯＝1：1)得到(3aR,5s,6aS)-5-((2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基酯17A(50mg，收率：27.7％)。
MS(ESI):m/z＝427.2[M+H] +.
第二步：(3aR,5s,6aS)-N-(2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺甲酸盐(化合物17)
Figure PCTCN2021095192-appb-000117
将(3aR,5s,6aS)-5-((2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基酯17A(40mg,0.093mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.5mL)，室温搅拌3小时。将反应液旋干溶剂，残留物经制备型HPLC纯化得到白色固体(3aR,5s,6aS)-N-(2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺甲酸盐(化合物17)(4mg，收率：13.3％)。
MS(ESI):m/z＝327.2[M+H] +.
1H NMR(400MHz,CD 3OD)δ8.56(s,1H),7.82(d,1H),7.45(d,1H),7.35(t,1H),7.07(t,1H),3.99(s,3H),3.50-3.40(m,2H),3.02-2.90(m,1H),2.89–2.72(m,4H),1.95-1.82(m,2H),1.78(s,6H),1.75-1.63(m,2H).
实施例18
1-甲基-N-(2-(1-甲基-1H-吲唑-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物18)
Figure PCTCN2021095192-appb-000118
第一步：1-甲基-6-((2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯(18A)
Figure PCTCN2021095192-appb-000119
3-(叔丁氧羰基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酸(中间体3-P2)(200mg,0.829mmol)和HATU(315mg,0.828mmol)在干燥的N,N-二甲基甲酰胺(10mL)中室温下搅拌半小时，然后加入2-(1-甲基-1H-吲唑-3-基)丙-2-胺(中间体2)(131mg,0.691mmol)和DIEA(0.5mL)，室温下搅拌过夜。反应液倒入水中，用乙酸乙酯萃取有机相，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥，真空旋干得 到粗品。该粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)分离纯化得1-甲基-6-((2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯18A(122mg，收率：：42.8％，淡黄色油状物)。
MS(ESI):m/z＝413.2[M+H] +.
第二步：1-甲基-N-(2-(1-甲基-1H-吲唑-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物18)
Figure PCTCN2021095192-appb-000120
将1-甲基-6-((2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯18A(122mg,0.296mmol)溶解在盐酸-二噁烷溶液(5mL)中，室温下反应过夜。反应液真空旋除溶剂得到粗品。该粗品经制备型HPLC纯化得到白色固体纯品化合物18(17mg，收率：18.4％)。
MS(ESI):m/z＝313.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.85(d,1H),7.51(d,1H),7.32(t,1H),7.03(t,1H),3.95(s,3H),2.90-2.70(m,3H),2.60-2.52(m,1H),1.66(d,7H),1.39(t,1H),1.24(s,1H),0.97(s,3H).
实施例19
1-甲基-N-(2-(1-甲基-1H-吲唑-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物19)
Figure PCTCN2021095192-appb-000121
第一步：1-甲基-6-((2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯(19A)
Figure PCTCN2021095192-appb-000122
将3-(叔丁氧羰基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酸(中间体3-P1)(200mg,0.829mmol)和HATU(315mg,0.828mmol)在干燥的N,N-二甲基甲酰胺(10mL)中的溶液在室温下搅拌半小时，然后加入2-(1-甲基-1H-吲唑-3-基)丙-2-胺(中间体2)(131mg,0.691mmol)和DIEA(0.5mL)，室温下搅拌过夜。反应液倒入水中，用乙酸乙酯萃取有机相，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥， 真空旋干得到粗品。该粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)分离纯化得1-甲基-6-((2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯19A(110mg，收率：：38.6％，淡黄色油状物)。
MS(ESI):m/z＝413.2[M+H] +.
第二步：1-甲基-N-(2-(1-甲基-1H-吲唑-3-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物19)
Figure PCTCN2021095192-appb-000123
将1-甲基-6-((2-(1-甲基-1H-吲唑-3-基)丙烷-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁基酯19A(110mg,0.267mmol)溶解在盐酸-二噁烷溶液(5mL)中，室温下反应过夜。反应液真空旋除溶剂得到粗品。该粗品经制备型HPLC纯化得到白色固体纯品(化合物19)(22mg，收率：26.4％)。
MS(ESI):M/Z＝313.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.85(d,1H),7.51(d,1H),7.32(t,1H),7.03(t,1H),3.95(s,3H),2.90-2.70(m,3H),2.60-2.52(m,1H),1.66(d,7H),1.39(t,1H),1.24(s,1H),0.97(s,3H).
实施例20
(3aR,5s,6aS)-N-(2-(8-氯咪唑并[1,5-a]吡啶-3-基)丙烷-2-基)八氢环戊二烯并[c]吡咯-5-甲酰胺(化合物20)
Figure PCTCN2021095192-appb-000124
第一步：(1-(((3-氯吡啶-2-基)甲基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁基酯(20B)
Figure PCTCN2021095192-appb-000125
将2-((叔丁氧羰基)氨基)-2-甲基丙酸(1.42g,6.99mmol)和HATU(2.93g,7.71mmol)在干燥四氢呋喃(200mL)中室温下搅拌半小时。然后加入(3-氯吡啶-2-基)甲胺20A(1.0g,7.01mmol)和三乙胺(1.96mL)，室温下搅拌过夜。反应液倒入水中，用乙酸乙酯萃取有机相，合并的有机相经饱和食盐水 洗涤、无水硫酸钠干燥，真空旋干得到黄色油状物粗品。该粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)纯化得纯品20B(2.0g，收率：87.3％)。
MS(ESI):M/Z＝328.1[M+H] +.
