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WO2021164661A1 - 2-phenylcyclopropylmethylamine derivative, and preparation method and use thereof - Google Patents

2-phenylcyclopropylmethylamine derivative, and preparation method and use thereof Download PDF

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Publication number
WO2021164661A1
WO2021164661A1 PCT/CN2021/076289 CN2021076289W WO2021164661A1 WO 2021164661 A1 WO2021164661 A1 WO 2021164661A1 CN 2021076289 W CN2021076289 W CN 2021076289W WO 2021164661 A1 WO2021164661 A1 WO 2021164661A1
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substituted
alkyl
group
independently
unsubstituted
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French (fr)
Chinese (zh)
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程建军
汪胜
闫文仲
樊鲁玉
余竞
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ShanghaiTech University
Center for Excellence in Molecular Cell Science of CAS
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ShanghaiTech University
Center for Excellence in Molecular Cell Science of CAS
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Definitions

  • the invention relates to a 2-phenylcyclopropylmethylamine derivative, and a preparation method and application thereof.
  • G protein-coupled receptors are the most important family of drug targets. According to statistics, as of 2017, among all small molecule drugs approved for marketing by the US FDA, drugs targeting GPCRs accounted for 34% (Santos et al., Nature Review Drug Discovery, 2017, 16, 19-34). As the largest family of receptors encoded by the human genome, GPCRs contain about 1,000 different receptors, including more than 300 potential drug targets. Studies have confirmed that GPCR is related to neuropsychiatric diseases (such as schizophrenia, pain, etc.), cardiovascular diseases (such as hypertension, heart failure, etc.), metabolic diseases (such as diabetes, obesity), immune diseases, and cancer. The occurrence and development of diseases are closely related.
  • monoamine GPCR receptors such as dopamine receptors and serotonin receptors
  • D1-5 dopamine receptors
  • D1 and D5 are D1 receptors, which are mainly coupled with G s protein, and increase the intracellular cAMP level after activation
  • D2, D3, and D4 are D2 receptors.
  • Body mainly coupled with G i protein, reduces intracellular cAMP level after activation.
  • the dopaminergic signaling pathway has been the focus of neuroscience research in recent decades. Abnormalities of the dopaminergic signaling pathway are related to many diseases such as schizophrenia and Parkinson's disease.
  • Small molecule antagonists or partial agonists targeting dopamine D2 receptors are effective anti-schizophrenics, such as haloperidol, olanzapine, aripiprazole, cariprazine, etc.
  • the main targets of action are all dopamine D2 receptors; dopamine D3 receptors of the same subfamily as D2 are also important targets for many anti-schizophrenics.
  • Highly selective D3 receptor antagonists or partial agonists also have treatments The potential for drug addiction.
  • Dopamine D1, D4 and D5 receptors have also been confirmed as potential drug targets.
  • Serotonin receptors include 14 subtypes. Except 5-HT 3 which is an ion channel, the other 13 subtypes are all GPCR receptors. Among them, serotonin 2A receptor (5-HT 2A ) antagonists are another important drug target for the treatment of schizophrenia, such as the 5-HT 2A selective inverse agonist pimavanserin approved by the US FDA in 2018. 5-HT 2A is also a major target of multi-target "atypical" antipsychotic drugs; 5-HT 2C receptor is a drug target that suppresses appetite and reduces weight.
  • Lorcaserin is a 5-HT 2C receptor agonist; at the same time, 5-HT 2C receptor agonists have the potential to treat schizophrenia (Pogorelov et al., Neuropsychopharmacology 2017, 42, 2163-2177); and so on.
  • 2-Phenylcyclopropylmethylamine is a collective term for another class of small molecule compounds, and it is also an important backbone for drug advantages.
  • the antidepressant drug levomilnacipran levomilnacipran
  • its main mechanism of action is as serotonin reuptake and demethylation.
  • Inhibitor of adrenaline reuptake The insomnia drug tasimelteon, which was launched in 2014, also contains the "2-phenylcyclopropylmethylamine” substructure, and its main target is the melatonin receptor MT1/MT2.
  • the technical problem to be solved by the present invention is to provide a new structure of 2-phenylcyclopropylmethylamine derivative and its preparation method and application.
  • the 2-phenylcyclopropylmethylamine derivative of the present invention has an affinity activity for dopamine receptors and/or serotonin receptors.
  • the present invention provides a compound represented by formula I:
  • R 1 is hydrogen, halogen (such as fluorine or chlorine), substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b ( For example, methylthio), -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group refer to the C 1 -C 4 alkyl group And C 3 -C 6 cycloalkyl are each independently substituted with 1, 2, 3 or 4 R 1a ;
  • R 2 is hydrogen, halogen (such as fluorine or chlorine), substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group refer to the C 1 -C 4 alkyl group and C 3 -C 6 cycloalkane
  • the groups are each independently substituted with 1, 2, 3 or 4 R 2a ;
  • R 3 is hydrogen, halogen (such as fluorine or chlorine), substituted or unsubstituted C 1 -C 4 alkyl (the substituted or unsubstituted C 1 -C 4 alkyl such as trifluoromethyl), substituted or unsubstituted Substituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 ring Alkyl means that the C 1 -C 4 alkyl group and C 3 -C 6 cycloalkyl group are each independently substituted with 1, 2, 3 or 4 R 3a ;
  • R 4 is hydrogen, halogen (such as fluorine or chlorine), substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group refer to the C 1 -C 4 alkyl group and C 3 -C 6 cycloalkane
  • the groups are each independently substituted with 1, 2, 3 or 4 R 4a ;
  • R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a (such as methoxy, ethoxy or 2-fluoro Ethoxy), -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group refer to the C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl are each independently substituted with 1, 2, 3 or 4 R 5a ;
  • substituted phenyl and substituted 5-6 membered heteroaryl groups refer to the C 5 -C 6 cycloalkyl group, 5-6 membered heterocycloalkyl group, phenyl group and 5-6 membered heteroaryl group independently Ground is replaced by 1, 2, 3 or 4 R 5b ;
  • R 1a , R 2a , R 3a , R 4a and R 5a are each independently halogen (e.g. fluorine), C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, -OR e , -SR f Or -NR g R h ;
  • Each R 5b is independently halogen (e.g. fluorine), C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
  • R 6 is hydrogen, C 1 -C 6 alkyl (e.g. methyl, ethyl, n-propyl or isopropyl), C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl) (e.g. cyclopropylmethyl);
  • L is -(CR 8 R 9 ) t -or
  • t is 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2 or 3;
  • n 1, 2 or 3;
  • Each of R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl refers to the C The 1- C 4 alkyl group is substituted with 1, 2, 3 or 4 R 8a ; provided that R 8 and R 9 attached to the same carbon atom are not at the same time -OR a ;
  • Each R 8a is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or -OR e ;
  • A is Or -XY
  • R 10 is hydrogen or C 1 -C 4 alkyl
  • R 11 is substituted or unsubstituted C 3 -C 8 cycloalkyl (the C 3 -C 8 cycloalkyl such as cyclohexyl), substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR 11a R 11b , a substituted or unsubstituted C 6 -C 14 aryl group (the C 6 -C 14 aryl group such as phenyl) or a substituted or unsubstituted 5-14 membered heteroaryl group (the 5-14 membered heteroaryl group Group such as indolyl), wherein the substituted C 3 -C 8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C 6 -C 14 aryl and substituted 5-14 membered hetero Aryl refers to the C 3 -C 8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 14 aryl
  • R 11 is substituted or unsubstituted C 3 -C 8 cycloalkyl (the C 3 -C 8 cycloalkyl such as cyclohexyl), substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR 11a R 11b , a substituted or unsubstituted C 6 -C 14 aryl group (the C 6 -C 14 aryl group such as phenyl) or a substituted or unsubstituted 5-14 membered heteroaryl group (the 5-14 membered heteroaryl group Base such as indolyl, such as ), wherein the substituted C 3 -C 8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C 6 -C 14 aryl and substituted 5-14 membered heteroaryl refer to The C 3 -C 8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 14
  • R 11a is hydrogen or C 1 -C 4 alkyl (e.g. methyl);
  • R 11b is hydrogen or C 1 -C 4 alkyl (e.g. methyl);
  • Each R 11c is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN;
  • Each R 11d is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN;
  • R 12 is hydrogen or C 1 -C 4 alkyl
  • R 13 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl (the C 6 -C 14 aryl such as phenyl) or substituted or unsubstituted 5-14 membered heteroaryl, wherein the substituted C 3 -C 8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C
  • the 6- C 14 aryl group and the substituted 5-14 membered heteroaryl group refer to the C 3 -C 8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 14 aryl group and 5-14 membered
  • Each heteroaryl group is independently optionally substituted with 1, 2, 3, or 4 R 13a ;
  • Each R 13a is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN;
  • X is -O- or -S-;
  • R 14 and R 15 are each independently hydrogen or C 1 -C 4 alkyl
  • Y is a substituted or unsubstituted C 6 -C 14 aryl group or a substituted or unsubstituted 5-14 membered heteroaryl group, the substituted C 6 -C 14 aryl group and the substituted 5-14 membered heteroaryl group Means that the C 6 -C 14 aryl group and the 5-14 membered heteroaryl group are each independently substituted with 1, 2, 3 or 4 R 30 ;
  • Each R 30 is independently halogen, oxo, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycle Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4- alkyl, substituted C 3 -C 6 cycloalkyl, substituted 4-6 membered heterocycloalkyl, substituted phenyl and substituted 5-6 membered heteroaryl refer to the C 1 -C 4 alkane , C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each independently substituted with 1,
  • Each R 40 is independently halogen, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN;
  • Each R a, R b, R c , R d, R e, R f and R g are each independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 4 Haloalkyl (e.g. C 1 -C 4 fluoroalkyl);
  • the number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S.
  • R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; and/or, R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; and/or, R 1 and R 2 and the adjacent two carbon atoms connecting them are together
  • a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-6 membered heterocycloalkyl group is formed; the definition of other variables is as described in any of the embodiments of the present invention.
  • each R 1a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.
  • each R 2a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; definitions of other variables As described in any aspect of the present invention.
  • each R 3a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.
  • R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; definitions of other variables As described in any aspect of the present invention.
  • each R 4a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.
  • R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; definitions of other variables As described in any aspect of the present invention.
  • each R 5a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.
  • each R 5b is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.
  • R 1 , R 2 , R 3 , R 4 and R 5 is independently as defined in the present invention; the definition of other variables is as described in any aspect of the present invention.
  • R 1 , R 2 , R 3 , R 4 and R 5 is independently as defined in the present invention; the definition of other variables is as described in any aspect of the present invention.
  • R 6 is hydrogen, C 1 -C 6 alkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 ring Alkyl); the definition of other variables is as described in any of the schemes of the present invention.
  • each R 8a is independently a C 1 -C 4 alkyl group; the definition of other variables is as described in any of the embodiments of the present invention.
  • t is 3, 4, 5 or 6; the definitions of other variables are as described in any of the embodiments of the present invention.
  • m is 1; other variables are defined as described in any of the aspects of the present invention.
  • n 1; other variables are defined as described in any of the aspects of the present invention.
  • L is -(CR 8 R 9 ) 3 -, -(CR 8 R 9 ) 4 -, -(CR 8 R 9 ) 5 -, Wherein k is 0, 1, 2 or 3; the definitions of other variables are as described in any of the schemes of the present invention.
  • the substituted or unsubstituted C 6 -C 14 aryl group can be (E.g ), (E.g )or (E.g ), wherein ring A is phenyl or 5-6 membered heteroaryl (5 membered heteroaryl such as furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl, 6-membered heteroaryl groups such as pyrazinyl, pyridazinyl, pyridinyl or pyrimidinyl), each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; others
  • the definition of the variable is as described in any aspect of the present invention.
  • the substituted or unsubstituted C 6 -C 14 aryl group can be wherein each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • the substituted or unsubstituted C 6 -C 14 aryl group can be wherein each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • ring B is 5-6 membered heteroaryl (5 membered heteroaryl such as furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl, 6-membered heteroaryl
  • ring C is 5-6 membered heteroaryl (5 membered heteroaryl such as furyl, thienyl, pyrrolyl , Pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl
  • 6-membered heteroaryl such as pyrazinyl, pyridazinyl, pyridinyl or pyrimidinyl
  • ring C is 5-6 membered heteroaryl (5 membered heteroaryl such as furyl, thienyl, pyrrolyl , Pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl, 6-membered
  • each p is independently 0, 1, 2 or 3
  • each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • the substituted or unsubstituted 5-14 membered heteroaryl group can be Wherein each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • the substituted or unsubstituted 5-14 membered heteroaryl group can be Wherein each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • each p is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is The definitions of other variables are as described in any aspect of the present invention.
  • A is The definitions of other variables are as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3, q is 0 or 1; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1 or 2; the definitions of other variables are as described in any of the aspects of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0 or 1, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • A is -XY, where Y is p is 0 or 1, q is 0, 1 or 2; the definition of other variables is as described in any aspect of the present invention.
  • R 14 is hydrogen; the definitions of other variables are as described in any of the embodiments of the present invention.
  • R 15 is hydrogen; the definitions of other variables are as described in any of the embodiments of the present invention.
  • X is -O- or -S-; the definition of other variables is as described in any aspect of the present invention.
  • -L-A is selected from any one of the following group definitions:
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is Each p is independently 0 or 1, and each q is independently 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is Where each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3;
  • L is-(CR 8 R 9 ) 3 -,-(CR 8 R 9 ) 4 -,-(CR 8 R 9 ) 5 -or
  • A is -XY, X is -O-, Y is Where each p is independently 0, 1, 2 or 3; or
  • L is A is Where k is 0, 1, 2 or 3, and each p is independently 0, 1, 2 or 3;
  • -L-A is selected from any one of the following group definitions:
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is Wherein p is 0 or 1, q is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is Where p is 0, 1, 2 or 3, and q is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 5 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 5 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Where p is 0, 1, 2 or 3;
  • (20)L is A is Where k is 0, 1, 2 or 3;
  • L is A is Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;
  • (22)L is A is Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;
  • (23)L is A is Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;
  • L is A is Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;
  • (25)L is A is Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;
  • L is A is Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 3 -
  • A is -XY
  • X is -S-
  • Y is Wherein p is 0 or 1, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, and Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, and Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -
  • A is -XY
  • X is -NHC(O)-
  • Y is Wherein p is 0, 1, 2 or 3, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, and Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 5 -, A is -XY, X is -O-, and Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 5 -, A is -XY, X is -O-, and Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is A is Wherein k is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is A is As described in any one of the options.
  • L is A is Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is A is Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is A is Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is A is Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • L is A is Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.
  • -LA is the definitions of other variables as described in any aspect of the present invention.
  • each R 10 is independently hydrogen; the definitions of other variables are as described in any of the embodiments of the present invention.
  • R 11a is a C 1 -C 4 alkyl group; other variables are defined as described in any of the embodiments of the present invention.
  • R 11b is a C 1 -C 4 alkyl group; other variables are defined as described in any of the embodiments of the present invention.
  • each R 11c is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.
  • each R 11d is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.
  • R 12 is hydrogen or C 1 -C 4 alkyl; the definition of other variables is as described in any of the embodiments of the present invention.
  • -LA is the definitions of other variables as described in any aspect of the present invention.
  • R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.
  • R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.
  • R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.
  • R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.
  • each of R 1a , R 2a , R 3a , R 4a and R 5a is independently halogen; other variables are defined as any of the present invention As described in the protocol.
  • L is -(CR 8 R 9 ) 3 -, -(CR 8 R 9 ) 4 -or Wherein k is 0, 1, 2 or 3; the definitions of other variables are as described in any of the schemes of the present invention.
  • A is Or -XY; the definition of other variables is as described in any aspect of the present invention.
  • Y is preferably The definitions of other variables are as described in any aspect of the present invention.
  • -L-A is selected from any one of the following group definitions:
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is p is 0 or 1, q is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is Where each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is p is 0, 1, 2 or 3; or
  • A is -X-Y; the definitions of other variables are as described in any of the aspects of the present invention.
  • each R 30 is independently halogen, oxo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; the definitions of other variables are as described in any of the aspects of the present invention.
  • each R 30 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.
  • each R 40 is independently halogen, oxo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; the definitions of other variables are as described in any of the aspects of the present invention.
  • each R 40 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.
  • each of R 8 and R 9 is independently hydrogen or C 1 -C 4 alkyl; other variables are defined as in any of the embodiments of the present invention As described in.
  • each group is defined as follows:
  • R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 1a substitutions;
  • R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 2a substitutions;
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 3a substitutions;
  • R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is 1 , 2, 3 or 4 R 4a substitutions;
  • R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 5a substitutions;
  • R 1a , R 2a , R 3a , R 4a and R 5a is independently halogen
  • R 6 is hydrogen, C 1 -C 6 alkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl);
  • -L-A is selected from any of the following group definitions:
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is p is 0 or 1, q is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is p is 0, 1, 2 or 3, q is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is p is 0, 1, 2 or 3; or
  • L is A is -NHC(O)NR 11a R 11b , and k is 0, 1, 2 or 3;
  • R 8 and R 9 are independently hydrogen or C 1 -C 4 alkyl
  • R 8a is C 1 -C 4 alkyl
  • R 10 is hydrogen or C 1 -C 4 alkyl
  • R 11a is hydrogen or C 1 -C 4 alkyl
  • R 11b is hydrogen or C 1 -C 4 alkyl
  • Each R 30 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl;
  • Each R 40 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl;
  • Each R a is independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • -L-A is preferably defined from any one of the following groups:
  • L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is p is 0 or 1, q is 0, 1, 2 or 3;
  • L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is p is 0, 1, 2 or 3, and q is 0, 1, 2 or 3.
  • -LA is the definitions of other variables as described in any aspect of the present invention.
  • -LA is preferably The definitions of other variables are as described in any aspect of the present invention.
  • each R 30 is independently a C 1 -C 4 alkyl group.
  • each R 40 is independently a C 1 -C 4 alkyl group.
  • R 8 and R 9 are both hydrogen.
  • R 11a is a C 1 -C 4 alkyl group.
  • R 11b is a C 1 -C 4 alkyl group.
  • each p is independently 0 or 1.
  • each q is independently 0 or 1.
  • k is zero in the compound of formula I as described in any of the preceding embodiments.
  • each group is defined as follows:
  • R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 1a substitutions;
  • R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 2a substitutions;
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 3a substitutions;
  • R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 4a substitutions;
  • R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 5a substitutions;
  • R 1a , R 2a , R 3a , R 4a and R 5a is independently halogen
  • R 6 is hydrogen, C 1 -C 6 alkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl);
  • R 11a is C 1 -C 4 alkyl
  • R 11b is a C 1 -C 4 alkyl group
  • Each R a is independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.
  • R 1 , R 2 , R 3 , R 4 and R 5 is independently as defined in the present invention; the definition of other variables is as described in any aspect of the present invention.
  • Part is selected from any one of the following group definitions:
  • R 2 is halogen (e.g. fluorine or chlorine);
  • R 3 is halogen (such as fluorine or chlorine) or substituted or unsubstituted C 1 -C 4 alkyl (the substituted or unsubstituted C 1 -C 4 alkyl such as trifluoromethyl); the substituted
  • the C 1 -C 4 alkyl group means that the C 1 -C 4 alkyl group is substituted with 1, 2, 3 or 4 R 3a ;
  • R 3a is halogen (for example, fluorine);
  • R 1 is halogen (e.g. chlorine) and R 2 is halogen (e.g. chlorine); and
  • R 2 is halogen (for example, fluorine or chlorine)
  • R 5 is -OR a (for example, methoxy, ethoxy or 2-fluoroethoxy)
  • R a is C 1 -C 4 alkyl or C 1- C 4 haloalkyl (e.g. C 1 -C 4 fluoroalkyl);
  • Y is preferably Further, -LA is preferably
  • Y is preferably Further, -LA is preferably
  • the compound represented by Formula I is selected from any of the following structures:
  • the compound represented by Formula I is selected from any of the following structures:
  • the structure of the three-membered ring formed by the carbon atoms marked with * and # is Or a mixture of the two.
  • the compound represented by formula I as described in any of the preceding schemes the structure of the three-membered ring formed by the carbon atoms marked with * and # is
  • the structure of the three-membered ring formed by the carbon atoms marked with * and # is
  • the pharmaceutically acceptable salt of the compound represented by Formula I is hydrochloride.
  • the present invention also provides a method for preparing the compound represented by formula I as described above, which is selected from any of the following schemes:
  • Scheme 1 includes the following steps: in a solvent (such as tetrahydrofuran), the compound represented by formula II-1 is subjected to the reduction reaction shown below in the presence of a reducing agent (such as borane) to obtain the formula I
  • a reducing agent such as borane
  • Scheme 2 includes the following steps: in a solvent (such as acetonitrile, methanol), the compound shown in formula II-2 and R 6a -CHO or Carry out the reductive amination reaction as shown below in the presence of a reducing agent (such as sodium triacetoxyborohydride) to obtain the compound represented by formula I; wherein, R 6a -CH 2 -or Namely R 6 ; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, A, * and # are defined as described above;
  • a solvent such as acetonitrile, methanol
  • a reducing agent such as sodium triacetoxyborohydride
  • Scheme 3 includes the following steps: in a solvent (such as acetonitrile, methanol), the compound represented by formula II-3 and AL 2 -CHO in the presence of a reducing agent (such as sodium triacetoxyborohydride) are carried out as follows
  • a reducing agent such as sodium triacetoxyborohydride
  • the reductive amination reaction shown is enough to obtain the compound represented by formula I; wherein, -CH 2 -L 2 -is -L-; R 1 , R 2 , R 3 , R 4 , R 5 , R 6.
  • the definitions of L, A, * and # are as mentioned above;
  • Scheme 4 includes the following steps: in a solvent (such as acetonitrile, methanol), the compound shown in formula II-4 and Carry out the reductive amination reaction as shown below in the presence of a reducing agent (such as sodium triacetoxyborohydride) to obtain the compound represented by formula I; wherein R 1 , R 2 , R 3 , R 4.
  • a reducing agent such as sodium triacetoxyborohydride
  • the method for preparing the compound represented by formula II-1 may include the following steps: in a solvent (for example, tetrahydrofuran, N,N-dimethylformamide), the compound represented by formula III-1 and Carry out the condensation reaction as shown below in the presence of a condensing agent (such as HATU) to obtain the compound represented by formula II-1; wherein R 1 , R 2 , R 3 , R 4 , R 5 , The definitions of R 6 , L 1 , A, * and # are as mentioned above;
  • a solvent for example, tetrahydrofuran, N,N-dimethylformamide
  • a condensing agent such as HATU
  • the present invention also provides the following compound:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , A, * and # are as described above.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula I or its tautomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable compound of any one of the foregoing , Or a crystal form or solvate of any of the foregoing, and at least one pharmaceutical excipient.
  • the compound represented by formula I or its tautomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or the foregoing can be a therapeutically effective amount.
  • the present invention also provides a compound of Formula I or its tautomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or any of the foregoing.
  • a compound of Formula I or its tautomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or any of the foregoing The use of one crystal form or solvate in the preparation of medicines.
  • the drug may be used to treat and/or prevent dopamine (e.g. dopamine D3 receptor or dopamine D2 receptor) signal pathway abnormalities and/or serotonin (e.g. 5-HT 2C ) signaling Pathway abnormalities related diseases drugs related diseases drugs.
  • dopamine e.g. dopamine D3 receptor or dopamine D2 receptor
  • serotonin e.g. 5-HT 2C
  • the drug may be a drug for the treatment and/or prevention of diseases related to abnormalities of dopamine (for example, dopamine D3 receptor or dopamine D2 receptor) signal pathways.
  • dopamine for example, dopamine D3 receptor or dopamine D2 receptor
  • the drug may be a drug used to treat and/or prevent diseases related to abnormalities in the serotonin (eg, 5-HT 2C) signaling pathway.
  • diseases related to abnormalities in the serotonin eg, 5-HT 2C
  • the abnormality of the dopaminergic signal pathway and/or the disease related to the abnormality of the serotonin (for example, 5-HT 2C ) signal pathway may be a psychiatric disease, such as Parkinson's disease, schizophrenia, dual Mental disorders such as phase disorder, mania, depression, anxiety, drug addiction, or Alzheimer’s disease.
  • the drug may be a drug for the treatment and/or prevention of mental diseases, such as the treatment and/or prevention of Parkinson’s disease, schizophrenia, bipolar disorder, mania, depression Medications for mental illnesses such as psychosis, anxiety, drug addiction, or Alzheimer’s disease.
  • mental diseases such as the treatment and/or prevention of Parkinson’s disease, schizophrenia, bipolar disorder, mania, depression Medications for mental illnesses such as psychosis, anxiety, drug addiction, or Alzheimer’s disease.
  • the present invention also provides a method for preventing and/or treating diseases associated with abnormal dopaminergic signaling pathways, which comprises administering a therapeutically effective amount of the compound represented by formula I or its interconversion to a patient in need of such treatment Isomers, stereoisomers or isotopic derivatives, or pharmaceutically acceptable salts of any of the foregoing, or crystal forms or solvates of any of the foregoing.
  • the present invention also provides a method for preventing and/or treating diseases associated with abnormal dopaminergic signaling pathways, which comprises administering a therapeutically effective amount of the compound represented by formula I or its interconversion to a patient in need of such treatment Isomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing, or the pharmaceutical composition.
  • the present invention also provides a method for preventing and/or treating Parkinson's disease, schizophrenia, bipolar disorder, mania, depression, anxiety, drug addiction or Alzheimer's disease and other mental diseases
  • a method which comprises administering to a patient in need of such treatment a therapeutically effective amount of the compound represented by formula I or its tautomer, stereoisomer or isotopic derivative, or any of the foregoing pharmacologically An acceptable salt, or a crystal form or solvate of any of the foregoing, or the pharmaceutical composition described above.
  • the present invention also provides a compound of Formula I or its tautomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or any of the foregoing.
  • a crystalline form or solvate of one in the preparation of a modulator of dopamine receptor for example, dopamine D3 receptor or dopamine D2 receptor
  • a serotonin for example, 5-HT 2C
  • the dopamine receptor modulator may be a dopamine receptor partial agonist or a dopamine receptor antagonist.
  • the serotonin receptor modulator may be a serotonin receptor partial agonist or a serotonin receptor antagonist.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt.
  • the acid addition can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • a pharmaceutically acceptable acid include inorganic acids, and the inorganic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
  • the compound of the present invention contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.
  • a base addition salt or an acid addition salt.
  • the pharmaceutically acceptable salt is hydrochloride.
  • the hydrochloride salt described herein includes possible monohydrochloric acid, dihydrochloride, polyhydrochloride, and combinations thereof.
  • solvate refers to a substance formed by combining a compound with a stoichiometric or non-stoichiometric solvent.
  • the solvent molecules in the solvate can exist in an ordered or non-ordered arrangement.
  • the solvents include but are not limited to: water, methanol, ethanol and the like.
  • stereoisomer refers to the isomers caused by the same order of interconnection of atoms or atomic groups in the molecule, but different spatial arrangements, such as cis-trans isomers, optical isomers, atropisomers and the like. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.). Optical isomers include enantiomers and diastereomers.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions. For example, acetone and 1-propene-2-ol can be converted into each other by the rapid movement of hydrogen atoms on oxygen and ⁇ -carbon.
  • isotopic derivative refers to the substitution of one or more atoms in a compound by one or more atoms having a specific atomic mass or mass number.
  • isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl).
  • the isotopic compounds of the present invention can generally be prepared by substituting isotopically-labeled reagents for non-isotopically-labeled reagents according to the methods described herein. Typical examples of isotopic derivatives include deuterated compounds.
  • crystal form means that the ions or molecules are arranged strictly and periodically in a three-dimensional space in a certain way, and have the regularity of periodic recurrence at a certain distance; due to the above-mentioned periodic arrangement, there may be multiple Crystal form, that is, polymorphism.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group having a specified number of carbon atoms, for example, a C 1 -C 4 alkyl group refers to an alkyl group having 1 to 4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl.
  • the C 1 -C 4 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl.
  • alkylene refers to a saturated linear or branched divalent hydrocarbon group having the specified number of carbon atoms.
  • alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -and -CH 2 (CH 3 )-CH 2 -.
  • alkoxy refers to -OR X , where R X is an alkyl group as defined above.
  • the C 1 -C 4 alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tertiary Butoxy.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group substituted with 1 to 4 halogen atoms, each halogen atom independently being fluorine, chlorine, bromine or iodine.
  • haloalkyl include, but are not limited to, trifluoromethyl and 1-fluoro-2-chloroethyl.
  • the C 1 -C 6 alkyl group and halogen in the C 1 -C 6 haloalkyl group are as defined herein.
  • the C 1 -C 4 alkyl group and halogen in the C 1 -C 4 haloalkyl group are as defined herein.
  • cycloalkyl refers to a non-aromatic saturated or partially unsaturated monovalent cyclic hydrocarbon group having a specified number of ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (for example, bicyclic and tricyclic), and can be fused, spiro, and bridged ring structures. The cycloalkyl group optionally contains one or more double bonds. In some embodiments, the cycloalkyl group is a monocyclic group. In some embodiments, the cycloalkyl group is a saturated group. In some embodiments, the cycloalkyl group is a saturated monocyclic group.
  • Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclopentyl Hexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl and cycloheptyl.
  • the C 3 -C 6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the C 3 -C 8 cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocycloalkyl refers to a non-aromatic saturated or partially unsaturated cyclic group formed by carbon atoms and at least one heteroatom selected from N, O, and S.
  • the heterocycloalkyl group can be connected to other parts of the molecule through a heteroatom or carbon atom.
  • the heterocycloalkyl group may be monocyclic or polycyclic (for example, bicyclic and tricyclic), and may be a fused ring, spiro ring, and bridged ring structure.
  • the heterocycloalkyl group optionally contains one or more double bonds.
  • the heterocycloalkyl group is a monocyclic group.
  • the heterocycloalkyl group is a saturated group.
  • the heterocycloalkyl group is a saturated monocyclic group.
  • heterocycloalkyl groups include, but are not limited to, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrothiophene- 2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • a 3-8 membered heterocycloalkyl is a 3, 4, 5, 6, 7 or 8 membered heterocycloalkyl.
  • the 3-8 membered heterocycloalkyl group can be a 3, 4, 5, or 6 membered heterocycloalkyl group.
  • 4-6 membered heterocycloalkyl is 4, 5 or 6 membered heterocycloalkyl.
  • aryl refers to any stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, in which at least one ring is aromatic.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, phenanthryl, anthracenyl, or acenaphthyl. It is understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
  • the C 6 -C 14 aryl group may be phenyl or naphthyl.
  • the C 6 -C 14 aryl group may be a phenyl group.
  • heteroaryl refers to a stable monocyclic or polycyclic (e.g., bicyclic and tricyclic) group with up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains at least A heteroatom selected from O, N and S. Heteroaryl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms.
  • the 5-14 membered heteroaryl group is a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered heteroaryl group.
  • a 5-6 membered heteroaryl group refers to a monocyclic heteroaryl group, a 5-membered heteroaryl group such as furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl, 6-membered Heteroaryl groups are for example pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl.
  • 8-10 membered bicyclic heteroaryl group is a combined ring structure, including 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered cycloalkyl, 5-6 membered Heteroaryl 5-6 membered heterocyclic group, phenyl 5-6 membered heterocyclic group and phenyl 5-6 membered heteroaryl group, such as indolyl, benzothienyl, benzofuranyl, quinoline Linyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, pyridothienyl, pyridofuranyl, 2H-chromenyl, benzothiazolyl, benzoxazolyl, benzo Pyrazolyl, pyridopyrazolyl, pyridothienyl, pyridofuranyl, benzimidazoly
  • connection site is any atom on the monocyclic or polycyclic ring. Examples are as follows: Groups include Structure Groups include Etc. but not including
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variables are only permitted if such combinations result in stable compounds.
  • w is 0, 1 or 2
  • each R is independently methyl or fluorine
  • connection direction is connected in the same direction as the reading order from left to right. Examples are as follows:
  • the linking group V in U 1 -VU 2 is -CD-, at this time -CD- connects U 1 and U 2 in the same direction as the reading order from left to right to form U 1 -CDU 2 , but not U 1 -DCU 2 .
  • pharmaceutical excipients refers to excipients and additives used in the production of drugs and formulating prescriptions, and are all substances contained in pharmaceutical preparations except for active ingredients. Please refer to the Fourth Edition of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition)
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) alleviating one or more biological manifestations of the disease or disease, (2) interfering with (a) one or more points in the biological cascade causing or causing the disease, or (b) ) One or more biological manifestations of the disorder, (3) Improve one or more symptoms, effects or side effects related to the disorder, or one or more symptoms, effects or side effects related to the disorder or its treatment, Or (4) to slow down the development of the disease or one or more biological manifestations of the disease.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound that is sufficient to effectively treat or prevent the diseases or conditions described herein when administered to a patient.
  • the “therapeutically effective amount” will vary according to the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed.
  • patient refers to any animal that is about to or has received administration of the compound or composition according to an embodiment of the present invention, mammals are preferred, and humans are preferred.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • the biological activity of the compounds of the present invention can be assessed by using any conventionally known methods. Appropriate detection methods are well known in the art. For example, the affinity activity, agonistic activity and/or antagonistic activity of the compound of the present invention for dopamine receptors, the pharmacokinetic activity and/or liver microsomal stability of the compound of the present invention, etc. can be tested by appropriate conventional methods.
  • the detection method provided by the present invention is presented only as an example and does not limit the present invention.
  • the compound of the present invention has activity in at least one of the detection methods provided by the present invention.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the compound of the present invention has dopamine receptor affinity activity, especially has better affinity activity to dopamine D3 receptor.
  • some of the compounds of the present invention exhibit affinity selectivity for dopamine D3 receptors, that is, they have better affinity activity for dopamine D3 receptors, and for dopamine D1, D2, D4, or D5 receptors.
  • the affinity activity is relatively weak.
  • some of the compounds of the present invention have agonist activity or antagonist activity on the dopamine D3 receptor.
  • some of the compounds of the present invention have agonist activity or antagonist activity on the dopamine D2 receptor.
  • Step 1 Intermediate INT-1 (4-methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol, cas:38942-51-7) was purchased commercially. Dissolve INT-1 (1.0 g, 5.26 mmol) in methyl acrylate (6 mL), and add cesium carbonate (3.43 g, 10.52 mmol). The reaction mixture was placed in a microwave reactor and reacted at 100°C for 30 minutes. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phase was separated and dried, and then concentrated.
  • Step 2 Intermediate INT-2 (4.0 g, 21 mmol) was dissolved in a mixed solution of tetrahydrofuran (50 mL) and water (20 mL), lithium hydroxide monohydrate (4.2 g, 100 mmol) was added, and the reaction was carried out at room temperature overnight.
  • the reaction solution was acidified with 3M hydrochloric acid, diluted with water, and extracted with ethyl acetate. After the organic phase was separated and dried, it was concentrated, and the residue was separated and purified by flash column chromatography (0-10% methanol/dichloromethane) to obtain a white solid INT-3 (2.26 g, yield 60%).
  • Step 3 Raw material trans-tert-butyl ((2-(5-fluoro-2-hydroxybenzene)cyclopropyl)methyl)carbamate (INT-4, trans mixture) can refer to the literature (ChemMedChem 2010, 5, The preparation method of compound 10 in 1221-1225) was synthesized.
  • the raw materials INT-4 (281 mg, 1.0 mmol) and methyl iodide (213 mg, 1.5 mmol) were dissolved in N, N-dimethylformamide (8 mL), potassium carbonate (828 mg, 6.0 mmol) was added, and the reaction mixture was placed in In a microwave reactor, react at 110°C for 30 minutes.
  • reaction solution was cooled to room temperature, it was diluted with water and extracted with ethyl acetate. After the organic phase was separated and dried, it was concentrated, and the residue was separated and purified by flash column chromatography (0-10% methanol/dichloromethane) to obtain a colorless oil INT-5 (trans mixture, 284 mg, yield 96%).
  • Step 4 Dissolve INT-5 (196 mg, 0.66 mmol) in tetrahydrofuran (4 mL), add hydrogen chloride ether solution (2M, 4 mL) and react overnight at room temperature. The reaction liquid changed from clear to white turbid liquid. The solvent was evaporated under reduced pressure and dried to obtain white solid INT-6 (trans mixture, 153 mg, yield 99%).
  • Step 5 Dissolve INT-3 (176mg, 0.67mmol), INT-6 (148mg, 0.64mmol) and HATU (363mg, 0.96mmol) in N,N-dimethylformamide (5mL), add sodium bicarbonate (161mg, 1.91mmol), react at room temperature for 5 hours. Add ethyl acetate to dilute, and wash with water and saturated brine successively. After the organic phase was separated and dried, concentrated, and the residue was separated and purified by flash column chromatography (0-20% ethyl acetate/petroleum ether) to obtain white solid INT-7 (trans mixture, 203 mg, yield 72%).
  • Step 6 Dissolve INT-7 (200mg, 0.46mmol) in dry tetrahydrofuran (15mL) and cool to 0°C. Under the protection of argon, 1M borane tetrahydrofuran solution (1.8 mL, 1.8 mmol) was slowly added dropwise. After the dripping was completed, the temperature was raised to reflux for 3 hours. Methanol (1 mL) and 3M aqueous hydrochloric acid (1 mL) were slowly added dropwise, and the reflux reaction was continued for 30 minutes. The reaction solution was cooled to room temperature, and the pH was adjusted to 8-10 with a saturated aqueous sodium bicarbonate solution.
  • Step 1 Following the method described in step 3 of Example 1, using ethyl iodide instead of methyl iodide to carry out an alkylation reaction with INT-4 to prepare a colorless oily compound INT-8 (trans mixture).
  • Step 2 Dissolve INT-8 (180 mg, 581.8 ⁇ mol) in 4M dioxane hydrochloride solution (5 mL), and react at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the residue was slurried in a mixed solution of ethyl acetate/petroleum ether (volume ratio 1/2) for 15 minutes. After filtration, the filter cake was rinsed with ethyl acetate (3 mL), and dried under vacuum to obtain white solid INT-9 (trans mixture, 134 mg, yield 94%).
  • Step 3 Following the method described in step 5 of Example 1, INT-9 and INT-3 were subjected to a condensation reaction to prepare a white solid compound INT-10 (trans mixture).
  • 1 H NMR 800MHz, CD 3 OD
  • Step 4 Following the method described in step 6 of Example 1, using INT-10 as a raw material for reduction reaction and salting the purified product I-7 with hydrogen chloride ether solution to obtain white solid I-7 hydrochloride (trans mixture ).
  • HRMS(ESI ) C 24 H 30 FN 4 OS
  • Step 1 Intermediate INT-4 (100mg, 0.36mmol), 2-fluoroethanol (52 ⁇ L, 0.89mmol) and triphenylphosphine (233mg, 0.89mmol) were dissolved in dry tetrahydrofuran (8mL), cooled to 0°C, Slowly add diethyl azodicarboxylate (140 ⁇ L, 0.89 mmol) dropwise. The reaction solution was reacted in a microwave reactor at 60°C for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-10% ethyl acetate/petroleum ether) to obtain INT-11 as a colorless oil (trans mixture, 110 mg, yield 95%).
  • Step 2 Following the method described in step 2 of Example 7, the Boc protection of INT-11 was removed to obtain a white solid compound INT-12 (trans mixture).
  • 1 H NMR 500MHz, CD 3 OD
  • ⁇ 6.96–6.87 (m, 2H), 6.76 (dd, J 9.4, 3.0 Hz, 1H), 4.87–4.70 (m, 2H), 4.34–4.18 (m, 2H), 3.05–2.97(m, 2H), 2.19–2.13(m, 1H), 1.27–1.22(m, 1H), 1.21–1.15(m, 1H), 1.05–1.00(m, 1H).
  • HRMS( ESI) C 12 H 16 F 2 NO + ([M+H] + ) calculated value: 228.1194, measured value: 228.1220.
  • Step 3 Following the method described in step 5 of Example 1, using INT-12 and INT-3 as raw materials for condensation reaction, a white solid compound INT-13 (trans mixture) is prepared.
  • Step 4 Following the method described in step 6 of Example 1, using INT-13 as a raw material for a reduction reaction, and purifying the product I-10 to form a salt with HCl to prepare a white solid I-10 hydrochloride (trans mixture).
  • Step 1 Intermediate INT-14 (trans mixture) can be prepared by referring to the literature method (J. Med. Chem. 2016, 59, 578-591). Using INT-14 as a raw material, the Boc removal reaction was carried out following the method described in step 2 of Example 7 to prepare a white solid compound INT-15 (trans mixture).
  • Step 2 Following the method described in step 5 of Example 1, using INT-15 and INT-3 as raw materials for condensation reaction, a white solid compound INT-16 (trans mixture) is obtained.
  • HRMS(ESI)C 23 H 26 ClN 4 O 2 S + ([M+H] + ) Calculated value: 457.1460, measured value: 457.1457.
  • Step 3 Following the method described in step 5 of Example 1, using INT-16 as a raw material for a reduction reaction, the product was purified and then salted with HCl to obtain a white solid I-13 hydrochloride (trans mixture).
  • Step 1 Dissolve the starting material 2-naphthoyl chloride (218mg, 1.14mmol) in dichloromethane (10mL), add triethylamine (174mg, 1.72mmol) and 4-aminobutanol (112mg, 1.26mmol) in turn at room temperature Stir for 2 hours.
  • the dichloromethane was evaporated under reduced pressure, diluted with ethyl acetate, and washed with saturated sodium bicarbonate aqueous solution and saturated brine successively.
  • the organic phase was separated, concentrated, and the residue was separated and purified by flash column chromatography (0-5% methanol/dichloromethane) to obtain white solid INT-17 (243 mg, yield 87%).
  • Step 2 Dissolve sulfur trioxide pyridine complex (1.99 g, 12.6 mmol) in dichloromethane (10 mL) and dimethyl sulfoxide (10 mL), and cool to 0°C. A dimethyl sulfoxide solution (5 mL) dissolved in intermediate INT-17 (613 mg, 2.52 mmol) and triethylamine (1.27 g, 12.6 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 1.5 hours. Dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain a colorless oil INT-18, which is directly used in the step 4 reaction.
  • Step 3 Intermediate INT-6 (150 mg, 647.40 ⁇ mol), propionaldehyde (37 mg, 647.40 ⁇ mol) and triethylamine (90 ⁇ L, 647.40 ⁇ mol) were dissolved in methanol (15 mL) and reacted at room temperature for 2 hours. Sodium borohydride (49 mg, 1.29 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and concentrated.
  • Step 4 Dissolve intermediate INT-19 (75mg, 316.03 ⁇ mol) and intermediate INT-18 (76mg, 316.03 ⁇ mol) in tetrahydrofuran (15mL), add sodium triacetoxyborohydride (100mg, 474.05 ⁇ mol) at room temperature React overnight. Add methanol (5 mL) and stir for 10 minutes. The reaction solution was concentrated, and the residue was separated and purified by flash column chromatography (0-5% methanol/dichloromethane) to obtain a colorless oil I-17 (trans mixture, 100 mg, yield 68%). The colorless oil was converted into I-17 hydrochloride (trans mixture, white solid) by using a 2M hydrogen chloride ether solution according to the method in step 6 of Example 1.
  • Step 1 Dissolve indole-2-carboxylic acid (200mg, 1.24mmol), 4-aminobutanol (132mg, 1.49mmol) in N,N-dimethylformamide (10mL), add HATU (708mg, 1.88 mmol) and sodium bicarbonate (313 mg, 3.72 mmol) at room temperature for 2 hours. Add ethyl acetate to dilute, wash sequentially with water and saturated brine, concentrate the organic phase, and separate and purify the residue by flash column chromatography (0–5% methanol/dichloromethane) to obtain white solid INT-20 (231 mg, yield) Rate 80%).
  • Step 2 Following the method described in step 2 of Example 17, INT-20 was oxidized to obtain oily compound INT-21, which was directly used in the step 3 reaction.
  • Step 3 Following the method described in step 4 of Example 17, the intermediate INT-21 and the intermediate INT-19 were subjected to reductive amination reaction, and the product I-18 (trans mixture) was purified and then salted with HCl to obtain a white solid I -18 Hydrochloride (trans mixture).
  • Step 1 Following the method described in step 1 of Example 18, 4-(2'-pyridyl)benzoic acid and 4-aminobutanol were used as raw materials for condensation reaction to obtain white solid compound INT-22.
  • 1 H NMR 800MHz, CD 3 OD
  • 7.96–7.92 m, 4H
  • 7.44–7.40 m ,1H
  • 3.63(t,J 6.5Hz,2H)
  • 3.45(t,J 7.1Hz,2H)
  • HRMS(ESI) C 16 H 19 N 2 O 2 + ([M+H] + ) calculated value: 271.1441, measured value: 271.1434.
  • Step 2 Following the method described in step 2 of Example 17, INT-22 was subjected to oxidation reaction to prepare aldehyde intermediate INT-23, which was directly used in the step 3 reaction.
  • Step 3 Following the method described in step 4 of Example 17, INT-23 and INT-19 were subjected to reductive amination reaction.
  • the product I-19 (trans mixture) was purified and then salted with HCl to obtain white solid I-19 salt Acid salt (trans mixture).
  • Step 1 Following the method described in step 3 of Example 17, the intermediate INT-15 and propionaldehyde were subjected to reductive amination reaction to prepare the oily compound INT-24 (trans mixture).
  • Step 2 Following the method described in step 4 of Example 17, the INT-24 and the intermediate INT-18 are subjected to reductive amination reaction, and the product I-20 (trans mixture) is purified and then salted with HCl to obtain a white solid I-20 Hydrochloride (trans mixture).
  • step 4 of Example 17 Following the method described in step 4 of Example 17, using INT-24 and INT-21 as raw materials for reductive amination reaction, the product I-21 (trans mixture) was purified and then salted with HCl to obtain white solid I-21 hydrochloric acid Salt (trans mixture).
  • Step 1 Following the method of step 3 in Example 17, the reductive amination reaction of INT-6 and acetaldehyde can be used to prepare intermediate INT-25 (trans mixture) as a yellow oil.
  • Step 2 Following the method described in step 4 of Example 17, using INT-25 and INT-18 as raw materials for reductive amination reaction, the product I-23 (trans mixture) was purified and then salted with HCl to obtain a white solid I- 23 Hydrochloride (trans mixture).
  • Step 1 Following the method described in step 3 of Example 17, using INT-15 as a raw material for reductive amination reaction with acetaldehyde, the intermediate INT-26 (trans mixture), a yellow oily compound, can be prepared.
  • Step 2 Following the method described in step 4 of Example 17, INT-26 and INT-18 were subjected to reductive amination reaction.
  • the product I-25 (trans mixture) was salted with 2M hydrogen chloride ether solution to obtain white solid I- 25 Hydrochloride (trans mixture).
  • Step 1 The starting material 3-fluorobenzaldehyde (200mg, 1.61mmol) was dissolved in dichloromethane (15mL), methoxyformylmethylenetriphenylphosphine (647mg, 1.93mmol) was added, and the reaction was carried out at room temperature overnight. The dichloromethane was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain a colorless oil INT-27 (193 mg, yield 67%).
  • Step 2 Dissolve INT-27 (260 mg, 1.44 mmol) in tetrahydrofuran (10 mL) and water (4 mL), add lithium hydroxide monohydrate (303 mg, 7.22 mmol), and stir at room temperature for 2 hours. Adjust the pH to about 5 with 4M hydrochloric acid, extract with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate, and separate and purify the residue by flash column chromatography (0–5% methanol/dichloromethane). A white solid INT-28 (180 mg, yield 75%) was obtained.
  • Step 3 Dissolve INT-28 (164mg, 987.05 ⁇ mol), N,O-dimethylhydroxylamine hydrochloride (115mg, 1.18mmol) and HATU (563mg, 1.48mmol) in N,N-dimethylformamide (8mL), sodium bicarbonate (248mg, 2.96mmol) was added and reacted overnight at room temperature. Add ethyl acetate to dilute, and wash with water and saturated brine successively. After the organic phase was separated and dried, it was concentrated, and the residue was separated and purified by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain colorless oil INT-29 (193 mg, yield 94%).
  • Step 4 Dissolve trimethyl sulfoxide iodide (290 mg, 1.32 mmol) in dry dimethyl sulfoxide (6 mL), and protect with argon. 60% sodium hydride (53mg, 1.32mmol) was added and reacted at room temperature for 1 hour. The reaction solution changed from turbidity to clear. Intermediate INT-29 (184 mg, 879.46 ⁇ mol) was dissolved in dry dimethyl sulfoxide (2 mL), added dropwise to the above clear reaction solution, and reacted at room temperature for 4 hours.
  • reaction was quenched by adding water, extracted with ethyl acetate, washed with saturated brine, the organic phase was concentrated, and the residue was separated and purified by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain a colorless oil INT- 30 (trans mixture, 140 mg, yield 71%).
  • Step 5 Dissolve the raw material INT-30 (136 mg, 609.19 ⁇ mol) in dry tetrahydrofuran (10 mL), protect with argon, and cool to -78°C. At low temperature, 1M diisobutylaluminum hydride tetrahydrofuran solution (1.2 mL) was slowly added dropwise and reacted for 2 hours. The reaction was quenched by adding saturated potassium sodium tartrate aqueous solution, stirred at room temperature for 1 hour, and filtered. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oil INT-31 (trans mixture, 100 mg), which was directly used in step 7.
  • Step 6 Intermediate INT-18 (607mg, 2.52mmol) was dissolved in tetrahydrofuran (10mL) and 1,2-dichloroethane (10mL), and then propylamine (743mg, 12.58mmol), NaHB(AcO) 3 ( 1.07g, 5.03mmol) and acetic acid (70 ⁇ L), react overnight at room temperature. Methanol (5mL) was added and stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-10% methanol/dichloromethane) to obtain a white solid compound INT-32 (485mg, yield Rate 68%).
  • Step 7 Intermediate INT-31 (50 mg, 304.54 ⁇ mol) and INT-32 (86 mg, 304.54 ⁇ mol) were dissolved in acetonitrile (10 mL), NaHB(AcO) 3 (129 mg, 609.09 ⁇ mol) was added, and the reaction was carried out overnight at room temperature. Methanol (5mL) was added and stirred at room temperature for 15 minutes. The solution became clear. The solvent was evaporated under reduced pressure. The residue was separated and purified by flash column chromatography (0-6% methanol/dichloromethane) to obtain a colorless oil I- 26 (trans mixture, 89 mg, yield 68%).
  • Step 1 Following the method described in step 6 of Example 26, INT-21 and propylamine were used for reductive amination to obtain INT-33, an oily compound.
  • HRMS (ESI) C 16 H 24 N 3 O + ([M+H] + ) calculated value: 274.1914, measured value: 274.1910.
  • Step 2 Following the method of step 7 of Example 26, INT-33 and INT-31 were used for reductive amination reaction.
  • the product I-27 (trans mixture) was purified and then salted with hydrogen chloride ether solution to obtain white solid I- 27 Hydrochloride (trans mixture).
  • Step 1 Following the method described in step 6 of Example 26, reductive amination reaction with INT-23 and propylamine was carried out to obtain INT-34, a white solid.
  • 1 H NMR 600MHz, CD 3 OD
  • 8.08-8.05 m, 2H
  • 7.97-7.92 m, 4H
  • 7.43-7.39 m, 1H
  • 3.46(t,J 6.5Hz,2H)
  • 3.05-2.99(m,2H),2.94-2.90(m,2H),1.78-1.66(m,6H),1.01(t,J 7.5Hz ,3H).
  • HRMS(ESI) C 19 H 26 N 3 O + ([M+H] + ) Calculated value: 312.2070, measured value: 312.2067.
  • Step 2 Following the method of step 7 in Example 26, INT-34 and INT-31 were used for reductive amination reaction.
  • the product I-28 (trans mixture) was purified and then salted with hydrogen chloride ether solution to obtain white solid I- 28 Hydrochloride (trans mixture).
  • Step 1 Following the method of Example 26 to prepare the intermediate INT-31 with 3-fluorobenzaldehyde, the intermediate INT-35 was prepared with 3-chlorobenzaldehyde as the raw material.
  • Step 2 Following the method in step 7 of Example 26, INT-35 and INT-32 were subjected to reductive amination reaction, and the product I-29 was purified and then salted with hydrogen chloride ether solution to prepare white solid I-29 hydrochloride. (Trans mixture).
  • Step 1 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, the intermediate INT-36 (trans mixture) was prepared with 4-fluorobenzaldehyde as a raw material.
  • Step 2 Following the method of step 7 in Example 26, INT-36 and INT-32 are used as raw materials for reductive amination reaction.
  • the product I-32 (trans mixture) is purified and then salted with hydrogen chloride to prepare white solid I- 32 Hydrochloride (trans mixture).
  • Step 1 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, 4-fluorobenzaldehyde was used as a raw material to prepare intermediate INT-37 (trans mixture, colorless oil).
  • Step 2 Following the method of step 7 in Example 26, INT-37 and INT-32 are used as raw materials for reductive amination reaction.
  • the product I-35 (trans mixture) is purified and then salted with hydrogen chloride to prepare white solid I- 35 Hydrochloride (trans mixture).
  • Step 1 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde is used as a raw material to prepare intermediate INT-38 (trans mixture).
  • Step 6 Following the method of step 7 in Example 26, INT-38 and INT-32 are used as raw materials to carry out reductive amination reaction.
  • the product I-38 (trans mixture) is purified and then salted with hydrogen chloride to prepare I-38 salt.
  • Acid salt (trans mixture), white solid.
  • Step 1 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, 2,3-dichlorobenzaldehyde was used as a raw material to prepare intermediate INT-39 (trans mixture).
  • Step 6 Following the method of step 7 in Example 26, INT-39 and INT-32 are used as raw materials for reductive amination reaction.
  • the product I-41 (trans mixture) is purified and then salted with hydrogen chloride to prepare white solid I- 41 Hydrochloride (trans mixture).
  • Step 1 Dissolve the raw material 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (2.20g, 13.48mmol) in N,N-dimethylformamide (20mL), add potassium carbonate ( 1.86g, 13.48mmol) and 1,4-dibromobutane (8.73g, 40.45mmol), react at room temperature for 24 hours. Water was added, extracted with ethyl acetate, washed with saturated brine, and concentrated. The residue was separated and purified by flash column chromatography (0-3% methanol/dichloromethane) to obtain a white solid compound INT-40 (3.09g, yield 79 %).
  • Step 2 Dissolve the raw material phthalimide (2.29g, 15.54mmol) in N,N-dimethylformamide (20mL), add potassium carbonate (2.86g, 20.73mmol) and INT-40 (3.09 g, 10.36mmol), heated to 80°C and reacted overnight. Water was added, extracted with ethyl acetate, washed with saturated brine, and concentrated. The residue was separated and purified by flash column chromatography (0-3% methanol/dichloromethane) to obtain a white solid compound INT-41 (3.36g, yield 89 %).
  • Step 3 Dissolve INT-41 (2.25 g, 6.17 mmol) in methanol (20 mL) and dichloromethane (5 mL), add hydrazine hydrate (773 mg, 15.44 mmol), heat to reflux, and react overnight. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-15% methanol/dichloromethane) to obtain white solid INT-42 (1.3g, yield 90%).
  • Step 4 Following the method described in step 7 of Example 26, INT-42 and INT-39 are used as raw materials to carry out reductive amination reaction to obtain I-44 (trans mixture). After purification, it is salted with hydrogen chloride to prepare I- 44 Hydrochloride (trans mixture).
  • Step 1 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, 5-fluoro-2-methoxybenzaldehyde is used as a raw material to prepare intermediate INT-43 (trans mixture).
  • Step 2 Following the method of step 7 in Example 26, using INT-43 and INT-42 as raw materials for reductive amination reaction, the product I-47 (trans mixture) was purified and then salted with hydrogen chloride to prepare a white solid I- 47 Hydrochloride (trans mixture).
  • Step 1 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-44 (trans mixture) was prepared with 2-methoxybenzaldehyde as a raw material.
  • Step 2 After INT-44 (155 mg, 0.88 mmol) was dissolved in methanol (10 mL), INT-42 (218 mg, 0.94 mmol) and sodium cyanoborohydride (87 mg, 1.32 mmol) were added in sequence, and reacted at room temperature for 12 hours. After the reaction was completed, it was filtered and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (1:10 methanol/dichloromethane) to obtain a pale yellow solid I-50 (trans mixture, 130 mg, yield 35%) .
  • Step 1 Dissolve 5-hydroxybenzothiazole (CAS: 7686-41-1,2.20g, 14.55mmol) and 1,4-dibromobutane (8.70g, 43.65mmol) in N,N-dimethyl
  • potassium carbonate (1.90 g, 14.55 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, it was diluted with water (20 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain white solid INT-46 (3.0 g, yield 72%).
  • HRMS(ESI) C 11 H 13 BrNOS + [M+H] + Calculated value: 285.9896, measured value: 285.9897.
  • Step 2 Dissolve INT-46 (3.0g, 10.52mmol) and phthalimide (2.40g, 15.80mmol) in N,N-dimethylformamide (40mL), add potassium carbonate (3.0g , 21.04mmol), heated to 80°C and reacted for 12 hours. After the reaction is complete, it is diluted with water (20 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent is evaporated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (1:20 methanol/dichloromethane). A white solid INT-47 (2.7 g, yield 72%) was obtained.
  • Step 3 Dissolve INT-47 (2.7 g, 7.57 mmol) in methanol (40 mL) and dichloromethane (10 mL), add hydrazine hydrate (1.0 g, 18.90 mmol), and react under reflux for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (1:10 methanol/dichloromethane) to obtain white solid INT-48 (1.5 g, yield 89%).
  • Step 4 Following the method of step 2 in Example 50, INT-48 and INT-44 were used as raw materials to carry out reductive amination reaction to prepare compound I-52 (trans mixture) as a pale yellow solid.
  • Step 1 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-49 (trans mixture) was prepared with 2-methylthiobenzaldehyde as a raw material.
  • Step 2 Following the method of step 2 in Example 50, INT-49 and INT-42 were used as raw materials to carry out reductive amination reaction to prepare compound I-53 (trans mixture) as a pale yellow solid.
  • Step 1 Dissolve INT-39 (1.33 g, 6.18 mmol) in methanol (20 mL), add sodium borohydride (350 mg, 9.28 mmol), and react at room temperature for 1 hour. 4M aqueous hydrochloric acid was added dropwise to adjust the pH of the reaction solution to neutral, extracted with ethyl acetate, washed with saturated brine, and concentrated. The residue was separated and purified by flash column chromatography (0-50% ethyl acetate/petroleum ether) to obtain no Color oil INT-50 (trans mixture, 1.12g, yield 83%).
  • Step 2 Dissolve the raw materials INT-50 (930mg, 4.28mmol), phthalimide (945mg, 6.43mmol) and triphenylphosphine (2.81g, 10.71mmol) in dry tetrahydrofuran (25mL) and slowly drop them Add diethyl azodicarboxylate (1.87 g, 10.71 mmol), and react at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain white solid INT-51 (trans mixture, 1.36 g, yield 92%).
  • Step 3 Dissolve the raw material INT-51 (0.9 g, 2.6 mmol) in methanol (15 mL), add hydrazine hydrate (260 mg, 5.2 mmol), heat to reflux, and react for 4 hours. The methanol was evaporated under reduced pressure, water was added, extracted with ethyl acetate, washed with saturated brine, dried with colorless sodium sulfate, filtered, and concentrated to obtain light yellow oil INT-52 (trans mixture, 526 mg, yield 94%). It was converted into its hydrochloride salt according to the method in step 6 of Example 1. H NMR HRMS (ESI) C 10 H 12 Cl 2 N + ([M+H] + ) calculated value: 216.0341, measured value: 216.0334.
  • Step 4 Dissolve the starting material (2-(2,3-dichlorophenyl)cyclopropyl)methylamine hydrochloride (INT-52, 160mg, 0.634mmol) in tetrahydrofuran (15mL), and add triethylamine ( 43mg, 0.424mmol) and INT-53 (90mg, 0.424mmol) (prepared by reference J.Org.Chem.2015, 80, 1059-1069). After reacting for 1 hour at room temperature, NaHB(AcO) 3 (180mg , 0.848mmol) and acetic acid (25mg, 0.424mmol), react overnight at room temperature. Methanol (5mL) was added and stirred at room temperature for 15 minutes.
  • Step 1 Intermediate INT-39 (2.3 g, 10.69 mmol) was dissolved in tetrahydrofuran (50 mL), propylamine (6.3 g, 106.9 mmol) and acetic acid (611 ⁇ L, 10.69 mmol) were added in sequence, and reacted at room temperature for 15 minutes. Add NaHB(AcO) 3 (6.8 g, 32.08 mmol) and react at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-5% methanol/dichloromethane) to obtain a pale yellow solid compound INT-54 (trans mixture, 1.94 g, yield 70%).
  • Step 2 Following the method described in step 4 of Example 56, INT-54 and INT-53 are used as raw materials for reductive amination to obtain compound I-57 (trans mixture), which is then reacted with hydrogen chloride to obtain I- 57 Hydrochloride (trans mixture).
  • Step 2 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-55 is used as a raw material to prepare intermediate INT-56 (trans mixture).
  • Step 3 Following the steps 1 to 3 of Example 56, the intermediate INT-56 was used as a raw material to prepare the intermediate INT-57.
  • Step 4 Following the method of step 2 of Example 50, using INT-53 and INT-57 as raw materials for reductive amination reaction, compound I-60 was prepared as a pale yellow solid (yield 39%).
  • Step 1 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-58 is prepared with intermediate 1-naphthaldehyde as a raw material.
  • Step 2 Following the steps 1 to 3 of Example 56, the intermediate INT-59 was prepared by using the intermediate INT-58 as a raw material.
  • Step 3 Following the method of step 2 in Example 50, using INT-53 and INT-59 as raw materials for reductive amination reaction, compound I-61 was prepared as a pale yellow solid (yield 44%).
  • Step 1 Imitating the method of step 1 to step 3 in Example 56, the intermediate INT-44 was used as the raw material to prepare the intermediate INT-60.
  • Step 2 Following the method of Step 2 in Example 50, using INT-53 and INT-60 as raw materials for reductive amination reaction, compound I-62 was prepared as a pale yellow solid (yield 34%).
  • Step 1 Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-61 (trans mixture) was prepared with intermediate 5-chloro-2-methoxybenzaldehyde as a raw material.
  • Step 2 Following the method of step 2 in Example 50, using INT-45 and INT-61 as raw materials for reductive amination reaction, compound I-68 was prepared as a white solid (yield 28%).
  • Step 1 Dissolve sesamol (CAS: 533-31-3, 1.38g, 10mmol) and tert-butyl 4-bromobutylcarbamate (CAS: 164365-88-2, 2.52g, 10mmol) in N, N -To dimethylformamide (20 mL), potassium carbonate (1.38 g, 10 mmol) was added, and the mixture was stirred at room temperature for 24 hours.
  • Step 2 Intermediate INT-62 (1.9 g, 6.1 mmol) was dissolved in dichloromethane (20 mL), 4M hydrogen chloride 1,4-dioxane solution (5 mL) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure to obtain intermediate INT-63 (1.5 g, yield 100%).
  • Step 3 Following the method of step 2 of Example 50, using INT-56 and INT-63 as raw materials for reductive amination reaction, compound I-74 (trans mixture) was prepared as a pale yellow solid (yield 37%).
  • Step 1 Following the method of preparing intermediate INT-62 with sesamol and tert-butyl 4-bromobutylcarbamate as described in step 1 of Example 74, 7-hydroxy-2-quinolone (CAS: 70500-72- 0) and tert-butyl 3-bromopropyl carbamate (CAS:83948-53-2) as raw materials to prepare intermediate INT-64.
  • Step 2 Following the method of preparing intermediate INT-63 from intermediate INT-62 in step 2 of Example 74, intermediate INT-65 is prepared using intermediate INT-64 as a raw material.
  • HRMS(ESI) C 12 H 15 N 2 O 2 + ([M+H] + ) calculated value: 219.1128, measured value: 219.1127.
  • Step 3 Following the method of step 2 of Example 50, using INT-43 and INT-65 as raw materials for reductive amination reaction, compound I-76 (trans mixture) was prepared as a white solid (yield 24%).
  • 1 H NMR 800MHz, CD 3 OD-d 4 ) ⁇ 7.80–7.75(m,1H), 7.47–7.42(m,1H), 6.78–6.68(m,4H), 6.55–6.50(m,1H) ,6.36–6.30(m,1H),4.07–4.03(m,2H), 3.69(s,3H), 2.85–2.76(m,2H), 2.75–2.69(m,1H), 2.53–2.45(m, 1H),2.02–1.92(m,2H),1.92–1.87(m,1H),1.11–1.05(m,1H),0.90–0.86(m,1H),0.79–0.73(m,1H).
  • Step 1 Following the method of preparing intermediate INT-62 with sesamol and tert-butyl 4-bromobutylcarbamate as described in step 1 of Example 74, 3,4-dihydro-7-hydroxy-2(1H )-Quinolinone (CAS: 22246-18-0) and tert-butyl 3-bromopropyl carbamate (CAS: 83948-53-2) were used as raw materials to prepare intermediate INT-66.
  • Step 2 Following the method of preparing intermediate INT-63 from intermediate INT-62 in step 2 of Example 74, intermediate INT-67 is prepared using intermediate INT-66 as a raw material.
  • HRMS (ESI C 12 H 17 N 2 O 2 + ([M+H] + ) Calculated value: 221.1285, measured value: 221.1288.
  • Step 3 Following the method of step 2 of Example 50, using INT-43 and INT-67 as raw materials for reductive amination reaction, compound I-79 was prepared as a white solid (yield: 48%).
  • Step 1 follow the steps 1 to 3 in Example 44 to prepare intermediate INT-42 with 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane Methods, 7-hydroxy-2-quinolone (CAS: 70500-72-0) and 1,5-dibromopentane (CAS: 111-24-0) were used as raw materials to prepare intermediate INT-68.
  • Step 2 Following the method of step 2 in Example 50, using INT-44 and INT-68 as raw materials for reductive amination reaction, compound I-82 was prepared as a white solid (yield 69%).
  • Step 1 follow the steps 1 to 3 in Example 44 to prepare intermediate INT-42 with 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane Methods, 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,5-dibromopentane (CAS: 111-24-0) were used as raw materials to prepare intermediate INT-69.
  • Step 2 Following the method of step 2 in Example 50, using INT-44 and INT-69 as raw materials for reductive amination reaction, compound I-83 was prepared as a white solid (yield 67%).
  • Step 1 follow the steps 1 to 3 in Example 44 to prepare intermediate INT-42 with 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane Method, using 7-hydroxy-2-quinolone (CAS: 70500-72-0) and trans-1,4-dibromo-2-butene (CAS: 821-06-7) as raw materials to prepare intermediate INT- 70.
  • Step 2 Following the method of Step 2 of Example 50, using INT-44 and INT-70 as raw materials for reductive amination reaction, compound I-84 was prepared as a white solid (yield 44%).
  • Step 1 follow the steps 1 to 3 in Example 44 to prepare intermediate INT-42 with 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane Method, using 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and trans-1,4-dibromo-2-butene (CAS:821-06-7) as raw materials to prepare intermediate Body INT-71.
  • Step 2 Following the method of step 2 of Example 50, using INT-44 and INT-71 as raw materials for reductive amination reaction, compound I-85 was prepared as a white solid (yield 52%).
  • 1-Pyrrolidinecarbonyl chloride CAS: 1192-63-8, 238 mg, 1.78 mmol
  • Step 2 Intermediate INT-73 (212 mg, 0.71 mmol) was dissolved in dry tetrahydrofuran (10 mL), protected with argon, and cooled to -78°C. At low temperature, 1M diisobutylaluminum hydride tetrahydrofuran solution (1.5 mL) was slowly added dropwise, and reacted for 6 hours. The reaction was quenched by adding saturated potassium sodium tartrate aqueous solution, stirred at room temperature for 1 hour, and filtered. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oil INT-74 (trans mixture, 140 mg), which was directly used in step 3.
  • Step 3 Following the method of step 2 in Example 50, using INT-60 and INT-74 as raw materials for reductive amination reaction, compound I-86 was prepared as a white solid (yield 38%).
  • Step 1 Following the method of preparing intermediate INT-73 with intermediate INT-72 and 1-pyrrolidinecarbonyl chloride as described in Example 86, step 1, intermediate INT-72 and benzoyl chloride are used as raw materials to prepare intermediate INT -75. White solid (69% yield).
  • Step 2 Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-75 with diisobutylaluminum hydride It is the intermediate INT-76 and used directly in step 3.
  • Step 3 Following the method of step 2 of Example 50, using INT-60 and INT-76 as raw materials for reductive amination reaction, compound I-87 was prepared as a white solid (yield 53%).
  • Step 1 Following the method of preparing intermediate INT-73 with intermediate INT-72 and 1-pyrrolidinecarbonyl chloride as described in step 1 of Example 86, intermediate INT-72 and benzenesulfonyl chloride are used as raw materials to prepare intermediate INT. -77. White solid (63% yield).
  • Step 2 Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride as described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-77 with diisobutylaluminum hydride It is an intermediate INT-78 and used directly in step 3.
  • Step 3 Following the method of step 2 of Example 50, using INT-60 and INT-78 as raw materials for reductive amination reaction, compound I-88 was prepared as a white solid (yield 51%).
  • Step 1 Following the method of preparing intermediate INT-73 with intermediate INT-72 and 1-pyrrolidinecarboxylic acid chloride as described in Example 86, step 1, the intermediate INT-72 and cyclohexylcarboxylic acid chloride are used as raw materials to prepare intermediate INT-79. White solid (yield 64%).
  • Step 2 Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-79 with diisobutylaluminum hydride It is an intermediate INT-80 and used directly in step 3.
  • Step 3 Following the method of step 2 in Example 50, using INT-60 and INT-80 as raw materials for reductive amination reaction, compound 1-89 was prepared as a white solid (yield 52%).
  • Step 1 Following the method of preparing intermediate INT-73 with intermediate INT-72 and 1-pyrrolidinecarboxylic acid chloride in step 1 of Example 86, using intermediate INT-72 and piperidine-1-carboxylic acid chloride (CAS :13939-69-0) as the raw material to prepare intermediate INT-81. White solid (62% yield).
  • Step 2 Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-81 with diisobutylaluminum hydride It is an intermediate INT-82 and used directly in step 3.
  • Step 3 Following the method of step 2 in Example 50, using INT-60 and INT-82 as raw materials for reductive amination reaction, compound I-90 was prepared as a white solid (yield 49%).
  • Step 1 Dissolve 2-indolecarboxylic acid (CAS:1477-50-5,191mg, 1.18mmol) and HATU (902mg, 2.37mmol) in anhydrous DMF (20mL), stir at room temperature for 0.5h, and then add DIPEA ( 459mg, 3.56mmol) and intermediate INT-72 (280mg, 1.18mmol), then stirred at room temperature overnight.
  • 2-indolecarboxylic acid CAS:1477-50-5,191mg, 1.18mmol
  • HATU 902mg, 2.37mmol
  • DIPEA 459mg, 3.56mmol
  • intermediate INT-72 280mg, 1.18mmol
  • Step 2 Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-83 with diisobutylaluminum hydride It is the intermediate INT-84 and used directly in step 3.
  • Step 3 Following the method of step 2 of Example 50, using INT-60 and INT-84 as raw materials for reductive amination reaction, compound I-91 was prepared as a white solid (yield 52%).
  • Step 2 The raw material (+)-INT-5 (378 mg, 1.28 mmol) was dissolved in a 4M hydrochloric acid dioxane solution (20 mL) and reacted overnight at room temperature. The solvent was evaporated under reduced pressure, and the remaining residue was suspended in a mixed solution of ethyl acetate/petroleum ether (volume ratio 1/2, 10 mL) for 10 minutes. Suction filtration, the filter cake was rinsed with ethyl acetate (3mL), and dried under vacuum to obtain (–)-INT-6, a yellow solid (290mg, yield 98%), [ ⁇ ] D 20 –14.80 (c 0.5, MeOH) .
  • (+)-INT-5 can be prepared to obtain (+)-INT-6, a yellow solid, [ ⁇ ] D 20 +14.20 (c 0.5, MeOH).
  • the optical signs of (–)-INT-6 and (+)-INT-6 are the same as those of similar compounds with the same configuration, refer to [J.Med.Chem.2015,58,1992-2002].
  • Step 3 According to the method described in step 3 of Example 17, (-)-INT-6 was converted into (-)-INT-19, [ ⁇ ] D 20 -14.60 (c 0.5, MeOH). Convert (+)-INT-6 to (+)-INT-19, [ ⁇ ] D 20 +16.13(c 0.5,MeOH).
  • Step 4 The raw material (-)-INT-19 (41 mg, 0.173 mmol) and the intermediate INT-23 (46 mg, 0.173 mmol) were dissolved in tetrahydrofuran (15 mL) and reacted at room temperature for 15 minutes. Sodium triacetoxyborohydride (73mg, 0.345mmol) was added and reacted overnight at room temperature. The reaction was quenched by adding water, extracted with ethyl acetate, washed with saturated brine, concentrated the organic phase, and the residue was subjected to silica gel column chromatography (0–5% methanol/dichloromethane) to obtain a colorless oil I-19a (28 mg, yield Rate 33%). I-19a was converted into its hydrochloride salt as a white solid according to the method in step 6 of Example 1. [ ⁇ ] D 20 -13.00 (c 0.5, MeOH).
  • (+)-INT-19 can be prepared to obtain I-19b hydrochloride, a white solid. [ ⁇ ] D 20 +11.80 (c 0.5, MeOH).
  • the specific rotation of I-19a hydrochloride prepared according to the chiral synthesis method is consistent with the specific rotation of I-19a hydrochloride obtained by the resolution method, and its absolute configuration is determined to be (R, R); In the same way, the absolute configuration of I-19b is determined as (S, S).
  • Affinity activity is tested using radioisotope ligand method.
  • the cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane separation particles, and the cell membrane particles were resuspended to form a 1mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use .
  • the compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10 ⁇ M, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM).
  • the cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane particles, and the cell membrane particles were resuspended to form a 1 mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use.
  • the compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10 ⁇ M, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM).
  • PBS phosphate buffered saline
  • the cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane particles, and the cell membrane particles were resuspended to form a 1 mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use.
  • the compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10 ⁇ M, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM).
  • the cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane separation particles, and the cell membrane particles were resuspended to form a 1mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use .
  • the compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10 ⁇ M, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM).
  • the cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane separation particles, and the cell membrane particles were resuspended to form a 1mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use .
  • the compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10 ⁇ M, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM).
  • Table 1 shows the affinity data of some compounds of the present invention for dopamine receptors.
  • Table 1 Affinity data of some compounds of general formula I for dopamine receptors D1-D5.
  • the activity of the compound on the dopamine D3 receptor was detected using the GloSensor cAMP method.
  • Cell plating 384-well plate pre-coated with poly-L-Lys, 15,000-20,000 cells per well (40 ⁇ L solvent).
  • Table 2 Functional activities of some compounds of general formula (I) on dopamine D3 receptors.
  • the BRET method was used to detect the activity of the downstream G protein signal pathway mediated by dopamine D 2 receptor.
  • dopamine D 2 receptor On the first day, use HEK-293T cells, 6 cm culture dish with 1 ⁇ g dopamine D 2 receptor, 1 ⁇ g G ⁇ i1 (G ⁇ i1 -Rluc) containing C-terminal seaweed luciferase, 1 ⁇ g G ⁇ 3 , and 1 ⁇ g containing C-terminal green fluorescence Protein G ⁇ 9 (G ⁇ 9 -GFP) and 16 ⁇ L PEI were transfected.
  • Table 3 Functional activities of some compounds on dopamine D2 receptors.
  • the receptor has strong agonist or partial agonist activity.
  • the cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane separation particles, and the cell membrane particles were resuspended to form a 1mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use .
  • the compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10 ⁇ M, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM).
  • the functional activity of compounds of general formula I on 5-HT 2C receptors was determined by the calcium flux test method. Using HEK-293 cells stably and highly expressing 5-HT 2C receptors, FLIPR TETRA (Molecular Dynamics) high-throughput fluorescence imaging analyzer was used for detection. Specifically, 384-well plates pretreated with polylysine were plated at a quantity of 10,000 cells/well; Fluo-4Direct dye (Invitrogen, 20 ⁇ L/well) was added the next day, and buffer (1 ⁇ HBSS, 2.5 mM probenecid, 20mM HEPES, pH 7.4) were incubated for 1 hour (37°C, 5% CO 2 ).
  • the compound to be tested was diluted with the same buffer as the solvent and the final concentration was 3 times isocratically diluted, 10 ⁇ L was added to each well, and then the calcium current intensity was tested on the FLIPR instrument for 300 seconds.
  • the tested concentration of the compound is 1 pM to 10 ⁇ M, but the highest concentration for the less active compound is increased to 100 ⁇ M.
  • the activity intensity of serotonin was standardized to 100%, and the dose-response curve was fitted with GraphPad Prism7.0.
  • 10 ⁇ L of 5-HT final concentration 1 nM
  • Table 5 Functional activity test of some compounds of general formula I on 5-HT 2C receptor.
  • LC-MS/MS measured the concentration of the compound in mouse plasma and brain tissue and calculated related pharmacokinetic parameters. The compound's pharmacokinetic characteristics, bioavailability and exposure in brain tissues of mice.
  • IV collection time point 0,5,15,30 minutes,1,2,4,6,8,24 hours
  • PO collection time point 0,15,30 minutes,1,2,4,6,8,24 Hour
  • Brain tissue sample collection time points 0.5 and 2 hours.
  • the drug concentration in the tissue samples was analyzed by LCMS/MS method.
  • the data acquisition and control system software is Analyst 1.5.1 software (Applied Biosystem).
  • the peak integration method of the spectrum sample is automatic integration; the ratio of the peak area of the sample to the peak area of the internal standard is used as an index, and the concentration of the sample is regressed. Regression method: linear regression, the weight coefficient is 1/X 2 .
  • the pharmacokinetic parameters were analyzed and processed with WinNonlin Professional v6.3 (Pharsight, USA) with a non-compartmental model.
  • C max is the measured maximum plasma concentration
  • the area under the plasma concentration-time curve AUC (0 ⁇ t) is calculated by the trapezoid method
  • T max is the peak time after the administration of the plasma concentration.

