WO2022012534A1 - Nitrogen-containing heterocyclic compound, pharmaceutical composition, and applications - Google Patents

Nitrogen-containing heterocyclic compound, pharmaceutical composition, and applications Download PDF

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WO2022012534A1
WO2022012534A1 PCT/CN2021/106015 CN2021106015W WO2022012534A1 WO 2022012534 A1 WO2022012534 A1 WO 2022012534A1 CN 2021106015 W CN2021106015 W CN 2021106015W WO 2022012534 A1 WO2022012534 A1 WO 2022012534A1
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alkyl
pharmaceutically acceptable
membered
halogenated
stereoisomer
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PCT/CN2021/106015
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French (fr)
Chinese (zh)
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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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    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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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
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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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
    • C07D209/52—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
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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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    • 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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    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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    • C07D513/06—Peri-condensed systems

Definitions

  • the present invention relates to organic compounds, especially nitrogen-containing heterocyclic compounds, pharmaceutical compositions and uses.
  • the somatostatin receptor family (somatostatin receptors, SSTRs) is a family of G protein-coupled receptors that mediate somatostatin and its analogs and have a variety of biological effects. pay attention to. Studies have shown that there are specific membrane receptors on these cell membranes, including SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, which can regulate growth hormone (GH) secretion, induce apoptosis, and inhibit tumor cells through cAMP, PTP and MAPK signaling pathways. It plays an important role in biological processes such as proliferation, inhibition of insulin action, and inhibition of cell growth, and also exhibits 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, and exists in two forms in vivo as 14-peptide (SST-14) and 28-peptide (SST-28).
  • SST-14 14-peptide
  • SST-28 28-peptide
  • SSTRs are structurally similar to other G protein-coupled receptors, with seven transmembrane (TM) ⁇ -helix structures, and N-terminal regions with N-glycosylation sites and palmitoylation sites (except SSTR3). In addition, there is a highly conserved amino acid sequence unique to SSTR in TM7.
  • SSTRs are coupled to a variety of cellular effector systems through G proteins, mainly involving the following four important signaling pathways: one is the cyclic adenylate (cAMP) pathway; the other is the voltage-dependent Ca 2+ pathway; the third is the mitogen The activated protein kinase (mitogen-activated protein kinases, MAPK) pathway; the fourth is the protein tyrosine phosphatase (protein tyrosine phosphatase, PTP) pathway.
  • cAMP cyclic adenylate
  • MAPK mitogen-activated protein kinases
  • PTP protein tyrosine phosphatase
  • SSTR1 is involved in the inhibition of cell growth; in addition to inducing apoptosis, SSTR3 is also involved in the inhibition of GH and insulin release, as well as the processing and regulation of sensory signals and the integration of sensory functions with visceral functions, smell and other sensory functions; SSTR4 also inhibits GH and insulin release, and coordinate extrapyramidal motor and sensory functions; 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 anti-proliferation and induction of tumors. Apoptosis, which is the dominant subtype mediating antitumor effects. These results reveal a close relationship between endocrine and immunity.
  • SSTR4 has come to the forefront as a potential mediator of CNS pathology, inflammation and even pain mechanisms.
  • Targeting SSTR4 has the added advantage of limiting pituitary secretion but not inhibiting glucagon, growth hormone or insulin secretion.
  • SSTR4 is expressed at relatively high levels in the hippocampus and neocortex, memory and learning regions, and Alzheimer's disease pathology.
  • SSTR4 agonists improve learning and memory in rodent models of Alzheimer's disease, which correspond to reduced levels of beta-amyloid.
  • SSTR4 receptor stimulation can dose-dependently enhance cued memory, which may have direct cognitive-enhancing activity.
  • SSTR4 binding to K+ ion channels can modulate hippocampal excitability, which has implications for the treatment of certain forms of epilepsy with SSTR4 agonists. Additionally, the effects of SSTR4 agonists are potent in rodent models of pain associated with acute and chronic associated anti-peripheral nociceptive and anti-inflammatory activity. Recent data show that SRIF released by nociceptors expressed by the capsaicin-sensitive receptor TRPV1 acts on SSTR4 and SSTR2 to produce antinociceptive effects.
  • Pain is the most common and most troublesome symptom in clinical practice, and it is also one of the main reasons for patients to seek medical treatment. 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. At present, the 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 preventing or treating medical conditions associated with SSTR4.
  • SSTR4 agonists with good efficacy, high bioavailability and good solubility.
  • a nitrogen-containing heterocyclic compound which is a class of somatostatin receptor subtype 4 (SSTR4) agonists with novel structure, better efficacy, high bioavailability and better solubility compound.
  • SSTR4 somatostatin receptor subtype 4
  • R 1 is selected from -H, C 1-6 alkyl
  • L 1 is selected from -NH- or -O-;
  • L 2 is selected from a single bond or -(CR a R b ) m -, wherein R a and R b are each independently selected from -H and C 1-6 alkyl;
  • R 2 and R 3 are each independently selected from -H, C 1-6 alkyl, C 3-6 cycloalkyl, or R 2 and R 3 together form 0 to 1 selected from -O-, -NR 9 A 3- to 6-membered saturated cyclic group of a group of -, -SO- and -SO 2 -; wherein R 2 and R 3 are not simultaneously -H;
  • R 4 , R 5 , R 6 , R 7 , R 8 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 carbocyclyl, -(CH 2 ) m -(3- to 10-membered heterocyclyl), -(CH 2 ) m -OC 3-10 carbocyclyl, or -( CH 2 ) m -O-(3- to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl, said heterocyclyl and heteroaryl containing 1 to 4 selected from N, O and S and the alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl described in R 4 , R 5 , R 6 , R 7 , R 8 are each independently optionally further substituted with 0 to 4 substituents selected from -H,
  • R 9 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkyl, halogen, hydroxyl, cyano and C 3-6 cycloalkyl;
  • Ring A is selected from C 9-10 aryl or 9- to 10-membered heteroaryl, 9- to 10-membered heterocyclic group, wherein the heteroaryl and heterocyclic group contain 1 to 4 selected from N, O and S heteroatom;
  • Ring B is selected from 5- to 7-membered rings containing 0, 1 or 2 heteroatoms selected from N, O and S, said 5- to 7-membered rings containing 0, 1 or 2 double atoms bond, the B ring and the A ring share two or three atoms;
  • each R 10 is independently selected from -H, C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl, - (CH 2 ) n -alkenyl, -(CH 2 ) n -alkynyl, -(CH 2 ) n -C 3-10 carbocyclyl, -(CH 2 ) n -(3 to 10 membered heterocyclyl) , C 6-10 aryl and 5- to 6-membered heteroaryl, the heterocyclic and heteroaryl contain 1 to 4 heteroatoms selected from N, O and S, the alkyl, alkoxy group, aryl, heteroaryl, carbocyclyl or heterocyclyl, each independently optionally further selected from 0 to 4 groups selected from -H, halogen, hydroxy, cyano, C1-4alkyl and C1-4alkane substituted by an oxy substituent;
  • n and n are independently selected from 0, 1, 2 and 3, respectively.
  • the A ring has the following structural features:
  • X is independently selected from CR 10 and N;
  • Y is selected from a single bond, N and CR 11 ;
  • R 10 and R 11 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclyl, -(CH 2 ) q -(3 to 10 membered heterocyclyl), -(CH 2 ) q -OC 3-10 carbocyclyl or -(CH 2 ) q -O-(3 to 10-membered heterocyclyl), phenyl or 5- to 6-membered heteroaryl, said heterocyclyl and heteroaryl contain 1 to 4 heteroatoms selected from N, O and S, and R 10 , R 11, said alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl is independently optionally further substituted with 0 to 4 substituents selected -H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino
  • the A ring is selected from one of the following groups:
  • * denotes the attachment site to the parent nucleus; the A ring is optionally further substituted with at least one R 10 .
  • R 10 is methyl
  • Ring A may also be selected from its cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl groups.
  • the nitrogen-containing heterocyclic compound is selected from one of the structural features represented by formulae (I-1) to (I-5):
  • ring B is selected from one of the following groups:
  • W represents an atom shared by ring B and ring A;
  • V 1 is selected from: O, S, NR 12 and CR 12 R 13 ;
  • V 2 is selected from: N and CR 14 ;
  • R 12 , R 13 , R 14 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkyl, -(CH 2 ) p -C 3-10 carbocyclic group, - (CH 2) p - (3 to 10-membered heterocyclic), - (CH 2) p -OC 3-10 carbon ring group or a - (CH 2) p -O -(3 to 10 membered heterocyclyl), phenyl or 5 to 6 membered heteroaryl, said heterocyclyl and heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and R
  • the alkyl, alkoxy, carbocyclic, phenyl, heteroaryl or heterocyclic groups described in 12 , R 13 , R 14 are each independently optionally further 0 to 4 selected from -H, -F, -Cl, -Br, -I, hydroxy, mercapto,
  • R 1 is -H.
  • L 1 is -NH-.
  • L 2 is a single bond.
  • R 2 , R 3 are methyl.
  • R 4 , R 5 , R 6 , R 7 , R 8 are -H.
  • R 4 is methyl
  • R 5 , R 6 , R 7 , R 8 are -H.
  • R 10 is -H or methyl.
  • the B ring is selected from one of the following groups:
  • B ring is optionally further substituted with at least one R 12 .
  • R 12 is methyl
  • ring B may also be selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl thereof.
  • the nitrogen-containing heterocyclic compound has the following structural features:
  • R 1 is selected from -H. In another specific embodiment, R 1 may also be selected from other alkyl groups, or amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl.
  • L 1 is -NH-. In another specific embodiment, L 1 can also be selected from other imino groups, or alkylene groups, alkyleneoxy groups, cycloalkylene groups, arylene groups, heteroarylene groups, heteroalkylene groups and heteroalkylene groups ring base.
  • L 2 is a single bond.
  • L 1 can also be selected from imino, alkylene, alkyleneoxy, cycloalkylene, arylene, heteroarylene, heteroalkylene and heterocyclylene .
  • R 2 and R 3 are methyl groups.
  • R 2 may also be selected from other alkyl groups, or amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl.
  • R 3 may also be selected from other alkyl, or amino, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl heteroalkyl.
  • R 4 , R 5 , R 6 , R 7 , R 8 are -H.
  • R 4 may also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl.
  • R 5 may also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl.
  • R 6 may also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl.
  • R 7 can also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl heteroalkyl.
  • R 8 may also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl heteroalkyl.
  • R 4 is methyl. Further, R 4 is methyl, and R 5 , R 6 , R 7 , and R 8 are -H.
  • R 5 is methyl. Further, R 5 is methyl, and R 4 , R 6 , R 7 , and R 8 are -H.
  • R 10 is -H. In another specific embodiment, R 10 is methyl. In yet another specific embodiment, R 10 may also be selected from other alkyl groups, amino groups, alkoxy groups, cycloalkyl groups, aryl groups, heteroaryl groups, heteroalkyl groups and heterocyclyl groups.
  • the nitrogen-containing heterocyclic compound is selected from one of the following compounds:
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelic acid Salt, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate acid salt, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, mesylate, ethanesulfonate, trifluoromethane Sulfonates or combinations thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the nitrogen-containing heterocyclic compound or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmacy acceptable salts, polymorphs or prodrugs, and pharmaceutically acceptable carriers or excipients.
  • the present invention also provides nitrogen-containing heterocyclic compounds as described above or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof or as described above Use of the pharmaceutical composition described in the manufacture of a medicament for treating and/or preventing diseases or symptoms affected by SSTR4 activation.
  • the present invention also provides nitrogen-containing heterocyclic compounds as described above or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof or as described above Use of the pharmaceutical composition described in the preparation of a medicine for treating and/or preventing pain.
  • the pain is neuralgia.
  • the pain is back pain, chronic back pain, trigeminal neuralgia, complex regional pain syndrome type I, complex regional pain syndrome type II, irritable bowel syndrome, diabetic neuropathy, bone Pain from arthritis, tumor pain, or muscle fiber pain.
  • the present invention has one or more of the following beneficial effects:
  • the nitrogen-containing heterocyclic compound provided by the present invention has an excellent SSTR4 agonistic effect, and can be used as an SSTR4 agonist to prevent and/or prevent and / Or to treat diseases or conditions 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 of various origins.
  • diseases or conditions affected by SSTR4 activation such as Alzheimer's disease and other CNS disorders, such as epilepsy and depression
  • experimental studies have shown that the compounds of the present invention have high metabolic stability, and/or excellent pharmacokinetics, and/or excellent pharmacodynamic effects.
  • Elements involved in the groups and compounds described in the present invention include carbon, hydrogen, oxygen, sulfur, nitrogen or halogen, including their isotopic conditions.
  • the present invention is a group element compound involved and carbon, hydrogen, oxygen, sulfur or nitrogen optionally further substituted with one or more thereof corresponding alternative isotopes, wherein isotopes of carbon include 12 C, 13 C, and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, and sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl, 36 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br .
  • alkyl refers to a saturated straight or branched chain aliphatic hydrocarbon group, specifically a saturated hydrocarbon containing primary (normal) carbon atoms, secondary carbon atoms, tertiary carbon atoms, quaternary carbon atoms, or combinations thereof.
  • C 1 - 6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms, at each occurrence, can be independently of one another are C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl.
  • an alkyl group containing 1 to 20 carbon atoms may be included, preferably an alkyl group containing 1 to 10 carbon atoms, 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 - 1 -propyl (i-Bu, i- butyl, -CH 2 CH (CH 3) 2), 2- butyl (s-Bu, s-butyl, -CH (CH 3) CH 2 CH 3), 2- methyl - propan-2-yl (t-Bu, t-butyl, -C (CH 3) 3) , 1 - pentyl (N- pentyl, -CH 2 CH 2 CH
  • Alkoxy refers to -O-alkyl, wherein alkyl is as defined herein above and preferably is an alkyl group having 1 to 12 carbon atoms.
  • Alkoxy can be substituted or unsubstituted, non-limiting examples of which include, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy Oxygen.
  • Alkoxyalkyl refers to an alkyl group substituted with an alkoxy group as described above. Phrases containing this term, for example, "C 1-6 alkoxy C 1-6 alkyl” means that the alkyl moiety contains from 1 to 6 carbon atoms, and each occurrence may independently be C 1-6 alkoxy base C 1-6 alkyl alkyl, C 2 alkoxy C 1-6 alkyl alkyl, C 3 alkoxy C 1-6 alkyl alkyl, C 4 alkoxy C 1-6 alkyl alkyl group, C 5 alkoxy C 1-6 alkyl alkyl, C 6 alkoxy C 1-6 alkyl alkyl.
  • alkenyl is an alkyl group as defined herein containing 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.
  • alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl or 4-decenyl and the like.
  • Alkynyl is an alkyl group as defined herein containing 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 2-6 carbon atoms.
  • Carbocyclyl or “cycloalkyl” refers to a saturated or partially unsaturated cyclic carbon-containing group.
  • the carbocyclyl group is a 3- to 6-membered monocycle, a 3- to 7-membered monocycle, a 3- to 8-membered monocycle, a 3- to 10-membered monocycle, a 4- to 12-membered bicycle, or a 10-membered monocycle. to the 15-member three-ring system.
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group containing 3 to 6 carbon atoms, and each occurrence may be independently saturated or partially unsaturated C3 cycloalkyl, C4 cycloalkane group, C5 cycloalkyl, C6 cycloalkyl.
  • Carbocycles include bridged or spiro rings.
  • Non-limiting examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, 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 et al. Carbocyclyl groups can be optionally substituted.
  • Heterocyclyl refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing a heteroatom selected from N, O and S.
  • the heterocyclyl group may be a 3- to 8-membered monocycle, a 3- to 7-membered monocycle, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic system, preferably a 3- to 10-membered heterocycle
  • the cyclic group preferably a 5-6 membered heterocyclic group, contains at least one, preferably 1 to 4, more preferably 1 to 2 heteroatoms selected from N, O and S.
  • heteroatom N or S in the heterocycle can be oxidized to various oxidation states to form eg N-oxides.
  • Heterocycles can be attached to other parts of the molecule through heteroatoms or carbon atoms.
  • Heterocycles include bridged or spirocycles.
  • heterocycles include, ethylene oxide, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxa Hexyl, 1,3-dioxane, azacyclohexyl, azacyclopentyl, azacycloheptyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3 -Dithiane, Dihydrofuran, Dihydropyran, Dithialanyl, Tetrahydrofuranyl, Tetrahydropyrrolyl, Dihydropyrrolyl, Tetrahydroimidazolyl, Tetrahydrothiazolyl, Tetrahydropyranyl, Chromodihydrofuran, Dihydrooxazinyl, Dihydropyridyl, Tetrahydropyridyl, Tetrahydrothienyl, Sulfur-oxid
  • Aryl refers to a substituted or unsubstituted all-carbon monocyclic or fused polycyclic unsaturated group having a conjugated pi 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, heterocyclyl, or cycloalkyl group, and the site of attachment to the moiety of the molecule 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 heteroatom selected from N, O, and S.
  • the heteroaryl group is a 5- to 15-membered heteroaryl, a 5- to 14-membered heteroaryl, or preferably a 5- to 10-membered heteroaryl, more preferably a 5- to 7-membered heteroaryl, more preferably is a 5- to 6-membered heteroaryl group, wherein the number of heteroatoms is 1 to 4, preferably 1 to 3, more preferably 1 to 2.
  • heteroaryl groups include pyridyl, furyl, thienyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzofuran, benzimidazole, benzopyridine Or pyrrolopyridine, etc.
  • Heteroalkyl refers to a group in which at least one carbon atom is replaced by a non-carbon atom on the basis of an alkyl group, and the non-carbon atom can be N atom, O atom and/or S atom, etc.
  • the carbon atom attached to the core structure is replaced by a non-carbon atoms in the alkyl group
  • the resulting heteroalkyl respectively alkoxy (e.g., -OCH 3, etc.), alkylamino (e.g., -NHCH 3 , -N (CH 3) 2, etc.) or alkylthio group (e.g., -SCH 3).
  • the resulting heteroalkyl groups are alkyloxy group (e.g., -CH 2 CH 2 -O-CH 3 and the like), alkylamino group (e.g., -CH 2 NHCH 3, -CH 2 N (CH 3) 2 , etc.) or alkylthio group (e.g., -CH 2 -S-CH 3 ).
  • a heteroalkyl group is a non-terminal carbon atom replaced by a carbon atom, the resulting hydroxy group respectively (e.g., -CH 2 CH 2 -OH), amino group (e.g., -CH 2 NH 2), or mercapto alkyl (e.g., -CH 2 CH 2 -SH).
  • Ammonia refers to a derivative of ammonia having the structural features of formula -N(X)2 or formula -NR'R", wherein each of "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.
  • Nonlimiting types of amino include -NH 2, -N (alkyl) 2, -NH (alkyl), - N (cycloalkyl) 2, -NH (cycloalkyl), - N (heterocyclyl) 2 , -NH(heterocyclyl), -N(aryl) 2 , -NH(aryl), -N(alkyl)(aryl), -N(alkyl)(heterocyclyl), -N (cycloalkyl)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), and the like.
  • Halogen means 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 pharmaceutically acceptable salt of a non-toxic acid or base, including salts formed with inorganic acids or bases or salts formed with organic acids and organic bases. 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, triethylamine , tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, Benzoicin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine or polyamine resins; derived from inorganic Salts of acids and organic acids include, but are not limited to, salts with the following acids: sulfuric, phosphoric, nitric, hydrobromic, hydrochloric, formic, acetic,
  • Steps refer to isomers resulting from 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 compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components. Other components such as physiological/pharmaceutically acceptable carriers or excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • Prodrug refers to a substance that can be converted to a biologically active compound of the present invention under physiological conditions or by degradation.
  • the prodrugs of the present invention are prepared by modifying the functional group in the compound, and the modification can be removed according to conventional procedures or removed in vivo to obtain the parent compound.
  • Prodrugs include compounds in which a hydroxyl, amino or sulfhydryl group in the compounds of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group, a free amino group, or a free mercapto 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 with formic acid, acetic acid, or benzoic acid.
  • an aryl group is optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes both instances where the aryl group is substituted with an alkyl group and instances where the aryl group is not substituted with an 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, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents and absorption agents compatible with pharmaceutical administration Delays and the like. Each carrier must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients in the formulation and not injurious 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 beta-cyclodextrins; (3) cellulose and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; Formulations such as cocoa butter and suppository waxes; (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) polyvalent Alcohols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers such as magnesium hydroxide and hydrogen
  • solvate refers to a solvent-bound compound or salt form thereof usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • metabolite refers to a substance including the products of the compounds of the present invention produced during metabolism in vivo, including intermediate metabolites and final metabolites.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the dosage form and administration mode of the compound of the present invention or the pharmaceutical composition thereof are not particularly limited.
  • Representative modes of administration 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 with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, complex silicates and sodium carbonate; (e) solvents, such as paraffin; (f) absorption accelerators, For example, quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate, or with
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms can contain inert diluents (eg, water or other solvents), solubilizers, and emulsifiers conventionally employed 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 a mixture of these substances.
  • compositions can also contain adjuvants such as wetting agents, suspending agents, sweetening, flavoring and perfuming agents.
  • suspensions may contain suspending agents. Specific examples are, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures thereof.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous 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.
  • the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier together with preservatives, buffers and/or propellants as may be required.
  • the present invention relates to a nitrogen-containing heterocyclic compound having the structural features of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable A salt, polymorph or prodrug of:
  • R 1 is selected from -H and C 1-6 alkyl
  • L 1 is selected from -NH- and -O-;
  • L 2 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;
  • R 2 and R 3 are each independently selected from -H, C 1-6 alkyl, C 3-6 cycloalkyl, or R 2 and R 3 together form 0 to 1 selected from -O-, -NR 9 A 3- to 6-membered saturated cyclic group of a group of -, -SO- and -SO 2 -; wherein R 2 and R 3 are not simultaneously -H;
  • R 4 , R 5 , R 6 , R 7 , R 8 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 carbocyclyl, -(CH 2 ) m -(3- to 10-membered heterocyclyl), -(CH 2 ) m -OC 3-10 carbocyclyl, or -( CH 2 ) m -O-(3- to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl, said heterocyclyl and heteroaryl containing 1 to 4 selected from N, O and S and the alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl described in R 4 , R 5 , R 6 , R 7 , R 8 are each independently optionally further substituted with 0 to 4 substituents selected from -H,
  • R 9 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkyl, halogen, hydroxyl, cyano and C 3-6 cycloalkyl;
  • Ring A is selected from C 9-10 aryl, 9 to 10 membered heteroaryl and 9 to 10 membered heterocyclyl, wherein the heteroaryl and heterocyclyl comprise 1 to 4 selected from N, O and S heteroatom;
  • Ring B is a 5- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S, and the 5- to 7-membered ring containing 0, 1 or 2 double bonds , the B ring and the A ring share two or three atoms;
  • each R 10 is independently selected from -H, C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl, - (CH 2 ) n -alkenyl, -(CH 2 ) n -alkynyl, -(CH 2 ) n -C 3-10 carbocyclyl, -(CH 2 ) n -(3 to 10 membered heterocyclyl) , C 6-10 aryl and 5- to 6-membered heteroaryl, the heterocyclic and heteroaryl contain 1 to 4 heteroatoms selected from N, O and S, the alkyl, alkoxy group, aryl, heteroaryl, carbocyclyl or heterocyclyl, each independently optionally further selected from 0 to 4 groups selected from -H, halogen, hydroxy, cyano, C1-4alkyl and C1-4alkane substituted by an oxy substituent;
  • n and n are independently selected from 0, 1, 2 and 3, respectively.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • the medicine is characterized in that the A ring has the following structural features:
  • X is independently selected from CR 10 and N;
  • Y is selected from a single bond, N and CR 11 ;
  • R 10 and R 11 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclyl, -(CH 2 ) q -(3 to 10 membered heterocyclyl), -(CH 2 ) q -OC 3-10 carbocyclyl, -(CH 2 ) q -O-(3 to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl groups, the heterocyclyl and heteroaryl groups contain 1 to 4 heteroatoms selected from N, O and S, and R 10 , R 11, said alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl is independently optionally further substituted with 0 to 4 substituents selected -H, -F, -Cl, -Br, -I, substituted by substituents of hydroxyl,
  • q is selected from 0, 1, 2 and 3.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • medicine characterized in that, One of the groups selected from the structural features shown below:
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • the medicine characterized in that the nitrogen-containing heterocyclic compound is selected from one of the structural features represented by formulae (I-1) to (I-5):
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • medicine is characterized in that, B ring is selected from one of the following groups:
  • W represents an atom shared by ring B and ring A;
  • V 1 is selected from O, S, NR 12 and CR 12 R 13 ;
  • V 2 is selected from N and CR 14;
  • R 12 , R 13 , R 14 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkyl, -(CH 2 ) p -C 3-10 carbocyclic group, - (CH 2) p - (3 to 10-membered heterocyclic), - (CH 2) p -OC 3-10 carbon ring group or a - (CH 2) p -O -(3- to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O and S, and R
  • the alkyl, alkoxy, carbocyclic, phenyl, heteroaryl or heterocyclic groups described in 12 , R 13 , R 14 are each independently optionally further 0 to 4 selected from -H, -F, -Cl, -Br, -I, hydroxyl, mercapto, cyano, amino, C
  • p is selected from 0, 1, 2 and 3.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • medicine characterized in that R 1 is -H.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof medicine, characterized in that L 1 is -NH-.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • medicine characterized in that L 2 is a single bond.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • the medicine is characterized in that R 2 and R 3 are methyl groups.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • a medicine characterized in that R 4 , R 5 , R 6 , R 7 , and R 8 are -H.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • the medicine is characterized in that R 4 is methyl, and R 5 , R 6 , R 7 and R 8 are -H.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • medicine characterized in that R 10 is -H or methyl.
  • the present invention relates to a compound of formula (a), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
  • X 1 is C or N
  • X 2 is C or N
  • R 15 and R 16 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; alternatively, R 16 and R 17 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S;
  • the carbocyclyl or heterocyclyl can be any Substituted with 1-3 substituents selected from the group consisting of: -H, halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(
  • R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
  • R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
  • R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
  • R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R' and R" are each selected from -H, C 1-6 alkyl and haloC 1-6 alkyl, or R' and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) t -C 2-6 alkenyl, -(CH 2 ) t -C 2-6 alkynyl , -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl and -(CH 2 ) t -C 6-10 aryl 2 ) t- (5- to 6-membered heteroaryl);
  • t 0, 1, 2 or 3.
  • the present invention relates to a compound of formula (a-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro-form thereof medicine,
  • R 15 and R 16 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; the carbocyclyl or heterocyclyl optionally Substituted with 1-3 substituents selected from: -H, halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3 to 10 membered heterocyclyl), -(CH 2 ) t -C 6-10
  • R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
  • R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
  • R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
  • R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R' and R" are each selected from -H, C 1-6 alkyl and haloC 1-6 alkyl, or R' and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) t -C 2-6 alkenyl, -(CH 2 ) t -C 2-6 alkynyl , -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl and -(CH 2 ) t -C 6-10 aryl 2 ) t- (5- to 6-membered heteroaryl);
  • t 0, 1, 2 or 3.
  • the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
  • R 15 and R 16 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S;
  • R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
  • R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl.
  • the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
  • R 15 and R 16 together with the atoms to which they are attached form a 5-6 membered carbocyclyl
  • R 2 and R 3 are each independently selected from H, C 1-4 alkyl and haloC 1-4 alkyl;
  • R 4 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl
  • R 5 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl
  • R 17 is selected from -H and C 1-4 alkyl.
  • the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
  • R 15 and R 16 together with the atoms to which they are attached form a 6-membered carbocyclyl
  • R 2 and R 3 are each independently C 1-4 alkyl, preferably methyl
  • R 4 is C 1-4 alkyl, preferably methyl
  • R 5 is -H
  • R 17 is -H.
  • the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
  • R 16 and R 17 together with the atoms to which they are attached form a 5-6 membered heterocyclyl group containing 1-2 heteroatoms selected from N, O and S;
  • R 2 and R 3 are each independently selected from H, C 1-4 alkyl and haloC 1-4 alkyl;
  • R 4 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl
  • R 5 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl
  • R 15 is selected from -H and C 1-4 alkyl.
  • the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
  • R 16 and R 17 together with the atoms to which they are attached form a 5-membered heterocyclic group containing 1-2 heteroatoms selected from N and O;
  • R 2 and R 3 are each independently C 1-4 alkyl
  • R 4 is selected from H and C 1-4 alkyl
  • R 5 is selected from -H and C 1-4 alkyl
  • R 15 is -H.
  • the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
  • R 16 and R 17 together with the atoms to which they are attached form a 5-membered heterocyclic group containing 1 oxygen heteroatom;
  • R 2 and R 3 are each independently C 1-4 alkyl, preferably methyl
  • R 4 is H
  • R 5 is -H
  • R 15 is -H.