第二步：(2-(8-氯咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酸叔丁基酯(20C)
Figure PCTCN2021095192-appb-000126
将(1-(((3-氯吡啶-2-基)甲基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁基酯20B(600mg,3.05mmol)溶解在二氯甲烷(40mL)中，然后加入伯吉斯试剂(2.9g,12.2mmol)，反应在40℃下搅拌过夜。将反应液倒入水中，有机相用二氯甲烷萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥，真空旋干溶剂得(2-(8-氯咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酸叔丁基酯20C(100mg,粗品)。
MS(ESI):M/Z＝310.1[M+H] +
第三步：2-(8-氯咪唑[1,5-a]吡啶-3-基)丙-2-胺盐酸盐(20D)
Figure PCTCN2021095192-appb-000127
(2-(8-氯咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酸叔丁基酯20C(30mg,0.097mmol)在盐酸-乙酸乙酯溶液(20mL)中室温下搅拌过夜。真空旋干溶剂得到2-(8-氯咪唑[1,5-a]吡啶-3-基)丙-2-胺盐酸盐20D(40mg,粗品)。
MS(ESI):M/Z＝210.1[M+H] +.
第四步：(3aR,5s,6aS)-N-(2-(8-氯咪唑并[1,5-a]吡啶-3-基)丙烷-2-基)八氢环戊二烯并[c]吡咯-5-甲酰胺(化合物20)
Figure PCTCN2021095192-appb-000128
将(3aR,5s,6aS)-2-(叔丁氧羰基)八氢环戊二烯并[c]吡咯-5-羧酸3A(37mg,0.145mmol)和HATU(60mg,0.158mmol)在N,N-二甲基甲酰胺(15mL)中室温搅拌半小时。然后加入2-(8-氯咪唑[1,5-a]吡啶-3-基)丙-2-胺盐酸盐20D(30mg,0.143mmol)和三乙胺(0.1mL)，反应在室温下搅拌过夜。反应液真空旋干得粗品(100mg)，该粗品加入甲醇溶液(10mL)中，滴加盐酸-二噁烷溶液(2mL)，室温 下搅拌过夜，真空旋干进一步得到粗品(化合物20)。该粗品经制备型HPLC纯化得到淡黄色油状物(2.27mg，收率：4.59％)。
MS(ESI):m/z＝347.1[M+H] +
1H NMR(400MHz,CDCl 3)δ8.10(d,1H),7.61(s,1H),7.49(m,1H),6.70(d,1H),6.44(t,1H),3.40-3.30(m,2H),3.10-2.90(m,5H),2.00-1.90(m,2H),1.85(s,6H),1.80-1.70(m,2H).
实施例21
(3aR,5s,6aS)-N-(2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺(化合物21)
Figure PCTCN2021095192-appb-000129
第一步：(3-甲氧基吡啶-2-基)甲胺(21B)
Figure PCTCN2021095192-appb-000130
将2-氰基-3-甲氧基吡啶21A(1.4g,10.45mmol)溶于甲醇(50mL)中,加入钯炭(200mg),氢气保护，反应过夜。反应结束后，过滤，取滤液，旋干有机相后得到白色固体，其为(3-甲氧基吡啶-2-基)甲胺21B(0.95g，收率：65.9％)。
MS(ESI):m/z＝139.1[M+H] +.
第二步：(1-(((3-甲氧基吡啶-2-基)甲基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁基酯(21C)
Figure PCTCN2021095192-appb-000131
将2-((叔丁氧基羰基)氨基)-2-甲基丙酸(1.68g,8.26mmol)，HATU(3.14g,8.26mmol)溶于DMF(20mL)中，然后加入(3-甲氧基吡啶-2-基)甲胺21B(0.95g,6.88mmol)和DIEA(2.66g，20.64mmol)，反应1h。反应完毕后，加水(50mL)淬灭，然后用乙酸乙酯(30mL×3)萃取，有机相用50mL饱和NaCl水溶液水洗一次，有机相用无水硫酸钠干燥，抽滤，旋干有机相，得到残留物。残余物用硅胶柱纯化(石油醚：乙酸乙酯＝2：1)得到白色固体，其为(1-(((3-甲氧基吡啶-2-基)甲基)氨基)-2-甲基 -1-氧代丙烷-2-基)氨基甲酸叔丁基酯21C(1.4g,收率：62.9％)。
MS(ESI):m/z＝324.1[M+H] +.
第三步:(2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酸叔丁酯(21D)
Figure PCTCN2021095192-appb-000132
将(1-(((3-甲氧基吡啶-2-基)甲基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁基酯21C(0.6g,1.86mmol)溶解在干燥DCM(10mL)中，加入伯吉斯试剂(0.89g,3.72mmol)，搅拌过夜。反应结束后，加水(40mL)淬灭，用乙酸乙酯(20mL×3)萃取。有机相用50mL饱和NaCl水溶液水洗一次并用无水硫酸钠干燥。抽滤，旋干有机相，得到残留物。残余物用硅胶柱纯化(石油醚：乙酸乙酯＝1：1)得到白色固体(2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酸叔丁酯21D(0.175g，收率：30.9％)。
MS(ESI):m/z＝306.1[M+H] +.