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Abstract

A 2-phenylcyclopropylmethylamine derivative as shown in formula I below, having affinity activity to dopamine receptors and/or 5-hydroxytryptamine receptors and used for treating mental diseases.

Description

2-苯基环丙基甲基胺衍生物及其制备方法和用途2-Phenylcyclopropylmethylamine derivative and preparation method and application thereof

相关申请的交叉引用Cross-references to related applications

本申请要求申请日为2020/2/20的中国专利申请2020101053938的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of the Chinese patent application 2020101053938 whose filing date is 2020/2/20. This application quotes the full text of the aforementioned Chinese patent application.

技术领域Technical field

本发明涉及一种2-苯基环丙基甲基胺衍生物及其制备方法和用途。The invention relates to a 2-phenylcyclopropylmethylamine derivative, and a preparation method and application thereof.

背景技术Background technique

G蛋白偶联受体(GPCR)是最为重要的药物靶标家族。据统计，截至2017年，在所有经美国FDA批准上市的小分子药物中，以GPCR为靶点的药物占34％(Santos等，Nature Review Drug Discovery,2017,16，19-34)。作为人类基因组编码的最大的受体家族，GPCR包含约1000种不同的受体，其中包含了超过300个潜在药物靶标。研究已经证实，GPCR与神经精神类疾病(如精神分裂症、疼痛等)、心血管疾病(如高血压、心衰等)、代谢性疾病(如糖尿病、肥胖)、免疫性疾病以及癌症等众多疾病的发生、发展都具有密切的关系。在众多的GPCR受体中，单胺类GPCR受体，例如多巴胺受体、5-羟色胺受体等都是成功的药物靶点(Santos等，Nature Review Drug Discovery,2017,16，19-34)，很多药物尤其是精神类药物都是以它们为主要靶标的。G protein-coupled receptors (GPCR) are the most important family of drug targets. According to statistics, as of 2017, among all small molecule drugs approved for marketing by the US FDA, drugs targeting GPCRs accounted for 34% (Santos et al., Nature Review Drug Discovery, 2017, 16, 19-34). As the largest family of receptors encoded by the human genome, GPCRs contain about 1,000 different receptors, including more than 300 potential drug targets. Studies have confirmed that GPCR is related to neuropsychiatric diseases (such as schizophrenia, pain, etc.), cardiovascular diseases (such as hypertension, heart failure, etc.), metabolic diseases (such as diabetes, obesity), immune diseases, and cancer. The occurrence and development of diseases are closely related. Among the many GPCR receptors, monoamine GPCR receptors, such as dopamine receptors and serotonin receptors, are all successful drug targets (Santos et al., Nature Review Drug Discovery, 2017, 16, 19-34) Many drugs, especially psychotropic drugs, are based on them as their main targets.

多巴胺受体有五种亚型(D1-5)，其中D1、D5为D1类受体，主要与G s蛋白偶联，激活后升高细胞内cAMP水平；D2、D3、D4为D2类受体，主要与G i蛋白偶联，激活后降低细胞内cAMP水平。多巴胺能信号通路是近几十年来神经科学研究的焦点，多巴胺能信号通路的异常与精神分裂症、帕金森氏症等多种疾病相关。靶向多巴胺D2受体的小分子拮抗剂或部分激动剂是有效的抗精神分裂药物，如氟哌啶醇、奥氮平、阿立哌唑(aripiprazole)、卡利拉嗪(cariprazine)等的主要作用靶点均为多巴胺D2受体；与D2同一个亚家族的多巴胺D3受体也是很多抗精神分裂药物的重要靶点，高选择性的D3受体拮抗剂或部分激动剂同时还具有治疗药物成瘾的潜力。多巴胺D1,D4和D5受体也被证实是潜在的药物靶标。 There are five subtypes of dopamine receptors (D1-5), among which D1 and D5 are D1 receptors, which are mainly coupled with G s protein, and increase the intracellular cAMP level after activation; D2, D3, and D4 are D2 receptors. Body, mainly coupled with G i protein, reduces intracellular cAMP level after activation. The dopaminergic signaling pathway has been the focus of neuroscience research in recent decades. Abnormalities of the dopaminergic signaling pathway are related to many diseases such as schizophrenia and Parkinson's disease. Small molecule antagonists or partial agonists targeting dopamine D2 receptors are effective anti-schizophrenics, such as haloperidol, olanzapine, aripiprazole, cariprazine, etc. The main targets of action are all dopamine D2 receptors; dopamine D3 receptors of the same subfamily as D2 are also important targets for many anti-schizophrenics. Highly selective D3 receptor antagonists or partial agonists also have treatments The potential for drug addiction. Dopamine D1, D4 and D5 receptors have also been confirmed as potential drug targets.

5-羟色胺受体包括14种亚型，除5-HT 3为离子通道外，其它13种亚型均为GPCR类受体。这其中，5-羟色胺2A受体(5-HT 2A)拮抗剂是治疗精神分裂症的另一个重要药物靶标，例如2018年美国FDA批准上市的5-HT 2A选择性反向激动剂pimavanserin，同时5-HT 2A也是多靶点的“非典型”抗精神失常药物的一个主要作用靶点；5-HT 2C受体是抑制食欲、降低体重的一个药物靶标，2012年上市的氯卡色林(lorcaserin)即为5-HT 2C受体激动剂；同时5-HT 2C受体激动剂还有治疗精神分裂症的潜力(Pogorelov等，Neuropsychopharmacology 2017，42，2163–2177)；等等。 Serotonin receptors include 14 subtypes. Except 5-HT 3 which is an ion channel, the other 13 subtypes are all GPCR receptors. Among them, serotonin 2A receptor (5-HT 2A ) antagonists are another important drug target for the treatment of schizophrenia, such as the 5-HT 2A selective inverse agonist pimavanserin approved by the US FDA in 2018. 5-HT 2A is also a major target of multi-target "atypical" antipsychotic drugs; 5-HT 2C receptor is a drug target that suppresses appetite and reduces weight. Lorcaserin ( Lorcaserin is a 5-HT 2C receptor agonist; at the same time, 5-HT 2C receptor agonists have the potential to treat schizophrenia (Pogorelov et al., Neuropsychopharmacology 2017, 42, 2163-2177); and so on.

对于多巴胺受体、5-羟色胺受体这类的GPCR受体，“4-芳基哌嗪”或“4-芳基哌啶”的 亚结构被发现是最为常见的药物优势骨架，例如利培酮(risperidone)、齐拉西酮(ziprasidone)、阿立哌唑(aripiprazole)、卡利拉嗪(cariprazine)等药物均具有“4-芳基哌嗪”的亚结构。近年来，有大量具有相似结构的类药性小分子被报道(Micheli,ChemMedChem 2011,6,1152-1162；Ye等,Chem.Rev.,2013,113,PR123-PR178)。For GPCR receptors such as dopamine receptors and serotonin receptors, the substructures of "4-arylpiperazine" or "4-arylpiperidine" have been found to be the most common drug dominance skeletons, such as risperidone Medicines such as risperidone, ziprasidone, aripiprazole, and cariprazine all have the substructure of "4-arylpiperazine". In recent years, a large number of small drug-like molecules with similar structures have been reported (Micheli, ChemMedChem 2011, 6, 1152-1162; Ye et al., Chem. Rev., 2013, 113, PR123-PR178).

“2-苯基环丙基甲基胺”是另一类小分子化合物的统称，也是一个重要的药物优势骨架。例如，2013年上市的抗抑郁药物左旋米那普仑(levomilnacipran)包含“2-苯基环丙基甲基胺”这一亚结构，其主要的作用机制是作为5-羟色胺重摄取、去甲肾上腺素重摄取的抑制剂。2014年上市的失眠药物他司美琼(tasimelteon)也包含“2-苯基环丙基甲基胺”亚结构，其主要的作用靶点是褪黑素受体MT1/MT2。此外，苯环上具有不同取代的2-苯基环丙基甲基胺类化合物还被报道是选择性的5-HT 2C受体激动剂(Cheng等,J.Med.Chem.,2015,58,1992-2002)。该类化合物被证实对于5-HT 2C具有较强的亲和力和激动剂活性，但对于多巴胺受体，该类化合物仅对多巴胺D3受体具有微弱的结合活性(Cheng等,J.Med.Chem.,2015,58,1992-2002)。 "2-Phenylcyclopropylmethylamine" is a collective term for another class of small molecule compounds, and it is also an important backbone for drug advantages. For example, the antidepressant drug levomilnacipran (levomilnacipran), which was launched in 2013, contains the substructure of "2-phenylcyclopropylmethylamine", and its main mechanism of action is as serotonin reuptake and demethylation. Inhibitor of adrenaline reuptake. The insomnia drug tasimelteon, which was launched in 2014, also contains the "2-phenylcyclopropylmethylamine" substructure, and its main target is the melatonin receptor MT1/MT2. In addition, 2-phenylcyclopropylmethylamine compounds with different substitutions on the benzene ring have also been reported to be selective 5-HT 2C receptor agonists (Cheng et al., J.Med.Chem., 2015, 58 , 1992-2002). This class of compounds has been confirmed to have strong affinity and agonist activity for 5-HT 2C , but for dopamine receptors, this class of compounds only has weak binding activity to dopamine D3 receptors (Cheng et al., J. Med. Chem. , 2015, 58, 1992-2002).

Figure PCTCN2021076289-appb-000001
Figure PCTCN2021076289-appb-000001

文献Zhang等,J.Med.Chem.,2017,60,6273-6288公开了如下具有2-苯基环丙基甲基胺结构的化合物，作为5-HT 2C受体的激动剂。该化合物对于多巴胺受体的几个亚型具有不同程度的亲和力：D1，K i＝881nM；D2，K i＝4217nM；D4，K i＝1189nM；而对于D3和D5受体没有明显亲和力。 The document Zhang et al., J. Med. Chem., 2017, 60, 6273-6288 discloses the following compounds having a 2-phenylcyclopropylmethylamine structure as agonists of 5-HT 2C receptors. The compound having dopamine receptor subtypes for several different degree of affinity: D1, K i = 881nM; D2, K i = 4217nM; D4, K i = 1189nM; D5 and D3 receptors and for no apparent affinity.

Figure PCTCN2021076289-appb-000002
Figure PCTCN2021076289-appb-000002

发明内容Summary of the invention

本发明所要解决的技术问题是提供一种全新结构的2-苯基环丙基甲基胺衍生物及其制备方法和应用。本发明的2-苯基环丙基甲基胺衍生物具有对多巴胺受体和/或5-羟色胺受体的亲和活性。The technical problem to be solved by the present invention is to provide a new structure of 2-phenylcyclopropylmethylamine derivative and its preparation method and application. The 2-phenylcyclopropylmethylamine derivative of the present invention has an affinity activity for dopamine receptors and/or serotonin receptors.

本发明提供了一种如式I所示的化合物：The present invention provides a compound represented by formula I:

Figure PCTCN2021076289-appb-000003
Figure PCTCN2021076289-appb-000003

或其互变异构体、立体异构体或同位素衍生物，或前述任一者(指前述如式I所示的化合物、互变异构体、立体异构体或同位素衍生物)的药学上可接受的盐，或前述任一者(指前述如式I所示的化合物、互变异构体、立体异构体、同位素衍生物或药学上可接受的盐)的晶型或溶剂化物；Or its tautomers, stereoisomers or isotopic derivatives, or any of the foregoing (referring to the aforementioned compounds, tautomers, stereoisomers or isotopic derivatives of formula I) The above-acceptable salt, or the crystal form or solvate of any of the foregoing (referring to the foregoing compound, tautomer, stereoisomer, isotopic derivative or pharmaceutically acceptable salt as shown in Formula I) ；

其中，R 1为氢、卤素(例如氟或氯)、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、-OR a、-SR b(例如甲硫基)、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 1a取代； Wherein, R 1 is hydrogen, halogen (such as fluorine or chlorine), substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b ( For example, methylthio), -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group refer to the C 1 -C 4 alkyl group And C 3 -C 6 cycloalkyl are each independently substituted with 1, 2, 3 or 4 R 1a ;

R 2为氢、卤素(例如氟或氯)、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、-OR a、-SR b、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 2a取代； R 2 is hydrogen, halogen (such as fluorine or chlorine), substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group refer to the C 1 -C 4 alkyl group and C 3 -C 6 cycloalkane The groups are each independently substituted with 1, 2, 3 or 4 R 2a ;

R 3为氢、卤素(例如氟或氯)、取代或未取代的C 1-C 4烷基(所述取代或未取代的C 1-C 4烷基例如三氟甲基)、取代或未取代的C 3-C 6环烷基、-OR a、-SR b、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 3a取代； R 3 is hydrogen, halogen (such as fluorine or chlorine), substituted or unsubstituted C 1 -C 4 alkyl (the substituted or unsubstituted C 1 -C 4 alkyl such as trifluoromethyl), substituted or unsubstituted Substituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 ring Alkyl means that the C 1 -C 4 alkyl group and C 3 -C 6 cycloalkyl group are each independently substituted with 1, 2, 3 or 4 R 3a ;

R 4为氢、卤素(例如氟或氯)、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、-OR a、-SR b、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 4a取代； R 4 is hydrogen, halogen (such as fluorine or chlorine), substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group refer to the C 1 -C 4 alkyl group and C 3 -C 6 cycloalkane The groups are each independently substituted with 1, 2, 3 or 4 R 4a ;

R 5为氢、卤素、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、-OR a(例如甲氧基、乙氧基或2-氟乙氧基)、-SR b、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 5a取代； R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a (such as methoxy, ethoxy or 2-fluoro Ethoxy), -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group refer to the C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl are each independently substituted with 1, 2, 3 or 4 R 5a ;

或者，“R 1和R 2”、“R 2和R 3”、“R 3和R 4”、或“R 4和R 5”，以及连接它们的相邻的两个碳原子一起共同形成取代或未取代的C 5-C 6环烷基、取代或未取代的5-6元杂环烷基、取代或未取代的苯基或取代或未取代的5-6元杂芳基，所述的取代的C 5-C 6环烷基、取代的5-6元杂环烷基(例如

Figure PCTCN2021076289-appb-000004
)、取代的苯基和取代的5-6元杂芳基是指所述C 5-C 6环烷基、5-6元杂环烷基、苯基和5-6元杂芳基各自独立地被1、2、3或4个R 5b取代； Or, "R 1 and R 2 ", "R 2 and R 3 ", "R 3 and R 4 ", or "R 4 and R 5 ", and two adjacent carbon atoms connecting them together form a substitution Or unsubstituted C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5-6 membered heteroaryl, said The substituted C 5 -C 6 cycloalkyl, substituted 5-6 membered heterocycloalkyl (e.g.
Figure PCTCN2021076289-appb-000004
), substituted phenyl and substituted 5-6 membered heteroaryl groups refer to the C 5 -C 6 cycloalkyl group, 5-6 membered heterocycloalkyl group, phenyl group and 5-6 membered heteroaryl group independently Ground is replaced by 1, 2, 3 or 4 R 5b ;

每个R 1a、R 2a、R 3a、R 4a和R 5a各自独立地为卤素(例如氟)、C 1-C 4烷基、C 3-C 6环烷基、-OR e、-SR f或-NR gR h； Each R 1a , R 2a , R 3a , R 4a and R 5a are each independently halogen (e.g. fluorine), C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, -OR e , -SR f Or -NR g R h ;

每个R 5b独立地为卤素(例如氟)、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基； Each R 5b is independently halogen (e.g. fluorine), C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;

R 6为氢、C 1-C 6烷基(例如甲基、乙基、正丙基或异丙基)、C 1-C 6卤代烷基、C 3-C 6环烷基或-(C 1-C 4亚烷基)-(C 3-C 6环烷基)(例如环丙基甲基)； R 6 is hydrogen, C 1 -C 6 alkyl (e.g. methyl, ethyl, n-propyl or isopropyl), C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl) (e.g. cyclopropylmethyl);

L为-(CR 8R 9) t-或

Figure PCTCN2021076289-appb-000005
L is -(CR 8 R 9 ) t -or
Figure PCTCN2021076289-appb-000005

t为2、3、4、5、6、7或8；t is 2, 3, 4, 5, 6, 7 or 8;

m为1、2或3；m is 1, 2 or 3;

n为1、2或3；n is 1, 2 or 3;

每个R 8和R 9各自独立地为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 8a取代；前提是连接于同一个碳原子上的R 8和R 9不同时为-OR a； Each of R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl refers to the C The 1- C 4 alkyl group is substituted with 1, 2, 3 or 4 R 8a ; provided that R 8 and R 9 attached to the same carbon atom are not at the same time -OR a ;

或者，一个R 8和一个R 9以及连接它们的一个或多个碳原子一起共同形成一个取代或未取代的单环C 3-C 6环烷基(即：所有的R 8和R 9中仅有一个R 8和一个R 9形成环)，所述的取代的单环C 3-C 6环烷基是指所述单环C 3-C 6环烷基被1、2、3或4个R 8a取代； Alternatively, one R 8 and one R 9 and one or more carbon atoms connecting them together form a substituted or unsubstituted monocyclic C 3 -C 6 cycloalkyl (ie: only in all R 8 and R 9 There is one R 8 and one R 9 forming a ring), the substituted monocyclic C 3 -C 6 cycloalkyl means that the monocyclic C 3 -C 6 cycloalkyl is divided by 1, 2, 3 or 4 Replaced by R 8a;

每个R 8a独立地为卤素、C 1-C 4烷基、C 3-C 6环烷基或-OR e； Each R 8a is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or -OR e ;

A为

Figure PCTCN2021076289-appb-000006
或-X-Y； A is
Figure PCTCN2021076289-appb-000006
Or -XY;

R 10为氢或C 1-C 4烷基； R 10 is hydrogen or C 1 -C 4 alkyl;

R 11为取代或未取代的C 3-C 8环烷基(所述C 3-C 8环烷基例如环己基)、取代或未取代的3-8元杂环烷基、-NR 11aR 11b、取代或未取代的C 6-C 14芳基(所述C 6-C 14芳基例如苯基)或取代或未取代的5-14元杂芳基(所述5-14元杂芳基例如吲哚基)，其中所述的取代的C 3-C 8环烷基、取代的3-8元杂环烷基、取代的C 6-C 14芳基和取代的5-14元杂芳基是指所述C 3-C 8环烷基、3-8元杂环烷基、C 6-C 14芳基和5-14元杂芳基各自独立地被1、2、3或4个R 11c取代； R 11 is substituted or unsubstituted C 3 -C 8 cycloalkyl (the C 3 -C 8 cycloalkyl such as cyclohexyl), substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR 11a R 11b , a substituted or unsubstituted C 6 -C 14 aryl group (the C 6 -C 14 aryl group such as phenyl) or a substituted or unsubstituted 5-14 membered heteroaryl group (the 5-14 membered heteroaryl group Group such as indolyl), wherein the substituted C 3 -C 8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C 6 -C 14 aryl and substituted 5-14 membered hetero Aryl refers to the C 3 -C 8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 14 aryl group and 5-14 membered heteroaryl group each independently by 1, 2, 3 or 4 R 11c substitution;

R 11为取代或未取代的C 3-C 8环烷基(所述C 3-C 8环烷基例如环己基)、取代或未取代的3-8元杂环烷基、-NR 11aR 11b、取代或未取代的C 6-C 14芳基(所述C 6-C 14芳基例如苯基)或取代或未取代的5-14元杂芳基(所述5-14元杂芳基例如吲哚基，例如

Figure PCTCN2021076289-appb-000007
)，其中所述的取代的C 3-C 8环烷基、取代的3-8元杂环烷基、取代的C 6-C 14芳基和取代的5-14元杂芳基是指所述C 3-C 8环烷基、3-8元杂环烷基、C 6-C 14芳基和5-14元杂芳基各自独立地被1、2、3或4个R 11c取代； R 11 is substituted or unsubstituted C 3 -C 8 cycloalkyl (the C 3 -C 8 cycloalkyl such as cyclohexyl), substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR 11a R 11b , a substituted or unsubstituted C 6 -C 14 aryl group (the C 6 -C 14 aryl group such as phenyl) or a substituted or unsubstituted 5-14 membered heteroaryl group (the 5-14 membered heteroaryl group Base such as indolyl, such as
Figure PCTCN2021076289-appb-000007
), wherein the substituted C 3 -C 8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C 6 -C 14 aryl and substituted 5-14 membered heteroaryl refer to The C 3 -C 8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 14 aryl group and 5-14 membered heteroaryl group are each independently substituted with 1, 2, 3 or 4 R 11c ;

R 11a为氢或C 1-C 4烷基(例如甲基)； R 11a is hydrogen or C 1 -C 4 alkyl (e.g. methyl);

R 11b为氢或C 1-C 4烷基(例如甲基)； R 11b is hydrogen or C 1 -C 4 alkyl (e.g. methyl);

或者，R 11a和R 11b以及连接它们的氮原子一起共同形成取代或未取代的4-8元杂环烷基(所述4-8元杂环烷基例如

Figure PCTCN2021076289-appb-000008
)，所述的取代的4-8元杂环烷基是指所述4-8元杂环烷基被1、2、3或4个R 11d取代； Alternatively, R 11a and R 11b and the nitrogen atom connecting them together form a substituted or unsubstituted 4-8 membered heterocycloalkyl group (the 4-8 membered heterocycloalkyl group is for example
Figure PCTCN2021076289-appb-000008
), the substituted 4-8 membered heterocycloalkyl group means that the 4-8 membered heterocycloalkyl group is substituted by 1, 2, 3 or 4 R 11d;

每个R 11c独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基、-OR a、-SR b、-NR cR d或-CN； Each R 11c is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN;

每个R 11d独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基、-OR a、-SR b、-NR cR d或-CN； Each R 11d is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN;

R 12为氢或C 1-C 4烷基； R 12 is hydrogen or C 1 -C 4 alkyl;

R 13为取代或未取代的C 3-C 8环烷基、取代或未取代的3-8元杂环烷基、取代或未取代的C 6-C 14芳基(所述C 6-C 14芳基例如苯基)或取代或未取代的5-14元杂芳基，其中所述的取代的C 3-C 8环烷基、取代的3-8元杂环烷基、取代的C 6-C 14芳基和取代的5-14元杂芳基是指所述C 3-C 8环烷基、3-8元杂环烷基、C 6-C 14芳基和5-14元杂芳基各自独立地任选被1、2、3或4个R 13a取代； R 13 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 14 aryl (the C 6 -C 14 aryl such as phenyl) or substituted or unsubstituted 5-14 membered heteroaryl, wherein the substituted C 3 -C 8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C The 6- C 14 aryl group and the substituted 5-14 membered heteroaryl group refer to the C 3 -C 8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 14 aryl group and 5-14 membered Each heteroaryl group is independently optionally substituted with 1, 2, 3, or 4 R 13a ;

每个R 13a独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基、-OR a、-SR b、-NR cR d或-CN； Each R 13a is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN;

X为

Figure PCTCN2021076289-appb-000009
-O-或-S-； X is
Figure PCTCN2021076289-appb-000009
-O- or -S-;

R 14和R 15各自独立地为氢或C 1-C 4烷基； R 14 and R 15 are each independently hydrogen or C 1 -C 4 alkyl;

Y为取代或未取代的C 6-C 14芳基或取代或未取代的5-14元杂芳基，所述的取代的C 6-C 14芳基和取代的5-14元杂芳基是指所述C 6-C 14芳基和5-14元杂芳基各自独立地被1、2、3或4个R 30取代； Y is a substituted or unsubstituted C 6 -C 14 aryl group or a substituted or unsubstituted 5-14 membered heteroaryl group, the substituted C 6 -C 14 aryl group and the substituted 5-14 membered heteroaryl group Means that the C 6 -C 14 aryl group and the 5-14 membered heteroaryl group are each independently substituted with 1, 2, 3 or 4 R 30 ;

每个R 30独立地为卤素、氧代、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、取代或未取代的4-6元杂环烷基、取代或未取代的苯基、取代或未取代的5-6元杂芳基、-OR a、-SR b、-NR cR d或-CN，其中所述取代的C 1-C 4烷基、取代的C 3-C 6环烷基、取代的4-6元杂环烷基、取代的苯基和取代的5-6元杂芳基是指所述C 1-C 4烷基、C 3-C 6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基各自独立地被1、2、3或4个R 40取代； Each R 30 is independently halogen, oxo, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycle Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4- alkyl, substituted C 3 -C 6 cycloalkyl, substituted 4-6 membered heterocycloalkyl, substituted phenyl and substituted 5-6 membered heteroaryl refer to the C 1 -C 4 alkane , C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each independently substituted with 1, 2, 3 or 4 R 40 ;

每个R 40独立地为卤素、氧代、C 1-C 4烷基、C 1-C 4卤代烷基、-OR a、-SR b、-NR cR d或-CN； Each R 40 is independently halogen, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN;

每个R a、R b、R c、R d、R e、R f和R g各自独立地为氢、C 1-C 4烷基、C 3-C 6环烷基或C 1-C 4卤代烷基(例如C 1-C 4氟代烷基)； Each R a, R b, R c , R d, R e, R f and R g are each independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 4 Haloalkyl (e.g. C 1 -C 4 fluoroalkyl);

*标记的碳原子为S构型、R构型或者两者的混合；*The marked carbon atom is S configuration, R configuration or a mixture of the two;

#标记的碳原子为S构型、R构型或者两者的混合；# The carbon atom marked with S configuration, R configuration or a mixture of the two;

所述杂环烷基和杂芳基中的杂原子个数独立地为1、2、3或4个，每个杂原子独立地为N、O或S。The number of heteroatoms in the heterocycloalkyl and heteroaryl groups is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S.

在一些实施方案中，所述的如式I所示的化合物中，R 1为氢、卤素、取代或未取代 的C 1-C 4烷基、-OR a或-SR b；和/或，R 2为氢、卤素、取代或未取代的C 1-C 4烷基、-OR a或-SR b；和/或，R 1和R 2以及连接它们的相邻的两个碳原子一起共同形成取代或未取代的苯基或者取代或未取代的5-6元杂环烷基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; and/or, R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; and/or, R 1 and R 2 and the adjacent two carbon atoms connecting them are together A substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-6 membered heterocycloalkyl group is formed; the definition of other variables is as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 1a独立地为卤素或-OR e；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each R 1a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 2a独立地为卤素或-OR e；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, each R 2a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 3为氢、卤素、取代或未取代的C 1-C 4烷基、-OR a或-SR b；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; definitions of other variables As described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 3a独立地为卤素或-OR e；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, each R 3a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 4为氢、卤素、取代或未取代的C 1-C 4烷基、-OR a或-SR b；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; definitions of other variables As described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 4a独立地为卤素或-OR e；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, each R 4a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 5为氢、卤素、取代或未取代的C 1-C 4烷基、-OR a或-SR b；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; definitions of other variables As described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 5a独立地为卤素或-OR e；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each R 5a is independently halogen or -OR e ; the definition of other variables is as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 5b独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each R 5b is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，

Figure PCTCN2021076289-appb-000010
部分为
Figure PCTCN2021076289-appb-000011
Figure PCTCN2021076289-appb-000012
每个R 1、R 2、R 3、R 4和R 5各自独立地如本发明中所定义；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I,
Figure PCTCN2021076289-appb-000010
Partly
Figure PCTCN2021076289-appb-000011
Figure PCTCN2021076289-appb-000012
Each of R 1 , R 2 , R 3 , R 4 and R 5 is independently as defined in the present invention; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，

Figure PCTCN2021076289-appb-000013
部分为
Figure PCTCN2021076289-appb-000014
Figure PCTCN2021076289-appb-000015
Figure PCTCN2021076289-appb-000016
每个R 1、R 2、R 3、R 4和R 5各自独立地如本发明中所定义；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I,
Figure PCTCN2021076289-appb-000013
Partly
Figure PCTCN2021076289-appb-000014
Figure PCTCN2021076289-appb-000015
Figure PCTCN2021076289-appb-000016
Each of R 1 , R 2 , R 3 , R 4 and R 5 is independently as defined in the present invention; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，

Figure PCTCN2021076289-appb-000017
部分为
Figure PCTCN2021076289-appb-000018
Figure PCTCN2021076289-appb-000019
Figure PCTCN2021076289-appb-000020
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I,
Figure PCTCN2021076289-appb-000017
Partly
Figure PCTCN2021076289-appb-000018
Figure PCTCN2021076289-appb-000019
Figure PCTCN2021076289-appb-000020
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，

Figure PCTCN2021076289-appb-000021
部分为
Figure PCTCN2021076289-appb-000022
Figure PCTCN2021076289-appb-000023
Figure PCTCN2021076289-appb-000024
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I,
Figure PCTCN2021076289-appb-000021
Partly
Figure PCTCN2021076289-appb-000022
Figure PCTCN2021076289-appb-000023
Figure PCTCN2021076289-appb-000024
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 6为氢、C 1-C 6烷基或-(C 1-C 4亚烷基)-(C 3-C 6环烷基)；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 6 is hydrogen, C 1 -C 6 alkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 ring Alkyl); the definition of other variables is as described in any of the schemes of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，当一个R 8和一个R 9以及连接它们的一个或多个碳原子一起共同形成一个取代或未取代的单环C 3-C 6环烷基时，L为

Figure PCTCN2021076289-appb-000025
其中k为0、1、2或3。 In some embodiments, in the compound represented by formula I, when one R 8 and one R 9 and one or more carbon atoms connecting them together form a substituted or unsubstituted monocyclic C 3- When C 6 cycloalkyl, L is
Figure PCTCN2021076289-appb-000025
Where k is 0, 1, 2 or 3.