  • the present invention relates to compounds of formula (a-2), (a-3) or (a-4), or stereoisomers, N-oxides, hydrates, solvates, metabolites, A pharmaceutically acceptable salt, polymorph or prodrug,
  • R 15 together with R 16 and the atoms to which they are attached form a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form 5 -7-membered carbocyclyl or 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; the carbocyclyl or heterocyclyl is optionally 1-3 selected from the following Substituent substitution of: -H, halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl, -( CH 2 ) t
  • R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
  • R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
  • R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
  • R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R' and R" are each selected from -H, C 1-6 alkyl and haloC 1-6 alkyl, or R' and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) t -C 2-6 alkenyl, -(CH 2 ) t -C 2-6 alkynyl , -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl and -(CH 2 ) t -C 6-10 aryl 2 ) t- (5- to 6-membered heteroaryl);
  • t 0, 1, 2 or 3.
  • the present invention relates to a compound of formula (a-2), (a-3) or (a-4) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite thereof
  • a product, pharmaceutically acceptable salt, polymorph or prodrug wherein:
  • R 15 together with R 16 and the atoms to which they are attached form a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form 5 -7-membered carbocyclyl or 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S;
  • R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 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.
  • the present invention relates to a compound of formula (a-2), (a-3) or (a-4) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite thereof
  • a product, pharmaceutically acceptable salt, polymorph or prodrug wherein:
  • R 15 and R 16 and the atoms to which they are attached together form a 5-6 membered heterocyclyl group containing 1-2 heteroatoms selected from N, O and S;
  • R 2 and R 3 are each independently selected from H, C 1-4 alkyl and haloC 1-4 alkyl;
  • R 4 is selected from H and C 1-4 alkyl
  • R 5 is selected from H and C 1-4 alkyl
  • R 17 is selected from -H and C 1-4 alkyl.
  • the present invention relates to a compound of formula (a-2), (a-3) or (a-4) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite thereof
  • a product, pharmaceutically acceptable salt, polymorph or prodrug wherein:
  • R 15 and R 16 and the atoms to which they are attached together form a 5-6 membered heterocyclic group containing 1-2 heteroatoms selected from N and O;
  • R 2 and R 3 are each independently C 1-4 alkyl, preferably methyl
  • R 4 is -H
  • R 5 is -H
  • R 17 is -H.
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • Medicine characterized in that the nitrogen-containing heterocyclic compound is selected from one of the following compounds:
  • the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof.
  • Medicine characterized in that 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, citric acid Salt, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, mesylate, ethanesulfonate, trifluoromethanesulfonate acid or a combination thereof.
  • the present invention relates to a pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective dose of the nitrogen-containing heterocyclic compound of the present invention or its stereoisomer, N-oxide , hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, and pharmaceutically acceptable carriers or excipients.
  • the present invention relates to said nitrogen-containing heterocyclic compounds or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof
  • the present invention relates to said nitrogen-containing heterocyclic compounds or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof Use of a medicine or a pharmaceutical composition according to the present invention in the preparation of a medicine for treating and/or preventing pain.
  • the present invention relates to said compounds or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof or as such Invention of the pharmaceutical composition for the treatment and/or prevention of diseases or symptoms affected by SSTR4 activation.
  • the present invention relates to said compounds or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof or as such Invention of the pharmaceutical composition for treating and/or preventing pain.
  • the present invention relates to a method of treating a disease or condition affected by activation of SSTR4, comprising administering a compound of the present invention or a stereoisomer, N-oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs or pharmaceutical compositions according to the invention.
  • the present invention relates to a method of treating pain comprising administering a compound according to the present invention or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable compound thereof Accepted salts, polymorphs or prodrugs or pharmaceutical compositions as described herein.
  • the pain is neuralgia.
  • the pain is back pain, chronic back pain, trigeminal neuralgia, complex regional pain syndrome type I, complex regional pain syndrome type II, irritable bowel syndrome, diabetic neuropathy, osteoarthritis Pain caused by inflammation, tumor pain or muscle fiber pain.
  • An embodiment of the present invention also provides a method for preparing the nitrogen-containing heterocyclic compound, comprising the following steps:
  • the condensation reaction is carried out with compound 1 and compound 2, wherein Q represents a nitrogen protecting group, ⁇ L 1 is -OH or -NH 2 ; R 2 -R 8 , L 2 , A and B are as defined in the specification.
  • the nitrogen protecting group Q is removed from the product of the condensation reaction.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC measurement was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6 mm).
  • 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 for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized by adopting or following methods known in the art, or can be purchased from Biopharma, Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • 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
  • Step 7 3-(tert-butoxycarbonyl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (Intermediate 1-P1 and Intermediate 1-P2)
  • the first step tert-butyl (2-methyl-1-oxo-1-((5,6,7,8-tetrahydroquinolin-8-yl)amino)propan-2-yl)carbamate ( 1B)
  • the first step 7-(2-Bromoethoxy)-1H-indazole (3B)
  • 6-Iodo-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazole 3D (1.5 g, 5.22 mmol), 2-dicyclohexylphosphino-2', 6'-Dimethoxybiphenyl (200 mg, 0.48 mmol), zinc cyanide (1.1 g, 9.38 mmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (223 mg, 0.24 mmol) were dissolved in DMF (15 mL), microwave reaction at 150°C for 2 hours under nitrogen protection.
  • the lyophilized fraction was obtained as a white solid compound (1R,5S,6r)-N-(2-(2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazole- 6-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 3) (1.45 mg, 8.63% yield).
  • the first step 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole 4B
  • reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain 7-bromo-1-((2-(trimethylmethane). Silyl)ethoxy)methyl)-1H-indazole 4B (crude).
  • the reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 1-((2-(trimethylsilyl) Ethoxy)methyl)-7-vinyl-1H-indazole 4C (crude).
  • reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 2-(1-((2-(trimethylmethane). Silyl)ethoxy)methyl)-1H-indazol-7-yl)ethane-1-ol 4D (crude).
  • Cerium trichloride (577 mg, 2.36 mmol) was stirred in dry tetrahydrofuran (6 mL) for 1 hour, cooled to -78°C, 1.3M methyllithium solution (1.8 mL, 2.36 mmol) was added dropwise, stirred for 1 hour, and then A solution of 6,7-dihydropyrrolo[3,2,1-hi]indazole-2-carbonitrile 4I (100 mg, 0.59 mmol) in tetrahydrofuran (2 mL) was added dropwise, slowly warmed to room temperature and stirred for 16 hours.
  • the organic phase was dried over anhydrous sodium sulfate and spun in vacuo to give an oil.
  • the first step 6-((2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-1 -Methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 5A
  • the first step 6-((2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-1 -Methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 6A
  • reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain a crude product.
  • Step 2 7-(3-((tert-butyldimethylsilyl)oxy)-prop-1-yn-1-yl)-1H-indazole 7C
  • the third step 7-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole 7D
  • the reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain the crude product.
  • Cerium trichloride 700 mg, 2.84 mmol was stirred in dry tetrahydrofuran (8 mL) for 1 hour, cooled to -78°C, methyl lithium (2.2 mL, 2.84 mmol, 1.3 M) was added dropwise, and the mixture was stirred for 1 hour. Then a solution of 7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-carbonitrile 7I (130 mg, 0.71 mmol) in tetrahydrofuran (1 mL) was added dropwise, slowly warmed to room temperature and Stir for 16 hours.
  • reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, and anhydrous sodium sulfate Dry and spin to dry in vacuo to obtain the crude product.
  • Test Example 1 Determination of human somatostatin type IV receptor SSTR4 agonist activity
  • a cell-based human SSTR4 cAMP assay was used to determine the agonistic effect of the test compound on the SSTR4 receptor.
  • Cell culture and reagent preparation cell strain: Flp-In-CHO-SSTR4 stable transgenic strain (stable pool);
  • the Flp-In-CHO-SSTR4 stably transformed cell line was cultured in complete medium at 37°C, 5% CO 2 to 70%-90% confluency.
  • the cells were resuspended in the seeding medium, seeded in a 384-well cell culture plate (384PE culture plate), 7,000 cells were seeded 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 wells, centrifuge at 200 g for 5 s at room temperature, and incubate at 37 °C for 10 min.
  • the compounds of the present invention have obvious agonistic activity of human growth hormone type IV receptor SSTR4.
  • Metabolic degradation of test compounds was analyzed using pooled human liver microsomes and male rat liver microsomes, respectively, at 37°C.
  • the final incubation reaction system solution contained phosphate buffer (pH 7.4), positive control compound (dextromethorphan) or test compound (200 ⁇ M, 1.5 ⁇ L) and liver microsomes (0.5 mg/mL, 238.5 ⁇ L).
  • NADPH 5 mM, 60 ⁇ L
  • a fixed volume of the reaction mixture (30 ⁇ L) was sampled into solution at fixed time points (0, 5, 15, 30, 60 min) to quench the reaction. After centrifugation (4000 rpm, 15 min), the supernatant (100 ⁇ L) was taken and mixed with distilled water (100 ⁇ L) and then subjected to LC-MS/MS analysis to test the amount of compound.
  • the compounds of the present invention have good metabolic stability in liver microsomes.
  • LC/MS/MS method was used to determine the drug concentrations in plasma at different times after oral and intravenous injection of test compounds in rats.
  • the pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.
  • DMA dimethylacetamide
  • solutol polyethylene glycol-15 hydroxystearate
  • Test compounds are administered orally and intravenously to rats.
  • 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 at 2-8°C for 6 minutes, stored at -80°C for LC/MS/MS analysis, and the rats were fed 4 hours after administration.
  • the mechanical allodynia method was used to evaluate the efficacy of oral administration (PO) of compounds in a rat model of chronic compression injury (CCI) pain of the sciatic nerve.
  • Sprague-Dawley rats 30 males, divided into 3 groups, were purchased from Shanghai Slack Laboratory Animal Co., Ltd.
  • the experimental animals were adaptively reared for 3 to 7 days before modeling.
  • the entire surgical procedure was performed aseptically, and surgical instruments (scissors, forceps, scalpels, surgical cotton, sutures) were sterilized before surgery.
  • sutai 50 20mg/kg + xylazine 8mg/kg intraperitoneal injection, 2mL/kg
  • squeeze the animal's toes to confirm that the animal has been completely anesthetized
  • apply ophthalmic ointment to the animal's eyes to prevent the animal's cornea dry.
  • the animal's waist operation area was shaved, and the skin was disinfected three times with iodophor and 70% ethanol, and the operation was started after the skin was dry.
  • the left sciatic nerve was isolated, and four ligatures were ligated with 4-0 chrome catgut approximately 7 mm upstream of the sciatic nerve bifurcation, approximately 1 mm apart, and the wound was sutured.
  • animals were placed on an electric blanket and injected subcutaneously with 5 mL of normal saline to prevent dehydration. After the animals are fully awake (free to move), return the animals to their cages.

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Abstract

Related are a nitrogen-containing heterocyclic compound, a pharmaceutical composition, and applications. The nitrogen-containing heterocyclic compound has the structural features of formula (I). The nitrogen-containing heterocyclic compound is a somatostatin receptor subtype 4 (sstr4) agonist compound having a novel structure, improved efficacy, high bioavailability, and improved solubility.

Description

含氮杂环化合物、药物组合物和应用Nitrogen-containing heterocyclic compounds, pharmaceutical compositions and applications 技术领域technical field
本发明涉及有机化合物，特别是含氮杂环化合物、药物组合物和应用。The present invention relates to organic compounds, especially nitrogen-containing heterocyclic compounds, pharmaceutical compositions and uses.
背景技术Background technique
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并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，同时还表现出与其它G蛋白偶联受体性质相似的动力学特征。The somatostatin receptor family (somatostatin receptors, SSTRs) is a family of G protein-coupled receptors that mediate somatostatin and its analogs and have a variety of biological effects. pay attention to. Studies have shown that there are specific membrane receptors on these cell membranes, including SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, which can regulate growth hormone (GH) secretion, induce apoptosis, and inhibit tumor cells through cAMP, PTP and MAPK signaling pathways. It plays an important role in biological processes such as proliferation, inhibition of insulin action, and inhibition of cell growth, and also exhibits kinetic characteristics similar to those of other G protein-coupled receptors.
生长抑素(somatostatin，SST)是一种广泛分布于中枢神经***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。Somatostatin (SST) is a cyclic polypeptide widely distributed in the central nervous system and surrounding tissues, and exists in two forms in vivo as 14-peptide (SST-14) and 28-peptide (SST-28). Previous studies have shown that SST as a signaling molecule is mediated by the SST receptor family on the cell membrane. There are only 2 forms of SST. The complexity of SST physiological function is reflected by the complexity of receptors. Therefore, the biological significance of SSTR is more important than that of SST to some extent. SSTRs are structurally similar to other G protein-coupled receptors, with seven transmembrane (TM) α-helix structures, and N-terminal regions with N-glycosylation sites and palmitoylation sites (except SSTR3). In addition, there is a highly conserved amino acid sequence unique to SSTR in TM7.
SSTRs通过G蛋白与多种细胞效应***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***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。 SSTRs are coupled to a variety of cellular effector systems through G proteins, mainly involving the following four important signaling pathways: one is the cyclic adenylate (cAMP) pathway; the other is the voltage-dependent Ca 2+ pathway; the third is the mitogen The activated protein kinase (mitogen-activated protein kinases, MAPK) pathway; the fourth is the protein tyrosine phosphatase (protein tyrosine phosphatase, PTP) pathway.
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，其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。SSTR1 is involved in the inhibition of cell growth; in addition to inducing apoptosis, SSTR3 is also involved in the inhibition of GH and insulin release, as well as the processing and regulation of sensory signals and the integration of sensory functions with visceral functions, smell and other sensory functions; SSTR4 also inhibits GH and insulin release, and coordinate extrapyramidal motor and sensory functions; 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 anti-proliferation and induction of tumors. Apoptosis, which is the dominant subtype mediating antitumor effects. These results reveal a close relationship between endocrine and immunity.
在这五种受体中，SSTR4作为中枢神经***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***中，SSTR4在海马体和新皮质、记忆和学***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***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。 Among these five receptors, SSTR4 has come to the forefront as a potential mediator of CNS pathology, inflammation and even pain mechanisms. Targeting SSTR4 has the added advantage of limiting pituitary secretion but not inhibiting glucagon, growth hormone or insulin secretion. In the central nervous system, SSTR4 is expressed at relatively high levels in the hippocampus and neocortex, memory and learning regions, and Alzheimer's disease pathology. Recent studies have indeed shown that SSTR4 agonists improve learning and memory in rodent models of Alzheimer's disease, which correspond to reduced levels of beta-amyloid. In addition, the study also found that SSTR4 receptor stimulation can dose-dependently enhance cued memory, which may have direct cognitive-enhancing activity. Other studies have shown that SSTR4 binding to K+ ion channels can modulate hippocampal excitability, which has implications for the treatment of certain forms of epilepsy with SSTR4 agonists. Additionally, the effects of SSTR4 agonists are potent in rodent models of pain associated with acute and chronic associated anti-peripheral nociceptive and anti-inflammatory activity. Recent data show that SRIF released by nociceptors expressed by the capsaicin-sensitive receptor TRPV1 acts on SSTR4 and SSTR2 to produce antinociceptive effects.
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。Pain is the most common and most troublesome symptom in clinical practice, and it is also one of the main reasons for patients to seek medical treatment. 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. At present, the 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. Although many patients can benefit from existing analgesics, these drugs only provide adequate relief of symptoms in a quarter of patients. In addition, existing drugs usually have problems such as low tolerance, large toxic and side effects, poor long-term safety, potential drug abuse, and inconvenience in use, making patients urgently in need of safer and more effective analgesics. The use of SSTR4 agonists for analgesia has received more and more attention, and the development of new SSTR4 agonists has broad application prospects and is also urgently needed.
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。CN105473574A discloses the following compound of formula (I), which is an agonist of SSTR4 and is suitable for preventing or treating medical conditions associated with SSTR4. However, there is still a broad need in the art for SSTR4 agonists with good efficacy, high bioavailability and good solubility.
Figure PCTCN2021106015-appb-000001
Figure PCTCN2021106015-appb-000001
发明内容SUMMARY OF THE INVENTION
基于此，有必要提供一种含氮杂环化合物，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。Based on this, it is necessary to provide a nitrogen-containing heterocyclic compound, which is a class of somatostatin receptor subtype 4 (SSTR4) agonists with novel structure, better efficacy, high bioavailability and better solubility compound.
具体技术方案如下：The specific technical solutions are as follows:
一种具有式(I)结构特征的含氮杂环化合物，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：A nitrogen-containing heterocyclic compound having the structural characteristics of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof :
Figure PCTCN2021106015-appb-000002
Figure PCTCN2021106015-appb-000002
其中，R 1选自-H、C 1-6烷基； Wherein, R 1 is selected from -H, C 1-6 alkyl;
L 1选自-NH-或-O-； L 1 is selected from -NH- or -O-;
L 2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 is selected from a single bond or -(CR a R b ) m -, wherein R a and R b are each independently selected from -H and C 1-6 alkyl;
R 2、R 3各自独立地选自-H、C 1-6烷基、C 3-6环烷基，或R 2和R 3一起形成包含0至1个选自-O-、-NR 9-、-SO-和-SO 2-的基团的3至6元饱和环基；其中R 2和R 3不同时为-H； R 2 and R 3 are each independently selected from -H, C 1-6 alkyl, C 3-6 cycloalkyl, or R 2 and R 3 together form 0 to 1 selected from -O-, -NR 9 A 3- to 6-membered saturated cyclic group of a group of -, -SO- and -SO 2 -; wherein R 2 and R 3 are not simultaneously -H;
R 4、R 5、R 6、R 7、R 8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碳环基或者-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，且R 4、R 5、R 6、R 7、R 8中所述的烷基、烷氧基、碳环基、苯基、杂芳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； R 4 , R 5 , R 6 , R 7 , R 8 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 carbocyclyl, -(CH 2 ) m -(3- to 10-membered heterocyclyl), -(CH 2 ) m -OC 3-10 carbocyclyl, or -( CH 2 ) m -O-(3- to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl, said heterocyclyl and heteroaryl containing 1 to 4 selected from N, O and S and the alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl described in R 4 , R 5 , R 6 , R 7 , R 8 are each independently optionally further substituted with 0 to 4 substituents selected from -H, -F, -Cl, -Br, -I, hydroxyl, mercapto, cyano, amino, C 1-4 alkyl and C 1-4 alkoxy;
R 9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； R 9 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkyl, halogen, hydroxyl, cyano and C 3-6 cycloalkyl;
A环选自C 9-10芳基或9至10元杂芳基、9至10元杂环基，其中所述杂芳基、杂环基包含1至4个选自N、O和S的杂原子； Ring A is selected from C 9-10 aryl or 9- to 10-membered heteroaryl, 9- to 10-membered heterocyclic group, wherein the heteroaryl and heterocyclic group contain 1 to 4 selected from N, O and S heteroatom;
B环选自5至7元环，所述5至7元环含有0、1或2个选自N、O和S的杂原子，所述5至7元环含有0、1或2个双键，所述B环与A环共有两个或三个原子；Ring B is selected from 5- to 7-membered rings containing 0, 1 or 2 heteroatoms selected from N, O and S, said 5- to 7-membered rings containing 0, 1 or 2 double atoms bond, the B ring and the A ring share two or three atoms;
所述A环和B环进一步被1至3个R 10取代，其中R 10各自独立地选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、-(CH 2) n-烯基、-(CH 2) n-炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、C 6-10芳基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，所述的烷基、烷氧基、芳基、杂芳基、碳环基或杂环基各自独立任选进一步被0至4个选自-H、卤素、羟基、氰基、C 1-4烷基和C 1-4烷氧基的取代基所取代； The A ring and the B ring are further substituted by 1 to 3 R 10 , wherein each R 10 is independently selected from -H, C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl, - (CH 2 ) n -alkenyl, -(CH 2 ) n -alkynyl, -(CH 2 ) n -C 3-10 carbocyclyl, -(CH 2 ) n -(3 to 10 membered heterocyclyl) , C 6-10 aryl and 5- to 6-membered heteroaryl, the heterocyclic and heteroaryl contain 1 to 4 heteroatoms selected from N, O and S, the alkyl, alkoxy group, aryl, heteroaryl, carbocyclyl or heterocyclyl, each independently optionally further selected from 0 to 4 groups selected from -H, halogen, hydroxy, cyano, C1-4alkyl and C1-4alkane substituted by an oxy substituent;
m和n分别独立地选自0、1、2和3。m and n are independently selected from 0, 1, 2 and 3, respectively.
在其中一个实施方案中，A环具有如下所示结构特征：In one embodiment, the A ring has the following structural features:
Figure PCTCN2021106015-appb-000003
Figure PCTCN2021106015-appb-000003
其中，X分别独立地选自CR 10和N； wherein X is independently selected from CR 10 and N;
Y选自单键、N和CR 11； Y is selected from a single bond, N and CR 11 ;
R 10、R 11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) q-C 3-10碳环基、-(CH 2) q-(3至10元杂环基)、-(CH 2) q-O-C 3-10碳环基或者-(CH 2) q-O-(3至10元杂环基)、苯基或5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，且R 10、R 11中所述的烷基、烷氧基、碳环基、苯基、杂芳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烷基或C 1-4烷氧基的取代基所取代；q选自0、1、2和3。 R 10 and R 11 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclyl, -(CH 2 ) q -(3 to 10 membered heterocyclyl), -(CH 2 ) q -OC 3-10 carbocyclyl or -(CH 2 ) q -O-(3 to 10-membered heterocyclyl), phenyl or 5- to 6-membered heteroaryl, said heterocyclyl and heteroaryl contain 1 to 4 heteroatoms selected from N, O and S, and R 10 , R 11, said alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl is independently optionally further substituted with 0 to 4 substituents selected -H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 alkyl or C 1-4 alkoxy substituent; q is selected from 0, 1, 2 and 3.
在其中一个具体的实施方案中，A环选自如下基团中的一个：In one of the specific embodiments, the A ring is selected from one of the following groups:
Figure PCTCN2021106015-appb-000004
Figure PCTCN2021106015-appb-000004
其中，*表示与母核的连接位点；A环任选进一步被至少一个R 10取代。 Wherein, * denotes the attachment site to the parent nucleus; the A ring is optionally further substituted with at least one R 10 .
在其中一个具体的实施方案中，R 10为甲基。 In one specific embodiment, R 10 is methyl.
在另外一个具体的实施方案中，A环还可以选自其环烷基、芳基、杂芳基、杂烷基和杂环基。In another specific embodiment, Ring A may also be selected from its cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl groups.
在其中一个具体的实施方案中，
Figure PCTCN2021106015-appb-000005
选自具有如下所示结构特征的基团中的一个： In one specific embodiment,
Figure PCTCN2021106015-appb-000005
One of the groups selected from the structural features shown below:
Figure PCTCN2021106015-appb-000006
Figure PCTCN2021106015-appb-000006
在其中一个具体的实施方案中，
Figure PCTCN2021106015-appb-000007
选自如下基团中的一个： In one specific embodiment,
Figure PCTCN2021106015-appb-000007
One of the following groups:
Figure PCTCN2021106015-appb-000008
Figure PCTCN2021106015-appb-000008
Figure PCTCN2021106015-appb-000009
Figure PCTCN2021106015-appb-000009
在其中一个实施方案中，
Figure PCTCN2021106015-appb-000010
选自具有如下所示结构特征的基团中的一个： In one embodiment,
Figure PCTCN2021106015-appb-000010
One of the groups selected from the structural features shown below:
Figure PCTCN2021106015-appb-000011
Figure PCTCN2021106015-appb-000011
在其中一个实施方案中，所述含氮杂环化合物选自式(I-1)～(I-5)所示结构特征中的一个：In one embodiment, the nitrogen-containing heterocyclic compound is selected from one of the structural features represented by formulae (I-1) to (I-5):
Figure PCTCN2021106015-appb-000012
Figure PCTCN2021106015-appb-000012
在其中一个实施方案中，B环选自如下基团中的一个：In one of these embodiments, ring B is selected from one of the following groups:
Figure PCTCN2021106015-appb-000013
Figure PCTCN2021106015-appb-000013
其中，W表示B环与A环共有的原子；Wherein, W represents an atom shared by ring B and ring A;
V 1选自：O、S、NR 12和CR 12R 13； V 1 is selected from: O, S, NR 12 and CR 12 R 13 ;
V 2选自：N和CR 14； V 2 is selected from: N and CR 14 ;
R 12、R 13、R 14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) p-C 3-10碳环基、-(CH 2) p-(3至10元杂环基)、-(CH 2) p-O-C 3-10碳环基或者-(CH 2) p-O-(3至10元杂环基)、苯基或5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，且R 12、R 13、R 14中所述的烷基、烷氧基、碳环基、苯基、杂芳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；p选自0、1、2或3。 R 12 , R 13 , R 14 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkyl, -(CH 2 ) p -C 3-10 carbocyclic group, - (CH 2) p - (3 to 10-membered heterocyclic), - (CH 2) p -OC 3-10 carbon ring group or a - (CH 2) p -O -(3 to 10 membered heterocyclyl), phenyl or 5 to 6 membered heteroaryl, said heterocyclyl and heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and R The alkyl, alkoxy, carbocyclic, phenyl, heteroaryl or heterocyclic groups described in 12 , R 13 , R 14 are each independently optionally further 0 to 4 selected from -H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 alkyl and C 1-4 alkoxy substituents; p is selected from 0, 1, 2 or 3.
在其中一个实施方案中，R 1为-H。 In one embodiment, R 1 is -H.
在其中一个实施方案中，L 1为-NH-。 In one of these embodiments, L 1 is -NH-.
在其中一个实施方案中，L 2为单键。 In one of these embodiments, L 2 is a single bond.
在其中一个实施方案中，R 2、R 3为甲基。 In one embodiment, R 2 , R 3 are methyl.
在其中一个实施方案中，R 4、R 5、R 6、R 7、R 8为-H。 In one of these embodiments, R 4 , R 5 , R 6 , R 7 , R 8 are -H.
在其中一个实施方案中，R 4为甲基，R 5、R 6、R 7、R 8为-H。 In one embodiment, R 4 is methyl, and R 5 , R 6 , R 7 , R 8 are -H.
在其中一个实施方案中，R 10为-H或甲基。 In one of these embodiments, R 10 is -H or methyl.
在其中一个具体的实施方案中，B环选自如下基团中的一个：In one of the specific embodiments, the B ring is selected from one of the following groups:
Figure PCTCN2021106015-appb-000014
Figure PCTCN2021106015-appb-000014
其中，B环任选进一步被至少一个R 12取代。 wherein the B ring is optionally further substituted with at least one R 12 .
在其中一个具体的实施方案中，R 12为甲基。 In one specific embodiment, R 12 is methyl.
在另外一个具体的实施方案中，B环还可以选自其环烷基、芳基、杂芳基、杂烷基和杂环基。In another specific embodiment, ring B may also be selected from the group consisting of cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl thereof.
在其中一个具体的实施方案中，所述含氮杂环化合物具有如下所示结构特征：In one specific embodiment, the nitrogen-containing heterocyclic compound has the following structural features:
Figure PCTCN2021106015-appb-000015
Figure PCTCN2021106015-appb-000015
在其中一个具体的实施方案中，R 1选自-H。在另外一个具体的实施方案中，R 1还可以选自其它 烷基，或氨基、烷氧基、环烷基、芳基、杂芳基、杂烷基和杂环基。 In one specific embodiment, R 1 is selected from -H. In another specific embodiment, R 1 may also be selected from other alkyl groups, or amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl.
在其中一个具体的实施方案中，L 1为-NH-。在另外一个具体的实施方案中，L 1还可以选自其它亚氨基，或亚烷基、亚烷氧基、亚环烷基、亚芳基、亚杂芳基、亚杂烷基和亚杂环基。 In one specific embodiment, L 1 is -NH-. In another specific embodiment, L 1 can also be selected from other imino groups, or alkylene groups, alkyleneoxy groups, cycloalkylene groups, arylene groups, heteroarylene groups, heteroalkylene groups and heteroalkylene groups ring base.
在其中一个具体的实施方案中，L 2为单键。在另外一个具体的实施方案中，L 1还可以选自亚氨基、亚烷基、亚烷氧基、亚环烷基、亚芳基、亚杂芳基、亚杂烷基和亚杂环基。 In one specific embodiment, L 2 is a single bond. In another specific embodiment, L 1 can also be selected from imino, alkylene, alkyleneoxy, cycloalkylene, arylene, heteroarylene, heteroalkylene and heterocyclylene .
在其中一个具体的实施方案中，R 2、R 3为甲基。在另外一个具体的实施方案中，R 2还可以选自其它烷基，或氨基、烷氧基、环烷基、芳基、杂芳基、杂烷基和杂环基。在另外一个具体的实施方案中，R 3还可以选自其它烷基，或氨基、烷氧基、环烷基、芳基、杂芳基、杂烷基和杂环基。 In one specific embodiment, R 2 and R 3 are methyl groups. In another specific embodiment, R 2 may also be selected from other alkyl groups, or amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl. In another particular embodiment, R 3 may also be selected from other alkyl, or amino, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl heteroalkyl.