第四步：2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-胺盐酸盐(21E)
Figure PCTCN2021095192-appb-000133
将(2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酸叔丁酯21D(0.05g,0.164mmol)加入4M盐酸的1,4-二噁烷溶液(3mL)中，搅拌30min。反应结束后，真空旋干得到粗品油状物，其为2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-胺盐酸盐21E(0.057g)。
MS(ESI):m/z＝206.1[M+H] +.
第五步：(3aR,5s,6aS)-5-((2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基酯(21F)
Figure PCTCN2021095192-appb-000134
将(3aR,5s,6aS)-2-(叔丁氧羰基)八氢环戊二烯并[c]吡咯-5-羧酸(74.6mg，0.29mmol)和HATU(111mg,0.29mmol)溶于DMF(2mL)中，然后加入2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-胺21E的油状物粗品(0.057g)和DIEA(94mg，0.73mmol)，反应1h。反应完毕后，加水(10mL)淬灭，然后用乙酸乙酯(5mL×3)萃取，有机相用20mL饱和NaCl水溶液水洗一次并用无水硫酸钠干燥。抽滤，旋干有 机相，得到残留物。残余物用制备型薄层色谱法纯化(石油醚：乙酸乙酯＝2：1)得到白色固体，其为(3aR,5s,6aS)-5-((2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基21F(50mg,收率：69.4％)。
MS(ESI):m/z＝443.1[M+H] +.
第六步：(3aR,5s,6aS)-N-(2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺(化合物21)
Figure PCTCN2021095192-appb-000135
向(3aR,5s,6aS)-5-((2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-基)氨基甲酰基)六氢环戊二烯并[c]吡咯-2(1H)-羧酸叔丁基酯21F(50mg,0.069mmol)中加入4M盐酸的1,4-二噁烷溶液(3mL)，搅拌30min。反应结束后，真空旋干，经Pre-HPLC纯化得到(3aR,5s,6aS)-N-(2-(8-甲氧基咪唑并[1,5-a]吡啶-3-基)丙-2-基)八氢环戊二烯并[c]吡咯-5-羧酰胺(化合物21)(25mg，收率：64.66％)。
MS(ESI):m/z＝343.1[M+H] +.
1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.87(d,1H),7.22(s,1H),6.52(t,1H),6.09(d,1H),3.88(s,3H),3.02-2.90(m,2H),2.75(s,1H),2.42(s,2H),2.32-2.20(m,2H),1.63(s,6H),1.60-1.42(m,4H),1.23(s,1H).
实施例22
N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙烷-2-基)-2-(哌啶-4-基)乙酰胺盐酸盐(化合物22)
Figure PCTCN2021095192-appb-000136
第一步：4-(2-((2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯(22A)
Figure PCTCN2021095192-appb-000137
将2-(8-甲基咪唑[1,5-a]吡啶-3-基)丙-2-胺中间体1(120mg，0.53mmol)，1-叔丁氧羰基-哌啶-4-乙酸(141mg，0.58mmol)，HATU(242mg，0.64mmol)和DIPEA(274mg，2.12mmol)溶解在DMF(2mL)中。将该溶液在25℃下搅拌12小时。将混合物用水(10mL)稀释，后用乙酸乙酯(8mL×3)萃取。合并的有机相用盐水(15mL)洗涤，用无水硫酸钠干燥，过滤并在真空下旋干溶剂。粗品通过快速硅胶色 谱纯化(石油醚：乙酸乙酯＝1：1)，得到浅黄色固体22A(170mg，收率：64.6％)。
MS(ESI):M/Z＝415.2[M+H] +.
1H NMR(400MHz,CDCl 3):δ7.99-7.90(m,1H),7.35(s,1H),6.93(s,1H),6.54-6.45(m,2H),2.75-2.65(m,2H),2.42(s,3H),2.16(d,2H),1.98-1.96(m,1H),1.92(s,6H),1.69(s,1H)1.66(s,2H),1.47-1.53(m,1H),1.46(s,9H),1.08-1.21(m,2H).
第二步：N-(2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙烷-2-基)-2-(哌啶-4-基)乙酰胺盐酸盐(化合物22)
Figure PCTCN2021095192-appb-000138
将4-(2-((2-(8-甲基咪唑并[1,5-a]吡啶-3-基)丙烷-2-基)氨基)-2-氧代乙基)哌啶-1-羧酸叔丁酯22A(150mg，0.36mmol)溶解在乙酸乙酯(2mL)中，降温至0℃，再加入盐酸/乙酸乙酯(4M，6mL)后在0℃下搅拌0.5小时。混合物在真空下旋干溶剂后用水(30mL)和乙腈(1mL)稀释，冻干后得到淡黄色固体化合物22(110mg，收率：86.6％)。
MS(ESI):M/Z＝315.2[M+H] +.