在一些实施方案中，所述的如式I所示的化合物中，每个R 8a独立地为C 1-C 4烷基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each R 8a is independently a C 1 -C 4 alkyl group; the definition of other variables is as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，t为3、4、5或6；其他变量的定义如本发明中任一方案中所述。In some embodiments, in the compound represented by Formula I, t is 3, 4, 5 or 6; the definitions of other variables are as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，m为1；其他变量的定义如本发明中任一方案中所述。In some embodiments, in the compound represented by formula I, m is 1; other variables are defined as described in any of the aspects of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，n为1；其他变量的定义如本发明中任一方案中所述。In some embodiments, in the compound represented by formula I, n is 1; other variables are defined as described in any of the aspects of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 3-、-(CR 8R 9) 4-、-(CR 8R 9) 5-、

Figure PCTCN2021076289-appb-000026
其中k为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, L is -(CR 8 R 9 ) 3 -, -(CR 8 R 9 ) 4 -, -(CR 8 R 9 ) 5 -,
Figure PCTCN2021076289-appb-000026
Wherein k is 0, 1, 2 or 3; the definitions of other variables are as described in any of the schemes of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，当Y为取代或未取代的C 6-C 14 芳基时，所述的取代或未取代的C 6-C 14芳基可以为

Figure PCTCN2021076289-appb-000027
(例如
Figure PCTCN2021076289-appb-000028
)、
Figure PCTCN2021076289-appb-000029
(例如
Figure PCTCN2021076289-appb-000030
)或
Figure PCTCN2021076289-appb-000031
(例如
Figure PCTCN2021076289-appb-000032
)，其中环A为苯基或5-6元杂芳基(5元杂芳基例如呋喃基、噻吩基、吡咯基、吡唑基、恶唑基、噻唑基、咪唑基或三唑基，6元杂芳基例如吡嗪基、哒嗪基、吡啶基或嘧啶基)，每个p独立地为0、1、2或3，每个q独立地为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, when Y is a substituted or unsubstituted C 6 -C 14 aryl group, the substituted or unsubstituted C 6 -C 14 aryl group Can be
Figure PCTCN2021076289-appb-000027
(E.g
Figure PCTCN2021076289-appb-000028
),
Figure PCTCN2021076289-appb-000029
(E.g
Figure PCTCN2021076289-appb-000030
)or
Figure PCTCN2021076289-appb-000031
(E.g
Figure PCTCN2021076289-appb-000032
), wherein ring A is phenyl or 5-6 membered heteroaryl (5 membered heteroaryl such as furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl, 6-membered heteroaryl groups such as pyrazinyl, pyridazinyl, pyridinyl or pyrimidinyl), each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; others The definition of the variable is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，当Y为取代或未取代的C 6-C 14芳基时，所述的取代或未取代的C 6-C 14芳基可以为

Figure PCTCN2021076289-appb-000033
Figure PCTCN2021076289-appb-000034
Figure PCTCN2021076289-appb-000035
其中每个p独立地为0、1、2或3，每个q独立地为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, when Y is a substituted or unsubstituted C 6 -C 14 aryl group, the substituted or unsubstituted C 6 -C 14 aryl group Can be
Figure PCTCN2021076289-appb-000033
Figure PCTCN2021076289-appb-000034
Figure PCTCN2021076289-appb-000035
Wherein each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，当Y为取代或未取代的C 6-C 14芳基时，所述的取代或未取代的C 6-C 14芳基可以为

Figure PCTCN2021076289-appb-000036
Figure PCTCN2021076289-appb-000037
Figure PCTCN2021076289-appb-000038
其中每个p独立地为0、1、2或3，每个q独立地为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, when Y is a substituted or unsubstituted C 6 -C 14 aryl group, the substituted or unsubstituted C 6 -C 14 aryl group Can be
Figure PCTCN2021076289-appb-000036
Figure PCTCN2021076289-appb-000037
Figure PCTCN2021076289-appb-000038
Wherein each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，当Y为取代或未取代的5-14元杂芳基时，所述的取代或未取代的5-14元杂芳基为

Figure PCTCN2021076289-appb-000039
其中环B为5-6元杂芳基(5元杂芳基例如呋喃基、噻吩基、吡咯基、吡唑基、恶唑基、噻唑基、咪唑基或三唑基，6元杂芳基例如吡嗪基、哒嗪基、吡啶基或嘧啶基)或8-10元双环杂芳基，环C为5-6元杂芳基(5元杂芳基例如呋喃基、噻吩基、吡咯基、吡唑基、恶唑基、噻唑基、咪唑基或三唑基，6元杂芳基例如吡嗪基、哒嗪基、吡啶基或嘧啶基)，环D为苯基或5-6元杂芳基(例如呋喃基、噻吩基、吡咯基、吡唑基、恶唑基、噻唑基、咪唑基或三唑基，6元杂芳基例如吡嗪基、哒嗪基、吡啶基或嘧啶基)，每个p独立地为0、1、2或3，每个q独立地为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, when Y is a substituted or unsubstituted 5-14 membered heteroaryl group, the substituted or unsubstituted 5-14 membered heteroaryl group for
Figure PCTCN2021076289-appb-000039
Wherein ring B is 5-6 membered heteroaryl (5 membered heteroaryl such as furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl, 6-membered heteroaryl Such as pyrazinyl, pyridazinyl, pyridinyl or pyrimidinyl) or 8-10 membered bicyclic heteroaryl, ring C is 5-6 membered heteroaryl (5 membered heteroaryl such as furyl, thienyl, pyrrolyl , Pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl, 6-membered heteroaryl such as pyrazinyl, pyridazinyl, pyridinyl or pyrimidinyl), ring D is phenyl or 5-6 members Heteroaryl groups (e.g. furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl, 6-membered heteroaryl such as pyrazinyl, pyridazinyl, pyridinyl or pyrimidine Base), each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，当Y为取代或未取代的5-14元杂芳基时，所述的取代或未取代的5-14元杂芳基可以为

Figure PCTCN2021076289-appb-000040
Figure PCTCN2021076289-appb-000041
Figure PCTCN2021076289-appb-000042
Figure PCTCN2021076289-appb-000043
其中每个p独立地为0、1、2或3，每个q独立地为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, when Y is a substituted or unsubstituted 5-14 membered heteroaryl group, the substituted or unsubstituted 5-14 membered heteroaryl group Can be
Figure PCTCN2021076289-appb-000040
Figure PCTCN2021076289-appb-000041
Figure PCTCN2021076289-appb-000042
Figure PCTCN2021076289-appb-000043
Wherein each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，当Y为取代或未取代的5-14元杂芳基时，所述的取代或未取代的5-14元杂芳基可以为

Figure PCTCN2021076289-appb-000044
Figure PCTCN2021076289-appb-000045
Figure PCTCN2021076289-appb-000046
其中每个p独立地为0、1、2或3，每个q独立地为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, when Y is a substituted or unsubstituted 5-14 membered heteroaryl group, the substituted or unsubstituted 5-14 membered heteroaryl group Can be
Figure PCTCN2021076289-appb-000044
Figure PCTCN2021076289-appb-000045
Figure PCTCN2021076289-appb-000046
Wherein each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，如前述任一方案所述的如式I所示的化合物中，当A为

Figure PCTCN2021076289-appb-000047
时，所述的
Figure PCTCN2021076289-appb-000048
为
Figure PCTCN2021076289-appb-000049
Figure PCTCN2021076289-appb-000050
Figure PCTCN2021076289-appb-000051
其中每个p独立地为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I as described in any of the preceding embodiments, when A is
Figure PCTCN2021076289-appb-000047
When the said
Figure PCTCN2021076289-appb-000048
for
Figure PCTCN2021076289-appb-000049
Figure PCTCN2021076289-appb-000050
Figure PCTCN2021076289-appb-000051
Wherein, each p is independently 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，当A为

Figure PCTCN2021076289-appb-000052
时，所述的
Figure PCTCN2021076289-appb-000053
为
Figure PCTCN2021076289-appb-000054
其中p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, when A is
Figure PCTCN2021076289-appb-000052
When the said
Figure PCTCN2021076289-appb-000053
for
Figure PCTCN2021076289-appb-000054
Wherein p is 0, 1, 2 or 3; the definitions of other variables are as described in any of the aspects of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为

Figure PCTCN2021076289-appb-000055
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, A is
Figure PCTCN2021076289-appb-000055
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为

Figure PCTCN2021076289-appb-000056
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, A is
Figure PCTCN2021076289-appb-000056
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000057
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000057
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000058
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000058
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000059
p为0、1、2或3，q为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000059
p is 0, 1, 2 or 3, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000060
p为0、1、2或3，q为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000060
p is 0, 1, 2 or 3, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000061
p为0、1、2或3，q为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000061
p is 0, 1, 2 or 3, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000062
p为0、1、2或3，q为0或1；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000062
p is 0, 1, 2 or 3, q is 0 or 1; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000063
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000063
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000064
p为0、1或2；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000064
p is 0, 1 or 2; the definitions of other variables are as described in any of the aspects of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000065
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000065
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000066
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000066
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000067
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000067
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000068
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000068
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000069
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000069
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000070
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000070
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000071
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000071
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000072
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000072
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000073
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000073
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000074
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000074
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000075
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000075
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000076
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000076
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000077
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000077
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000078
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000078
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000079
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000079
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000080
p为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000080
p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000081
p为0或1，q为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000081
p is 0 or 1, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y，其中Y为

Figure PCTCN2021076289-appb-000082
p为0或1，q为0、1或2；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, A is -XY, where Y is
Figure PCTCN2021076289-appb-000082
p is 0 or 1, q is 0, 1 or 2; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 14为氢；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 14 is hydrogen; the definitions of other variables are as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 15为氢；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 15 is hydrogen; the definitions of other variables are as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，X为-O-或-S-；其他变量的定义如本发明中任一方案中所述。In some embodiments, in the compound represented by formula I, X is -O- or -S-; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，-L-A选自以下任一组定义：In some embodiments, in the compound represented by formula I, -L-A is selected from any one of the following group definitions:

(i)L为-(CR 8R 9) 3-，A为-X-Y，X为-S-，Y为

Figure PCTCN2021076289-appb-000083
Figure PCTCN2021076289-appb-000084
每个p独立地为0或1，每个q独立地为0、1、2或3； (i) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is
Figure PCTCN2021076289-appb-000083
Figure PCTCN2021076289-appb-000084
Each p is independently 0 or 1, and each q is independently 0, 1, 2 or 3;

(ii)L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000085
Figure PCTCN2021076289-appb-000086
Figure PCTCN2021076289-appb-000087
其中每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； (ii) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is
Figure PCTCN2021076289-appb-000085
Figure PCTCN2021076289-appb-000086
Figure PCTCN2021076289-appb-000087
Where each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3;

(iii)L为-(CR 8R 9) 3-、-(CR 8R 9) 4-、-(CR 8R 9) 5-或

Figure PCTCN2021076289-appb-000088
A为-X-Y，X为-O-，Y为
Figure PCTCN2021076289-appb-000089
Figure PCTCN2021076289-appb-000090
其中每个p独立地为0、1、2或3；或 (iii) L is-(CR 8 R 9 ) 3 -,-(CR 8 R 9 ) 4 -,-(CR 8 R 9 ) 5 -or
Figure PCTCN2021076289-appb-000088
A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000089
Figure PCTCN2021076289-appb-000090
Where each p is independently 0, 1, 2 or 3; or

(iv)L为

Figure PCTCN2021076289-appb-000091
A为
Figure PCTCN2021076289-appb-000092
Figure PCTCN2021076289-appb-000093
Figure PCTCN2021076289-appb-000094
其中k为0、1、2或3，每个p独立地为0、1、2或3； (iv) L is
Figure PCTCN2021076289-appb-000091
A is
Figure PCTCN2021076289-appb-000092
Figure PCTCN2021076289-appb-000093
Figure PCTCN2021076289-appb-000094
Where k is 0, 1, 2 or 3, and each p is independently 0, 1, 2 or 3;

其他变量的定义如本发明中任一方案中所述。The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，-L-A选自以下任一组定义：In some embodiments, in the compound represented by formula I, -L-A is selected from any one of the following group definitions:

(1)L为-(CR 8R 9) 3-，A为-X-Y，X为-S-，Y为

Figure PCTCN2021076289-appb-000095
其中p为0或1，q为0、1、2或3； (1) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is
Figure PCTCN2021076289-appb-000095
Wherein p is 0 or 1, q is 0, 1, 2 or 3;

(2)L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000096
其中p为0、1、2或3； (2) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is
Figure PCTCN2021076289-appb-000096
Where p is 0, 1, 2 or 3;

(3)L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000097
其中p为0、1、2或3； (3) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is
Figure PCTCN2021076289-appb-000097
Where p is 0, 1, 2 or 3;

(4)L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000098
其中p为0、1、2或3，q为0、1、2或3； (4) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is
Figure PCTCN2021076289-appb-000098
Where p is 0, 1, 2 or 3, and q is 0, 1, 2 or 3;

(5)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000099
其中p为0、1、2或3； (5) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000099
Where p is 0, 1, 2 or 3;

(6)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000100
其中p为0、1、2或3； (6) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000100
Where p is 0, 1, 2 or 3;

(7)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000101
其中p为0、1、2或3； (7) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000101
Where p is 0, 1, 2 or 3;

(8)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000102
其中p为0、1、2或3； (8) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000102
Where p is 0, 1, 2 or 3;

(9)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000103
其中p为0、1、2或3； (9) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000103
Where p is 0, 1, 2 or 3;

(10)L为

Figure PCTCN2021076289-appb-000104
A为-X-Y，X为-O-，Y为
Figure PCTCN2021076289-appb-000105
其中p为0、1、2或3； (10) L is
Figure PCTCN2021076289-appb-000104
A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000105
Where p is 0, 1, 2 or 3;

(11)L为

Figure PCTCN2021076289-appb-000106
A为-X-Y，X为-O-，Y为
Figure PCTCN2021076289-appb-000107
其中p为0、1、2或3； (11) L is
Figure PCTCN2021076289-appb-000106
A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000107
Where p is 0, 1, 2 or 3;

(12)L为-(CR 8R 9) 3-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000108
其中p为0、1、 2或3； (12) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000108
Where p is 0, 1, 2 or 3;

(13)L为-(CR 8R 9) 3-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000109
其中p为0、1、2或3； (13) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000109
Where p is 0, 1, 2 or 3;

(14)L为-(CR 8R 9) 3-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000110
其中p为0、1、2或3； (14) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000110
Where p is 0, 1, 2 or 3;

(15)L为-(CR 8R 9) 3-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000111
其中p为0、1、2或3； (15) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000111
Where p is 0, 1, 2 or 3;

(16)L为-(CR 8R 9) 5-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000112
其中p为0、1、2或3； (16) L is -(CR 8 R 9 ) 5 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000112
Where p is 0, 1, 2 or 3;

(17)L为-(CR 8R 9) 5-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000113
其中p为0、1、2或3； (17) L is -(CR 8 R 9 ) 5 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000113
Where p is 0, 1, 2 or 3;

(18)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000114
其中p为0、1、2或3； (18) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000114
Where p is 0, 1, 2 or 3;

(19)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000115
其中p为0、1、2或3； (19) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000115
Where p is 0, 1, 2 or 3;

(20)L为

Figure PCTCN2021076289-appb-000116
A为
Figure PCTCN2021076289-appb-000117
其中k为0、1、2或3； (20)L is
Figure PCTCN2021076289-appb-000116
A is
Figure PCTCN2021076289-appb-000117
Where k is 0, 1, 2 or 3;

(21)L为

Figure PCTCN2021076289-appb-000118
A为
Figure PCTCN2021076289-appb-000119
其中k为0、1、2或3，p为0、1、2或3； (21) L is
Figure PCTCN2021076289-appb-000118
A is
Figure PCTCN2021076289-appb-000119
Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;

(22)L为

Figure PCTCN2021076289-appb-000120
A为
Figure PCTCN2021076289-appb-000121
其中k为0、1、2或3，p为0、1、2或3； (22)L is
Figure PCTCN2021076289-appb-000120
A is
Figure PCTCN2021076289-appb-000121
Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;

(23)L为

Figure PCTCN2021076289-appb-000122
A为
Figure PCTCN2021076289-appb-000123
其中k为0、1、2或3，p为0、1、2或3； (23)L is
Figure PCTCN2021076289-appb-000122
A is
Figure PCTCN2021076289-appb-000123
Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;

(24)L为

Figure PCTCN2021076289-appb-000124
A为
Figure PCTCN2021076289-appb-000125
其中k为0、1、2或3，p为0、1、2或3； (24) L is
Figure PCTCN2021076289-appb-000124
A is
Figure PCTCN2021076289-appb-000125
Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;

(25)L为

Figure PCTCN2021076289-appb-000126
A为
Figure PCTCN2021076289-appb-000127
其中k为0、1、2或3，p为0、1、2或3； (25)L is
Figure PCTCN2021076289-appb-000126
A is
Figure PCTCN2021076289-appb-000127
Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;

(26)L为

Figure PCTCN2021076289-appb-000128
A为
Figure PCTCN2021076289-appb-000129
其中k为0、1、2或3，p为0、1、2或3； (26) L is
Figure PCTCN2021076289-appb-000128
A is
Figure PCTCN2021076289-appb-000129
Where k is 0, 1, 2 or 3, and p is 0, 1, 2 or 3;

其他变量的定义如本发明任一方案中所述。The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 3-，A为-X-Y，X为-S-，Y为

Figure PCTCN2021076289-appb-000130
其中p为0或1，q为0、1、2或3；其他变量的定 义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, and Y is
Figure PCTCN2021076289-appb-000130
Wherein p is 0 or 1, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000131
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, and Y is
Figure PCTCN2021076289-appb-000131
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000132
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, and Y is
Figure PCTCN2021076289-appb-000132
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000133
其中p为0、1、2或3，q为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, and Y is
Figure PCTCN2021076289-appb-000133
Wherein p is 0, 1, 2 or 3, q is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000134
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000134
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000135
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000135
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000136
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000136
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X 为-O-，Y为

Figure PCTCN2021076289-appb-000137
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by Formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000137
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000138
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000138
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为

Figure PCTCN2021076289-appb-000139
A为-X-Y，X为-O-，Y为
Figure PCTCN2021076289-appb-000140
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is
Figure PCTCN2021076289-appb-000139
A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000140
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为

Figure PCTCN2021076289-appb-000141
A为-X-Y，X为-O-，Y为
Figure PCTCN2021076289-appb-000142
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is
Figure PCTCN2021076289-appb-000141
A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000142
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 3-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000143
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000143
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 3-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000144
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000144
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 3-，A为-X-Y，X 为-O-，Y为

Figure PCTCN2021076289-appb-000145
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, and Y is
Figure PCTCN2021076289-appb-000145
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 3-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000146
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 3 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000146
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 5-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000147
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 5 -, A is -XY, X is -O-, and Y is
Figure PCTCN2021076289-appb-000147
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 5-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000148
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 5 -, A is -XY, X is -O-, and Y is
Figure PCTCN2021076289-appb-000148
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000149
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000149
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000150
其中p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000150
Wherein p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为

Figure PCTCN2021076289-appb-000151
A为
Figure PCTCN2021076289-appb-000152
其中k为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is
Figure PCTCN2021076289-appb-000151
A is
Figure PCTCN2021076289-appb-000152
Wherein k is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为

Figure PCTCN2021076289-appb-000153
A为
Figure PCTCN2021076289-appb-000154
Figure PCTCN2021076289-appb-000155
明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is
Figure PCTCN2021076289-appb-000153
A is
Figure PCTCN2021076289-appb-000154
Figure PCTCN2021076289-appb-000155
As described in any one of the options.

在一些实施方案中，所述的如式I所示的化合物中，L为

Figure PCTCN2021076289-appb-000156
A为
Figure PCTCN2021076289-appb-000157
其中k为0、1、2或3，p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is
Figure PCTCN2021076289-appb-000156
A is
Figure PCTCN2021076289-appb-000157
Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为

Figure PCTCN2021076289-appb-000158
A为
Figure PCTCN2021076289-appb-000159
其中k为0、1、2或3，p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is
Figure PCTCN2021076289-appb-000158
A is
Figure PCTCN2021076289-appb-000159
Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为

Figure PCTCN2021076289-appb-000160
A为
Figure PCTCN2021076289-appb-000161
其中k为0、1、2或3，p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is
Figure PCTCN2021076289-appb-000160
A is
Figure PCTCN2021076289-appb-000161
Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为

Figure PCTCN2021076289-appb-000162
A为
Figure PCTCN2021076289-appb-000163
其中k为0、1、2或3，p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is
Figure PCTCN2021076289-appb-000162
A is
Figure PCTCN2021076289-appb-000163
Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，L为

Figure PCTCN2021076289-appb-000164
A为
Figure PCTCN2021076289-appb-000165
其中k为0、1、2或3，p为0、1、2或3；其他变量的定义如本发明任一方案中所述。 In some embodiments, in the compound represented by formula I, L is
Figure PCTCN2021076289-appb-000164
A is
Figure PCTCN2021076289-appb-000165
Wherein k is 0, 1, 2 or 3, p is 0, 1, 2 or 3; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，-L-A为

Figure PCTCN2021076289-appb-000166
Figure PCTCN2021076289-appb-000167
Figure PCTCN2021076289-appb-000168
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, -LA is
Figure PCTCN2021076289-appb-000166
Figure PCTCN2021076289-appb-000167
Figure PCTCN2021076289-appb-000168
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 10独立地为氢；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each R 10 is independently hydrogen; the definitions of other variables are as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 11a为C 1-C 4烷基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 11a is a C 1 -C 4 alkyl group; other variables are defined as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 11b为C 1-C 4烷基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 11b is a C 1 -C 4 alkyl group; other variables are defined as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 11c独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each R 11c is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 11d独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each R 11d is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 12为氢或C 1-C 4烷基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 12 is hydrogen or C 1 -C 4 alkyl; the definition of other variables is as described in any of the embodiments of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，-L-A为

Figure PCTCN2021076289-appb-000169
Figure PCTCN2021076289-appb-000170
Figure PCTCN2021076289-appb-000171
Figure PCTCN2021076289-appb-000172
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, -LA is
Figure PCTCN2021076289-appb-000169
Figure PCTCN2021076289-appb-000170
Figure PCTCN2021076289-appb-000171
Figure PCTCN2021076289-appb-000172
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，R 1为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.

在一些实施方案中，所述的如式I所示的化合物中，R 2为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.

在一些实施方案中，所述的如式I所示的化合物中，R 3为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.

在一些实施方案中，所述的如式I所示的化合物中，R 4为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.

在一些实施方案中，所述的如式I所示的化合物中，R 5为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; other variables are defined as in the present invention As described in either scenario.

在一些实施方案中，所述的如式I所示的化合物中，每个R 1a、R 2a、R 3a、R 4a和R 5a各自独立地为卤素；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each of R 1a , R 2a , R 3a , R 4a and R 5a is independently halogen; other variables are defined as any of the present invention As described in the protocol.

在一些实施方案中，所述的如式I所示的化合物中，L为-(CR 8R 9) 3-、-(CR 8R 9) 4-或

Figure PCTCN2021076289-appb-000173
其中k为0、1、2或3；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, L is -(CR 8 R 9 ) 3 -, -(CR 8 R 9 ) 4 -or
Figure PCTCN2021076289-appb-000173
Wherein k is 0, 1, 2 or 3; the definitions of other variables are as described in any of the schemes of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，当A为

Figure PCTCN2021076289-appb-000174
时，所述的
Figure PCTCN2021076289-appb-000175
为
Figure PCTCN2021076289-appb-000176
In some embodiments, in the compound represented by formula I, when A is
Figure PCTCN2021076289-appb-000174
When the said
Figure PCTCN2021076289-appb-000175
for
Figure PCTCN2021076289-appb-000176

在一些实施方案中，所述的如式I所示的化合物中，A为

Figure PCTCN2021076289-appb-000177
或-X-Y；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, A is
Figure PCTCN2021076289-appb-000177
Or -XY; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，Y优选为

Figure PCTCN2021076289-appb-000178
Figure PCTCN2021076289-appb-000179
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, Y is preferably
Figure PCTCN2021076289-appb-000178
Figure PCTCN2021076289-appb-000179
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，-L-A选自以下任一组定义：In some embodiments, in the compound represented by formula I, -L-A is selected from any one of the following group definitions:

(i)L为-(CR 8R 9) 3-，A为-X-Y，X为-S-，Y为

Figure PCTCN2021076289-appb-000180
p为0或1，q为0、1、2或3； (i) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is
Figure PCTCN2021076289-appb-000180
p is 0 or 1, q is 0, 1, 2 or 3;

(ii)L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000181
Figure PCTCN2021076289-appb-000182
其中每个p独立地为0、1、2或3，每个q为独立地0、1、2或3； (ii) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is
Figure PCTCN2021076289-appb-000181
Figure PCTCN2021076289-appb-000182
Where each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3;

(iii)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000183
p为0、1、2或3；或 (iii) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000183
p is 0, 1, 2 or 3; or

(iv)L为

Figure PCTCN2021076289-appb-000184
A为
Figure PCTCN2021076289-appb-000185
(iv) L is
Figure PCTCN2021076289-appb-000184
A is
Figure PCTCN2021076289-appb-000185

其他变量的定义如本发明中任一方案中所述。The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，A为-X-Y；其他变量的定义如 本发明中任一方案中所述。In some embodiments, in the compound represented by formula I, A is -X-Y; the definitions of other variables are as described in any of the aspects of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 30独立地为卤素、氧代、羟基、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, each R 30 is independently halogen, oxo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; the definitions of other variables are as described in any of the aspects of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 30独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by Formula I, each R 30 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 40独立地为卤素、氧代、羟基、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each R 40 is independently halogen, oxo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; the definitions of other variables are as described in any of the aspects of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 40独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each R 40 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy Base; the definition of other variables is as described in any of the schemes of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，每个R 8和R 9各自独立地为氢或C 1-C 4烷基；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, each of R 8 and R 9 is independently hydrogen or C 1 -C 4 alkyl; other variables are defined as in any of the embodiments of the present invention As described in.

在一些实施方案中，所述的如式I所示的化合物中，各基团定义如下：In some embodiments, in the compound represented by Formula I, each group is defined as follows:

R 1为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 1a取代； R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 1a substitutions;

R 2为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 2a取代； R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 2a substitutions;

R 3为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 3a取代； R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 3a substitutions;

R 4为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 4a取代； R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is 1 , 2, 3 or 4 R 4a substitutions;

R 5为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 5a取代； R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 5a substitutions;

每个R 1a、R 2a、R 3a、R 4a和R 5a各自独立地为卤素； Each of R 1a , R 2a , R 3a , R 4a and R 5a is independently halogen;

R 6为氢、C 1-C 6烷基或-(C 1-C 4亚烷基)-(C 3-C 6环烷基)； R 6 is hydrogen, C 1 -C 6 alkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl);

-L-A选自以下任一组定义：-L-A is selected from any of the following group definitions:

(i)L为-(CR 8R 9) 3-，A为-X-Y，X为-S-，Y为

Figure PCTCN2021076289-appb-000186
p为0或1，q为0、1、2或3； (i) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is
Figure PCTCN2021076289-appb-000186
p is 0 or 1, q is 0, 1, 2 or 3;

(ii)L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000187
Figure PCTCN2021076289-appb-000188
p为0、1、2或3，q为0、1、2或3； (ii) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is
Figure PCTCN2021076289-appb-000187
Figure PCTCN2021076289-appb-000188
p is 0, 1, 2 or 3, q is 0, 1, 2 or 3;

(iii)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为

Figure PCTCN2021076289-appb-000189
p为0、1、2或3；或 (iii) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-000189
p is 0, 1, 2 or 3; or

(iv)L为

Figure PCTCN2021076289-appb-000190
A为-NHC(O)NR 11aR 11b，k为0、1、2或3； (iv) L is
Figure PCTCN2021076289-appb-000190
A is -NHC(O)NR 11a R 11b , and k is 0, 1, 2 or 3;

每个R 8和R 9各自独立地为氢或C 1-C 4烷基； Each of R 8 and R 9 is independently hydrogen or C 1 -C 4 alkyl;

R 8a为C 1-C 4烷基； R 8a is C 1 -C 4 alkyl;

R 10为氢或C 1-C 4烷基； R 10 is hydrogen or C 1 -C 4 alkyl;

R 11a为氢或C 1-C 4烷基； R 11a is hydrogen or C 1 -C 4 alkyl;

R 11b为氢或C 1-C 4烷基； R 11b is hydrogen or C 1 -C 4 alkyl;

每个R 30独立地为卤素、C 1-C 4烷基、C 1-C 4烷氧基或C 1-C 4卤代烷基； Each R 30 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl;

每个R 40独立地为卤素、C 1-C 4烷基、C 1-C 4烷氧基或C 1-C 4卤代烷基； Each R 40 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl;

每个R a独立地为C 1-C 4烷基或C 1-C 4卤代烷基。 Each R a is independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.

在一些实施方案中，所述的如式I所示的化合物中，-L-A优选自以下任一组定义：In some embodiments, in the compound represented by formula I, -L-A is preferably defined from any one of the following groups:

(i)L为-(CR 8R 9) 3-，A为-X-Y，X为-S-，Y为

Figure PCTCN2021076289-appb-000191
p为0或1，q为0、1、2或3； (i) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is
Figure PCTCN2021076289-appb-000191
p is 0 or 1, q is 0, 1, 2 or 3;

(ii)L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为

Figure PCTCN2021076289-appb-000192
Figure PCTCN2021076289-appb-000193
p为0、1、2或3，q为0、1、2或3。 (ii) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is
Figure PCTCN2021076289-appb-000192
Figure PCTCN2021076289-appb-000193
p is 0, 1, 2 or 3, and q is 0, 1, 2 or 3.

在一些实施方案中，所述的如式I所示的化合物中，-L-A为

Figure PCTCN2021076289-appb-000194
Figure PCTCN2021076289-appb-000195
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, -LA is
Figure PCTCN2021076289-appb-000194
Figure PCTCN2021076289-appb-000195
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，-L-A优选为

Figure PCTCN2021076289-appb-000196
Figure PCTCN2021076289-appb-000197
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I, -LA is preferably
Figure PCTCN2021076289-appb-000196
Figure PCTCN2021076289-appb-000197
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，如前述任一方案所述的如式I所示的化合物中，每个R 30独立地为C 1-C 4烷基。 In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, each R 30 is independently a C 1 -C 4 alkyl group.

在一些实施方案中，如前述任一方案所述的如式I所示的化合物中，每个R 40独立地为C 1-C 4烷基。 In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, each R 40 is independently a C 1 -C 4 alkyl group.

在一些实施方案中，如前述任一方案所述的如式I所示的化合物中，R 8和R 9均为氢。 In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, R 8 and R 9 are both hydrogen.

在一些实施方案中，如前述任一方案所述的如式I所示的化合物中，R 11a为C 1-C 4烷基。 In some embodiments, in the compound of Formula I as described in any one of the preceding embodiments, R 11a is a C 1 -C 4 alkyl group.

在一些实施方案中，如前述任一方案所述的如式I所示的化合物中，R 11b为C 1-C 4烷基。 In some embodiments, in the compound of formula I as described in any one of the preceding embodiments, R 11b is a C 1 -C 4 alkyl group.

在一些实施方案中，如前述任一方案所述的如式I所示的化合物中，每个p独立地为0或1。In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, each p is independently 0 or 1.

在一些实施方案中，如前述任一方案所述的如式I所示的化合物中，每个q独立地为0或1。In some embodiments, in the compound of Formula I as described in any of the preceding embodiments, each q is independently 0 or 1.

在一些实施方案中，如前述任一方案所述的如式I所示的化合物中，k为0。In some embodiments, k is zero in the compound of formula I as described in any of the preceding embodiments.

在一些实施方案中，所述的如式I所示的化合物中，其中Y为

Figure PCTCN2021076289-appb-000198
Figure PCTCN2021076289-appb-000199
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, wherein Y is
Figure PCTCN2021076289-appb-000198
Figure PCTCN2021076289-appb-000199
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，其中-L-A为

Figure PCTCN2021076289-appb-000200
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound of formula I, wherein -LA is
Figure PCTCN2021076289-appb-000200
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，各基团定义如下：In some embodiments, in the compound represented by Formula I, each group is defined as follows:

R 1为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 1a取代； R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 1a substitutions;

R 2为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 2a取代； R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 2a substitutions;

R 3为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 3a取代； R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 3a substitutions;

R 4为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 4a取代； R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 4a substitutions;

R 5为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 5a取代； R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 5a substitutions;

每个R 1a、R 2a、R 3a、R 4a和R 5a各自独立地为卤素； Each of R 1a , R 2a , R 3a , R 4a and R 5a is independently halogen;

R 6为氢、C 1-C 6烷基或-(C 1-C 4亚烷基)-(C 3-C 6环烷基)； R 6 is hydrogen, C 1 -C 6 alkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl);

-L-A为

Figure PCTCN2021076289-appb-000201
Figure PCTCN2021076289-appb-000202
-LA is
Figure PCTCN2021076289-appb-000201
Figure PCTCN2021076289-appb-000202

R 11a为C 1-C 4烷基； R 11a is C 1 -C 4 alkyl;

R 11b为C 1-C 4烷基； R 11b is a C 1 -C 4 alkyl group;

每个R a独立地为C 1-C 4烷基或C 1-C 4卤代烷基。 Each R a is independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl.

在一些实施方案中，所述的如式I所示的化合物中，

Figure PCTCN2021076289-appb-000203
部分为
Figure PCTCN2021076289-appb-000204
Figure PCTCN2021076289-appb-000205
每个R 1、R 2、R 3、R 4和R 5各自独立地如本发明中所定义；其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I,
Figure PCTCN2021076289-appb-000203
Partly
Figure PCTCN2021076289-appb-000204
Figure PCTCN2021076289-appb-000205
Each of R 1 , R 2 , R 3 , R 4 and R 5 is independently as defined in the present invention; the definition of other variables is as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，

Figure PCTCN2021076289-appb-000206
部分选自以下任一组定义： In some embodiments, in the compound represented by formula I,
Figure PCTCN2021076289-appb-000206
Part is selected from any one of the following group definitions:

(i)

Figure PCTCN2021076289-appb-000207
其中R 2为卤素(例如氟或氯)； (i)
Figure PCTCN2021076289-appb-000207
Wherein R 2 is halogen (e.g. fluorine or chlorine);

(ii)

Figure PCTCN2021076289-appb-000208
其中R 3为卤素(例如氟或氯)或取代或未取代的C 1-C 4烷基(所述取代或未取代的C 1-C 4烷基例如三氟甲基)；所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 3a取代；R 3a为卤素(例如氟)； (ii)
Figure PCTCN2021076289-appb-000208
Wherein R 3 is halogen (such as fluorine or chlorine) or substituted or unsubstituted C 1 -C 4 alkyl (the substituted or unsubstituted C 1 -C 4 alkyl such as trifluoromethyl); the substituted The C 1 -C 4 alkyl group means that the C 1 -C 4 alkyl group is substituted with 1, 2, 3 or 4 R 3a ; R 3a is halogen (for example, fluorine);

(iii)

Figure PCTCN2021076289-appb-000209
其中R 1为卤素(例如氯)，R 2为卤素(例如氯)；和 (iii)
Figure PCTCN2021076289-appb-000209
Wherein R 1 is halogen (e.g. chlorine) and R 2 is halogen (e.g. chlorine); and

(iv)

Figure PCTCN2021076289-appb-000210
其中R 2为卤素(例如氟或氯)，R 5为-OR a(例如甲氧基、乙氧基或2-氟乙氧基)，R a为C 1-C 4烷基或C 1-C 4卤代烷基(例如C 1-C 4氟代烷基)； (iv)
Figure PCTCN2021076289-appb-000210
Wherein R 2 is halogen (for example, fluorine or chlorine), R 5 is -OR a (for example, methoxy, ethoxy or 2-fluoroethoxy), and R a is C 1 -C 4 alkyl or C 1- C 4 haloalkyl (e.g. C 1 -C 4 fluoroalkyl);

其他变量的定义如本发明中任一方案中所述。The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，

Figure PCTCN2021076289-appb-000211
部分为
Figure PCTCN2021076289-appb-000212
Figure PCTCN2021076289-appb-000213
Figure PCTCN2021076289-appb-000214
其他变量的定义如本发明中任一方案中所述。 In some embodiments, in the compound represented by formula I,
Figure PCTCN2021076289-appb-000211
Partly
Figure PCTCN2021076289-appb-000212
Figure PCTCN2021076289-appb-000213
Figure PCTCN2021076289-appb-000214
The definitions of other variables are as described in any aspect of the present invention.

在一些实施方案中，所述的如式I所示的化合物中，对于多巴胺D3受体的亲和活性，Y优选为

Figure PCTCN2021076289-appb-000215
进一步地，-L-A优选为
Figure PCTCN2021076289-appb-000216
Figure PCTCN2021076289-appb-000217
In some embodiments, in the compound represented by formula I, for the affinity activity of the dopamine D3 receptor, Y is preferably
Figure PCTCN2021076289-appb-000215
Further, -LA is preferably
Figure PCTCN2021076289-appb-000216
Figure PCTCN2021076289-appb-000217

在一些实施方案中，所述的如式I所示的化合物中，相对于多巴胺D2受体，化合物具有对多巴胺D3受体的亲和选择性时，Y优选为

Figure PCTCN2021076289-appb-000218
Figure PCTCN2021076289-appb-000219
进一步地，-L-A优选为
Figure PCTCN2021076289-appb-000220
Figure PCTCN2021076289-appb-000221
In some embodiments, in the compound represented by formula I, when the compound has an affinity selectivity for dopamine D3 receptor relative to dopamine D2 receptor, Y is preferably
Figure PCTCN2021076289-appb-000218
Figure PCTCN2021076289-appb-000219
Further, -LA is preferably
Figure PCTCN2021076289-appb-000220
Figure PCTCN2021076289-appb-000221

在一些实施方案中，所述的如式I所示的化合物选自以下任一结构：In some embodiments, the compound represented by Formula I is selected from any of the following structures:

Figure PCTCN2021076289-appb-000222
Figure PCTCN2021076289-appb-000222

Figure PCTCN2021076289-appb-000223
Figure PCTCN2021076289-appb-000223

Figure PCTCN2021076289-appb-000224
Figure PCTCN2021076289-appb-000224

Figure PCTCN2021076289-appb-000225
Figure PCTCN2021076289-appb-000225

Figure PCTCN2021076289-appb-000226
Figure PCTCN2021076289-appb-000226

Figure PCTCN2021076289-appb-000227
Figure PCTCN2021076289-appb-000227

Figure PCTCN2021076289-appb-000228
Figure PCTCN2021076289-appb-000228

Figure PCTCN2021076289-appb-000229
Figure PCTCN2021076289-appb-000229

在一些实施方案中，所述的如式I所示的化合物选自以下任一结构：In some embodiments, the compound represented by Formula I is selected from any of the following structures:

Figure PCTCN2021076289-appb-000230
Figure PCTCN2021076289-appb-000230

Figure PCTCN2021076289-appb-000231
Figure PCTCN2021076289-appb-000231

在一些实施方案中，如前述任一方案所述的如式I所示化合物中，*和#标记的碳原子形成的三元环的结构为

Figure PCTCN2021076289-appb-000232
或两者的混合。 In some embodiments, in the compound represented by formula I as described in any of the preceding schemes, the structure of the three-membered ring formed by the carbon atoms marked with * and # is
Figure PCTCN2021076289-appb-000232
Or a mixture of the two.

在一些实施方案中，如前述任一方案所述的如式I所示化合物，*和#标记的碳原子形成的三元环的结构为

Figure PCTCN2021076289-appb-000233
In some embodiments, the compound represented by formula I as described in any of the preceding schemes, the structure of the three-membered ring formed by the carbon atoms marked with * and # is
Figure PCTCN2021076289-appb-000233

在一些实施方案中，如前述任一方案所述的如式I所示化合物中，*和#标记的碳原子形成的三元环的结构为

Figure PCTCN2021076289-appb-000234
In some embodiments, in the compound represented by formula I as described in any of the preceding schemes, the structure of the three-membered ring formed by the carbon atoms marked with * and # is
Figure PCTCN2021076289-appb-000234

在一些实施方案中，所述的如式I所示的化合物的药学上可接受的盐为盐酸盐。In some embodiments, the pharmaceutically acceptable salt of the compound represented by Formula I is hydrochloride.

本发明还提供了一种如前所述的如式I所示化合物的制备方法，其选自如下任一方案：The present invention also provides a method for preparing the compound represented by formula I as described above, which is selected from any of the following schemes:

方案1：plan 1:

方案1包括如下步骤：在溶剂(例如四氢呋喃)中，将如式II-1所示的化合物在还原剂(例如硼烷)的存在下进行如下所示的还原反应，得到所述的如式I所示化合物即可；其中，-CH 2-L 1-即-L-；R 1、R 2、R 3、R 4、R 5、R 6、L、A、*和#的定义如前所述； Scheme 1 includes the following steps: in a solvent (such as tetrahydrofuran), the compound represented by formula II-1 is subjected to the reduction reaction shown below in the presence of a reducing agent (such as borane) to obtain the formula I The compound shown is sufficient; wherein, -CH 2 -L 1 -is -L-; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, A, * and # are as defined above Narrate

Figure PCTCN2021076289-appb-000235
Figure PCTCN2021076289-appb-000235

方案2：Scenario 2:

方案2包括如下步骤：在溶剂(例如乙腈、甲醇)中，将如式II-2所示的化合物和R 6a-CHO或

Figure PCTCN2021076289-appb-000236
在还原剂(例如三乙酰氧基硼氢化钠)的存在下进行如下所示的还原 胺化反应，得到所述的如式I所示化合物即可；其中，R 6a-CH 2-或
Figure PCTCN2021076289-appb-000237
即R 6；R 1、R 2、R 3、R 4、R 5、R 6、L、A、*和#的定义如前所述； Scheme 2 includes the following steps: in a solvent (such as acetonitrile, methanol), the compound shown in formula II-2 and R 6a -CHO or
Figure PCTCN2021076289-appb-000236
Carry out the reductive amination reaction as shown below in the presence of a reducing agent (such as sodium triacetoxyborohydride) to obtain the compound represented by formula I; wherein, R 6a -CH 2 -or
Figure PCTCN2021076289-appb-000237
Namely R 6 ; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, A, * and # are defined as described above;

Figure PCTCN2021076289-appb-000238
Figure PCTCN2021076289-appb-000238

方案3：Option 3:

方案3包括如下步骤：在溶剂(例如乙腈、甲醇)中，将如式II-3所示的化合物和A-L 2-CHO在还原剂(例如三乙酰氧基硼氢化钠)的存在下进行如下所示的还原胺化反应，得到所述的如式I所示化合物即可；其中，-CH 2-L 2-即-L-；R 1、R 2、R 3、R 4、R 5、R 6、L、A、*和#的定义如前所述； Scheme 3 includes the following steps: in a solvent (such as acetonitrile, methanol), the compound represented by formula II-3 and AL 2 -CHO in the presence of a reducing agent (such as sodium triacetoxyborohydride) are carried out as follows The reductive amination reaction shown is enough to obtain the compound represented by formula I; wherein, -CH 2 -L 2 -is -L-; R 1 , R 2 , R 3 , R 4 , R 5 , R 6. The definitions of L, A, * and # are as mentioned above;

Figure PCTCN2021076289-appb-000239
Figure PCTCN2021076289-appb-000239

方案4：Option 4:

方案4包括如下步骤：在溶剂(例如乙腈、甲醇)中，将如式II-4所示的化合物和

Figure PCTCN2021076289-appb-000240
在还原剂(例如三乙酰氧基硼氢化钠)的存在下进行如下所示的还原胺化反应，得到所述的如式I所示化合物即可；其中R 1、R 2、R 3、R 4、R 5、R 6、L、A、*和#的定义如前所述； Scheme 4 includes the following steps: in a solvent (such as acetonitrile, methanol), the compound shown in formula II-4 and
Figure PCTCN2021076289-appb-000240
Carry out the reductive amination reaction as shown below in the presence of a reducing agent (such as sodium triacetoxyborohydride) to obtain the compound represented by formula I; wherein R 1 , R 2 , R 3 , R 4. The definitions of R 5 , R 6 , L, A, * and # are as mentioned above;

Figure PCTCN2021076289-appb-000241
Figure PCTCN2021076289-appb-000241

所述的如式II-1所示的化合物的制备方法可以包括如下步骤：在溶剂(例如四氢呋喃、N,N-二甲基甲酰胺)中，将如式III-1所示的化合物与

Figure PCTCN2021076289-appb-000242
在缩合剂(例如HATU)的存在下进行如下所示的缩合反应，得到所述的如式II-1所示的化合物即可；其中R 1、 R 2、R 3、R 4、R 5、R 6、L 1、A、*和#的定义如前所述； The method for preparing the compound represented by formula II-1 may include the following steps: in a solvent (for example, tetrahydrofuran, N,N-dimethylformamide), the compound represented by formula III-1 and
Figure PCTCN2021076289-appb-000242
Carry out the condensation reaction as shown below in the presence of a condensing agent (such as HATU) to obtain the compound represented by formula II-1; wherein R 1 , R 2 , R 3 , R 4 , R 5 , The definitions of R 6 , L 1 , A, * and # are as mentioned above;

Figure PCTCN2021076289-appb-000243
Figure PCTCN2021076289-appb-000243

本发明还提供一种如下化合物：The present invention also provides the following compound:

Figure PCTCN2021076289-appb-000244
Figure PCTCN2021076289-appb-000244

其中R 1、R 2、R 3、R 4、R 5、R 6、L 1、A、*和#的定义如前所述。 The definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , A, * and # are as described above.

本发明还提供了一种药物组合物，其包含所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，以及至少一种药用辅料。The present invention also provides a pharmaceutical composition comprising the compound represented by formula I or its tautomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable compound of any one of the foregoing , Or a crystal form or solvate of any of the foregoing, and at least one pharmaceutical excipient.

所述的药物组合物中，所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物的含量可以为治疗有效量。In the pharmaceutical composition, the compound represented by formula I or its tautomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or the foregoing The content of either crystal form or solvate can be a therapeutically effective amount.

本发明还提供了一种所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物在制备药物中的应用。The present invention also provides a compound of Formula I or its tautomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or any of the foregoing The use of one crystal form or solvate in the preparation of medicines.

在一些实施方案中，所述的药物可以为用于治疗和/或预防多巴胺(例如多巴胺D3受体或多巴胺D2受体)能信号通路异常和/或5-羟色胺(例如5-HT 2C)信号通路异常相关的疾病的药物相关的疾病的药物。 In some embodiments, the drug may be used to treat and/or prevent dopamine (e.g. dopamine D3 receptor or dopamine D2 receptor) signal pathway abnormalities and/or serotonin (e.g. 5-HT 2C ) signaling Pathway abnormalities related diseases drugs related diseases drugs.

在一些实施方案中，所述的药物可以为用于治疗和/或预防多巴胺(例如多巴胺D3受体或多巴胺D2受体)能信号通路异常相关的疾病的药物。In some embodiments, the drug may be a drug for the treatment and/or prevention of diseases related to abnormalities of dopamine (for example, dopamine D3 receptor or dopamine D2 receptor) signal pathways.

在一些实施方案中，所述的药物可以为用于治疗和/或预防5-羟色胺(例如5-HT 2C)信号通路异常相关的疾病的药物。 In some embodiments, the drug may be a drug used to treat and/or prevent diseases related to abnormalities in the serotonin (eg, 5-HT 2C) signaling pathway.

在一些实施方案中，所述的多巴胺能信号通路异常和/或5-羟色胺(例如5-HT 2C)信号通路异常相关的疾病可以为精神类疾病，例如帕金森氏症、精神分裂症、双相情感障碍、躁狂症、抑郁症、焦虑症、药物成瘾或阿尔茨海默症等精神类疾病。 In some embodiments, the abnormality of the dopaminergic signal pathway and/or the disease related to the abnormality of the serotonin (for example, 5-HT 2C ) signal pathway may be a psychiatric disease, such as Parkinson's disease, schizophrenia, dual Mental disorders such as phase disorder, mania, depression, anxiety, drug addiction, or Alzheimer’s disease.

在一些实施方案中，所述的药物可以为用于治疗和/或预防精神类疾病的药物，例如治疗和/或预防帕金森氏症、精神分裂症、双相情感障碍、躁狂症、抑郁症、焦虑症、药物成瘾或阿尔茨海默症等精神类疾病的药物。In some embodiments, the drug may be a drug for the treatment and/or prevention of mental diseases, such as the treatment and/or prevention of Parkinson’s disease, schizophrenia, bipolar disorder, mania, depression Medications for mental illnesses such as psychosis, anxiety, drug addiction, or Alzheimer’s disease.

本发明还提供了一种预防和/或治疗多巴胺能信号通路异常相关的疾病的方法，其包括向需要此治疗的患者给予治疗有效量的所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物。The present invention also provides a method for preventing and/or treating diseases associated with abnormal dopaminergic signaling pathways, which comprises administering a therapeutically effective amount of the compound represented by formula I or its interconversion to a patient in need of such treatment Isomers, stereoisomers or isotopic derivatives, or pharmaceutically acceptable salts of any of the foregoing, or crystal forms or solvates of any of the foregoing.

本发明还提供了一种预防和/或治疗多巴胺能信号通路异常相关的疾病的方法，其包括向需要此治疗的患者给予治疗有效量的所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，或者所述的药物组合物。The present invention also provides a method for preventing and/or treating diseases associated with abnormal dopaminergic signaling pathways, which comprises administering a therapeutically effective amount of the compound represented by formula I or its interconversion to a patient in need of such treatment Isomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing, or the pharmaceutical composition.

本发明还提供了一种预防和/或治疗帕金森氏症、精神分裂症、双相情感障碍、躁狂症、抑郁症、焦虑症、药物成瘾或阿尔茨海默症等精神类疾病的方法，其包括向需要此治疗的患者给予治疗有效量的所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，或者所述的药物组合物。The present invention also provides a method for preventing and/or treating Parkinson's disease, schizophrenia, bipolar disorder, mania, depression, anxiety, drug addiction or Alzheimer's disease and other mental diseases A method, which comprises administering to a patient in need of such treatment a therapeutically effective amount of the compound represented by formula I or its tautomer, stereoisomer or isotopic derivative, or any of the foregoing pharmacologically An acceptable salt, or a crystal form or solvate of any of the foregoing, or the pharmaceutical composition described above.

本发明还提供了一种所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物在制备多巴胺受体(例如多巴胺D3受体或多巴胺D2受体)调节剂和/或5-羟色胺(例如5-HT 2C)受体调节剂中的应用。 The present invention also provides a compound of Formula I or its tautomer, stereoisomer or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or any of the foregoing The use of a crystalline form or solvate of one in the preparation of a modulator of dopamine receptor (for example, dopamine D3 receptor or dopamine D2 receptor) and/or a serotonin (for example, 5-HT 2C ) receptor modulator.

在一些实施方案中，所述的多巴胺受体调节剂可以为多巴胺受体部分激动剂或多巴胺受体拮抗剂。In some embodiments, the dopamine receptor modulator may be a dopamine receptor partial agonist or a dopamine receptor antagonist.

在一些实施方案中，所述的5-羟色胺受体调节剂可以为5-羟色胺受体部分激动剂或5-羟色胺受体拮抗剂。In some embodiments, the serotonin receptor modulator may be a serotonin receptor partial agonist or a serotonin receptor antagonist.

除非另外说明，本发明所使用的术语具有如下定义，下文中未涉及的术语的定义如本发明所属领域技术人员的通常理解。Unless otherwise specified, the terms used in the present invention have the following definitions, and the definitions of terms not involved in the following are as commonly understood by those skilled in the art to which the present invention belongs.

术语“药学上可接受的盐”是指化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的 化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。在一些实施方案中，所述的药学上可接受的盐为盐酸盐。除非另有指明，本文所述的盐酸盐包括可能的一盐酸、二盐酸盐、多盐酸盐以及其组合。The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, it can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt. When the compound of the present invention contains a relatively basic functional group, the acid addition can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. A salt. The pharmaceutically acceptable acids include inorganic acids, and the inorganic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine) and the like. When the compound of the present invention contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt. For details, please refer to Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002). In some embodiments, the pharmaceutically acceptable salt is hydrochloride. Unless otherwise indicated, the hydrochloride salt described herein includes possible monohydrochloric acid, dihydrochloride, polyhydrochloride, and combinations thereof.

术语“溶剂合物”是指化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。The term "solvate" refers to a substance formed by combining a compound with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate can exist in an ordered or non-ordered arrangement. The solvents include but are not limited to: water, methanol, ethanol and the like.

术语“立体异构体”是指分子中原子或原子团相互连接次序相同，但空间排列不同而引起的异构体，例如顺反异构体、旋光异构体、阻转异构体等。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。旋光异构体包括对映异构体和非对映异构体。The term "stereoisomer" refers to the isomers caused by the same order of interconnection of atoms or atomic groups in the molecule, but different spatial arrangements, such as cis-trans isomers, optical isomers, atropisomers and the like. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.). Optical isomers include enantiomers and diastereomers.

术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。例如，丙酮和1-丙烯-2-醇可以通过氢原子在氧上和α-碳上的迅速移动而互相转变。The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions. For example, acetone and 1-propene-2-ol can be converted into each other by the rapid movement of hydrogen atoms on oxygen and α-carbon.

术语“同位素衍生物”是指化合物中的一个或多个原子被一个或多个具有特定原子质量或质量数的原子取代。可以掺入本发明化合物中的同位素的实例包括但不限于氢、碳、氮、氧、氟、硫和氯的同位素(例如 2H、 3H、 13C、 14C、 15N、 18O、 17O、 18F、 35S和 36Cl)。本发明的同位素化合物通常可以根据本文所述的方法通过用同位素标记的试剂取代非同位素标记的试剂来制备。同位素衍生物的典型实例包括氘代化合物。 The term "isotopic derivative" refers to the substitution of one or more atoms in a compound by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl). The isotopic compounds of the present invention can generally be prepared by substituting isotopically-labeled reagents for non-isotopically-labeled reagents according to the methods described herein. Typical examples of isotopic derivatives include deuterated compounds.

术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列，并具有间隔一定距离周期重复出现规律；因上述周期性排列的不同，可存在多种晶型，也即多晶型现象。The term "crystal form" means that the ions or molecules are arranged strictly and periodically in a three-dimensional space in a certain way, and have the regularity of periodic recurrence at a certain distance; due to the above-mentioned periodic arrangement, there may be multiple Crystal form, that is, polymorphism.

术语“烷基”是指具有指定数目碳原子的饱和的直链或支链的一价烃基，例如C 1-C 4烷基是指具有1-4个碳原子的烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基和戊基。在一些实施方案中，C 1-C 4烷基可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。在一些实施方案中，C 1-C 6烷基可以为C 1-C 4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group having a specified number of carbon atoms, for example, a C 1 -C 4 alkyl group refers to an alkyl group having 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. In some embodiments, the C 1 -C 4 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl.

术语“亚烷基”是指具有指定数目碳原子的饱和的直链或支链的二价烃基。亚烷基的实例包括但不限于-CH 2-、-CH(CH 3)-、-CH 2-CH 2-、-CH 2-CH 2-CH 2-和-CH 2(CH 3)-CH 2-。 The term "alkylene" refers to a saturated linear or branched divalent hydrocarbon group having the specified number of carbon atoms. Examples of alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -and -CH 2 (CH 3 )-CH 2 -.

术语“烷氧基”是指-O-R X，其中R X为如上文所定义的烷基。在一些实施方案中，C 1-C 4烷氧基可以为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。 The term "alkoxy" refers to -OR X , where R X is an alkyl group as defined above. In some embodiments, the C 1 -C 4 alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tertiary Butoxy.

术语“氧代”是指＝O。The term "oxo" refers to =O.

术语“卤素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.

术语“卤代烷基”是指被1-4个卤素原子取代的烷基，每个卤素原子独立地为氟、氯、溴或碘。卤代烷基的实例包括但不限于三氟甲基和1-氟-2-氯乙基。C 1-C 6卤代烷基中的C 1-C 6烷基和卤素如本文中定义。C 1-C 4卤代烷基中的C 1-C 4烷基和卤素如本文中定义。 The term "haloalkyl" refers to an alkyl group substituted with 1 to 4 halogen atoms, each halogen atom independently being fluorine, chlorine, bromine or iodine. Examples of haloalkyl include, but are not limited to, trifluoromethyl and 1-fluoro-2-chloroethyl. The C 1 -C 6 alkyl group and halogen in the C 1 -C 6 haloalkyl group are as defined herein. The C 1 -C 4 alkyl group and halogen in the C 1 -C 4 haloalkyl group are as defined herein.

术语“环烷基”是指具有指定数目环碳原子数的非芳香族的饱和或部分不饱和的一价环烃基。环烷基可以为单环或多环(例如二环和三环)，可以为并环、螺环和桥环结构。环烷基内任选包含一个或多个双键。在一些实施方案中，环烷基为单环基团。在一些实施方案中，环烷基为饱和的基团。在一些实施方案中，环烷基为饱和的单环基团。环烷基包括但不限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环己二烯基和环庚基。在一些实施方案中，C 3-C 6环烷基可以为环丙基、环丁基、环戊基或环己基。在一些实施方案中，C 3-C 8环烷基可以为环丙基、环丁基、环戊基或环己基。 The term "cycloalkyl" refers to a non-aromatic saturated or partially unsaturated monovalent cyclic hydrocarbon group having a specified number of ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (for example, bicyclic and tricyclic), and can be fused, spiro, and bridged ring structures. The cycloalkyl group optionally contains one or more double bonds. In some embodiments, the cycloalkyl group is a monocyclic group. In some embodiments, the cycloalkyl group is a saturated group. In some embodiments, the cycloalkyl group is a saturated monocyclic group. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclopentyl Hexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl and cycloheptyl. In some embodiments, the C 3 -C 6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the C 3 -C 8 cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

术语“杂环烷基”是指由碳原子和至少一个选自N、O和S的杂原子形成的非芳香性的饱和或部分不饱和的环状基团。杂环烷基可以通过其中的杂原子或碳原子连接到分子中的其他部分。杂环烷基可以为单环或多环(例如二环和三环)，可以为并环、螺环和桥环结构。杂环烷基内任选包含一个或多个双键。在一些实施方案中，杂环烷基为单环基团。在一些实施方案中，杂环烷基为饱和的基团。在一些实施方案中，杂环烷基为饱和的单环基团。杂环烷基的例子包括但不限于1-哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基和2-哌嗪基。3-8元杂环烷基为3、4、5、6、7或8元杂环烷基。在一些实施方案中，3-8元杂环烷基可以为3、4、5或6元杂环烷基。4-6元杂环烷基为4、5或6元杂环烷基。The term "heterocycloalkyl" refers to a non-aromatic saturated or partially unsaturated cyclic group formed by carbon atoms and at least one heteroatom selected from N, O, and S. The heterocycloalkyl group can be connected to other parts of the molecule through a heteroatom or carbon atom. The heterocycloalkyl group may be monocyclic or polycyclic (for example, bicyclic and tricyclic), and may be a fused ring, spiro ring, and bridged ring structure. The heterocycloalkyl group optionally contains one or more double bonds. In some embodiments, the heterocycloalkyl group is a monocyclic group. In some embodiments, the heterocycloalkyl group is a saturated group. In some embodiments, the heterocycloalkyl group is a saturated monocyclic group. Examples of heterocycloalkyl groups include, but are not limited to, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrothiophene- 2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl. A 3-8 membered heterocycloalkyl is a 3, 4, 5, 6, 7 or 8 membered heterocycloalkyl. In some embodiments, the 3-8 membered heterocycloalkyl group can be a 3, 4, 5, or 6 membered heterocycloalkyl group. 4-6 membered heterocycloalkyl is 4, 5 or 6 membered heterocycloalkyl.

术语“芳基”是指任何稳定的在各环中可高达7个原子的单环或者多环(例如双环或三环)碳环，其中至少一个环是芳香环。芳基的实例包括不限于苯基、萘基、四氢萘基、2,3-二氢化茚基、菲基、蒽基或者苊基(acenaphthyl)。可以理解，在芳基取代基是二环取代基，且其中一个环是非芳香环的情况中，连接是通过芳环进行的。在一些实施方案中，C 6-C 14芳基可以为苯基或萘基。在一些实施方案中，C 6-C 14芳基可以为苯基。 The term "aryl" refers to any stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocyclic ring of up to 7 atoms in each ring, in which at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, phenanthryl, anthracenyl, or acenaphthyl. It is understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring. In some embodiments, the C 6 -C 14 aryl group may be phenyl or naphthyl. In some embodiments, the C 6 -C 14 aryl group may be a phenyl group.

术语“杂芳基”是指各环中可高达7个原子的稳定单环或多环(例如双环并环、三环并环)基团，其中至少一个环是芳香环并且至少一个环含有至少一个选自O、N和S的杂原子。杂芳基可以通过其中的杂原子或碳原子连接到分子中的其他部分。5-14元杂芳基为5、6、7、8、9、10、11、12、13或14元杂芳基。5-6元杂芳基是指单环杂芳基，5元杂芳基例如呋喃基、噻吩基、吡咯基、吡唑基、恶唑基、噻唑基、咪唑基或三唑基，6元杂芳基例如吡嗪基、哒嗪基、吡啶基或嘧啶基。8-10元双环杂芳基为并环结构，包括5-6元杂芳基并5-6元杂芳基、5-6元杂芳基并5-6元环烷基、5-6元杂芳基并5-6元杂环基、苯基并5-6元杂环基和苯基并5-6元杂芳基，例如吲哚基、苯并噻吩基、苯并呋喃基、喹啉基、四氢喹啉基、异喹啉基、四氢异喹啉基、吡啶并噻吩基、吡啶并呋喃基、2H-色 烯基、苯并噻唑基、苯并恶唑基、苯并吡唑基、吡啶并吡唑基、吡啶并噻吩基、吡啶并呋喃基、苯并咪唑基、吡啶并吡咯基或吡啶并吡唑基。可以理解，在杂芳基取代基是二环取代基，且其中一个环是非芳香环的情况中，连接是通过芳香环进行的。The term "heteroaryl" refers to a stable monocyclic or polycyclic (e.g., bicyclic and tricyclic) group with up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains at least A heteroatom selected from O, N and S. Heteroaryl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms. The 5-14 membered heteroaryl group is a 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered heteroaryl group. A 5-6 membered heteroaryl group refers to a monocyclic heteroaryl group, a 5-membered heteroaryl group such as furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl or triazolyl, 6-membered Heteroaryl groups are for example pyrazinyl, pyridazinyl, pyridyl or pyrimidinyl. 8-10 membered bicyclic heteroaryl group is a combined ring structure, including 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered cycloalkyl, 5-6 membered Heteroaryl 5-6 membered heterocyclic group, phenyl 5-6 membered heterocyclic group and phenyl 5-6 membered heteroaryl group, such as indolyl, benzothienyl, benzofuranyl, quinoline Linyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, pyridothienyl, pyridofuranyl, 2H-chromenyl, benzothiazolyl, benzoxazolyl, benzo Pyrazolyl, pyridopyrazolyl, pyridothienyl, pyridofuranyl, benzimidazolyl, pyridopyrrolyl or pyridopyrazolyl. It is understood that in the case where the heteroaryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through an aromatic ring.