在其中一个具体的实施方案中，R 4、R 5、R 6、R 7、R 8为-H。在另外一个具体的实施方案中，R 4还可以选自烷基、氨基、烷氧基、环烷基、芳基、杂芳基、杂烷基和杂环基。在另外一个具体的实施方案中，R 5还可以选自烷基、氨基、烷氧基、环烷基、芳基、杂芳基、杂烷基和杂环基。在另外一个具体的实施方案中，R 6还可以选自烷基、氨基、烷氧基、环烷基、芳基、杂芳基、杂烷基和杂环基。在另外一个具体的实施方案中，R 7还可以选自烷基、氨基、烷氧基、环烷基、芳基、杂芳基、杂烷基和杂环基。在另外一个具体的实施方案中，R 8还可以选自烷基、氨基、烷氧基、环烷基、芳基、杂芳基、杂烷基和杂环基。 In one specific embodiment, R 4 , R 5 , R 6 , R 7 , R 8 are -H. In another specific embodiment, R 4 may also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl. In another specific embodiment, R 5 may also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl. In another specific embodiment, R 6 may also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, heteroalkyl and heterocyclyl. In another particular embodiment, R 7 can also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl heteroalkyl. In another particular embodiment, R 8 may also be selected from alkyl, amino, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl heteroalkyl.
在其中一个具体的实施方案中，R 4为甲基。进一步地，R 4为甲基，且R 5、R 6、R 7、R 8为-H。 In one particular embodiment, R 4 is methyl. Further, R 4 is methyl, and R 5 , R 6 , R 7 , and R 8 are -H.
在其中一个具体的实施方案中，R 5为甲基。进一步地，R 5为甲基，且R 4、R 6、R 7、R 8为-H。 In one particular embodiment, R 5 is methyl. Further, R 5 is methyl, and R 4 , R 6 , R 7 , and R 8 are -H.
在其中一个具体的实施方案中，R 10为-H。在另外一个具体的实施方案中，R 10为甲基。在又一个具体的实施方案中，R 10还可以选自其它烷基、氨基、烷氧基、环烷基、芳基、杂芳基、杂烷基和杂环基。 In one specific embodiment, R 10 is -H. In another specific embodiment, R 10 is methyl. In yet another specific embodiment, R 10 may also be selected from other alkyl groups, amino groups, alkoxy groups, cycloalkyl groups, aryl groups, heteroaryl groups, heteroalkyl groups and heterocyclyl groups.
在其中一个实施方案中，所述的含氮杂环化合物选自如下化合物中的一个：In one of the embodiments, the nitrogen-containing heterocyclic compound is selected from one of the following compounds:
Figure PCTCN2021106015-appb-000016
Figure PCTCN2021106015-appb-000016
在其中一个实施方案中，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、三氟甲磺酸盐或它们的组合。In one of these embodiments, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelic acid Salt, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate acid salt, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, mesylate, ethanesulfonate, trifluoromethane Sulfonates or combinations thereof.
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剂量的所述的含氮杂环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。The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the nitrogen-containing heterocyclic compound or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmacy acceptable salts, polymorphs or prodrugs, and pharmaceutically acceptable carriers or excipients.
本发明还提供如上所述的含氮杂环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。The present invention also provides nitrogen-containing heterocyclic compounds as described above or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof or as described above Use of the pharmaceutical composition described in the manufacture of a medicament for treating and/or preventing diseases or symptoms affected by SSTR4 activation.
本发明还提供如上所述的含氮杂环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。The present invention also provides nitrogen-containing heterocyclic compounds as described above or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof or as described above Use of the pharmaceutical composition described in the preparation of a medicine for treating and/or preventing pain.
在其中一个实施方案中，所述疼痛为神经痛。In one of these embodiments, the pain is neuralgia.
在其中一个实施方案中，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、肿瘤疼痛或肌肉纤维疼痛。In one embodiment, the pain is back pain, chronic back pain, trigeminal neuralgia, complex regional pain syndrome type I, complex regional pain syndrome type II, irritable bowel syndrome, diabetic neuropathy, bone Pain from arthritis, tumor pain, or muscle fiber pain.
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：Compared with the prior art, the present invention has one or more of the following beneficial effects:
本发明提供的含氮杂环化合物，通过在母核结构引入特定的A环和B环组成的并环结构，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/或优异的药代动力学、和/或优异的药效学作用。The nitrogen-containing heterocyclic compound provided by the present invention has an excellent SSTR4 agonistic effect, and can be used as an SSTR4 agonist to prevent and/or prevent and / Or to treat diseases or conditions 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 of various origins. In addition, experimental studies have shown that the compounds of the present invention have high metabolic stability, and/or excellent pharmacokinetics, and/or excellent pharmacodynamic effects.
附图说明Description of drawings
图1.化合物在大鼠CCI疼痛模型中的药效学研究测试结果。Figure 1. Results of pharmacodynamic studies testing of compounds in the rat CCI pain model.
具体实施方式detailed description
以下结合具体实施例对本发明的含氮杂环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。The nitrogen-containing heterocyclic compound of the present invention and its preparation method, pharmaceutical composition and application will be further described in detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the present disclosure will be provided.
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。Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art. The terms used herein in the specification are for the purpose of describing particular embodiments only and are not intended to limit the present invention. As used herein, the term "and/or" means any and all combinations of one or more of the associated listed items.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的元素包括碳、氢、氧、硫、氮或卤素均包括它们的同位素情况。进一步，本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 19F，氯的同位素包括 35Cl、 36Cl和 37Cl，溴的同位素包括 79Br和 81Br。 Elements involved in the groups and compounds described in the present invention include carbon, hydrogen, oxygen, sulfur, nitrogen or halogen, including their isotopic conditions. Further, the present invention is a group element compound involved and carbon, hydrogen, oxygen, sulfur or nitrogen optionally further substituted with one or more thereof corresponding alternative isotopes, wherein isotopes of carbon include 12 C, 13 C, and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, and sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl, 36 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br .
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、i-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)、1-己基(-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。 The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group, specifically a saturated hydrocarbon containing primary (normal) carbon atoms, secondary carbon atoms, tertiary carbon atoms, quaternary carbon atoms, or combinations thereof. The term phrases comprising, for example, "C 1 - 6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, at each occurrence, can be independently of one another are C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl. In one of these embodiments, an alkyl group containing 1 to 20 carbon atoms may be included, preferably an alkyl group containing 1 to 10 carbon atoms, 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 - 1 -propyl (i-Bu, i- butyl, -CH 2 CH (CH 3) 2), 2- butyl (s-Bu, s-butyl, -CH (CH 3) CH 2 CH 3), 2- methyl - propan-2-yl (t-Bu, t-butyl, -C (CH 3) 3) , 1 - pentyl (N- pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3), 2- pentyl (-CH (CH3) CH2CH2CH3), 3- pentyl (-CH (CH 2 CH 3) 2) , 2-methyl-butan-2-yl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-but-2-yl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-Methyl-butan-1-yl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-but-1-yl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1 - Hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), Hexyl-2-yl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), Hexyl-3-yl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-pent-2-yl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-pent-2-yl (-CH (CH 3) CH ( CH 3) CH 2 CH 3), 4- methyl - 2-pentyl (-CH (CH 3) CH 2 CH (CH 3) 2), 3- methyl - Pent-3-yl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-pent-3-yl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2, 3-dimethylamino - but-2-yl (-C (CH 3) 2 CH (CH 3) 2), 3,3- dimethyl - butan-2-yl (-CH (CH 3) C ( CH 3 ) 3 , octyl (-(CH 2 ) 7 CH 3 ) and n-nonyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent Preferably from 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano and amino.
“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。 "Alkoxy" refers to -O-alkyl, wherein alkyl is as defined herein above and preferably is an alkyl group having 1 to 12 carbon atoms. The term phrases comprising, for example, "C 1-4 alkoxy" refers to a -O- moiety comprises an alkyl group having 1 to 4 carbon atoms. At each occurrence, C 1-4 alkoxy may independently of one another be C 1 alkoxy, C 2 alkoxy, C 3 alkoxy, C 4 alkoxy. Alkoxy can be substituted or unsubstituted, non-limiting examples of which include, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy Oxygen. When substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano and amino.
“烷氧基烷基”指与被如上所述烷氧基取代的烷基。包含该术语的短语，例如，“C 1-6烷氧基C 1-6烷基”是指烷基部分包含1～6个碳原子，每次出现时，可以互相独立地为C 1烷氧基C 1-6烷基烷基、C 2烷氧基C 1-6烷基烷基、C 3烷氧基C 1-6烷基烷基、C 4烷氧基C 1-6烷基烷基、C 5烷氧基C 1-6烷基烷基、C 6烷氧基C 1-6烷基烷基。烷氧基烷基可以是取代的或未取代的，其非限制性实施例包括，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，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。 "Alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group as described above. Phrases containing this term, for example, "C 1-6 alkoxy C 1-6 alkyl" means that the alkyl moiety contains from 1 to 6 carbon atoms, and each occurrence may independently be C 1-6 alkoxy base C 1-6 alkyl alkyl, C 2 alkoxy C 1-6 alkyl alkyl, C 3 alkoxy C 1-6 alkyl alkyl, C 4 alkoxy C 1-6 alkyl alkyl group, C 5 alkoxy C 1-6 alkyl alkyl, C 6 alkoxy C 1-6 alkyl alkyl. Alkoxyalkyl groups may be substituted or unsubstituted, non-limiting examples of which include, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl , propoxyethyl, isopropoxymethyl, butoxypropyl, tert-butoxyethyl, pentoxyethyl, hexyloxyethyl, cyclopropoxymethyl, cyclopropoxy ethyl, cyclopropoxypropyl or cyclohexyloxymethyl; when substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkane group, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano and amino.
“烯基”是本发明定义的烷基中包含至少一个碳-碳双键。在其中一个实例中，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。"Alkenyl" is an alkyl group as defined herein containing at least one carbon-carbon double bond. In one example, 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. Non-limiting examples of alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl or 4-decenyl and the like. When substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano and amino.
“炔基”是本发明定义的烷基中包含至少一个碳-碳叁键。在其中一个实例中，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。"Alkynyl" is an alkyl group as defined herein containing at least one carbon-carbon triple bond. In one example, 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 2-6 carbon atoms. Non-limiting examples of alkynyl groups include substituted or unsubstituted ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentynyl , 3-pentynyl, 2-hexynyl, 3-hexynyl, 3-butynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3 -nonynyl or 4-decynyl, etc., when substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, Alkynyl, alkoxy, hydroxyl, nitro, cyano and amino.
“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7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***。例如，“C 3～C 6环烷基”是指包含3～6个碳原子的环烷基，每次出现时，可以互相独立地为饱和或部分不饱和的C3环烷基、C4环烷基、C5环烷基、C6环烷基。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、环庚基、环戊烯基、环己烯基、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。 "Carbocyclyl" or "cycloalkyl" refers to a saturated or partially unsaturated cyclic carbon-containing group. In one embodiment, the carbocyclyl group is a 3- to 6-membered monocycle, a 3- to 7-membered monocycle, a 3- to 8-membered monocycle, a 3- to 10-membered monocycle, a 4- to 12-membered bicycle, or a 10-membered monocycle. to the 15-member three-ring system. For example, "C 3 -C 6 cycloalkyl" refers to a cycloalkyl group containing 3 to 6 carbon atoms, and each occurrence may be independently saturated or partially unsaturated C3 cycloalkyl, C4 cycloalkane group, C5 cycloalkyl, C6 cycloalkyl. Carbocycles include bridged or spiro rings. Non-limiting examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, 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 et al. Carbocyclyl groups can be optionally substituted. When substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro group, cyano group and amino group.
“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、3至7元的单环、4至12元双环或者10至15元三环***，优选3至10元杂环基，优选5-6元杂环基，且包含至少一个，优选1至4个，更优选1至2个选自N、O和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、1,3-二氧杂己环、氮杂环己基、氮杂环戊基、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、二氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并二氢呋喃、二氢噁嗪基、二氢吡啶基、四氢吡啶基、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。"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing a heteroatom selected from N, O and S. In one of these embodiments, the heterocyclyl group may be a 3- to 8-membered monocycle, a 3- to 7-membered monocycle, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic system, preferably a 3- to 10-membered heterocycle The cyclic group, preferably a 5-6 membered heterocyclic group, contains at least one, preferably 1 to 4, more preferably 1 to 2 heteroatoms selected from N, O and S. The heteroatom N or S in the heterocycle can be oxidized to various oxidation states to form eg N-oxides. Heterocycles can be attached to other parts of the molecule through heteroatoms or carbon atoms. Heterocycles include bridged or spirocycles. Non-limiting examples of heterocycles include, ethylene oxide, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxa Hexyl, 1,3-dioxane, azacyclohexyl, azacyclopentyl, azacycloheptyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3 -Dithiane, Dihydrofuran, Dihydropyran, Dithialanyl, Tetrahydrofuranyl, Tetrahydropyrrolyl, Dihydropyrrolyl, Tetrahydroimidazolyl, Tetrahydrothiazolyl, Tetrahydropyranyl, Chromodihydrofuran, Dihydrooxazinyl, Dihydropyridyl, Tetrahydropyridyl, Tetrahydrothienyl, Sulfur-oxidized Tetrahydrothienyl, Tetrahydroquinolinyl, Tetrahydroisoquinolinyl, Dihydro Indolyl, etc.; when substituted, the substituents are preferably 1 to 5 and independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro group, cyano group and amino group.
“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；所述芳基可以与杂芳基、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。"Aryl" refers to a substituted or unsubstituted all-carbon monocyclic or fused polycyclic unsaturated group having a conjugated pi electron system. In one of these embodiments, 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, heterocyclyl, or cycloalkyl group, and the site of attachment to the moiety of the molecule is on the aryl group. Non-limiting examples of aryl groups include benzofuran, benzocyclopentyl, or benzothiazole, and the like. When the aryl group is substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro group, cyano group and amino group.
“杂芳基”是指取代或未取代的且含有至少一个选自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，更优选为5至7元杂芳基，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。"Heteroaryl" refers to a substituted or unsubstituted monocyclic or fused polycyclic unsaturated group containing at least one heteroatom selected from N, O, and S. In one of these embodiments, the heteroaryl group is a 5- to 15-membered heteroaryl, a 5- to 14-membered heteroaryl, or preferably a 5- to 10-membered heteroaryl, more preferably a 5- to 7-membered heteroaryl, more preferably is a 5- to 6-membered heteroaryl group, wherein the number of heteroatoms is 1 to 4, preferably 1 to 3, more preferably 1 to 2. Non-limiting examples of heteroaryl groups include pyridyl, furyl, thienyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzofuran, benzimidazole, benzopyridine Or pyrrolopyridine, etc. When heteroaryl is substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, Nitro, cyano and amino.
“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)。 "Heteroalkyl" refers to a group in which at least one carbon atom is replaced by a non-carbon atom on the basis of an alkyl group, and the non-carbon atom can be N atom, O atom and/or S atom, etc. For example, if the carbon atom attached to the core structure is replaced by a non-carbon atoms in the alkyl group, the resulting heteroalkyl respectively alkoxy (e.g., -OCH 3, etc.), alkylamino (e.g., -NHCH 3 , -N (CH 3) 2, etc.) or alkylthio group (e.g., -SCH 3). If the carbon atom attached to the core structure is not replaced by a non-carbon atoms in the alkyl group and the hetero atom is embedded within the group, then the resulting heteroalkyl groups are alkyloxy group (e.g., -CH 2 CH 2 -O-CH 3 and the like), alkylamino group (e.g., -CH 2 NHCH 3, -CH 2 N (CH 3) 2 , etc.) or alkylthio group (e.g., -CH 2 -S-CH 3 ). If a heteroalkyl group is a non-terminal carbon atom replaced by a carbon atom, the resulting hydroxy group respectively (e.g., -CH 2 CH 2 -OH), amino group (e.g., -CH 2 NH 2), or mercapto alkyl (e.g., -CH 2 CH 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。 "Amino" refers to a derivative of ammonia having the structural features of formula -N(X)2 or formula -NR'R", wherein each of "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. Nonlimiting types of amino include -NH 2, -N (alkyl) 2, -NH (alkyl), - N (cycloalkyl) 2, -NH (cycloalkyl), - N (heterocyclyl) 2 , -NH(heterocyclyl), -N(aryl) 2 , -NH(aryl), -N(alkyl)(aryl), -N(alkyl)(heterocyclyl), -N (cycloalkyl)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), and the like.
“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。"Halogen" means 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.
“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。"Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a non-toxic acid or base, including salts formed with inorganic acids or bases or salts formed with organic acids and organic bases. 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, triethylamine , tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, Benzoicin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine or polyamine resins; derived from inorganic Salts of acids and organic acids include, but are not limited to, salts with the following acids: sulfuric, phosphoric, nitric, hydrobromic, hydrochloric, formic, acetic, propionic, benzenesulfonic, benzoic, phenylacetic, salicylic, Alginic acid, anthranilic acid, camphoric acid, citric acid, ethylene sulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid acid, malic acid, mandelic acid, mucilic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid, etc.
“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。"Stereoisomers" refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
“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。"Pharmaceutical composition" means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components. Other components such as physiological/pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
“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。"Prodrug" refers to a substance that can be converted to a biologically active compound of the present invention under physiological conditions or by degradation. The prodrugs of the present invention are prepared by modifying the functional group in the compound, and the modification can be removed according to conventional procedures or removed in vivo to obtain the parent compound. Prodrugs include compounds in which a hydroxyl, amino or sulfhydryl group in the compounds of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group, a free amino group, or a free mercapto 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 with formic acid, acetic acid, or benzoic acid.
"任选"或"任选地"意味着随后所描述地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，该说明包括芳基被烷基取代的情形和芳基不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, including where it does or does not occur. For example, "an aryl group is optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes both instances where the aryl group is substituted with an alkyl group and instances where the aryl group is not substituted with an alkyl group.
“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。"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. As used herein, the term "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents and absorption agents compatible with pharmaceutical administration Delays and the like. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not injurious 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 beta-cyclodextrins; (3) cellulose and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; Formulations such as cocoa butter and suppository waxes; (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) polyvalent Alcohols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers such as magnesium hydroxide and hydrogen (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) pharmaceutical formulation other non-toxic compatible substances used in the product.
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、***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。The term "solvate" refers to a solvent-bound compound or salt form thereof usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
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。The term "metabolite" refers to a substance including the products of the compounds of the present invention produced during metabolism in vivo, including intermediate metabolites and final metabolites.
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。The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
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。The dosage form and administration mode of the compound of the present invention or the pharmaceutical composition thereof are not particularly limited.
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。Representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intraperitoneal, intramuscular or subcutaneous) injection and/or topical administration.
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***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、十二烷基硫酸钠，或其混合物。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, complex silicates and sodium carbonate; (e) solvents, such as paraffin; (f) absorption accelerators, For example, quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.
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。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms can contain inert diluents (eg, water or other solvents), solubilizers, and emulsifiers conventionally employed 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 a mixture of these substances. Besides inert diluents, the compositions can also contain adjuvants such as wetting agents, suspending agents, sweetening, flavoring and perfuming agents. For example, suspensions may contain suspending agents. Specific examples are, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures thereof.
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。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous 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.
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。Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier together with preservatives, buffers and/or propellants as may be required.
以下为本发明的实施方案。The following are embodiments of the present invention.
在一个实施方案中，本发明涉及一种具有式(I)结构特征的含氮杂环化合物，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：In one embodiment, the present invention relates to a nitrogen-containing heterocyclic compound having the structural features of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable A salt, polymorph or prodrug of:
Figure PCTCN2021106015-appb-000017
Figure PCTCN2021106015-appb-000017
其中，R 1选自-H和C 1-6烷基； wherein, R 1 is selected from -H and C 1-6 alkyl;
L 1选自-NH-和-O-； L 1 is selected from -NH- and -O-;
L 2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 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;
R 2、R 3各自独立地选自-H、C 1-6烷基、C 3-6环烷基，或R 2和R 3一起形成包含0至1个选自-O-、-NR 9-、-SO-和-SO 2-的基团的3至6元饱和环基；其中R 2和R 3不同时为-H； R 2 and R 3 are each independently selected from -H, C 1-6 alkyl, C 3-6 cycloalkyl, or R 2 and R 3 together form 0 to 1 selected from -O-, -NR 9 A 3- to 6-membered saturated cyclic group of a group of -, -SO- and -SO 2 -; wherein R 2 and R 3 are not simultaneously -H;
R 4、R 5、R 6、R 7、R 8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碳环基或者-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，且R 4、R 5、R 6、R 7、R 8中所述的烷基、烷氧基、碳环基、苯基、杂芳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； R 4 , R 5 , R 6 , R 7 , R 8 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 carbocyclyl, -(CH 2 ) m -(3- to 10-membered heterocyclyl), -(CH 2 ) m -OC 3-10 carbocyclyl, or -( CH 2 ) m -O-(3- to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl, said heterocyclyl and heteroaryl containing 1 to 4 selected from N, O and S and the alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl described in R 4 , R 5 , R 6 , R 7 , R 8 are each independently optionally further substituted with 0 to 4 substituents selected from -H, -F, -Cl, -Br, -I, hydroxyl, mercapto, cyano, amino, C 1-4 alkyl and C 1-4 alkoxy;
R 9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； R 9 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkyl, halogen, hydroxyl, cyano and C 3-6 cycloalkyl;
A环选自C 9-10芳基、9至10元杂芳基和9至10元杂环基，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； Ring A is selected from C 9-10 aryl, 9 to 10 membered heteroaryl and 9 to 10 membered heterocyclyl, wherein the heteroaryl and heterocyclyl comprise 1 to 4 selected from N, O and S heteroatom;
B环为5至7元环，所述5至7元环含有0、1或2个选自N、O和S的杂原子，所述5至7元环含有0、1或2个双键，所述B环与A环共有两个或三个原子；Ring B is a 5- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S, and the 5- to 7-membered ring containing 0, 1 or 2 double bonds , the B ring and the A ring share two or three atoms;
所述A环和B环进一步被1至3个R 10取代，其中R 10各自独立地选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、-(CH 2) n-烯基、-(CH 2) n-炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、C 6-10芳 基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，所述的烷基、烷氧基、芳基、杂芳基、碳环基或杂环基各自独立任选进一步被0至4个选自-H、卤素、羟基、氰基、C 1-4烷基和C 1-4烷氧基的取代基所取代； The A ring and the B ring are further substituted by 1 to 3 R 10 , wherein each R 10 is independently selected from -H, C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl, - (CH 2 ) n -alkenyl, -(CH 2 ) n -alkynyl, -(CH 2 ) n -C 3-10 carbocyclyl, -(CH 2 ) n -(3 to 10 membered heterocyclyl) , C 6-10 aryl and 5- to 6-membered heteroaryl, the heterocyclic and heteroaryl contain 1 to 4 heteroatoms selected from N, O and S, the alkyl, alkoxy group, aryl, heteroaryl, carbocyclyl or heterocyclyl, each independently optionally further selected from 0 to 4 groups selected from -H, halogen, hydroxy, cyano, C1-4alkyl and C1-4alkane substituted by an oxy substituent;
m和n分别独立地选自0、1、2和3。m and n are independently selected from 0, 1, 2 and 3, respectively.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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环具有如下所示结构特征：In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. The medicine is characterized in that the A ring has the following structural features:
Figure PCTCN2021106015-appb-000018
Figure PCTCN2021106015-appb-000018
其中，X分别独立地选自CR 10和N； wherein X is independently selected from CR 10 and N;
Y选自单键、N和CR 11； Y is selected from a single bond, N and CR 11 ;
R 10、R 11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) q-C 3-10碳环基、-(CH 2) q-(3至10元杂环基)、-(CH 2) q-O-C 3-10碳环基、-(CH 2) q-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，且R 10、R 11中所述的烷基、烷氧基、碳环基、苯基、杂芳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； R 10 and R 11 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclyl, -(CH 2 ) q -(3 to 10 membered heterocyclyl), -(CH 2 ) q -OC 3-10 carbocyclyl, -(CH 2 ) q -O-(3 to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl groups, the heterocyclyl and heteroaryl groups contain 1 to 4 heteroatoms selected from N, O and S, and R 10 , R 11, said alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl is independently optionally further substituted with 0 to 4 substituents selected -H, -F, -Cl, -Br, -I, substituted by substituents of hydroxyl, mercapto, cyano, amino, C 1-4 alkyl and C 1-4 alkoxy;
q选自0、1、2和3。q is selected from 0, 1, 2 and 3.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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，
Figure PCTCN2021106015-appb-000019
选自具有如下所示结构特征的基团中的一个： In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. medicine, characterized in that,
Figure PCTCN2021106015-appb-000019
One of the groups selected from the structural features shown below:
Figure PCTCN2021106015-appb-000020
Figure PCTCN2021106015-appb-000020
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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，所述含氮杂环化合物选自式(I-1)～(I-5)所示结构特征中的一个：In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. The medicine, characterized in that the nitrogen-containing heterocyclic compound is selected from one of the structural features represented by formulae (I-1) to (I-5):
Figure PCTCN2021106015-appb-000021
Figure PCTCN2021106015-appb-000021
Figure PCTCN2021106015-appb-000022
Figure PCTCN2021106015-appb-000022
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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，B环选自如下基团中的一个：In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. medicine, is characterized in that, B ring is selected from one of the following groups:
Figure PCTCN2021106015-appb-000023
Figure PCTCN2021106015-appb-000023
其中，W表示B环与A环共有的原子；Wherein, W represents an atom shared by ring B and ring A;
V 1选自O、S、NR 12和CR 12R 13； V 1 is selected from O, S, NR 12 and CR 12 R 13 ;
V 2选自N和CR 14； V 2 is selected from N and CR 14;
R 12、R 13、R 14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) p-C 3-10碳环基、-(CH 2) p-(3至10元杂环基)、-(CH 2) p-O-C 3-10碳环基或者-(CH 2) p-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，且R 12、R 13、R 14中所述的烷基、烷氧基、碳环基、苯基、杂芳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； R 12 , R 13 , R 14 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkyl, -(CH 2 ) p -C 3-10 carbocyclic group, - (CH 2) p - (3 to 10-membered heterocyclic), - (CH 2) p -OC 3-10 carbon ring group or a - (CH 2) p -O -(3- to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O and S, and R The alkyl, alkoxy, carbocyclic, phenyl, heteroaryl or heterocyclic groups described in 12 , R 13 , R 14 are each independently optionally further 0 to 4 selected from -H, -F, -Cl, -Br, -I, hydroxyl, mercapto, cyano, amino, C 1-4 alkyl and C 1-4 alkoxy substituents;
p选自0、1、2和3。p is selected from 0, 1, 2 and 3.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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为-H。 In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. medicine, characterized in that R 1 is -H.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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，L 1为-NH-。 In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof medicine, characterized in that L 1 is -NH-.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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，L 2为单键。 In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. medicine, characterized in that L 2 is a single bond.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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 2、R 3为甲基。 In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. The medicine is characterized in that R 2 and R 3 are methyl groups.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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、R 6、R 7、R 8为-H。 In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. A medicine, characterized in that R 4 , R 5 , R 6 , R 7 , and R 8 are -H.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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为甲基，R 5、R 6、R 7、R 8为-H。 In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. The medicine is characterized in that R 4 is methyl, and R 5 , R 6 , R 7 and R 8 are -H.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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 10为-H或甲基。 In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. medicine, characterized in that R 10 is -H or methyl.
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，In one embodiment, the present invention relates to a compound of formula (a), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
Figure PCTCN2021106015-appb-000024
Figure PCTCN2021106015-appb-000024
其中：in:
X 1为C或N； X 1 is C or N;
X 2为C或N； X 2 is C or N;
Figure PCTCN2021106015-appb-000025
表示单键或双键，条件是两个
Figure PCTCN2021106015-appb-000026
中有且仅有一个表示双键；
Figure PCTCN2021106015-appb-000025
Indicates a single or double bond, provided that both
Figure PCTCN2021106015-appb-000026
There is and only one represents a double bond;
R 15与R 16以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者，R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；所述碳环基或杂环基任选经1-3个选自以下的取代基取代：-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) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基、-(CH 2) t-(5至6元杂芳基)和-SR x； R 15 and R 16 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; alternatively, R 16 and R 17 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; the carbocyclyl or heterocyclyl can be any Substituted with 1-3 substituents selected from the group consisting of: -H, halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t - C 6-10 aryl, -(CH 2 ) t -(5- to 6-membered heteroaryl) and -SR x ;
当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
R 4选自H、C 1-6烷基和卤代C 1-6烷基； R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 5选自H、C 1-6烷基和卤代C 1-6烷基； R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R选自-H、C 1-6烷基和卤代C 1-6烷基； R is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
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' and R" are each selected from -H, C 1-6 alkyl and haloC 1-6 alkyl, or R' and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl;
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) t-C 2-6烯基、-(CH 2) t-C 2-6炔基、-(CH 2) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基和-(CH 2) t-(5至6元杂芳基)； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) t -C 2-6 alkenyl, -(CH 2 ) t -C 2-6 alkynyl , -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl and -(CH 2 ) t -C 6-10 aryl 2 ) t- (5- to 6-membered heteroaryl);
t为0、1、2或3。t is 0, 1, 2 or 3.