1HNMR(400MHz，CD 3OD)：δ8.39(d,1H),8.08(s,1H),7.06-7.15(m,1H),7.03(d,1H),3.29(s,2H),2.82-2.97(m,2H),2.52(s,3H),2.27(d,2H),1.92-2.00(m,1H),1.90(s,6H),1.75-1.72(m,2H),1.36-1.48(m,2H).
采用类似于实施例8的制备方法来合成如下化合物：
Figure PCTCN2021095192-appb-000139
Figure PCTCN2021095192-appb-000140
Figure PCTCN2021095192-appb-000141
测试例：
测试例1、人类生长抑制素IV型受体SSTR4激动剂活性测定
试验目的：利用Cell-based human SSTR4 cAMP测定法测定待测化合物对SSTR4受体的激动作用。
细胞培养及试剂配制：细胞株：Flp-In-CHO-SSTR4稳转株(stable pool)；完全培养基:Ham's F-12K+10％FBS+1x青霉素-链霉素(PS)+600μg/ml潮霉素B；细胞接种培养基:Ham's F-12K+10％FBS；实验缓冲液:1X HBSS+20mM HEPES+0.1％BSA+500uM IBMX。
试验操作：
Flp-In-CHO-SSTR4 stable pool细胞株培养于完全培养基，于37℃,5％CO 2至70％～90％融合度。
TrypLE消化处理后将细胞重悬于接种培养基中，接种于384孔细胞培养板(384 PE培养板)，每孔接种7,000个细胞，于37℃,5％CO 2培养过夜。
1.配制阳性对照化合物和待测化合物工作液(8X)。
2.取出细胞培养板，室温200g倒置离心5s除去培养基，然后迅速加入15μl实验缓冲液至各实验孔中，室温200g离心5s。
3.加入2.5μl步骤3中稀释好的8X化合物工作液至相应试验孔中，室温200g离心5s，于37℃孵育10min。
4.配制4uM Forskolin工作液(8X)。
5.取出细胞板平衡至室温，然后加入2.5μl步骤6中配制好的8 X Forskolin工作液至相应试验孔中，200g,RT,5s，于37℃，静置30min。
6.冻融Eu-cAMP示踪剂和Uliaght-抗cAMP，用检测缓冲液将Eu-cAMP示踪剂稀释50倍，将Uliaght-抗cAMP稀释150倍。
7.加入10μl Eu-cAMP示踪剂至所有实验孔中，然后加入10μl检测缓冲液至NC孔中，加入10μl Uliaght-抗cAMP至其余实验孔中。
8.将反应板于室温200g离心30s，25℃静置1h后，利用Envision收集数据
数据分析
1)Z’因子＝1-3*(SD Max+SD Min)/(平均 Max-平均 Min)
2)CV Max＝(SD Max/平均 Max)*100％
3)CV Min＝(SD Min/平均 Min)*100％
4)S/B＝信号/背景
5)媒剂对照(Min)：测定缓冲液
6)阳性对照(Max):1,000nM Somatostatin 14
7)利用GraphPad非线性拟合公式计算化合物EC 50:
Y＝底部+(顶部-底部)/(1+10^((LogEC 50-X)*HillSlope))
X:化合物浓度log值；Y:HTRF比例
表1、人类生长抑制素IV型受体SSTR4激动剂活性测定结果
化合物编号 SSTR4,EC 50(nM)
阳性对照化合物 0.58
化合物1 2.0
化合物2 41.88
化合物3 0.4
化合物4 0.58
化合物5 8.21
化合物6 123.6
化合物7 0.37
化合物8 0.14
化合物12 0.70
化合物13 0.46
化合物15 0.46
化合物17 2.93
化合物18 0.16
化合物20 2.80
化合物21 2.53
化合物22 28.33
化合物23 65.26
化合物24 109.20
化合物25 0.40
化合物26 5.15
化合物27 76.33
化合物28 51.70
化合物29 165.40
结论：本发明化合物具有明显的人类生长制剂素IV型受体SSTR4激动活性。
测试例2、肝微粒体代谢稳定性
在37℃下分别用汇集的人类肝微粒体和雄性大鼠肝微粒体分析测试化合物的代谢降解。
最终的培育反应体系溶液中含有磷酸缓冲液(pH 7.4)、阳性对照化合物(右美沙芬)或测试化合物 (200μM,1.5μL)和肝微粒体(0.5mg/mL,238.5μL)。在37℃预培育5分钟后，添加NADPH(5mM，60μL)开始反应。在固定时间点(0,5,15,30,60min)取样固定体积的反应混合物(30μL)至溶液中以淬灭反应。在离心(4000rpm,15min)后，取上清液(100μL)与蒸馏水(100μL)混合，然后进行LC-MS/MS分析以测试化合物的量。通过一级反应动力学方程(C t＝C 0×e -ket，T 1/2＝Ln2/ke)计算出半衰期。
表2、人类肝微粒体和雄性大鼠肝微粒体分析测试结果
Figure PCTCN2021095192-appb-000142
结论：本发明化合物在肝微粒体中有较好的代谢稳定性。
测试例3、药代动力学评价
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠口服和静脉注射给予受试化合物后不同时刻血浆中的药物浓度。研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
试验动物：
每个化合物使用6只健康成年SD(Sprague-Dawley)大鼠，雄性，分成口服和静脉给药组，每组3只，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2008-0016。
药物配制：
称取一定量药物溶于5％二甲基乙酰胺(DMA)+5％聚乙二醇-15羟基硬脂酸酯(solutol)+90％盐溶液配置成0.2mg/mL溶液。
给药：
SD大鼠禁食过夜后口服和静脉注射给药。
试验操作：
向大鼠口服和静脉注给予受试化合物。于给药后0.083,0.25,0.5,1,2,4,8和24小时由颌下静脉或其他合适血管采血0.2mL，置于K2-EDTA试管中，然后储存于冰上。在一小时内，于2-8℃温度下、6800g离心6分钟分离血浆，于-80℃保存，进行LC/MS/MS分析，大鼠在给药后4小时进食。
表3、大鼠药代动力学参数
Figure PCTCN2021095192-appb-000143
Figure PCTCN2021095192-appb-000144
结论：本发明化合物的药代吸收良好。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (63)

  1. 一种具有式(I)结构的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药：
    Figure PCTCN2021095192-appb-100001
    其中，A选自C 6-14芳基、5至14元杂芳基、5至14元杂环基和5至14元环烷基，且A中所述芳基、杂芳基、杂环基和环烷基任选进一步被0至5个R 3取代；其中所述杂芳基和杂环基包含1至4个选自N、O和S的杂原子；
    R 3各自独立地选自-H、-F、-Cl、-Br、-I、羟基、氰基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、-(CH 2) m-烯基、-(CH 2) m-炔基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-O-(CH 2) m-C 3-10碳环基和-O-(CH 2) m-(3至10元杂环基)，所述的杂环基含有1至4个选自N、O和S的杂原子，且R 3中所述的烷基、烷氧基、碳环基或杂环基各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；
    L 1选自单键和-(CR aR b) m-，其中R a和R b各自独立地选自-H和C 1-6烷基；
    L 2选自-NH-和-O-；
    R 1和R 2各自独立地选自-H、C 1-6烷基和C 3-6环烷基，其中R 1和R 2不同时为-H；
    或R 1和R 2一起形成包含0至1个选自-O-、-NR 16-、-SO-和-SO 2-的基团的3至6元饱和环状基团；