本申请描述基团的结构式中所使用的

Figure PCTCN2021076289-appb-000245
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。例如，在
Figure PCTCN2021076289-appb-000246
中，R’为
Figure PCTCN2021076289-appb-000247
时，则形成
Figure PCTCN2021076289-appb-000248
当
Figure PCTCN2021076289-appb-000249
标记在环上并且没有指明连接位点时，连接位点为该单环或多环上的任意原子，举例说明如下：
Figure PCTCN2021076289-appb-000250
基团包括
Figure PCTCN2021076289-appb-000251
等结构；
Figure PCTCN2021076289-appb-000252
基团包括
Figure PCTCN2021076289-appb-000253
等，但不包括
Figure PCTCN2021076289-appb-000254
Used in the structural formula of the group described in this application
Figure PCTCN2021076289-appb-000245
It means that the corresponding group is connected to other fragments and groups in the compound through this site. For example, in
Figure PCTCN2021076289-appb-000246
Where R'is
Figure PCTCN2021076289-appb-000247
, Then form
Figure PCTCN2021076289-appb-000248
when
Figure PCTCN2021076289-appb-000249
When the label is on the ring and the connection site is not specified, the connection site is any atom on the monocyclic or polycyclic ring. Examples are as follows:
Figure PCTCN2021076289-appb-000250
Groups include
Figure PCTCN2021076289-appb-000251
Structure
Figure PCTCN2021076289-appb-000252
Groups include
Figure PCTCN2021076289-appb-000253
Etc. but not including
Figure PCTCN2021076289-appb-000254

当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或变量的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，

Figure PCTCN2021076289-appb-000255
中，w为0、1或2，每个R独立地为甲基或氟，则
Figure PCTCN2021076289-appb-000256
包括
Figure PCTCN2021076289-appb-000257
等。 When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variables are only permitted if such combinations result in stable compounds. E.g,
Figure PCTCN2021076289-appb-000255
Where w is 0, 1 or 2, and each R is independently methyl or fluorine, then
Figure PCTCN2021076289-appb-000256
include
Figure PCTCN2021076289-appb-000257
Wait.

为了表述方便，本发明所列举的具有两侧连接位点的基团没有指明其连接方向时，其连接方向是按与从左往右的读取顺序相同的方向进行连接的，举例说明如下：U 1-V-U 2中连接基团V为-C-D-，此时-C-D-按与从左往右的读取顺序相同的方向连接U 1和U 2构成U 1-C-D-U 2，而不构成U 1-D-C-U 2。 For the convenience of expression, when the groups with connecting sites on both sides listed in the present invention do not indicate the connection direction, the connection direction is connected in the same direction as the reading order from left to right. Examples are as follows: The linking group V in U 1 -VU 2 is -CD-, at this time -CD- connects U 1 and U 2 in the same direction as the reading order from left to right to form U 1 -CDU 2 , but not U 1 -DCU 2 .

术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009Sixth Edition)The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and formulating prescriptions, and are all substances contained in pharmaceutical preparations except for active ingredients. Please refer to the Fourth Edition of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition)

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

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

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

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

本文涉及的所有专利和公开出版物通过引用方式整体并入本文中。All patents and publications referred to herein are incorporated herein by reference in their entirety.

本发明化合物的生物活性可通过使用任何常规已知方法评定。适当的检测方法是本领域众所周知的。例如，可以通过适当的常规方法检测本发明化合物对多巴胺受体的亲和活性、激动活性和/或拮抗活性，本发明化合物的药代动力学活性和/或肝微粒体稳定性等。本发明提供的检测方法仅作为实例呈现且不限制本发明。本发明化合物在至少一种本发明提供的检测方法中具有活性。The biological activity of the compounds of the present invention can be assessed by using any conventionally known methods. Appropriate detection methods are well known in the art. For example, the affinity activity, agonistic activity and/or antagonistic activity of the compound of the present invention for dopamine receptors, the pharmacokinetic activity and/or liver microsomal stability of the compound of the present invention, etc. can be tested by appropriate conventional methods. The detection method provided by the present invention is presented only as an example and does not limit the present invention. The compound of the present invention has activity in at least one of the detection methods provided by the present invention.

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

本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.

本发明的化合物具有多巴胺受体亲和活性，尤其是对多巴胺D3受体具有较佳的亲和活性。在一些实施方案中，本发明的一些化合物表现出对多巴胺D3受体的亲和选择性，即对多巴胺D3受体具有较佳的亲和活性，而对多巴胺D1、D2、D4或D5受体的亲和活性相对较弱。在一些实施方案中，本发明的一些化合物具有对多巴胺D3受体的激动剂活性或者拮抗剂活性。在一些实施方案中，本发明的一些化合物具有对多巴胺D2受体的激动剂活性或者拮抗剂活性。The compound of the present invention has dopamine receptor affinity activity, especially has better affinity activity to dopamine D3 receptor. In some embodiments, some of the compounds of the present invention exhibit affinity selectivity for dopamine D3 receptors, that is, they have better affinity activity for dopamine D3 receptors, and for dopamine D1, D2, D4, or D5 receptors. The affinity activity is relatively weak. In some embodiments, some of the compounds of the present invention have agonist activity or antagonist activity on the dopamine D3 receptor. In some embodiments, some of the compounds of the present invention have agonist activity or antagonist activity on the dopamine D2 receptor.

具体实施方式Detailed ways

下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention will be further described by way of examples below, but the present invention is not limited to the scope of the described examples. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to the product specification.

实施例1：反式N-((2-(5-氟-2-甲氧苯基)环丙基)甲基)-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(化合物I-1)盐酸盐的制备Example 1: trans N-((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)-3-((4-methyl-5-phenyl-4H-1, Preparation of 2,4-triazol-3-yl)thio)propyl-1-amine (compound I-1) hydrochloride

Figure PCTCN2021076289-appb-000258
Figure PCTCN2021076289-appb-000258

步骤1：中间体INT-1(4-甲基-5-苯基-4H-[1,2,4]三唑-3-硫醇，cas:38942-51-7)商业购买获得。将INT-1(1.0g,5.26mmol)溶于丙烯酸甲酯(6mL)，加入碳酸铯(3.43g，10.52mmol)。该反应混合物置于微波反应器中，100℃反应30分钟。反应液冷却至室温，加入水稀释，乙酸乙酯萃取，有机相分离干燥后，浓缩，剩余物用快速柱层析分离纯化(0–20％乙酸乙酯/石油醚)，得到无色油状物INT-2(4.0g，收率69％)。 1H NMR(800MHz,CDCl 3)δ7.59–7.51(m,5H),4.58(t,J＝7.4Hz,2H),3.72(s,3H),3.66(s,3H),2.96(t,J＝7.4Hz,2H).HRMS(ESI)C 13H 16N 3O 2S +[M+H] +计算值：278.0958,实测值:278.0953。 Step 1: Intermediate INT-1 (4-methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol, cas:38942-51-7) was purchased commercially. Dissolve INT-1 (1.0 g, 5.26 mmol) in methyl acrylate (6 mL), and add cesium carbonate (3.43 g, 10.52 mmol). The reaction mixture was placed in a microwave reactor and reacted at 100°C for 30 minutes. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phase was separated and dried, and then concentrated. The residue was separated and purified by flash column chromatography (0-20% ethyl acetate/petroleum ether) to obtain a colorless oil INT-2 (4.0 g, yield 69%). 1 H NMR(800MHz,CDCl 3 )δ7.59–7.51(m,5H), 4.58(t,J=7.4Hz,2H), 3.72(s,3H), 3.66(s,3H), 2.96(t, J = 7.4 Hz, 2H). HRMS (ESI) C 13 H 16 N 3 O 2 S + [M+H] + Calculated value: 278.0958, measured value: 278.0953.

步骤2：将中间体INT-2(4.0g,21mmol)溶于四氢呋喃(50mL)和水(20mL)的混合溶液，加入氢氧化锂一水合物(4.2g,100mmol)，室温反应过夜。将反应液用3M盐酸酸化，加入水稀释，乙酸乙酯萃取。有机相分离干燥后，浓缩，剩余物用快速柱层析分离纯化(0–10％甲醇/二氯甲烷)，得到白色固体INT-3(2.26g，收率60％)。 1H NMR(800MHz,CDCl 3)δ7.66–7.44(m,5H),4.58(t,J＝7.4Hz,2H),3.67(s,3H),3.03(t,J＝7.4Hz,2H). 1H NMR(800MHz,CD 3OD)δ7.68–7.66(m,2H),7.58–7.52(m,3H),4.47(t,J＝7.3Hz,1H),3.60(s,1H),2.89(t,J＝7.3Hz,1H).HRMS(ESI)C 12H 14N 3O 2S +([M+H] +)计算值：264.0801，实测值：264.0830。 Step 2: Intermediate INT-2 (4.0 g, 21 mmol) was dissolved in a mixed solution of tetrahydrofuran (50 mL) and water (20 mL), lithium hydroxide monohydrate (4.2 g, 100 mmol) was added, and the reaction was carried out at room temperature overnight. The reaction solution was acidified with 3M hydrochloric acid, diluted with water, and extracted with ethyl acetate. After the organic phase was separated and dried, it was concentrated, and the residue was separated and purified by flash column chromatography (0-10% methanol/dichloromethane) to obtain a white solid INT-3 (2.26 g, yield 60%). 1 H NMR(800MHz, CDCl 3 )δ7.66–7.44(m,5H), 4.58(t,J=7.4Hz,2H), 3.67(s,3H), 3.03(t,J=7.4Hz,2H) . 1 H NMR(800MHz,CD 3 OD)δ7.68–7.66(m,2H), 7.58–7.52(m,3H), 4.47(t,J=7.3Hz,1H), 3.60(s,1H), 2.89 (t, J=7.3 Hz, 1H). HRMS (ESI) C 12 H 14 N 3 O 2 S + ([M+H] + ) Calculated value: 264.0801, measured value: 264.0830.

步骤3：原料反式叔丁基((2-(5-氟-2-羟基苯)环丙基)甲基)氨基甲酸酯(INT-4，反式混合物)可参照文献(ChemMedChem 2010,5,1221-1225中化合物10的制备方法)合成得到。将原料INT-4(281mg,1.0mmol)和碘甲烷(213mg,1.5mmol)溶于N,N-二甲基甲酰胺(8mL)，加入碳酸钾(828mg，6.0mmol)，该反应混合物置于微波反应器中，110℃反应30分钟。反应液冷却至室温后，加水稀释，乙酸乙酯萃取。有机相分离干燥后，浓缩，剩余物用快速柱层析分离纯化(0–10％甲醇/二氯甲烷)，得到无色油状物INT-5(反式混合物，284mg，收率96％)。 1H NMR(800MHz,CDCl 3)δ6.84(td,J＝8.5,3.1Hz, 1H),6.75(dd,J＝9.0,4.5Hz,1H),6.64(dd,J＝9.3,3.1Hz,1H),5.28(s,1H),3.88(s,3H),3.56(s,1H),2.76–2.66(m,1H),1.87–1.81(m,1H),1.47(s,9H),1.05–0.97(m,2H),0.88–0.81(m,1H).HRMS(ESI)C 16H 22FNO 3Na +([M+Na] +)计算值：318.1476，实测值：318.1484。 Step 3: Raw material trans-tert-butyl ((2-(5-fluoro-2-hydroxybenzene)cyclopropyl)methyl)carbamate (INT-4, trans mixture) can refer to the literature (ChemMedChem 2010, 5, The preparation method of compound 10 in 1221-1225) was synthesized. The raw materials INT-4 (281 mg, 1.0 mmol) and methyl iodide (213 mg, 1.5 mmol) were dissolved in N, N-dimethylformamide (8 mL), potassium carbonate (828 mg, 6.0 mmol) was added, and the reaction mixture was placed in In a microwave reactor, react at 110°C for 30 minutes. After the reaction solution was cooled to room temperature, it was diluted with water and extracted with ethyl acetate. After the organic phase was separated and dried, it was concentrated, and the residue was separated and purified by flash column chromatography (0-10% methanol/dichloromethane) to obtain a colorless oil INT-5 (trans mixture, 284 mg, yield 96%). 1 H NMR (800MHz, CDCl 3 ) δ 6.84 (td, J = 8.5, 3.1 Hz, 1H), 6.75 (dd, J = 9.0, 4.5 Hz, 1H), 6.64 (dd, J = 9.3, 3.1 Hz, 1H), 5.28 (s, 1H), 3.88 (s, 3H), 3.56 (s, 1H), 2.76-2.66 (m, 1H), 1.87-1.81 (m, 1H), 1.47 (s, 9H), 1.05 -0.97 (m, 2H), 0.88-0.81 (m, 1H). HRMS (ESI) C 16 H 22 FNO 3 Na + ([M+Na] + ) calculated value: 318.1476, measured value: 318.1484.

步骤4：将INT-5(196mg,0.66mmol)溶于四氢呋喃(4mL)，加入氯化氢乙醚溶液(2M,4mL)并室温下反应过夜。反应液由澄清变白色浑浊液。将溶剂减压蒸除，干燥得白色固体INT-6(反式混合物，153mg,收率99％)。 1H NMR(800MHz,CD 3OD)δ6.92–6.87(m,2H),6.72(dd,J＝9.3,2.9Hz,1H),3.86(s,3H),3.07(dd,J＝13.0,7.1Hz,1H),2.93(dd,J＝13.1,8.0Hz,1H),2.14–2.10(m,1H),1.28–1.22(m,1H),1.14–1.09(m,1H),1.04–1.00(m,1H).HRMS(ESI)C 11H 15FNO +([M+H] +)计算值：196.1132，实测值：196.1135。 Step 4: Dissolve INT-5 (196 mg, 0.66 mmol) in tetrahydrofuran (4 mL), add hydrogen chloride ether solution (2M, 4 mL) and react overnight at room temperature. The reaction liquid changed from clear to white turbid liquid. The solvent was evaporated under reduced pressure and dried to obtain white solid INT-6 (trans mixture, 153 mg, yield 99%). 1 H NMR (800MHz, CD 3 OD) δ 6.92–6.87 (m, 2H), 6.72 (dd, J = 9.3, 2.9 Hz, 1H), 3.86 (s, 3H), 3.07 (dd, J = 13.0, 7.1Hz, 1H), 2.93 (dd, J = 13.1, 8.0 Hz, 1H), 2.14–2.10 (m, 1H), 1.28–1.22 (m, 1H), 1.14–1.09 (m, 1H), 1.04–1.00 (m, 1H). HRMS (ESI) C 11 H 15 FNO + ([M+H] + ) Calculated value: 196.1132, measured value: 196.1135.

步骤5：将INT-3(176mg,0.67mmol)，INT-6(148mg,0.64mmol)和HATU(363mg，0.96mmol)溶于N，N-二甲基甲酰胺(5mL)，加入碳酸氢钠(161mg，1.91mmol)，室温下反应5小时。加入乙酸乙酯稀释，依次用水和饱和食盐水洗涤。有机相分离干燥后，浓缩，剩余物用快速柱层析分离纯化(0–20％乙酸乙酯/石油醚)，得到白色固体INT-7(反式混合物，203mg，收率72％)。 1H NMR(800MHz,CD 3OD)δ7.67–7.49(m,5H),6.86–6.78(m,2H),6.53(dd,J＝9.5,3.1Hz,1H),4.53(t,J＝7.0Hz,2H),3.82(s,3H),3.60(s,3H),3.21(d,J＝6.9Hz,2H),2.86–2.74(m,2H),2.00–1.96(m,1H),1.19–1.11(m,1H),0.86–0.76(m,2H).HRMS(ESI)C 23H 26FN 4O 2S +([M+H] +)计算值：441.1755，实测值：441.1749。 Step 5: Dissolve INT-3 (176mg, 0.67mmol), INT-6 (148mg, 0.64mmol) and HATU (363mg, 0.96mmol) in N,N-dimethylformamide (5mL), add sodium bicarbonate (161mg, 1.91mmol), react at room temperature for 5 hours. Add ethyl acetate to dilute, and wash with water and saturated brine successively. After the organic phase was separated and dried, concentrated, and the residue was separated and purified by flash column chromatography (0-20% ethyl acetate/petroleum ether) to obtain white solid INT-7 (trans mixture, 203 mg, yield 72%). 1 H NMR(800MHz,CD 3 OD)δ7.67–7.49(m,5H), 6.86–6.78(m,2H), 6.53(dd,J=9.5,3.1Hz,1H), 4.53(t,J= 7.0Hz, 2H), 3.82 (s, 3H), 3.60 (s, 3H), 3.21 (d, J = 6.9 Hz, 2H), 2.86-2.74 (m, 2H), 2.00-1.96 (m, 1H), 1.19–1.11(m,1H), 0.86–0.76(m,2H).HRMS(ESI) C 23 H 26 FN 4 O 2 S + ([M+H] + ) calculated value: 441.1755, measured value: 441.1749.

步骤6：将INT-7(200mg,0.46mmol)溶于干燥四氢呋喃(15mL)，冷却至0℃。氩气保护下，缓慢滴加1M硼烷四氢呋喃溶液(1.8mL，1.8mmol)。滴加完毕后，升温至回流3小时。缓慢滴加甲醇(1mL)和3M盐酸水溶液(1mL)，继续回流反应30分钟。将反应液冷却至室温，用饱和碳酸氢钠水溶液调pH至8-10。乙酸乙酯萃取，饱和食盐水洗涤，有机相无水硫酸钠干燥后浓缩，剩余物用快速柱层析分离纯化(0–3％甲醇/二氯甲烷)，得无色油状物I-1。将该油状物溶于二氯甲烷，加入氯化氢乙醚溶液(2M,2mL)，室温下搅拌15分钟。将溶剂减压蒸除得白色固体I-1盐酸盐(反式混合物，121mg，62％)。 1H NMR(500MHz,CD 3OD)δ7.71(d,J＝7.3Hz,2H),7.61(m,2H),6.90(m,2H),6.72(d,J＝9.4Hz,1H),4.45(t,J＝6.6Hz,2H),3.65(d,J＝2.7Hz,2H),3.32(s,7H),3.21(m,3H),3.07(m,1H),2.32(m,2H),2.19(m,1H),1.27(d,J＝12.4Hz,1H),1.16(m,1H),1.05(m,1H).HRMS(ESI)C 23H 28FN 4OS +([M+H] +)计算值：427.1962，实测值：427.1966。 Step 6: Dissolve INT-7 (200mg, 0.46mmol) in dry tetrahydrofuran (15mL) and cool to 0°C. Under the protection of argon, 1M borane tetrahydrofuran solution (1.8 mL, 1.8 mmol) was slowly added dropwise. After the dripping was completed, the temperature was raised to reflux for 3 hours. Methanol (1 mL) and 3M aqueous hydrochloric acid (1 mL) were slowly added dropwise, and the reflux reaction was continued for 30 minutes. The reaction solution was cooled to room temperature, and the pH was adjusted to 8-10 with a saturated aqueous sodium bicarbonate solution. It was extracted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by flash column chromatography (0-3% methanol/dichloromethane) to obtain a colorless oil 1-1. The oil was dissolved in dichloromethane, and hydrogen chloride ether solution (2M, 2 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure to obtain a white solid 1-1 hydrochloride (trans mixture, 121 mg, 62%). 1 H NMR (500MHz, CD 3 OD) δ 7.71 (d, J = 7.3 Hz, 2H), 7.61 (m, 2H), 6.90 (m, 2H), 6.72 (d, J = 9.4 Hz, 1H), 4.45(t,J=6.6Hz,2H), 3.65(d,J=2.7Hz,2H), 3.32(s,7H), 3.21(m,3H),3.07(m,1H), 2.32(m,2H ),2.19(m,1H),1.27(d,J=12.4Hz,1H),1.16(m,1H),1.05(m,1H).HRMS(ESI)C 23 H 28 FN 4 OS + ([M +H] + ) Calculated value: 427.1962, measured value: 427.1966.

实施例2：反式N-甲基-N-((2-(5-氟-2-甲氧苯基)环丙基)甲基)-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(化合物I-2)盐酸盐的制备Example 2: trans N-methyl-N-((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)-3-((4-methyl-5-phenyl) Preparation of -4H-1,2,4-triazol-3-yl)thio)propyl-1-amine (compound 1-2) hydrochloride

Figure PCTCN2021076289-appb-000259
Figure PCTCN2021076289-appb-000259

将化合物I-1(38mg，0.09mmol)和37％甲醛水溶液(0.2mL,2.67mmol)溶于乙腈 (5mL)，加入NaHB(AcO) 3(60mg，0.28mmol)，室温下反应1.5小时。加入水淬灭反应，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，剩余物用快速柱层析分离纯化(0–3％甲醇/二氯甲烷)，得无色油状物I-2。油状物经二氯甲烷稀释，加入2M氯化氢乙醚溶液(2mL)，搅拌15分钟，将溶剂减压蒸除得I-2盐酸盐(反式混合物，38mg，89％)，为白色固体。 1H NMR(500MHz,CD 3OD)δ7.71–7.65(m,2H),7.60(m,3H),6.90(m,2H),6.74–6.67(m,1H),4.43(m,2H),3.85(s,3H),3.63(d,J＝2.6Hz,3H),3.49–3.39(m,2H),3.20(m,1H),3.00(s,3H),2.44–2.36(m,2H),2.30–2.24(m,1H),1.31(m,2H),1.25–1.17(m,1H),1.06(m,1H).HRMS(ESI)C 24H 30FN 4OS +([M+H] +)计算值：441.2119，实测值：441.2117。 Compound I-1 (38 mg, 0.09 mmol) and 37% aqueous formaldehyde solution (0.2 mL, 2.67 mmol) were dissolved in acetonitrile (5 mL), NaHB(AcO) 3 (60 mg, 0.28 mmol) was added, and the reaction was carried out at room temperature for 1.5 hours. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by flash column chromatography (0-3% methanol/dichloromethane) to obtain nothing Color oil I-2. The oil was diluted with dichloromethane, added 2M hydrogen chloride ether solution (2 mL), stirred for 15 minutes, the solvent was evaporated under reduced pressure to obtain 1-2 hydrochloride (trans mixture, 38 mg, 89%) as a white solid. 1 H NMR (500MHz, CD 3 OD) δ 7.71--7.65 (m, 2H), 7.60 (m, 3H), 6.90 (m, 2H), 6.74 - 6.67 (m, 1H), 4.43 (m, 2H) ,3.85(s,3H),3.63(d,J=2.6Hz,3H), 3.49–3.39(m,2H), 3.20(m,1H), 3.00(s,3H), 2.44–2.36(m,2H ),2.30–2.24(m,1H),1.31(m,2H),1.25–1.17(m,1H),1.06(m,1H).HRMS(ESI)C 24 H 30 FN 4 OS + ((M+ H] + ) Calculated value: 441.2119, measured value: 441.2117.

实施例3：反式N-乙基-N-((2-(5-氟-2-甲氧苯基)环丙基)甲基)-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-3)盐酸盐的制备Example 3: trans N-ethyl-N-((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)-3-((4-methyl-5-phenyl) Preparation of -4H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-3) hydrochloride

Figure PCTCN2021076289-appb-000260
Figure PCTCN2021076289-appb-000260

参照实施例2的方法，以乙醛替代甲醛水溶液与化合物I-1进行还原胺化反应，然后与氯化氢进行成盐，制备得到白色固体化合物I-3盐酸盐(反式混合物)。 1H NMR(500MHz,CD 3OD)δ7.66(d,J＝7.5Hz,2H),7.60(m,3H),6.90(t,J＝5.2Hz,2H),6.69(m,1H),4.47–4.39(m,2H),3.85(s,3H),3.62(d,J＝6.0Hz,3H),3.41(m,5H),3.26(s,1H),2.39(m,2H),2.27(m,1H),1.40–1.26(m,4H),1.26(d,J＝6.9Hz,1H),1.23–1.15(m,1H),1.06(m,1H).HRMS(ESI)C 25H 32FN 4OS +([M+H] +)计算值：455.2275，实测值：455.2270。 With reference to the method of Example 2, acetaldehyde was substituted for the aqueous formaldehyde solution to carry out reductive amination reaction with compound I-1, and then to form a salt with hydrogen chloride to prepare a white solid compound I-3 hydrochloride (trans mixture). 1 H NMR(500MHz,CD 3 OD)δ7.66(d,J=7.5Hz,2H), 7.60(m,3H), 6.90(t,J=5.2Hz,2H), 6.69(m,1H), 4.47–4.39 (m, 2H), 3.85 (s, 3H), 3.62 (d, J = 6.0 Hz, 3H), 3.41 (m, 5H), 3.26 (s, 1H), 2.39 (m, 2H), 2.27 (m,1H),1.40–1.26(m,4H),1.26(d,J=6.9Hz,1H),1.23–1.15(m,1H),1.06(m,1H).HRMS(ESI)C 25 H 32 FN 4 OS + ([M+H] + ) Calculated value: 455.2275, measured value: 455.2270.

实施例4：反式N-丙基-N-((2-(5-氟-2-甲氧苯基)环丙基)甲基)-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-4)盐酸盐的制备Example 4: trans N-propyl-N-((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)-3-((4-methyl-5-phenyl) Preparation of -4H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-4) hydrochloride

Figure PCTCN2021076289-appb-000261
Figure PCTCN2021076289-appb-000261

参照实施例2的方法，以丙醛替代甲醛水溶液与化合物I-1进行还原胺化反应，然后与氯化氢成盐，制备得到白色固体化合物I-4盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.66–7.59(m,3H),7.58–7.54(m,2H),6.91–6.85(m,2H),6.67(dd,J＝9.4,2.9Hz,1H),4.44–4.38(m,2H),3.84(s,3/2H),3.83(s,3/2H),3.61(s,3/2H),3.60(s,3/2H),3.49–3.36(m,3H),3.28–3.18(m,3H),2.43–2.35(m,2H),2.30–2.23(m,1H),1.82–1.72(m,2H),1.29–1.25(m,1H),1.20–1.16(m,1H),1.07–0.98(m,4H).HRMS(ESI)C 26H 34FN 4OS +([M+H] +)计算值：469.2432，实测值：469.2434。 With reference to the method of Example 2, the aqueous solution of formaldehyde was replaced by propionaldehyde for reductive amination reaction with compound I-1, and then the salt was formed with hydrogen chloride to prepare a white solid compound I-4 hydrochloride (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ7.66–7.59(m,3H), 7.58–7.54(m,2H), 6.91–6.85(m,2H), 6.67(dd,J=9.4,2.9Hz, 1H), 4.44--4.38 (m, 2H), 3.84 (s, 3/2H), 3.83 (s, 3/2H), 3.61 (s, 3/2H), 3.60 (s, 3/2H), 3.49-- 3.36(m,3H), 3.28–3.18(m,3H), 2.43–2.35(m,2H), 2.30–2.23(m,1H), 1.82–1.72(m,2H), 1.29–1.25(m,1H) ), 1.20-1.16 (m, 1H), 1.07-0.98 (m, 4H). HRMS (ESI) C 26 H 34 FN 4 OS + ([M+H] + ) calculated value: 469.2432, measured value: 469.2434.

实施例5：反式N-环丙甲基-N-((2-(5-氟-2-甲氧苯基)环丙基)甲基)-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-5)盐酸盐的制备Example 5: trans N-cyclopropylmethyl-N-((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)-3-((4-methyl-5- Preparation of phenyl-4H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-5) hydrochloride

Figure PCTCN2021076289-appb-000262
Figure PCTCN2021076289-appb-000262

参照实施例2的方法，以环丙基甲醛替代甲醛水溶液与化合物I-1进行还原胺化反应，然后与氯化氢成盐，制备得到白色固体I-5盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.66–7.63(m,2H),7.62–7.59(m,1H),7.58–7.55(m,2H),6.92–6.85(m,2H),6.68(dd,J＝9.4,2.3Hz,1H),4.43(t,J＝6.4Hz,2/2H),4.41(t,J＝6.4Hz,2/2H),3.84(s,3H),3.62(s,3/2H),3.60(s,3/2H),3.53–3.42(m,3H),3.34–3.24(m,2H),3.19–3.15(m,1H),2.41–2.34(m,2H),2.30–2.24(m,1H),1.31–1.26(m,1H),1.21–1.18(m,1H),1.18–1.11(m,1H),1.09–1.02(m,1H),0.79–0.72(m,2H),0.48–0.39(m,2H).HRMS(ESI)C 27H 34FN 4OS +([M+H] +)计算值：481.2432，实测值：481.2436。 With reference to the method of Example 2, cyclopropylformaldehyde was substituted for the aqueous formaldehyde solution to perform reductive amination reaction with compound I-1, and then form a salt with hydrogen chloride to prepare a white solid I-5 hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 7.66–7.63 (m, 2H), 7.62–7.59 (m, 1H), 7.58–7.55 (m, 2H), 6.92–6.85 (m, 2H), 6.68 ( dd, J = 9.4, 2.3 Hz, 1H), 4.43 (t, J = 6.4 Hz, 2/2H), 4.41 (t, J = 6.4 Hz, 2/2H), 3.84 (s, 3H), 3.62 (s ,3/2H), 3.60(s,3/2H), 3.53-3.42(m,3H), 3.34-3.24(m,2H), 3.19-3.15(m,1H), 2.41-2.34(m,2H) ,2.30–2.24(m,1H),1.31–1.26(m,1H),1.21–1.18(m,1H),1.18–1.11(m,1H),1.09–1.02(m,1H),0.79–0.72( m, 2H), 0.48–0.39 (m, 2H). HRMS (ESI) C 27 H 34 FN 4 OS + ([M+H] + ) Calculated value: 481.2432, measured value: 481.2436.

实施例6：反式N-异丙基-N-((2-(5-氟-2-甲氧苯基)环丙基)甲基)-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-6)盐酸盐的制备Example 6: trans N-isopropyl-N-((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)-3-((4-methyl-5-benzene Preparation of 4-H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-6) hydrochloride

Figure PCTCN2021076289-appb-000263
Figure PCTCN2021076289-appb-000263

参照实施例2的方法，以丙酮替代甲醛水溶液与化合物I-1进行还原胺化反应得化合物I-6，然后与氯化氢进行成盐，制备得到白色固体I-6盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.67–7.64(m,2H),7.60–7.54(m,3H),6.83(dd,J＝8.9,4.6Hz,1H),6.77(td,J＝8.5,3.1Hz,1H),6.54(dd,J＝9.8,3.1Hz,1H),4.30–4.23(m,2H),3.81(s,3H),3.61(s,3H),3.18–3.10(m,1H),2.74–2.50(m,4H),2.12–2.01(m,3H),1.13–1.07(m,1H),1.06–1.01(m,6H),0.93–0.88(m,1H),0.85–0.79(m,1H).HRMS(ESI)C 26H 34FN 4OS +([M+H] +)计算值：469.2432，实测值：469.2438。 With reference to the method of Example 2, acetone was used to replace the aqueous formaldehyde solution with compound I-1 for reductive amination to obtain compound I-6, which was then salted with hydrogen chloride to prepare white solid I-6 hydrochloride (trans mixture) . 1 H NMR(800MHz,CD 3 OD)δ7.67–7.64(m,2H), 7.60–7.54(m,3H), 6.83(dd,J=8.9,4.6Hz,1H), 6.77(td,J= 8.5, 3.1 Hz, 1H), 6.54 (dd, J = 9.8, 3.1 Hz, 1H), 4.30-4.23 (m, 2H), 3.81 (s, 3H), 3.61 (s, 3H), 3.18-3.10 (m ,1H), 2.74–2.50(m,4H), 2.12–2.01(m,3H), 1.13–1.07(m,1H), 1.06–1.01(m,6H), 0.93–0.88(m,1H), 0.85 -0.79(m,1H).HRMS(ESI)C 26 H 34 FN 4 OS + ([M+H] + ) Calculated value: 469.2432, measured value: 469.2438.

实施例7：反式N-((2-(2-乙氧基-5-氟苯基)环丙基)甲基)-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-7)盐酸盐的制备Example 7: trans N-((2-(2-ethoxy-5-fluorophenyl)cyclopropyl)methyl)-3-((4-methyl-5-phenyl-4H-1 ,2,4-Triazol-3-yl)thio)propyl-1-amine (I-7) preparation of hydrochloride

Figure PCTCN2021076289-appb-000264
Figure PCTCN2021076289-appb-000264

步骤1：仿照实施例1步骤3所述的方法，以碘乙烷代替碘甲烷与INT-4进行烷基化反应，制备得到无色油状化合物INT-8(反式混合物)。 1H NMR(800MHz,CDCl 3)δ6.81(td,J＝8.4,3.1Hz,1H),6.75(dd,J＝8.9,4.5Hz,1H),6.63(dd,J＝9.3,3.1Hz,1H),5.15(s,1H),4.15–4.02(m,2H),3.59(s,1H),2.75–2.68(m,1H),1.88–1.84(m,1H),1.51(t,J＝7.0Hz,3H),1.46(s,9H),1.04–0.99(m,2H).HRMS(ESI)C 17H 24FNO 3Na +([M+Na] +)计算值：332.1632，实测值：332.1629。 Step 1: Following the method described in step 3 of Example 1, using ethyl iodide instead of methyl iodide to carry out an alkylation reaction with INT-4 to prepare a colorless oily compound INT-8 (trans mixture). 1 H NMR (800MHz, CDCl 3 ) δ 6.81 (td, J = 8.4, 3.1 Hz, 1H), 6.75 (dd, J = 8.9, 4.5 Hz, 1H), 6.63 (dd, J = 9.3, 3.1 Hz, 1H), 5.15(s, 1H), 4.15–4.02(m, 2H), 3.59(s, 1H), 2.75–2.68(m, 1H), 1.88–1.84(m, 1H), 1.51(t, J= 7.0Hz,3H),1.46(s,9H),1.04–0.99(m,2H).HRMS(ESI)C 17 H 24 FNO 3 Na + ([M+Na] + ) Calculated value: 332.1632, measured value: 332.1629.

步骤2：将INT-8(180mg，581.8μmol)溶于4M盐酸二氧六环溶液(5mL)，室温下反应5小时。将溶剂减压蒸除，剩余物在乙酸乙酯/石油醚(体积比1/2)混合溶液中打浆15分钟。过滤，滤饼用乙酸乙酯(3mL)淋洗，真空干燥得白色固体INT-9(反式混合物，134mg，收率94％)。 1H NMR(500MHz,CD 3OD)δ6.91–6.82(m,2H),6.70(dd,J＝9.5,2.8Hz,1H),4.11–4.02(m,2H),3.08–2.93(m,2H),2.17–2.12(m,1H),1.43(t,J＝7.0Hz,3H),1.34–1.27(m,1H),1.12–1.08(m,1H),1.05–1.00(m,1H).HRMS(ESI)C 12H 17FNO +([M+H] +)计算值：210.1289，实测值：210.1285。 Step 2: Dissolve INT-8 (180 mg, 581.8 μmol) in 4M dioxane hydrochloride solution (5 mL), and react at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the residue was slurried in a mixed solution of ethyl acetate/petroleum ether (volume ratio 1/2) for 15 minutes. After filtration, the filter cake was rinsed with ethyl acetate (3 mL), and dried under vacuum to obtain white solid INT-9 (trans mixture, 134 mg, yield 94%). 1 H NMR (500MHz, CD 3 OD) δ 6.91-6.82 (m, 2H), 6.70 (dd, J=9.5, 2.8Hz, 1H), 4.11-4.02 (m, 2H), 3.08-2.93 (m, 2H), 2.17–2.12(m,1H), 1.43(t,J=7.0Hz,3H), 1.34–1.27(m,1H), 1.12–1.08(m,1H), 1.05–1.00(m,1H) .HRMS (ESI) C 12 H 17 FNO + ([M+H] + ) calculated value: 210.1289, measured value: 210.1285.

步骤3：仿照实施例1步骤5所述方法，将INT-9与INT-3进行缩合反应，制备得到白色固体化合物INT-10(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.68(d,J＝7.9Hz,2H),7.59(t,J＝7.3Hz,1H),7.55(t,J＝7.6Hz,2H),6.85(dd,J＝8.9,4.7Hz,1H),6.80(td,J＝8.5,3.0Hz,1H),6.53(dd,J＝9.6,3.0Hz,1H),4.55(t,J＝7.0Hz,2H),4.07–4.00(m,2H),3.62(s,3H),3.35(dd,J＝13.5,6.2Hz,1H),3.14(dd,J＝13.8,7.2Hz,1H),2.82(t,J＝7.0Hz,2H),2.06–2.01(m,1H),1.42(t,J＝7.0Hz,3H),1.22–1.16(m,1H),0.88–0.84(m,1H),0.83–0.79(m,1H).HRMS(ESI)C 24H 28FN 4O 2S +([M+H] +)计算值：455.1912，实测值：455.1906。 Step 3: Following the method described in step 5 of Example 1, INT-9 and INT-3 were subjected to a condensation reaction to prepare a white solid compound INT-10 (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 7.68 (d, J = 7.9 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 6.85 ( dd,J=8.9,4.7Hz,1H),6.80(td,J=8.5,3.0Hz,1H),6.53(dd,J=9.6,3.0Hz,1H),4.55(t,J=7.0Hz,2H ), 4.07–4.00 (m, 2H), 3.62 (s, 3H), 3.35 (dd, J = 13.5, 6.2 Hz, 1H), 3.14 (dd, J = 13.8, 7.2 Hz, 1H), 2.82 (t, J=7.0Hz,2H),2.06–2.01(m,1H),1.42(t,J=7.0Hz,3H),1.22–1.16(m,1H),0.88–0.84(m,1H),0.83–0.79 (m, 1H). HRMS (ESI) C 24 H 28 FN 4 O 2 S + ([M+H] + ) Calculated value: 455.1912, measured value: 455.1906.

步骤4：仿照实施例1步骤6所述方法，以INT-10为原料进行还原反应并将纯化产物I-7与氯化氢乙醚溶液进行成盐，得到白色固体I-7盐酸盐(反式混合物)。 1H NMR(500MHz,CDCl 3)δ7.70(d,J＝7.3Hz,2H),7.64–7.55(m,3H),6.91–6.82(m,2H),6.68(d,J＝9.4Hz,1H),4.44(t,J＝6.1Hz,2H),4.11–4.00(m,2H),3.65(s,3H),3.22–3.07(m,4H),2.34–2.28(m,2H),2.24–2.18(m,1H),1.42(t,J＝6.8Hz,3H),1.38–1.31(m,1H),1.15–1.09(m,1H),1.08–1.03(m,1H).HRMS(ESI)C 24H 30FN 4OS +([M+H] +)计算值：441.2119，实测值：441.2112。 Step 4: Following the method described in step 6 of Example 1, using INT-10 as a raw material for reduction reaction and salting the purified product I-7 with hydrogen chloride ether solution to obtain white solid I-7 hydrochloride (trans mixture ). 1 H NMR(500MHz, CDCl 3 )δ7.70(d,J=7.3Hz,2H), 7.64–7.55(m,3H), 6.91–6.82(m,2H), 6.68(d,J=9.4Hz, 1H), 4.44 (t, J = 6.1Hz, 2H), 4.11–4.00(m, 2H), 3.65(s, 3H), 3.22–3.07(m, 4H), 2.34–2.28(m, 2H), 2.24 –2.18(m,1H),1.42(t,J=6.8Hz,3H),1.38–1.31(m,1H),1.15–1.09(m,1H),1.08–1.03(m,1H).HRMS(ESI ) C 24 H 30 FN 4 OS + ([M+H] + ) calculated value: 441.2119, measured value: 441.2112.

实施例8：反式N-((2-(2-乙氧基-5-氟苯基)环丙基)甲基)-N-甲基-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-8)盐酸盐的制备Example 8: trans N-((2-(2-ethoxy-5-fluorophenyl)cyclopropyl)methyl)-N-methyl-3-((4-methyl-5-benzene Preparation of 4-H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-8) hydrochloride

Figure PCTCN2021076289-appb-000265
Figure PCTCN2021076289-appb-000265

仿照实施例2所述方法，以I-7为原料与甲醛水溶液进行还原胺化反应，然后与氯化氢成盐，制备得到白色固体I-8盐酸盐(反式混合物)。 1H NMR(500MHz,CD 3OD)δ7.68(d,J＝7.1Hz,2H),7.63–7.54(m,3H),6.91–6.81(m,2H),6.66(dd,J＝9.5,2.4Hz,1H),4.41(t,J＝5.9Hz,2H),4.12–4.00(m,2H),3.62(s,3H),3.37–3.30(m,4H),2.99(s,3H),2.41–2.34(m,2H),2.32–2.25(m,1H),1.40(t,J＝7.0Hz,3H),1.35–1.30(m,1H),1.21–1.16(m,1H),1.10–1.02(m,1H).HRMS(ESI)C 25H 32FN 4OS +([M+H] +)计算值：455.2275，实测值：455.2275。 Following the method described in Example 2, I-7 was used as a raw material to perform reductive amination with an aqueous formaldehyde solution, and then form a salt with hydrogen chloride to prepare a white solid I-8 hydrochloride (trans mixture). 1 H NMR (500MHz, CD 3 OD) δ 7.68 (d, J = 7.1 Hz, 2H), 7.63-7.54 (m, 3H), 6.91-6.81 (m, 2H), 6.66 (dd, J = 9.5, 2.4Hz,1H), 4.41(t,J=5.9Hz,2H), 4.12–4.00(m,2H), 3.62(s,3H), 3.37–3.30(m,4H), 2.99(s,3H), 2.41–2.34(m,2H),2.32–2.25(m,1H),1.40(t,J=7.0Hz,3H),1.35–1.30(m,1H),1.21–1.16(m,1H),1.10– 1.02(m,1H).HRMS(ESI) C 25 H 32 FN 4 OS + ([M+H] + ) Calculated value: 455.2275, measured value: 455.2275.

实施例9：反式N-((2-(2-乙氧基-5-氟苯基)环丙基)甲基)-N-乙基-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-9)盐酸盐的制备Example 9: trans N-((2-(2-ethoxy-5-fluorophenyl)cyclopropyl)methyl)-N-ethyl-3-((4-methyl-5-benzene Preparation of 4-H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-9) hydrochloride

Figure PCTCN2021076289-appb-000266
Figure PCTCN2021076289-appb-000266

仿照实施例2所述方法，以I-7为原料与乙醛进行还原胺化反应，然后与氯化氢成盐，制备得到白色固体I-9盐酸盐(反式混合物)。 1H NMR(500MHz,CD 3OD)δ7.70–7.53(m,5H),6.91–6.81(m,2H),6.66(dd,J＝9.4,2.4Hz,1H),4.41(t,J＝6.6Hz,2H),4.14–3.98(m,2H),3.62(s,3H),3.43–3.34(m,6H),2.41–2.33(m,2H),2.32–2.26(m,1H),1.41(t,J＝6.9Hz,3H),1.35(t,J＝7.2Hz,3H),1.32–1.27(m,1H),1.20–1.14(m,1H),1.10–1.03(m,1H).HRMS(ESI)C 26H 34FN 4OS +([M+H] +)计算值：469.2432，实测值：469.2439。 Following the method described in Example 2, I-7 was used as a raw material to perform reductive amination with acetaldehyde, and then form a salt with hydrogen chloride to prepare a white solid I-9 hydrochloride (trans mixture). 1 H NMR(500MHz,CD 3 OD)δ7.70–7.53(m,5H), 6.91–6.81(m,2H), 6.66(dd,J=9.4,2.4Hz,1H), 4.41(t,J= 6.6Hz, 2H), 4.14–3.98(m, 2H), 3.62(s, 3H), 3.43–3.34(m, 6H), 2.41–2.33(m, 2H), 2.32–2.26(m, 1H), 1.41 (t,J=6.9Hz,3H), 1.35(t,J=7.2Hz,3H), 1.32–1.27(m,1H), 1.20–1.14(m,1H), 1.10–1.03(m,1H). HRMS (ESI) C 26 H 34 FN 4 OS + ([M+H] + ) calculated value: 469.2432, measured value: 469.2439.

实施例10：反式N-((2-(5-氟-2-(2-氟乙氧基)苯基)环丙基)甲基)-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-10)盐酸盐的制备Example 10: trans N-((2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methyl)-3-((4-methyl-5-benzene Preparation of 4-H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-10) hydrochloride

Figure PCTCN2021076289-appb-000267
Figure PCTCN2021076289-appb-000267

步骤1：将中间体INT-4(100mg，0.36mmol)，2-氟乙醇(52μL，0.89mmol)和三苯基膦(233mg，0.89mmol)溶于干燥四氢呋喃(8mL)，冷却至0℃，缓慢滴加偶氮二甲酸二乙酯(140μL,0.89mmol)。反应液于微波反应器中60℃反应30分钟。减压蒸除溶剂，剩余物用快速柱层析分离纯化(0–10％乙酸乙酯/石油醚)，得到无色油状物INT-11(反式混合物，110mg，收率95％)。 1H NMR(800MHz,CDCl 3)δ6.82(td,J＝8.4,3.1Hz,1H),6.77(dd,J＝8.9,4.6Hz,1H),6.62(dd,J＝9.3,3.1Hz,1H),5.00(s,1H),4.90–4.74(m,1H),4.31–4.18(m,2H),3.51(d,J＝13.3Hz,1H),2.81(dd,J＝13.4,8.5Hz,1H),1.96–1.92(m,1H),1.46(s,9H),1.11–1.04(m,1H),1.02–0.99(m,1H),0.87–0.83(m,1H).HRMS(ESI)C 17H 23F 2NO 3Na +([M+Na] +)计算值：350.1538，实测值：350.1548。 Step 1: Intermediate INT-4 (100mg, 0.36mmol), 2-fluoroethanol (52μL, 0.89mmol) and triphenylphosphine (233mg, 0.89mmol) were dissolved in dry tetrahydrofuran (8mL), cooled to 0°C, Slowly add diethyl azodicarboxylate (140 μL, 0.89 mmol) dropwise. The reaction solution was reacted in a microwave reactor at 60°C for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-10% ethyl acetate/petroleum ether) to obtain INT-11 as a colorless oil (trans mixture, 110 mg, yield 95%). 1 H NMR (800MHz, CDCl 3 ) δ 6.82 (td, J = 8.4, 3.1 Hz, 1H), 6.77 (dd, J = 8.9, 4.6 Hz, 1H), 6.62 (dd, J = 9.3, 3.1 Hz, 1H),5.00(s,1H),4.90–4.74(m,1H),4.31–4.18(m,2H),3.51(d,J=13.3Hz,1H),2.81(dd,J=13.4,8.5Hz ,1H),1.96-1.92(m,1H),1.46(s,9H),1.11-1.04(m,1H),1.02-0.99(m,1H),0.87-0.83(m,1H).HRMS(ESI ) Calculated value for C 17 H 23 F 2 NO 3 Na + ([M+Na] + ): 350.1538, measured value: 350.1548.

步骤2：仿照实施例7步骤2所述方法，将INT-11脱除Boc保护得到白色固体化合物INT-12(反式混合物)。 1H NMR(500MHz,CD 3OD)δ6.96–6.87(m,2H),6.76(dd,J＝9.4,3.0Hz,1H),4.87–4.70(m,2H),4.34–4.18(m,2H),3.05–2.97(m,2H),2.19–2.13(m,1H),1.27–1.22(m,1H),1.21–1.15(m,1H),1.05–1.00(m,1H).HRMS(ESI)C 12H 16F 2NO +([M+H] +)计算值：228.1194，实测值：228.1220。 Step 2: Following the method described in step 2 of Example 7, the Boc protection of INT-11 was removed to obtain a white solid compound INT-12 (trans mixture). 1 H NMR (500MHz, CD 3 OD) δ 6.96–6.87 (m, 2H), 6.76 (dd, J = 9.4, 3.0 Hz, 1H), 4.87–4.70 (m, 2H), 4.34–4.18 (m, 2H), 3.05–2.97(m, 2H), 2.19–2.13(m, 1H), 1.27–1.22(m, 1H), 1.21–1.15(m, 1H), 1.05–1.00(m, 1H).HRMS( ESI) C 12 H 16 F 2 NO + ([M+H] + ) calculated value: 228.1194, measured value: 228.1220.

步骤3：仿照实施例1步骤5所述方法，以INT-12和INT-3为原料进行缩合反应，制备得到白色固体化合物INT-13(反式混合物)。 1H NMR(500MHz,CD 3OD)δ7.67–7.63(m,2H),7.59–7.50(m,3H),6.87(dd,J＝8.9,4.7Hz,1H),6.80(td,J＝8.5,3.1Hz,1H),6.54(dd,J＝9.7,3.0Hz,1H),4.79(t,J＝4.0Hz,1H),4.69(t,J＝4.0Hz,1H),4.52(t,J＝6.9Hz,2H),4.26–4.16(m,2H),3.60(s,3H),3.22(ddd,J＝20.8,12.8,6.8Hz,2H),2.79(t,J＝6.9Hz,2H),2.05–1.99(m,1H),1.19–1.12(m,1H),0.87–0.80(m,2H).HRMS(ESI)C 24H 27F 2N 4O 2S +([M+H] +)计算值：473.1817，实测值：473.1815。 Step 3: Following the method described in step 5 of Example 1, using INT-12 and INT-3 as raw materials for condensation reaction, a white solid compound INT-13 (trans mixture) is prepared. 1 H NMR(500MHz,CD 3 OD)δ7.67–7.63(m,2H), 7.59–7.50(m,3H), 6.87(dd,J=8.9,4.7Hz,1H), 6.80(td,J= 8.5,3.1Hz,1H),6.54(dd,J=9.7,3.0Hz,1H), 4.79(t,J=4.0Hz,1H), 4.69(t,J=4.0Hz,1H),4.52(t, J = 6.9Hz, 2H), 4.26–4.16 (m, 2H), 3.60 (s, 3H), 3.22 (ddd, J = 20.8, 12.8, 6.8 Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H ),2.05–1.99(m,1H),1.19–1.12(m,1H),0.87–0.80(m,2H).HRMS(ESI)C 24 H 27 F 2 N 4 O 2 S + ((M+H ] + ) Calculated value: 473.1817, measured value: 473.1815.

步骤4：仿照实施例1步骤6所述方法，以INT-13为原料进行还原反应，并将产物I-10纯化与HCl成盐，制备白色固体I-10盐酸盐(反式混合物)。 1H NMR(500MHz,CD 3OD)δ7.72(d,J＝7.0Hz,2H),7.66–7.57(m,3H),6.97–6.87(m,2H),6.75(dd,J＝9.4,2.5Hz,1H),4.88–4.69(m,2H),4.45(t,J＝6.4Hz,2H),4.33–4.19(m,2H),3.66(s,3H),3.24–3.14(m,4H),2.36–2.28(m,2H),2.28–2.21(m,1H),1.37–1.29(m,1H),1.24–1.17(m,1H),1.10–1.04(m,1H).HRMS(ESI)C 24H 29F 2N 4OS +([M+H] +)计算值：459.2025，实测值：459.2022。 Step 4: Following the method described in step 6 of Example 1, using INT-13 as a raw material for a reduction reaction, and purifying the product I-10 to form a salt with HCl to prepare a white solid I-10 hydrochloride (trans mixture). 1 H NMR(500MHz,CD 3 OD)δ7.72(d,J=7.0Hz,2H), 7.66–7.57(m,3H), 6.97–6.87(m,2H), 6.75(dd,J=9.4, 2.5Hz, 1H), 4.88–4.69 (m, 2H), 4.45 (t, J = 6.4 Hz, 2H), 4.33–4.19 (m, 2H), 3.66 (s, 3H), 3.24–3.14 (m, 4H) ), 2.36–2.28(m, 2H), 2.28–2.21(m, 1H), 1.37–1.29(m, 1H), 1.24–1.17(m, 1H), 1.10–1.04(m, 1H).HRMS(ESI ) C 24 H 29 F 2 N 4 OS + ([M+H] + ) Calculated value: 459.2025, measured value: 459.2022.

实施例11：反式N-((2-(5-氟-2-(2-氟乙氧基)苯基)环丙基)甲基)-N-甲基-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-11)盐酸盐的制备Example 11: trans N-((2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methyl)-N-methyl-3-((4-methyl Preparation of 5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-11) hydrochloride

Figure PCTCN2021076289-appb-000268
Figure PCTCN2021076289-appb-000268

仿照实施例2所述方法，以I-10和甲醛水溶液为原料进行还原胺化反应，然后与氯化氢成盐，制备得到白色固体I-11盐酸盐(反式混合物)。 1H NMR(500MHz,CD 3OD)δ7.68(d,J＝7.1Hz,2H),7.63–7.53(m,3H),6.95–6.84(m,2H),6.71(dd,J＝9.4,2.4Hz,1H),4.85–4.67(m,2H),4.40(s,2H),4.33–4.15(m,2H),3.62(s,3H),3.42–3.22(m,4H),2.97(s,3H),2.41–2.34(m,2H),2.32–2.23(m,1H),1.35–1.29(m,1H),1.28–1.22(m,1H),1.10–1.03(m,1H).HRMS(ESI)C 25H 31F 2N 4OS +([M+H] +)计算值：473.2181，实测值：473.2182。 Following the method described in Example 2, the reductive amination reaction was carried out with I-10 and aqueous formaldehyde solution as raw materials, and then the salt was formed with hydrogen chloride to prepare a white solid I-11 hydrochloride (trans mixture). 1 H NMR(500MHz,CD 3 OD)δ7.68(d,J=7.1Hz,2H), 7.63–7.53(m,3H), 6.95–6.84(m,2H), 6.71(dd,J=9.4, 2.4Hz, 1H), 4.85-4.67 (m, 2H), 4.40 (s, 2H), 4.33--4.15 (m, 2H), 3.62 (s, 3H), 3.42-3.22 (m, 4H), 2.97 (s ,3H),2.41–2.34(m,2H),2.32–2.23(m,1H),1.35–1.29(m,1H),1.28–1.22(m,1H),1.10–1.03(m,1H).HRMS (ESI) C 25 H 31 F 2 N 4 OS + ([M+H] + ) Calculated value: 473.2181, measured value: 473.2182.

实施例12：反式N-((2-(5-氟-2-(2-氟乙氧基)苯基)环丙基)甲基)-N-乙基-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-12)盐酸盐的制备Example 12: trans N-((2-(5-fluoro-2-(2-fluoroethoxy)phenyl)cyclopropyl)methyl)-N-ethyl-3-((4-methyl Preparation of 5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-12) hydrochloride

Figure PCTCN2021076289-appb-000269
Figure PCTCN2021076289-appb-000269

仿照实施例2所述方法，以I-10和乙醛为原料进行还原胺化反应，然后与氯化氢成盐，制备得到白色固体I-12盐酸盐(反式混合物)。 1H NMR(500MHz,CD 3OD)δ7.66(d,J＝6.7Hz,2H),7.63–7.53(m,3H),6.95–6.84(m,2H),6.71(dd,J＝9.3,2.4Hz,1H),4.84–4.66(m,2H),4.40(s,2H),4.32–4.14(m,2H),3.61(s,3H),3.42–3.32(m,6H),2.40–2.32(m,2H),2.30–2.23(m,1H),1.33(t,J＝7.2Hz,3H),1.30–1.26(m,1H),1.23–1.20(m,1H),1.10–1.00(m,1H).HRMS(ESI)C 26H 33F 2N 4OS +([M+H] +)计算值：487.2338，实测值：487.2333。 Following the method described in Example 2, I-10 and acetaldehyde were used as raw materials to carry out reductive amination reaction, and then form a salt with hydrogen chloride to prepare a white solid I-12 hydrochloride (trans mixture). 1 H NMR (500MHz, CD 3 OD) δ 7.66 (d, J = 6.7 Hz, 2H), 7.63-7.53 (m, 3H), 6.95-6.84 (m, 2H), 6.71 (dd, J = 9.3, 2.4Hz, 1H), 4.84-4.66 (m, 2H), 4.40 (s, 2H), 4.32-4.14 (m, 2H), 3.61 (s, 3H), 3.42--3.32 (m, 6H), 2.40-2.32 (m,2H),2.30–2.23(m,1H),1.33(t,J=7.2Hz,3H),1.30–1.26(m,1H),1.23–1.20(m,1H),1.10–1.00(m ,1H).HRMS(ESI) C 26 H 33 F 2 N 4 OS + ([M+H] + ) Calculated value: 487.2338, measured value: 487.2333.

实施例13：反式N-((2-(5-氯-2-甲氧苯基)环丙基)甲基)-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-13)盐酸盐的制备Example 13: trans N-((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)-3-((4-methyl-5-phenyl-4H-1, Preparation of 2,4-triazol-3-yl)thio)propyl-1-amine (I-13) hydrochloride

Figure PCTCN2021076289-appb-000270
Figure PCTCN2021076289-appb-000270

步骤1：中间体INT-14(反式混合物)可参考文献方法(J.Med.Chem.2016,59,578-591)进行制备。以INT-14为原料，仿照实施例7步骤2所述方法进行脱除Boc的反应，制备得到白色固体化合物INT-15(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.17(dd,J＝8.7,2.6Hz,1H),6.97(d,J＝2.6Hz,1H),6.93(d,J＝8.7Hz,1H),3.88(s,3H),3.09(m,1H),2.94(m,1H),2.10(m,1H),1.30–1.24(m,1H),1.12(m,1H),1.03(m,1H).HRMS(ESI)C 11H 15ClNO +([M+H] +)计算值：212.0837，实测值：212.0834。 Step 1: Intermediate INT-14 (trans mixture) can be prepared by referring to the literature method (J. Med. Chem. 2016, 59, 578-591). Using INT-14 as a raw material, the Boc removal reaction was carried out following the method described in step 2 of Example 7 to prepare a white solid compound INT-15 (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ7.17(dd,J=8.7,2.6Hz,1H), 6.97(d,J=2.6Hz,1H), 6.93(d,J=8.7Hz,1H), 3.88 (s, 3H), 3.09 (m, 1H), 2.94 (m, 1H), 2.10 (m, 1H), 1.30-1.24 (m, 1H), 1.12 (m, 1H), 1.03 (m, 1H) .HRMS (ESI) C 11 H 15 ClNO + ([M+H] + ) calculated value: 212.0837, measured value: 212.0834.