在一个实施方案中，本发明涉及式(a-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，In one embodiment, the present invention relates to a compound of formula (a-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro-form thereof medicine,
Figure PCTCN2021106015-appb-000027
Figure PCTCN2021106015-appb-000027
其中：in:
R 15与R 16以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；所述碳环基或杂环基任选经1-3个选自以下的取代基取代：-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) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基、-(CH 2) t-(5至6元杂芳基)和-SR x； R 15 and R 16 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; the carbocyclyl or heterocyclyl optionally Substituted with 1-3 substituents selected from: -H, halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3 to 10 membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl, -(CH 2 ) t -(5- to 6-membered heteroaryl) and -SR x ;
当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
R 4选自H、C 1-6烷基和卤代C 1-6烷基； R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 5选自H、C 1-6烷基和卤代C 1-6烷基； R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R选自-H、C 1-6烷基和卤代C 1-6烷基； R is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
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' and R" are each selected from -H, C 1-6 alkyl and haloC 1-6 alkyl, or R' and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl;
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) t-C 2-6烯基、-(CH 2) t-C 2-6炔基、-(CH 2) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基和-(CH 2) t-(5至6元杂芳基)； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) t -C 2-6 alkenyl, -(CH 2 ) t -C 2-6 alkynyl , -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl and -(CH 2 ) t -C 6-10 aryl 2 ) t- (5- to 6-membered heteroaryl);
t为0、1、2或3。t is 0, 1, 2 or 3.
在一个实施方案中，本发明涉及上述的式(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：In one embodiment, the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
R 15与R 16以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S 的杂原子的5-7元杂环基； R 15 and R 16 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S;
当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基和卤代C 1-6烷基； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基和卤代C 1-6烷基； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
R 4选自H、C 1-6烷基和卤代C 1-6烷基； R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 5选自H、C 1-6烷基和卤代C 1-6烷基。 R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl.
在一个实施方案中，本发明涉及上述的式(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：In one embodiment, the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
R 15与R 16以及它们连接的原子一起形成5-6元碳环基； R 15 and R 16 together with the atoms to which they are attached form a 5-6 membered carbocyclyl;
R 2和R 3各自独立地选自H、C 1-4烷基和卤代C 1-4烷基； R 2 and R 3 are each independently selected from H, C 1-4 alkyl and haloC 1-4 alkyl;
R 4选自-H、C 1-4烷基和卤代C 1-4烷基； R 4 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl;
R 5选自-H、C 1-4烷基和卤代C 1-4烷基； R 5 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl;
R 17选自-H和C 1-4烷基。 R 17 is selected from -H and C 1-4 alkyl.
在一个实施方案中，本发明涉及上述的式(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：In one embodiment, the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
R 15与R 16以及它们连接的原子一起形成6元碳环基； R 15 and R 16 together with the atoms to which they are attached form a 6-membered carbocyclyl;
R 2和R 3各自独立地为C 1-4烷基，优选为甲基； R 2 and R 3 are each independently C 1-4 alkyl, preferably methyl;
R 4为C 1-4烷基，优选为甲基； R 4 is C 1-4 alkyl, preferably methyl;
R 5为-H； R 5 is -H;
R 17为-H。 R 17 is -H.
在一个实施方案中，本发明涉及上述的式(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：In one embodiment, the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
R 16与R 17以及它们连接的原子一起形成含有1-2个选自N、O和S的杂原子的5-6元杂环基； R 16 and R 17 together with the atoms to which they are attached form a 5-6 membered heterocyclyl group containing 1-2 heteroatoms selected from N, O and S;
R 2和R 3各自独立地选自H、C 1-4烷基和卤代C 1-4烷基； R 2 and R 3 are each independently selected from H, C 1-4 alkyl and haloC 1-4 alkyl;
R 4选自-H、C 1-4烷基和卤代C 1-4烷基； R 4 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl;
R 5选自-H、C 1-4烷基和卤代C 1-4烷基； R 5 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl;
R 15选自-H和C 1-4烷基。 R 15 is selected from -H and C 1-4 alkyl.
在一个实施方案中，本发明涉及上述的式(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：In one embodiment, the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
R 16与R 17以及它们连接的原子一起形成含有1-2个选自N和O的杂原子的5元杂环基； R 16 and R 17 together with the atoms to which they are attached form a 5-membered heterocyclic group containing 1-2 heteroatoms selected from N and O;
R 2和R 3各自独立地为C 1-4烷基； R 2 and R 3 are each independently C 1-4 alkyl;
R 4选自H和C 1-4烷基； R 4 is selected from H and C 1-4 alkyl;
R 5选自-H和C 1-4烷基； R 5 is selected from -H and C 1-4 alkyl;
R 15为-H。 R 15 is -H.
在一个实施方案中，本发明涉及上述的式(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：In one embodiment, the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or pro- medicine, which:
R 16与R 17以及它们连接的原子一起形成含有1个氧杂原子的5元杂环基； R 16 and R 17 together with the atoms to which they are attached form a 5-membered heterocyclic group containing 1 oxygen heteroatom;
R 2和R 3各自独立地为C 1-4烷基，优选为甲基； R 2 and R 3 are each independently C 1-4 alkyl, preferably methyl;
R 4为H； R 4 is H;
R 5为-H； R 5 is -H;
R 15为-H。 R 15 is -H.
在一个实施方案中，本发明涉及式(a-2)、(a-3)或(a-4)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，In one embodiment, the present invention relates to compounds of formula (a-2), (a-3) or (a-4), or stereoisomers, N-oxides, hydrates, solvates, metabolites, A pharmaceutically acceptable salt, polymorph or prodrug,
Figure PCTCN2021106015-appb-000028
Figure PCTCN2021106015-appb-000028
其中：in:
R 15与R 16以及它们连接的原子一起形成含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；所述碳环基或杂环基任选经1-3个选自以下的取代基取代：-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) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基、-(CH 2) t-(5至6元杂芳基)和-SR x； R 15 together with R 16 and the atoms to which they are attached form a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form 5 -7-membered carbocyclyl or 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; the carbocyclyl or heterocyclyl is optionally 1-3 selected from the following Substituent substitution of: -H, halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl, -( CH 2 ) t -(5- to 6-membered heteroaryl) and -SR x ;
当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
R 4选自H、C 1-6烷基和卤代C 1-6烷基； R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 5选自H、C 1-6烷基和卤代C 1-6烷基； R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
R选自-H、C 1-6烷基和卤代C 1-6烷基； R is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
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' and R" are each selected from -H, C 1-6 alkyl and haloC 1-6 alkyl, or R' and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl;
R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) t-C 2-6烯基、-(CH 2) t-C 2-6炔基、-(CH 2) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基和-(CH 2) t-(5至6元杂芳基)； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) t -C 2-6 alkenyl, -(CH 2 ) t -C 2-6 alkynyl , -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl and -(CH 2 ) t -C 6-10 aryl 2 ) t- (5- to 6-membered heteroaryl);
t为0、1、2或3。t is 0, 1, 2 or 3.
在一个实施方案中，本发明涉及上述的式(a-2)、(a-3)或(a-4)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：In one embodiment, the present invention relates to a compound of formula (a-2), (a-3) or (a-4) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite thereof A product, pharmaceutically acceptable salt, polymorph or prodrug, wherein:
R 15与R 16以及它们连接的原子一起形成含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基； R 15 together with R 16 and the atoms to which they are attached form a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form 5 -7-membered carbocyclyl or 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S;
当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基和卤代C 1-6烷基； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基和卤代C 1-6烷基； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
R 4选自H和C 1-6烷基； R 4 is selected from H and C 1-6 alkyl;
R 5选自H和C 1-6烷基。 R 5 is selected from H and C 1-6 alkyl.
在一个实施方案中，本发明涉及上述的式(a-2)、(a-3)或(a-4)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：In one embodiment, the present invention relates to a compound of formula (a-2), (a-3) or (a-4) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite thereof A product, pharmaceutically acceptable salt, polymorph or prodrug, wherein:
R 15与R 16以及它们连接的原子一起形成含有1-2个选自N、O和S的杂原子的5-6元杂环基； R 15 and R 16 and the atoms to which they are attached together form a 5-6 membered heterocyclyl group containing 1-2 heteroatoms selected from N, O and S;
R 2和R 3各自独立地选自H、C 1-4烷基和卤代C 1-4烷基； R 2 and R 3 are each independently selected from H, C 1-4 alkyl and haloC 1-4 alkyl;
R 4选自H和C 1-4烷基； R 4 is selected from H and C 1-4 alkyl;
R 5选自H和C 1-4烷基； R 5 is selected from H and C 1-4 alkyl;
R 17选自-H和C 1-4烷基。 R 17 is selected from -H and C 1-4 alkyl.
在一个实施方案中，本发明涉及上述的式(a-2)、(a-3)或(a-4)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：In one embodiment, the present invention relates to a compound of formula (a-2), (a-3) or (a-4) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite thereof A product, pharmaceutically acceptable salt, polymorph or prodrug, wherein:
R 15与R 16以及它们连接的原子一起形成含有1-2个选自N和O的杂原子的5-6元杂环基； R 15 and R 16 and the atoms to which they are attached together form a 5-6 membered heterocyclic group containing 1-2 heteroatoms selected from N and O;
R 2和R 3各自独立地为C 1-4烷基，优选为甲基； R 2 and R 3 are each independently C 1-4 alkyl, preferably methyl;
R 4为-H； R 4 is -H;
R 5为-H； R 5 is -H;
R 17为-H。 R 17 is -H.
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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，所述的含氮杂环化合物选自如下化合物中的一个：In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. Medicine, characterized in that the nitrogen-containing heterocyclic compound is selected from one of the following compounds:
Figure PCTCN2021106015-appb-000029
Figure PCTCN2021106015-appb-000029
在一个实施方案中，本发明涉及上述的含氮杂环化合物，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。In one embodiment, the present invention relates to the aforementioned nitrogen-containing heterocyclic compounds, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof. Medicine, characterized in that 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, citric acid Salt, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, mesylate, ethanesulfonate, trifluoromethanesulfonate acid or a combination thereof.
在一个实施方案中，本发明涉及一种药物组合物，其特征在于，所述药物组合物含有治疗有效剂量的本发明所述的含氮杂环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。In one embodiment, the present invention relates to a pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective dose of the nitrogen-containing heterocyclic compound of the present invention or its stereoisomer, N-oxide , hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, and pharmaceutically acceptable carriers or excipients.
在一个实施方案中，本发明涉及所述的含氮杂环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、多晶型或前药或如本发明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。In one embodiment, the present invention relates to said nitrogen-containing heterocyclic compounds or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof Use of a medicament or a pharmaceutical composition according to the present invention in the manufacture of a medicament for treating and/or preventing diseases or symptoms affected by SSTR4 activation.
在一个实施方案中，本发明涉及所述的含氮杂环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、多晶型或前药或如本发明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。In one embodiment, the present invention relates to said nitrogen-containing heterocyclic compounds or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or pro-forms thereof Use of a medicine or a pharmaceutical composition according to the present invention in the preparation of a medicine for treating and/or preventing pain.
在一个实施方案中，本发明涉及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、多晶型或前药或如本发明所述的药物组合物，其用于治疗和/或预防受SSTR4活化影响的疾病或症状。In one embodiment, the present invention relates to said compounds or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof or as such Invention of the pharmaceutical composition for the treatment and/or prevention of diseases or symptoms affected by SSTR4 activation.
在一个实施方案中，本发明涉及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、多晶型或前药或如本发明所述的药物组合物，其用于治疗和/或预 防疼痛。In one embodiment, the present invention relates to said compounds or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs thereof or as such Invention of the pharmaceutical composition for treating and/or preventing pain.
在一个实施方案中，本发明涉及一种治疗受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、多晶型或前药或如本发明所述的药物组合物。In one embodiment, the present invention relates to a method of treating a disease or condition affected by activation of SSTR4, comprising administering a compound of the present invention or a stereoisomer, N-oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs or pharmaceutical compositions according to the invention.
在一个实施方案中，本发明涉及一种治疗疼痛的方法，其包括给予如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、多晶型或前药或如本发明所述的药物组合物。In one embodiment, the present invention relates to a method of treating pain comprising administering a compound according to the present invention or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable compound thereof Accepted salts, polymorphs or prodrugs or pharmaceutical compositions as described herein.
在一个实施方案中，所述疼痛为神经痛。In one embodiment, the pain is neuralgia.
在一个实施方案中，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、肿瘤疼痛或肌肉纤维疼痛。In one embodiment, the pain is back pain, chronic back pain, trigeminal neuralgia, complex regional pain syndrome type I, complex regional pain syndrome type II, irritable bowel syndrome, diabetic neuropathy, osteoarthritis Pain caused by inflammation, tumor pain or muscle fiber pain.
本发明的实施例还提供所述含氮杂环化合物的制备方法，包括如下步骤：An embodiment of the present invention also provides a method for preparing the nitrogen-containing heterocyclic compound, comprising the following steps:
Figure PCTCN2021106015-appb-000030
Figure PCTCN2021106015-appb-000030
以化合物1和化合物2进行缩合反应，其中Q表示氮保护基，`L 1为-OH或-NH 2；R 2-R 8、L 2、A和B如说明书中所定义。 The condensation reaction is carried out with compound 1 and compound 2, wherein Q represents a nitrogen protecting group, `L 1 is -OH or -NH 2 ; R 2 -R 8 , L 2 , A and B are as defined in the specification.
脱除所述缩合反应的产物中的氮保护基Q。The nitrogen protecting group Q is removed from the product of the condensation reaction.
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。The implementation process and beneficial effects of the present invention are described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of the present case.
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)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<"6> (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS).
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。For MS measurement (Agilent 6120B (ESI) and 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)。The HPLC measurement was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm).
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。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 for thin layer chromatography (TLC) is 0.15mm ~ 0.20mm, and the size of the TLC separation and purification products is 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。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
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，或可购买于毕得医药、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。The known starting materials of the present invention can be synthesized by adopting or following methods known in the art, or can be purchased from Biopharma, Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.
氮气氛是指反应瓶连接一个约1L容积的氮气气球。Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
实施例中无特殊说明，反应在氮气氛下进行。There is no special description in the examples, and the reaction is carried out under nitrogen atmosphere.
实施例中无特殊说明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温。There is no special description in the examples, and the reaction temperature is room temperature.
室温为最适宜的反应温度，为20℃～30℃。Room temperature is the most suitable reaction temperature, which is 20°C to 30°C.
化学合成相关缩写：Abbreviations related to chemical synthesis:
Ac：乙酰基Ac: Acetyl
AcOH：乙酸AcOH: acetic acid
Bn：苄基Bn: benzyl
Boc：叔丁氧羰基Boc: tert-butoxycarbonyl
Bz：苯甲酰基Bz: Benzoyl
DIPEA：二异丙基乙胺DIPEA: Diisopropylethylamine
DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
DCM：二氯甲烷DCM: dichloromethane
DIEA：N,N-二异丙基乙胺DIEA: N,N-Diisopropylethylamine
EA：乙酸乙酯EA: Ethyl acetate
Et：乙基Et: Ethyl
EtOAc：乙酸乙酯EtOAc: ethyl acetate
Et 3N:三乙胺 Et 3 N: triethylamine
HATU：2-(7-氮杂1H-苯并***-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐HATU: 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
HPLC：高效液相色谱HPLC: High Performance Liquid Chromatography
LiHMDS：六甲基二硅基氨基锂LiHMDS: lithium hexamethyldisilazide
Me：甲基Me: methyl
MeLi：甲基锂MeLi: methyl lithium
NMP：N-甲基吡咯烷酮NMP: N-Methylpyrrolidone
Raney-Ni：雷尼镍Raney-Ni: Raney Nickel
NEt3：三乙胺NEt3: Triethylamine
overnight：过夜overnight: overnight
Raney-Ni：雷尼镍Raney-Ni: Raney Nickel
SEM：(三甲基硅)乙氧基甲基SEM: (trimethylsilyl)ethoxymethyl
SEMCl：2-(三甲基甲硅烷基)乙氧基甲基氯化物SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride
SFC：超临界流体色谱法SFC: Supercritical Fluid Chromatography
TBTU：2-(1H-苯并***-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
TEA：三乙胺TEA: Triethylamine
TEMPO：2,2,6,6-四甲基哌啶氧化物TEMPO: 2,2,6,6-Tetramethylpiperidine oxide
THF：四氢呋喃THF: Tetrahydrofuran
TLC：薄层色谱TLC: Thin Layer Chromatography
TFA：三氟乙酸TFA: trifluoroacetic acid
TBAF：四正丁基氟化铵TBAF: Tetra-n-butylammonium fluoride
Burgess’reagent：伯吉斯试剂，CAS No.：29684-56-8Burgess'reagent: Burgess' reagent, CAS No.: 29684-56-8
rt：室温rt: room temperature
h：小时h: hours
合成内容：Synthesized content:
中间体1-P1和中间体1-P2：Intermediate 1-P1 and Intermediate 1-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1-P1和中间体1-P2)3-(tert-Butoxycarbonyl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (Intermediate 1-P1 and Intermediate 1-P2)
Figure PCTCN2021106015-appb-000031
Figure PCTCN2021106015-appb-000031
第一步：1-苄基-3-甲基-1H-吡咯-2,5-二酮1bThe first step: 1-benzyl-3-methyl-1H-pyrrole-2,5-dione 1b
Figure PCTCN2021106015-appb-000032
Figure PCTCN2021106015-appb-000032
将3-甲基呋喃-2,5-二酮1a(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1b(28g，收率：80％)。3-Methylfuran-2,5-dione 1a (20 g, 0.179 mol) and benzylamine (19.1 g, 0.179 mol) were stirred in glacial acetic acid (80 mL) at 100 °C for 4 hours. The solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether:ethyl acetate=10:1) to give 1-benzyl-3-methyl-1H-pyrrole-2,5-dione 1b (28 g, collected as a white solid) rate: 80%).
MS(ESI):m/z＝202.1[M+H] +. 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1cStep 2: 5-benzyl-6a-methyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3- Ethyl carboxylate 1c
Figure PCTCN2021106015-appb-000033
Figure PCTCN2021106015-appb-000033
将1-苄基-3-甲基-1H-吡咯-2,5-二酮1b(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1c(42g,收率： 95％)。1-Benzyl-3-methyl-1H-pyrrole-2,5-dione 1b (28 g, 0.139 mol) and ethyl diazoacetate (48 g, 0.418 mol) were stirred in toluene (100 mL) at 50°C 3 days. The solvent was removed in vacuo. The residue was purified by silica gel column (petroleum ether:ethyl acetate=8:1) to give 5-benzyl-6a-methyl-4,6-dioxo-1,3a,4,5,6,6a as white solid - Hexahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester 1c (42 g, yield: 95%).
MS(ESI):m/z＝316.1[M+H] +. 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1dStep 3: Ethyl 3-benzyl-1-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate 1d
Figure PCTCN2021106015-appb-000034
Figure PCTCN2021106015-appb-000034
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1c(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1d(22g，收率：57.4％)。Ethyl 5-benzyl-6a-methyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylate Ester 1c (14 g, 44.4 mmol) was suspended in toluene (50 mL), the temperature was raised to 200° C. (temperature of the oil bath), and the mixture was stirred for 1 hour. Monitoring by thin layer chromatography showed complete conversion of starting material. 3-pot reactions in parallel. The obtained black viscous residues were combined and purified by silica gel column (petroleum ether:ethyl acetate=30:1) to obtain 3-benzyl-1-methyl-2,4-dioxo-3 as a white solid product - Azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester 1d (22 g, yield: 57.4%).
MS(ESI):m/z＝288.1[M+H] +. 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1eStep 4: 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde 1e
Figure PCTCN2021106015-appb-000035
Figure PCTCN2021106015-appb-000035
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1d(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1e(15g，收率：91％)收率。不用纯化，直接投下一步。3-Benzyl-1-methyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate ethyl ester 1d (22 g, 76.6 mmol) was divided into 2 batches (ie, 11 g×2) were respectively dissolved in dry THF (190 mL×2), and tetrahydroaluminum lithium (5.8 g×2, 153.2 mmol) was added in batches under an ice-water bath, and stirred at room temperature for 18 hours. The reaction solution was quenched with sodium sulfate decahydrate (59.2 g×2, 183.8 mmol) in an ice-water bath. The solid was filtered off, and the filtrate was spin-dried in vacuo to obtain a pale yellow oil crude product, which was 3-benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde 1e (15 g, yield: 91%) yield. No purification is required, and it is directly cast to the next step.
MS(ESI):m/z＝216.1[M+H] +. 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1fStep 5: (3-benzyl-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)methanol 1f
Figure PCTCN2021106015-appb-000036
Figure PCTCN2021106015-appb-000036
将3-苄基-1-甲基-3-氮杂双环[3.1.0]己烷-6-甲醛1e(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1f(10.1g，淡黄色油状物，收率：66.7％)。3-Benzyl-1-methyl-3-azabicyclo[3.1.0]hexane-6-carbaldehyde 1e (15 g, 69.8 mmol) was dissolved in methanol (240 mL), and boron was added in portions under an ice-water bath Sodium hydride (660 mg, 17.4 mmol) was stirred at room temperature for 2 hours. Acetone (30 mL) was slowly added dropwise under an ice-water bath to quench the reaction and stirred for 30 minutes. Spin dry in vacuo to give crude oil. The crude product was purified by silica gel column (dichloromethane:methanol=60:1) to give racemate (3-benzyl-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)methanol 1f (10.1 g, pale yellow oil, yield: 66.7%).
MS(ESI):m/z＝218.1[M+H] +. MS(ESI): m/z=218.1[M+H] + .
将上述得到的10.1克外消旋体化合物1f进行手性拆分，分别得到1f-P1(保留时间较短的化合物)和1f-P2(保留时间较长的化合物)各4.5g。10.1 g of the racemate compound 1f obtained above were subjected to chiral resolution to obtain 4.5 g each of 1f-P1 (compound with shorter retention time) and 1f-P2 (compound with longer retention time).
手性拆分的具体条件如下表所示：The specific conditions for chiral resolution are shown in the following table:
Figure PCTCN2021106015-appb-000037
Figure PCTCN2021106015-appb-000037
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1gThe sixth step: 6-(hydroxymethyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 1g
Figure PCTCN2021106015-appb-000038
Figure PCTCN2021106015-appb-000038
将(3-苄基-1-甲基-3-氮杂双环[3.1.0]己-6-基)甲醇1f-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)。***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1g-P1(3.1g，淡黄色油状物，收率：65.9％)。Dissolve (3-benzyl-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)methanol 1f-P1 (4.5, 20.7 mmol) in methanol (60 mL) and add palladium/charcoal (0.45 g), triethylamine (6.3 g, 62.2 mmol) and di-tert-butyl dicarbonate (6.8 g, 31.1 mmol). A balloon of hydrogen was inserted, the hydrogen was replaced three times, and then stirred at room temperature overnight. After the reaction was completed, the palladium/carbon was filtered off, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=6:1) to obtain tert-butyl 6-(hydroxymethyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate Ester 1 g-P1 (3.1 g, pale yellow oil, yield: 65.9%).
MS(ESI):m/z＝228.1[M+H] +. 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1f-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)。***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1g-P2(3.5g，淡黄色油状物，收率：74.4％)。(3-benzyl-1-methyl-3-azabicyclo[3.1.0]hex-6-yl)methanol 1f-P2 (4.5 g, 20.7 mmol) was dissolved in methanol (60 mL) and palladium/ Charcoal (0.45 g), triethylamine (6.3 g, 62.2 mmol) and di-tert-butyl dicarbonate (6.8 g, 31.1 mmol). A balloon of hydrogen was inserted, the hydrogen was replaced three times, and then stirred at room temperature overnight. After the reaction was completed, the palladium/carbon was filtered off, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by silica gel column (petroleum ether:ethyl acetate=6:1) to obtain tert-butyl 6-(hydroxymethyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate Ester 1 g-P2 (3.5 g, pale yellow oil, yield: 74.4%).
MS(ESI):m/z＝228.1[M+H] +. 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1-P1和中间体1-P2)Step 7: 3-(tert-butoxycarbonyl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (Intermediate 1-P1 and Intermediate 1-P2)
Figure PCTCN2021106015-appb-000039
Figure PCTCN2021106015-appb-000039
将6-(羟甲基)-1-甲基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯1g-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1-P1)(3.0g,收率：90％)。不用纯化直接投到下一步。6-(Hydroxymethyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 1 g-P1 (3.1 g, 13.7 mmol) was dissolved in acetonitrile (30 mL) To this, 2,2,6,6-tetramethylpiperidine nitroxide (TEMPO) (0.13 g, 0.819 mmol) and 18% aqueous sodium chlorite (18 mL) were added at room temperature. After stirring for 5 minutes, a 10% sodium hypochlorite aqueous solution (2 mL was dissolved in 20 mL of water, 12 mL was taken) was added dropwise, and the mixture was stirred at room temperature overnight. Extract with ethyl acetate (40 mL×2), dry the organic phase with anhydrous sodium sulfate, and spin dry in vacuo to obtain an oily substance, which is 3-(tert-butoxycarbonyl)-1-methyl-3-azabicyclo[3.1 .0] Hexane-6-carboxylic acid (Intermediate 1-P1) (3.0 g, yield: 90%). It was directly sent to the next step without purification.
MS(ESI):m/z＝242.1[M+H] +. 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). 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1g-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1-P2)(3.3g,收率：81％)，不用纯化直接投到下一步。6-(Hydroxymethyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 1 g-P2 (3.5 g, 15.4 mmol) was dissolved in acetonitrile (35 mL) To this, 2,2,6,6-tetramethylpiperidine nitroxide (0.144 g, 0.925 mmol) and 18% aqueous sodium chlorite (21 mL) were added at room temperature. After stirring for 5 minutes, a 10% aqueous sodium hypochlorite solution (2 mL was dissolved in 20 mL of water, 14 mL was taken) was added dropwise, and the mixture was stirred at room temperature overnight. Extract with ethyl acetate (40 mL×2), dry the organic phase with anhydrous sodium sulfate, and spin dry in vacuo to obtain an oily substance, which is 3-(tert-butoxycarbonyl)-1-methyl-3-azabicyclo[3.1 .0] Hexane-6-carboxylic acid (Intermediate 1-P2) (3.3 g, yield: 81%), which was directly sent to the next step without purification.
MS(ESI):m/z＝242.1[M+H] +. 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). 1 HNMR (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).
实施例1Example 1
(1R,5S,6r)-N-(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物1)(1R,5S,6r)-N-(2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-yl)-3- Azabicyclo[3.1.0]hexane-6-carboxamide (Compound 1)
Figure PCTCN2021106015-appb-000040
Figure PCTCN2021106015-appb-000040
第一步：(2-甲基-1-氧代-1-((5,6,7,8-四氢喹啉-8-基)氨基)丙烷-2-基)氨基甲酸叔丁酯(1B)The first step: tert-butyl (2-methyl-1-oxo-1-((5,6,7,8-tetrahydroquinolin-8-yl)amino)propan-2-yl)carbamate ( 1B)
Figure PCTCN2021106015-appb-000041
Figure PCTCN2021106015-appb-000041
将5,6,7,8-四氢喹啉-8-胺1A(500mg,3.38mmol)溶解在DMF(5mL)中，加入2-((叔丁氧羰基)氨基)-2-甲基丙酸(686mg,3.38mmol)、DIEA(872mg,6.76mmol)和HATU(1.93g,5.07mmol)，室温反应8小时。向反应液里加入乙酸乙酯(50mL)，用饱和食盐水(25mL×3)洗涤有机相并用无水硫酸钠干燥。过滤，浓缩，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1～1:3)得到白色固体状的化合物(2-甲基-1-氧代-1-((5,6,7,8-四氢喹啉-8-基)氨基)丙烷-2-基)氨基甲酸叔丁酯1B(950mg，产率84.4％)。5,6,7,8-Tetrahydroquinolin-8-amine 1A (500 mg, 3.38 mmol) was dissolved in DMF (5 mL), 2-((tert-butoxycarbonyl)amino)-2-methylpropane was added Acid (686 mg, 3.38 mmol), DIEA (872 mg, 6.76 mmol) and HATU (1.93 g, 5.07 mmol) were reacted at room temperature for 8 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the organic phase was washed with saturated brine (25 mL×3) and dried over anhydrous sodium sulfate. Filtration and concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1～1:3) to obtain compound (2-methyl-1-oxo- tert-Butyl 1-((5,6,7,8-tetrahydroquinolin-8-yl)amino)propan-2-yl)carbamate 1B (950 mg, 84.4% yield).