    R 16选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、卤素基、羟基、氰基和C 3-6环烷基；
    M选自单键、-(CR cR d) m-和-(CR cR d) mO-，其中R c和R d各自独立地选自-H和C 1-6烷基；
    Q选自如下结构之一：
    Figure PCTCN2021095192-appb-100002
    其中，X 1、X 2和X 3各自独立地选自单键和-(CR eR f) n-；
    X 4选自-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-；
    R 4、R 5、R 6、R 7、R 9、R 10、R e和R f各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环基或杂芳基含有1至4个选自N、O和S的杂原子，且R 4、R 5、R 6、R 7、R 9、R 10、R e、R f中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；
    R 8、R 11、R 12、R 13、R 14、R 15各自独立地选自-H、C 1-6烷基和C 3-6环烷基；
    m、n、p、q每次出现时各自独立地选自0、1、2和3；
    当X 1和X 2同时为单键时，R 4、R 5、R 6、R 7不同时为-H。
  2. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，所述化合物具有式(II)结构：
    Figure PCTCN2021095192-appb-100003
    其中，L 2为-NH-。
  3. 根据权利要求2所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，其具有式(III)结构：
    Figure PCTCN2021095192-appb-100004
    其中，X 1选自单键或-CH 2-。
  4. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，所述化合物具有式(IV)结构：
    Figure PCTCN2021095192-appb-100005
    其中，R 4、R 5、R 6、R 7各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环和杂芳基各自含有1至4个选自N、O和S的杂原子，且R 4、R 5、R 6、R 7中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；
    R 4、R 5、R 6和R 7不同时为-H。
  5. 根据权利要求4所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 4、R 5和R 6各自为-H；
    R 7选自C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环或杂芳基含有1至4个选自N、O和S的杂原子，且R 7中所述的烷基、烷氧基、碳环基、苯基、 杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。
  6. 根据权利要求4所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 5、R 6和R 7各自为-H；
    R 4选自C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基、-(CH 2) m-C 3-10碳环基、-(CH 2) m-(3至10元杂环基)、-(CH 2) m-O-C 3-10碳环基、-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环和杂芳基各自含有1至4个选自N、O和S的杂原子，且R 4中所述的烷基、烷氧基、碳环基、苯基、杂芳基或杂环各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代。
  7. 根据权利要求5所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 7选自C 1-6烷基、C 1-6烷氧基、甲氧基甲基、羟甲基、一氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、苯基、吡啶基、呋喃基、咪唑基和噻唑基；且R 7各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；
    L 1为单键；
    M为单键。
  8. 根据权利要求6所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 4选自C 1-6烷基、甲氧基甲基、羟甲基、一氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环丁氧基、环戊基、四氢呋喃基、苯基、吡啶基、呋喃基、咪唑基和噻唑基，所述的苯基、吡啶基、呋喃基、咪唑基和噻唑基各自独立任选进一步被0至4个选自H、F、Cl、Br、I、羟基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；
    L 1为单键；
    M为单键。
  9. 根据权利要求3所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 6、R 7和R 8各自为-H；
    L 1为单键。
  10. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，具有式(V)结构：
    Figure PCTCN2021095192-appb-100006
    X 3为单键、-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-；
    p、q每次出现时各自独立地选自0、1、2和3。
  11. 根据权利要求10所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    P和q各自为1；
    X 3为-CH 2-；
    R 9、R 10和R 11各自为-H；
    L 1为单键；
    L 2为-NH-；
    M为单键。
  12. 根据权利要求10所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，具有式(VI)结构：
    Figure PCTCN2021095192-appb-100007
    其中，L 2为-NH-。
  13. 根据权利要求10所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 9、R 10、R 11为-H；
    L 1为单键；
    M为单键。
  14. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    X 4选自-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-；
    R 12、R 13、R 14、R 15各自为-H。
  15. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    A选自如下结构之一：
    Figure PCTCN2021095192-appb-100008
  16. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    A选自如下结构之一：
    Figure PCTCN2021095192-appb-100009
  17. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    A选自如下结构之一：
    Figure PCTCN2021095192-appb-100010