步骤2：仿照实施例1步骤5所述方法，以INT-15和INT-3为原料进行缩合反应，得白色固体化合物INT-16(反式混合物)。 1H NMR(800MHz,CDCl 3)δ7.58–7.52(m,3H),7.51(m,2H),7.12(dd,J＝8.7,2.6Hz,1H),6.84(d,J＝2.6Hz,1H),6.76(d,J＝8.7Hz,1H),6.43(s,1H),4.67–4.58(m,2H),3.89(s,3H),3.68–3.62(m,1H),3.64(s,3H),2.96–2.83(m,3H),1.85(m,1H),1.05–0.95(m,2H),0.85(m,1H).HRMS(ESI)C 23H 26ClN 4O 2S +([M+H] +)计算值：457.1460，实测值：457.1457。 Step 2: Following the method described in step 5 of Example 1, using INT-15 and INT-3 as raw materials for condensation reaction, a white solid compound INT-16 (trans mixture) is obtained. 1 H NMR(800MHz, CDCl 3 )δ7.58–7.52(m,3H), 7.51(m,2H), 7.12(dd,J=8.7,2.6Hz,1H), 6.84(d,J=2.6Hz, 1H), 6.76(d,J=8.7Hz,1H), 6.43(s,1H), 4.67–4.58(m,2H), 3.89(s,3H), 3.68–3.62(m,1H), 3.64(s ,3H),2.96-2.83(m,3H),1.85(m,1H),1.05-0.95(m,2H),0.85(m,1H).HRMS(ESI)C 23 H 26 ClN 4 O 2 S + ([M+H] + ) Calculated value: 457.1460, measured value: 457.1457.

步骤3：仿照实施例1步骤5所述方法，以INT-16为原料进行还原反应，并将产物纯化后与HCl成盐，得白色固体I-13盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.70–7.65(m,2H),7.62–7.53(m,3H),7.10(dd,J＝8.7,2.6Hz,1H),6.87(d,J＝8.7Hz,1H),6.86(d,J＝2.7Hz,1H),4.41–4.35(m,2H),3.85(s,3H),3.62(s,3H),2.85(dd,J＝12.4,6.3Hz,1H),2.79(t,J＝7.1Hz,2H),2.62(dd,J＝12.4,7.8Hz,1H),2.20–2.12(m,2H),2.02–1.98(m,1H),1.20–1.15(m,1H),0.99–0.96(m,1H),0.89–0.85(m,1H).HRMS(ESI)m/z计算值C 23H 28ClN 4OS +([M+H] +):443.1667；实测值:443.1675. Step 3: Following the method described in step 5 of Example 1, using INT-16 as a raw material for a reduction reaction, the product was purified and then salted with HCl to obtain a white solid I-13 hydrochloride (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ7.70–7.65(m,2H), 7.62–7.53(m,3H), 7.10(dd,J=8.7,2.6Hz,1H), 6.87(d,J= 8.7Hz, 1H), 6.86 (d, J = 2.7Hz, 1H), 4.41-4.35 (m, 2H), 3.85 (s, 3H), 3.62 (s, 3H), 2.85 (dd, J = 12.4, 6.3 Hz, 1H), 2.79 (t, J = 7.1 Hz, 2H), 2.62 (dd, J = 12.4, 7.8 Hz, 1H), 2.20-2.12 (m, 2H), 2.02-1.98 (m, 1H), 1.20 –1.15(m,1H),0.99–0.96(m,1H),0.89–0.85(m,1H).HRMS(ESI) m/z calculated value C 23 H 28 ClN 4 OS + ([M+H] + ): 443.1667; Found: 443.1675.

实施例14：反式N-((2-(5-氯-2-甲氧苯基)环丙基)甲基)-N-乙基-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-14)盐酸盐的制备Example 14: trans N-((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)-N-ethyl-3-((4-methyl-5-phenyl) Preparation of -4H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-14) hydrochloride

Figure PCTCN2021076289-appb-000271
Figure PCTCN2021076289-appb-000271

仿照实施例2所述方法，以I-13和乙醛为原料进行还原胺化反应，并将产物与HCl成盐，得白色固体I-14盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.64–7.59(m,3H),7.58–7.54(m,2H),7.15(t,J＝7.0Hz,1H),6.92–6.90(m,2H),4.47–4.37(m,2H), 3.85(s,2H),3.60(s,3/2H),3.59(s,3/2H),3.46–3.34(m,5H),3.28–3.21(m,1H),2.40–2.34(m,2H),2.25–2.17(m,1H),1.35(t,J＝7.3Hz,3H),1.27–1.21(m,1H),1.19–1.15(m,1H),1.05–0.99(m,1H).HRMS(ESI)C 25H 32ClN 4OS +([M+H] +)计算值：471.1980，实测值：471.1977。 Following the method described in Example 2, using I-13 and acetaldehyde as raw materials for reductive amination reaction, and salting the product with HCl, a white solid I-14 hydrochloride (trans mixture) was obtained. 1 H NMR(800MHz,CD 3 OD)δ7.64-7.59(m,3H), 7.58-7.54(m,2H), 7.15(t,J=7.0Hz,1H), 6.92-6.90(m,2H) ,4.47–4.37(m,2H), 3.85(s,2H), 3.60(s,3/2H), 3.59(s,3/2H), 3.46–3.34(m,5H), 3.28–3.21(m, 1H), 2.40–2.34(m,2H), 2.25–2.17(m,1H), 1.35(t,J=7.3Hz,3H), 1.27–1.21(m,1H), 1.19–1.15(m,1H) , 1.05-0.99 (m, 1H). HRMS (ESI) C 25 H 32 ClN 4 OS + ([M+H] + ) calculated value: 471.1980, measured value: 471.1977.

实施例15：反式N-((2-(5-氯-2-甲氧苯基)环丙基)甲基)-N-丙基-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-15)盐酸盐的制备Example 15: trans N-((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)-N-propyl-3-((4-methyl-5-phenyl) Preparation of -4H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-15) hydrochloride

Figure PCTCN2021076289-appb-000272
Figure PCTCN2021076289-appb-000272

仿照实施例2所述方法，以I-13和丙醛为原料进行还原胺化反应，并将产物与HCl成盐，得白色固体I-15盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.64–7.58(m,3H),7.57–7.53(m,2H),7.14(td,J＝8.3,2.7Hz,1H),6.92–6.87(m,2H),4.45–4.36(m,2H),3.84(s,3H),3.60(s,3/2H),3.59(s,3/2H),3.48–3.35(m,3H),3.27–3.17(m,3H),2.41–2.33(m,2H),2.24–2.17(m,1H),1.81–1.71(m,2H),1.27–1.22(m,1H),1.18–1.14(m,1H),1.05–0.98(m,4H).HRMS(ESI)C 26H 34ClN 4OS +([M+H] +)计算值：485.2136，实测值：485.2131。 Following the method described in Example 2, the reductive amination reaction was carried out with I-13 and propionaldehyde as raw materials, and the product was salted with HCl to obtain the white solid I-15 hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 7.64–7.58 (m, 3H), 7.57–7.53 (m, 2H), 7.14 (td, J = 8.3, 2.7 Hz, 1H), 6.92–6.87 (m, 2H), 4.45--4.36(m, 2H), 3.84(s, 3H), 3.60(s, 3/2H), 3.59(s, 3/2H), 3.48--3.35(m, 3H), 3.27--3.17( m,3H),2.41–2.33(m,2H), 2.24–2.17(m,1H), 1.81–1.71(m,2H), 1.27–1.22(m,1H), 1.18–1.14(m,1H), 1.05-0.98 (m, 4H). HRMS (ESI) C 26 H 34 ClN 4 OS + ([M+H] + ) calculated value: 485.2136, measured value: 485.2131.

实施例16：反式N-((2-(5-氯-2-甲氧苯基)环丙基)甲基)-N-环丙甲基-3-((4-甲基-5-苯基-4H-1,2,4-三唑-3-基)硫)丙基-1-胺(I-16)盐酸盐的制备Example 16: trans N-((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)-N-cyclopropylmethyl-3-((4-methyl-5- Preparation of phenyl-4H-1,2,4-triazol-3-yl)thio)propyl-1-amine (I-16) hydrochloride

Figure PCTCN2021076289-appb-000273
Figure PCTCN2021076289-appb-000273

仿照实施例2所述方法，以I-13和环丙基甲醛为原料进行还原胺化反应，并将产物与HCl成盐，得白色固体I-16盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.66–7.56(m,5H),7.19–7.14(m,1H),6.95–6.90(m,2H),4.46–4.40(m,2H),3.86(s,3H),3.62(s,3/2H),3.60(s,3/2H),3.55–3.49(m,2H),3.49–3.39(m,1H),3.35–3.30(m,1H),3.30–3.24(m,1H),3.20–3.15(m,1H),2.43–2.35(m,2H),2.28–2.20(m,1H),1.29–1.24(m,1H),1.22–1.17(m,1H),1.17–1.13(m,1H),1.08–1.02(m,1H),0.80–0.73(m,2H),0.48–0.41(m,2H).HRMS(ESI)C 27H 34ClN 4OS +([M+H] +)计算值：497.2136，实测值：497.2133。 Following the method described in Example 2, the reductive amination reaction was carried out with I-13 and cyclopropylformaldehyde as raw materials, and the product was salted with HCl to obtain a white solid I-16 hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ7.66-7.56(m,5H), 7.19-7.14(m,1H), 6.95-6.90(m,2H), 4.46-4.40(m,2H), 3.86( s,3H),3.62(s,3/2H),3.60(s,3/2H),3.55–3.49(m,2H), 3.49–3.39(m,1H), 3.35–3.30(m,1H), 3.30–3.24(m,1H), 3.20–3.15(m,1H), 2.43–2.35(m,2H), 2.28–2.20(m,1H), 1.29–1.24(m,1H), 1.22–1.17(m ,1H),1.17–1.13(m,1H),1.08–1.02(m,1H),0.80–0.73(m,2H),0.48–0.41(m,2H).HRMS(ESI)C 27 H 34 ClN 4 OS + ([M+H] + ) calculated value: 497.2136, measured value: 497.2133.

实施例17：反式N-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-17)盐酸盐的制备Example 17: trans N-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthylamide ( I-17) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000274
Figure PCTCN2021076289-appb-000274

步骤1：将原料2-萘酰氯(218mg，1.14mmol)溶于二氯甲烷(10mL)，依次加入三乙胺(174mg，1.72mmol)和4-氨基丁醇(112mg，1.26mmol)，室温下搅拌2小时。将二氯甲烷减压蒸除，加入乙酸乙酯稀释，依次用饱和碳酸氢钠水溶液，饱和食盐水洗涤。分离有机相，浓缩，剩余物用快速柱层析分离纯化(0–5％甲醇/二氯甲烷)，得到白色固体INT-17(243mg，收率87％)。 1H NMR(800MHz,CDCl 3)δ8.30(s,1H),7.93(d,J＝8.0Hz,1H),7.90(d,J＝8.5Hz,1H),7.88(d,J＝8.0Hz,1H),7.84(dd,J＝8.5,1.6Hz,1H),7.59–7.53(m,2H),3.77(t,J＝6.1Hz,2H),3.59(t,J＝6.9Hz,2H),1.82–1.77(m,3H),1.75–1.71(m,2H).HRMS(ESI)C 15H 18NO 2 +([M+H] +)计算值：244.1332，实测值：244.1329。 Step 1: Dissolve the starting material 2-naphthoyl chloride (218mg, 1.14mmol) in dichloromethane (10mL), add triethylamine (174mg, 1.72mmol) and 4-aminobutanol (112mg, 1.26mmol) in turn at room temperature Stir for 2 hours. The dichloromethane was evaporated under reduced pressure, diluted with ethyl acetate, and washed with saturated sodium bicarbonate aqueous solution and saturated brine successively. The organic phase was separated, concentrated, and the residue was separated and purified by flash column chromatography (0-5% methanol/dichloromethane) to obtain white solid INT-17 (243 mg, yield 87%). 1 H NMR(800MHz,CDCl 3 )δ8.30(s,1H),7.93(d,J=8.0Hz,1H),7.90(d,J=8.5Hz,1H),7.88(d,J=8.0Hz ,1H),7.84(dd,J=8.5,1.6Hz,1H),7.59–7.53(m,2H),3.77(t,J=6.1Hz,2H),3.59(t,J=6.9Hz,2H) ,1.82–1.77(m,3H),1.75–1.71(m,2H).HRMS(ESI) C 15 H 18 NO 2 + ([M+H] + ) Calculated value: 244.1332, measured value: 244.1329.

步骤2：将三氧化硫吡啶络合物(1.99g，12.6mmol)溶于二氯甲烷(10mL)和二甲基亚砜(10mL)，冷却至0℃。缓慢滴加溶有中间体INT-17(613mg，2.52mmol)和三乙胺(1.27g，12.6mmol)的二甲亚砜溶液(5mL)，室温下反应1.5小时。加水稀释，乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到无色油状物INT-18，直接用于步骤4反应。Step 2: Dissolve sulfur trioxide pyridine complex (1.99 g, 12.6 mmol) in dichloromethane (10 mL) and dimethyl sulfoxide (10 mL), and cool to 0°C. A dimethyl sulfoxide solution (5 mL) dissolved in intermediate INT-17 (613 mg, 2.52 mmol) and triethylamine (1.27 g, 12.6 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 1.5 hours. Dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain a colorless oil INT-18, which is directly used in the step 4 reaction.

步骤3：将中间体INT-6(150mg，647.40μmol)，丙醛(37mg，647.40μmol)和三乙胺(90μL,647.40μmol)溶于甲醇(15mL)，室温下反应2小时。加入硼氢化钠(49mg，1.29mmol)，室温下搅拌1小时。加入水淬灭反应，乙酸乙酯萃取，有机相饱和食盐水洗涤，浓缩，剩余物用快速柱层析分离纯化(0–9％甲醇/二氯甲烷)，得到无色油状物INT-19(反式混合物，36mg，收率23％)。 1H NMR(800MHz,CD 3OD)δ6.89(dd,J＝8.9,4.6Hz,1H),6.87–6.84(m,1H),6.67(dd,J＝9.5,3.0Hz,1H),3.84(s,3H),2.93(dd,J＝12.5,6.5Hz,1H),2.82–2.76(m,2H),2.73(dd,J＝12.5,7.8Hz,1H),2.07–2.03(m,1H),1.67–1.60(m,2H),1.22–1.16(m,1H),1.08–1.04(m,1H),0.99(t,J＝7.4Hz,3H),0.95–0.91(m,1H).HRMS(ESI)C 14H 21FNO +([M+H] +)计算值：238.1602，实测值：238.1603。 Step 3: Intermediate INT-6 (150 mg, 647.40 μmol), propionaldehyde (37 mg, 647.40 μmol) and triethylamine (90 μL, 647.40 μmol) were dissolved in methanol (15 mL) and reacted at room temperature for 2 hours. Sodium borohydride (49 mg, 1.29 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and concentrated. The residue was separated and purified by flash column chromatography (0-9% methanol/dichloromethane) to obtain a colorless oil INT-19 ( Trans mixture, 36mg, yield 23%). 1 H NMR (800MHz, CD 3 OD) δ 6.89 (dd, J = 8.9, 4.6 Hz, 1H), 6.87-6.84 (m, 1H), 6.67 (dd, J = 9.5, 3.0 Hz, 1H), 3.84 (s, 3H), 2.93 (dd, J = 12.5, 6.5 Hz, 1H), 2.82–2.76 (m, 2H), 2.73 (dd, J = 12.5, 7.8 Hz, 1H), 2.07–2.03 (m, 1H ),1.67–1.60(m,2H),1.22–1.16(m,1H),1.08–1.04(m,1H),0.99(t,J=7.4Hz,3H),0.95–0.91(m,1H). HRMS(ESI) C 14 H 21 FNO + ([M+H] + ) calculated value: 238.1602, measured value: 238.1603.

步骤4：将中间体INT-19(75mg，316.03μmol)和中间体INT-18(76mg，316.03μmol)溶于四氢呋喃(15mL)，加入三乙酰氧基硼氢化钠(100mg，474.05μmol)，室温下反应过夜。加入甲醇(5mL)并搅拌10分钟。将反应液浓缩，剩余物用快速柱层析分 离纯化(0–5％甲醇/二氯甲烷)，得到无色油状物I-17(反式混合物，100mg，收率68％)。将该无色油状物按照实施例1步骤6中的方法经2M氯化氢乙醚溶液转换成I-17盐酸盐(反式混合物，白色固体)。 1H NMR(800MHz,CD 3OD)δ8.39(d,J＝7.4Hz,1H),7.97(t,J＝7.6Hz,1H),7.95–7.88(m,3H),7.62–7.53(m,2H),6.92–6.84(m,2H),6.71–6.66(m,1H),3.82(s,3H),3.54–3.48(m,2H),3.40–3.28(m,3H),3.28–3.16(m,3H),2.32–2.27(m,1H),1.90–1.82(m,2H),1.81–1.72(m,4H),1.36–1.32(m,1H),1.23–1.19(m,1H),1.09–1.04(m,1H),1.02–0.97(m,3H).HRMS(ESI)C 29H 36FN 2O 2 +([M+H] +)计算值：463.2755，实测值：463.2764。 Step 4: Dissolve intermediate INT-19 (75mg, 316.03μmol) and intermediate INT-18 (76mg, 316.03μmol) in tetrahydrofuran (15mL), add sodium triacetoxyborohydride (100mg, 474.05μmol) at room temperature React overnight. Add methanol (5 mL) and stir for 10 minutes. The reaction solution was concentrated, and the residue was separated and purified by flash column chromatography (0-5% methanol/dichloromethane) to obtain a colorless oil I-17 (trans mixture, 100 mg, yield 68%). The colorless oil was converted into I-17 hydrochloride (trans mixture, white solid) by using a 2M hydrogen chloride ether solution according to the method in step 6 of Example 1. 1 H NMR (800MHz, CD 3 OD) δ 8.39 (d, J = 7.4 Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.95-7.88 (m, 3H), 7.62-7.53 (m ,2H),6.92--6.84(m,2H),6.71--6.66(m,1H),3.82(s,3H),3.54--3.48(m,2H),3.40-3.28(m,3H),3.28-3.16 (m,3H),2.32-2.27(m,1H),1.90-1.82(m,2H),1.81-1.72(m,4H),1.36-1.32(m,1H),1.23--1.19(m,1H) ,1.09–1.04(m,1H),1.02–0.97(m,3H).HRMS(ESI) C 29 H 36 FN 2 O 2 + ([M+H] + ) calculated value: 463.2755, measured value: 463.2764.

实施例18：N-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)(丙基)氨)丁基)-1-H-吲哚-2-甲酰胺(I-18)盐酸盐的制备Example 18: N-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1-H-indole- Preparation of 2-formamide (I-18) hydrochloride

Figure PCTCN2021076289-appb-000275
Figure PCTCN2021076289-appb-000275

步骤1：将吲哚-2-甲酸(200mg，1.24mmol)，4-氨基丁醇(132mg，1.49mmol)溶于N，N-二甲基甲酰胺(10mL)，依次加入HATU(708mg，1.88mmol)和碳酸氢钠(313mg，3.72mmol)，室温下反应2小时。加入乙酸乙酯稀释，依次用水和饱和食盐水洗涤，将有机相浓缩，剩余物用快速柱层析分离纯化(0–5％甲醇/二氯甲烷)，得到白色固体INT-20(231mg，收率80％)。 1H NMR(800MHz,CD 3OD)δ7.61(d,J＝8.0Hz,1H),7.45(dd,J＝8.3,0.7Hz,1H),7.24–7.20(m,1H),7.08–7.05(m,2H),3.63(t,J＝6.5Hz,2H),3.44(t,J＝7.1Hz,2H),1.75–1.69(m,2H),1.68–1.63(m,2H).HRMS(ESI)C 13H 17N 2O 2 +([M+H] +)计算值：233.1285，实测值：233.1280。 Step 1: Dissolve indole-2-carboxylic acid (200mg, 1.24mmol), 4-aminobutanol (132mg, 1.49mmol) in N,N-dimethylformamide (10mL), add HATU (708mg, 1.88 mmol) and sodium bicarbonate (313 mg, 3.72 mmol) at room temperature for 2 hours. Add ethyl acetate to dilute, wash sequentially with water and saturated brine, concentrate the organic phase, and separate and purify the residue by flash column chromatography (0–5% methanol/dichloromethane) to obtain white solid INT-20 (231 mg, yield) Rate 80%). 1 H NMR (800MHz, CD 3 OD) δ 7.61 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 8.3, 0.7 Hz, 1H), 7.24-7.20 (m, 1H), 7.08-7.05 (m,2H),3.63(t,J=6.5Hz,2H),3.44(t,J=7.1Hz,2H),1.75-1.69(m,2H),1.68-1.63(m,2H).HRMS( ESI) C 13 H 17 N 2 O 2 + ([M+H] + ) calculated value: 233.1285, measured value: 233.1280.

步骤2：仿照实施例17步骤2所述方法，将INT-20氧化得到油状化合物INT-21，直接用于步骤3反应。Step 2: Following the method described in step 2 of Example 17, INT-20 was oxidized to obtain oily compound INT-21, which was directly used in the step 3 reaction.

步骤3：仿照实施例17步骤4所述方法，将中间体INT-21与中间体INT-19进行还原胺化反应，产物I-18(反式混合物)纯化后与HCl成盐得白色固体I-18盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.61–7.58(m,1H),7.45–7.43(m,1H),7.23–7.19(m,1H),7.09–7.05(m,2H),6.91–6.85(m,2H),6.68(dt,J＝9.5,3.0Hz,1H),3.82(s,3H),3.49–3.44(m,2H),3.35–3.25(m,3H),3.25–3.14(m,3H),2.31–2.26(m,1H),1.86–1.69(m,6H),1.34–1.28(m,1H),1.23–1.19(m,1H),1.07–1.03(m,1H),1.03–0.97(m,3H).HRMS(ESI)C 27H 35FN 3O 2 +([M+H] +)计算值：452.2708，实测值：452.2714。 Step 3: Following the method described in step 4 of Example 17, the intermediate INT-21 and the intermediate INT-19 were subjected to reductive amination reaction, and the product I-18 (trans mixture) was purified and then salted with HCl to obtain a white solid I -18 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 7.61--7.58 (m, 1H), 7.45--7.43 (m, 1H), 7.23--7.19 (m, 1H), 7.09--7.05 (m, 2H), 6.91-- 6.85(m,2H),6.68(dt,J=9.5,3.0Hz,1H), 3.82(s,3H), 3.49–3.44(m,2H), 3.35–3.25(m,3H), 3.25–3.14( m,3H), 2.31–2.26(m,1H), 1.86–1.69(m,6H), 1.34–1.28(m,1H), 1.23–1.19(m,1H), 1.07–1.03(m,1H), 1.03-0.97(m,3H).HRMS(ESI) C 27 H 35 FN 3 O 2 + ([M+H] + ) Calculated value: 452.2708, measured value: 452.2714.

实施例19：反式N-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)(丙基)氨基)丁基)-4-(2’-吡啶基)苯甲酰胺(I-19)盐酸盐的制备Example 19: trans N-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2' -Pyridyl) benzamide (I-19) hydrochloride

Figure PCTCN2021076289-appb-000276
Figure PCTCN2021076289-appb-000276

步骤1：仿照实施例18步骤1所述方法，以4-(2’-吡啶基)苯甲酸与4-氨基丁醇为原料进行缩合反应，得白色固体化合物INT-22。 1H NMR(800MHz,CD 3OD)δ8.66(d,J＝4.8Hz,1H),8.07(d,J＝8.3Hz,2H),7.96–7.92(m,4H),7.44–7.40(m,1H),3.63(t,J＝6.5Hz,2H),3.45(t,J＝7.1Hz,2H),1.76–1.70(m,2H),1.68–1.61(m,2H).HRMS(ESI)C 16H 19N 2O 2 +([M+H] +)计算值：271.1441，实测值：271.1434。 Step 1: Following the method described in step 1 of Example 18, 4-(2'-pyridyl)benzoic acid and 4-aminobutanol were used as raw materials for condensation reaction to obtain white solid compound INT-22. 1 H NMR (800MHz, CD 3 OD) δ8.66 (d, J = 4.8Hz, 1H), 8.07 (d, J = 8.3Hz, 2H), 7.96–7.92 (m, 4H), 7.44–7.40 (m ,1H),3.63(t,J=6.5Hz,2H),3.45(t,J=7.1Hz,2H),1.76-1.70(m,2H),1.68-1.61(m,2H).HRMS(ESI) C 16 H 19 N 2 O 2 + ([M+H] + ) calculated value: 271.1441, measured value: 271.1434.

步骤2：仿照实施例17步骤2所述方法，将INT-22进行氧化反应，制备得到醛类中间体INT-23，直接用于步骤3反应。Step 2: Following the method described in step 2 of Example 17, INT-22 was subjected to oxidation reaction to prepare aldehyde intermediate INT-23, which was directly used in the step 3 reaction.

步骤3：仿照实施例17步骤4所述方法，将INT-23与INT-19进行还原胺化反应，产物I-19(反式混合物)纯化后与HCl成盐，得白色固体I-19盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.90(d,J＝5.6Hz,1H),8.71(td,J＝7.9,1.6Hz,1H),8.45(d,J＝8.2Hz,1H),8.15(t,J＝8.2Hz,2H),8.11–8.06(m,3H),6.93–6.91(m,1H),6.89–6.86(m,1H),6.72–6.69(m,1H),3.85(s,3H),3.52–3.47(m,2H),3.40–3.32(m,2H),3.31–3.18(m,4H),2.34–2.30(m,1H),1.91–1.84(m,2H),1.82–1.72(m,4H),1.40–1.34(m,1H),1.25–1.20(m,1H),1.11–1.07(m,1H),1.05–1.00(m,3H).HRMS(ESI)C 30H 37FN 3O 2 +([M+H] +)计算值：490.2864，实测值：490.2863。 Step 3: Following the method described in step 4 of Example 17, INT-23 and INT-19 were subjected to reductive amination reaction. The product I-19 (trans mixture) was purified and then salted with HCl to obtain white solid I-19 salt Acid salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 8.90 (d, J = 5.6 Hz, 1H), 8.71 (td, J = 7.9, 1.6 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.15(t,J=8.2Hz,2H), 8.11–8.06(m,3H), 6.93–6.91(m,1H), 6.89–6.86(m,1H), 6.72–6.69(m,1H), 3.85( s, 3H), 3.52–3.47(m, 2H), 3.40–3.32(m, 2H), 3.31–3.18(m, 4H), 2.34–2.30(m, 1H), 1.91–1.84(m, 2H), 1.82–1.72(m,4H),1.40–1.34(m,1H),1.25–1.20(m,1H),1.11–1.07(m,1H),1.05–1.00(m,3H).HRMS(ESI)C 30 H 37 FN 3 O 2 + ([M+H] + ) Calculated value: 490.2864, measured value: 490.2863.

实施例20：反式N-(4-(((2-(5-氯-2-甲氧苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-20)盐酸盐的制备Example 20: trans N-(4-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthamide( I-20) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000277
Figure PCTCN2021076289-appb-000277

步骤1：仿照实施例17步骤3所述方法，将中间体INT-15与丙醛进行还原胺化反应制备得到油状化合物INT-24(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.16(dd,J ＝8.7,2.6Hz,1H),6.95(d,J＝2.6Hz,1H),6.93(d,J＝8.7Hz,1H),3.86(s,3H),3.13(dd,J＝12.9,7.1Hz,1H),3.05–2.96(m,3H),2.17–2.13(m,1H),1.77–1.71(m,2H),1.31–1.24(m,1H),1.17–1.12(m,1H),1.06–1.01(m,4H).HRMS(ESI)C 14H 21ClNO +([M+H] +)计算值：254.1306，实测值：254.1310。 Step 1: Following the method described in step 3 of Example 17, the intermediate INT-15 and propionaldehyde were subjected to reductive amination reaction to prepare the oily compound INT-24 (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ7.16(dd,J=8.7,2.6Hz,1H), 6.95(d,J=2.6Hz,1H), 6.93(d,J=8.7Hz,1H), 3.86(s,3H),3.13(dd,J=12.9,7.1Hz,1H),3.05–2.96(m,3H),2.17–2.13(m,1H),1.77–1.71(m,2H),1.31– 1.24(m,1H),1.17–1.12(m,1H),1.06–1.01(m,4H).HRMS(ESI)C 14 H 21 ClNO + ([M+H] + )Calculated value: 254.1306, measured value : 254.1310.

步骤2：仿照实施例17步骤4所述方法，将INT-24与中间体INT-18进行还原胺化反应，产物I-20(反式混合物)纯化后与HCl成盐得白色固体I-20盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.38(d,J＝5.8Hz,1H),7.99–7.93(m,3H),7.91–7.88(m,1H),7.62–7.57(m,2H),7.15(dd,J＝8.7,2.6Hz,1H),6.94–6.91(m,2H),3.85(d,J＝3.9Hz,3H),3.52(dd,J＝15.5,6.8Hz,2H),3.40–3.33(m,2H),3.30–3.17(m,4H),2.29–2.26(m,1H),1.88–1.81(m,2H),1.81–1.73(m,4H),1.37–1.32(m,1H),1.26–1.21(m,1H),1.09–1.05(m,1H),1.02(dt,J＝10.3,7.4Hz,3H).HRMS(ESI)C 29H 36ClN 2O 2 +([M+H] +)计算值：479.2460，实测值：479.2458。 Step 2: Following the method described in step 4 of Example 17, the INT-24 and the intermediate INT-18 are subjected to reductive amination reaction, and the product I-20 (trans mixture) is purified and then salted with HCl to obtain a white solid I-20 Hydrochloride (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ8.38(d,J=5.8Hz,1H),7.99–7.93(m,3H),7.91–7.88(m,1H),7.62–7.57(m,2H) ,7.15(dd,J＝8.7,2.6Hz,1H), 6.94–6.91(m,2H), 3.85(d,J＝3.9Hz,3H), 3.52(dd,J＝15.5,6.8Hz,2H), 3.40–3.33(m,2H), 3.30–3.17(m,4H), 2.29–2.26(m,1H), 1.88–1.81(m,2H), 1.81–1.73(m,4H), 1.37–1.32(m ,1H),1.26–1.21(m,1H),1.09–1.05(m,1H),1.02(dt,J=10.3,7.4Hz,3H).HRMS(ESI)C 29 H 36 ClN 2 O 2 + ( [M+H] + ) Calculated value: 479.2460, measured value: 479.2458.

实施例21：反式N-(4-(((2-(5-氯-2-甲氧苯基)环丙基)甲基)(丙基)氨)丁基)-1-H-吲哚-2-甲酰胺(I-21)盐酸盐的制备Example 21: trans N-(4-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1-H-indole Preparation of indole-2-carboxamide (I-21) hydrochloride

Figure PCTCN2021076289-appb-000278
Figure PCTCN2021076289-appb-000278

仿照实施例17步骤4所述方法，以INT-24与INT-21为原料进行还原胺化反应，产物I-21(反式混合物)纯化后与HCl成盐，得白色固体I-21盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.60(d,J＝8.0Hz,1H),7.45(d,J＝9.0Hz,1H),7.21(t,J＝7.6Hz,1H),7.13(dd,J＝8.7,2.5Hz,1H),7.10–7.08(m,1H),7.06(t,J＝7.5Hz,1H),6.91–6.90(m,1H),6.89(d,J＝8.7Hz,1H),3.82(s,3H),3.49–3.44(m,2H),3.35–3.13(m,6H),2.28–2.22(m,1H),1.87–1.80(m,2H),1.79–1.68(m,4H),1.35–1.30(m,1H),1.23–1.19(m,1H),1.07–1.03(m,1H),1.01–0.96(m,3H).HRMS(ESI)C 27H 35ClN 3O 2 +([M+H] +)计算值：468.2412，实测值：468.2410。 Following the method described in step 4 of Example 17, using INT-24 and INT-21 as raw materials for reductive amination reaction, the product I-21 (trans mixture) was purified and then salted with HCl to obtain white solid I-21 hydrochloric acid Salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 7.60 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.13 ( dd,J=8.7,2.5Hz,1H), 7.10–7.08(m,1H), 7.06(t,J=7.5Hz,1H), 6.91–6.90(m,1H), 6.89(d,J=8.7Hz ,1H), 3.82(s,3H), 3.49–3.44(m,2H), 3.35–3.13(m,6H), 2.28–2.22(m,1H), 1.87–1.80(m,2H), 1.79–1.68 (m,4H),1.35--1.30(m,1H),1.23--1.19(m,1H),1.07-1.03(m,1H),1.01-0.96(m,3H).HRMS(ESI)C 27 H 35 ClN 3 O 2 + ([M+H] + ) calculated value: 468.2412, measured value: 468.2410.

实施例22：反式N-(4-(((2-(5-氯-2-甲氧苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-22)盐酸盐的制备Example 22: trans N-(4-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2' -Pyridyl) benzamide (I-22) hydrochloride

Figure PCTCN2021076289-appb-000279
Figure PCTCN2021076289-appb-000279

仿照实施例17步骤4所述方法，以INT-24与INT-23为原料进行还原胺化反应，产物I-22(反式混合物)纯化后与HCl成盐，得白色固体I-22盐酸盐(反式混合物)。 1H  NMR(800MHz,CD 3OD)δ8.87(d,J＝5.5Hz,1H),8.69(t,J＝7.9Hz,1H),8.42(d,J＝8.1Hz,1H),8.13–8.10(m,2H),8.09–8.04(m,3H),7.14(dt,J＝8.8,2.5Hz,1H),6.93–6.91(m,2H),3.85(s,3H),3.52–3.48(m,2H),3.39–3.14(m,5H),3.08–2.98(m,1H),2.30–2.25(m,1H),1.89–1.72(m,6H),1.37–1.31(m,1H),1.24–1.21(m,1H),1.09–1.06(m,1H),1.05–0.99(m,3H).HRMS(ESI)C 30H 37ClN 3O 2 +([M+H] +)计算值：506.2569，实测值：506.2566。 Following the method described in step 4 of Example 17, INT-24 and INT-23 were used as raw materials for reductive amination reaction. The product I-22 (trans mixture) was purified and then salted with HCl to obtain white solid I-22 hydrochloric acid. Salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 8.87 (d, J = 5.5 Hz, 1H), 8.69 (t, J = 7.9 Hz, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.13- 8.10(m,2H), 8.09–8.04(m,3H), 7.14(dt,J=8.8,2.5Hz,1H), 6.93–6.91(m,2H), 3.85(s,3H),3.52–3.48( m,2H), 3.39–3.14(m,5H), 3.08–2.98(m,1H), 2.30–2.25(m,1H), 1.89–1.72(m,6H), 1.37–1.31(m,1H), 1.24–1.21(m,1H),1.09–1.06(m,1H),1.05–0.99(m,3H).HRMS(ESI)C 30 H 37 ClN 3 O 2 + ([M+H] + )Calculated value : 506.2569, measured value: 506.2566.

实施例23：反式N-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)(乙基)氨)丁基)-2-萘酰胺(I-23)盐酸盐的制备Example 23: trans N-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(ethyl)amino)butyl)-2-naphthylamide ( I-23) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000280
Figure PCTCN2021076289-appb-000280

步骤1：仿照实施例17步骤3的方法，将INT-6与乙醛进行还原胺化反应，可制备得到中间体INT-25(反式混合物)，黄色油状物。 1H NMR(800MHz,CD 3OD)δ7.17(dd,J＝8.7,2.5Hz,1H),6.96(d,J＝2.6Hz,1H),6.93(d,J＝8.7Hz,1H),3.87(s,3H),3.16–3.08(m,3H),3.03(dd,J＝13.3,8.3Hz,1H),2.18–2.11(m,1H),1.35(t,J＝7.3Hz,3H),1.30–1.23(m,1H),1.18–1.12(m,1H),1.07–1.00(m,1H).HRMS(ESI)C 13H 19ClNO +([M+H] +)计算值：240.1150，实测值：240.1156。 Step 1: Following the method of step 3 in Example 17, the reductive amination reaction of INT-6 and acetaldehyde can be used to prepare intermediate INT-25 (trans mixture) as a yellow oil. 1 H NMR(800MHz,CD 3 OD)δ7.17(dd,J=8.7,2.5Hz,1H), 6.96(d,J=2.6Hz,1H), 6.93(d,J=8.7Hz,1H), 3.87(s,3H),3.16–3.08(m,3H),3.03(dd,J＝13.3,8.3Hz,1H), 2.18–2.11(m,1H),1.35(t,J＝7.3Hz,3H) ,1.30–1.23(m,1H),1.18–1.12(m,1H),1.07–1.00(m,1H).HRMS(ESI)C 13 H 19 ClNO + ([M+H] + )Calculated value: 240.1150 , Measured value: 240.1156.

步骤2：仿照实施例17步骤4所述方法，以INT-25与INT-18为原料进行还原胺化反应，产物I-23(反式混合物)纯化后与HCl成盐，得白色固体I-23盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.38(d,J＝7.6Hz,1H),7.97(t,J＝8.1Hz,1H),7.95–7.91(m,2H),7.91–7.87(m,1H),7.61–7.56(m,2H),6.91–6.85(m,2H),6.71–6.69(m,1H),3.83(s,3/2H),3.83(s,3/2H),3.54–3.48(m,2H),3.42–3.32(m,4H),3.30–3.21(m,2H),2.32–2.28(m,1H),1.90–1.80(m,2H),1.79–1.71(m,2H),1.36(td,J＝7.3,2.4Hz,3H),1.34–1.29(m,1H),1.24–1.19(m,1H),1.08–1.04(m,1H).HRMS(ESI)C 28H 34FN 2O 2 +([M+H] +)计算值：449.2599，实测值：449.2604。 Step 2: Following the method described in step 4 of Example 17, using INT-25 and INT-18 as raw materials for reductive amination reaction, the product I-23 (trans mixture) was purified and then salted with HCl to obtain a white solid I- 23 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 8.38 (d, J = 7.6 Hz, 1H), 7.97 (t, J = 8.1 Hz, 1H), 7.95-7.91 (m, 2H), 7.91-7.87 (m ,1H), 7.61–7.56(m,2H), 6.91–6.85(m,2H), 6.71–6.69(m,1H), 3.83(s,3/2H), 3.83(s,3/2H), 3.54 --3.48(m,2H),3.42–3.32(m,4H),3.30–3.21(m,2H),2.32–2.28(m,1H),1.90–1.80(m,2H),1.79–1.71(m, 2H), 1.36(td,J=7.3,2.4Hz,3H),1.34-1.29(m,1H),1.24-1.19(m,1H),1.08-1.04(m,1H).HRMS(ESI)C 28 H 34 FN 2 O 2 + ([M+H] + ) calculated value: 449.2599, measured value: 449.2604.

实施例24：反式N-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)(乙基)氨)丁基)-1-H-吲哚-2-甲酰胺(I-24)盐酸盐的制备Example 24: trans N-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(ethyl)amino)butyl)-1-H-indole Preparation of indole-2-carboxamide (I-24) hydrochloride

Figure PCTCN2021076289-appb-000281
Figure PCTCN2021076289-appb-000281

仿照实施例17步骤4所述的方法，将INT-25与INT-21进行还原胺化反应，然后产物I-24(反式混合物)以2M氯化氢乙醚溶液成盐，可制备得到白色固体I-24盐酸盐(反 式混合物)。 1H NMR(800MHz,CD 3OD)δ7.60(d,J＝8.0Hz,1H),7.44(dd,J＝8.3,0.7Hz,1H),7.23–7.19(m,1H),7.07–7.04(m,2H),6.91–6.85(m,2H),6.69(dd,J＝9.5,2.9Hz,1H),3.82(s,3H),3.46(t,J＝6.8Hz,2H),3.37–3.20(m,6H),2.30–2.26(m,1H),1.84–1.76(m,2H),1.75–1.69(m,2H),1.34(t,J＝7.3Hz,3H),1.30–1.26(m,1H),1.23–1.20(m,1H),1.06–1.01(m,1H).HRMS(ESI)C 26H 33FN 3O 2 +([M+H] +)计算值：438.2551，实测值：438.2550。 Following the method described in step 4 of Example 17, the INT-25 and INT-21 were subjected to reductive amination reaction, and then the product I-24 (trans mixture) was salted with a 2M hydrogen chloride ether solution to prepare a white solid I- 24 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 7.60 (d, J = 8.0 Hz, 1H), 7.44 (dd, J = 8.3, 0.7 Hz, 1H), 7.23–7.19 (m, 1H), 7.07–7.04 (m,2H), 6.91–6.85(m,2H), 6.69(dd,J=9.5,2.9Hz,1H), 3.82(s,3H), 3.46(t,J=6.8Hz,2H), 3.37– 3.20(m,6H),2.30–2.26(m,1H),1.84–1.76(m,2H),1.75–1.69(m,2H),1.34(t,J=7.3Hz,3H),1.30–1.26( m,1H),1.23–1.20(m,1H),1.06–1.01(m,1H).HRMS(ESI)C 26 H 33 FN 3 O 2 + ([M+H] + ) Calculated value: 438.2551, measured Value: 438.2550.

实施例25：反式N-(4-(((2-(5-氯-2-甲氧苯基)环丙基)甲基)(乙基)氨)丁基)-2-萘酰胺(I-25)盐酸盐的制备Example 25: trans N-(4-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)(ethyl)amino)butyl)-2-naphthamide( I-25) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000282
Figure PCTCN2021076289-appb-000282

步骤1：仿照实施例17步骤3所描述的方法，以INT-15为原料与乙醛进行还原胺化反应，可制备得到中间体INT-26(反式混合物)，黄色油状化合物。 1H NMR(800MHz,CD 3OD)δ7.17(dd,J＝8.7,2.5Hz,1H),6.96(d,J＝2.6Hz,1H),6.93(d,J＝8.7Hz,1H),3.87(s,3H),3.16–3.08(m,3H),3.03(dd,J＝13.3,8.3Hz,1H),2.18–2.11(m,1H),1.35(t,J＝7.3Hz,3H),1.30–1.23(m,1H),1.18–1.12(m,1H),1.07–1.00(m,1H).HRMS(ESI)C 13H 19ClNO +([M+H] +)计算值：240.1150，实测值240.1156。 Step 1: Following the method described in step 3 of Example 17, using INT-15 as a raw material for reductive amination reaction with acetaldehyde, the intermediate INT-26 (trans mixture), a yellow oily compound, can be prepared. 1 H NMR(800MHz,CD 3 OD)δ7.17(dd,J=8.7,2.5Hz,1H), 6.96(d,J=2.6Hz,1H), 6.93(d,J=8.7Hz,1H), 3.87(s,3H),3.16–3.08(m,3H),3.03(dd,J＝13.3,8.3Hz,1H), 2.18–2.11(m,1H),1.35(t,J＝7.3Hz,3H) ,1.30–1.23(m,1H),1.18–1.12(m,1H),1.07–1.00(m,1H).HRMS(ESI)C 13 H 19 ClNO + ([M+H] + )Calculated value: 240.1150 , The measured value is 240.1156.

步骤2：仿照实施例17步骤4所描述的方法，将INT-26与INT-18进行还原胺化反应，产物I-25(反式混合物)以2M氯化氢乙醚溶液成盐，得白色固体I-25盐酸盐(反式混合物)。 1H NMR(600MHz,CD 3OD)δ8.37(d,J＝3.9Hz,1H),7.99–7.91(m,3H),7.89–7.85(m,1H),7.62–7.54(m,2H),7.15(dd,J＝8.7,2.6Hz,1H),6.95–6.86(m,2H),3.84(d,J＝4.9Hz,2H),3.51(q,J＝6.6Hz,2H),3.42–3.32(m,4H),3.29–3.22(m,2H),2.29–2.24(m,1H),1.88–1.80(m,2H),1.79–1.72(m,2H),1.35(t,J＝7.2Hz,3H),1.33–1.29(m,1H),1.26–1.20(m,1H),1.08–1.02(m,1H).HRMS(ESI)C 28H 34ClN 2O 2 +([M+H] +)计算值：465.2303，实测值：465.2309。 Step 2: Following the method described in step 4 of Example 17, INT-26 and INT-18 were subjected to reductive amination reaction. The product I-25 (trans mixture) was salted with 2M hydrogen chloride ether solution to obtain white solid I- 25 Hydrochloride (trans mixture). 1 H NMR(600MHz,CD 3 OD)δ8.37(d,J=3.9Hz,1H),7.99–7.91(m,3H),7.89–7.85(m,1H),7.62–7.54(m,2H) ,7.15(dd,J=8.7,2.6Hz,1H), 6.95–6.86(m,2H), 3.84(d,J=4.9Hz,2H), 3.51(q,J=6.6Hz,2H),3.42– 3.32(m,4H), 3.29–3.22(m,2H), 2.29–2.24(m,1H), 1.88–1.80(m,2H), 1.79–1.72(m,2H), 1.35(t,J=7.2 Hz,3H),1.33--1.29(m,1H),1.26--1.20(m,1H),1.08-1.02(m,1H).HRMS(ESI)C 28 H 34 ClN 2 O 2 + ((M+H ] + ) Calculated value: 465.2303, measured value: 465.2309.

实施例26：反式N-(4-(((2-(3-氟苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-26)盐酸盐的制备Example 26: trans N-(4-(((2-(3-fluorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthylamide (I-26) salt Preparation of acid salt

Figure PCTCN2021076289-appb-000283
Figure PCTCN2021076289-appb-000283

步骤1：将原料3-氟苯甲醛(200mg，1.61mmol)溶于二氯甲烷(15mL)，加入甲氧甲酰基亚甲基三苯基膦(647mg，1.93mmol)，室温反应过夜。将二氯甲烷减压蒸除，剩余物用快速柱层析分离纯化(0–30％乙酸乙酯/石油醚)，得到无色油状物INT-27(193mg，收率67％)。 1H NMR(600MHz,CDCl 3)δ7.67(d,J＝16.0Hz,1H),7.41–7.35(m,1H),7.31(d,J＝7.7Hz,1H),7.24(d,J＝9.7Hz,1H),7.11(td,J＝8.3,1.9Hz,1H),6.46(d,J＝16.0Hz,1H),3.84(s,3H).HRMS(ESI)C 10H 10FO 2 +([M+H] +)计算值：181.0659，实测值：181.0657。 Step 1: The starting material 3-fluorobenzaldehyde (200mg, 1.61mmol) was dissolved in dichloromethane (15mL), methoxyformylmethylenetriphenylphosphine (647mg, 1.93mmol) was added, and the reaction was carried out at room temperature overnight. The dichloromethane was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain a colorless oil INT-27 (193 mg, yield 67%). 1 H NMR (600MHz, CDCl 3 ) δ7.67 (d, J = 16.0 Hz, 1H), 7.41-7.35 (m, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 9.7Hz, 1H), 7.11 (td, J = 8.3, 1.9 Hz, 1H), 6.46 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H). HRMS (ESI) C 10 H 10 FO 2 + ([M+H] + ) Calculated value: 181.0659, measured value: 181.0657.

步骤2：将INT-27(260mg，1.44mmol)溶于四氢呋喃(10mL)和水(4mL)，加入氢氧化锂一水合物(303mg，7.22mmol)，室温搅拌2小时。4M盐酸调pH至5左右，乙酸乙酯萃取，饱和食盐水洗涤，有机相用无水硫酸钠干燥，浓缩，剩余物用快速柱层析分离纯化(0–5％甲醇/二氯甲烷)，得到白色固体状物INT-28(180mg，收率75％)。 1H NMR(800MHz,CDCl 3)δ7.75(d,J＝15.9Hz,1H),7.40–7.37(m,1H),7.33(d,J＝7.7Hz,1H),7.26–7.24(m,1H),7.12(td,J＝8.2,1.9Hz,1H),6.45(d,J＝16.0Hz,1H). Step 2: Dissolve INT-27 (260 mg, 1.44 mmol) in tetrahydrofuran (10 mL) and water (4 mL), add lithium hydroxide monohydrate (303 mg, 7.22 mmol), and stir at room temperature for 2 hours. Adjust the pH to about 5 with 4M hydrochloric acid, extract with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate, and separate and purify the residue by flash column chromatography (0–5% methanol/dichloromethane). A white solid INT-28 (180 mg, yield 75%) was obtained. 1 H NMR (800MHz, CDCl 3 ) δ 7.75 (d, J = 15.9 Hz, 1H), 7.40-7.37 (m, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.26-7.24 (m, 1H), 7.12 (td, J = 8.2, 1.9 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H).

步骤3：将INT-28(164mg,987.05μmol)，N,O-二甲基羟胺盐酸盐(115mg,1.18mmol)和HATU(563mg，1.48mmol)溶于N,N-二甲基甲酰胺(8mL)，加入碳酸氢钠(248mg，2.96mmol)，室温下反应过夜。加入乙酸乙酯稀释，依次用水和饱和食盐水洗涤。有机相分离干燥后，浓缩，剩余物用快速柱层析分离纯化(0–30％乙酸乙酯/石油醚)，得到无色油状物INT-29(193mg，收率94％)。 1H NMR(800MHz,CDCl 3)δ7.68(d,J＝15.8Hz,1H),7.36–7.31(m,2H),7.28–7.25(m,1H),7.07–7.04(m,1H),7.02(d,J＝15.8Hz,1H),3.77(s,3H),3.31(s,3H).HRMS(ESI)C 11H 13FNO 2 +([M+H] +)计算值：210.0925，实测值：210.0921。 Step 3: Dissolve INT-28 (164mg, 987.05μmol), N,O-dimethylhydroxylamine hydrochloride (115mg, 1.18mmol) and HATU (563mg, 1.48mmol) in N,N-dimethylformamide (8mL), sodium bicarbonate (248mg, 2.96mmol) was added and reacted overnight at room temperature. Add ethyl acetate to dilute, and wash with water and saturated brine successively. After the organic phase was separated and dried, it was concentrated, and the residue was separated and purified by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain colorless oil INT-29 (193 mg, yield 94%). 1 H NMR(800MHz, CDCl 3 )δ7.68(d,J=15.8Hz,1H), 7.36–7.31(m,2H), 7.28–7.25(m,1H), 7.07–7.04(m,1H), 7.02(d,J=15.8Hz,1H),3.77(s,3H),3.31(s,3H).HRMS(ESI)C 11 H 13 FNO 2 + ([M+H] + ) Calculated value: 210.0925, Found: 210.0921.

步骤4：将三甲基碘化亚砜(290mg，1.32mmol)溶于干燥二甲基亚砜(6mL)，氩气保护。加入60％氢化钠(53mg，1.32mmol)，室温下反应1小时，反应液由浑浊变澄清。将中间体INT-29(184mg，879.46μmol)溶于干燥二甲基亚砜(2mL)，滴加至上述澄清反应液，室温下反应4小时。加入水淬灭反应，乙酸乙酯萃取，饱和食盐水洗涤， 将有机相浓缩，剩余物用快速柱层析分离纯化(0–30％乙酸乙酯/石油醚)，得到无色油状物INT-30(反式混合物，140mg，收率71％)。 1H NMR(800MHz,CDCl 3)δ7.26–7.22(m,1H),6.94(d,J＝7.7Hz,1H),6.89(td,J＝8.4,2.5Hz,1H),6.82–6.79(m,1H),3.71(s,3H),3.25(s,3H),2.52–2.47(m,1H),2.42(s,1H),1.67–1.62(m,1H),1.32–1.28(m,1H).HRMS(ESI)C 12H 15FNO 2 +([M+H] +)计算值：224.1081，实测值：224.1076。 Step 4: Dissolve trimethyl sulfoxide iodide (290 mg, 1.32 mmol) in dry dimethyl sulfoxide (6 mL), and protect with argon. 60% sodium hydride (53mg, 1.32mmol) was added and reacted at room temperature for 1 hour. The reaction solution changed from turbidity to clear. Intermediate INT-29 (184 mg, 879.46 μmol) was dissolved in dry dimethyl sulfoxide (2 mL), added dropwise to the above clear reaction solution, and reacted at room temperature for 4 hours. The reaction was quenched by adding water, extracted with ethyl acetate, washed with saturated brine, the organic phase was concentrated, and the residue was separated and purified by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain a colorless oil INT- 30 (trans mixture, 140 mg, yield 71%). 1 H NMR(800MHz, CDCl 3 )δ7.26–7.22(m,1H), 6.94(d,J=7.7Hz,1H), 6.89(td,J=8.4,2.5Hz,1H), 6.82–6.79( m, 1H), 3.71 (s, 3H), 3.25 (s, 3H), 2.52-2.47 (m, 1H), 2.42 (s, 1H), 1.67-1.62 (m, 1H), 1.32-1.28 (m, 1H). HRMS (ESI) C 12 H 15 FNO 2 + ([M+H] + ) Calculated value: 224.1081, measured value: 224.1076.

步骤5：将原料INT-30(136mg，609.19μmol)溶于干燥四氢呋喃(10mL)，氩气保护，冷却至-78℃。低温下，缓慢滴加1M二异丁基氢化铝四氢呋喃溶液(1.2mL)，反应2小时。加入饱和酒石酸钾钠水溶液淬灭反应，室温下搅拌1小时，过滤。滤液用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得无色油状物INT-31(反式混合物，100mg)，直接用于步骤7。Step 5: Dissolve the raw material INT-30 (136 mg, 609.19 μmol) in dry tetrahydrofuran (10 mL), protect with argon, and cool to -78°C. At low temperature, 1M diisobutylaluminum hydride tetrahydrofuran solution (1.2 mL) was slowly added dropwise and reacted for 2 hours. The reaction was quenched by adding saturated potassium sodium tartrate aqueous solution, stirred at room temperature for 1 hour, and filtered. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oil INT-31 (trans mixture, 100 mg), which was directly used in step 7.

步骤6：将中间体INT-18(607mg，2.52mmol)溶于四氢呋喃(10mL)和1,2-二氯乙烷(10mL)，依次加入丙胺(743mg，12.58mmol)，NaHB(AcO) 3(1.07g,5.03mmol)和乙酸(70μL)，室温反应过夜。加入甲醇(5mL)并室温搅拌15分钟，将溶剂减压蒸除，剩余物用快速柱层析分离纯化(0–10％甲醇/二氯甲烷)，得到白色固体化合物INT-32(485mg，收率68％)。 1H NMR(600MHz,DMSO-d 6)δ8.83–8.74(m,2H),8.49(s,1H),8.04–7.94(m,4H),7.65–7.57(m,2H),3.36–3.33(m,2H),2.94–2.89(m,2H),2.84–2.79(m,2H),1.74–1.68(m,2H),1.66–1.59(m,4H),0.91(t,J＝7.4Hz,3H).HRMS(ESI)C 18H 25N 2O +([M+H] +)计算值：285.1961，实测值：285.1958。 Step 6: Intermediate INT-18 (607mg, 2.52mmol) was dissolved in tetrahydrofuran (10mL) and 1,2-dichloroethane (10mL), and then propylamine (743mg, 12.58mmol), NaHB(AcO) 3 ( 1.07g, 5.03mmol) and acetic acid (70μL), react overnight at room temperature. Methanol (5mL) was added and stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-10% methanol/dichloromethane) to obtain a white solid compound INT-32 (485mg, yield Rate 68%). 1 H NMR (600MHz, DMSO-d 6 ) δ 8.83-8.74 (m, 2H), 8.49 (s, 1H), 8.04-7.94 (m, 4H), 7.65-7.57 (m, 2H), 3.36-3.33 (m,2H),2.94-2.89(m,2H),2.84-2.79(m,2H),1.74-1.68(m,2H),1.66-1.59(m,4H),0.91(t,J=7.4Hz , 3H). HRMS (ESI) C 18 H 25 N 2 O + ([M+H] + ) calculated value: 285.1961, measured value: 285.1958.