MS(ESI):m/z＝334.0[M+H] +. MS(ESI): m/z=334.0[M+H] + .
第二步：(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)氨基甲酸叔丁酯(1C)The second step: tert-butyl (2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-yl)carbamate (1C)
Figure PCTCN2021106015-appb-000042
Figure PCTCN2021106015-appb-000042
将(2-甲基-1-氧代-1-((5,6,7,8-四氢喹啉-8-基)氨基)丙烷-2-基)氨基甲酸叔丁酯1B(750mg,2.25mmol)溶于DCE(10mL)中，加入伯吉斯试剂(1.15g,4.50mmol)，80℃反应16小时。将反应混合物加入水(50mL)中，分液，水相用DCM(20mL×2)萃取，合并有机相。有机相用无水硫酸钠干燥，蒸发，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:3～1:10)得到白色固体状的化合物(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)氨基甲酸叔丁酯1C(200mg，产率29.6％)。(2-Methyl-1-oxo-1-((5,6,7,8-tetrahydroquinolin-8-yl)amino)propan-2-yl)carbamic acid tert-butyl ester 1B (750 mg, 2.25 mmol) was dissolved in DCE (10 mL), Burgess reagent (1.15 g, 4.50 mmol) was added, and the reaction was carried out at 80° C. for 16 hours. The reaction mixture was added to water (50 mL), and the layers were separated. The aqueous phase was extracted with DCM (20 mL×2), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, evaporated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:3～1:10) to obtain compound (2-( 8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-yl)carbamate tert-butyl ester 1C (200 mg, 29.6% yield).
MS(ESI):m/z＝316.1[M+H] +. MS(ESI): m/z=316.1[M+H] + .
第三步：2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-胺(1D)Step 3: 2-(8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-amine (1D)
Figure PCTCN2021106015-appb-000043
Figure PCTCN2021106015-appb-000043
(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)氨基甲酸叔丁酯1C(200mg，0.63mmol)溶于盐酸二氧六环溶液(2mL)中，室温反应1小时。将反应混合物过滤，滤饼用乙酸乙酯淋洗得到绿色固体状的化合物2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-胺1D(100mg，产率73.3％)。(2-(8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-yl)carbamate 1C (200 mg, 0.63 mmol) in In a solution of hydrochloric acid in dioxane (2 mL), the reaction was carried out at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was rinsed with ethyl acetate to give compound 2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propane as a green solid -2-amine 1D (100 mg, 73.3% yield).
MS(ESI):m/z＝216.0[M+H] +. MS(ESI): m/z=216.0[M+H] + .
第四步：(1R,5S,6r)-6-((2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-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(1F)The fourth step: (1R,5S,6r)-6-((2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propane-2- yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester (1F)
Figure PCTCN2021106015-appb-000044
Figure PCTCN2021106015-appb-000044
将2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-胺1D(100mg,0.24mmol)溶于DMF(1mL)中，室温下加入(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-羧酸1E(55mg,0.24mmol)、DIEA(62mg,0.48mmol)和HATU(137mg,0.36mmol)，室温搅拌反应8小时。向反应液中加入乙酸乙酯(30mL)，用饱和食盐水(10mL×3)洗涤，浓缩。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1～1:3)得到 白色固体状的化合物(1R,5S,6r)-6-((2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-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1F(180mg,产率91.3％)。2-(8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-amine 1D (100 mg, 0.24 mmol) was dissolved in DMF (1 mL) , (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1E (55mg, 0.24mmol), DIEA (62mg, 0.48 mmol) and HATU (137 mg, 0.36 mmol), and the reaction was stirred at room temperature for 8 hours. Ethyl acetate (30 mL) was added to the reaction solution, washed with saturated brine (10 mL×3), and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1～1:3) to obtain compound (1R,5S,6r)-6-((2-( 8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane -3-Carboxylic acid tert-butyl ester 1F (180 mg, 91.3% yield).
MS(ESI):m/z＝425.1[M+H] +. MS(ESI): m/z=425.1[M+H] + .
第五步：(1R,5S,6r)-N-(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物1)The fifth step: (1R,5S,6r)-N-(2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-yl )-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 1)
Figure PCTCN2021106015-appb-000045
Figure PCTCN2021106015-appb-000045
将(1R,5S,6r)-6-((2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-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1F(180mg,0.42mmol)溶于盐酸二氧六环溶液(2mL)中，室温反应1小时。浓缩反应液，加入乙酸乙酯(3mL)，打浆，过滤，冻干得白色固体状的化合物(1R,5S,6r)-N-(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物1)(46.8mg，产率34.0％)。(1R,5S,6r)-6-((2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)amino Formyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 1F (180 mg, 0.42 mmol) was dissolved in hydrochloric acid dioxane solution (2 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated, ethyl acetate (3 mL) was added, slurried, filtered, and lyophilized to obtain a white solid compound (1R,5S,6r)-N-(2-(8,9-dihydro-7H-imidazo[ 4,5,1-ij]quinolin-2-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 1) (46.8 mg, yield 34.0 %).
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),8.27(d,1H),7.05(t,1H),6.79(d,1H),3.75-3.65(m,2H),3.52-3.42(m,4H),3.09(t,2H),2.97(t,2H),2.40-2.30(m,1H),2.25-2.15(m,2H),1.88(s,6H)。 1 H NMR (400MHz, CD 3 OD) δ 9.21(s, 1H), 8.27(d, 1H), 7.05(t, 1H), 6.79(d, 1H), 3.75-3.65(m, 2H), 3.52 -3.42(m, 4H), 3.09(t, 2H), 2.97(t, 2H), 2.40-2.30(m, 1H), 2.25-2.15(m, 2H), 1.88(s, 6H).
MS(ESI):m/z＝325.2[M+H] +. MS(ESI): m/z=325.2[M+H] + .
实施例2Example 2
(1R,5S,6r)-N-(2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺盐酸盐(化合物2)(1R,5S,6r)-N-(2-(2,3-dihydrofuro[2,3-c]imidazo[1,5-a]pyridin-7-yl)propan-2-yl) -3-Azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (compound 2)
Figure PCTCN2021106015-appb-000046
Figure PCTCN2021106015-appb-000046
第一步：呋喃并[2,3-c]吡啶-7-甲腈(2B)The first step: furo[2,3-c]pyridine-7-carbonitrile (2B)
Figure PCTCN2021106015-appb-000047
Figure PCTCN2021106015-appb-000047
将7-氯呋喃并[2,3-c]吡啶2A(1.0g,6.51mmol)、2-二环己基膦-2',6'-二甲氧基联苯(0.10g,0.24mmol)、氰化锌(2.29g,19.53mmol)及三(二亚苄基丙酮)二钯氯仿络合物(0.05g,0.05mmol)溶于DMF(10mL)中， 氮气保护下于150℃微波反应1小时。用乙酸乙酯(100mLx3)萃取反应混合物，有机相用无水硫酸钠干燥。真空除去溶剂，残留物经硅胶柱纯化(石油醚/乙酸乙酯＝1/5)得到白色固体呋喃并[2,3-c]吡啶-7-甲腈2B(0.7g，收率74.5％)。7-Chlorofuro[2,3-c]pyridine 2A (1.0 g, 6.51 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.10 g, 0.24 mmol), Zinc cyanide (2.29g, 19.53mmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (0.05g, 0.05mmol) were dissolved in DMF (10mL) and reacted in microwave at 150°C for 1 hour under nitrogen protection . The reaction mixture was extracted with ethyl acetate (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether/ethyl acetate = 1/5) to give furo[2,3-c]pyridine-7-carbonitrile 2B (0.7 g, yield 74.5%) as a white solid .
MS(ESI):m/z＝325.2[M+H] +. MS(ESI): m/z=325.2[M+H] + .
第二步：(2,3-二氢呋喃并[2,3-c]吡啶-7-基)甲胺(2C)Step 2: (2,3-Dihydrofuro[2,3-c]pyridin-7-yl)methanamine (2C)
Figure PCTCN2021106015-appb-000048
Figure PCTCN2021106015-appb-000048
将呋喃并[2,3-c]吡啶-7-甲腈2B(0.70g,4.86mmol)及钯/炭(0.20g)加入甲醇/盐酸(10mL，v/v＝10/1)中，***氢气球，置换三次氢气于室温下搅拌3h。反应完毕后，过滤掉钯/炭，旋干滤液，得到粗品白色固体(2,3-二氢呋喃并[2,3-c]吡啶-7-基)甲胺2C(0.5g,收率68.6％)。Furo[2,3-c]pyridine-7-carbonitrile 2B (0.70 g, 4.86 mmol) and palladium/charcoal (0.20 g) were added to methanol/hydrochloric acid (10 mL, v/v=10/1) and inserted into Hydrogen balloon, replaced hydrogen three times and stirred at room temperature for 3h. After the reaction was completed, the palladium/carbon was filtered off, and the filtrate was spin-dried to obtain a crude white solid (2,3-dihydrofuro[2,3-c]pyridin-7-yl)methanamine 2C (0.5 g, yield 68.6 %).
MS m/z(ESI)：151.0[M+H] +. MS m/z(ESI): 151.0[M+H] + .
第三步:(1-(((2,3-二氢呋喃并[2,3-c]吡啶-7-基)甲基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁基酯(2D)The third step: (1-(((2,3-dihydrofuro[2,3-c]pyridin-7-yl)methyl)amino)-2-methyl-1-oxopropane-2- base) tert-butyl carbamate (2D)
Figure PCTCN2021106015-appb-000049
Figure PCTCN2021106015-appb-000049
将(2,3-二氢呋喃并[2,3-c]吡啶-7-基)甲胺2C(0.5g,3.33mmol)、2-((叔丁氧羰基)氨基)-2-甲基丙酸(1.02g,5.0mmol)、HATU(1.52g,4.0mmol)和DIEA(1.29g,10.0mmol)在DMF(6mL)中室温搅拌2小时。反应混合物用乙酸乙酯(100mLx3)萃取，有机相用无水硫酸钠干燥。真空除去溶剂，残留物经硅胶柱纯化(石油醚/乙酸乙酯＝1/1)得到白色固体(1-(((2,3-二氢呋喃并[2,3-c]吡啶-7-基)甲基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁基酯2D(0.3g，收率27％)。(2,3-Dihydrofuro[2,3-c]pyridin-7-yl)methanamine 2C (0.5 g, 3.33 mmol), 2-((tert-butoxycarbonyl)amino)-2-methyl Propionic acid (1.02 g, 5.0 mmol), HATU (1.52 g, 4.0 mmol) and DIEA (1.29 g, 10.0 mmol) were stirred in DMF (6 mL) at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give a white solid (1-(((2,3-dihydrofuro[2,3-c]pyridine-7- (0.3 g, 27% yield).
MS(ESI):m/z＝336.1[M+H] +. MS(ESI): m/z=336.1[M+H] + .
第四步：(2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-基)丙-2-基)氨基甲酸叔丁基酯(2E)The fourth step: tert-butyl (2-(2,3-dihydrofuro[2,3-c]imidazo[1,5-a]pyridin-7-yl)propan-2-yl)carbamate (2E)
Figure PCTCN2021106015-appb-000050
Figure PCTCN2021106015-appb-000050
将(1-(((2,3-二氢呋喃并[2,3-c]吡啶-7-基)甲基)氨基)-2-甲基-1-氧代丙烷-2-基)氨基甲酸叔丁基酯2D(0.3g,0.90mmol)和伯吉斯试剂(0.43g,1.80mmol)溶解在干燥DCM(5mL)中，搅拌4小时。用乙酸乙酯(100mLx3)萃取反应混合物，有机相用无水硫酸钠干燥，真空旋干得到油状物。所述油状物经硅胶柱纯化(石油醚/乙酸乙酯＝1/1)得到白色固体，其为(2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-基)丙-2-基)氨基甲酸叔丁基酯2E(57mg,收率20％)。(1-(((2,3-Dihydrofuro[2,3-c]pyridin-7-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)amino tert-Butyl formate 2D (0.3 g, 0.90 mmol) and Burgess reagent (0.43 g, 1.80 mmol) were dissolved in dry DCM (5 mL) and stirred for 4 hours. The reaction mixture was extracted with ethyl acetate (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate and dried in vacuo to obtain an oil. The oil was purified by silica gel column (petroleum ether/ethyl acetate=1/1) to give a white solid, which was (2-(2,3-dihydrofuro[2,3-c]imidazo[1, 5-a]Pyridin-7-yl)prop-2-yl)carbamate tert-butyl ester 2E (57 mg, 20% yield).
MS(ESI):m/z＝318.1[M+H] +. MS(ESI): m/z=318.1[M+H] + .
第五步：2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-基)丙-2-胺(2F)Step 5: 2-(2,3-Dihydrofuro[2,3-c]imidazo[1,5-a]pyridin-7-yl)propan-2-amine (2F)
Figure PCTCN2021106015-appb-000051
Figure PCTCN2021106015-appb-000051
将(2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-基)丙-2-基)氨基甲酸叔丁基酯2E(36mg，0.11mmol)溶于盐酸/1,4-二氧六环溶液(2mL)中，于室温搅拌1h。反应完毕后，旋干反应混合物，得到粗品粉红色固体2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-基)丙-2-胺2F(30mg，粗品)，未经纯化直接用于下步反应。(2-(2,3-Dihydrofuro[2,3-c]imidazo[1,5-a]pyridin-7-yl)propan-2-yl)carbamic acid tert-butyl ester 2E (36 mg , 0.11 mmol) was dissolved in hydrochloric acid/1,4-dioxane solution (2 mL) and stirred at room temperature for 1 h. After the completion of the reaction, the reaction mixture was spin-dried to obtain a crude pink solid 2-(2,3-dihydrofuro[2,3-c]imidazo[1,5-a]pyridin-7-yl)propan-2 - Amine 2F (30 mg, crude), used directly in the next reaction without purification.
MS(ESI):m/z＝218.0[M+H] +. MS(ESI): m/z=218.0[M+H] + .
第六步：(1R,5S,6r)-6-((2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-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(2G)The sixth step: (1R,5S,6r)-6-((2-(2,3-dihydrofuro[2,3-c]imidazo[1,5-a]pyridin-7-yl)propane -2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester (2G)
Figure PCTCN2021106015-appb-000052
Figure PCTCN2021106015-appb-000052
将粗品2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-基)丙-2-胺2F(30mg，粉红色固体)、(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-羧酸1E(63mg,0.28mmol)、HATU(106mg,0.28mmol)、DIEA(90mg,0.7mmol)在DMF(4mL)中室温搅拌2小时。用乙酸乙酯(100mLx3)萃取，有机相经无水硫酸钠干燥。真空除去溶剂，得到淡绿色固体。粗品通过反相制备色谱法纯化得到(1R,5S,6r)-6-((2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-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2G(10mg，粗品)。The crude 2-(2,3-dihydrofuro[2,3-c]imidazo[1,5-a]pyridin-7-yl)propan-2-amine 2F (30 mg, pink solid), ( 1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1E (63 mg, 0.28 mmol), HATU (106 mg, 0.28 mmol), DIEA (90 mg, 0.7 mmol) in DMF (4 mL) and stirred at room temperature for 2 hours. Extracted with ethyl acetate (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield a pale green solid. The crude product was purified by reverse-phase preparative chromatography to give (1R,5S,6r)-6-((2-(2,3-dihydrofuro[2,3-c]imidazo[1,5-a]pyridine- 7-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 2G (10 mg, crude).
MS(ESI):m/z＝427.1[M+H] +. MS(ESI): m/z=427.1[M+H] + .
第七步：(1R,5S,6r)-N-(2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺盐酸盐(化合物2)The seventh step: (1R,5S,6r)-N-(2-(2,3-dihydrofuro[2,3-c]imidazo[1,5-a]pyridin-7-yl)propane- 2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (compound 2)
Figure PCTCN2021106015-appb-000053
Figure PCTCN2021106015-appb-000053
将(1R,5S,6r)-6-((2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-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2G(10mg)溶于盐酸/1,4-二氧六环溶液(1mL)中，于室温搅拌1小时。反应完毕后，旋干溶剂。残余物冻干后得到灰色固体(1R,5S,6r)-N-(2-(2,3-二氢呋喃并[2,3-c]咪唑并[1,5-a]吡啶-7-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺盐酸盐(化合物2)(6mg，收率78.4％)。(1R,5S,6r)-6-((2-(2,3-dihydrofuro[2,3-c]imidazo[1,5-a]pyridin-7-yl)propan-2- (yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 2G (10 mg) was dissolved in a solution of hydrochloric acid/1,4-dioxane (1 mL), Stir at room temperature for 1 hour. After the reaction was completed, the solvent was spin-dried. The residue was lyophilized to give a grey solid (1R,5S,6r)-N-(2-(2,3-dihydrofuro[2,3-c]imidazo[1,5-a]pyridine-7- yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (compound 2) (6 mg, 78.4% yield).
MS(ESI):m/z＝327.1[M+H] +. MS(ESI): m/z=327.1[M+H] + .
1H NMR(400MHz,CD 3OD)δ8.15(d,1H),7.90(s,1H),7.18(d,1H),4.92-4.89(m,2H),3.74-3.63(m,2H),3.51-3.43(m,4H),2.21-2.17(m,1H),1.99-1.98(m,2H),1.89(s,6H) 1 H NMR (400MHz, CD 3 OD) δ 8.15(d, 1H), 7.90(s, 1H), 7.18(d, 1H), 4.92-4.89(m, 2H), 3.74-3.63(m, 2H) ,3.51-3.43(m,4H),2.21-2.17(m,1H),1.99-1.98(m,2H),1.89(s,6H)
实施例3Example 3
(1R,5S,6r)-N-(2-(2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物3)(1R,5S,6r)-N-(2-(2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazol-6-yl)propan-2-yl )-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 3)
Figure PCTCN2021106015-appb-000054
Figure PCTCN2021106015-appb-000054
第一步：7-(2-溴乙氧基)-1H-吲唑(3B)The first step: 7-(2-Bromoethoxy)-1H-indazole (3B)
Figure PCTCN2021106015-appb-000055
Figure PCTCN2021106015-appb-000055
将1H-吲唑-7-醇3A(2.00g,14.9mmol)溶解在THF(30mL)中，加入2-溴乙烷-1-醇(2.43g,19.3mmol)、三苯基膦(5.81g,22.1mmol)，然后滴加偶氮二甲酸二乙酯(3.91g,22.4mmol)，室温反应12小时。向反应液里加入乙酸乙酯(200mL)，有机相用饱和食盐水(200mL×3)洗涤并用无水硫酸钠干燥。过滤，浓缩，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:10～1:5)得到无色油状的化合物7-(2-溴乙氧基)-1H-吲唑3B(2.3g，产率65.7％)。1H-Indazol-7-ol 3A (2.00 g, 14.9 mmol) was dissolved in THF (30 mL), 2-bromoethane-1-ol (2.43 g, 19.3 mmol), triphenylphosphine (5.81 g) were added , 22.1 mmol), then diethyl azodicarboxylate (3.91 g, 22.4 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. Ethyl acetate (200 mL) was added to the reaction solution, and the organic phase was washed with saturated brine (200 mL×3) and dried over anhydrous sodium sulfate. Filtration, concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:10～1:5) to obtain compound 7-(2-bromoethoxy)- as colorless oil 1H-Indazole 3B (2.3 g, 65.7% yield).
MS(ESI):m/z＝241.1[M+H] +. MS(ESI): m/z=241.1[M+H] + .
第二步：7-(2-溴乙氧基)-3-碘-1H-吲唑(3C)Step 2: 7-(2-Bromoethoxy)-3-iodo-1H-indazole (3C)
Figure PCTCN2021106015-appb-000056
Figure PCTCN2021106015-appb-000056
将7-(2-溴乙氧基)-1H-吲唑3B(2.30g,9.54mmol)溶解在DCM(30mL)中，加入N-碘代丁二酰亚胺(2.34g,10.44mmol)，室温反应12小时。向反应液里加入二氯甲烷(20mL)，用饱和食盐水(100mL×3)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，得到无色油状的化合物7-(2-溴乙氧基)-3-碘-1H-吲唑3C(3.0g，粗品)。7-(2-Bromoethoxy)-1H-indazole 3B (2.30 g, 9.54 mmol) was dissolved in DCM (30 mL), N-iodosuccinimide (2.34 g, 10.44 mmol) was added, The reaction was carried out at room temperature for 12 hours. Dichloromethane (20 mL) was added to the reaction solution, washed with saturated brine (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless oily compound 7-(2-bromoethoxy) yl)-3-iodo-1H-indazole 3C (3.0 g, crude).
MS(ESI):m/z＝367.0[M+H] +. MS(ESI): m/z=367.0[M+H] + .
第三步：6-碘-2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑(3D)Step 3: 6-Iodo-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazole (3D)
Figure PCTCN2021106015-appb-000057
Figure PCTCN2021106015-appb-000057
将7-(2-溴乙氧基)-3-碘-1H-吲唑3C(3.00g,8.17mmol)溶解在DMF(30mL)中，加入碳酸钾(3.00g,23.4mmol),油浴加热至100℃，反应12小时。向反应液里加入乙酸乙酯(50mL)，用饱和食盐水(100mL×3)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:10～1:5)得到无色油状的化合物6-碘-2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑3D(1.5g，产率65.2％)。7-(2-Bromoethoxy)-3-iodo-1H-indazole 3C (3.00 g, 8.17 mmol) was dissolved in DMF (30 mL), potassium carbonate (3.00 g, 23.4 mmol) was added, and the oil bath was heated to 100°C and reacted for 12 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with saturated brine (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate) Ester (v/v)=1:10～1:5) to obtain compound 6-iodo-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indone as colorless oil azole 3D (1.5 g, 65.2% yield).
MS(ESI):m/z＝287.1[M+H] +. MS(ESI): m/z=287.1[M+H] + .
第四步：2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-甲腈(3E)Step 4: 2,3-Dihydro-[1,4]oxazino[2,3,4-hi]indazole-6-carbonitrile (3E)
Figure PCTCN2021106015-appb-000058
Figure PCTCN2021106015-appb-000058
将6-碘-2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑3D(1.5g,5.22mmol)、2-二环己基膦-2',6'-二甲氧基联苯(200mg,0.48mmol)、氰化锌(1.1g,9.38mmol)及三(二亚苄基丙酮)二钯氯仿络合物(223mg,0.24mmol)溶于DMF(15mL)中，氮气保护下于150℃微波反应2小时。反应混合物用乙酸乙酯(100mLx3)萃取，用饱和食盐水(100mLx3)洗涤有机相并用无水硫酸钠干燥。过滤，浓缩，残留物经硅胶柱纯化(石油醚/乙酸乙酯＝1/5)得到白色固体2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-甲腈3E(250mg，收率27.4％)。6-Iodo-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazole 3D (1.5 g, 5.22 mmol), 2-dicyclohexylphosphino-2', 6'-Dimethoxybiphenyl (200 mg, 0.48 mmol), zinc cyanide (1.1 g, 9.38 mmol) and tris(dibenzylideneacetone)dipalladium chloroform complex (223 mg, 0.24 mmol) were dissolved in DMF (15 mL), microwave reaction at 150°C for 2 hours under nitrogen protection. The reaction mixture was extracted with ethyl acetate (100 mL×3), and the organic phase was washed with saturated brine (100 mL×3) and dried over anhydrous sodium sulfate. Filtration, concentration, and the residue was purified by silica gel column (petroleum ether/ethyl acetate=1/5) to obtain 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole as a white solid Azole-6-carbonitrile 3E (250 mg, 27.4% yield).
MS(ESI):m/z＝186.0[M+H] +. MS(ESI): m/z=186.0[M+H] + .
第五步：2-(2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-基)丙-2-胺(3F)Step 5: 2-(2,3-Dihydro-[1,4]oxazino[2,3,4-hi]indazol-6-yl)propan-2-amine (3F)
Figure PCTCN2021106015-appb-000059
Figure PCTCN2021106015-appb-000059
在一个50mL的三口圆底烧瓶中加入三氯化铈(529mg,2.15mmol)，溶于THF(5mL)中，氮气保护下于室温搅拌0.5小时。降温至-60℃，缓慢滴加甲基锂(47.2mg,2.15mmol)，反应0.5小时。然后将2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-甲腈3E(100mg,0.53mmol)溶于THF中，缓慢加入甲基锂，室温反应12小时。向反应混合物中加入15％的氢氧化钠溶液，产生沉淀。过滤，收集有机相。有机相用无水硫酸钠干燥，浓缩，得到油状液体2-(2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-基)丙-2-胺3F(50mg，粗品)。A 50 mL three-necked round bottom flask was added with cerium trichloride (529 mg, 2.15 mmol), dissolved in THF (5 mL), and stirred at room temperature for 0.5 hours under nitrogen protection. The temperature was lowered to -60°C, methyl lithium (47.2 mg, 2.15 mmol) was slowly added dropwise, and the reaction was carried out for 0.5 hour. 2,3-Dihydro-[1,4]oxazino[2,3,4-hi]indazole-6-carbonitrile 3E (100 mg, 0.53 mmol) was then dissolved in THF and methyllithium was added slowly , and react at room temperature for 12 hours. A 15% sodium hydroxide solution was added to the reaction mixture, resulting in a precipitate. Filter and collect the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated to give 2-(2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazol-6-yl)propan- 2-amine 3F (50 mg, crude).
MS(ESI):m/z＝218.1[M+H] +. MS(ESI): m/z=218.1[M+H] + .
第六步：(1R,5S,6r)-6-((2-(2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-基)丙-2-基)氨基甲酰基)-3-氮杂双环[3.1.0]-3-羧酸叔丁基酯(3G)The sixth step: (1R,5S,6r)-6-((2-(2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazol-6-yl) Prop-2-yl)carbamoyl)-3-azabicyclo[3.1.0]-3-carboxylate tert-butyl ester (3G)
Figure PCTCN2021106015-appb-000060
Figure PCTCN2021106015-appb-000060
将2-(2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-基)丙-2-胺3F(50mg,0.24mmol)溶于DMF(3mL)中，室温下加入(1R,5S,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-羧酸1E(47mg,0.24mmol)、DIEA(89mg,0.71mmol)和HATU(96mg,0.36mmol)，室温搅拌反应3小时。向反应液中加入乙酸乙酯(30mL)，用饱和食盐水(10mL×3)洗涤有机相，浓缩。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1～1:3)得到白色固体状的化合物(1R,5S,6r)-6-((2-(2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-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3G(22mg,产率22.3％)。2-(2,3-Dihydro-[1,4]oxazino[2,3,4-hi]indazol-6-yl)propan-2-amine 3F (50 mg, 0.24 mmol) was dissolved in DMF (3 mL), (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1E (47 mg, 0.24 mmol), DIEA (89 mg, 0.71 mmol) and HATU (96 mg, 0.36 mmol) were stirred at room temperature for 3 hours. Ethyl acetate (30 mL) was added to the reaction solution, and the organic phase was washed with saturated brine (10 mL×3) and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1～1:3) to obtain compound (1R,5S,6r)-6-((2-( 2,3-Dihydro-[1,4]oxazino[2,3,4-hi]indazol-6-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1. 0] Hexane-3-carboxylate tert-butyl ester 3G (22 mg, 22.3% yield).
MS(ESI):m/z＝427.1[M+H] +. MS(ESI): m/z=427.1[M+H] + .
第七步：(1R,5S,6r)-N-(2-(2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物3)The seventh step: (1R,5S,6r)-N-(2-(2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazol-6-yl)propane -2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 3)
Figure PCTCN2021106015-appb-000061
Figure PCTCN2021106015-appb-000061
将(1R,5S,6r)-6-((2-(2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-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3G(22mg,0.05mmol)溶于盐酸的甲醇溶液(1mL)中，室温反应2小时。浓缩反应液，然后残余物用制备色谱柱纯化。冻干馏分得白色固体状的化合物(1R,5S,6r)-N-(2-(2,3-二氢-[1,4]噁嗪并[2,3,4-hi]吲唑-6-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物3)(1.45mg，产率8.63％)。(1R,5S,6r)-6-((2-(2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazol-6-yl)propan-2 -yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 3G (22 mg, 0.05 mmol) was dissolved in a methanolic solution of hydrochloric acid (1 mL), and reacted at room temperature for 2 Hour. The reaction solution was concentrated, and the residue was purified by preparative chromatography. The lyophilized fraction was obtained as a white solid compound (1R,5S,6r)-N-(2-(2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazole- 6-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 3) (1.45 mg, 8.63% yield).