  18. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    A选自如下结构之一：
    Figure PCTCN2021095192-appb-100011
  19. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    A选自如下结构之一：
    Figure PCTCN2021095192-appb-100012
  20. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 3各自独立地选自-H、-F、-Cl、-Br、-I、羟基、氰基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、-(CH 2) m-C 3-10碳环基、-O-(CH 2) m-C 3-10碳环基和-O-(CH 2) m-(3至10元杂环基)，所述的杂环含有1至4个选自N、O和S的杂原子，且R 3中所述的烷基、烷氧基、碳环或杂环各自独立任选进一步被0至4个选自H、F、Cl、Br、I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基取代基所取代。
  21. 根据权利要求20所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 3各自独立地选自-H、-F、-Cl、-Br、-I、羟基、氰基、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、环丙基、环丁基和环丙基甲基。
  22. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 1、R 2各自独立地选自C 1-6烷基和C 3-6环烷基；
    或R 1和R 2一起形成包含0至1个选自-O-、-SO-和-SO 2-的基团的3至6元饱和环状基团。
  23. 根据权利要求22所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    R 1、R 2各自独立地选自甲基、乙基、丙基、环丙基和环丁基；
    或R 1和R 2一起形成3元饱和碳环基。
  24. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，
    Q选自如下结构之一：
    Figure PCTCN2021095192-appb-100013
    R 4、R 5、R 6、R 7不同时为-H。
  25. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、 药学上可以接受的盐、多晶型或前药，其特征在于，具有式(V)结构：
    Figure PCTCN2021095192-appb-100014
    其中，A选自C 6-14芳基、5至14元杂芳基、5至14元杂环基和5至14元环烷基，且A中所述芳基、杂芳基、杂环基或环烷基任选进一步被0至5个R 3取代；其中所述杂芳基或杂环基包含1至4个选自N、O和S的杂原子；
    R 3各自独立地选自-H、-F、-Cl、-Br、-I、羟基、氰基、氨基、C 1-4烷基、C 1-4烷氧基和C 1-4烷氧基C 1-4烷基，且R 3中所述的烷基或烷氧基各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；
    R 1、R 2各自独立地选自-H、C 1-6烷基和C 3-6环烷基，其中R 1和R 2不同时为-H；
    或R 1和R 2一起形成3至6元饱和环状基团；
    M选自单键、-(CR cR d) m-和-(CR cR d) mO-，其中R c或R d独立地选自-H和C 1-6烷基；
    Q选自如下结构之一：
    Figure PCTCN2021095192-appb-100015
    其中，X 1，X 2，X 3各自独立地选自单键和-(CR eR f) n-；
    X 4选自-CH 2-、-CH 2CH 2-和-CH 2CH 2CH 2-；
    R 4、R 5、R 6、R 7、R 9、R 10、R e、R f各自独立地选自-H、C 1-6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷基和苯基，且R 4、R 5、R 6、R 7、R 9、R 10、R e、R f中所述的烷基、烷氧基和苯基各自独立任选进一步被0至4个选自-H、-F、-Cl、-Br、-I、羟基、巯基、氰基、氨基、C 1-4烷基和C 1-4烷氧基的取代基所取代；
    R 8、R 11、R 12、R 13、R 14、R 15各自独立地选自-H、C 1-6烷基和C 3-6环烷基；
    m、n、p、q每次出现时各自独立地选自0、1、2和3；
    当X 1，X 2同时为单键时，R 4、R 5、R 6、R 7不同时为-H。
  26. 式(a)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    Figure PCTCN2021095192-appb-100016
    其中，
    Figure PCTCN2021095192-appb-100017
    表示单键或双键，条件是两个
    Figure PCTCN2021095192-appb-100018
    中有且仅有一个表示双键；
    X 1为CR 3’或NR 3；
    X 2为CR 3’或NR 3；
    或者，X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环任选被1-4个R 3’取代；
    R 3选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
    R 4选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；其中所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3；
    s为0、1或2；
    r为0、1或2。
  27. 根据权利要求26的式(a)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    Figure PCTCN2021095192-appb-100019
    表示单键或双键，条件是两个
    Figure PCTCN2021095192-appb-100020
    中有且仅有一个表示双键；
    X 1为CR 3’或NR 3；
    X 2为CR 3’；
    X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环被1-4个R 3’取代；
    R 3选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
    R 4选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3；
    s为0或1；
    r为0或1。
  28. 根据权利要求26的式(a)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    Figure PCTCN2021095192-appb-100021
    表示单键或双键，条件是两个
    Figure PCTCN2021095192-appb-100022
    中有且仅有一个表示双键；
    X 1为CR 3’或NR 3；
    X 2为NR 3；
    X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环被1-4个R 3’取代；
    R 3选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
    R 4选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至 10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3；
    s为0或1；