步骤7：将中间体INT-31(50mg，304.54μmol)和INT-32(86mg，304.54μmol)溶于乙腈(10mL)，加入NaHB(AcO) 3(129mg,609.09μmol)，室温反应过夜。加入甲醇(5mL)并室温搅拌15分钟，溶液变澄清，将溶剂减压蒸除，剩余物用快速柱层析分离纯化(0–6％甲醇/二氯甲烷)，得到无色油状物I-26(反式混合物，89mg，收率68％)。将该无色油状物按照实施例1步骤6中所述的方法经2M氯化氢乙醚溶液转换成白色固体I-26盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.39(t,J＝2.3Hz,1H),7.99–7.92(m,3H),7.89(dt,J＝8.5,2.3Hz,1H),7.62–7.56(m,2H),7.27–7.23(m,1H),6.96(t,J＝7.7Hz,1H),6.91–6.85(m,2H),3.52–3.49(m,2H),3.34–3.25(m,4H),3.24–3.14(m,2H),2.10–2.06(m,1H),1.89–1.82(m,2H),1.81–1.72(m,4H),1.51–1.45(m,1H),1.25–1.21(m,1H),1.17–1.14(m,1H),1.00(t,J＝7.4Hz,3H).HRMS(ESI)C 28H 34FN 2O +([M+H] +)计算值：433.2650，实测值：433.2645。 Step 7: Intermediate INT-31 (50 mg, 304.54 μmol) and INT-32 (86 mg, 304.54 μmol) were dissolved in acetonitrile (10 mL), NaHB(AcO) 3 (129 mg, 609.09 μmol) was added, and the reaction was carried out overnight at room temperature. Methanol (5mL) was added and stirred at room temperature for 15 minutes. The solution became clear. The solvent was evaporated under reduced pressure. The residue was separated and purified by flash column chromatography (0-6% methanol/dichloromethane) to obtain a colorless oil I- 26 (trans mixture, 89 mg, yield 68%). The colorless oil was converted into a white solid I-26 hydrochloride (trans mixture) with a 2M hydrogen chloride ether solution according to the method described in step 6 of Example 1. 1 H NMR (800MHz, CD 3 OD) δ 8.39 (t, J = 2.3 Hz, 1H), 7.99–7.92 (m, 3H), 7.89 (dt, J = 8.5, 2.3 Hz, 1H), 7.62–7.56 (m,2H),7.27–7.23(m,1H),6.96(t,J=7.7Hz,1H),6.91–6.85(m,2H),3.52–3.49(m,2H),3.34–3.25(m ,4H), 3.24–3.14(m,2H), 2.10–2.06(m,1H), 1.89–1.82(m,2H), 1.81–1.72(m,4H), 1.51–1.45(m,1H),1.25 –1.21(m,1H),1.17–1.14(m,1H),1.00(t,J=7.4Hz,3H).HRMS(ESI)C 28 H 34 FN 2 O + ([M+H] + ) calculation Value: 433.2650, measured value: 433.2645.

实施例27：反式N-(4-(((2-(3-氟苯基)环丙基)甲基)(丙基)氨)丁基)-1H-吲哚-2-甲酰胺(I-27)盐酸盐的制备Example 27: trans N-(4-(((2-(3-fluorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1H-indole-2-carboxamide( I-27) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000284
Figure PCTCN2021076289-appb-000284

步骤1：仿照实施例26步骤6所述的方法，以INT-21与丙胺进行还原胺化反应得到INT-33，油状化合物。 1H NMR(800MHz,CD 3OD)δ7.59(d,J＝8.0Hz,1H),7.44(d,J＝8.2Hz,1H),7.21(t,J＝7.6Hz,1H),7.08–7.05(m,2H),3.45(t,J＝6.6Hz,3H),3.05–3.01(m,2H),2.94–2.91(m,2H),1.79–1.74(m,2H),1.74–1.65(m,4H),1.00(t,J＝7.3Hz,3H).HRMS(ESI)C 16H 24N 3O +([M+H] +)计算值：274.1914，实测值：274.1910。 Step 1: Following the method described in step 6 of Example 26, INT-21 and propylamine were used for reductive amination to obtain INT-33, an oily compound. 1 H NMR (800MHz, CD 3 OD) δ 7.59 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.08- 7.05(m,2H),3.45(t,J=6.6Hz,3H),3.05-3.01(m,2H),2.94-2.91(m,2H),1.79-1.74(m,2H),1.74-1.65( m, 4H), 1.00 (t, J=7.3 Hz, 3H). HRMS (ESI) C 16 H 24 N 3 O + ([M+H] + ) calculated value: 274.1914, measured value: 274.1910.

步骤2：仿照实施例26步骤7的方法，以INT-33与INT-31进行还原胺化反应，产物I-27(反式混合物)纯化后与氯化氢乙醚溶液进行成盐，得到白色固体I-27盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.60(dd,J＝8.0,2.5Hz,1H),7.45(d,J＝8.3Hz,1H),7.25–7.20(m,2H),7.11(d,J＝3.3Hz,1H),7.06(t,J＝7.5Hz,1H),6.93(t,J＝8.7Hz,1H),6.89–6.85(m,2H),3.47–3.43(m,2H),3.29–3.21(m,4H),3.20–3.09(m,2H),2.09–2.03(m,1H),1.87–1.79(m,2H),1.78–1.65(m,4H),1.47–1.42(m,1H),1.22–1.19(m,1H),1.16–1.11(m,1H),0.97(t,J＝7.3Hz,3H).HRMS(ESI)C 26H 33FN 3O +([M+H] +)计算值：422.2602，实测值：422.2609。 Step 2: Following the method of step 7 of Example 26, INT-33 and INT-31 were used for reductive amination reaction. The product I-27 (trans mixture) was purified and then salted with hydrogen chloride ether solution to obtain white solid I- 27 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 7.60 (dd, J = 8.0, 2.5 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.25-7.20 (m, 2H), 7.11 (d ,J=3.3Hz,1H),7.06(t,J=7.5Hz,1H),6.93(t,J=8.7Hz,1H),6.89–6.85(m,2H),3.47–3.43(m,2H) , 3.29–3.21(m,4H), 3.20–3.09(m,2H), 2.09–2.03(m,1H), 1.87–1.79(m,2H), 1.78–1.65(m,4H), 1.47–1.42( m,1H),1.22–1.19(m,1H),1.16–1.11(m,1H),0.97(t,J=7.3Hz,3H).HRMS(ESI)C 26 H 33 FN 3 O + ([M +H] + ) Calculated value: 422.2602, measured value: 422.2609.

实施例28：反式N-(4-(((2-(3-氟苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-28)盐酸盐的制备Example 28: trans N-(4-(((2-(3-fluorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2'-pyridyl)benzene Preparation of formamide (I-28) hydrochloride

Figure PCTCN2021076289-appb-000285
Figure PCTCN2021076289-appb-000285

步骤1：仿照实施例26步骤6所述的方法，以INT-23与丙胺进行还原胺化反应得到INT-34，白色固体。 1H NMR(600MHz,CD 3OD)δ8.65(dt,J＝4.9,1.3Hz,1H),8.08–8.05(m,2H),7.97–7.92(m,4H),7.43–7.39(m,1H),3.46(t,J＝6.5Hz,2H),3.05–2.99(m,2H),2.94–2.90(m,2H),1.78–1.66(m,6H),1.01(t,J＝7.5Hz,3H).HRMS(ESI)C 19H 26N 3O +([M+H] +)计算值：312.2070，实测值：312.2067。 Step 1: Following the method described in step 6 of Example 26, reductive amination reaction with INT-23 and propylamine was carried out to obtain INT-34, a white solid. 1 H NMR (600MHz, CD 3 OD) δ8.65 (dt, J = 4.9, 1.3Hz, 1H), 8.08-8.05 (m, 2H), 7.97-7.92 (m, 4H), 7.43-7.39 (m, 1H), 3.46(t,J=6.5Hz,2H),3.05-2.99(m,2H),2.94-2.90(m,2H),1.78-1.66(m,6H),1.01(t,J=7.5Hz ,3H).HRMS(ESI) C 19 H 26 N 3 O + ([M+H] + ) Calculated value: 312.2070, measured value: 312.2067.

步骤2：仿照实施例26步骤7的方法，以INT-34与INT-31进行还原胺化反应，产物I-28(反式混合物)纯化后与氯化氢乙醚溶液进行成盐，得白色固体I-28盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.90(d,J＝5.3Hz,1H),8.72(td,J＝8.0,1.4Hz,1H),8.45(d,J＝8.2Hz,1H),8.15(d,J＝8.1Hz,2H),8.12–8.05(m,3H),7.30–7.23(m,1H), 7.02–6.96(m,1H),6.92–6.86(m,3H),3.52–3.46(m,2H),3.36–3.28(m,4H),3.25–3.17(m,2H),2.14–2.11(m,1H),1.90–1.84(m,2H),1.83–1.78(m,2H),1.77–1.69(m,2H),1.53–1.48(m,1H),1.26–1.22(m,1H),1.21–1.16(m,1H),1.01(t,J＝7.4Hz,3H).HRMS(ESI)C 29H 35FN 3O +([M+H] +)计算值：460.2759，实测值：460.2769。 Step 2: Following the method of step 7 in Example 26, INT-34 and INT-31 were used for reductive amination reaction. The product I-28 (trans mixture) was purified and then salted with hydrogen chloride ether solution to obtain white solid I- 28 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 8.90 (d, J = 5.3 Hz, 1H), 8.72 (td, J = 8.0, 1.4 Hz, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.15(d,J=8.1Hz,2H), 8.12–8.05(m,3H), 7.30–7.23(m,1H), 7.02–6.96(m,1H), 6.92–6.86(m,3H), 3.52– 3.46 (m, 2H), 3.36-3.28 (m, 4H), 3.25-3.17 (m, 2H), 2.14-2.11 (m, 1H), 1.90-1.84 (m, 2H), 1.83-1.78 (m, 2H) ),1.77–1.69(m,2H),1.53–1.48(m,1H),1.26–1.22(m,1H),1.21–1.16(m,1H),1.01(t,J=7.4Hz,3H). HRMS(ESI) C 29 H 35 FN 3 O + ([M+H] + ) calculated value: 460.2759, measured value: 460.2769.

实施例29：反式N-(4-(((2-(3-氯苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-29)盐酸盐的制备Example 29: trans N-(4-(((2-(3-chlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthylamide (I-29) salt Preparation of acid salt

Figure PCTCN2021076289-appb-000286
Figure PCTCN2021076289-appb-000286

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以3-氯苯甲醛为原料制备中间体INT-35。Step 1: Following the method of Example 26 to prepare the intermediate INT-31 with 3-fluorobenzaldehyde, the intermediate INT-35 was prepared with 3-chlorobenzaldehyde as the raw material.

步骤2：仿照实施例26步骤7的方法，将INT-35与INT-32进行还原胺化反应，产物I-29纯化后与氯化氢乙醚溶液进行成盐，制备得到白色固体I-29盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.41(t,J＝2.3Hz,1H),7.97(t,J＝7.3Hz,1H),7.95–7.89(m,3H),7.60–7.55(m,2H),7.23–7.20(m,1H),7.17–7.14(m,2H),7.06–7.04(m,1H),3.52–3.49(m,2H),3.34–3.12(m,6H),2.09–2.05(m,1H),1.89–1.82(m,2H),1.81–1.72(m,4H),1.51–1.45(m,1H),1.24–1.19(m,1H),1.17–1.13(m,1H),0.99(t,J＝7.3Hz,3H).HRMS(ESI)C 28H 34ClN 2O +([M+H] +)计算值：449.2354，实测值：449.2361。 Step 2: Following the method in step 7 of Example 26, INT-35 and INT-32 were subjected to reductive amination reaction, and the product I-29 was purified and then salted with hydrogen chloride ether solution to prepare white solid I-29 hydrochloride. (Trans mixture). 1 H NMR (800MHz, CD 3 OD) δ8.41 (t, J = 2.3 Hz, 1H), 7.97 (t, J = 7.3 Hz, 1H), 7.95-7.89 (m, 3H), 7.60-7.55 (m ,2H),7.23–7.20(m,1H),7.17–7.14(m,2H),7.06–7.04(m,1H),3.52–3.49(m,2H),3.34–3.12(m,6H),2.09 --2.05(m,1H),1.89–1.82(m,2H),1.81–1.72(m,4H),1.51–1.45(m,1H),1.24–1.19(m,1H),1.17–1.13(m, 1H), 0.99 (t, J=7.3 Hz, 3H). HRMS (ESI) C 28 H 34 ClN 2 O + ([M+H] + ) calculated value: 449.2354, measured value: 449.2361.

实施例30：反式N-(4-(((2-(3-氯苯基)环丙基)甲基)(丙基)氨)丁基)-1H-吲哚-2-甲酰胺(I-30)盐酸盐的制备Example 30: trans N-(4-(((2-(3-chlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1H-indole-2-carboxamide( I-30) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000287
Figure PCTCN2021076289-appb-000287

仿照实施例26步骤7的方法，以INT-35与INT-33进行还原胺化反应，产物I-30(反式混合物)纯化后与氯化氢乙醚溶液成盐，制备得到白色固体I-30盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.60(dd,J＝8.0,2.8Hz,1H),7.47–7.44(m,1H),7.23–7.19(m,2H),7.16–7.13(m,2H),7.12–7.11(m,1H),7.06(t,J＝7.5Hz,1H),7.05–7.01(m,1H),3.47–3.43(m,2H),3.30–3.19(m,4H),3.19–3.09(m,2H),2.07–2.01(m,1H),1.87–1.79(m,2H),1.78–1.68(m,4H),1.48–1.42(m,1H),1.23–1.18(m,1H),1.15–1.10(m,1H),0.99–0.95(m,3H).HRMS(ESI)C 26H 33ClN 3O +([M+H] +)计算值：438.2307，实测值：438.2317。 Following the method of step 7 of Example 26, INT-35 and INT-33 were used for reductive amination reaction. The product I-30 (trans mixture) was purified and then salted with hydrogen chloride ether solution to prepare white solid I-30 hydrochloric acid. Salt (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ7.60(dd,J=8.0,2.8Hz,1H), 7.47–7.44(m,1H), 7.23–7.19(m,2H), 7.16–7.13(m, 2H), 7.12–7.11(m,1H), 7.06(t,J=7.5Hz,1H), 7.05–7.01(m,1H), 3.47–3.43(m,2H), 3.30–3.19(m,4H) ,3.19–3.09(m,2H),2.07–2.01(m,1H),1.87–1.79(m,2H),1.78–1.68(m,4H),1.48–1.42(m,1H),1.23–1.18( m,1H),1.15–1.10(m,1H),0.99–0.95(m,3H).HRMS(ESI)C 26 H 33 ClN 3 O + ([M+H] + ) Calculated value: 438.2307, measured value : 438.2317.

实施例31：反式N-(4-(((2-(3-氯苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-31)盐酸盐的制备Example 31: trans N-(4-(((2-(3-chlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2'-pyridyl)benzene Preparation of formamide (I-31) hydrochloride

Figure PCTCN2021076289-appb-000288
Figure PCTCN2021076289-appb-000288

仿照实施例26步骤7的方法，以INT-35与INT-34进行还原胺化反应，产物I-31(反式混合物)纯化后与氯化氢乙醚溶液成盐，得白色固体I-31盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.91(d,J＝5.7Hz,1H),8.75–8.71(m,1H),8.46(d,J＝8.1Hz,1H),8.16(d,J＝8.1Hz,2H),8.12–8.07(m,3H),7.25(td,J＝7.8,2.2Hz,1H),7.19–7.16(m,2H),7.11–7.08(m,1H),3.51–3.47(m,2H),3.36–3.27(m,4H),3.25–3.16(m,2H),2.13–2.09(m,1H),1.91–1.84(m,2H),1.84–1.78(m,2H),1.77–1.72(m,2H),1.54–1.49(m,1H),1.26–1.22(m,1H),1.20–1.16(m,1H),1.01(t,J＝7.3Hz,3H).HRMS(ESI)C 29H 35ClN 3O +([M+H] +)计算值：476.2463，实测值：476.2468。 Following the method in step 7 of Example 26, INT-35 and INT-34 were used for reductive amination reaction. The product I-31 (trans mixture) was purified and then salted with hydrogen chloride ether solution to obtain white solid I-31 hydrochloride. (Trans mixture). 1 H NMR(800MHz,CD 3 OD)δ8.91(d,J=5.7Hz,1H), 8.75–8.71(m,1H), 8.46(d,J=8.1Hz,1H), 8.16(d,J =8.1Hz,2H),8.12–8.07(m,3H),7.25(td,J＝7.8,2.2Hz,1H),7.19–7.16(m,2H),7.11–7.08(m,1H),3.51– 3.47 (m, 2H), 3.36-3.27 (m, 4H), 3.25-3.16 (m, 2H), 2.13-2.09 (m, 1H), 1.91-1.84 (m, 2H), 1.84-1.78 (m, 2H) ), 1.77–1.72(m,2H), 1.54–1.49(m,1H), 1.26–1.22(m,1H), 1.20–1.16(m,1H), 1.01(t,J=7.3Hz,3H). HRMS (ESI) C 29 H 35 ClN 3 O + ([M+H] + ) calculated value: 476.2463, measured value: 476.2468.

实施例32：反式N-(4-(((2-(4-氟苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-32)盐酸盐的制备Example 32: trans N-(4-(((2-(4-fluorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthamide (I-32) salt Preparation of acid salt

Figure PCTCN2021076289-appb-000289
Figure PCTCN2021076289-appb-000289

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以4-氟苯甲醛为原料制备中间体INT-36(反式混合物)。Step 1: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, the intermediate INT-36 (trans mixture) was prepared with 4-fluorobenzaldehyde as a raw material.

步骤2：仿照实施例26步骤7的方法，以INT-36与INT-32为原料进行还原胺化反应，产物I-32(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-32盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.40(d,J＝3.3Hz,1H),7.97(t,J＝7.3Hz,1H),7.95–7.89(m,3H),7.61–7.55(m,2H),7.15–7.11(m,2H),6.99–6.95(m,2H),3.53–3.48(m,2H),3.33–3.24(m,4H),3.23–3.14(m,2H),2.08–2.04(m,1H),1.90–1.82(m,2H),1.81–1.72(m,4H),1.44–1.38(m,1H),1.18–1.15(m,1H),1.13–1.09(m,1H),0.99(t,J＝7.3Hz,3H).HRMS(ESI)C 28H 34FN 2O +([M+H] +)计算值：433.2650，实测值：433.2645。 Step 2: Following the method of step 7 in Example 26, INT-36 and INT-32 are used as raw materials for reductive amination reaction. The product I-32 (trans mixture) is purified and then salted with hydrogen chloride to prepare white solid I- 32 Hydrochloride (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ8.40(d,J=3.3Hz,1H),7.97(t,J=7.3Hz,1H),7.95-7.89(m,3H),7.61-7.55(m ,2H),7.15–7.11(m,2H),6.99–6.95(m,2H),3.53–3.48(m,2H),3.33–3.24(m,4H),3.23–3.14(m,2H),2.08 --2.04(m,1H),1.90–1.82(m,2H),1.81–1.72(m,4H),1.44–1.38(m,1H),1.18–1.15(m,1H),1.13–1.09(m, 1H), 0.99 (t, J=7.3 Hz, 3H). HRMS (ESI) C 28 H 34 FN 2 O + ([M+H] + ) calculated value: 433.2650, measured value: 433.2645.

实施例33：反式N-(4-(((2-(4-氟苯基)环丙基)甲基)(丙基)氨)丁基)-1H-吲哚-2-甲酰胺(I-33)盐酸盐的制备Example 33: trans N-(4-(((2-(4-fluorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1H-indole-2-carboxamide( I-33) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000290
Figure PCTCN2021076289-appb-000290

仿照实施例26步骤7的方法，以INT-36与INT-33为原料进行还原胺化反应，产物I-33(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-33盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.60(dd,J＝8.0,2.5Hz,1H),7.47–7.44(m,1H),7.23–7.20(m,1H),7.14–7.05(m,4H),6.97–6.92(m,2H),3.47–3.43(m,2H),3.28–3.21(m,4H),3.18–3.11(m,2H),2.05–1.99(m,1H),1.86–1.80(m,2H),1.77–1.67(m,4H),1.40–1.35(m,1H),1.16–1.12(m,1H),1.10–1.06(m,1H),1.00–0.93(m,3H).HRMS(ESI)C 26H 33FN 3O +([M+H] +)计算值：422.2602，实测值：422.2611。 Imitating the method of step 7 in Example 26, using INT-36 and INT-33 as raw materials for reductive amination reaction, the product I-33 (trans mixture) was purified and then salted with hydrogen chloride to prepare white solid I-33 hydrochloric acid Salt (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ7.60(dd,J=8.0,2.5Hz,1H), 7.47–7.44(m,1H), 7.23–7.20(m,1H), 7.14–7.05(m, 4H), 6.97--6.92(m,2H), 3.47--3.43(m,2H), 3.28--3.21(m,4H), 3.18--3.11(m,2H), 2.05--1.99(m,1H), 1.86-- 1.80 (m, 2H), 1.77-1.67 (m, 4H), 1.40-1.35 (m, 1H), 1.16-1.12 (m, 1H), 1.10-1.06 (m, 1H), 1.00-0.93 (m, 3H) ). HRMS (ESI) C 26 H 33 FN 3 O + ([M+H] + ) calculated value: 422.2602, measured value: 422.2611.

实施例34：反式N-(4-(((2-(4-氟苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-34)盐酸盐的制备Example 34: trans N-(4-(((2-(4-fluorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2'-pyridyl)benzene Preparation of formamide (I-34) hydrochloride

Figure PCTCN2021076289-appb-000291
Figure PCTCN2021076289-appb-000291

仿照实施例26步骤7的方法，以INT-36与INT-34为原料进行还原胺化反应，产物I-34(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-34盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.90–8.86(m,1H),8.67–8.62(m,1H),8.42–8.38(m,1H),8.14–8.11(m,2H),8.08–8.06(m,2H),8.05–8.01(m,1H),7.18–7.14(m,2H),7.02–6.98(m,2H),3.50–3.47(m,2H),3.33–3.26(m,4H),3.24–3.16(m,2H),2.11–2.06(m,1H),1.89–1.82(m,2H),1.81–1.71(m,4H),1.46–1.41(m,1H),1.21–1.18(m,1H),1.15–1.11(m,1H),1.02(t,J＝7.4Hz,3H).HRMS(ESI)C 29H 35FN 3O +([M+H] +)计算值：460.2759，实测值：460.2754。 Imitating the method in step 7 of Example 26, using INT-36 and INT-34 as raw materials for reductive amination reaction, the product I-34 (trans mixture) was purified and then salted with hydrogen chloride to prepare white solid I-34 hydrochloric acid Salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 8.90--8.86 (m, 1H), 8.67--8.62 (m, 1H), 8.42--8.38 (m, 1H), 8.14--8.11 (m, 2H), 8.08-- 8.06 (m, 2H), 8.05-8.01 (m, 1H), 7.18-7.14 (m, 2H), 7.02-6.98 (m, 2H), 3.50-3.47 (m, 2H), 3.33-3.26 (m, 4H) ), 3.24–3.16(m,2H), 2.11–2.06(m,1H), 1.89–1.82(m,2H), 1.81–1.71(m,4H), 1.46–1.41(m,1H), 1.21–1.18 (m,1H),1.15–1.11(m,1H),1.02(t,J=7.4Hz,3H).HRMS(ESI)C 29 H 35 FN 3 O + ([M+H] + ) Calculated value: 460.2759, measured value: 460.2754.

实施例35：反式N-(4-(((2-(4-氯苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-35)盐酸盐的制备Example 35: trans N-(4-(((2-(4-chlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthamide (I-35) salt Preparation of acid salt

Figure PCTCN2021076289-appb-000292
Figure PCTCN2021076289-appb-000292

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以4-氟苯甲醛为 原料制备中间体INT-37(反式混合物，无色油状物)。Step 1: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, 4-fluorobenzaldehyde was used as a raw material to prepare intermediate INT-37 (trans mixture, colorless oil).

步骤2：仿照实施例26步骤7的方法，以INT-37与INT-32为原料进行还原胺化反应，产物I-35(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-35盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.40(d,J＝4.1Hz,1H),7.97(t,J＝7.7Hz,1H),7.95–7.88(m,3H),7.60–7.55(m,2H),7.24–7.21(m,2H),7.11–7.08(m,2H),3.53–3.47(m,2H),3.34–3.24(m,4H),3.22–3.12(m,2H),2.08–2.03(m,1H),1.89–1.82(m,2H),1.81–1.72(m,4H),1.47–1.42(m,1H),1.20–1.16(m,1H),1.15–1.11(m,1H),0.99(t,J＝7.4Hz,3H).HRMS(ESI)C 28H 34ClN 2O +([M+H] +)计算值：449.2354，实测值：449.2356。 Step 2: Following the method of step 7 in Example 26, INT-37 and INT-32 are used as raw materials for reductive amination reaction. The product I-35 (trans mixture) is purified and then salted with hydrogen chloride to prepare white solid I- 35 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ8.40 (d, J = 4.1 Hz, 1H), 7.97 (t, J = 7.7 Hz, 1H), 7.95-7.88 (m, 3H), 7.60-7.55 (m ,2H),7.24–7.21(m,2H),7.11–7.08(m,2H),3.53–3.47(m,2H),3.34–3.24(m,4H),3.22–3.12(m,2H),2.08 --2.03(m,1H),1.89–1.82(m,2H),1.81–1.72(m,4H),1.47–1.42(m,1H),1.20–1.16(m,1H),1.15–1.11(m, 1H), 0.99 (t, J=7.4 Hz, 3H). HRMS (ESI) C 28 H 34 ClN 2 O + ([M+H] + ) calculated value: 449.2354, measured value: 449.2356.

实施例36：反式N-(4-(((2-(4-氯苯基)环丙基)甲基)(丙基)氨)丁基)-1H-吲哚-2-甲酰胺(I-36)盐酸盐的制备Example 36: trans N-(4-(((2-(4-chlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1H-indole-2-carboxamide( I-36) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000293
Figure PCTCN2021076289-appb-000293

仿照实施例26步骤7的方法，以INT-37与INT-33为原料进行还原胺化反应，产物I-36(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-36盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.41(t,J＝2.3Hz,1H),7.97(t,J＝7.3Hz,1H),7.95–7.89(m,3H),7.60–7.55(m,2H),7.23–7.20(m,1H),7.17–7.14(m,2H),7.06–7.04(m,1H),3.52–3.49(m,2H),3.34–3.12(m,6H),2.09–2.05(m,1H),1.89–1.82(m,2H),1.81–1.72(m,4H),1.51–1.45(m,1H),1.24–1.19(m,1H),1.17–1.13(m,1H),0.99(t,J＝7.3Hz,3H).HRMS(ESI)C 26H 33ClN 3O +([M+H] +)计算值：438.2307，实测值：423.2307。 Imitating the method of step 7 in Example 26, using INT-37 and INT-33 as raw materials for reductive amination reaction, the product I-36 (trans mixture) was purified and then salted with hydrogen chloride to prepare white solid I-36 hydrochloric acid Salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ8.41 (t, J = 2.3 Hz, 1H), 7.97 (t, J = 7.3 Hz, 1H), 7.95-7.89 (m, 3H), 7.60-7.55 (m ,2H),7.23–7.20(m,1H),7.17–7.14(m,2H),7.06–7.04(m,1H),3.52–3.49(m,2H),3.34–3.12(m,6H),2.09 --2.05(m,1H),1.89–1.82(m,2H),1.81–1.72(m,4H),1.51–1.45(m,1H),1.24–1.19(m,1H),1.17–1.13(m, 1H), 0.99 (t, J=7.3 Hz, 3H). HRMS (ESI) C 26 H 33 ClN 3 O + ([M+H] + ) calculated value: 438.2307, measured value: 423.2307.

实施例37：反式N-(4-(((2-(4-氯苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-37)盐酸盐的制备Example 37: trans N-(4-(((2-(4-chlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2'-pyridyl)benzene Preparation of formamide (I-37) hydrochloride

Figure PCTCN2021076289-appb-000294
Figure PCTCN2021076289-appb-000294

仿照实施例26步骤7的方法，以INT-37与INT-34为原料进行还原胺化反应，产物I-37(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-37盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.91(dd,J＝5.9,1.6Hz,1H),8.72(td,J＝8.0,1.6Hz,1H),8.46(d,J＝8.1Hz,1H),8.16–8.14(m,2H),8.12–8.06(m,3H),7.26–7.23(m,2H),7.16–7.12(m,2H),3.52–3.45(m,2H),3.35–3.27(m,4H),3.24–3.15(m,2H),2.12–2.07(m,1H),1.90–1.84(m,2H),1.82–1.77(m,2H),1.76–1.72(m,2H),1.50–1.45(m,1H),1.23– 1.19(m,1H),1.18–1.14(m,1H),1.01(t,J＝7.4Hz,3H).HRMS(ESI)C 29H 35ClN 3O +([M+H] +)计算值：476.2463，实测值：476.2473。 Imitating the method in step 7 of Example 26, using INT-37 and INT-34 as raw materials for reductive amination reaction, the product I-37 (trans mixture) was purified and then salted with hydrogen chloride to prepare white solid I-37 hydrochloric acid Salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 8.91 (dd, J = 5.9, 1.6 Hz, 1H), 8.72 (td, J = 8.0, 1.6 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H ), 8.16–8.14(m,2H), 8.12–8.06(m,3H), 7.26–7.23(m,2H), 7.16–7.12(m,2H), 3.52–3.45(m,2H), 3.35–3.27 (m,4H), 3.24–3.15(m,2H), 2.12–2.07(m,1H), 1.90–1.84(m,2H), 1.82–1.77(m,2H), 1.76–1.72(m,2H) ,1.50–1.45(m,1H),1.23– 1.19(m,1H),1.18–1.14(m,1H),1.01(t,J=7.4Hz,3H).HRMS(ESI)C 29 H 35 ClN 3 O + ([M+H] + ) calculated value: 476.2463, measured value: 476.2473.

实施例38：反式N-(4-(丙基((2-(4-三氟甲基)苯基)环丙基)甲基)氨)丁基)-2-萘酰胺(I-38)盐酸盐的制备Example 38: trans N-(4-(propyl((2-(4-trifluoromethyl)phenyl)cyclopropyl)methyl)amino)butyl)-2-naphthamide (I-38 ) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000295
Figure PCTCN2021076289-appb-000295

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以4-三氟甲基苯甲醛为原料制备中间体INT-38(反式混合物)。Step 1: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde is used as a raw material to prepare intermediate INT-38 (trans mixture).

步骤6：仿照实施例26步骤7的方法，以INT-38与INT-32为原料进行还原胺化反应，产物I-38(反式混合物)纯化后与氯化氢成盐，制备得到I-38盐酸盐(反式混合物)，为白色固体。 1H NMR(800MHz,CD 3OD)δ8.42(d,J＝3.3Hz,1H),7.99(t,J＝7.9Hz,1H),7.97–7.90(m,3H),7.62–7.56(m,2H),7.54(d,J＝7.9Hz,2H),7.33–7.29(m,2H),3.56–3.49(m,2H),3.37–3.27(m,4H),3.24–3.15(m,2H),2.19–2.14(m,1H),1.90–1.84(m,2H),1.82–1.74(m,4H),1.59–1.53(m,1H),1.31–1.28(m,1H),1.25–1.19(m,1H),1.01(t,J＝7.3Hz,3H).HRMS(ESI)C 29H 34F 3N 2O +([M+H] +)计算值：483.2618，实测值：483.2617。 Step 6: Following the method of step 7 in Example 26, INT-38 and INT-32 are used as raw materials to carry out reductive amination reaction. The product I-38 (trans mixture) is purified and then salted with hydrogen chloride to prepare I-38 salt. Acid salt (trans mixture), white solid. 1 H NMR(800MHz,CD 3 OD)δ8.42(d,J=3.3Hz,1H),7.99(t,J=7.9Hz,1H),7.97–7.90(m,3H),7.62–7.56(m ,2H),7.54(d,J=7.9Hz,2H),7.33–7.29(m,2H),3.56–3.49(m,2H),3.37–3.27(m,4H),3.24–3.15(m,2H) ), 2.19–2.14(m,1H),1.90–1.84(m,2H),1.82–1.74(m,4H),1.59–1.53(m,1H),1.31–1.28(m,1H),1.25–1.19 (m, 1H), 1.01 (t, J=7.3 Hz, 3H). HRMS (ESI) C 29 H 34 F 3 N 2 O + ([M+H] + ) calculated value: 483.2618, measured value: 483.2617.

实施例39：反式N-(4-(丙基)((2-(4-三氟甲基)苯基)环丙基)甲基)氨)丁基)-1H-吲哚-2-甲酰胺(I-39)盐酸盐的制备Example 39: trans N-(4-(propyl)((2-(4-trifluoromethyl)phenyl)cyclopropyl)methyl)amino)butyl)-1H-indole-2- Preparation of formamide (I-39) hydrochloride

Figure PCTCN2021076289-appb-000296
Figure PCTCN2021076289-appb-000296

仿照实施例26步骤7的方法，以INT-38与INT-33为原料进行还原胺化反应，产物I-39(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-39盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.60(dd,J＝8.0,3.1Hz,1H),7.53–7.50(m,2H),7.45(dd,J＝8.2,3.3Hz,1H),7.28–7.25(m,2H),7.23–7.21(m,1H),7.10(s,1H),7.08–7.05(m,1H),3.48–3.44(m,2H),3.30–3.22(m,4H),3.20–3.11(m,2H),2.16–2.11(m,1H),1.88–1.80(m,2H),1.79–1.68(m,4H),1.55–1.49(m,1H),1.28–1.24(m,1H),1.21–1.17(m,1H),0.98(t,J＝7.3Hz,3H).HRMS(ESI)C 27H 33F 3N 3O +([M+H] +)计算值：472.2570，实测值：472.2572。 Imitating the method in step 7 of Example 26, using INT-38 and INT-33 as raw materials for reductive amination reaction, the product I-39 (trans mixture) was purified and then salted with hydrogen chloride to prepare white solid I-39 hydrochloric acid Salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 7.60 (dd, J = 8.0, 3.1 Hz, 1H), 7.53-7.50 (m, 2H), 7.45 (dd, J = 8.2, 3.3 Hz, 1H), 7.28 --7.25(m,2H),7.23–7.21(m,1H),7.10(s,1H),7.08–7.05(m,1H), 3.48–3.44(m,2H), 3.30–3.22(m,4H) , 3.20–3.11(m,2H), 2.16–2.11(m,1H), 1.88–1.80(m,2H), 1.79–1.68(m,4H), 1.55–1.49(m,1H), 1.28–1.24( m,1H),1.21–1.17(m,1H),0.98(t,J=7.3Hz,3H).HRMS(ESI)C 27 H 33 F 3 N 3 O + ([M+H] + )Calculated value : 472.2570, measured value: 472.2572.

实施例40：反式N-(4-(丙基)((2-(4-三氟甲基)苯基)环丙基)甲基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-40)盐酸盐的制备Example 40: trans N-(4-(propyl)((2-(4-trifluoromethyl)phenyl)cyclopropyl)methyl)amino)butyl)-4-(2'-pyridine Yl)benzamide (I-40) hydrochloride

Figure PCTCN2021076289-appb-000297
Figure PCTCN2021076289-appb-000297

仿照实施例26步骤7的方法，以INT-38与INT-34为原料进行还原胺化反应，产物I-40(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-40盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.91(d,J＝5.8Hz,1H),8.74(td,J＝8.0,1.2Hz,1H),8.51–8.42(m,1H),8.17–8.15(m,2H),8.12(t,J＝6.8Hz,1H),8.10–8.07(m,2H),7.56(d,J＝7.8Hz,2H),7.35(dd,J＝8.1,3.6Hz,2H),3.51–3.46(m,2H),3.37–3.32(m,3H),3.30–3.16(m,3H),2.23–2.17(m,1H),1.92–1.85(m,2H),1.83–1.79(m,2H),1.78–1.70(m,2H),1.63–1.57(m,1H),1.34–1.28(m,2H),1.27–1.22(m,1H),1.01(t,J＝7.3Hz,3H).HRMS(ESI)C 30H 35F 3N 3O +([M+H] +)计算值：510.2727，实测值：510.2731。 Following the method of step 7 in Example 26, INT-38 and INT-34 were used as raw materials for reductive amination reaction. The product I-40 (trans mixture) was purified and then salted with hydrogen chloride to prepare white solid I-40 hydrochloric acid. Salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 8.91 (d, J = 5.8 Hz, 1H), 8.74 (td, J = 8.0, 1.2 Hz, 1H), 8.51-8.42 (m, 1H), 8.17-8.15 (m, 2H), 8.12 (t, J = 6.8 Hz, 1H), 8.10-8.07 (m, 2H), 7.56 (d, J = 7.8 Hz, 2H), 7.35 (dd, J = 8.1, 3.6 Hz, 2H), 3.51--3.46(m,2H), 3.37--3.32(m,3H), 3.30--3.16(m,3H), 2.23--2.17(m,1H), 1.92--1.85(m,2H), 1.83-- 1.79(m,2H),1.78–1.70(m,2H),1.63–1.57(m,1H),1.34–1.28(m,2H),1.27–1.22(m,1H),1.01(t,J=7.3 Hz, 3H). HRMS (ESI) C 30 H 35 F 3 N 3 O + ([M+H] + ) Calculated value: 510.2727, measured value: 510.2731.

实施例41：反式N-(4-(((2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-41)盐酸盐的制备Example 41: trans N-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthylamide (I- 41) Preparation of hydrochloride

Figure PCTCN2021076289-appb-000298
Figure PCTCN2021076289-appb-000298

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以2,3-二氯苯甲醛为原料制备中间体INT-39(反式混合物)。Step 1: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, 2,3-dichlorobenzaldehyde was used as a raw material to prepare intermediate INT-39 (trans mixture).

步骤6：仿照实施例26步骤7的方法，以INT-39与INT-32为原料进行还原胺化反应，产物I-41(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-41盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.39(d,J＝11.4Hz,1H),8.00–7.92(m,3H),7.91–7.87(m,1H),7.63–7.56(m,2H),7.38(d,J＝8.0Hz,1H),7.22–7.19(m,1H),7.07(d,J＝7.8Hz,1H),3.62–3.58(m,1H),3.56–3.51(m,2H),3.41–3.34(m,2H),3.28–3.17(m,3H),2.37–2.33(m,1H),1.93–1.84(m,2H),1.83–1.72(m,4H),1.50–1.45(m,1H),1.31–1.28(m,1H),1.27–1.23(m,1H),1.05–1.01(m,3H).HRMS(ESI)C 28H 33Cl 2N 2O +([M+H] +)计算值：483.1964，实测值：483.1970。 Step 6: Following the method of step 7 in Example 26, INT-39 and INT-32 are used as raw materials for reductive amination reaction. The product I-41 (trans mixture) is purified and then salted with hydrogen chloride to prepare white solid I- 41 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 8.39 (d, J = 11.4 Hz, 1H), 8.00–7.92 (m, 3H), 7.91–7.87 (m, 1H), 7.63–7.56 (m, 2H) ,7.38(d,J=8.0Hz,1H),7.22–7.19(m,1H),7.07(d,J=7.8Hz,1H),3.62–3.58(m,1H),3.56–3.51(m,2H ), 3.41--3.34 (m, 2H), 3.28--3.17 (m, 3H), 2.37--2.33 (m, 1H), 1.93-1.84 (m, 2H), 1.83--1.72 (m, 4H), 1.50-1.45 (m,1H),1.31–1.28(m,1H),1.27–1.23(m,1H),1.05–1.01(m,3H).HRMS(ESI)C 28 H 33 Cl 2 N 2 O + ((M +H] + ) Calculated value: 483.1964, measured value: 483.1970.

实施例42：反式N-(4-(((2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-1H-吲哚-2-甲 酰胺(I-42)盐酸盐的制备Example 42: trans N-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1H-indole-2- Preparation of formamide (I-42) hydrochloride

Figure PCTCN2021076289-appb-000299
Figure PCTCN2021076289-appb-000299

仿照实施例26步骤7的方法，以INT-39与INT-33为原料进行还原胺化反应，产物I-42(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-42盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.60(d,J＝8.0Hz,1H),7.44(d,J＝8.2Hz,1H),7.37(d,J＝8.0Hz,1H),7.22(t,J＝7.6Hz,1H),7.17(td,J＝7.9,3.6Hz,1H),7.08–7.05(m,2H),7.02(d,J＝7.4Hz,1H),3.60–3.56(m,1H),3.51–3.46(m,2H),3.37–3.32(m,2H),3.26–3.15(m,3H),2.35–2.31(m,1H),1.89–1.70(m,6H),1.46–1.40(m,1H),1.27–1.24(m,1H),1.23–1.20(m,1H),1.03–0.99(m,3H).HRMS(ESI)C 26H 32Cl 2N 3O +([M+H] +)计算值：472.1917，实测值：472.1916。 Imitating the method of step 7 in Example 26, using INT-39 and INT-33 as raw materials for reductive amination reaction, the product I-42 (trans mixture) was purified and then salted with hydrogen chloride to prepare white solid I-42 hydrochloric acid Salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 7.60 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.22 ( t,J=7.6Hz,1H), 7.17(td,J=7.9,3.6Hz,1H), 7.08–7.05(m,2H), 7.02(d,J=7.4Hz,1H), 3.60–3.56(m ,1H),3.51–3.46(m,2H), 3.37–3.32(m,2H), 3.26–3.15(m,3H), 2.35–2.31(m,1H), 1.89–1.70(m,6H), 1.46 –1.40(m,1H),1.27–1.24(m,1H),1.23–1.20(m,1H),1.03–0.99(m,3H).HRMS(ESI)C 26 H 32 Cl 2 N 3 O + ( [M+H] + ) Calculated value: 472.1917, measured value: 472.1916.

实施例43：反式N-(4-(((2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-43)盐酸盐的制备Example 43: trans N-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2'-pyridine Yl)benzamide (I-43) hydrochloride

Figure PCTCN2021076289-appb-000300
Figure PCTCN2021076289-appb-000300

仿照实施例26步骤7的方法，以INT-39与INT-34为原料进行还原胺化反应，产物I-43(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-43盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ8.90–8.87(m,1H),8.72–8.67(m,1H),8.45–8.42(m,1H),8.16–8.11(m,2H),8.10–8.05(m,3H),7.40(d,J＝7.9Hz,1H),7.24(t,J＝7.9Hz,1H),7.12–7.09(m,1H),3.62–3.57(m,1H),3.52–3.47(m,2H),3.40–3.32(m,2H),3.28–3.18(m,3H),2.39–2.34(m,1H),1.91–1.84(m,2H),1.83–1.73(m,4H),1.51–1.45(m,1H),1.32–1.25(m,2H),1.06–1.01(m,3H).HRMS(ESI)C 29H 34Cl 2N 3O +([M+H] +)计算值：510.2073，实测值：510.2082。 Imitating the method of step 7 in Example 26, using INT-39 and INT-34 as raw materials for reductive amination reaction, the product I-43 (trans mixture) was purified and then salted with hydrogen chloride to prepare white solid I-43 hydrochloric acid Salt (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ 8.90--8.87 (m, 1H), 8.72--8.67 (m, 1H), 8.45--8.42 (m, 1H), 8.16--8.11 (m, 2H), 8.10-- 8.05(m,3H),7.40(d,J=7.9Hz,1H),7.24(t,J=7.9Hz,1H),7.12–7.09(m,1H),3.62–3.57(m,1H),3.52 --3.47(m,2H), 3.40–3.32(m,2H), 3.28–3.18(m,3H), 2.39–2.34(m,1H), 1.91–1.84(m,2H), 1.83–1.73(m, 4H),1.51–1.45(m,1H),1.32–1.25(m,2H),1.06–1.01(m,3H).HRMS(ESI)C 29 H 34 Cl 2 N 3 O + ([M+H] + )Calculated value: 510.2073, measured value: 510.2082.

实施例44：反式7-(4-(((2-(2,3-二氯苯基)环丙基)甲基)氨基)丁氧)-3,4-二氢-2(1H)-喹啉酮(I-44)盐酸盐的制备Example 44: trans 7-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)amino)butoxy)-3,4-dihydro-2(1H) -Preparation of Quinolinone (I-44) Hydrochloride

Figure PCTCN2021076289-appb-000301
Figure PCTCN2021076289-appb-000301

步骤1：将原料3,4-二氢-7-羟基-2(1H)-喹啉酮(2.20g，13.48mmol)溶于N,N-二甲基甲酰胺(20mL)，加入碳酸钾(1.86g，13.48mmol)和1,4-二溴丁烷(8.73g，40.45mmol)，室温下反应24小时。加入水，乙酸乙酯萃取，饱和食盐水洗涤，浓缩，剩余物用快速柱层析分离纯化(0–3％甲醇/二氯甲烷)，得白色固体化合物INT-40(3.09g，收率79％)。 1H NMR(500MHz,CDCl 3)δ8.54(s,1H),7.04(d,J＝8.3Hz,1H),6.51(dd,J＝8.2,2.1Hz,1H),6.35(d,J＝2.1Hz,1H),3.96(t,J＝6.0Hz,2H),3.48(t,J＝6.6Hz,2H),2.90(t,J＝7.5Hz,2H),2.65–2.59(m,2H),2.09–2.02(m,2H),1.96–1.89(m,2H).HRMS(ESI)C 13H 17NO 2Br +([M+H] +)计算值：298.0437，实测值：298.0436。 Step 1: Dissolve the raw material 3,4-dihydro-7-hydroxy-2(1H)-quinolinone (2.20g, 13.48mmol) in N,N-dimethylformamide (20mL), add potassium carbonate ( 1.86g, 13.48mmol) and 1,4-dibromobutane (8.73g, 40.45mmol), react at room temperature for 24 hours. Water was added, extracted with ethyl acetate, washed with saturated brine, and concentrated. The residue was separated and purified by flash column chromatography (0-3% methanol/dichloromethane) to obtain a white solid compound INT-40 (3.09g, yield 79 %). 1 H NMR(500MHz,CDCl 3 )δ8.54(s,1H), 7.04(d,J=8.3Hz,1H), 6.51(dd,J=8.2,2.1Hz,1H), 6.35(d,J= 2.1Hz, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.48 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.65-2.59 (m, 2H) ,2.09-2.02(m,2H),1.96-1.89(m,2H).HRMS(ESI) C 13 H 17 NO 2 Br + ([M+H] + ) calculated value: 298.0437, measured value: 298.0436.

步骤2：将原料邻苯二甲酰亚胺(2.29g，15.54mmol)溶于N,N-二甲基甲酰胺(20mL)，加入碳酸钾(2.86g，20.73mmol)和INT-40(3.09g，10.36mmol)，加热至80℃反应过夜。加入水，乙酸乙酯萃取，饱和食盐水洗涤，浓缩，剩余物用快速柱层析分离纯化(0–3％甲醇/二氯甲烷)，得白色固体化合物INT-41(3.36g，收率89％)。 1H NMR(800MHz,CDCl 3)δ7.84(dd,J＝5.4,3.1Hz,2H),7.71(dd,J＝5.5,3.0Hz,2H),7.02(d,J＝8.3Hz,1H),6.50(dd,J＝8.3,2.4Hz,1H),6.33(d,J＝2.4Hz,1H),3.97(t,J＝6.2Hz,2H),3.76(t,J＝7.0Hz,2H),2.88(t,J＝7.5Hz,2H),2.62–2.59(m,3H),1.90–1.85(m,2H),1.84–1.79(m,2H).HRMS(ESI)C 21H 21N 2O 4 +([M+H] +)计算值：365.1496，实测值：365.1500. Step 2: Dissolve the raw material phthalimide (2.29g, 15.54mmol) in N,N-dimethylformamide (20mL), add potassium carbonate (2.86g, 20.73mmol) and INT-40 (3.09 g, 10.36mmol), heated to 80°C and reacted overnight. Water was added, extracted with ethyl acetate, washed with saturated brine, and concentrated. The residue was separated and purified by flash column chromatography (0-3% methanol/dichloromethane) to obtain a white solid compound INT-41 (3.36g, yield 89 %). 1 H NMR(800MHz, CDCl 3 )δ7.84(dd,J=5.4,3.1Hz,2H), 7.71(dd,J=5.5,3.0Hz,2H), 7.02(d,J=8.3Hz,1H) ,6.50(dd,J=8.3,2.4Hz,1H), 6.33(d,J=2.4Hz,1H), 3.97(t,J=6.2Hz,2H), 3.76(t,J=7.0Hz,2H) ,2.88(t,J=7.5Hz,2H),2.62–2.59(m,3H),1.90–1.85(m,2H),1.84–1.79(m,2H).HRMS(ESI)C 21 H 21 N 2 O 4 + ([M+H] + ) Calculated value: 365.1496, measured value: 365.1500.

步骤3：将INT-41(2.25g，6.17mmol)溶于甲醇(20mL)和二氯甲烷(5mL)，加入水合肼(773mg，15.44mmol)，加热至回流，反应过夜。将溶剂减压蒸除，剩余物用快速柱层析分离纯化(0–15％甲醇/二氯甲烷)得白色固体INT-42(1.3g，收率90％)。 1H NMR(800MHz,DMSO-d 6)δ9.96(s,1H),7.03(d,J＝8.2Hz,1H),6.47(dd,J＝8.2,2.5Hz,1H),6.42(d,J＝2.5Hz,1H),3.87(t,J＝6.5Hz,2H),2.79–2.75(m,3H),2.56(t,J＝7.0Hz,2H),2.44–2.36(m,2H),1.73–1.66(m,2H),1.49–1.40(m,2H).HRMS(ESI)C 13H 19N 2O 2 +([M+H] +)计算值：235.1441，实测值：235.1448。 Step 3: Dissolve INT-41 (2.25 g, 6.17 mmol) in methanol (20 mL) and dichloromethane (5 mL), add hydrazine hydrate (773 mg, 15.44 mmol), heat to reflux, and react overnight. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-15% methanol/dichloromethane) to obtain white solid INT-42 (1.3g, yield 90%). 1 H NMR(800MHz,DMSO-d 6 )δ9.96(s,1H), 7.03(d,J=8.2Hz,1H), 6.47(dd,J=8.2,2.5Hz,1H), 6.42(d, J=2.5Hz,1H), 3.87(t,J=6.5Hz,2H), 2.79–2.75(m,3H), 2.56(t,J=7.0Hz,2H), 2.44–2.36(m,2H), 1.73–1.66(m,2H),1.49–1.40(m,2H).HRMS(ESI) C 13 H 19 N 2 O 2 + ([M+H] + ) calculated value: 235.1441, measured value: 235.1448.

步骤4：仿照实施例26步骤7所述的方法，以INT-42和INT-39为原料进行还原胺化反应得I-44(反式混合物)，纯化之后与氯化氢成盐，制备得到I-44盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.40(dd,J＝8.0,1.4Hz,1H),7.22(t,J＝7.9Hz,1H),7.09(dd,J＝7.8,1.5Hz,1H),7.06(d,J＝8.3Hz,1H),6.55(dd,J＝8.3,2.5Hz,1H),6.45(d,J＝2.5Hz,1H),4.01(t,J＝5.7Hz,2H),3.38(dd,J＝13.0,6.4Hz,1H),3.16(t,J＝7.7Hz,2H), 3.04(dd,J＝13.0,8.4Hz,1H),2.87(t,J＝7.5Hz,2H),2.55–2.51(m,3H),2.32–2.27(m,1H),1.96–1.86(m,4H),1.45–1.40(m,1H),1.22–1.16(m,2H).HRMS(ESI)C 23H 27Cl 2N 2O 2 +([M+H] +)计算值：433.1444，实测值：433.1438。 Step 4: Following the method described in step 7 of Example 26, INT-42 and INT-39 are used as raw materials to carry out reductive amination reaction to obtain I-44 (trans mixture). After purification, it is salted with hydrogen chloride to prepare I- 44 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ7.40 (dd, J = 8.0, 1.4 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.09 (dd, J = 7.8, 1.5 Hz, 1H ), 7.06 (d, J = 8.3 Hz, 1H), 6.55 (dd, J = 8.3, 2.5 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 4.01 (t, J = 5.7 Hz, 2H ), 3.38 (dd, J = 13.0, 6.4 Hz, 1H), 3.16 (t, J = 7.7 Hz, 2H), 3.04 (dd, J = 13.0, 8.4 Hz, 1H), 2.87 (t, J = 7.5 Hz ,2H),2.55–2.51(m,3H),2.32–2.27(m,1H),1.96–1.86(m,4H),1.45–1.40(m,1H),1.22–1.16(m,2H).HRMS (ESI) Calculated value for C 23 H 27 Cl 2 N 2 O 2 + ([M+H] + ): 433.1444, measured value: 433.1438.

实施例45：反式7-(4-(((2-(2,3-二氯苯基)环丙基)甲基)(甲基)氨基)丁氧基)-3,4-二氢-2(1H)-喹啉酮(I-45)盐酸盐的制备Example 45: trans 7-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)(methyl)amino)butoxy)-3,4-dihydro Preparation of -2(1H)-quinolinone (I-45) hydrochloride

Figure PCTCN2021076289-appb-000302
Figure PCTCN2021076289-appb-000302

仿照实施例2的方法，以I-44和37％甲醛水溶液为原料进行还原胺化反应，产物I-45(反式混合物)与HCl成盐，得I-45盐酸盐(反式混合物，白色固体)。 1H NMR(800MHz,CD 3OD)δ7.41–7.38(m,1H),7.24–7.19(m,1H),7.10–7.02(m,2H),6.57–6.50(m,1H),6.48–6.43(m,1H),4.07–3.95(m,2H),3.64–3.48(m,1H),3.43–3.36(m,1H),3.26–3.11(m,2H),2.97(s,3H),2.88–2.84(m,2H),2.56–2.52(m,2H),2.38–2.31(m,1H),2.04–1.92(m,2H),1.90–1.83(m,2H),1.51–1.45(m,1H),1.27–1.21(m,2H).HRMS(ESI)C 24H 29Cl 2N 2O 2 +([M+H] +)计算值：447.1601，实测值：447.1594。 Following the method of Example 2, using I-44 and 37% aqueous formaldehyde solution as raw materials for reductive amination reaction, the product I-45 (trans mixture) was salted with HCl to obtain I-45 hydrochloride (trans mixture, White solid). 1 H NMR(800MHz, CD 3 OD) δ7.41--7.38(m,1H), 7.24-7.19(m,1H), 7.10-7.02(m,2H), 6.57-6.50(m,1H), 6.48- 6.43(m,1H),4.07–3.95(m,2H), 3.64–3.48(m,1H), 3.43–3.36(m,1H), 3.26–3.11(m,2H), 2.97(s,3H), 2.88–2.84(m,2H),2.56–2.52(m,2H),2.38–2.31(m,1H),2.04–1.92(m,2H),1.90–1.83(m,2H),1.51–1.45(m , 1H), 1.27-1.21 (m, 2H). HRMS (ESI) C 24 H 29 Cl 2 N 2 O 2 + ([M+H] + ) calculated value: 447.1601, measured value: 447.1594.

实施例46：反式7-(4-(((2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨基)丁氧基)-3,4-二氢-2(1H)-喹啉酮(I-46)盐酸盐的制备Example 46: trans 7-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butoxy)-3,4-dihydro Preparation of -2(1H)-quinolinone (I-46) hydrochloride

Figure PCTCN2021076289-appb-000303
Figure PCTCN2021076289-appb-000303

仿照实施例2的方法，以I-44和丙醛为原料制备化合物I-46(反式混合物)，并与HCl成盐，得I-46盐酸盐(反式混合物，白色固体)。 1H NMR(800MHz,CD 3OD)δ7.42–7.37(m,1H),7.24–7.19(m,1H),7.08–7.02(m,2H),6.56–6.50(m,1H),6.46–6.41(m,1H),4.06–3.97(m,2H),3.61–3.54(m,1H),3.41–3.32(m,2H),3.24–3.18(m,3H),2.88–2.83(m,2H),2.56–2.50(m,2H),2.37–2.32(m,1H),2.00–1.92(m,2H),1.91–1.84(m,2H),1.83–1.73(m,2H),1.47–1.42(m,1H),1.28–1.20(m,2H),1.06–0.99(m,3H).HRMS(ESI)C 26H 33Cl 2N 2O 2 +([M+H] +)计算值：475.1914，实测值：475.1912。 Following the method of Example 2, compound 1-46 (trans mixture) was prepared from I-44 and propionaldehyde, and salt was formed with HCl to obtain 1-46 hydrochloride (trans mixture, white solid). 1 H NMR (800MHz, CD 3 OD) δ7.42--7.37 (m, 1H), 7.24--7.19 (m, 1H), 7.08-7.02 (m, 2H), 6.56--6.50 (m, 1H), 6.46- 6.41(m,1H),4.06–3.97(m,2H),3.61–3.54(m,1H),3.41–3.32(m,2H), 3.24–3.18(m,3H), 2.88–2.83(m,2H) ), 2.56–2.50(m, 2H), 2.37–2.32(m, 1H), 2.00–1.92(m, 2H), 1.91–1.84(m, 2H), 1.83–1.73(m, 2H), 1.47–1.42 (m,1H),1.28–1.20(m,2H),1.06–0.99(m,3H).HRMS(ESI)C 26 H 33 Cl 2 N 2 O 2 + ([M+H] + ) Calculated value: 475.1914, measured value: 475.1912.

实施例47：反式7-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)氨基)丁氧基)-3,4-二氢-2(1H)-喹啉酮(I-47)盐酸盐的制备Example 47: trans 7-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)amino)butoxy)-3,4-dihydro-2 Preparation of (1H)-quinolinone (I-47) hydrochloride

Figure PCTCN2021076289-appb-000304
Figure PCTCN2021076289-appb-000304

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以5-氟-2-甲氧基苯甲醛为原料制备中间体INT-43(反式混合物)。Step 1: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, 5-fluoro-2-methoxybenzaldehyde is used as a raw material to prepare intermediate INT-43 (trans mixture).