1H NMR(400MHz,CD 3OD)δ7.33-7.30(d,1H),6.94(t,1H),6.66(d,1H),4.58(t,2H),4.40(t,2H),3.06-2.97(m,2H),2.93-2.86(m,2H),1.77(s,6H),1.74-1.73(m,2H),1.51-1.50(m,1H). 1 H NMR (400MHz, CD 3 OD) δ 7.33-7.30(d, 1H), 6.94(t, 1H), 6.66(d, 1H), 4.58(t, 2H), 4.40(t, 2H), 3.06 -2.97(m,2H),2.93-2.86(m,2H),1.77(s,6H),1.74-1.73(m,2H),1.51-1.50(m,1H).
MS(ESI):m/z＝327.0[M+H] +. MS(ESI): m/z=327.0[M+H] + .
实施例4：Example 4:
(1R,5S,6r)-N-(2-(6,7-二氢吡咯并[3,2,1-hi]吲唑-2-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物4)(1R,5S,6r)-N-(2-(6,7-dihydropyrrolo[3,2,1-hi]indazol-2-yl)propan-2-yl)-3-azabicyclo [3.1.0] Hexane-6-carboxamide (Compound 4)
Figure PCTCN2021106015-appb-000062
Figure PCTCN2021106015-appb-000062
第一步：7-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑4BThe first step: 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole 4B
Figure PCTCN2021106015-appb-000063
Figure PCTCN2021106015-appb-000063
将7-溴-1H-吲唑4A(5.5g,27.9mmol)溶解在四氢呋喃(50mL)中，然后将反应液降温至0℃。然后加入氢化钠(1.34g,55.8mmol)，搅拌反应半小时后，在0℃下加入2-(三甲硅烷基)乙氧甲基氯(9.3g,55.8mmol)。氮气置换后，室温下搅拌过夜。将反应液倒入水中，水相用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋干得7-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑4B(粗品)。粗产品经柱层析(硅胶，石油醚：乙酸乙酯＝3:1)分离纯化得7-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑4B(7.5g，收率：82％，黄色油状物)。7-Bromo-1H-indazole 4A (5.5 g, 27.9 mmol) was dissolved in tetrahydrofuran (50 mL), and the reaction solution was cooled to 0°C. Then sodium hydride (1.34 g, 55.8 mmol) was added, and after stirring the reaction for half an hour, 2-(trisilyl)ethoxymethyl chloride (9.3 g, 55.8 mmol) was added at 0°C. After nitrogen replacement, the mixture was stirred at room temperature overnight. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain 7-bromo-1-((2-(trimethylmethane). Silyl)ethoxy)methyl)-1H-indazole 4B (crude). The crude product was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate=3:1) to obtain 7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H - Indazole 4B (7.5 g, yield: 82%, yellow oil).
MS(ESI)：327.0[M+H] +. MS(ESI): 327.0[M+H] + .
第二步：1-((2-(三甲基甲硅烷基)乙氧基)甲基)-7-乙烯基-1H-吲唑4CStep 2: 1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-indazole 4C
Figure PCTCN2021106015-appb-000064
Figure PCTCN2021106015-appb-000064
将7-溴-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑4B(7.5g,23mmol)溶解在四氢呋喃(72mL)/水(24mL)溶液中，加入三氟(乙烯基)硼酸钾(4.62g,34.5mmol)和碳酸铯(15g,46mmol)。然后在搅拌下加入二(三苯基膦)二氯化钯(1.61g,2.29mmol)。氮气置换后，在90℃(油浴的温度)下反应过夜。将反应液倒入水中，水相用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋除溶剂得1-((2-(三甲基甲硅烷基)乙氧基)甲基)-7-乙烯基-1H-吲唑4C(粗品)。粗品经柱层析(硅胶，乙酸乙酯/石油醚＝20％)分离纯化得到1-((2-(三甲基甲硅烷基)乙氧基)甲基)-7-乙烯基-1H-吲唑4C(6.0g,收率：95.2％，黄色油状物)。7-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole 4B (7.5 g, 23 mmol) was dissolved in a solution of tetrahydrofuran (72 mL)/water (24 mL) To this, potassium trifluoro(vinyl)borate (4.62 g, 34.5 mmol) and cesium carbonate (15 g, 46 mmol) were added. Then bis(triphenylphosphine)palladium dichloride (1.61 g, 2.29 mmol) was added with stirring. After nitrogen replacement, the reaction was carried out at 90° C. (temperature of the oil bath) overnight. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 1-((2-(trimethylsilyl) Ethoxy)methyl)-7-vinyl-1H-indazole 4C (crude). The crude product was separated and purified by column chromatography (silica gel, ethyl acetate/petroleum ether=20%) to obtain 1-((2-(trimethylsilyl)ethoxy)methyl)-7-vinyl-1H- Indazole 4C (6.0 g, yield: 95.2%, yellow oil).
MS(ESI)：275.1[M+H] +. MS(ESI): 275.1[M+H] + .
第三步：2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-基)乙烷-1-醇4DStep 3: 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethane-1-ol 4D
Figure PCTCN2021106015-appb-000065
Figure PCTCN2021106015-appb-000065
将1-((2-(三甲基甲硅烷基)乙氧基)甲基)-7-乙烯基-1H-吲唑4C(6.0g,21.9mmol)溶解在四氢呋喃(100mL)中。反应液降温至0℃，然后逐滴加入1M硼烷四氢呋喃(60mL,60mmol)。氮气置换后，在室温下反应过夜。向反应液中加入10％氢氧化钠水溶液(1.31g,32.8mmol)和35％浓度的双氧水(4.5mL)，室温下再反应6小时。将反应液倒入水中，水相用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋除溶剂得2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-基)乙烷-1-醇4D(粗品)。粗品经柱层析(硅胶，乙酸乙酯/石油醚＝20％)分离纯化得到2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-基)乙烷-1-醇4D(3.6g,收率：56.3％，黄色油状物)。1-((2-(Trimethylsilyl)ethoxy)methyl)-7-vinyl-1H-indazole 4C (6.0 g, 21.9 mmol) was dissolved in tetrahydrofuran (100 mL). The reaction solution was cooled to 0°C, and then 1M borane tetrahydrofuran (60 mL, 60 mmol) was added dropwise. After nitrogen replacement, the reaction was carried out at room temperature overnight. 10% aqueous sodium hydroxide solution (1.31 g, 32.8 mmol) and 35% concentration of hydrogen peroxide (4.5 mL) were added to the reaction solution, and the reaction was continued for 6 hours at room temperature. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 2-(1-((2-(trimethylmethane). Silyl)ethoxy)methyl)-1H-indazol-7-yl)ethane-1-ol 4D (crude). The crude product was separated and purified by column chromatography (silica gel, ethyl acetate/petroleum ether=20%) to obtain 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole -7-yl)Ethan-1-ol 4D (3.6 g, yield: 56.3%, yellow oil).
MS(ESI)：293.2[M+H] +. MS(ESI): 293.2[M+H] + .
第四步：2-(1H-吲唑-7-基)乙烷-1-醇4EStep 4: 2-(1H-Indazol-7-yl)ethane-1-ol 4E
Figure PCTCN2021106015-appb-000066
Figure PCTCN2021106015-appb-000066
将2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-7-基)乙烷-1-醇4D(3.6g,12.3mmol)溶解在盐酸-二氧六环溶液(50mL)中。氮气置换后，室温下反应过夜。真空旋除溶剂得2-(1H-吲唑-7-基)乙烷-1-醇4E(粗品)。粗品经柱层析(硅胶，乙酸乙酯：石油醚＝1:1)分离纯化得到2-(1H-吲唑-7-基)乙烷-1-醇4E(800mg,收率：40％，棕色固体)。2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethane-1-ol 4D (3.6 g, 12.3 mmol) was dissolved In hydrochloric acid-dioxane solution (50 mL). After nitrogen replacement, the reaction was carried out at room temperature overnight. Removal of the solvent in vacuo gave 2-(1H-indazol-7-yl)ethane-1-ol 4E (crude). The crude product was separated and purified by column chromatography (silica gel, ethyl acetate: petroleum ether=1:1) to obtain 2-(1H-indazol-7-yl)ethane-1-ol 4E (800 mg, yield: 40%, brown solid).
MS(ESI):M/Z＝163.2[M+H] +. MS(ESI): M/Z=163.2[M+H] + .
第五步：7-(2-氯乙基)-1H-吲唑4FStep 5: 7-(2-Chloroethyl)-1H-indazole 4F
Figure PCTCN2021106015-appb-000067
Figure PCTCN2021106015-appb-000067
将2-(1H-吲唑-7-基)乙烷-1-醇4E(800mg,4.94mmol)溶解在氯仿(20mL)中，然后加入氯化亚砜(1.18g,9.92mmol)。氮气置换后，于60℃(油浴的温度)下反应5小时。将反应液倒入水中，水相用二氯甲烷萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋除溶剂得7-(2-氯乙基)-1H-吲唑4F(粗品)。粗品经柱层析(硅胶，乙酸乙酯/石油醚＝30％)分离纯化得到7-(2-氯乙基)-1H-吲唑4F(500mg,收率：56.3％，白色固体)。2-(1H-Indazol-7-yl)ethane-1-ol 4E (800 mg, 4.94 mmol) was dissolved in chloroform (20 mL) and thionyl chloride (1.18 g, 9.92 mmol) was added. After nitrogen substitution, it was made to react at 60 degreeC (temperature of an oil bath) for 5 hours. The reaction solution was poured into water, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 7-(2-chloroethyl)-1H-indazole 4F (crude). The crude product was separated and purified by column chromatography (silica gel, ethyl acetate/petroleum ether=30%) to obtain 7-(2-chloroethyl)-1H-indazole 4F (500 mg, yield: 56.3%, white solid).
MS(ESI):M/Z＝181.1[M+H] +. MS(ESI): M/Z=181.1[M+H] + .
第六步：7-(2-氯乙基)-3-碘-1H-吲唑4GStep 6: 7-(2-Chloroethyl)-3-iodo-1H-indazole 4G
Figure PCTCN2021106015-appb-000068
Figure PCTCN2021106015-appb-000068
将7-(2-氯乙基)-1H-吲唑4F(450mg,2.5mmol)溶解在二氯甲烷(20mL)中，然后加入N-碘代丁二酰亚胺(562mg,2.5mmol)。氮气置换后，室温下反应2小时。将反应液倒入水中，水相用二氯甲烷萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋除溶剂得7-(2-氯乙基)-3-碘-1H-吲唑4G(粗品)。粗品经柱层析(硅胶，乙酸乙酯/石油醚＝30％)分离纯化得到7-(2-氯乙基)-3-碘-1H-吲唑4G(580mg,收率：75.8％，淡粉色固体)。7-(2-Chloroethyl)-1H-indazole 4F (450 mg, 2.5 mmol) was dissolved in dichloromethane (20 mL) and N-iodosuccinimide (562 mg, 2.5 mmol) was added. After nitrogen replacement, the reaction was carried out at room temperature for 2 hours. The reaction solution was poured into water, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 7-(2-chloroethyl)-3-iodo- 1H-Indazole 4G (crude). The crude product was separated and purified by column chromatography (silica gel, ethyl acetate/petroleum ether=30%) to obtain 7-(2-chloroethyl)-3-iodo-1H-indazole 4G (580 mg, yield: 75.8%, pale pink solid).
MS(ESI):M/Z＝306.9[M+H] +. MS(ESI): M/Z=306.9[M+H] + .
第七步：2-碘-6,7-二氢吡咯并[3,2,1-hi]吲唑4HStep 7: 2-Iodo-6,7-dihydropyrrolo[3,2,1-hi]indazole 4H
Figure PCTCN2021106015-appb-000069
Figure PCTCN2021106015-appb-000069
将7-(2-氯乙基)-3-碘-1H-吲唑4G(540mg,1.76mmol)溶解在N,N-二甲基甲酰胺(20mL)中，然后加入碳酸铯(1.72g,5.28mmol)。氮气置换后，于80℃(油浴的温度)下反应过夜。将反应液倒入水中，水相用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋除溶剂得2-碘-6,7-二氢吡咯并[3,2,1-hi]吲唑4H(粗品)。粗品经柱层析(硅胶，乙酸乙酯/石油醚＝30％)分离纯化得到2-碘-6,7-二氢吡咯并[3,2,1-hi]吲唑4H(410mg,收率：86.1％，黄色固体)。7-(2-Chloroethyl)-3-iodo-1H-indazole 4G (540 mg, 1.76 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of cesium carbonate (1.72 g, 5.28 mmol). After nitrogen replacement, the reaction was carried out at 80°C (temperature of oil bath) overnight. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 2-iodo-6,7-dihydropyrrolo[3 ,2,1-hi]indazole 4H (crude). The crude product was separated and purified by column chromatography (silica gel, ethyl acetate/petroleum ether=30%) to obtain 2-iodo-6,7-dihydropyrrolo[3,2,1-hi]indazole 4H (410 mg, yield : 86.1%, yellow solid).
MS(ESI):M/Z＝271.1[M+H] +. MS(ESI): M/Z=271.1[M+H] + .
第八步：6,7-二氢吡咯并[3,2,1-hi]吲唑-2-甲腈4IStep 8: 6,7-Dihydropyrrolo[3,2,1-hi]indazole-2-carbonitrile 4I
Figure PCTCN2021106015-appb-000070
Figure PCTCN2021106015-appb-000070
将2-碘-6,7-二氢吡咯并[3,2,1-hi]吲唑4H(350mg,1.3mmol)溶解在N,N-二甲基乙酰胺(50mL)中，然后加入锌粉(42.5mg,0.65mmol)、氰化锌(305mg,2.6mmol)、1,1'-双(二苯基膦)二茂铁(72mg,0.13mmol)、Pd 2(dba) 3(119mg,0.13mmol)。氮气置换后，120℃油浴下反应5小时。将反应液倒入水中，水相用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋除溶剂得6,7-二氢吡咯并[3,2,1-hi]吲唑-2-甲腈4I(粗品)。粗品经柱层析(硅胶，乙酸乙酯/石油醚＝20％)分离纯化得到6,7-二氢吡咯并[3,2,1-hi]吲唑-2-甲腈4I(170mg,收率：77.6％，黄色固体)。 2-Iodo-6,7-dihydropyrrolo[3,2,1-hi]indazole 4H (350 mg, 1.3 mmol) was dissolved in N,N-dimethylacetamide (50 mL) followed by the addition of zinc powder (42.5mg, 0.65mmol), zinc cyanide (305mg, 2.6mmol), 1,1'-bis(diphenylphosphino)ferrocene (72mg, 0.13mmol), Pd 2 (dba) 3 (119mg, 0.13 mmol). After nitrogen replacement, the reaction was carried out in an oil bath at 120°C for 5 hours. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to obtain 6,7-dihydropyrrolo[3,2,1 -hi]indazole-2-carbonitrile 4I (crude). The crude product was separated and purified by column chromatography (silica gel, ethyl acetate/petroleum ether=20%) to obtain 6,7-dihydropyrrolo[3,2,1-hi]indazole-2-carbonitrile 4I (170 mg, yield yield: 77.6%, yellow solid).
MS(ESI):M/Z＝170.1[M+H] +. MS(ESI): M/Z=170.1[M+H] + .
第九步：2-(6,7-二氢吡咯并[3,2,1-hi]吲唑-2-基)丙-2-胺4JStep 9: 2-(6,7-Dihydropyrrolo[3,2,1-hi]indazol-2-yl)propan-2-amine 4J
Figure PCTCN2021106015-appb-000071
Figure PCTCN2021106015-appb-000071
三氯化铈(577mg，2.36mmol)在干燥的四氢呋喃(6mL)中搅拌1小时，降温至-78℃,滴入1.3M的甲基锂溶液(1.8mL,2.36mmol),搅拌1小时，再滴入6,7-二氢吡咯并[3,2,1-hi]吲唑-2-甲腈4I(100mg,0.59mmol)的四氢呋喃(2mL)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，滤液无水硫酸钠干燥，真空旋干得到黄色油状物2-(6,7-二氢吡咯并[3,2,1-hi]吲唑-2-基)丙-2-胺4J粗品,硅胶柱纯化(流动相：石油醚：乙酸乙酯＝1：1)得到2-(6,7-二氢吡咯并[3,2,1-hi]吲唑-2-基)丙-2-胺4J(80mg,收率：75％)。Cerium trichloride (577 mg, 2.36 mmol) was stirred in dry tetrahydrofuran (6 mL) for 1 hour, cooled to -78°C, 1.3M methyllithium solution (1.8 mL, 2.36 mmol) was added dropwise, stirred for 1 hour, and then A solution of 6,7-dihydropyrrolo[3,2,1-hi]indazole-2-carbonitrile 4I (100 mg, 0.59 mmol) in tetrahydrofuran (2 mL) was added dropwise, slowly warmed to room temperature and stirred for 16 hours. Quenched with 1 mL of 10% aqueous sodium hydroxide solution, filtered, the filtrate was dried over anhydrous sodium sulfate, and dried in vacuo to obtain 2-(6,7-dihydropyrrolo[3,2,1-hi]indazole- The crude 2-yl)propan-2-amine 4J was purified by silica gel column (mobile phase: petroleum ether:ethyl acetate=1:1) to obtain 2-(6,7-dihydropyrrolo[3,2,1-hi] ]Indazol-2-yl)propan-2-amine 4J (80 mg, yield: 75%).
MS(ESI):M/Z＝185.1[M-16] + MS(ESI): M/Z=185.1[M-16] +
第十步：(1R,5S,6r)-6-((2-(6,7-二氢吡咯并[3,2,1-hi]吲唑-2-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4KThe tenth step: (1R,5S,6r)-6-((2-(6,7-dihydropyrrolo[3,2,1-hi]indazol-2-yl)propan-2-yl)amino Formyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 4K
Figure PCTCN2021106015-appb-000072
Figure PCTCN2021106015-appb-000072
将2-(6,7-二氢吡咯并[3,2,1-hi]吲唑-2-基)丙-2-胺4J(100mg,0.5mmol)、化合物(1R,5R,6r)-3-(叔丁氧羰基)-3-氮杂双环[3.1.0]己烷-6-羧酸(113mg,0.5mmol)、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。反应液加水淬灭并用乙酸乙酯萃取。有机相经无水硫酸钠干燥，真空旋干得到油状物。所述油状物经硅胶柱纯化(流动相：石油醚：乙酸乙酯＝1：1)得到(1R,5S,6r)-6-((2-(6,7-二氢吡咯并[3,2,1-hi]吲唑-2-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4K(110mg，收率：53.6％)。2-(6,7-Dihydropyrrolo[3,2,1-hi]indazol-2-yl)propan-2-amine 4J (100 mg, 0.5 mmol), compound (1R,5R,6r)- 3-(tert-Butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (113 mg, 0.5 mmol), HATU (190 mg, 0.5 mmol) and triethylamine (150 mg, 1.5 mmol) It was dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 16 hours. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spun in vacuo to give an oil. The oily substance was purified by silica gel column (mobile phase: petroleum ether:ethyl acetate=1:1) to obtain (1R,5S,6r)-6-((2-(6,7-dihydropyrrolo[3, 2,1-hi]indazol-2-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 4K (110 mg, received rate: 53.6%).
MS(ESI):M/Z＝411.2[M+H] +. MS(ESI): M/Z=411.2[M+H] + .
第十一步：(1R,5S,6r)-N-(2-(6,7-二氢吡咯并[3,2,1-hi]吲唑-2-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物4)The eleventh step: (1R,5S,6r)-N-(2-(6,7-dihydropyrrolo[3,2,1-hi]indazol-2-yl)propan-2-yl)- 3-Azabicyclo[3.1.0]hexane-6-carboxamide (Compound 4)
Figure PCTCN2021106015-appb-000073
Figure PCTCN2021106015-appb-000073
将(1R,5S,6r)-6-((2-(6,7-二氢吡咯并[3,2,1-hi]吲唑-2-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4K(130mg,0.31mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.5mL)，室温搅拌3小时。然后旋干溶剂，加氨水调节PH值至碱性，接着旋干得到粗品。粗品经制备型HPLC纯化后得到白色固体纯品(化合物4)(50mg，收率：53.2％)。(1R,5S,6r)-6-((2-(6,7-dihydropyrrolo[3,2,1-hi]indazol-2-yl)propan-2-yl)carbamoyl) -3-Azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 4K (130 mg, 0.31 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and stirred at room temperature 3 hours. Then spin dry the solvent, add ammonia water to adjust the pH value to alkaline, and then spin dry to obtain a crude product. The crude product was purified by preparative HPLC to give pure white solid (compound 4) (50 mg, yield: 53.2%).
MS(ESI):m/z＝311.0[M+H] +. MS(ESI): m/z=311.0[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.29(d,1H),7.38(d,1H),6.98(d,1H),6.94-6.89(m,1H),4.56(t,2H),3.80(t,2H),3.52-3.27(dd,2H),2.90-2.69(dd,2H),1.66(s,6H),1.65-1.52(m,3H). 1 H NMR (400MHz, DMSO-d6)δ8.29(d,1H), 7.38(d,1H), 6.98(d,1H), 6.94-6.89(m,1H), 4.56(t,2H), 3.80 (t,2H),3.52-3.27(dd,2H),2.90-2.69(dd,2H),1.66(s,6H),1.65-1.52(m,3H).
实施例5Example 5
N-(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物5)N-(2-(8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-yl)-1-methyl-3-azabicyclo [3.1.0] Hexane-6-carboxamide (Compound 5)
Figure PCTCN2021106015-appb-000074
Figure PCTCN2021106015-appb-000074
第一步：6-((2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-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5AThe first step: 6-((2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-1 -Methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 5A
Figure PCTCN2021106015-appb-000075
Figure PCTCN2021106015-appb-000075
将2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-胺1D(179mg,0.83mmol)溶于DMF(2mL)中，室温下加入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1-P1)(200mg,0.83mmol)、DIEA(214mg,1.66mmol)和HATU(347mg,0.91mmol)，室温搅拌反应8小时。向反应液中加入乙酸乙酯(60mL)，用饱和食盐水(20mL×3)洗涤有机相，浓缩。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1～1:3)得到白色固体状的化合物6-((2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-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5A(200mg,收率：55％)。2-(8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-amine 1D (179 mg, 0.83 mmol) was dissolved in DMF (2 mL) , 3-(tert-butoxycarbonyl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (intermediate 1-P1) (200 mg, 0.83 mmol), DIEA was added at room temperature (214 mg, 1.66 mmol) and HATU (347 mg, 0.91 mmol), and the reaction was stirred at room temperature for 8 hours. Ethyl acetate (60 mL) was added to the reaction solution, and the organic phase was washed with saturated brine (20 mL×3) and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1～1:3) to obtain compound 6-((2-(8,9-dihydro-7H) as a white solid -imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-1-methyl-3-azabicyclo[3.1.0]hexane-3- Carboxylic acid tert-butyl ester 5A (200 mg, yield: 55%).
MS(ESI):m/z＝439.1[M+H] +. MS(ESI): m/z=439.1[M+H] + .
第二步：N-(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物5)The second step: N-(2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-yl)-1-methyl-3 - azabicyclo[3.1.0]hexane-6-carboxamide (compound 5)
Figure PCTCN2021106015-appb-000076
Figure PCTCN2021106015-appb-000076
6-((2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-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5A(190mg,0.43mmol)溶于盐酸二氧六环溶液(2mL)中，室温反应1小时。反应液真空旋除溶剂，粗品经制备型HPLC纯化后得到目标化合物N-(2-(8,9-二氢-7H-咪唑并[4,5,1-ij] 喹啉-2-基)丙-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物5)(30mg，收率：20.6％，白色固体)。6-((2-(8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-1-methyl- 3-Azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 5A (190 mg, 0.43 mmol) was dissolved in hydrochloric acid dioxane solution (2 mL), and reacted at room temperature for 1 hour. The solvent was removed and the crude product was purified by preparative HPLC to give the target compound N-(2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2- yl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 5) (30 mg, yield: 20.6%, white solid).
MS(ESI):m/z＝339.2[M+H] +. MS(ESI): m/z=339.2[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.90(d,1H),6.42(t,1H),6.21(d,1H),2.87(d,1H),2.81(m,3H),2.74(m,3H),2.57(d,1H),1.97(m,2H),1.67(d,1H),1.64(s,3H),1.61(s,3H),1.42(m,1H),0.99(s,3H). 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.90(d,1H),6.42(t,1H),6.21(d,1H),2.87(d,1H),2.81(m ,3H),2.74(m,3H),2.57(d,1H),1.97(m,2H),1.67(d,1H),1.64(s,3H),1.61(s,3H),1.42(m, 1H),0.99(s,3H).
实施例6Example 6
N-(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物6)N-(2-(8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-yl)-1-methyl-3-azabicyclo [3.1.0] Hexane-6-carboxamide (Compound 6)
Figure PCTCN2021106015-appb-000077
Figure PCTCN2021106015-appb-000077
第一步：6-((2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-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6AThe first step: 6-((2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-1 -Methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 6A
Figure PCTCN2021106015-appb-000078
Figure PCTCN2021106015-appb-000078
将2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-胺1D(179mg,0.83mmol)溶于DMF(2mL)中，室温下加入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1-P2)(200mg,0.83mmol)、DIEA(214mg,1.66mmol)和HATU(347mg,0.91mmol)，室温搅拌反应8小时。向反应液中加入乙酸乙酯(60mL)，用饱和食盐水(20mL×3)洗涤有机层，浓缩。残留物用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1:1～1:3)得到白色固体状的化合物，其为6-((2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-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6A(190mg,收率：52％)。2-(8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-amine 1D (179 mg, 0.83 mmol) was dissolved in DMF (2 mL) , 3-(tert-butoxycarbonyl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (intermediate 1-P2) (200 mg, 0.83 mmol), DIEA was added at room temperature (214 mg, 1.66 mmol) and HATU (347 mg, 0.91 mmol), and the reaction was stirred at room temperature for 8 hours. Ethyl acetate (60 mL) was added to the reaction solution, and the organic layer was washed with saturated brine (20 mL×3) and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1～1:3) to obtain a white solid compound, which was 6-((2-(8,9-di Hydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-1-methyl-3-azabicyclo[3.1.0]hexane -3-Carboxylic acid tert-butyl ester 6A (190 mg, yield: 52%).
MS(ESI):m/z＝439.1[M+H] +. MS(ESI): m/z=439.1[M+H] + .
第二步：N-(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物6)The second step: N-(2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2-yl)-1-methyl-3 - azabicyclo[3.1.0]hexane-6-carboxamide (compound 6)
Figure PCTCN2021106015-appb-000079
Figure PCTCN2021106015-appb-000079
6-((2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-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6A(190mg,0.43mmol)溶于盐酸二氧六环溶液(2mL)中，室温反应1小时。反应液真空旋除溶剂，粗品经制备型HPLC纯化后得到目标化合物N-(2-(8,9-二氢-7H-咪唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-1-甲基-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物6)(51mg，收率：35.1％，白色固体)。6-((2-(8,9-Dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-1-methyl- 3-Azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 6A (190 mg, 0.43 mmol) was dissolved in hydrochloric acid dioxane solution (2 mL), and reacted at room temperature for 1 hour. The solvent was removed and the crude product was purified by preparative HPLC to give the target compound N-(2-(8,9-dihydro-7H-imidazo[4,5,1-ij]quinolin-2-yl)propan-2- yl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 6) (51 mg, yield: 35.1%, white solid).
MS(ESI):m/z＝339.1[M+H] +. MS(ESI): m/z=339.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.90(d,1H),6.42(t,1H),6.21(d,1H),2.87(d,1H),2.81(m,3H),2.75-2.72(m,3H),2.57(d,1H),2.03-1.96(m,2H),1.66(d,1H),1.64(s,3H),1.61(s,3H),1.42(m,1H),0.99(s,3H). 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.90(d,1H),6.42(t,1H),6.21(d,1H),2.87(d,1H),2.81(m ,3H),2.75-2.72(m,3H),2.57(d,1H),2.03-1.96(m,2H),1.66(d,1H),1.64(s,3H),1.61(s,3H), 1.42(m,1H),0.99(s,3H).
实施例7Example 7
(1R,5S,6r)-N-(2-(7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物7)(1R,5S,6r)-N-(2-(7,8-Dihydro-6H-pyrazolo[4,5,1-ij]quinolin-2-yl)propan-2-yl)-3 - azabicyclo[3.1.0]hexane-6-carboxamide (compound 7)
Figure PCTCN2021106015-appb-000080
Figure PCTCN2021106015-appb-000080
第一步：7-碘-1H-吲唑7BThe first step: 7-iodo-1H-indazole 7B
Figure PCTCN2021106015-appb-000081
Figure PCTCN2021106015-appb-000081
将7-氨基吲唑7A(4.8g，7.2mmol)溶解在稀硫酸(20％)(30mL)中，室温下搅拌一小时。然后将此溶液降温至零下5-0℃，缓慢加入亚硝酸钠(745mg，10.8mmol)，在约30分钟内加完。加完后再搅拌30分钟。然后向此溶液中缓慢加入碘化钾的水溶液(1.79g，10.8mmol，20毫升)，在约30分钟内加完。加完后再搅拌1小时，LCMS监测显示反应完全。将反应液倒入水中，水相用乙酸乙酯萃取，合 并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋干得粗品。该粗品经柱层析(硅胶，石油醚：乙酸乙酯＝5:1)分离纯化得到7-碘-1H-吲唑7B(4.2g，收率：54.5％，淡黄色固体)。7-Aminoindazole 7A (4.8 g, 7.2 mmol) was dissolved in dilute sulfuric acid (20%) (30 mL) and stirred at room temperature for one hour. The solution was then cooled to minus 5-0°C, and sodium nitrite (745 mg, 10.8 mmol) was added slowly over about 30 minutes. Stir for an additional 30 minutes after the addition is complete. To this solution was then slowly added an aqueous solution of potassium iodide (1.79 g, 10.8 mmol, 20 mL) over a period of about 30 minutes. After the addition was complete, stirring was continued for an additional hour, and LCMS monitoring showed that the reaction was complete. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain a crude product. The crude product was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to obtain 7-iodo-1H-indazole 7B (4.2 g, yield: 54.5%, pale yellow solid).