    r为0或1。
  29. 根据权利要求26的式(a)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    Figure PCTCN2021095192-appb-100023
    表示单键或双键，条件是两个
    Figure PCTCN2021095192-appb-100024
    中有且仅有一个表示双键；
    X 1为CR 3’；
    X 2为NR 3；
    X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环，所述苯环被1-4个R 3’取代；
    R 3选自-H和C 1-6烷基；
    R 3’为C 1-6烷基；
    R 4选自-H和C 1-6烷基；
    R 5选自-H和C 1-6烷基；
    R 1和R 2各自独立地为甲基；
    s为1；
    r为1。
  30. 式(b)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    Figure PCTCN2021095192-appb-100025
    其中，
    Figure PCTCN2021095192-appb-100026
    表示单键或双键，条件是两个
    Figure PCTCN2021095192-appb-100027
    中有且仅有一个表示双键；
    X 1为CR 3’或NR 3；
    X 2为CR 3’或NR 3；
    或者，X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环任选被1-4个R 3’取代；
    R 3选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；其中所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3。
  31. 根据权利要求30的式(b)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    其中，
    Figure PCTCN2021095192-appb-100028
    表示单键或双键，条件是两个
    Figure PCTCN2021095192-appb-100029
    中有且仅有一个表示双键；
    X 1为CR 3’或NR 3；
    X 2为CR 3’；
    X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环被1-4个R 3’取代；
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3。
  32. 根据权利要求30的式(b)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    Figure PCTCN2021095192-appb-100030
    表示单键或双键，条件是两个
    Figure PCTCN2021095192-appb-100031
    中有且仅有一个表示双键；
    X 1为CR 3’或NR 3；
    X 2为NR 3；
    X 1及其取代基与相邻的碳原子及其取代基R 3’一起形成苯环或5-至6-元杂芳环，所述苯环或5-至6-元杂芳环被1-4个R 3’取代；
    R 3选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3。
  33. 式(c)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    Figure PCTCN2021095192-appb-100032
    其中，
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；其中所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基取代；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3；
    t为0、1、2、3、4或5。
  34. 根据权利要求33的式(c)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    R 3’选自卤素、氰基、C 1-6烷基、卤代C 1-6烷基和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R x选自C 1-6烷基、卤代C 1-6烷基和-(CH 2) n-C 3-6碳环基；
    n为0、1、2或3；
    t为0、1或2。
  35. 根据权利要求33的式(c)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    R 3’选自C 1-4烷基和-SR x；
    R 4为C 1-4烷基；
    R 5选自-H和C 1-4烷基；
    R 1和R 2各自独立地选自-H和C 1-4烷基；
    R x选自C 1-4烷基和卤代C 1-4烷基；
    t为1或2。
  36. 根据权利要求33的式(c)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    其中，
    R 3’为C 1-4烷基；
    R 4为C 1-4烷基；
    R 5为-H；
    R 1和R 2各自独立地为甲基；
    t为1。
  37. 式(c-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    Figure PCTCN2021095192-appb-100033
    其中，
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3。
  38. 根据权利要求37的式(c-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢 产物、药学上可以接受的盐、多晶型或前药，其中，
    R 3’选自卤素、C 1-4烷基、卤代C 1-4烷基和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R x选自C 1-6烷基、卤代C 1-6烷基和-(CH 2) n-C 3-6碳环基；
    n为0、1、2或3。
  39. 根据权利要求37的式(c-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    其中，
    R 3’选自C 1-4烷基和-SR x；
    R 4为C 1-4烷基和卤代C 1-4烷基；
    R 5选自-H和C 1-4烷基；
    R x选自C 1-4烷基和卤代C 1-4烷基。
  40. 根据权利要求37的式(c-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    其中，
    R 3’为C 1-4烷基；
    R 4为C 1-4烷基；
    R 5为-H。
  41. 式(d)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    Figure PCTCN2021095192-appb-100034
    其中，
    R 3选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基、-(CH 2) n-(5至6元杂芳基)和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；其中所述烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基任选地被卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6 炔基取代；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3；