步骤2：仿照实施例26步骤7的方法，以INT-43和INT-42为原料进行还原胺化反应，产物I-47(反式混合物)纯化后与氯化氢成盐，制备得到白色固体I-47盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.06(d,J＝8.3Hz,1H),6.92–6.87(m,2H),6.71(dd,J＝9.4,2.9Hz,1H),6.54(dd,J＝8.3,2.5Hz,1H),6.45(d,J＝2.5Hz,1H),4.01(t,J＝5.7Hz,2H),3.85(s,2H),3.21–3.12(m,3H),3.08–3.03(m,1H),2.89–2.85(m,2H),2.57–2.49(m,2H),2.22–2.17(m,1H),1.96–1.85(m,4H),1.31–1.23(m,1H),1.19–1.14(m,1H),1.06–1.01(m,1H).HRMS(ESI)C 24H 30FN 2O 3 +([M+H] +)计算值：413.2235，实测值：413.2231。 Step 2: Following the method of step 7 in Example 26, using INT-43 and INT-42 as raw materials for reductive amination reaction, the product I-47 (trans mixture) was purified and then salted with hydrogen chloride to prepare a white solid I- 47 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ7.06 (d, J = 8.3 Hz, 1H), 6.92-6.87 (m, 2H), 6.71 (dd, J = 9.4, 2.9 Hz, 1H), 6.54 (dd ,J=8.3,2.5Hz,1H),6.45(d,J=2.5Hz,1H),4.01(t,J=5.7Hz,2H),3.85(s,2H),3.21-3.12(m,3H) ,3.08–3.03(m,1H), 2.89–2.85(m,2H), 2.57–2.49(m,2H), 2.22–2.17(m,1H), 1.96–1.85(m,4H), 1.31–1.23( m,1H),1.19–1.14(m,1H),1.06–1.01(m,1H).HRMS(ESI)C 24 H 30 FN 2 O 3 + ([M+H] + ) Calculated value: 413.2235, measured Value: 413.2231.

实施例48：7-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)(甲基)氨基)丁氧基)-3,4-二氢-2(1H)-喹啉酮(I-48)盐酸盐的制备Example 48: 7-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(methyl)amino)butoxy)-3,4-dihydro Preparation of -2(1H)-quinolinone (I-48) hydrochloride

Figure PCTCN2021076289-appb-000305
Figure PCTCN2021076289-appb-000305

仿照实施例2的方法，以I-47和甲醛为原料进行还原胺化反应，产物I-48(反式混合物)纯化后与氯化氢成盐，得白色固体I-48盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.05(dd,J＝8.3,4.4Hz,1H),6.92–6.86(m,2H),6.69(dt,J＝9.4,2.9Hz,1H),6.53(td,J＝8.4,2.5Hz,1H),6.44(dd,J＝4.7,2.5Hz,1H),4.03–3.99(m,2H),3.84(s,2H),3.84(s,2H),3.44–3.34(m,2H),3.28(d,J＝7.2Hz,1H),3.25–3.19(m,1H),2.97(d,J＝3.8Hz,3H),2.86(t,J＝7.6Hz,2H),2.57–2.51(m,2H),2.32–2.26(m,1H),2.02–1.90(m,2H),1.89–1.83(m,2H),1.37–1.28(m,1H),1.25–1.20(m,1H),1.09–1.02(m,1H).HRMS(ESI)C 25H 32FN 2O 3 +([M+H] +)计算值：427.2391，实测值：427.2389。 Following the method of Example 2, the reductive amination reaction was carried out with I-47 and formaldehyde as raw materials. The product I-48 (trans mixture) was purified and then salted with hydrogen chloride to obtain white solid I-48 hydrochloride (trans mixture) ). 1 H NMR (800MHz, CD 3 OD) δ7.05 (dd, J = 8.3, 4.4 Hz, 1H), 6.92-6.86 (m, 2H), 6.69 (dt, J = 9.4, 2.9 Hz, 1H), 6.53 (td,J=8.4,2.5Hz,1H),6.44(dd,J=4.7,2.5Hz,1H),4.03-3.99(m,2H),3.84(s,2H),3.84(s,2H), 3.44–3.34(m,2H), 3.28(d,J=7.2Hz,1H), 3.25–3.19(m,1H), 2.97(d,J=3.8Hz,3H), 2.86(t,J=7.6Hz , 2H), 2.57--2.51 (m, 2H), 2.32 - 2.26 (m, 1H), 2.02 - 1.90 (m, 2H), 1.89 - 1.83 (m, 2H), 1.37 - 1.28 (m, 1H), 1.25 -1.20 (m, 1H), 1.09-1.02 (m, 1H). HRMS (ESI) C 25 H 32 FN 2 O 3 + ([M+H] + ) Calculated value: 427.2391, measured value: 427.2389.

实施例49：7-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)(丙基)氨基)丁氧基)-3,4-二氢-2(1H)-喹啉酮(I-49)盐酸盐的制备Example 49: 7-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butoxy)-3,4-dihydro Preparation of -2(1H)-quinolinone (I-49) hydrochloride

Figure PCTCN2021076289-appb-000306
Figure PCTCN2021076289-appb-000306

仿照实施例2的方法，以I-47和丙醛为原料进行还原胺化反应，产物I-49(反式混合物)与氯化氢成盐，得I-49盐酸盐(反式混合物，白色固体)。 1H NMR(800MHz,CD 3OD)δ7.05(dd,J＝8.3,5.3Hz,1H),6.92–6.86(m,2H),6.67(td,J＝9.9,3.0Hz,1H),6.54–6.50(m,1H),6.43(dd,J＝8.1,2.5Hz,1H),4.04–3.96(m,2H),3.84(d,J＝3.1Hz,3H),3.41–3.32(m,3H),3.27–3.16(m,3H),2.88–2.84(m,2H),2.55–2.50(m,2H),2.33–2.27(m,1H),1.99–1.90(m,2H),1.89–1.83(m,2H),1.82–1.72(m,2H),1.35–1.28(m,1H),1.24– 1.19(m,1H),1.08–1.05(m,1H),1.04–1.00(m,3H).HRMS(ESI)C 27H 36FN 2O 3 +([M+H] +)计算值：455.2704，实测值：455.2697。 Imitating the method of Example 2, using I-47 and propionaldehyde as raw materials for reductive amination reaction, the product I-49 (trans mixture) is salted with hydrogen chloride to obtain I-49 hydrochloride (trans mixture, white solid ). 1 H NMR (800MHz, CD 3 OD) δ7.05 (dd, J = 8.3, 5.3 Hz, 1H), 6.92-6.86 (m, 2H), 6.67 (td, J = 9.9, 3.0 Hz, 1H), 6.54 –6.50(m,1H),6.43(dd,J=8.1,2.5Hz,1H),4.04-3.96(m,2H),3.84(d,J=3.1Hz,3H),3.41-3.32(m,3H ), 3.27–3.16(m,3H), 2.88–2.84(m,2H), 2.55–2.50(m,2H), 2.33–2.27(m,1H), 1.99–1.90(m,2H), 1.89–1.83 (m,2H),1.82–1.72(m,2H), 1.35–1.28(m,1H), 1.24– 1.19(m,1H), 1.08–1.05(m,1H), 1.04–1.00(m,3H) .HRMS (ESI) C 27 H 36 FN 2 O 3 + ([M+H] + ) calculated value: 455.2704, measured value: 455.2697.

实施例50：反式7-(4-(((2-(2-甲氧基苯基)环丙基)甲基)胺基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(I-50)的制备Example 50: trans 7-(4-(((2-(2-methoxyphenyl)cyclopropyl)methyl)amino)butoxy)-3,4-dihydroquinoline-2 (1H) Preparation of ketone (I-50)

Figure PCTCN2021076289-appb-000307
Figure PCTCN2021076289-appb-000307

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以2-甲氧基苯甲醛为原料制备中间体INT-44(反式混合物)。HRMS(ESI)C 11H 13O 2 +[M+H] +计算值：177.0910，实测值：177.0911。 Step 1: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-44 (trans mixture) was prepared with 2-methoxybenzaldehyde as a raw material. HRMS(ESI) C 11 H 13 O 2 + [M+H] + Calculated value: 177.0910, measured value: 177.0911.

步骤2：将INT-44(155mg,0.88mmol)溶于甲醇(10mL)后，依次加入INT-42(218mg,0.94mmol)，氰基硼氢钠(87mg,1.32mmol)，室温反应12小时。反应完毕后过滤，减压蒸除溶剂，残余物用硅胶柱层析分离纯化(1:10甲醇/二氯甲烷)，得到淡黄色固体I-50(反式混合物，130mg，收率35％)。 1H NMR(800MHz,CD 3OD)δ7.18(td,J＝8.2,1.6Hz,1H),7.06(d,J＝8.3Hz,1H),6.95(dd,J＝7.5,1.3Hz,1H),6.93(d,J＝8.1Hz,1H),6.88–6.84(m,1H),6.55(dd,J＝8.3,2.5Hz,1H),6.45(d,J＝2.5Hz,1H),4.01(t,J＝5.5Hz,2H),3.86(s,3H),3.22–3.16(m,1H),3.16–3.09(m,2H),2.89–2.83(m,1H),2.90–2.83(m,2H),2.56–2.48(m,2H),2.17–2.08(m,1H),1.95–1.83(m,4H),1.24–1.14(m,2H),1.01–0.97(m,1H).HRMS(ESI)C 24H 31N 2O 3 +[M+H] +计算值：395.2329，实测值：395.2322。 Step 2: After INT-44 (155 mg, 0.88 mmol) was dissolved in methanol (10 mL), INT-42 (218 mg, 0.94 mmol) and sodium cyanoborohydride (87 mg, 1.32 mmol) were added in sequence, and reacted at room temperature for 12 hours. After the reaction was completed, it was filtered and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (1:10 methanol/dichloromethane) to obtain a pale yellow solid I-50 (trans mixture, 130 mg, yield 35%) . 1 H NMR (800MHz, CD 3 OD) δ7.18 (td, J = 8.2, 1.6 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.95 (dd, J = 7.5, 1.3 Hz, 1H ), 6.93 (d, J = 8.1 Hz, 1H), 6.88-6.84 (m, 1H), 6.55 (dd, J = 8.3, 2.5 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 4.01 (t,J=5.5Hz,2H),3.86(s,3H),3.22–3.16(m,1H), 3.16–3.09(m,2H), 2.89–2.83(m,1H), 2.90–2.83(m ,2H),2.56–2.48(m,2H),2.17–2.08(m,1H),1.95–1.83(m,4H),1.24–1.14(m,2H),1.01–0.97(m,1H).HRMS (ESI) C 24 H 31 N 2 O 3 + [M+H] + Calculated value: 395.2329, measured value: 395.2322.

实施例51：反式7-(4-(((2-(2-甲氧基苯基)环丙基)甲基)胺基)丁氧基)喹啉-2(1H)-酮(化合物I-51)的制备Example 51: trans 7-(4-(((2-(2-methoxyphenyl)cyclopropyl)methyl)amino)butoxy)quinoline-2(1H)-one (compound I-51) Preparation

Figure PCTCN2021076289-appb-000308
Figure PCTCN2021076289-appb-000308

仿照实施例50步骤2的方法，以INT-44和7-(4-氨基丁氧基)-2-喹啉酮(INT-45，参考文献WO2018172463所述方法进行制备)为原料进行还原胺化反应，制备得到化合物I-51(反式混合物)，淡黄色固体。 1H NMR(800MHz,CD 3OD)δ7.88(d,J＝9.4Hz,1H),7.57(d,J＝8.7Hz,1H),7.17–7.14(m,1H),6.95–6.90(m,2H),6.88–6.82(m,3H),6.44(d,J＝9.4Hz,1H),4.14(t,J＝5.5Hz,2H),3.86(s,3H),3.19–3.02(m,3H),2.99–2.90(m,1H),2.16–2.08(m,1H),1.97–1.90(m,4H),1.24–1.17(m,1H),1.15–1.11(m,1H),0.99–0.94 (m,1H).HRMS(ESI)C 24H 29N 2O 3 +[M+H] +计算值：393.2173，实测值：393.2168。 Imitating the method of step 2 in Example 50, using INT-44 and 7-(4-aminobutoxy)-2-quinolinone (INT-45, prepared by the method described in reference WO2018172463) as raw materials for reductive amination After reaction, compound I-51 (trans mixture) was prepared as a pale yellow solid. 1 H NMR (800MHz, CD 3 OD) δ 7.88 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.17-7.14 (m, 1H), 6.95-6.90 (m , 2H), 6.88–6.82 (m, 3H), 6.44 (d, J = 9.4 Hz, 1H), 4.14 (t, J = 5.5 Hz, 2H), 3.86 (s, 3H), 3.19–3.02 (m, 3H), 2.99–2.90(m,1H), 2.16–2.08(m,1H), 1.97–1.90(m,4H), 1.24–1.17(m,1H), 1.15–1.11(m,1H), 0.99– 0.94 (m, 1H). HRMS (ESI) C 24 H 29 N 2 O 3 + [M+H] + Calculated value: 393.2173, measured value: 393.2168.

实施例52：反式4-(苯并[d]噻唑-5-基氧基)-N-((2-(2-甲氧基苯基)环丙基)甲基)丁基-1-胺(化合物I-52)的制备Example 52: trans 4-(benzo[d]thiazol-5-yloxy)-N-((2-(2-methoxyphenyl)cyclopropyl)methyl)butyl-1- Preparation of Amine (Compound I-52)

Figure PCTCN2021076289-appb-000309
Figure PCTCN2021076289-appb-000309

步骤1：将5-羟基苯并噻唑(CAS:7686-41-1,2.20g，14.55mmol)和1,4-二溴丁烷(8.70g，43.65mmol)溶于N,N-二甲基甲酰胺(40mL)后，加入碳酸钾(1.90g，14.55mmol)，室温反应12小时。反应完毕后加水(20mL)稀释，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，得到白色固体INT-46(3.0g，收率72％)。HRMS(ESI)C 11H 13BrNOS +[M+H] +计算值：285.9896，实测值：285.9897。 Step 1: Dissolve 5-hydroxybenzothiazole (CAS: 7686-41-1,2.20g, 14.55mmol) and 1,4-dibromobutane (8.70g, 43.65mmol) in N,N-dimethyl After formamide (40 mL), potassium carbonate (1.90 g, 14.55 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, it was diluted with water (20 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain white solid INT-46 (3.0 g, yield 72%). HRMS(ESI) C 11 H 13 BrNOS + [M+H] + Calculated value: 285.9896, measured value: 285.9897.

步骤2：将INT-46(3.0g，10.52mmol)和邻苯二甲酰亚胺(2.40g，15.80mmol)溶于N,N-二甲基甲酰胺(40mL)，加入碳酸钾(3.0g，21.04mmol)，加热至80℃反应12小时。反应完毕后加水(20mL)稀释，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残余物硅胶柱层析分离纯化(1:20甲醇/二氯甲烷)，得到白色固体INT-47(2.7g，收率72％)。 1H NMR(800MHz,CDCl 3)δ9.04(s,1H),7.84(dd,J＝5.4,3.0Hz,2H),7.79(d,J＝8.8Hz,1H),7.71(dd,J＝5.5,3.0Hz,2H),7.61(d,J＝2.3Hz,1H),7.10(dd,J＝8.8,2.3Hz,1H),4.10(t,J＝5.9Hz,2H),3.79(t,J＝6.8Hz,2H),1.99–1.81(m,4H).HRMS(ESI)C 19H 17N 2O 3S +[M+H] +计算值：353.0954，实测值：353.0955。 Step 2: Dissolve INT-46 (3.0g, 10.52mmol) and phthalimide (2.40g, 15.80mmol) in N,N-dimethylformamide (40mL), add potassium carbonate (3.0g , 21.04mmol), heated to 80°C and reacted for 12 hours. After the reaction is complete, it is diluted with water (20 mL), extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent is evaporated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (1:20 methanol/dichloromethane). A white solid INT-47 (2.7 g, yield 72%) was obtained. 1 H NMR(800MHz, CDCl 3 )δ9.04(s,1H), 7.84(dd,J=5.4,3.0Hz,2H), 7.79(d,J=8.8Hz,1H), 7.71(dd,J= 5.5,3.0Hz,2H), 7.61(d,J=2.3Hz,1H), 7.10(dd,J=8.8,2.3Hz,1H), 4.10(t,J=5.9Hz,2H), 3.79(t, J = 6.8 Hz, 2H), 1.99-1.81 (m, 4H). HRMS (ESI) C 19 H 17 N 2 O 3 S + [M+H] + calculated value: 353.0954, measured value: 353.0955.

步骤3：将INT-47(2.7g，7.57mmol)溶于甲醇(40mL)和二氯甲烷(10mL)，加入水合肼(1.0g，18.90mmol)，回流反应12小时。反应完毕后减压蒸除溶剂，残余物用硅胶柱层析分离纯化(1:10甲醇/二氯甲烷)，得到白色固体INT-48(1.5g，收率89％)。 1H NMR(800MHz,DMSO-d 6)δ9.35(s,1H),8.03(d,J＝8.8Hz,1H),7.63(d,J＝2.4Hz,1H),7.12–7.11(m,1H),4.11(t,J＝6.3Hz,2H),2.90–2.86(m,2H),1.77–1.68(m,,4H).HRMS(ESI)C 11H 15N 2OS +[M+H] +计算值：223.0900，实测值：223.0906。 Step 3: Dissolve INT-47 (2.7 g, 7.57 mmol) in methanol (40 mL) and dichloromethane (10 mL), add hydrazine hydrate (1.0 g, 18.90 mmol), and react under reflux for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (1:10 methanol/dichloromethane) to obtain white solid INT-48 (1.5 g, yield 89%). 1 H NMR(800MHz,DMSO-d 6 )δ9.35(s,1H), 8.03(d,J=8.8Hz,1H), 7.63(d,J=2.4Hz,1H), 7.12–7.11(m, 1H),4.11(t,J=6.3Hz,2H),2.90–2.86(m,2H),1.77–1.68(m,,4H).HRMS(ESI)C 11 H 15 N 2 OS + [M+H ] + Calculated value: 223.0900, measured value: 223.0906.

步骤4：仿照实施例50步骤2的方法，以INT-48和INT-44为原料进行还原胺化反应，制备得到化合物I-52(反式混合物)，淡黄色固体。 1H NMR(800MHz,CD 3OD)δ9.22(s,1H),7.92(d,J＝8.8Hz,1H),7.57(d,J＝2.4Hz,1H),7.18–7.15(m,1H),7.14(dd,J＝8.8,2.4Hz,1H),6.95(dd,J＝7.5,1.4Hz,1H),6.92(d,J＝8.2Hz,1H),6.87–6.84(m,1H),4.17(d,J＝5.2Hz,2H),3.86(s,3H),3.24–3.19(m,1H),3.19–3.14(m,2H),3.05–2.99(m,1H),2.19–2.11(m,1H),2.00–1.92(m,4H),1.25–1.19(m,1H),1.18–1.15(m,1H),1.05–0.94 (m,1H).HRMS(ESI)C 22H 27N 2O 2S +[M+H] +计算值：383.1788，实测值：383.1787。 Step 4: Following the method of step 2 in Example 50, INT-48 and INT-44 were used as raw materials to carry out reductive amination reaction to prepare compound I-52 (trans mixture) as a pale yellow solid. 1 H NMR(800MHz,CD 3 OD)δ9.22(s,1H),7.92(d,J=8.8Hz,1H), 7.57(d,J=2.4Hz,1H), 7.18–7.15(m,1H ), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.95 (dd, J = 7.5, 1.4 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.87–6.84 (m, 1H) ,4.17(d,J=5.2Hz,2H),3.86(s,3H),3.24–3.19(m,1H),3.19–3.14(m,2H),3.05–2.99(m,1H),2.19–2.11 (m,1H),2.00-1.92(m,4H),1.25-1.19(m,1H),1.18-1.15(m,1H),1.05-0.94 (m,1H).HRMS(ESI)C 22 H 27 N 2 O 2 S + [M+H] + Calculated value: 383.1788, measured value: 383.1787.

实施例53：反式7-(4-(((2-(2-甲硫基苯基)环丙基)甲基)氨基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(化合物I-53)的制备Example 53: trans 7-(4-(((2-(2-methylthiophenyl)cyclopropyl)methyl)amino)butoxy)-3,4-dihydroquinoline-2( Preparation of 1H)-ketone (Compound I-53)

Figure PCTCN2021076289-appb-000310
Figure PCTCN2021076289-appb-000310

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以2-甲基硫基苯甲醛为原料制备中间体INT-49(反式混合物)。Step 1: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-49 (trans mixture) was prepared with 2-methylthiobenzaldehyde as a raw material.

步骤2：仿照实施例50步骤2的方法，以INT-49和INT-42为原料进行还原胺化反应，制备得到化合物I-53(反式混合物)，淡黄色固体。 1H NMR(800MHz,CD 3OD)δ7.24–7.19(m,2H),7.09–7.02(m,3H),6.55(dd,J＝8.3,2.5Hz,1H),6.45(d,J＝2.5Hz,1H),4.01(t,J＝4.8Hz,2H),3.34–3.32(m,1H),3.13–3.05(m,2H),2.95–2.89(m,1H),2.89–2.83(m,2H),2.56–2.50(m,2H),2.48(s,3H),2.08–1.99(m,1H),1.93–1.82(m,4H),1.29–1.22(m,1H),1.17–1.13(m,1H),1.08–1.03(m,1H).HRMS(ESI)C 24H 31N 2O 2S +[M+H] +计算值：411.2101，实测值：411.2098。 Step 2: Following the method of step 2 in Example 50, INT-49 and INT-42 were used as raw materials to carry out reductive amination reaction to prepare compound I-53 (trans mixture) as a pale yellow solid. 1 H NMR(800MHz,CD 3 OD)δ7.24–7.19(m,2H), 7.09–7.02(m,3H), 6.55(dd,J=8.3,2.5Hz,1H), 6.45(d,J= 2.5Hz,1H),4.01(t,J=4.8Hz,2H), 3.34–3.32(m,1H), 3.13–3.05(m,2H), 2.95–2.89(m,1H), 2.89–2.83(m ,2H),2.56–2.50(m,2H),2.48(s,3H),2.08–1.99(m,1H),1.93-1.82(m,4H),1.29–1.22(m,1H),1.17–1.13 (m,1H),1.08–1.03(m,1H).HRMS(ESI)C 24 H 31 N 2 O 2 S + [M+H] + calculated value: 411.2101, measured value: 411.2098.

实施例54：反式7-(4-(((2-(2-(甲硫基)苯基)环丙基)甲基)胺基)丁氧基)喹啉-2(1H)-酮(I-54)的制备Example 54: trans 7-(4-(((2-(2-(methylthio)phenyl)cyclopropyl)methyl)amino)butoxy)quinolin-2(1H)-one (I-54) Preparation

Figure PCTCN2021076289-appb-000311
Figure PCTCN2021076289-appb-000311

按实施例50步骤2的方法，将INT-49与INT-45进行还原胺化反应，可制备化合物I-54(反式混合物)。 1H NMR(800MHz,CD 3OD)δ7.88(d,J＝9.4Hz,1H),7.57(d,J＝8.7Hz,1H),7.21(qd,J＝7.9,1.3Hz,2H),7.07(td,J＝7.4,1.6Hz,1H),7.03(d,J＝7.5Hz,1H),6.87(dd,J＝8.7,2.4Hz,1H),6.84(d,J＝2.3Hz,1H),6.46–6.41(m,1H),4.14(t,J＝5.6Hz,2H),3.35–3.33(m,1H),3.14–3.07(m,2H),2.97–2.90(m,1H),2.48(s,3H),2.07–2.02(m,1H),1.97–1.89(m,4H),1.28–1.23(m,1H),1.16–1.13(m,1H),1.08–1.04(m,1H)。HRMS(ESI)C 24H 31N 2O 3 +[M+H] +计算值：409.1944，实测值：409.1938。 According to the method of step 2 in Example 50, INT-49 and INT-45 were subjected to reductive amination reaction to prepare compound I-54 (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ7.88(d,J=9.4Hz,1H), 7.57(d,J=8.7Hz,1H), 7.21(qd,J=7.9,1.3Hz,2H), 7.07 (td, J = 7.4, 1.6 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.87 (dd, J = 8.7, 2.4 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H) ), 6.46–6.41(m,1H), 4.14(t,J=5.6Hz,2H), 3.35–3.33(m,1H), 3.14–3.07(m,2H), 2.97–2.90(m,1H), 2.48(s,3H),2.07-2.02(m,1H),1.97-1.89(m,4H),1.28-1.23(m,1H),1.16-1.13(m,1H),1.08-1.04(m,1H) ). HRMS(ESI) C 24 H 31 N 2 O 3 + [M+H] + Calculated value: 409.1944, measured value: 409.1938.

实施例55：反式4-(苯并[d]噻唑-5-基氧基)-N-((2-(2-(甲硫基)苯基)环丙基)甲基)丁基-1-胺(I-55)的制备Example 55: trans 4-(benzo[d]thiazol-5-yloxy)-N-((2-(2-(methylthio)phenyl)cyclopropyl)methyl)butyl- Preparation of 1-amine (I-55)

Figure PCTCN2021076289-appb-000312
Figure PCTCN2021076289-appb-000312

按实施例50步骤2的方法，将INT-49与INT-48进行还原胺化反应，可制备化合物I-55(反式混合物)。 1H NMR(800MHz,CD 3OD)δ9.22(s,1H),7.92(d,J＝8.8Hz,1H),7.57(d,J＝2.4Hz,1H),7.25–7.18(m,2H),7.14(dd,J＝8.8,2.4Hz,1H),7.07(td,J＝7.3,1.7Hz,1H),7.04(d,J＝7.4Hz,1H),4.16(t,J＝5.3Hz,2H),3.42–3.38(m,1H),3.18–3.14(m,2H),2.99–2.95(m,1H),2.48(s,3H),2.09–2.05(m,1H),1.98–1.93(m,4H),1.30–1.25(m,1H),1.18–1.14(m,1H),1.10–1.06(m,1H)。HRMS(ESI)C 22H 27N 2OS 2 +[M+H] +计算值：399.1559，实测值：399.1563。 According to the method of step 2 in Example 50, INT-49 and INT-48 were subjected to reductive amination reaction to prepare compound I-55 (trans mixture). 1 H NMR(800MHz,CD 3 OD)δ9.22(s,1H),7.92(d,J=8.8Hz,1H), 7.57(d,J=2.4Hz,1H), 7.25–7.18(m,2H ), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 7.07 (td, J = 7.3, 1.7 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 4.16 (t, J = 5.3 Hz ,2H),3.42–3.38(m,1H),3.18–3.14(m,2H),2.99–2.95(m,1H),2.48(s,3H),2.09–2.05(m,1H),1.98–1.93 (m,4H), 1.30–1.25(m,1H), 1.18–1.14(m,1H), 1.10–1.06(m,1H). HRMS(ESI) C 22 H 27 N 2 OS 2 + [M+H] + Calculated value: 399.1559, measured value: 399.1563.

实施例56：3-(4-(2-(((2-(2,3-二氯苯基)反式环丙基)甲基)氨基)反式环己基)-1,1-二甲基脲(I-56)的制备Example 56: 3-(4-(2-(((2-(2,3-Dichlorophenyl)transcyclopropyl)methyl)amino)transcyclohexyl)-1,1-dimethyl Preparation of urea (I-56)

Figure PCTCN2021076289-appb-000313
Figure PCTCN2021076289-appb-000313

步骤1：将INT-39(1.33g，6.18mmol)溶于甲醇(20mL)，加入硼氢化钠(350mg，9.28mmol)，室温下反应1小时。滴加4M盐酸水溶液将反应液pH调至中性，乙酸乙酯萃取，饱和食盐水洗涤，浓缩，剩余物用快速柱层析分离纯化(0–50％乙酸乙酯/石油醚)，得到无色油状物INT-50(反式混合物，1.12g，收率83％)。 1H NMR(800MHz,CDCl 3)δ7.27(dt,J＝8.0,1.3Hz,1H),7.08(t,J＝7.9Hz,1H),6.89(dd,J＝7.9,1.5Hz,1H),3.70–3.63(m,2H),2.21–2.14(m,1H),2.11–2.04(m,1H),1.37–1.29(m,1H),1.03–0.94(m,2H). Step 1: Dissolve INT-39 (1.33 g, 6.18 mmol) in methanol (20 mL), add sodium borohydride (350 mg, 9.28 mmol), and react at room temperature for 1 hour. 4M aqueous hydrochloric acid was added dropwise to adjust the pH of the reaction solution to neutral, extracted with ethyl acetate, washed with saturated brine, and concentrated. The residue was separated and purified by flash column chromatography (0-50% ethyl acetate/petroleum ether) to obtain no Color oil INT-50 (trans mixture, 1.12g, yield 83%). 1 H NMR (800MHz, CDCl 3 ) δ7.27 (dt, J = 8.0, 1.3 Hz, 1H), 7.08 (t, J = 7.9 Hz, 1H), 6.89 (dd, J = 7.9, 1.5 Hz, 1H) ,3.70-3.63(m,2H),2.21-2.14(m,1H),2.11-2.04(m,1H),1.37-1.29(m,1H),1.03-0.94(m,2H).

步骤2：将原料INT-50(930mg，4.28mmol)，邻苯二甲酰亚胺(945mg，6.43mmol)和三苯基膦(2.81g，10.71mmol)溶于干燥四氢呋喃(25mL)，缓慢滴加偶氮二甲酸二乙酯(1.87g，10.71mmol)，室温下反应4小时。将溶剂减压蒸除，剩余物用快速柱层析分离纯化(0–30％乙酸乙酯/石油醚)，得到白色固体INT-51(反式混合物，1.36g，收率92％)。 1H NMR(800MHz,CDCl 3)δ7.86(dd,J＝5.4,3.0Hz,2H),7.72(dd,J＝5.5,3.0Hz,2H),7.26–7.24(m,1H),7.06(t,J＝7.9Hz,1H),6.86–6.83(m,2H),3.78(d,J＝7.3Hz,2H),2.29–2.25(m,1H),1.56–1.50(m,1H),1.16–1.12(m,1H),1.05–1.00(m,1H). Step 2: Dissolve the raw materials INT-50 (930mg, 4.28mmol), phthalimide (945mg, 6.43mmol) and triphenylphosphine (2.81g, 10.71mmol) in dry tetrahydrofuran (25mL) and slowly drop them Add diethyl azodicarboxylate (1.87 g, 10.71 mmol), and react at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-30% ethyl acetate/petroleum ether) to obtain white solid INT-51 (trans mixture, 1.36 g, yield 92%). 1 H NMR (800MHz, CDCl 3 ) δ 7.86 (dd, J = 5.4, 3.0 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 7.26-7.24 (m, 1H), 7.06 ( t,J=7.9Hz,1H),6.86–6.83(m,2H),3.78(d,J=7.3Hz,2H),2.29–2.25(m,1H),1.56–1.50(m,1H),1.16 –1.12(m,1H),1.05–1.00(m,1H).

步骤3：将原料INT-51(0.9g，2.6mmol)溶于甲醇(15mL)，加入水合肼(260mg，5.2mmol)，加热至回流，反应4小时。将甲醇减压蒸除，加入水，乙酸乙酯萃取，饱和食盐水洗涤，无色硫酸钠干燥，过滤，浓缩得淡黄色油状物INT-52(反式混合物，526mg，收率94％)。按照实施例1步骤6中方法将其转换成其盐酸盐。H NMR HRMS(ESI)C 10H 12Cl 2N +([M+H] +)计算值：216.0341，实测值：216.0334。 Step 3: Dissolve the raw material INT-51 (0.9 g, 2.6 mmol) in methanol (15 mL), add hydrazine hydrate (260 mg, 5.2 mmol), heat to reflux, and react for 4 hours. The methanol was evaporated under reduced pressure, water was added, extracted with ethyl acetate, washed with saturated brine, dried with colorless sodium sulfate, filtered, and concentrated to obtain light yellow oil INT-52 (trans mixture, 526 mg, yield 94%). It was converted into its hydrochloride salt according to the method in step 6 of Example 1. H NMR HRMS (ESI) C 10 H 12 Cl 2 N + ([M+H] + ) calculated value: 216.0341, measured value: 216.0334.

步骤4：将原料(2-(2,3-二氯苯基)环丙基)甲胺盐酸盐(INT-52，160mg，0.634mmol)溶于四氢呋喃(15mL)，依次加入三乙胺(43mg，0.424mmol)和INT-53(90mg，0.424mmol)(参考文献J.Org.Chem.2015,80,1059-1069制备)，室温下反应1小时后，再加入NaHB(AcO) 3(180mg,0.848mmol)和乙酸(25mg，0.424mmol)，室温反应过夜。加入甲醇(5mL)并室温搅拌15分钟，溶液变澄清，将溶剂减压蒸除，剩余物用快速柱层析分离纯化(0–5％甲醇/二氯甲烷)，得到白色固体I-56(反式混合物，56mg，两步收率32％)。 1H NMR(800MHz,CD 3OD)δ7.41(dd,J＝8.0,1.5Hz,1H),7.24(t,J＝7.9Hz,1H),7.09(dd,J＝7.8,1.5Hz,1H),3.51–3.46(m,1H),3.35(dd,J＝13.0,6.4Hz,1H),3.12–3.07(m,2H),3.03(dd,J＝13.0,8.3Hz,1H),2.88(s,6H),2.32–2.28(m,1H),1.95–1.89(m,2H),1.86–1.79(m,2H),1.65–1.58(m,2H),1.44–1.40(m,1H),1.39–1.33(m,1H),1.32–1.26(m,2H),1.22–1.18(m,2H),1.14–1.07(m,2H).HRMS(ESI)C 21H 32Cl 2N 3O +([M+H] +)计算值：412.1917，实测值：412.1921。 Step 4: Dissolve the starting material (2-(2,3-dichlorophenyl)cyclopropyl)methylamine hydrochloride (INT-52, 160mg, 0.634mmol) in tetrahydrofuran (15mL), and add triethylamine ( 43mg, 0.424mmol) and INT-53 (90mg, 0.424mmol) (prepared by reference J.Org.Chem.2015, 80, 1059-1069). After reacting for 1 hour at room temperature, NaHB(AcO) 3 (180mg , 0.848mmol) and acetic acid (25mg, 0.424mmol), react overnight at room temperature. Methanol (5mL) was added and stirred at room temperature for 15 minutes. The solution became clear. The solvent was evaporated under reduced pressure. The residue was separated and purified by flash column chromatography (0–5% methanol/dichloromethane) to obtain a white solid I-56 ( Trans mixture, 56mg, two-step yield 32%). 1 H NMR (800MHz, CD 3 OD) δ7.41 (dd, J = 8.0, 1.5 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.09 (dd, J = 7.8, 1.5 Hz, 1H ), 3.51–3.46 (m, 1H), 3.35 (dd, J = 13.0, 6.4 Hz, 1H), 3.12–3.07 (m, 2H), 3.03 (dd, J = 13.0, 8.3 Hz, 1H), 2.88 ( s, 6H), 2.32–2.28 (m, 1H), 1.95–1.89 (m, 2H), 1.86–1.79 (m, 2H), 1.65–1.58 (m, 2H), 1.44–1.40 (m, 1H), 1.39–1.33(m,1H),1.32–1.26(m,2H),1.22–1.18(m,2H),1.14–1.07(m,2H).HRMS(ESI)C 21 H 32 Cl 2 N 3 O + ([M+H] + ) Calculated value: 412.1917, measured value: 412.1921.

实施例57：3-(4-(2-(((2-(2,3-二氯苯基)反式环丙基)甲基)(丙基)氨基)乙基)反式环己基)-1,1-二甲基脲(I-57)盐酸盐的制备Example 57: 3-(4-(2-(((2-(2,3-Dichlorophenyl)transcyclopropyl)methyl)(propyl)amino)ethyl)transcyclohexyl) Preparation of -1,1-dimethylurea (I-57) hydrochloride

Figure PCTCN2021076289-appb-000314
Figure PCTCN2021076289-appb-000314

步骤1：将中间体INT-39(2.3g，10.69mmol)溶于四氢呋喃(50mL)，依次加入丙胺(6.3g，106.9mmol)和乙酸(611μL，10.69mmol)，室温下反应15分钟。加入NaHB(AcO) 3(6.8g,32.08mmol)，室温反应3小时。将溶剂减压蒸除，剩余物用快速柱层析分离纯化(0–5％甲醇/二氯甲烷)，得到淡黄色固体化合物INT-54(反式混合物，1.94g，收率70％)。按照实施例1步骤6中方法将其转换成其盐酸盐。 1H NMR(800MHz,CD 3OD)δ7.38(dd,J＝8.0,1.5Hz,1H),7.22(t,J＝7.9Hz,1H),7.08–7.06(m,1H),3.24(dd,J＝12.9,6.4Hz,1H),2.96–2.92(m,3H),2.27–2.23(m,1H),1.75–1.68(m,2H),1.44–1.38(m,1H),1.17–1.11(m,2H),1.01(t,J＝7.4Hz,3H).HRMS(ESI)C 13H 18Cl 2N +([M+H] +)计算值：258.0811，实测值：258.0813。 Step 1: Intermediate INT-39 (2.3 g, 10.69 mmol) was dissolved in tetrahydrofuran (50 mL), propylamine (6.3 g, 106.9 mmol) and acetic acid (611 μL, 10.69 mmol) were added in sequence, and reacted at room temperature for 15 minutes. Add NaHB(AcO) 3 (6.8 g, 32.08 mmol) and react at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was separated and purified by flash column chromatography (0-5% methanol/dichloromethane) to obtain a pale yellow solid compound INT-54 (trans mixture, 1.94 g, yield 70%). It was converted into its hydrochloride salt according to the method in step 6 of Example 1. 1 H NMR (800MHz, CD 3 OD) δ 7.38 (dd, J = 8.0, 1.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.08–7.06 (m, 1H), 3.24 (dd ,J=12.9,6.4Hz,1H),2.96–2.92(m,3H),2.27–2.23(m,1H),1.75–1.68(m,2H),1.44–1.38(m,1H),1.17–1.11 (m, 2H), 1.01 (t, J=7.4 Hz, 3H). HRMS (ESI) C 13 H 18 Cl 2 N + ([M+H] + ) calculated value: 258.0811, measured value: 258.0813.

步骤2：仿照实施例56步骤4所描述的方法，以INT-54与INT-53为原料进行还原胺化反应得化合物I-57(反式混合物)，并将其与氯化氢反应，得I-57盐酸盐(反式混合 物)。 1H NMR(800MHz,CD 3OD)δ7.42–7.39(m,1H),7.25(t,J＝7.8Hz,1H),7.11–7.08(m,1H),3.56–3.47(m,2H),3.34–3.17(m,5H),2.94–2.89(m,6H),2.41–2.36(m,1H),1.95–1.87(m,2H),1.86–1.75(m,4H),1.72–1.63(m,2H),1.53–1.46(m,1H),1.40–1.23(m,5H),1.17–1.06(m,2H),1.05–1.00(m,3H).HRMS(ESI)C 24H 38Cl 2N 3O +([M+H] +)计算值：454.2386，实测值：454.2390。 Step 2: Following the method described in step 4 of Example 56, INT-54 and INT-53 are used as raw materials for reductive amination to obtain compound I-57 (trans mixture), which is then reacted with hydrogen chloride to obtain I- 57 Hydrochloride (trans mixture). 1 H NMR (800MHz, CD 3 OD) δ7.42–7.39(m,1H), 7.25(t,J=7.8Hz,1H), 7.11–7.08(m,1H), 3.56–3.47(m,2H) , 3.34–3.17(m,5H), 2.94–2.89(m,6H), 2.41–2.36(m,1H), 1.95–1.87(m,2H), 1.86–1.75(m,4H), 1.72–1.63( m,2H),1.53–1.46(m,1H),1.40–1.23(m,5H),1.17–1.06(m,2H),1.05–1.00(m,3H).HRMS(ESI)C 24 H 38 Cl 2 N 3 O + ([M+H] + ) Calculated value: 454.2386, measured value: 454.2390.

实施例58：3-(4-(2-(((2-(5-氟-2-甲氧基苯基)反式环丙基)甲基)胺基)乙基)反式环己基)-1,1-二甲基脲(I-58)盐酸盐的制备Example 58: 3-(4-(2-(((2-(5-fluoro-2-methoxyphenyl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl) Preparation of -1,1-dimethylurea (I-58) hydrochloride

Figure PCTCN2021076289-appb-000315
Figure PCTCN2021076289-appb-000315

仿照实施例56步骤4所述方法，以INT-6和INT-53为原料制备化合物I-58(反式混合物)，并与HCl反应制备I-58盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD-d 4)δ6.90–6.85(m,1H),6.85–6.80(m,1H),6.62(dd,J＝9.6,3.0Hz,1H),3.84(s,3H),3.52–3.44(m,1H),2.87(s,6H),2.78(dd,J＝11.7,6.4Hz,1H),2.72–2.63(m,2H),2.49(dd,J＝12.2,8.0Hz,1H),1.99–1.94(m,1H),1.92–1.85(m,2H),1.83–1.75(m,2H),1.49–1.41(m,2H),1.32–1.22(m,3H),1.16–1.10(m,1H),1.08–1.02(m,2H),1.01–0.95(m,1H),0.87–0.82(m,1H).HRMS(ESI)C 22H 35FN 3O 2 +([M+H] +)计算值：392.2708实测值：392.2718。 Following the method described in step 4 of Example 56, compound 1-58 (trans mixture) was prepared using INT-6 and INT-53 as raw materials, and reacted with HCl to prepare 1-58 hydrochloride (trans mixture). 1 H NMR(800MHz, CD 3 OD-d 4 )δ 6.90–6.85(m,1H), 6.85–6.80(m,1H), 6.62(dd,J=9.6,3.0Hz,1H), 3.84(s ,3H),3.52–3.44(m,1H), 2.87(s,6H), 2.78(dd,J=11.7,6.4Hz,1H), 2.72–2.63(m,2H), 2.49(dd,J=12.2 ,8.0Hz,1H),1.99–1.94(m,1H),1.92–1.85(m,2H),1.83–1.75(m,2H),1.49–1.41(m,2H),1.32–1.22(m,3H) ), 1.16–1.10(m,1H),1.08–1.02(m,2H),1.01–0.95(m,1H),0.87–0.82(m,1H).HRMS(ESI)C 22 H 35 FN 3 O 2 + ([M+H] + ) Calculated value: 392.2708 Observed value: 392.2718.

实施例59：3-(4-(2-(((2-(5-氟-2-甲氧苯基)反式环丙基)甲基)(丙基)氨基)乙基)反式环己基)-1,1-二甲基脲(I-59)盐酸盐Example 59: 3-(4-(2-(((2-(5-fluoro-2-methoxyphenyl)transcyclopropyl)methyl)(propyl)amino)ethyl)trans Hexyl)-1,1-dimethylurea (I-59) hydrochloride

Figure PCTCN2021076289-appb-000316
Figure PCTCN2021076289-appb-000316

仿照实施例56步骤4所述方法，以INT-19和INT-53为原料制备化合物I-59(反式混合物)并与HCl反应制备I-59盐酸盐(反式混合物)。 1H NMR(800MHz,CD 3OD)δ6.95–6.92(m,1H),6.90–6.87(m,1H),6.72–6.68(m,1H),3.86(d,J＝3.7Hz,3H),3.52–3.45(m,1H),3.42–3.33(m,1H),3.29–3.16(m,5H),2.90(s,3H),2.90(s,3H),2.36–2.30(m,1H),1.95–1.86(m,2H),1.84–1.73(m,4H),1.70–1.58(m,2H),1.38–1.27(m,4H),1.23–1.19(m,1H),1.15–1.06(m,3H),1.04–1.00(m,3H).HRMS(ESI)C 25H 41FN 3O 2 +([M+H] +)计算值：434.3177，实测值：434.3181。 Following the method described in step 4 of Example 56, compound 1-59 (trans mixture) was prepared using INT-19 and INT-53 as raw materials and reacted with HCl to prepare 1-59 hydrochloride (trans mixture). 1 H NMR(800MHz, CD 3 OD)δ 6.95–6.92(m,1H), 6.90–6.87(m,1H), 6.72–6.68(m,1H), 3.86(d,J=3.7Hz,3H) ,3.52–3.45(m,1H),3.42–3.33(m,1H), 3.29–3.16(m,5H), 2.90(s,3H), 2.90(s,3H), 2.36-2.30(m,1H) ,1.95–1.86(m,2H),1.84–1.73(m,4H),1.70–1.58(m,2H),1.38–1.27(m,4H),1.23–1.19(m,1H),1.15–1.06( m,3H),1.04–1.00(m,3H).HRMS(ESI)C 25 H 41 FN 3 O 2 + ([M+H] + ) Calculated value: 434.3177, measured value: 434.3181.

实施例60：3-(4-(2-(((2-(苯并[b][1,4]二氧六环-5-基)反式环丙基)甲基)胺基)乙基)反式环己基)-1,1-二甲基脲(I-60)盐酸盐的制备Example 60: 3-(4-(2-(((2-(Benzo[b][1,4]dioxane-5-yl)transcyclopropyl)methyl)amino)ethyl (Base) trans-cyclohexyl)-1,1-dimethylurea (I-60) hydrochloride

Figure PCTCN2021076289-appb-000317
Figure PCTCN2021076289-appb-000317

步骤1：将2,3-二羟基苯甲醛(2.49g，18mmol)溶于DMF(100mL)，加入1,2-二溴乙烷(13.53g，72mmol)和碳酸钾(9.95g，72mmol)，70℃下搅拌过夜。加入1.2N盐酸水溶液(100mL)并用乙酸乙酯萃取三次，饱和食盐水洗涤，浓缩，剩余物用硅胶柱层析分离纯化(乙酸乙酯/石油醚＝1/8)，得到无色油状物INT-55(2.69g，收率91％)。 1H NMR(800MHz,CDCl 3)δ10.36(s,1H),7.38–7.37(m,1H),7.10–7.07(m,1H),6.91–6.88(m,1H),4.39–4.37(m,2H),4.33–4.31(m,2H). Step 1: Dissolve 2,3-dihydroxybenzaldehyde (2.49g, 18mmol) in DMF (100mL), add 1,2-dibromoethane (13.53g, 72mmol) and potassium carbonate (9.95g, 72mmol), Stir overnight at 70°C. A 1.2N aqueous hydrochloric acid solution (100 mL) was added and extracted three times with ethyl acetate, washed with saturated brine, concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/8) to obtain a colorless oil INT -55 (2.69g, yield 91%). 1 H NMR(800MHz, CDCl 3 )δ10.36(s,1H), 7.38--7.37(m,1H), 7.10-7.07(m,1H), 6.91-6.88(m,1H), 4.39-4.37(m ,2H),4.33-4.31(m,2H).

步骤2：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以中间体INT-55为原料制备中间体INT-56(反式混合物)。Step 2: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-55 is used as a raw material to prepare intermediate INT-56 (trans mixture).

步骤3：仿照实施例56步骤1～步骤3的方法，以中间体INT-56为原料制备得到中间体INT-57。Step 3: Following the steps 1 to 3 of Example 56, the intermediate INT-56 was used as a raw material to prepare the intermediate INT-57.

步骤4：仿照实施例50步骤2的方法，以INT-53和INT-57为原料进行还原胺化反应，制备得到化合物I-60，淡黄色固体(收率39％)。 1H NMR(800MHz,CD 3OD-d 4)δ6.70–6.66(m,1H),6.64–6.61(m,1H),6.44–6.42(m,1H),4.30–4.27(m,2H),4.23–4.20(m,2H),3.50–3.44(m,1H),2.86(s,6H),2.82(dd,J＝12.4,6.1Hz,1H),2.75–2.68(m,2H),2.53(dd,J＝12.4,7.9Hz,1H),1.93–1.86(m,3H),1.82–1.77(m,2H),1.50–1.42(m,2H),1.30–1.22(m,3H),1.18–1.13(m,1H),1.09–1.02(m,2H),1.00–0.96(m,1H),0.84–0.79(m,1H).HRMS(ESI)C 23H 36N 3O 3 +([M+H] +)计算值：402.2751实测值：402.2747。 Step 4: Following the method of step 2 of Example 50, using INT-53 and INT-57 as raw materials for reductive amination reaction, compound I-60 was prepared as a pale yellow solid (yield 39%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 6.70-6.66 (m, 1H), 6.64-6.61 (m, 1H), 6.44-6.42 (m, 1H), 4.30-4.27 (m, 2H) ,4.23–4.20(m,2H), 3.50–3.44(m,1H), 2.86(s,6H), 2.82(dd,J=12.4,6.1Hz,1H), 2.75–2.68(m,2H), 2.53 (dd,J=12.4,7.9Hz,1H),1.93–1.86(m,3H),1.82–1.77(m,2H),1.50–1.42(m,2H),1.30–1.22(m,3H),1.18 –1.13(m,1H),1.09–1.02(m,2H),1.00–0.96(m,1H),0.84–0.79(m,1H).HRMS(ESI)C 23 H 36 N 3 O 3 + ([ M+H] + ) Calculated value: 402.2751 Actual measured value: 402.2747.

实施例61：3-(4-(2-(((2-(萘-1-基)反式环丙基)甲基)胺基)乙基)反式环己基)-1,1-二甲基脲(I-61)的制备Example 61: 3-(4-(2-(((2-(naphthalene-1-yl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl)-1,1-di Preparation of methylurea (I-61)

Figure PCTCN2021076289-appb-000318
Figure PCTCN2021076289-appb-000318

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以中间体1-萘甲醛为原料制备中间体INT-58。Step 1: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-58 is prepared with intermediate 1-naphthaldehyde as a raw material.

步骤2：仿照实施例56步骤1～步骤3的方法，以中间体INT-58为原料制备得到中间体INT-59。Step 2: Following the steps 1 to 3 of Example 56, the intermediate INT-59 was prepared by using the intermediate INT-58 as a raw material.

步骤3：仿照实施例50步骤2的方法，以INT-53和INT-59为原料进行还原胺化反应，制备得到化合物I-61，淡黄色固体(收率44％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.33(d,J＝8.4Hz,1H),7.84(d,J＝8.1Hz,1H),7.69(d,J＝8.2Hz,1H),7.55–7.52(m,1H),7.50–7.45(m,1H),7.36(t,J＝7.6Hz,1H),7.26(d,J＝7.1Hz,1H),3.50–3.43(m,1H),2.99(dd,J＝12.5,6.5Hz,1H),2.86(s,6H),2.81–2.74(m,3H),2.33–2.28(m,1H),1.90–1.84(m,2H),1.81–1.75(m,2H),1.52–1.46(m,2H),1.44–1.38(m,1H),1.30–1.22(m,3H),1.08–0.98(m,4H).HRMS(ESI)C 25H 36N 3O +([M+H] +)计算值：394.2853，实测值：394.2847。 Step 3: Following the method of step 2 in Example 50, using INT-53 and INT-59 as raw materials for reductive amination reaction, compound I-61 was prepared as a pale yellow solid (yield 44%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ8.33(d,J=8.4Hz,1H), 7.84(d,J=8.1Hz,1H), 7.69(d,J=8.2Hz,1H) ,7.55–7.52(m,1H),7.50–7.45(m,1H),7.36(t,J=7.6Hz,1H),7.26(d,J=7.1Hz,1H),3.50–3.43(m,1H ), 2.99(dd,J=12.5,6.5Hz,1H), 2.86(s,6H), 2.81–2.74(m,3H),2.33–2.28(m,1H),1.90–1.84(m,2H), 1.81–1.75(m,2H), 1.52–1.46(m,2H), 1.44–1.38(m,1H), 1.30–1.22(m,3H), 1.08–0.98(m,4H).HRMS(ESI)C 25 H 36 N 3 O + ([M+H] + ) Calculated value: 394.2853, measured value: 394.2847.

实施例62：3-(4-(2-(((2-(2-甲氧基苯基)反式环丙基)甲基)胺基)乙基)反式环己基)-1,1-二甲基脲(I-62)的制备Example 62: 3-(4-(2-(((2-(2-methoxyphenyl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl)-1,1 -Preparation of dimethylurea (I-62)

Figure PCTCN2021076289-appb-000319
Figure PCTCN2021076289-appb-000319

步骤1：仿照实施例56步骤1～步骤3的方法，以中间体INT-44为原料制备得到中间体INT-60。Step 1: Imitating the method of step 1 to step 3 in Example 56, the intermediate INT-44 was used as the raw material to prepare the intermediate INT-60.

步骤2：仿照实施例50步骤2的方法，以INT-53和INT-60为原料进行还原胺化反应，制备得到化合物I-62，淡黄色固体(收率34％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.05–7.01(m,1H),6.82–6.77(m,2H),6.73(td,J＝7.4,0.8Hz,1H),3.75(s,3H),3.41–3.33(m,1H),2.77(s,6H),2.74(dd,J＝12.3,5.9Hz,1H),2.66–2.58(m,2H),2.43(dd,J＝12.3,8.0Hz,1H),1.88–1.82(m,1H),1.81–1.78(m,2H),1.72–1.66(m,2H),1.41–1.33(m,2H), 1.21–1.13(m,3H),1.03–0.99(m,1H),0.99–0.92(m,2H),0.92–0.88(m,1H),0.75–0.68(m,1H).HRMS(ESI)C 22H 36N 3O 2 +([M+H] +)计算值：374.2802，实测值：374.2803。 Step 2: Following the method of Step 2 in Example 50, using INT-53 and INT-60 as raw materials for reductive amination reaction, compound I-62 was prepared as a pale yellow solid (yield 34%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ7.05–7.01(m,1H), 6.82–6.77(m,2H), 6.73(td,J=7.4,0.8Hz,1H), 3.75(s ,3H),3.41–3.33(m,1H),2.77(s,6H), 2.74(dd,J=12.3,5.9Hz,1H),2.66-2.58(m,2H),2.43(dd,J=12.3 ,8.0Hz,1H),1.88–1.82(m,1H),1.81–1.78(m,2H),1.72–1.66(m,2H),1.41–1.33(m,2H), 1.21–1.13(m,3H) ),1.03-0.99(m,1H),0.99-0.92(m,2H),0.92-0.88(m,1H),0.75-0.68(m,1H).HRMS(ESI)C 22 H 36 N 3 O 2 + ([M+H] + ) Calculated value: 374.2802, measured value: 374.2803.

实施例63：3-(4-(2-(((2-(5-氯-2-甲氧基苯基)反式环丙基)甲基)胺基)乙基)反式环己基)-1,1-二甲基脲(I-63)的制备Example 63: 3-(4-(2-(((2-(5-chloro-2-methoxyphenyl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl) Preparation of -1,1-dimethylurea (I-63)

Figure PCTCN2021076289-appb-000320
Figure PCTCN2021076289-appb-000320

仿照实施例50步骤2的方法，以INT-15和INT-53为原料进行还原胺化反应，制备得到化合物I-63，淡黄色固体(收率37％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.03(dd,J＝8.7,2.6Hz,1H),6.80(d,J＝8.7Hz,1H),6.78(d,J＝2.6Hz,1H),3.76(s,3H),3.41–3.36(m,1H),2.78(s,6H),2.76(dd,J＝12.4,6.2Hz,1H),2.69–2.61(m,2H),2.49(dd,J＝12.4,7.9Hz,1H),1.90–1.86(m,1H),1.82–1.79(m,2H),1.73–1.68(m,2H),1.43–1.35(m,2H),1.22–1.14(m,3H),1.09–1.04(m,1H),1.01–0.94(m,2H),0.93–0.90(m,1H),0.80–0.76(m,1H).HRMS(ESI)C 22H 35ClN 3O 2 +([M+H] +)计算值：408.2412实测值：408.2413。 Imitating the method of step 2 in Example 50, using INT-15 and INT-53 as raw materials to carry out reductive amination reaction to prepare compound I-63 as a pale yellow solid (yield 37%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ7.03(dd,J=8.7,2.6Hz,1H), 6.80(d,J=8.7Hz,1H), 6.78(d,J=2.6Hz, 1H), 3.76(s, 3H), 3.41–3.36(m, 1H), 2.78(s, 6H), 2.76(dd, J = 12.4, 6.2Hz, 1H), 2.69–2.61(m, 2H), 2.49 (dd,J=12.4,7.9Hz,1H),1.90–1.86(m,1H),1.82–1.79(m,2H),1.73–1.68(m,2H),1.43–1.35(m,2H),1.22 –1.14(m,3H),1.09–1.04(m,1H),1.01–0.94(m,2H),0.93–0.90(m,1H),0.80–0.76(m,1H).HRMS(ESI)C 22 H 35 ClN 3 O 2 + ([M+H] + ) Calculated value: 408.2412 Observed value: 408.2413.