MS(ESI):M/Z＝245.0[M+H] +. MS(ESI): M/Z=245.0[M+H] + .
第二步：7-(3-((叔丁基二甲基甲硅烷基)氧基)-丙-1-炔-1-基)-1H-吲唑7CStep 2: 7-(3-((tert-butyldimethylsilyl)oxy)-prop-1-yn-1-yl)-1H-indazole 7C
Figure PCTCN2021106015-appb-000082
Figure PCTCN2021106015-appb-000082
7-碘-1H-吲唑(4.2g,17.2mmol)7B溶解于DMF(50mL)，然后向其中加入Pd(PPh 3) 4(196mg，0.17mmol)和叔丁基二甲基(丙-2-炔-1-基氧基)硅烷(8.77g，51.6mmol)、三乙胺(8.7g，86mmol)和碘化亚铜(653mg，3.44mmol)，氮气置换三次，于80℃下反应3小时。将反应液倒入水中，水相用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋干得粗品，经柱层析(硅胶，石油醚：乙酸乙酯＝10：1)分离纯化得到7-(3-((叔丁基二甲基甲硅烷基)氧基)-丙-1-炔-1-基)-1H-吲唑7C(2.6g，收率：53％，黄色油状物)。 7-Iodo-1H-indazole (4.2 g, 17.2 mmol) 7B was dissolved in DMF (50 mL), to which were added Pd(PPh 3 ) 4 (196 mg, 0.17 mmol) and tert-butyldimethyl (propane-2 -Alkyn-1-yloxy)silane (8.77g, 51.6mmol), triethylamine (8.7g, 86mmol) and cuprous iodide (653mg, 3.44mmol), replaced by nitrogen three times, and reacted at 80°C for 3 hours . The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and dried in vacuo to obtain the crude product, which was subjected to column chromatography (silica gel, petroleum ether: ethyl acetate) =10:1) separation and purification to obtain 7-(3-((tert-butyldimethylsilyl)oxy)-prop-1-yn-1-yl)-1H-indazole 7C (2.6 g, collected Yield: 53%, yellow oil).
MS(ESI):M/Z＝287.1[M+H] +. MS(ESI): M/Z=287.1[M+H] + .
第三步：7-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)-1H-吲唑7DThe third step: 7-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole 7D
Figure PCTCN2021106015-appb-000083
Figure PCTCN2021106015-appb-000083
将7-(3-((叔丁基二甲基甲硅烷基)氧基)-丙-1-炔-1-基)-1H-吲唑7C(2.6g，9.09mmol)溶解在甲醇(30mL)中，然后加入钯/炭(催化剂量)，氢气球下室温反应18小时。反应液抽滤后得7-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)-1H-吲唑7D(粗品，2.6g，黄色油状物)。没有纯化直接投下一步反应。7-(3-((tert-butyldimethylsilyl)oxy)-prop-1-yn-1-yl)-1H-indazole 7C (2.6 g, 9.09 mmol) was dissolved in methanol (30 mL) ), then palladium/carbon (catalyst amount) was added, and the reaction was carried out at room temperature for 18 hours under a hydrogen balloon. The reaction solution was suction filtered to obtain 7-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole 7D (crude product, 2.6 g, yellow oil). No purification was carried out directly to the next reaction.
MS(ESI):M/Z＝291.2[M+H] +. MS(ESI): M/Z=291.2[M+H] + .
第四步：3-(1H-吲唑-7-基)丙-1-醇7EThe fourth step: 3-(1H-indazol-7-yl)propan-1-ol 7E
Figure PCTCN2021106015-appb-000084
Figure PCTCN2021106015-appb-000084
将7-(3-((叔丁基二甲基甲硅烷基)氧基)丙基)-1H-吲唑7D(2.6g，8.96mmol)溶解在四氢呋喃(30mL)中，加入四丁基氟化铵(3.5g，13.44mmol)，室温搅拌过夜。旋干四氢呋喃，将反应液倒入水中，水相用乙酸乙酯萃取，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋干得3-(1H-吲唑-7-基)丙-1-醇7E(1.6g，粗品，淡黄色油状物)，没有纯化直接投下一步反应。7-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-indazole 7D (2.6 g, 8.96 mmol) was dissolved in tetrahydrofuran (30 mL) and tetrabutyl fluoride was added Ammonium chloride (3.5 g, 13.44 mmol) was stirred at room temperature overnight. Spin dry tetrahydrofuran, pour the reaction solution into water, extract the aqueous phase with ethyl acetate, wash the combined organic phases with saturated brine, dry over anhydrous sodium sulfate, and spin dry in vacuo to obtain 3-(1H-indazol-7-yl ) propan-1-ol 7E (1.6 g, crude product, pale yellow oil), which was directly sent to the next reaction without purification.
MS(ESI):M/Z＝177.1[M+H] +. MS(ESI): M/Z=177.1[M+H] + .
第五步：7-(3-氯丙基)-1H-吲唑7FStep 5: 7-(3-Chloropropyl)-1H-indazole 7F
Figure PCTCN2021106015-appb-000085
Figure PCTCN2021106015-appb-000085
将3-(1H-吲唑-7-基)丙-1-醇7E(1.6g，9.09mmol)溶解在氯仿(30mL)中，加入氯化亚砜(2.16g，18.2mmol)，加热到60℃反应两个小时。将氯化亚砜旋干得到粗品，经柱层析(硅胶，石油醚：二氯甲烷＝1:1)分离纯化得7-(3-氯丙基)-1H-吲唑7F(1.15g，收率：65.3％，淡黄色固体)。3-(1H-Indazol-7-yl)propan-1-ol 7E (1.6 g, 9.09 mmol) was dissolved in chloroform (30 mL), thionyl chloride (2.16 g, 18.2 mmol) was added and heated to 60 °C for two hours. The thionyl chloride was spin-dried to obtain the crude product, which was separated and purified by column chromatography (silica gel, petroleum ether: dichloromethane=1:1) to obtain 7-(3-chloropropyl)-1H-indazole 7F (1.15 g, Yield: 65.3%, pale yellow solid).
MS(ESI):M/Z＝195.1[M+H] +. MS(ESI): M/Z=195.1[M+H] + .
第六步：7-(3-氯丙基)-3-碘-1H-吲唑7GStep 6: 7-(3-Chloropropyl)-3-iodo-1H-indazole 7G
Figure PCTCN2021106015-appb-000086
Figure PCTCN2021106015-appb-000086
7-(3-氯丙基)-1H-吲唑7F(800mg，4.12mmol)溶解在二氯甲烷(10mL)中，室温下加入N-碘代丁二酰亚胺(1.12g，5.0mmol)，室温下反应2小时。反应液倒入水中，二氯甲烷萃取，有机相用无水硫酸钠干燥，真空旋干得7-(3-氯丙基)-3-碘-1H-吲唑7G(860mg，粗品)，直接用于下一步。7-(3-Chloropropyl)-1H-indazole 7F (800 mg, 4.12 mmol) was dissolved in dichloromethane (10 mL), and N-iodosuccinimide (1.12 g, 5.0 mmol) was added at room temperature , at room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and dried in vacuo to give 7-(3-chloropropyl)-3-iodo-1H-indazole 7G (860 mg, crude product), which was directly for the next step.
MS(ESI):M/Z＝321.0[M+H] +. MS(ESI): M/Z=321.0[M+H] + .
第七步：2-碘-7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉7HStep 7: 2-iodo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline 7H
Figure PCTCN2021106015-appb-000087
Figure PCTCN2021106015-appb-000087
将7-(3-氯丙基)-3-碘-1H-吲唑7G(1.3g，4.06mmol)溶解在N,N-二甲基甲酰胺(20mL)中，然后加入碳酸钾(1.65g，12mmol)。加热到100℃反应3小时，将反应液倒入水中，水相用乙酸乙酯萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥，真空旋干得粗品。该粗品经柱层析(硅胶，石油醚：二氯甲烷＝5:1)分离纯化得到2-碘-7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉7H(900mg，收率：78.2％，黄色固体)。7-(3-Chloropropyl)-3-iodo-1H-indazole 7G (1.3 g, 4.06 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by potassium carbonate (1.65 g) , 12 mmol). The reaction was heated to 100° C. for 3 hours, the reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain the crude product. The crude product was separated and purified by column chromatography (silica gel, petroleum ether:dichloromethane=5:1) to obtain 2-iodo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline 7H (900 mg, yield: 78.2%, yellow solid).
MS(ESI):M/Z＝285.0[M+H] +. MS(ESI): M/Z=285.0[M+H] + .
第八步：7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-甲腈7IStep 8: 7,8-Dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-carbonitrile 7I
Figure PCTCN2021106015-appb-000088
Figure PCTCN2021106015-appb-000088
将2-碘-7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉7H(600mg，2.11mmol)溶解在N,N-二甲基甲酰胺(8mL) 中，加入氰化锌(740mg，6.33mmol)、三(二亚苄基丙酮)二钯(120mg，0.21mmol)和2-双环己基膦-2',6'-二甲氧基联苯(86.1mg，0.21mmol)，氮气置换三次，在微波下150℃反应两小时。将反应液倒入水中，水相用乙酸乙酯萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋干得粗品。该粗品经柱层析(硅胶，石油醚：二氯甲烷＝2:1)分离纯化得到7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-甲腈7I(180mg，收率：46.6％，黄色固体)。2-Iodo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline 7H (600 mg, 2.11 mmol) was dissolved in N,N-dimethylformamide (8 mL) , were added zinc cyanide (740mg, 6.33mmol), tris(dibenzylideneacetone)dipalladium (120mg, 0.21mmol) and 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (86.1mg , 0.21 mmol), replaced with nitrogen three times, and reacted at 150 °C for two hours under microwave. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried in vacuo to obtain the crude product. The crude product was separated and purified by column chromatography (silica gel, petroleum ether:dichloromethane=2:1) to obtain 7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-methan Nitrile 7I (180 mg, yield: 46.6%, yellow solid).
MS(ESI):M/Z＝184.1[M+H] +. MS(ESI): M/Z=184.1[M+H] + .
第九步：2-(7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-基)丙-2-胺7JStep 9: 2-(7,8-Dihydro-6H-pyrazolo[4,5,1-ij]quinolin-2-yl)propan-2-amine 7J
Figure PCTCN2021106015-appb-000089
Figure PCTCN2021106015-appb-000089
将三氯化铈(700mg，2.84mmol)在干燥四氢呋喃(8mL)中搅拌1小时，降温至-78℃,滴入甲基锂(2.2mL，2.84mmol，1.3M),搅拌1小时。然后滴入7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-甲腈7I(130mg，0.71mmol)的四氢呋喃(1mL)溶液，缓慢升至室温并搅拌16小时。用1mL 10％氢氧化钠水溶液淬灭，过滤，滤液用无水硫酸钠干燥，真空旋干得到粗品。该粗品经柱层析(硅胶，石油醚：乙酸乙酯＝1:1)分离纯化得到2-(7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-基)丙-2-胺7J(50mg，收率：35.6％，黄色油状物)。Cerium trichloride (700 mg, 2.84 mmol) was stirred in dry tetrahydrofuran (8 mL) for 1 hour, cooled to -78°C, methyl lithium (2.2 mL, 2.84 mmol, 1.3 M) was added dropwise, and the mixture was stirred for 1 hour. Then a solution of 7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-carbonitrile 7I (130 mg, 0.71 mmol) in tetrahydrofuran (1 mL) was added dropwise, slowly warmed to room temperature and Stir for 16 hours. Quenched with 1 mL of 10% aqueous sodium hydroxide solution, filtered, the filtrate was dried over anhydrous sodium sulfate, and dried in vacuo to obtain the crude product. The crude product was separated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:1) to obtain 2-(7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline- 2-yl)propan-2-amine 7J (50 mg, yield: 35.6%, yellow oil).
MS(ESI):M/Z＝216.0[M+H] +. MS(ESI): M/Z=216.0[M+H] + .
第十步：(1R,5S,6r)-6-((2-(7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-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7KThe tenth step: (1R,5S,6r)-6-((2-(7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinolin-2-yl]propane-2 -yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 7K
Figure PCTCN2021106015-appb-000090
Figure PCTCN2021106015-appb-000090
2-(7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-基)丙-2-胺7J(110mg，0.60mmol)，化合物(1R,5S,6r)-3-(叔丁氧羰基-3-氮杂双环[3.1.0]己烷-6-羧酸(137mg,0.60mmol)、HATU(342mg,0.9mmoL)和三乙胺(505mg,5.0mmol)溶于N,N-二甲基甲酰胺(2mL)中，室温搅拌16小时。将反应液倒入水中，水相用乙酸乙酯萃取，有机相经饱和食盐水洗涤、无水硫酸钠干燥、真空旋干得粗品。该粗品经柱层析(硅胶，石油醚：二氯甲烷＝2:1)分离纯化得到(1R,5S,6r)-6-((2-(7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-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7K(130mg，收率：59.9％，黄色固体)。2-(7,8-Dihydro-6H-pyrazolo[4,5,1-ij]quinolin-2-yl)propan-2-amine 7J (110 mg, 0.60 mmol), compound (1R,5S, 6r)-3-(tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (137 mg, 0.60 mmol), HATU (342 mg, 0.9 mmol) and triethylamine (505 mg, 5.0 mmol) was dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 16 hours. The reaction solution was poured into water, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, and anhydrous sodium sulfate Dry and spin to dry in vacuo to obtain the crude product. The crude product was separated and purified by column chromatography (silica gel, petroleum ether: dichloromethane=2:1) to obtain (1R,5S,6r)-6-((2-(7,8-) Dihydro-6H-pyrazolo[4,5,1-ij]quinolin-2-yl]propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3- tert-Butyl carboxylate 7K (130 mg, yield: 59.9%, yellow solid).
MS(ESI):M/Z＝425.1[M+H] +. MS(ESI): M/Z=425.1[M+H] + .
第十一步：(1R,5S,6r)-N-(2-(7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物7)The eleventh step: (1R,5S,6r)-N-(2-(7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinolin-2-yl)propane-2 -yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 7)
Figure PCTCN2021106015-appb-000091
Figure PCTCN2021106015-appb-000091
将(1R,5S,6r)-6-((2-(7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-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7K(110mg，0.26mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.5mL)，然后在室温搅拌3小时。旋干反应混合物中的溶剂得到粗品，经反相制备色谱纯化得到(1R,5S,6r)-N-(2-(7,8-二氢-6H-吡唑并[4,5,1-ij]喹啉-2-基)丙-2-基)-3-氮杂双环[3.1.0]己烷-6-羧酰胺(化合物7)(31mg，白色固体，产率37％)。(1R,5S,6r)-6-((2-(7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinolin-2-yl]propan-2-yl) Carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate tert-butyl ester 7K (110 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added ), then stirred at room temperature for 3 hours. The solvent in the reaction mixture was spin-dried to obtain the crude product, which was purified by reverse-phase preparative chromatography to obtain (1R,5S,6r)-N-(2-(7,8-dihydro-6H-pyridine) Azolo[4,5,1-ij]quinolin-2-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 7) (31 mg, white solid, 37% yield).
MS(ESI):m/z＝325.1[M+H] +. MS(ESI): m/z=325.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.58(d,1H),7.01(d,1H),6.95-6.92(m,1H),4.27(t,2H),2.93(t,2H),2.87(d,2H),2.68(d,2H),2.23-2.17(m,2H),1.66(s,6H),1.61-1.62(m,1H),1.49-1.48(m,2H). 1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.58(d,1H),7.01(d,1H),6.95-6.92(m,1H),4.27(t,2H),2.93 (t, 2H), 2.87(d, 2H), 2.68(d, 2H), 2.23-2.17(m, 2H), 1.66(s, 6H), 1.61-1.62(m, 1H), 1.49-1.48(m , 2H).
测试例：Test case:
测试例1、人类生长抑制素IV型受体SSTR4激动剂活性测定Test Example 1. Determination of human somatostatin type IV receptor SSTR4 agonist activity
试验目的：利用基于细胞的人SSTR4cAMP测定法测定待测化合物对SSTR4受体的激动作用。Purpose of the test: A cell-based human SSTR4 cAMP assay was used to determine the agonistic effect of the test compound on the SSTR4 receptor.
細胞培养及试剂配制：细胞株：Flp-In-CHO-SSTR4稳转株(stable pool)；Cell culture and reagent preparation: cell strain: Flp-In-CHO-SSTR4 stable transgenic strain (stable pool);
完全培养基:Ham'sF-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'sF-12K+10％FBS；实验缓冲液:1XHBSS+20mMHEPES+0.1％BSA+500uMIBMX。Complete medium: Ham'sF-12K+10%FBS+1x penicillin-streptomycin (PS)+600μg/ml hygromycin B; cell seeding medium: Ham'sF-12K+10%FBS; assay buffer : 1XHBSS+20mM HEPES+0.1%BSA+500uMIBMX.
试验操作：Test operation:
(1)Flp-In-CHO-SSTR4稳转株细胞株培养于完全培养基，于37℃，5％CO 2至70％～90％融合度。 (1) The Flp-In-CHO-SSTR4 stably transformed cell line was cultured in complete medium at 37°C, 5% CO 2 to 70%-90% confluency.
(2)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(384PE培养板)，每孔接种7,000个细胞，于37℃，5％CO 2培养过夜。 (2) After TrypLE digestion, the cells were resuspended in the seeding medium, seeded in a 384-well cell culture plate (384PE culture plate), 7,000 cells were seeded per well, and cultured overnight at 37°C, 5% CO 2 .
(3)配制阳性对照化合物和待测化合物工作液(8X)。(3) Prepare positive control compound and test compound working solution (8X).
(4)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。(4) Take out the cell culture plate, invert and centrifuge at 200g for 5s at room temperature to remove the medium, then quickly add 15 μl of experimental buffer to each experimental well, and centrifuge at 200g for 5s at room temperature.
(5)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。(5) Add 2.5 μl of the 8X compound working solution diluted in step 3 to the corresponding test wells, centrifuge at 200 g for 5 s at room temperature, and incubate at 37 °C for 10 min.
(6)配制4uM Forskolin工作液(8X)。(6) Prepare 4uM Forskolin working solution (8X).
(7)取出细胞板平衡至室温，然后加入2.5μl步骤6中配制好的8XForskolin工作液至相应试验孔中，200g，RT，5s，于37℃，静置30min。(7) Take out the cell plate and equilibrate to room temperature, then add 2.5 μl of the 8X Forskolin working solution prepared in step 6 to the corresponding test well, 200 g, RT, 5 s, stand at 37° C. for 30 min.
(8)冻融Eu-cAMP示踪剂和Uliaght-抗cAMP，用检测缓冲液将Eu-cAMPtracer稀释50倍，将Uliaght-抗cAMP稀释150倍。(8) Freeze-thaw Eu-cAMP tracer and Uliaght-anti-cAMP, dilute Eu-cAMPtracer 50-fold and Uliaght-anti-cAMP 150-fold with detection buffer.
(9)加入10μlEu-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 10μlUliaght-抗cAMP至其余实验孔中。(9) Add 10 μl of Eu-cAMP tracer to all experimental wells, then add 10 μl of detection buffer to NC wells, and add 10 μl of Uliaght-anti-cAMP to the remaining experimental wells.
(10)将反应板于室温200g离心30s，25℃静置1h后，利用Envision收集数据。(10) Centrifuge the reaction plate at 200 g for 30 s at room temperature, and after standing at 25° C. for 1 h, use Envision to collect data.
数据分析：data analysis:
Z’因子＝1-3*(SDMax+SDMin)/(平均Max-平均Min)Z' factor = 1-3*(SDMax+SDMin)/(Average Max-Average Min)
CVMax＝(SDMax/平均Max)*100％CVMax=(SDMax/Average Max)*100%
CVMin＝(SDMin/平均Min)*100％CVMin=(SDMin/average Min)*100%
S/B＝信号/背景S/B = signal/background
媒剂对照(Min)：测定缓冲液Vehicle Control (Min): Assay Buffer
阳性对照(Max):1,000nM Somatostatin 14Positive control (Max): 1,000nM Somatostatin 14
利用GraphPad非线性拟合公式计算化合物EC50:Compound EC50s were calculated using the GraphPad nonlinear fitting formula:
Y＝底部+(顶部-底部)/(1+10^((LogEC50-X)*HillSlope))Y=Bottom+(Top-Bottom)/(1+10^((LogEC50-X)*HillSlope))
X:化合物浓度log值；Y:HTRF比例X: compound concentration log value; Y: HTRF ratio
表1、人类生长抑制素IV型受体SSTR4激动剂活性测定结果Table 1. Measurement results of human somatostatin type IV receptor SSTR4 agonist activity
化合物编号Compound number SSTR4,EC 50(nM) SSTR4, EC 50 (nM)
化合物1Compound 1 0.0950.095
化合物2 Compound 2 0.4070.407
化合物3Compound 3 0.2040.204
化合物4Compound 4 0.0750.075
化合物5 Compound 5 0.2280.228
化合物6Compound 6 0.1710.171
化合物7Compound 7 0.1180.118
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。Conclusion: The compounds of the present invention have obvious agonistic activity of human growth hormone type IV receptor SSTR4.
测试例2、肝微粒体代谢稳定性Test Example 2. Metabolic Stability of Liver Microsomes
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。Metabolic degradation of test compounds was analyzed using pooled human liver microsomes and male rat liver microsomes, respectively, at 37°C.
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。 The final incubation reaction system solution contained phosphate buffer (pH 7.4), positive control compound (dextromethorphan) or test compound (200 μM, 1.5 μL) and liver microsomes (0.5 mg/mL, 238.5 μL). After a 5 min pre-incubation at 37°C, NADPH (5 mM, 60 μL) was added to start the reaction. A fixed volume of the reaction mixture (30 μL) was sampled into solution at fixed time points (0, 5, 15, 30, 60 min) to quench the reaction. After centrifugation (4000 rpm, 15 min), the supernatant (100 μL) was taken and mixed with distilled water (100 μL) and then subjected to LC-MS/MS analysis to test the amount of compound. The half-life was calculated by the first-order reaction kinetic equation (C t =C 0 xe-ket , T 1/2 =Ln2/ke).
表2、人类肝微粒体和雄性大鼠肝微粒体分析测试结果Table 2. Analysis test results of human liver microsomes and male rat liver microsomes
Figure PCTCN2021106015-appb-000092
Figure PCTCN2021106015-appb-000092
Figure PCTCN2021106015-appb-000093
Figure PCTCN2021106015-appb-000093
结论：本发明化合物在肝微粒体中有较好的代谢稳定性。Conclusion: The compounds of the present invention have good metabolic stability in liver microsomes.
测试例3、药代动力学评价Test Example 3. Pharmacokinetic Evaluation
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。Using rats as test animals, LC/MS/MS method was used to determine the drug concentrations in plasma at different times after oral and intravenous injection of test compounds in rats. The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.
试验动物：Test animals:
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。For each compound, 6 healthy adult SD (Sprague-Dawley) rats, male, were divided into oral and intravenous administration groups, 3 rats in each group, purchased from Shanghai Sipple-Bike Laboratory Animal Co., Ltd., animal production license number : SCXK (Shanghai) 2008-0016.
药物配制：Drug preparation:
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。A certain amount of the drug was weighed and dissolved in 5% dimethylacetamide (DMA) + 5% polyethylene glycol-15 hydroxystearate (solutol) + 90% salt solution to prepare a 0.2 mg/mL solution.
给药：Dosing:
SD大鼠禁食过夜后口服和静脉注射给药。SD rats were fasted overnight and administered orally and intravenously.
试验操作：Test operation:
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。Test compounds are administered orally and intravenously to rats. At 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, 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. Within one hour, the plasma was separated by centrifugation at 6800g at 2-8°C for 6 minutes, stored at -80°C for LC/MS/MS analysis, and the rats were fed 4 hours after administration.
表3、大鼠药代动力学参数Table 3. Pharmacokinetic parameters in rats
Figure PCTCN2021106015-appb-000094
Figure PCTCN2021106015-appb-000094
结论：本发明化合物的药代吸收良好。Conclusion: The pharmacokinetics of the compounds of the present invention are well absorbed.
测试例4、动物药效评价Test Example 4. Animal efficacy evaluation
化合物在大鼠坐骨神经慢性压迫性损伤(CCI)疼痛模型中的药效学研究Pharmacodynamic study of compounds in a rat model of chronic compression injury (CCI) of the sciatic nerve
1、摘要1. Abstract
采用机械痛觉超敏法评估化合物口服给药(PO)在大鼠坐骨神经慢性压迫性损伤(CCI)疼痛模型中的药效。The mechanical allodynia method was used to evaluate the efficacy of oral administration (PO) of compounds in a rat model of chronic compression injury (CCI) pain of the sciatic nerve.
2、试验方案2. Test plan
2.1试验药物2.1 Test drug
普瑞巴林(阳性对照)、化合物5Pregabalin (positive control), compound 5
2.2实验动物2.2 Experimental animals
Sprague-Dawley大鼠，30只，雄性，平均分成3组，购自上海斯莱克实验动物有限公司Sprague-Dawley rats, 30 males, divided into 3 groups, were purchased from Shanghai Slack Laboratory Animal Co., Ltd.
2.3试验方法2.3 Test method
2.3.1造模2.3.1 Modeling
实验动物适应性饲养3～7天后进行造模。手术过程全程执行无菌操作，手术器械(剪刀，镊子，手术刀，手术棉，缝合线)在手术前进行消毒。手术前使用舒泰50 20mg/kg+塞拉嗪8mg/kg(腹腔注射,2mL/kg)麻醉动物，挤压动物脚趾以确认动物已经完全麻醉，并在动物眼部涂抹眼用软膏以防止动物角膜干燥。随后，对动物腰部手术区域进行剃毛，并使用碘伏和70％乙醇对皮肤消毒三遍，待皮肤干燥后开始手术。首先分离左侧坐骨神经，在坐骨神经分叉上游大约7毫米的位置，使用4-0铬制肠线松结扎四道，间距约为1mm，然后缝合伤口。手术后将动物放置在电热毯上，皮下注射5mL生理盐水以防止脱水。等动物完全苏醒后(可自由活动)将动物放回笼中。The experimental animals were adaptively reared for 3 to 7 days before modeling. The entire surgical procedure was performed aseptically, and surgical instruments (scissors, forceps, scalpels, surgical cotton, sutures) were sterilized before surgery. Before surgery, use sutai 50 20mg/kg + xylazine 8mg/kg (intraperitoneal injection, 2mL/kg) to anesthetize the animal, squeeze the animal's toes to confirm that the animal has been completely anesthetized, and apply ophthalmic ointment to the animal's eyes to prevent the animal's cornea dry. Subsequently, the animal's waist operation area was shaved, and the skin was disinfected three times with iodophor and 70% ethanol, and the operation was started after the skin was dry. First, the left sciatic nerve was isolated, and four ligatures were ligated with 4-0 chrome catgut approximately 7 mm upstream of the sciatic nerve bifurcation, approximately 1 mm apart, and the wound was sutured. After surgery, animals were placed on an electric blanket and injected subcutaneously with 5 mL of normal saline to prevent dehydration. After the animals are fully awake (free to move), return the animals to their cages.
2.3.2动物分组2.3.2 Animal grouping
术后第11天，将动物放在实验测试环境中适应，每天15分钟，连续适应3天。术后第13天，对大鼠进行机械痛觉超敏基础值测定，将没有表现出机械痛觉超敏的动物(缩脚阈值(PWT)大于5g)剔除后随机分成三组。On the 11th day after the operation, the animals were acclimated in the experimental test environment for 15 minutes a day for 3 consecutive days. On the 13th day after the operation, the basal value of mechanical hyperalgesia was measured on the rats, and the animals without mechanical hyperalgesia (the foot withdrawal threshold (PWT) greater than 5 g) were excluded and randomly divided into three groups.