    t为0、1、2、3或4。
  42. 根据权利要求41的式(d)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    R 3选自C 1-6烷基和卤代C 1-6烷基；
    R 3’选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 1和R 2各自独立地选自-H、C 1-6烷基和卤代C 1-6烷基；
    R x选自C 1-6烷基、卤代C 1-6烷基和-(CH 2) n-C 3-6碳环基；
    n为0、1、2或3；
    t为0、1或2。
  43. 根据权利要求41的式(d)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    R 3为C 1-4烷基；
    R 3’选自-H、C 1-4烷基和-SR x；
    R 4为C 1-4烷基；
    R 5选自-H和C 1-4烷基；
    R 1和R 2各自独立地选自-H和C 1-4烷基；
    R x选自C 1-4烷基和卤代C 1-4烷基；
    t为0或1。
  44. 根据权利要求41的式(d)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    其中，
    R 3为C 1-4烷基；
    R 3’选自-H和C 1-4烷基；
    R 4为C 1-4烷基；
    R 5为-H；
    R 1和R 2各自独立地为甲基；
    t为0或1。
  45. 式(d-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，
    Figure PCTCN2021095192-appb-100035
    其中，
    R 3选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 3’选自-H、卤素、氰基、-OR、-NR’R”、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基、C 2-6炔基和-SR x；
    R 4选自C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R 5选自-H、C 1-6烷基、卤代C 1-6烷基、C 2-6烯基和C 2-6炔基；
    R选自-H、C 1-6烷基和卤代C 1-6烷基；
    R’和R”各自选自-H、C 1-6烷基和卤代C 1-6烷基，或者R’和R”与它们连接的氮原子一起形成3至10元杂环基；
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) n-C 2-6烯基、-(CH 2) n-C 2-6炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、-(CH 2) n-C 6-10芳基和-(CH 2) n-(5至6元杂芳基)；
    n为0、1、2或3。
  46. 根据权利要求45的式(d-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    R 3选自C 1-6烷基和卤代C 1-6烷基；
    R 3’选自-H、卤素、氰基、C 1-6烷基和卤代C 1-烷基和-SR x；
    R 4选自C 1-6烷基和卤代C 1-6烷基；
    R 5选自-H、C 1-6烷基和卤代C 1-6烷基；
    R x选自C 1-6烷基、卤代C 1-6烷基和-(CH 2) n-C 3-6碳环基；
    n为0、1、2或3。
  47. 根据权利要求45的式(d-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    R 3为C 1-4烷基；
    R 3’选自-H、C 1-4烷基和-SR x；
    R 4为C 1-4烷基；
    R 5选自-H和C 1-4烷基；
    R x选自C 1-4烷基和卤代C 1-4烷基。
  48. 根据权利要求45的式(d-1)化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其中，
    R 3为C 1-4烷基；
    R 3’选自-H和C 1-4烷基；
    R 4为C 1-4烷基；
    R 5为-H。
  49. 根据权利要求1所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，所述化合物选自：
    Figure PCTCN2021095192-appb-100036
  50. 根据权利要求1-49任一项所述的化合物，或其立体异构体、N-氧化物、水合物、溶剂化物、 代谢产物、药学上可以接受的盐、多晶型或前药，其特征在于，所述药学上可以接受的盐选自盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合。
  51. 一种药物组合物，其特征在于，所述药物组合物含有治疗有效剂量的权利要求1-50中任一项所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药，以及药学上可接受的载体或者赋形剂。
  52. 如权利要求1-50中任一项所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或如权利要求51所述的药物组合物，在制备具有治疗和/或预防受SSTR4活化影响的疾病或症状的药物中的应用。
  53. 如权利要求1-50中任一项所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或如权利要求51所述的药物组合物，在制备具有治疗和/或预防疼痛的药物中的应用。
  54. 根据权利要求53所述的应用，其特征在于，所述疼痛为神经痛。
  55. 根据权利要求53所述的应用，其特征在于，所述疼痛为背痛、慢性背痛、三叉神经痛、I型复杂区域疼痛综合征、II型复杂区域疼痛综合征、肠激惹综合征、糖尿病性神经病变、骨关节炎所引起的疼痛、肿瘤疼痛或肌肉纤维疼痛。
  56. 如权利要求1-50中任一项所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或如权利要求51所述的药物组合物，其用于治疗和/或预防受SSTR4活化影响的疾病或症状。
  57. 如权利要求1-50中任一项所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或如权利要求51所述的药物组合物，其用于治疗和/或预防疼痛。
  58. 根据权利要求57所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或权利要求57所述的药物组合物，其特征在于，所述疼痛为神经痛。
  59. 根据权利要求57所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或权利要求57所述的药物组合物，其特征在于，所述疼痛为背痛、慢性背痛、三叉神经痛、I型复杂区域疼痛综合征、II型复杂区域疼痛综合征、肠激惹综合征、糖尿病性神经病变、骨关节炎所引起的疼痛、肿瘤疼痛、肌肉纤维疼痛。
  60. 一种治疗受SSTR4活化影响的疾病或症状的方法，其包括给予如权利要求1-50中任一项所述的化合物或其立体异构体、N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或如权利要求51所述的药物组合物。
  61. 一种治疗疼痛的方法，其包括给予如权利要求1-50中任一项所述的化合物或其立体异构体、 N-氧化物、水合物、溶剂化物、代谢产物、药学上可以接受的盐、多晶型或前药或如权利要求51所述的药物组合物。
  62. 根据权利要求61的方法，其中所述疼痛为神经痛。
  63. 根据权利要求61的方法，其中所述疼痛为背痛、慢性背痛、三叉神经痛、I型复杂区域疼痛综合征、II型复杂区域疼痛综合征、肠激惹综合征、糖尿病性神经病变、骨关节炎所引起的疼痛、肿瘤疼痛、肌肉纤维疼痛。
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