2.3.3动物给药与机械痛觉超敏测试2.3.3 Animal administration and mechanical allodynia test
术后第14天，动物按表4进行给药，大鼠分别于给药后1、2和6小时后进行机械痛觉超敏测试。首轮给药测试后，动物洗脱3天，再次进行机械痛觉超敏基础值测定后再次分成三组，并按表5进行给药，于给药后1、2和4小时后进行机械痛觉超敏测试。On the 14th day after the operation, the animals were administered according to Table 4, and the rats were tested for mechanical hyperalgesia 1, 2 and 6 hours after administration, respectively. After the first round of dosing test, the animals were washed out for 3 days, and the basal value of mechanical allodynia was measured again and divided into three groups again. Hypersensitivity test.
表4 第一轮药效学测试试验分组与给药信息Table 4 Grouping and dosing information of the first round of pharmacodynamic testing
Figure PCTCN2021106015-appb-000095
Figure PCTCN2021106015-appb-000095
表5 第二轮药效学测试试验分组与给药信息Table 5 Grouping and dosing information of the second round of pharmacodynamic testing
Figure PCTCN2021106015-appb-000096
Figure PCTCN2021106015-appb-000096
Figure PCTCN2021106015-appb-000097
Figure PCTCN2021106015-appb-000097
2.4试验结果：2.4 Test results:
如表6、7以及图1所示，大鼠手术14天后，PWT降至3.3g左右，明显低于正常大鼠PWT，提示机械痛觉超敏模型造模成功。两轮试验阳性对照化合物普瑞巴林给药后1至4或6小时后均可显著抑制手术诱导的大鼠机械痛觉超敏。与此同时，化合物5组30和100mg/kg给药后可呈剂量依赖性地抑制大鼠的机械痛觉超敏，100mg/kg剂量下药效等同于阳性药普瑞巴林。As shown in Tables 6, 7 and Figure 1, 14 days after the operation of the rats, the PWT decreased to about 3.3 g, which was significantly lower than the PWT of the normal rats, indicating that the mechanical allodynia model was successfully established. Both rounds of test positive control compound pregabalin significantly inhibited surgically induced mechanical hyperalgesia in rats 1 to 4 or 6 hours after administration. At the same time, compound 5 group can inhibit mechanical hyperalgesia in rats in a dose-dependent manner after administration of 30 and 100 mg/kg, and the efficacy at 100 mg/kg is equivalent to the positive drug pregabalin.
表6 第一轮药效学测试试验结果Table 6 Results of the first round of pharmacodynamic testing
Figure PCTCN2021106015-appb-000098
Figure PCTCN2021106015-appb-000098
注：**p<0.01，****p<0.0001与溶剂对照组相比较，使用Two-way ANOVA统计Note: **p<0.01, ****p<0.0001 compared with the solvent control group, using Two-way ANOVA statistics
表7 第二轮药效学测试试验结果Table 7 Results of the second round of pharmacodynamic testing
Figure PCTCN2021106015-appb-000099
Figure PCTCN2021106015-appb-000099
注：****p<0.0001与溶剂对照组相比较，使用Two-way ANOVA统计Note: ****p<0.0001 compared with the solvent control group, using Two-way ANOVA statistics
结论：本发明化合物有良好的镇痛效果。Conclusion: The compounds of the present invention have good analgesic effect.
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。The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.
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。The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can also be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

Claims (39)

  1. 一种具有式(I)结构特征的含氮杂环化合物，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：A nitrogen-containing heterocyclic compound having the structural characteristics of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof :
    Figure PCTCN2021106015-appb-100001
    Figure PCTCN2021106015-appb-100001
    其中，R 1选自-H和C 1-6烷基； wherein, R 1 is selected from -H and C 1-6 alkyl;
    L 1选自-NH-和-O-； L 1 is selected from -NH- and -O-;
    L 2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 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;
    R 2、R 3各自独立地选自-H、C 1-6烷基、C 3-6环烷基，或R 2和R 3一起形成包含0至1个选自-O-、-NR 9-、-SO-和-SO 2-的基团的3至6元饱和环基；其中R 2和R 3不同时为-H； R 2 and R 3 are each independently selected from -H, C 1-6 alkyl, C 3-6 cycloalkyl, or R 2 and R 3 together form 0 to 1 selected from -O-, -NR 9 A 3- to 6-membered saturated cyclic group of a group of -, -SO- and -SO 2 -; wherein R 2 and R 3 are not simultaneously -H;
    R 4、R 5、R 6、R 7、R 8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碳环基或者-(CH 2) m-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，且R 4、R 5、R 6、R 7、R 8中所述的烷基、烷氧基、碳环基、苯基、杂芳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； R 4 , R 5 , R 6 , R 7 , R 8 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 carbocyclyl, -(CH 2 ) m -(3- to 10-membered heterocyclyl), -(CH 2 ) m -OC 3-10 carbocyclyl, or -( CH 2 ) m -O-(3- to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl, said heterocyclyl and heteroaryl containing 1 to 4 selected from N, O and S and the alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl described in R 4 , R 5 , R 6 , R 7 , R 8 are each independently optionally further substituted with 0 to 4 substituents selected from -H, -F, -Cl, -Br, -I, hydroxyl, mercapto, cyano, amino, C 1-4 alkyl and C 1-4 alkoxy;
    R 9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； R 9 is selected from -H, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkyl, halogen, hydroxyl, cyano and C 3-6 cycloalkyl;
    A环选自C 9-10芳基、9至10元杂芳基和9至10元杂环基，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； Ring A is selected from C 9-10 aryl, 9 to 10 membered heteroaryl and 9 to 10 membered heterocyclyl, wherein the heteroaryl and heterocyclyl comprise 1 to 4 selected from N, O and S heteroatom;
    B环为5至7元环，所述5至7元环含有0、1或2个选自N、O和S的杂原子，所述5至7元环含有0、1或2个双键，所述B环与A环共有两个或三个原子；Ring B is a 5- to 7-membered ring containing 0, 1 or 2 heteroatoms selected from N, O and S, and the 5- to 7-membered ring containing 0, 1 or 2 double bonds , the B ring and the A ring share two or three atoms;
    所述A环和B环进一步被1至3个R 10取代，其中R 10各自独立地选自-H、C 1-6烷基、C 1-4烷氧基C 1-4烷基、-(CH 2) n-烯基、-(CH 2) n-炔基、-(CH 2) n-C 3-10碳环基、-(CH 2) n-(3至10元杂环基)、C 6-10芳基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，所述的烷基、烷氧基、芳基、杂芳基、碳环基或杂环基各自独立任选进一步被0至4个选自-H、卤素、羟基、氰基、C 1-4烷基和C 1-4烷氧基的取代基所取代； The A ring and the B ring are further substituted by 1 to 3 R 10 , wherein each R 10 is independently selected from -H, C 1-6 alkyl, C 1-4 alkoxy C 1-4 alkyl, - (CH 2 ) n -alkenyl, -(CH 2 ) n -alkynyl, -(CH 2 ) n -C 3-10 carbocyclyl, -(CH 2 ) n -(3 to 10 membered heterocyclyl) , C 6-10 aryl and 5- to 6-membered heteroaryl, the heterocyclic and heteroaryl contain 1 to 4 heteroatoms selected from N, O and S, the alkyl, alkoxy group, aryl, heteroaryl, carbocyclyl or heterocyclyl, each independently optionally further selected from 0 to 4 groups selected from -H, halogen, hydroxy, cyano, C1-4alkyl and C1-4alkane substituted by an oxy substituent;
    m和n分别独立地选自0、1、2和3。m and n are independently selected from 0, 1, 2 and 3, respectively.
  2. 根据权利要求1所述的含氮杂环化合物，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环具有如下所示结构特征：The nitrogen-containing heterocyclic compound according to claim 1, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein That is, the A ring has the following structural features:
    Figure PCTCN2021106015-appb-100002
    Figure PCTCN2021106015-appb-100002
    其中，X分别独立地选自CR 10和N； wherein X is independently selected from CR 10 and N;
    Y选自单键、N和CR 11； Y is selected from a single bond, N and CR 11 ;
    R 10、R 11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) q-C 3-10碳环基、-(CH 2) q-(3至10元杂环基)、-(CH 2) q-O-C 3-10碳环基、-(CH 2) q-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，且R 10、R 11中所述的烷基、烷氧基、碳环基、苯基、杂芳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； R 10 and R 11 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclyl, -(CH 2 ) q -(3 to 10 membered heterocyclyl), -(CH 2 ) q -OC 3-10 carbocyclyl, -(CH 2 ) q -O-(3 to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl groups, the heterocyclyl and heteroaryl groups contain 1 to 4 heteroatoms selected from N, O and S, and R 10 , R 11, said alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocyclyl is independently optionally further substituted with 0 to 4 substituents selected -H, -F, -Cl, -Br, -I, substituted by substituents of hydroxyl, mercapto, cyano, amino, C 1-4 alkyl and C 1-4 alkoxy;
    q选自0、1、2和3。q is selected from 0, 1, 2 and 3.
  3. 根据权利要求2所述的含氮杂环化合物，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，
    Figure PCTCN2021106015-appb-100003
    选自具有如下所示结构特征的基团中的一个：     The nitrogen-containing heterocyclic compound according to claim 2, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein is,
    Figure PCTCN2021106015-appb-100003
    One of the groups selected from the structural features shown below:
    Figure PCTCN2021106015-appb-100004
    Figure PCTCN2021106015-appb-100004
  4. 根据权利要求3所述的含氮杂环化合物，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，所述含氮杂环化合物选自式(I-1)～(I-5)所示结构特征中的一个：The nitrogen-containing heterocyclic compound according to claim 3, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein In that, the nitrogen-containing heterocyclic compound is selected from one of the structural features represented by formulae (I-1) to (I-5):
    Figure PCTCN2021106015-appb-100005
    Figure PCTCN2021106015-appb-100005
    Figure PCTCN2021106015-appb-100006
    Figure PCTCN2021106015-appb-100006
  5. 根据权利要求1～4任一项所述的含氮杂环化合物，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，B环选自如下基团中的一个：The nitrogen-containing heterocyclic compound according to any one of claims 1 to 4, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or A prodrug, characterized in that the B ring is selected from one of the following groups:
    Figure PCTCN2021106015-appb-100007
    Figure PCTCN2021106015-appb-100007
    其中，W表示B环与A环共有的原子；Wherein, W represents an atom shared by ring B and ring A;
    V 1选自O、S、NR 12和CR 12R 13； V 1 is selected from O, S, NR 12 and CR 12 R 13 ;
    V 2选自N和CR 14； V 2 is selected from N and CR 14;
    R 12、R 13、R 14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) p-C 3-10碳环基、-(CH 2) p-(3至10元杂环基)、-(CH 2) p-O-C 3-10碳环基或者-(CH 2) p-O-(3至10元杂环基)、苯基和5至6元杂芳基，所述的杂环基和杂芳基含有1至4个选自N、O和S的杂原子，且R 12、R 13、R 14中所述的烷基、烷氧基、碳环基、苯基、杂芳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； R 12 , R 13 , R 14 are each independently selected from -H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkyl, -(CH 2 ) p -C 3-10 carbocyclic group, - (CH 2) p - (3 to 10-membered heterocyclic), - (CH 2) p -OC 3-10 carbon ring group or a - (CH 2) p -O -(3- to 10-membered heterocyclyl), phenyl and 5- to 6-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O and S, and R The alkyl, alkoxy, carbocyclic, phenyl, heteroaryl or heterocyclic groups described in 12 , R 13 , R 14 are each independently optionally further 0 to 4 selected from -H, -F, -Cl, -Br, -I, hydroxyl, mercapto, cyano, amino, C 1-4 alkyl and C 1-4 alkoxy substituents;
    p选自0、1、2和3。p is selected from 0, 1, 2 and 3.
  6. 根据权利要求1～4任一项所述的含氮杂环化合物，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为-H。 The nitrogen-containing heterocyclic compound according to any one of claims 1 to 4, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or A prodrug, characterized in that R 1 is -H.
  7. 根据权利要求1～4任一项所述的含氮杂环化合物，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，L 1为-NH-。 The nitrogen-containing heterocyclic compound according to any one of claims 1 to 4, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or A prodrug, characterized in that L 1 is -NH-.
  8. 根据权利要求1～4任一项所述的含氮杂环化合物，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，L 2为单键。 The nitrogen-containing heterocyclic compound according to any one of claims 1 to 4, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or The prodrug is characterized in that L 2 is a single bond.
  9. 根据权利要求1～4任一项所述的含氮杂环化合物，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 2、R 3为甲基。 The nitrogen-containing heterocyclic compound according to any one of claims 1 to 4, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or A prodrug, wherein R 2 and R 3 are methyl groups.
  10. 根据权利要求1～4任一项所述的含氮杂环化合物，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、R 6、R 7、R 8为-H。 The nitrogen-containing heterocyclic compound according to any one of claims 1 to 4, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or A prodrug, wherein R 4 , R 5 , R 6 , R 7 , and R 8 are -H.
  11. 根据权利要求1～4任一项所述的含氮杂环化合物，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为甲基，R 5、R 6、R 7、R 8为-H。 The nitrogen-containing heterocyclic compound according to any one of claims 1 to 4, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or A prodrug, characterized in that R 4 is methyl, and R 5 , R 6 , R 7 and R 8 are -H.
  12. 根据权利要求1～4任一项所述的含氮杂环化合物，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 10为-H或甲基。 The nitrogen-containing heterocyclic compound according to any one of claims 1 to 4, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or A prodrug, characterized in that R 10 is -H or methyl.
  13. 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，A compound of formula (a), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
    Figure PCTCN2021106015-appb-100008
    Figure PCTCN2021106015-appb-100008
    其中：in:
    X 1为C或N； X 1 is C or N;
    X 2为C或N； X 2 is C or N;
    Figure PCTCN2021106015-appb-100009
    表示单键或双键，条件是两个
    Figure PCTCN2021106015-appb-100010
    中有且仅有一个表示双键；
    Figure PCTCN2021106015-appb-100009
    Indicates a single or double bond, provided that both
    Figure PCTCN2021106015-appb-100010
    There is and only one represents a double bond;
    R 15与R 16以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者，R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；所述碳环基或杂环基任选经1-3个选自以下的取代基取代：-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) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基、-(CH 2) t-(5至6元杂芳基)和-SR x； R 15 and R 16 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; alternatively, R 16 and R 17 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; the carbocyclyl or heterocyclyl can be any Substituted with 1-3 substituents selected from the group consisting of: -H, halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t - C 6-10 aryl, -(CH 2 ) t -(5- to 6-membered heteroaryl) and -SR x ;
    当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
    当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
    R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 4选自H、C 1-6烷基和卤代C 1-6烷基； R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 5选自H、C 1-6烷基和卤代C 1-6烷基； R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R选自-H、C 1-6烷基和卤代C 1-6烷基； R is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    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' and R" are each selected from -H, C 1-6 alkyl and haloC 1-6 alkyl, or R' and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl;
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) t-C 2-6烯基、-(CH 2) t-C 2-6炔基、-(CH 2) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基和-(CH 2) t-(5至6元杂芳基)； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) t -C 2-6 alkenyl, -(CH 2 ) t -C 2-6 alkynyl , -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl and -(CH 2 ) t -C 6-10 aryl 2 ) t- (5- to 6-membered heteroaryl);
    t为0、1、2或3。t is 0, 1, 2 or 3.
  14. 式(a-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，A compound of formula (a-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
    Figure PCTCN2021106015-appb-100011
    Figure PCTCN2021106015-appb-100011
    其中：in:
    R 15与R 16以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；所述碳环基或杂环基任选经1-3个选自以下的取代基取代：-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) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基、-(CH 2) t-(5至6元杂芳基)和-SR x； R 15 and R 16 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; the carbocyclyl or heterocyclyl optionally Substituted with 1-3 substituents selected from: -H, halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3 to 10 membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl, -(CH 2 ) t -(5- to 6-membered heteroaryl) and -SR x ;
    当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
    当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
    R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 4选自H、C 1-6烷基和卤代C 1-6烷基； R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 5选自H、C 1-6烷基和卤代C 1-6烷基； R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R选自-H、C 1-6烷基和卤代C 1-6烷基； R is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    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' and R" are each selected from -H, C 1-6 alkyl and haloC 1-6 alkyl, or R' and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl;
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) t-C 2-6烯基、-(CH 2) t-C 2-6炔基、-(CH 2) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基和-(CH 2) t-(5至6元杂芳基)； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) t -C 2-6 alkenyl, -(CH 2 ) t -C 2-6 alkynyl , -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl and -(CH 2 ) t -C 6-10 aryl 2 ) t- (5- to 6-membered heteroaryl);
    t为0、1、2或3。t is 0, 1, 2 or 3.
  15. 权利要求14的式(a-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：The compound of formula (a-1) of claim 14, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:
    R 15与R 16以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基； R 15 and R 16 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form a 5-7 membered carbocyclyl or a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S;
    当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基和卤代C 1-6烷基； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
    当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基和卤代C 1-6烷基； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
    R 4选自H、C 1-6烷基和卤代C 1-6烷基； R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 5选自H、C 1-6烷基和卤代C 1-6烷基。 R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl.
  16. 权利要求14的式(a-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：The compound of formula (a-1) of claim 14, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:
    R 15与R 16以及它们连接的原子一起形成5-6元碳环基； R 15 and R 16 together with the atoms to which they are attached form a 5-6 membered carbocyclyl;
    R 2和R 3各自独立地选自H、C 1-4烷基和卤代C 1-4烷基； R 2 and R 3 are each independently selected from H, C 1-4 alkyl and haloC 1-4 alkyl;
    R 4选自-H、C 1-4烷基和卤代C 1-4烷基； R 4 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl;
    R 5选自-H、C 1-4烷基和卤代C 1-4烷基； R 5 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl;
    R 17选自-H和C 1-4烷基。 R 17 is selected from -H and C 1-4 alkyl.
  17. 权利要求14的式(a-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：The compound of formula (a-1) of claim 14, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:
    R 15与R 16以及它们连接的原子一起形成6元碳环基； R 15 and R 16 together with the atoms to which they are attached form a 6-membered carbocyclyl;
    R 2和R 3各自独立地为C 1-4烷基，优选为甲基； R 2 and R 3 are each independently C 1-4 alkyl, preferably methyl;
    R 4为C 1-4烷基，优选为甲基； R 4 is C 1-4 alkyl, preferably methyl;
    R 5为-H； R 5 is -H;
    R 17为-H。 R 17 is -H.
  18. 权利要求14的式(a-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：The compound of formula (a-1) of claim 14, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:
    R 16与R 17以及它们连接的原子一起形成含有1-2个选自N、O和S的杂原子的5-6元杂环基； R 16 and R 17 together with the atoms to which they are attached form a 5-6 membered heterocyclyl group containing 1-2 heteroatoms selected from N, O and S;
    R 2和R 3各自独立地选自H、C 1-4烷基和卤代C 1-4烷基； R 2 and R 3 are each independently selected from H, C 1-4 alkyl and haloC 1-4 alkyl;
    R 4选自-H、C 1-4烷基和卤代C 1-4烷基； R 4 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl;
    R 5选自-H、C 1-4烷基和卤代C 1-4烷基； R 5 is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl;
    R 15选自-H和C 1-4烷基。 R 15 is selected from -H and C 1-4 alkyl.
  19. 权利要求14的式(a-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：The compound of formula (a-1) of claim 14, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:
    R 16与R 17以及它们连接的原子一起形成含有1-2个选自N和O的杂原子的5元杂环基； R 16 and R 17 together with the atoms to which they are attached form a 5-membered heterocyclic group containing 1-2 heteroatoms selected from N and O;
    R 2和R 3各自独立地为C 1-4烷基； R 2 and R 3 are each independently C 1-4 alkyl;
    R 4选自H和C 1-4烷基； R 4 is selected from H and C 1-4 alkyl;
    R 5选自-H和C 1-4烷基； R 5 is selected from -H and C 1-4 alkyl;
    R 15为-H。 R 15 is -H.
  20. 权利要求14的式(a-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：The compound of formula (a-1) of claim 14, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein:
    R 16与R 17以及它们连接的原子一起形成含有1个氧杂原子的5元杂环基； R 16 and R 17 together with the atoms to which they are attached form a 5-membered heterocyclic group containing 1 oxygen heteroatom;
    R 2和R 3各自独立地为C 1-4烷基，优选为甲基； R 2 and R 3 are each independently C 1-4 alkyl, preferably methyl;
    R 4为H； R 4 is H;
    R 5为-H； R 5 is -H;
    R 15为-H。 R 15 is -H.
  21. 式(a-2)、(a-3)或(a-4)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，Compounds of formula (a-2), (a-3) or (a-4), or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs thereof type or prodrug,
    Figure PCTCN2021106015-appb-100012
    Figure PCTCN2021106015-appb-100012
    其中：in:
    R 15与R 16以及它们连接的原子一起形成含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基；所述碳环基或杂环基任选经1-3个选自以下的取代基取代：-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) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基、-(CH 2) t-(5至6元杂芳基)和-SR x； R 15 together with R 16 and the atoms to which they are attached form a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form 5 -7-membered carbocyclyl or 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; the carbocyclyl or heterocyclyl is optionally 1-3 selected from the following Substituent substitution of: -H, halogen, cyano, -OR, -NR'R", C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl, -( CH 2 ) t -(5- to 6-membered heteroaryl) and -SR x ;
    当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
    当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、-NR’R”、-OR和-SR x； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR and -SR x ;
    R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
    R 4选自H、C 1-6烷基和卤代C 1-6烷基； R 4 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 5选自H、C 1-6烷基和卤代C 1-6烷基； R 5 is selected from H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R选自-H、C 1-6烷基和卤代C 1-6烷基； R is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
    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' and R" are each selected from -H, C 1-6 alkyl and haloC 1-6 alkyl, or R' and R" together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl;
    R x选自-H、C 1-6烷基、卤代C 1-6烷基、-(CH 2) t-C 2-6烯基、-(CH 2) t-C 2-6炔基、-(CH 2) t-C 3-10碳环基、-(CH 2) t-(3至10元杂环基)、-(CH 2) t-C 6-10芳基和-(CH 2) t-(5至6元杂芳基)； R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) t -C 2-6 alkenyl, -(CH 2 ) t -C 2-6 alkynyl , -(CH 2 ) t -C 3-10 carbocyclyl, -(CH 2 ) t -(3- to 10-membered heterocyclyl), -(CH 2 ) t -C 6-10 aryl and -(CH 2 ) t -C 6-10 aryl 2 ) t- (5- to 6-membered heteroaryl);
    t为0、1、2或3。t is 0, 1, 2 or 3.
  22. 权利要求21的式(a-2)、(a-3)或(a-4)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：The compound of formula (a-2), (a-3) or (a-4) of claim 21, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable Salts, polymorphs or prodrugs, wherein:
    R 15与R 16以及它们连接的原子一起形成含有1-2个选自N、O和S的杂原子的5-7元杂环基；或者R 16与R 17以及它们连接的原子一起形成5-7元碳环基或含有1-2个选自N、O和S的杂原子的5-7元杂环基； R 15 together with R 16 and the atoms to which they are attached form a 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S; or R 16 and R 17 and the atoms to which they are attached together form 5 -7-membered carbocyclyl or 5-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S;
    当R 15未成环时，其选自-H、卤素、氰基、C 1-6烷基和卤代C 1-6烷基； When R 15 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
    当R 17未成环时，其选自-H、卤素、氰基、C 1-6烷基和卤代C 1-6烷基； When R 17 is not cyclic, it is selected from -H, halogen, cyano, C 1-6 alkyl and halogenated C 1-6 alkyl;
    R 2和R 3各自独立地选自H、C 1-6烷基和卤代C 1-6烷基； R 2 and R 3 are each independently selected from H, C 1-6 alkyl and haloC 1-6 alkyl;
    R 4选自H和C 1-6烷基； R 4 is selected from H and C 1-6 alkyl;
    R 5选自H和C 1-6烷基。 R 5 is selected from H and C 1-6 alkyl.
  23. 权利要求21的式(a-2)、(a-3)或(a-4)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：The compound of formula (a-2), (a-3) or (a-4) of claim 21, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable Salts, polymorphs or prodrugs, wherein:
    R 15与R 16以及它们连接的原子一起形成含有1-2个选自N、O和S的杂原子的5-6元杂环基； R 15 and R 16 and the atoms to which they are attached together form a 5-6 membered heterocyclyl group containing 1-2 heteroatoms selected from N, O and S;
    R 2和R 3各自独立地选自H、C 1-4烷基和卤代C 1-4烷基； R 2 and R 3 are each independently selected from H, C 1-4 alkyl and haloC 1-4 alkyl;
    R 4选自H和C 1-4烷基； R 4 is selected from H and C 1-4 alkyl;
    R 5选自H和C 1-4烷基； R 5 is selected from H and C 1-4 alkyl;
    R 17选自-H和C 1-4烷基。 R 17 is selected from -H and C 1-4 alkyl.
  24. 权利要求21的式(a-2)、(a-3)或(a-4)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：The compound of formula (a-2), (a-3) or (a-4) of claim 21, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable Salts, polymorphs or prodrugs, wherein:
    R 15与R 16以及它们连接的原子一起形成含有1-2个选自N和O的杂原子的5-6元杂环基； R 15 and R 16 and the atoms to which they are attached together form a 5-6 membered heterocyclic group containing 1-2 heteroatoms selected from N and O;
    R 2和R 3各自独立地为C 1-4烷基，优选为甲基； R 2 and R 3 are each independently C 1-4 alkyl, preferably methyl;
    R 4为-H； R 4 is -H;
    R 5为-H； R 5 is -H;
    R 17为-H。 R 17 is -H.
  25. 根据权利要求1所述的含氮杂环化合物，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，所述的含氮杂环化合物选自如下化合物中的一个：The nitrogen-containing heterocyclic compound according to claim 1, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein In that, the nitrogen-containing heterocyclic compound is selected from one of the following compounds:
    Figure PCTCN2021106015-appb-100013
    Figure PCTCN2021106015-appb-100013
  26. 根据权利要求1所述的含氮杂环化合物，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。The nitrogen-containing heterocyclic compound according to claim 1, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein In that the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumaric acid Salt, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate , aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, triflate or their The combination.
  27. 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1～26中任一项所述的含氮杂环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。A pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective dose of the nitrogen-containing heterocyclic compound according to any one of claims 1 to 26 or a stereoisomer, N-oxide, hydrated Compounds, solvates, metabolites, pharmaceutically acceptable salts, polymorphs or prodrugs, and pharmaceutically acceptable carriers or excipients.
  28. 如权利要求1～26中任一项所述的含氮杂环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27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。The nitrogen-containing heterocyclic compound according to any one of claims 1 to 26 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or Use of a prodrug or a pharmaceutical composition as claimed in claim 27 in the manufacture of a medicament for the treatment and/or prevention of a disease or condition affected by SSTR4 activation.
  29. 如权利要求1～26中任一项所述的含氮杂环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27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。The nitrogen-containing heterocyclic compound according to any one of claims 1 to 26 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or Use of a prodrug or a pharmaceutical composition as claimed in claim 27 in the preparation of a medicament for treating and/or preventing pain.
  30. 根据权利要求29所述的应用，其特征在于，所述疼痛为神经痛。The use according to claim 29, wherein the pain is neuralgia.
  31. 根据权利要求29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。The application according to claim 29, wherein 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, Pain from diabetic neuropathy, osteoarthritis, tumor pain, or muscle fiber pain.
  32. 如权利要求1～26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27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。The compound of any one of claims 1 to 26, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or such as The pharmaceutical composition of claim 27 for use in the treatment and/or prevention of diseases or symptoms affected by SSTR4 activation.
  33. 如权利要求1～26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27所述的药物组合物，其用于治疗和/或预防疼痛。The compound of any one of claims 1 to 26, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or such as The pharmaceutical composition of claim 27 for the treatment and/or prevention of pain.
  34. 根据权利要求33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33所述的药物组合物，其特征在于，所述疼痛为神经痛。The compound of claim 33 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or the drug of claim 33 A composition, wherein the pain is neuralgia.
  35. 根据权利要求33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33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、肿瘤疼痛和肌肉纤维疼痛。The compound of claim 33 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or the drug of claim 33 A composition, characterized in that 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, osteoarthritis Pain from arthritis, tumor pain, and muscle fiber pain.
  36. 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1～26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27所述的药物组合物。A method of treating a disease or condition affected by SSTR4 activation, comprising administering a compound according to any one of claims 1 to 26 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, The product, pharmaceutically acceptable salt, polymorph or prodrug or pharmaceutical composition of claim 27.
  37. 一种治疗疼痛的方法，其包括给予如权利要求1～26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27所述的药物组合物。A method of treating pain, comprising administering a compound according to any one of claims 1 to 26 or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable compound thereof A salt, polymorph or prodrug or the pharmaceutical composition of claim 27.
  38. 权利要求37的方法，其中所述疼痛为神经痛。38. The method of claim 37, wherein the pain is neuralgia.
  39. 权利要求37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、肿瘤疼痛和肌肉纤维疼痛。The method of claim 37, wherein 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, bone Pain from arthritis, tumor pain, and muscle fiber pain.
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