实施例64：反式7-(4-(((2-(2,3-二氯苯基)环丙基)甲基)胺基)丁氧基)喹啉-2(1H)-酮(化合物I-64)的制备Example 64: trans 7-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)amino)butoxy)quinoline-2(1H)-one( Compound I-64) Preparation

Figure PCTCN2021076289-appb-000321
Figure PCTCN2021076289-appb-000321

仿照实施例50步骤2的方法，以INT-39和INT-45为原料进行还原胺化反应，制备得到化合物I-64，白色固体(收率58％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.44–8.28(m,1H),7.88–7.79(m,1H),7.40(d,J＝8.0Hz,1H),7.24(t,J＝7.9Hz,1H),7.18–7.04(m,3H),6.91–6.77(m,1H),4.27–4.21(m,2H),3.41(dd,J＝13.0,6.4Hz,1H),3.25–3.17(m,2H),3.09(dd,J＝12.7,8.6Hz,1H),2.35–2.29(m,1H),2.06–1.96(m,4H),1.53–1.43(m,1H),1.26–1.22(m,1H),1.22–1.18(m,1H).HRMS(ESI)C 23H 25Cl 2N 2O 2 +([M+H] +)计算值：431.1288，实测值：431.1287。 Following the method of step 2 in Example 50, using INT-39 and INT-45 as raw materials for reductive amination reaction, compound I-64 was prepared as a white solid (yield 58%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ8.44-8.28(m,1H),7.88-7.79(m,1H),7.40(d,J=8.0Hz,1H), 7.24(t,J =7.9Hz,1H), 7.18–7.04(m,3H), 6.91–6.77(m,1H), 4.27–4.21(m,2H), 3.41(dd,J=13.0,6.4Hz,1H), 3.25– 3.17(m,2H), 3.09(dd,J=12.7,8.6Hz,1H), 2.35–2.29(m,1H), 2.06–1.96(m,4H), 1.53–1.43(m,1H), 1.26– 1.22 (m, 1H), 1.22-1.18 (m, 1H). HRMS (ESI) C 23 H 25 Cl 2 N 2 O 2 + ([M+H] + ) calculated value: 431.1288, measured value: 431.1287.

实施例65：反式7-(4-(((2-(苯并[b][1,4]二氧六环-5-基)环丙基)甲基)胺基)丁氧基)喹啉-2(1H)-酮(化合物I-65)的制备Example 65: trans 7-(4-(((2-(benzo[b][1,4]dioxane-5-yl)cyclopropyl)methyl)amino)butoxy) Preparation of Quinolin-2(1H)-one (Compound I-65)

Figure PCTCN2021076289-appb-000322
Figure PCTCN2021076289-appb-000322

仿照实施例50步骤2的方法，以INT-45和INT-56为原料进行还原胺化反应，制备得到化合物I-65，白色固体(收率38％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.23(d,J＝9.2Hz,1H),7.75(d,J＝8.8Hz,1H),7.05(dd,J＝8.8,2.3Hz,1H),7.03–7.00(m,1H),6.73(d,J＝9.2Hz,1H),6.70(t,J＝7.8Hz,1H),6.67–6.63(m,1H),6.50(dd,J＝7.5,0.8Hz,1H),4.33–4.27(m,2H),4.25–4.16(m,4H),3.24–3.14(m,3H),3.06(dd,J＝12.9,8.0Hz,1H),2.15–2.11(m,1H),2.03–1.90(m,4H),1.35–1.26(m,1H),1.17–1.11(m,1H),1.05–0.99(m,1H).HRMS(ESI)C 25H 29N 2O 4 +([M+H] +)计算值：421.2122，实测值：421.2128。 Imitating the method of step 2 of Example 50, using INT-45 and INT-56 as raw materials for reductive amination reaction to prepare compound I-65 as a white solid (yield 38%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 8.23 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 8.8, 2.3 Hz, 1H), 7.03–7.00(m,1H), 6.73(d,J=9.2Hz,1H), 6.70(t,J=7.8Hz,1H), 6.67–6.63(m,1H), 6.50(dd,J ＝7.5,0.8Hz,1H),4.33-4.27(m,2H),4.25-4.16(m,4H),3.24-3.14(m,3H),3.06(dd,J＝12.9,8.0Hz,1H), 2.15–2.11(m,1H), 2.03–1.90(m,4H), 1.35–1.26(m,1H), 1.17–1.11(m,1H), 1.05–0.99(m,1H).HRMS(ESI)C 25 H 29 N 2 O 4 + ([M+H] + ) Calculated value: 421.2122, measured value: 421.2128.

实施例66：反式7-(4-(((2-(萘-1-基)环丙基)甲基)胺基)丁氧基)喹啉-2(1H)-酮(化合物I-66)的制备Example 66: trans 7-(4-(((2-(naphthalene-1-yl)cyclopropyl)methyl)amino)butoxy)quinolin-2(1H)-one (Compound I- 66) Preparation

Figure PCTCN2021076289-appb-000323
Figure PCTCN2021076289-appb-000323

仿照实施例50步骤2的方法，以INT-45和INT-58为原料进行还原胺化反应，制备得到化合物I-66，白色固体(收率42％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.32–8.28(m,2H),7.84(d,J＝8.1Hz,1H),7.76(d,J＝8.8Hz,1H),7.71(d,J＝8.2Hz,1H),7.58–7.54(m,1H),7.49(t,J＝7.2Hz,1H),7.37(t,J＝7.6Hz,1H),7.30(d,J＝7.0Hz,1H),7.08(dd,J＝8.8,2.2Hz,1H),7.04(d,J＝2.0Hz,1H),6.80(d,J＝9.2Hz,1H),4.20(t,J＝5.2Hz,2H),3.50–3.43(m,1H),3.24(t,J＝7.0Hz,2H),3.20(dd,J＝12.9,8.2Hz,1H),2.59–2.50(m,1H),2.03–1.96(m,4H),1.66–1.54(m,1H),1.30–1.26(m,1H),1.16–1.08(m,1H).HRMS(ESI)C 27H 29N 2O 2 +([M+H] +)计算值：413.2224，实测值：413.2228。 Following the method of step 2 of Example 50, using INT-45 and INT-58 as raw materials for reductive amination reaction, compound I-66 was prepared as a white solid (yield 42%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ8.32-8.28 (m, 2H), 7.84 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.71 ( d,J=8.2Hz,1H),7.58–7.54(m,1H),7.49(t,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),7.30(d,J=7.0 Hz, 1H), 7.08 (dd, J = 8.8, 2.2 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 9.2 Hz, 1H), 4.20 (t, J = 5.2 Hz, 2H), 3.50–3.43 (m, 1H), 3.24 (t, J = 7.0 Hz, 2H), 3.20 (dd, J = 12.9, 8.2 Hz, 1H), 2.59–2.50 (m, 1H), 2.03 –1.96(m,4H),1.66–1.54(m,1H),1.30–1.26(m,1H),1.16–1.08(m,1H).HRMS(ESI)C 27 H 29 N 2 O 2 + ([ M+H] + ) Calculated value: 413.2224, measured value: 413.2228.

实施例67：反式7-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)胺基)丁氧基)喹啉-2(1H)-酮(化合物I-67)的制备Example 67: trans 7-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)amino)butoxy)quinoline-2(1H)- Preparation of Ketone (Compound I-67)

Figure PCTCN2021076289-appb-000324
Figure PCTCN2021076289-appb-000324

仿照实施例50步骤2的方法，以INT-43和INT-45为原料进行还原胺化反应，制备得到化合物I-67，浅黄色固体(收率39％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.93–7.86 (m,1H),7.59–7.54(m,1H),6.91–6.80(m,4H),6.66–6.62(m,1H),6.47–6.43(m,1H),4.11(t,J＝5.9Hz,2H),3.84(s,3H),2.88–2.83(m,1H),2.82–2.75(m,2H),2.59(dd,J＝12.2,7.9Hz,1H),2.02–1.97(m,1H),1.92–1.87(m,2H),1.82–1.73(m,2H),1.21–1.14(m,1H),1.04–0.98(m,1H),0.92–0.84(m,1H).HRMS(ESI)C 24H 28FN 2O 3 +([M+H] +)计算值：411.2078，实测值：411.2079。 Imitating the method of step 2 in Example 50, using INT-43 and INT-45 as raw materials for reductive amination reaction to prepare compound I-67 as a light yellow solid (yield 39%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 7.93-7.86 (m, 1H), 7.59-7.54 (m, 1H), 6.91-6.80 (m, 4H), 6.66-6.62 (m, 1H) ,6.47–6.43(m,1H), 4.11(t,J=5.9Hz,2H), 3.84(s,3H), 2.88–2.83(m,1H), 2.82–2.75(m,2H), 2.59(dd ,J=12.2,7.9Hz,1H),2.02–1.97(m,1H),1.92–1.87(m,2H),1.82–1.73(m,2H),1.21–1.14(m,1H),1.04–0.98 (m, 1H), 0.92-0.84 (m, 1H). HRMS (ESI) C 24 H 28 FN 2 O 3 + ([M+H] + ) calculated value: 411.2078, measured value: 411.2079.

实施例68：反式7-(4-(((2-(5--氯-2-甲氧苯基)环丙基)甲基)胺基)丁氧基)喹啉-2(1H)-酮(化合物I-68)的制备Example 68: trans 7-(4-(((2-(5--chloro-2-methoxyphenyl)cyclopropyl)methyl)amino)butoxy)quinoline-2(1H) -Preparation of Ketone (Compound I-68)

Figure PCTCN2021076289-appb-000325
Figure PCTCN2021076289-appb-000325

步骤1：仿照实施例26以3-氟苯甲醛制备中间体INT-31的方法，以中间体5-氯-2-甲氧基苯甲醛为原料制备中间体INT-61(反式混合物)。Step 1: Following the method of Example 26 to prepare intermediate INT-31 with 3-fluorobenzaldehyde, intermediate INT-61 (trans mixture) was prepared with intermediate 5-chloro-2-methoxybenzaldehyde as a raw material.

步骤2：仿照实施例50步骤2的方法，以INT-45和INT-61为原料进行还原胺化反应，制备得到化合物I-68，白色固体(收率28％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.20(d,J＝9.2Hz,1H),7.74(d,J＝8.8Hz,1H),7.16–7.11(m,1H),7.04(dd,J＝8.8,2.2Hz,1H),7.03–6.99(m,1H),6.94(d,J＝2.5Hz,1H),6.91–6.88(m,1H),6.71(d,J＝9.2Hz,1H),4.19(s,2H),3.86(s,3H),3.23–3.13(m,3H),3.12–3.02(m,1H),2.21–2.12(m,1H),2.01–1.92(m,4H),1.34–1.27(m,1H),1.17–1.13(m,1H),1.08–1.03(m,1H).HRMS(ESI)C 24H 28ClN 2O 3 +([M+H] +)计算值：427.1783，实测值：427.1787。 Step 2: Following the method of step 2 in Example 50, using INT-45 and INT-61 as raw materials for reductive amination reaction, compound I-68 was prepared as a white solid (yield 28%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 8.20 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.16-7.11 (m, 1H), 7.04 ( dd,J=8.8,2.2Hz,1H), 7.03–6.99(m,1H), 6.94(d,J=2.5Hz,1H), 6.91–6.88(m,1H), 6.71(d,J=9.2Hz ,1H),4.19(s,2H),3.86(s,3H),3.23-3.13(m,3H),3.12-3.02(m,1H),2.21-2.12(m,1H),2.01-1.92(m ,4H),1.34–1.27(m,1H),1.17–1.13(m,1H),1.08–1.03(m,1H).HRMS(ESI)C 24 H 28 ClN 2 O 3 + ([M+H] + ) Calculated value: 427.1783, measured value: 427.1787.

实施例69：反式7-(4-(((2-(苯并[b][1,4]二氧六环-5-基)环丙基)甲基)氨基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(化合物I-69)的制备Example 69: trans 7-(4-(((2-(benzo[b][1,4]dioxan-5-yl)cyclopropyl)methyl)amino)butoxy)- Preparation of 3,4-dihydroquinoline-2(1H)-one (Compound I-69)

Figure PCTCN2021076289-appb-000326
Figure PCTCN2021076289-appb-000326

仿照实施例50步骤2的方法，以INT-42和INT-56为原料进行还原胺化反应，制备得到化合物I-69，浅黄色固体(收率52％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.06(d,J＝8.3Hz,1H),6.73–6.69(m,1H),6.69–6.65(m,1H),6.54(dd,J＝8.3,2.5Hz,1H),6.50(dd,J＝7.5,1.4Hz,1H),6.45(d,J＝2.5Hz,1H),4.30–4.27(m,2H),4.24–4.18(m,2H),4.01(t,J＝5.7Hz,2H),3.23–3.18(m,1H),3.19–3.12(m,2H),3.06–3.00(m,1H),2.89–2.83(m,2H),2.55–2.50(m,2H),2.15–2.09(m,1H),1.96–1.84(m,4H),1.31–1.25(m,1H),1.16–1.12(m,1H),1.04–0.97(m,1H).HRMS(ESI)C 25H 31N 2O 4 +([M+H] +)计算值：423.2278， 实测值：423.2281。 Imitating the method of step 2 in Example 50, using INT-42 and INT-56 as raw materials to carry out reductive amination reaction to prepare compound I-69 as a light yellow solid (yield 52%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ7.06(d,J=8.3Hz,1H), 6.73–6.69(m,1H), 6.69–6.65(m,1H), 6.54(dd,J =8.3,2.5Hz,1H),6.50(dd,J=7.5,1.4Hz,1H),6.45(d,J=2.5Hz,1H), 4.30–4.27(m,2H), 4.24–4.18(m, 2H),4.01(t,J=5.7Hz,2H), 3.23–3.18(m,1H), 3.19–3.12(m,2H),3.06–3.00(m,1H), 2.89–2.83(m,2H) ,2.55–2.50(m,2H),2.15–2.09(m,1H),1.96–1.84(m,4H),1.31–1.25(m,1H),1.16–1.12(m,1H),1.04–0.97( m,1H).HRMS(ESI) C 25 H 31 N 2 O 4 + ([M+H] + ) Calculated value: 423.2278, measured value: 423.2281.

实施例70：反式7-(4-(((2-(萘-1-基)环丙基)甲基)氨基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(化合物I-70)的制备Example 70: trans 7-(4-(((2-(naphthalene-1-yl)cyclopropyl)methyl)amino)butoxy)-3,4-dihydroquinoline-2(1H) -Preparation of Ketone (Compound I-70)

Figure PCTCN2021076289-appb-000327
Figure PCTCN2021076289-appb-000327

仿照实施例50步骤2的方法，以INT-42和INT-58为原料进行还原胺化反应，制备得到化合物I-70，浅黄色固体(收率57％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.30(d,J＝8.4Hz,1H),7.87(d,J＝8.1Hz,1H),7.74(d,J＝8.2Hz,1H),7.56(t,J＝7.2Hz,1H),7.50(t,J＝7.3Hz,1H),7.38(t,J＝7.6Hz,1H),7.29(d,J＝7.0Hz,1H),7.04(d,J＝8.3Hz,1H),6.53(dd,J＝8.3,2.4Hz,1H),6.45(d,J＝2.3Hz,1H),4.01(t,J＝5.8Hz,2H),3.47(dd,J＝12.9,6.5Hz,1H),3.20(t,J＝7.9Hz,2H),3.15(dd,J＝12.9,8.4Hz,1H),2.85(t,J＝7.5Hz,2H),2.55–2.48(m,3H),1.99–1.92(m,2H),1.93–1.85(m,2H),1.60–1.53(m,1H),1.30–1.23(m,1H),1.18–1.11(m,1H).HRMS(ESI)C 27H 31N 2O 2 +([M+H] +)计算值：415.2380，实测值：415.2384。 Imitating the method of step 2 in Example 50, using INT-42 and INT-58 as raw materials to carry out reductive amination reaction to prepare compound I-70 as a pale yellow solid (yield 57%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ8.30(d,J=8.4Hz,1H), 7.87(d,J=8.1Hz,1H), 7.74(d,J=8.2Hz,1H) ,7.56(t,J=7.2Hz,1H),7.50(t,J=7.3Hz,1H),7.38(t,J=7.6Hz,1H),7.29(d,J=7.0Hz,1H),7.04 (d,J=8.3Hz,1H),6.53(dd,J=8.3,2.4Hz,1H),6.45(d,J=2.3Hz,1H),4.01(t,J=5.8Hz,2H),3.47 (dd,J=12.9,6.5Hz,1H), 3.20(t,J=7.9Hz,2H), 3.15(dd,J=12.9,8.4Hz,1H), 2.85(t,J=7.5Hz,2H) ,2.55–2.48(m,3H),1.99–1.92(m,2H),1.93–1.85(m,2H),1.60–1.53(m,1H),1.30–1.23(m,1H),1.18–1.11( m,1H).HRMS(ESI) C 27 H 31 N 2 O 2 + ([M+H] + ) Calculated value: 415.2380, measured value: 415.2384.

实施例71：反式7-(4-(((2-(5-氯-2-甲氧苯基)环丙基)甲基)氨基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(化合物I-71)的制备Example 71: trans 7-(4-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)amino)butoxy)-3,4-dihydroquinoline Preparation of -2(1H)-one (Compound I-71)

Figure PCTCN2021076289-appb-000328
Figure PCTCN2021076289-appb-000328

仿照实施例50步骤2的方法，以INT-42和INT-61为原料进行还原胺化反应，制备得到化合物I-71，浅黄色固体(收率53％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.18(dd,J＝8.7,2.6Hz,1H),7.08(d,J＝8.3Hz,1H),6.96(d,J＝2.6Hz,1H),6.94(d,J＝8.7Hz,1H),6.56(dd,J＝8.3,2.5Hz,1H),6.47(d,J＝2.4Hz,1H),4.03(t,J＝5.7Hz,2H),3.88(s,3H),3.23–3.13(m,3H),3.10–3.05(m,1H),2.91–2.86(m,2H),2.59–2.53(m,2H),2.20–2.16(m,1H),1.98–1.88(m,4H),1.32–1.28(m,1H),1.20–1.16(m,1H),1.09–1.03(m,1H).HRMS(ESI)C 24H 30ClN 2O 3 +([M+H] +)计算值：429.1939，实测值：429.1941。 Following the method of step 2 in Example 50, using INT-42 and INT-61 as raw materials for reductive amination reaction, compound I-71 was prepared as a light yellow solid (yield 53%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ7.18(dd,J=8.7,2.6Hz,1H), 7.08(d,J=8.3Hz,1H), 6.96(d,J=2.6Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.56 (dd, J = 8.3, 2.5 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.03 (t, J = 5.7 Hz, 2H), 3.88(s, 3H), 3.23–3.13(m,3H), 3.10–3.05(m,1H), 2.91–2.86(m,2H), 2.59–2.53(m,2H), 2.20–2.16( m,1H),1.98–1.88(m,4H),1.32–1.28(m,1H),1.20–1.16(m,1H),1.09–1.03(m,1H).HRMS(ESI)C 24 H 30 ClN 2 O 3 + ([M+H] + ) Calculated value: 429.1939, measured value: 429.1941.

实施例72：反式4-(苯并[d]噻唑-5-基氧基)-N-((2-(苯并[b][1,4]二氧六环-5-基)环丙基)甲基)丁基-1-胺(I-72)的制备Example 72: trans 4-(benzo[d]thiazol-5-yloxy)-N-((2-(benzo[b][1,4]dioxane-5-yl) ring (Propyl) methyl) butyl-1-amine (I-72) preparation

Figure PCTCN2021076289-appb-000329
Figure PCTCN2021076289-appb-000329

仿照实施例50步骤2的方法，以INT-48和INT-56为原料进行还原胺化反应，制备得到化合物I-72，棕色固体(收率24％)。 1H NMR(800MHz,CD 3OD-d 4)δ9.50(s,1H),8.02–7.96(m,1H),7.59(d,J＝2.4Hz,1H),7.20(dd,J＝8.9,2.4Hz,1H),6.73–6.68(m,1H),6.68–6.64(m,1H),6.50(dd,J＝7.6,1.3Hz,1H),4.29(t,J＝4.1Hz,2H),4.22–4.19(m,2H),4.20–4.16(m,2H),3.24–3.14(m,3H),3.07–3.02(m,1H),2.17–2.08(m,1H),2.00–1.93(m,4H),1.34–1.26(m,1H),1.15–1.12(m,1H),1.06–0.99(m,1H).HRMS(ESI)C 23H 27N 2O 3S +([M+H] +)计算值：411.1737，实测值：411.1741。 Imitating the method of step 2 in Example 50, using INT-48 and INT-56 as raw materials for reductive amination reaction to prepare compound I-72 as a brown solid (yield 24%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ9.50(s,1H), 8.02–7.96(m,1H), 7.59(d,J=2.4Hz,1H), 7.20(dd,J=8.9 ,2.4Hz,1H), 6.73–6.68(m,1H), 6.68–6.64(m,1H), 6.50(dd,J=7.6,1.3Hz,1H), 4.29(t,J=4.1Hz,2H) ,4.22–4.19(m,2H), 4.20–4.16(m,2H), 3.24–3.14(m,3H), 3.07–3.02(m,1H), 2.17–2.08(m,1H), 2.00–1.93( m,4H),1.34–1.26(m,1H),1.15–1.12(m,1H),1.06–0.99(m,1H).HRMS(ESI)C 23 H 27 N 2 O 3 S + ((M+ H] + ) Calculated value: 411.1737, measured value: 411.1741.

实施例73：反式4-(苯并[d]噻唑-5-基氧基)-N-((2-(萘-1-基)环丙基)甲基)丁基-1-胺(I-73)的制备Example 73: trans 4-(benzo[d]thiazol-5-yloxy)-N-((2-(naphthalene-1-yl)cyclopropyl)methyl)butyl-1-amine ( I-73) Preparation

Figure PCTCN2021076289-appb-000330
Figure PCTCN2021076289-appb-000330

仿照实施例50步骤2的方法，以INT-48和INT-58为原料进行还原胺化反应，制备得到化合物I-73，棕色固体(收率28％)。 1H NMR(800MHz,CD 3OD-d 4)δ9.75–9.71(m,1H),8.30(d,J＝8.4Hz,1H),8.02(d,J＝8.9Hz,1H),7.85(d,J＝8.1Hz,1H),7.72(d,J＝8.2Hz,1H),7.58(d,J＝2.3Hz,1H),7.57–7.54(m,1H),7.49(t,J＝7.2Hz,1H),7.38–7.36(m,1H),7.30(d,J＝7.0Hz,1H),7.24(dd,J＝8.9,2.0Hz,1H),4.18(t,J＝5.4Hz,2H),3.47(dd,J＝12.9,6.6Hz,1H),3.26–3.21(m,2H),3.19(dd,J＝12.9,8.2Hz,1H),2.56–2.51(m,1H),2.03–1.96(m,4H),1.59–1.58(m,1H),1.30–1.26(m,1H),1.15–1.10(m,1H).HRMS(ESI)C 25H 27N 2OS +([M+H] +)计算值：403.1839，实测值：403.1842。 Imitating the method of step 2 of Example 50, using INT-48 and INT-58 as raw materials to carry out reductive amination reaction to prepare compound I-73 as a brown solid (yield 28%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ9.75–9.71 (m, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.85 ( d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.57-7.54 (m, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.38–7.36 (m, 1H), 7.30 (d, J = 7.0 Hz, 1H), 7.24 (dd, J = 8.9, 2.0 Hz, 1H), 4.18 (t, J = 5.4 Hz, 2H ), 3.47 (dd, J = 12.9, 6.6 Hz, 1H), 3.26–3.21 (m, 2H), 3.19 (dd, J = 12.9, 8.2 Hz, 1H), 2.56–2.51 (m, 1H), 2.03– 1.96(m,4H),1.59–1.58(m,1H),1.30–1.26(m,1H),1.15–1.10(m,1H).HRMS(ESI)C 25 H 27 N 2 OS + ((M+ H] + ) Calculated value: 403.1839, measured value: 403.1842.

实施例74：反式4-(苯并[d][1,3]二氧戊烷-5-基氧基)-N-((2-(苯并[b][1,4]二氧六环-5-基)环丙基)甲基)丁基-1-胺(I-74)的制备Example 74: trans 4-(benzo[d][1,3]dioxolan-5-yloxy)-N-((2-(benzo[b][1,4]diox Preparation of hexacyclo-5-yl)cyclopropyl)methyl)butyl-1-amine (I-74)

Figure PCTCN2021076289-appb-000331
Figure PCTCN2021076289-appb-000331

步骤1：将芝麻酚(CAS:533-31-3,1.38g,10mmol)和4-溴丁基氨基甲酸叔丁酯(CAS:164365-88-2,2.52g,10mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入碳酸钾(1.38g，10mmol)，室温搅拌24小时。反应完毕加水(30mL)稀释，乙酸乙酯萃取，酯相合并然后用饱和食盐水洗，无水硫酸钠干燥后，减压蒸除溶剂，残留物用硅胶柱层析纯化得到中间体INT-62(1.9g，收率62％)。 1H NMR(800MHz,DMSO-d 6)δ6.84–6.81(m,1H),6.78(d,J＝8.5Hz,1H),6.59(d,J＝2.5Hz,1H),6.34(dd,J＝8.5,2.5Hz,1H),5.94(s,2H),3.86(t,J＝6.5Hz,2H),2.97–2.92(m,2H),1.68–1.60(m,2H),1.50–1.48(m,2H),1.37(s,9H). Step 1: Dissolve sesamol (CAS: 533-31-3, 1.38g, 10mmol) and tert-butyl 4-bromobutylcarbamate (CAS: 164365-88-2, 2.52g, 10mmol) in N, N -To dimethylformamide (20 mL), potassium carbonate (1.38 g, 10 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was completed, diluted with water (30 mL), extracted with ethyl acetate, the ester phases were combined and then washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate INT-62( 1.9g, yield 62%). 1 H NMR(800MHz,DMSO-d 6 )δ6.84-6.81(m,1H), 6.78(d,J=8.5Hz,1H), 6.59(d,J=2.5Hz,1H), 6.34(dd, J=8.5,2.5Hz,1H),5.94(s,2H),3.86(t,J=6.5Hz,2H),2.97–2.92(m,2H),1.68–1.60(m,2H),1.50–1.48 (m, 2H), 1.37 (s, 9H).

步骤2：将中间体INT-62(1.9g,6.1mmol)溶于二氯甲烷(20mL)中，加入4M的氯化氢1,4-二氧六环溶液(5mL)，室温搅拌24小时。减压蒸干溶剂，得到中间体INT-63(1.5g，收率100％)。 1H NMR(800MHz,DMSO-d 6)δ7.99(s,3H),6.82–6.78(m,1H),6.62(d,J＝2.5Hz,1H),6.36(dd,J＝8.5,2.5Hz,1H),5.95(s,2H),3.92–3.87(m,2H),2.85–2.80(m,2H),1.74–1.68(m,4H).HRMS(ESI)C 1H 16NO 3 +([M+H] +)计算值：210.1125，实测值：210.1126。 Step 2: Intermediate INT-62 (1.9 g, 6.1 mmol) was dissolved in dichloromethane (20 mL), 4M hydrogen chloride 1,4-dioxane solution (5 mL) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure to obtain intermediate INT-63 (1.5 g, yield 100%). 1 H NMR(800MHz,DMSO-d 6 )δ7.99(s,3H), 6.82–6.78(m,1H), 6.62(d,J=2.5Hz,1H), 6.36(dd,J=8.5,2.5 Hz, 1H), 5.95 (s, 2H), 3.92 - 3.87 (m, 2H), 2.85 - 2.80 (m, 2H), 1.74 - 1.68 (m, 4H).HRMS (ESI) C 1 H 16 NO 3 + ([M+H] + ) Calculated value: 210.1125, measured value: 210.1126.

步骤3：仿照实施例50步骤2的方法，以INT-56和INT-63为原料进行还原胺化反应，制备得到化合物I-74(反式混合物)，淡黄色固体(收率37％)。 1H NMR(800MHz,CD 3OD-d 4)δ6.75–6.63(m,3H),6.51–6.46(m,2H),6.34(dd,J＝8.4,2.4Hz,1H),5.87(s,2H),4.29(t,J＝4.0Hz,2H),4.25–4.16(m,2H),3.96(t,J＝5.8Hz,2H),3.22–3.17(m,1H),3.17–3.11(m,2H),3.05–2.98(m,1H),2.15–2.09(m,1H),1.94–1.88(m,2H),1.88–1.82(m,2H),1.31–1.25(m,1H),1.17–1.12(m,1H),1.03–0.97(m,1H).HRMS(ESI)C 23H 28NO 5 +([M+H] +)计算值：398.1962，实测值：398.1963。 Step 3: Following the method of step 2 of Example 50, using INT-56 and INT-63 as raw materials for reductive amination reaction, compound I-74 (trans mixture) was prepared as a pale yellow solid (yield 37%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ6.75–6.63(m,3H), 6.51–6.46(m,2H), 6.34(dd,J=8.4,2.4Hz,1H), 5.87(s ,2H), 4.29(t,J=4.0Hz,2H),4.25-4.16(m,2H),3.96(t,J=5.8Hz,2H),3.22-3.17(m,1H),3.17-3.11( m,2H),3.05–2.98(m,1H), 2.15–2.09(m,1H), 1.94–1.88(m,2H), 1.88–1.82(m,2H), 1.31–1.25(m,1H), 1.17–1.12(m,1H),1.03–0.97(m,1H).HRMS(ESI)C 23 H 28 NO 5 + ([M+H] + ) Calculated value: 398.1962, measured value: 398.1963.

实施例75：反式4-(苯并[d][1,3]二氧戊烷-5-基氧基)-N-((2-(萘-1-基)环丙基)甲基)丁基-1-胺(I-75)的制备Example 75: trans 4-(benzo[d][1,3]dioxolan-5-yloxy)-N-((2-(naphthalen-1-yl)cyclopropyl)methyl ) Preparation of Butyl-1-amine (I-75)

Figure PCTCN2021076289-appb-000332
Figure PCTCN2021076289-appb-000332

仿照实施例50步骤2的方法，以INT-58和INT-63为原料进行还原胺化反应，制备得到化合物I-75，淡黄色固体(收率41％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.30(d,J＝8.5Hz,1H),7.87(d,J＝8.1Hz,1H),7.74(d,J＝8.2Hz,1H),7.59–7.55(m,1H),7.53–7.49(m,1H),7.40–7.37(m,1H),7.29(d,J＝7.1Hz,1H),6.69–6.67(m,1H),6.49(d,J＝2.5Hz,1H),6.34(dd,J＝8.5,2.5Hz,1H),5.87(s,2H),3.96(t,J＝5.9Hz,2H),3.50–3.43(m,1H),3.19(t,J＝8.0Hz,2H),3.15(dd,J＝13.0,8.4Hz,1H),2.56–2.50(m,1H),1.96–1.91(m,2H),1.89–1.83(m,2H),1.59–1.52(m,1H),1.28–1.24(m,1H),1.18–1.10(m,1H).HRMS(ESI)C 25H 28NO 3 +([M+H] +)计算值：390.2064，实测值：390.2068。 Imitating the method of step 2 in Example 50, using INT-58 and INT-63 as raw materials for reductive amination reaction to prepare compound I-75 as a pale yellow solid (yield 41%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ8.30(d,J=8.5Hz,1H), 7.87(d,J=8.1Hz,1H), 7.74(d,J=8.2Hz,1H) ,7.59–7.55(m,1H),7.53–7.49(m,1H),7.40–7.37(m,1H),7.29(d,J=7.1Hz,1H),6.69–6.67(m,1H),6.49 (d,J=2.5Hz,1H),6.34(dd,J=8.5,2.5Hz,1H),5.87(s,2H),3.96(t,J=5.9Hz,2H),3.50–3.43(m, 1H), 3.19(t,J=8.0Hz,2H),3.15(dd,J=13.0,8.4Hz,1H),2.56–2.50(m,1H),1.96–1.91(m,2H),1.89–1.83 (m,2H),1.59–1.52(m,1H),1.28–1.24(m,1H),1.18–1.10(m,1H).HRMS(ESI)C 25 H 28 NO 3 + ([M+H] + )Calculated value: 390.2064, measured value: 390.2068.

实施例76：反式7-(3-(((2-(5-氟-2-甲氧基苯基)环丙基)甲基)胺基)丙氧基)喹啉-2(1H)-酮(I-76)的制备Example 76: trans 7-(3-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)amino)propoxy)quinoline-2(1H) -Preparation of ketone (I-76)

Figure PCTCN2021076289-appb-000333
Figure PCTCN2021076289-appb-000333

步骤1：仿照实施例74步骤1中所述以芝麻酚和4-溴丁基氨基甲酸叔丁酯制备中间体INT-62的方法，以7-羟基-2-喹诺酮(CAS:70500-72-0)和3-溴丙基氨基甲酸叔丁酯(CAS:83948-53-2)为原料制备中间体INT-64。 1H NMR(800MHz,DMSO-d 6)δ11.58(s,1H),7.80(d,J＝9.5Hz,1H),7.55(d,J＝9.2Hz,1H),6.91(t,J＝5.3Hz,1H),6.81–6.74(m,2H),6.29(dd,J＝9.4,1.5Hz,1H),4.00(t,J＝6.2Hz,2H),3.09(dd,J＝12.7,6.7Hz,2H),1.85(p,J＝6.5Hz,2H),1.37(s,9H).HRMS(ESI)C 17H 23N 2O 4 +([M+H] +)计算值：319.1652，实测值：319.1674。 Step 1: Following the method of preparing intermediate INT-62 with sesamol and tert-butyl 4-bromobutylcarbamate as described in step 1 of Example 74, 7-hydroxy-2-quinolone (CAS: 70500-72- 0) and tert-butyl 3-bromopropyl carbamate (CAS:83948-53-2) as raw materials to prepare intermediate INT-64. 1 H NMR (800MHz, DMSO-d 6 ) δ 11.58 (s, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 6.91 (t, J = 5.3Hz, 1H), 6.81–6.74 (m, 2H), 6.29 (dd, J = 9.4, 1.5 Hz, 1H), 4.00 (t, J = 6.2 Hz, 2H), 3.09 (dd, J = 12.7, 6.7 Hz,2H),1.85(p,J=6.5Hz,2H),1.37(s,9H).HRMS(ESI)C 17 H 23 N 2 O 4 + ([M+H] + ) Calculated value: 319.1652, Found: 319.1674.

步骤2：仿照实施例74步骤2中所述以中间体INT-62制备中间体INT-63的方法，以中间体INT-64为原料制备中间体INT-65。 1H NMR(800MHz,DMSO-d 6)δ11.71(s,1H),8.13(s,3H),7.83(d,J＝9.4Hz,1H),7.58(d,J＝8.6Hz,1H),6.84(d,J＝2.3Hz,1H),6.82(dd,J＝8.6,2.4Hz,1H),6.32(d,J＝9.4Hz,1H),4.12(t,J＝6.0Hz,2H),3.00–2.91(m,2H),2.12–2.02(m,2H).HRMS(ESI)C 12H 15N 2O 2 +([M+H] +)计算值：219.1128，实测值：219.1127。 Step 2: Following the method of preparing intermediate INT-63 from intermediate INT-62 in step 2 of Example 74, intermediate INT-65 is prepared using intermediate INT-64 as a raw material. 1 H NMR (800MHz, DMSO-d 6 ) δ 11.71 (s, 1H), 8.13 (s, 3H), 7.83 (d, J = 9.4 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H) ,6.84(d,J=2.3Hz,1H), 6.82(dd,J=8.6,2.4Hz,1H), 6.32(d,J=9.4Hz,1H), 4.12(t,J=6.0Hz,2H) ,3.00–2.91(m,2H),2.12–2.02(m,2H).HRMS(ESI) C 12 H 15 N 2 O 2 + ([M+H] + ) calculated value: 219.1128, measured value: 219.1127.

步骤3：仿照实施例50步骤2的方法，以INT-43和INT-65为原料进行还原胺化反应，制备得到化合物I-76(反式混合物)，白色固体(收率24％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.80–7.75(m,1H),7.47–7.42(m,1H),6.78–6.68(m,4H),6.55–6.50(m,1H),6.36–6.30(m,1H),4.07–4.03(m,2H),3.69(s,3H),2.85–2.76(m,2H),2.75–2.69(m,1H),2.53–2.45(m,1H),2.02–1.92(m,2H),1.92–1.87(m,1H),1.11–1.05(m,1H),0.90–0.86(m,1H),0.79–0.73(m,1H).HRMS(ESI)C 23H 26FN 2O 3 +([M+H] +)计算值：397.1922，实测值：397.1927。 Step 3: Following the method of step 2 of Example 50, using INT-43 and INT-65 as raw materials for reductive amination reaction, compound I-76 (trans mixture) was prepared as a white solid (yield 24%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ7.80–7.75(m,1H), 7.47–7.42(m,1H), 6.78–6.68(m,4H), 6.55–6.50(m,1H) ,6.36–6.30(m,1H),4.07–4.03(m,2H), 3.69(s,3H), 2.85–2.76(m,2H), 2.75–2.69(m,1H), 2.53–2.45(m, 1H),2.02–1.92(m,2H),1.92–1.87(m,1H),1.11–1.05(m,1H),0.90–0.86(m,1H),0.79–0.73(m,1H).HRMS( ESI) C 23 H 26 FN 2 O 3 + ([M+H] + ) calculated value: 397.1922, measured value: 397.1927.

实施例77：反式7-(3-(((2-(2-甲氧基苯基)环丙基)甲基)胺基)丙氧基)喹啉-2(1H)-酮(I-77)的制备Example 77: trans 7-(3-(((2-(2-methoxyphenyl)cyclopropyl)methyl)amino)propoxy)quinoline-2(1H)-one (I -77) Preparation

Figure PCTCN2021076289-appb-000334
Figure PCTCN2021076289-appb-000334

仿照实施例50步骤2的方法，以INT-44和INT-65为原料进行还原胺化反应，制备得到化合物I-77，白色固体(收率35％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.36–8.23(m,1H),7.84–7.75(m,1H),7.18(t,J＝7.8Hz,1H),7.14–7.03(m,2H),6.96(d,J＝6.7Hz,1H),6.93(d,J＝8.2Hz,1H),6.86(t,J＝7.4Hz,1H),6.84–6.74(m,1H),4.36–4.24(m,2H),3.85(s,3H),3.37–3.32(m,2H),3.26(dd,J＝12.9,6.9Hz,1H),3.13–3.07(m,1H),2.36–2.27(m,2H),2.22–2.15(m,1H),1.30–1.27(m,1H),1.19–1.14(m,1H),1.08–0.98(m,1H).HRMS(ESI)C 23H 27N 2O 3 +([M+H] +)计算值：379.2016，实测值：379.2014。 Imitating the method of step 2 in Example 50, using INT-44 and INT-65 as raw materials for reductive amination reaction to prepare compound I-77 as a white solid (yield 35%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ8.36–8.23(m,1H),7.84–7.75(m,1H),7.18(t,J=7.8Hz,1H),7.14–7.03(m , 2H), 6.96 (d, J = 6.7 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.84-6.74 (m, 1H), 4.36 –4.24(m,2H),3.85(s,3H), 3.37–3.32(m,2H), 3.26(dd,J=12.9,6.9Hz,1H), 3.13–3.07(m,1H),2.36–2.27 (m,2H),2.22–2.15(m,1H),1.30–1.27(m,1H),1.19–1.14(m,1H),1.08–0.98(m,1H).HRMS(ESI)C 23 H 27 N 2 O 3 + ([M+H] + ) calculated value: 379.2016, measured value: 379.2014.

实施例78：反式7-(3-(((2-(5-氯-2-甲氧基苯基)环丙基)甲基)胺基)丙氧基)喹啉-2(1H)-酮(I-78)的制备Example 78: trans 7-(3-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)amino)propoxy)quinoline-2(1H) -Preparation of ketone (I-78)

Figure PCTCN2021076289-appb-000335
Figure PCTCN2021076289-appb-000335

仿照实施例50步骤2的方法，以INT-61和INT-65为原料进行还原胺化反应，制备得到化合物I-78，白色固体(收率22％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.44–8.19(m,1H),7.90–7.75(m,1H),7.21–7.02(m,3H),6.97(d,J＝2.6Hz,1H),6.94(d,J＝8.7Hz,1H),6.91–6.72(m,1H),4.35–4.28(m,2H),3.87(s,3H),3.39–3.34(m,2H),3.28–3.22(m,1H),3.17–3.11(m,1H),2.37–2.29(m,2H),2.24–2.18(m,1H),1.39–1.33(m,1H),1.22–1.15(m,1H),1.13–1.06(m,1H).HRMS(ESI)C 23H 26ClN 2O 3 +([M+H] +)计算值：413.1626，实测值：413.1631。 Imitating the method of step 2 in Example 50, using INT-61 and INT-65 as raw materials to carry out reductive amination reaction to prepare compound I-78 as a white solid (yield 22%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ8.44–8.19(m,1H), 7.90–7.75(m,1H), 7.21–7.02(m,3H), 6.97(d,J=2.6Hz ,1H), 6.94(d,J=8.7Hz,1H), 6.91–6.72(m,1H), 4.35–4.28(m,2H), 3.87(s,3H), 3.39–3.34(m,2H), 3.28–3.22(m,1H), 3.17–3.11(m,1H), 2.37–2.29(m,2H), 2.24–2.18(m,1H), 1.39–1.33(m,1H), 1.22–1.15(m , 1H), 1.13-1.06 (m, 1H). HRMS (ESI) C 23 H 26 ClN 2 O 3 + ([M+H] + ) calculated value: 413.1626, measured value: 413.1631.

实施例79：反式7-(3-(((2-(5-氟-2-甲氧基苯基)环丙基)甲基)胺基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-79)的制备Example 79: trans 7-(3-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)amino)propoxy)-3,4-dihydro Preparation of Quinolin-2(1H)-one (I-79)

Figure PCTCN2021076289-appb-000336
Figure PCTCN2021076289-appb-000336

步骤1：仿照实施例74步骤1中所述以芝麻酚和4-溴丁基氨基甲酸叔丁酯制备中间体INT-62的方法，以3,4-二氢-7-羟基-2(1H)-喹啉酮(CAS:22246-18-0)和3-溴丙基氨基甲酸叔丁酯(CAS:83948-53-2)为原料制备中间体INT-66。 1H NMR(800MHz,DMSO-d 6)δ9.98(s,1H),7.04(d,J＝8.3Hz,1H),6.91–6.85(m,1H),6.46(dd,J＝8.2,2.5Hz,1H),6.42(d,J＝2.4Hz,1H),3.88(t,J＝6.2Hz,2H),3.05(dd,J＝12.9,6.7Hz,2H),2.77(t,J＝7.5Hz,2H),2.42–2.37(m,2H),1.80(p,J＝6.5Hz,2H),1.37(s,9H).HRMS(ESI)C 17H 25N 2O 4 +([M+H] +)计算值：321.1809，实测值：321.1832。 Step 1: Following the method of preparing intermediate INT-62 with sesamol and tert-butyl 4-bromobutylcarbamate as described in step 1 of Example 74, 3,4-dihydro-7-hydroxy-2(1H )-Quinolinone (CAS: 22246-18-0) and tert-butyl 3-bromopropyl carbamate (CAS: 83948-53-2) were used as raw materials to prepare intermediate INT-66. 1 H NMR(800MHz,DMSO-d 6 )δ9.98(s,1H),7.04(d,J=8.3Hz,1H),6.91-6.85(m,1H),6.46(dd,J=8.2,2.5 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 3.88 (t, J = 6.2 Hz, 2H), 3.05 (dd, J = 12.9, 6.7 Hz, 2H), 2.77 (t, J = 7.5 Hz,2H),2.42–2.37(m,2H),1.80(p,J=6.5Hz,2H),1.37(s,9H).HRMS(ESI)C 17 H 25 N 2 O 4 + ((M+ H] + ) Calculated value: 321.1809, measured value: 321.1832.

步骤2：仿照实施例74步骤2中所述以中间体INT-62制备中间体INT-63的方法，以中间体INT-66为原料制备中间体INT-67。 1H NMR(800MHz,DMSO-d 6)δ10.05(s,1H),8.13(s,3H),7.06(d,J＝8.2Hz,1H),6.50(dd,J＝8.2,2.5Hz,1H),6.48–6.45(m,1H),3.99(t,J＝6.1Hz,2H),2.96–2.90(m,2H),2.78(t,J＝7.5Hz,2H),2.44–2.38(m,2H),2.04–1.99(m,2H).HRMS(ESI C 12H 17N 2O 2 +([M+H] +)计算值：221.1285，实测值：221.1288。 Step 2: Following the method of preparing intermediate INT-63 from intermediate INT-62 in step 2 of Example 74, intermediate INT-67 is prepared using intermediate INT-66 as a raw material. 1 H NMR(800MHz,DMSO-d 6 )δ10.05(s,1H),8.13(s,3H),7.06(d,J=8.2Hz,1H), 6.50(dd,J=8.2,2.5Hz, 1H), 6.48–6.45(m,1H), 3.99(t,J=6.1Hz,2H), 2.96–2.90(m,2H), 2.78(t,J=7.5Hz,2H), 2.44–2.38(m , 2H), 2.04-1.99 (m, 2H). HRMS (ESI C 12 H 17 N 2 O 2 + ([M+H] + ) Calculated value: 221.1285, measured value: 221.1288.

步骤3：仿照实施例50步骤2的方法，以INT-43和INT-67为原料进行还原胺化反应，制备得到化合物I-79，白色固体(收率48％)。 1H NMR(800MHz,CD 3OD-d 4)δ6.98(d,J＝8.3Hz,1H),6.82–6.78(m,2H),6.62(dd,J＝9.4,2.7Hz,1H),6.46(dd,J＝8.3,2.5Hz,1H),6.38(d,J＝2.5Hz,1H),4.00(t,J＝5.7Hz,2H),3.74(s,3H),3.21–3.15(m,2H),3.15–3.07(m,1H),3.04–2.95(m,1H),2.80–2.75(m,2H),2.45–2.41(m,2H),2.14–2.09(m,3H),1.22–1.19(m,1H),1.11–1.03(m,1H),1.01–0.92(m,1H).HRMS(ESI)C 23H 28FN 2O 3 +([M+H] +)计算值：399.2078，实测值：399.2083。 Step 3: Following the method of step 2 of Example 50, using INT-43 and INT-67 as raw materials for reductive amination reaction, compound I-79 was prepared as a white solid (yield: 48%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 6.98 (d, J = 8.3 Hz, 1H), 6.82-6.78 (m, 2H), 6.62 (dd, J = 9.4, 2.7 Hz, 1H), 6.46 (dd, J = 8.3, 2.5 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 4.00 (t, J = 5.7 Hz, 2H), 3.74 (s, 3H), 3.21–3.15 (m ,2H),3.15-3.07(m,1H),3.04-2.95(m,1H),2.80-2.75(m,2H),2.45-2.41(m,2H),2.14-2.09(m,3H),1.22 –1.19(m,1H),1.11–1.03(m,1H),1.01–0.92(m,1H).HRMS(ESI)C 23 H 28 FN 2 O 3 + ([M+H] + )Calculated value: 399.2078, measured value: 399.2083.

实施例80：反式7-(3-(((2-(2-甲氧基苯基)环丙基)甲基)胺基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-80)的制备Example 80: trans 7-(3-(((2-(2-methoxyphenyl)cyclopropyl)methyl)amino)propoxy)-3,4-dihydroquinoline-2 Preparation of (1H)-ketone (I-80)

Figure PCTCN2021076289-appb-000337
Figure PCTCN2021076289-appb-000337

仿照实施例50步骤2的方法，以INT-44和INT-67为原料进行还原胺化反应，制备 得到化合物I-80，白色固体(收率41％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.20–7.16(m,1H),7.07(d,J＝8.3Hz,1H),6.96(d,J＝6.7Hz,1H),6.93(d,J＝8.2Hz,1H),6.87(t,J＝7.4Hz,1H),6.56(dd,J＝8.3,2.4Hz,1H),6.46(d,J＝2.4Hz,1H),4.10(t,J＝5.7Hz,2H),3.85(s,3H),3.30–3.27(m,2H),3.26–3.22(m,1H),3.06(dd,J＝12.9,8.1Hz,1H),2.87(t,J＝7.5Hz,2H),2.57–2.50(m,2H),2.23–2.14(m,3H),1.26–1.21(m,1H),1.21–1.14(m,1H),1.05–0.98(m,1H).HRMS(ESI)C 23H 29N 2O 3 +([M+H] +)计算值：381.2173，实测值：381.2171。 Imitating the method of step 2 in Example 50, using INT-44 and INT-67 as raw materials for reductive amination reaction to prepare compound I-80 as a white solid (yield 41%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ7.20–7.16 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 6.7 Hz, 1H), 6.93 ( d, J = 8.2 Hz, 1H), 6.87 (t, J = 7.4 Hz, 1H), 6.56 (dd, J = 8.3, 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 4.10 ( t,J＝5.7Hz,2H),3.85(s,3H),3.30–3.27(m,2H), 3.26–3.22(m,1H),3.06(dd,J＝12.9,8.1Hz,1H),2.87 (t,J=7.5Hz,2H), 2.57–2.50(m,2H), 2.23–2.14(m,3H), 1.26–1.21(m,1H), 1.21–1.14(m,1H), 1.05–0.98 (m,1H).HRMS(ESI) C 23 H 29 N 2 O 3 + ([M+H] + ) Calculated value: 381.2173, measured value: 381.2171.

实施例81：反式7-(3-(((2-(5-氯-2-甲氧基苯基)环丙基)甲基)胺基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-81)的制备Example 81: trans 7-(3-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)amino)propoxy)-3,4-dihydro Preparation of Quinolin-2(1H)-one (I-81)

Figure PCTCN2021076289-appb-000338
Figure PCTCN2021076289-appb-000338

仿照实施例50步骤2的方法，以INT-61和INT-67为原料进行还原胺化反应，制备得到化合物I-81，浅黄色固体(收率51％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.21–7.16(m,1H),7.12–7.07(m,1H),6.97(d,J＝2.5Hz,1H),6.96–6.92(m,1H),6.58(dd,J＝8.3,2.4Hz,1H),6.52–6.47(m,1H),4.12(t,J＝5.7Hz,2H),3.87(s,3H),3.33–3.28(m,2H),3.26–3.22(m,1H),3.14–3.08(m,1H),2.92–2.86(m,2H),2.58–2.52(m,2H),2.26–2.17(m,3H),1.36–1.29(m,1H),1.21–1.16(m,1H),1.10–1.05(m,1H).HRMS(ESI)C 23H 28ClN 2O 3 +([M+H] +)计算值：415.1783，实测值：415.1785。 Following the method of step 2 in Example 50, using INT-61 and INT-67 as raw materials for reductive amination reaction, compound I-81 was prepared as a light yellow solid (yield 51%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ7.21–7.16(m,1H), 7.12–7.07(m,1H), 6.97(d,J=2.5Hz,1H), 6.96–6.92(m ,1H), 6.58(dd,J=8.3,2.4Hz,1H), 6.52–6.47(m,1H), 4.12(t,J=5.7Hz,2H), 3.87(s,3H),3.33–3.28( m,2H), 3.26–3.22(m,1H), 3.14–3.08(m,1H), 2.92–2.86(m,2H), 2.58–2.52(m,2H), 2.26–2.17(m,3H), 1.36–1.29(m,1H),1.21–1.16(m,1H),1.10–1.05(m,1H).HRMS(ESI)C 23 H 28 ClN 2 O 3 + ([M+H] + )Calculated value : 415.1783, measured value: 415.1785.

实施例82：反式7-(5-(((2-(2-甲氧基苯基)环丙基)甲基)胺基)戊氧基)喹啉-2(1H)-酮(I-82)的制备Example 82: trans 7-(5-(((2-(2-methoxyphenyl)cyclopropyl)methyl)amino)pentyloxy)quinoline-2(1H)-one (I -82) Preparation

Figure PCTCN2021076289-appb-000339
Figure PCTCN2021076289-appb-000339

步骤1：仿照实施例44步骤1～3中所述以3,4-二氢-7-羟基-2(1H)-喹啉酮和1,4-二溴丁烷制备中间体INT-42的方法，以7-羟基-2-喹诺酮(CAS:70500-72-0)和1,5-二溴戊烷(CAS:111-24-0)为原料制备中间体INT-68。 1H NMR(800MHz,CD 3OD-d 4)δ7.87(d,J ＝9.4Hz,1H),7.55(d,J＝8.7Hz,1H),6.86(dd,J＝8.7,2.4Hz,1H),6.83(d,J＝2.3Hz,1H),6.43(d,J＝9.4Hz,1H),4.07(t,J＝6.4Hz,2H),2.68(t,J＝6.8Hz,2H),1.87–1.82(m,2H),1.61–1.51(m,4H).HRMS(ESI)C 14H 19N 2O 2 +([M+H] +)计算值：247.1441，实测值:247.1446。 Step 1: Follow the steps 1 to 3 in Example 44 to prepare intermediate INT-42 with 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane Methods, 7-hydroxy-2-quinolone (CAS: 70500-72-0) and 1,5-dibromopentane (CAS: 111-24-0) were used as raw materials to prepare intermediate INT-68. 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 7.87 (d, J = 9.4 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.86 (dd, J = 8.7, 2.4 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.43 (d, J = 9.4 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 2.68 (t, J = 6.8 Hz, 2H) ,1.87–1.82(m,2H),1.61–1.51(m,4H).HRMS(ESI)C 14 H 19 N 2 O 2 + ([M+H] + ) Calculated value: 247.1441, measured value: 247.1446.

步骤2：仿照实施例50步骤2的方法，以INT-44和INT-68为原料进行还原胺化反应，制备得到化合物I-82，白色固体(收率69％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.18(d,J＝9.2Hz,1H),7.73(d,J＝8.8Hz,1H),7.19–7.16(m,1H),7.04(dd,J＝8.8,2.4Hz,1H),7.00–6.99(m,1H),6.96(dd,J＝7.5,1.4Hz,1H),6.93(dd,J＝8.2,1.1Hz,1H),6.86(td,J＝7.5,1.1Hz,1H),6.69(d,J＝9.2Hz,1H),4.16(t,J＝6.1Hz,2H),3.86(s,3H),3.20(dd,J＝12.9,6.9Hz,1H),3.15–3.08(m,2H),3.04(dd,J＝12.9,8.0Hz,1H),2.19–2.14(m,1H),1.96–1.90(m,2H),1.87–1.81(m,2H),1.68–1.62(m,2H),1.27–1.21(m,1H),1.18–1.15(m,1H),1.03–1.00(m,1H).HRMS(ESI)C 25H 31N 2O 3 +([M+H] +)计算值：407.2329，实测值：407.2337。 Step 2: Following the method of step 2 in Example 50, using INT-44 and INT-68 as raw materials for reductive amination reaction, compound I-82 was prepared as a white solid (yield 69%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 8.18 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.19-7.16 (m, 1H), 7.04 ( dd,J=8.8,2.4Hz,1H), 7.00–6.99(m,1H), 6.96(dd,J=7.5,1.4Hz,1H), 6.93(dd,J=8.2,1.1Hz,1H), 6.86 (td, J = 7.5, 1.1 Hz, 1H), 6.69 (d, J = 9.2 Hz, 1H), 4.16 (t, J = 6.1 Hz, 2H), 3.86 (s, 3H), 3.20 (dd, J = 12.9, 6.9 Hz, 1H), 3.15–3.08 (m, 2H), 3.04 (dd, J = 12.9, 8.0 Hz, 1H), 2.19–2.14 (m, 1H), 1.96–1.90 (m, 2H), 1.87 --1.81(m,2H),1.68–1.62(m,2H),1.27–1.21(m,1H),1.18–1.15(m,1H),1.03–1.00(m,1H).HRMS(ESI)C 25 H 31 N 2 O 3 + ([M+H] + ) Calculated value: 407.2329, actually measured value: 407.2337.

实施例83：反式7-(5-(((2-(2-甲氧基苯基)环丙基)甲基)胺基)戊氧基)-3,4-二氢喹啉-2(1H)-酮(I-83)的制备Example 83: trans 7-(5-(((2-(2-methoxyphenyl)cyclopropyl)methyl)amino)pentyloxy)-3,4-dihydroquinoline-2 Preparation of (1H)-ketone (I-83)

Figure PCTCN2021076289-appb-000340
Figure PCTCN2021076289-appb-000340

步骤1：仿照实施例44步骤1～3中所述以3,4-二氢-7-羟基-2(1H)-喹啉酮和1,4-二溴丁烷制备中间体INT-42的方法，以3,4-二氢-7-羟基-2(1H)-喹啉酮和1,5-二溴戊烷(CAS:111-24-0)为原料制备中间体INT-69。 1H NMR(800MHz,CD 3OD-d 4)δ7.04(d,J＝8.3Hz,1H),6.53(dd,J＝8.3,2.5Hz,1H),6.44(d,J＝2.5Hz,1H),3.94(t,J＝6.4Hz,2H),2.87–2.84(m,2H),2.70–2.67(m,2H),2.54–2.51(m,2H),1.80–1.75(m,1H),1.58–1.48(m,3H).HRMS(ESI)C 14H 21N 2O 2 +([M+H] +)计算值：249.1598，实测值：249.1604。 Step 1: Follow the steps 1 to 3 in Example 44 to prepare intermediate INT-42 with 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane Methods, 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,5-dibromopentane (CAS: 111-24-0) were used as raw materials to prepare intermediate INT-69. 1 H NMR (800MHz, CD 3 OD-d 4 ) δ7.04 (d, J = 8.3 Hz, 1H), 6.53 (dd, J = 8.3, 2.5 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 3.94(t,J=6.4Hz,2H), 2.87–2.84(m,2H), 2.70–2.67(m,2H), 2.54–2.51(m,2H), 1.80–1.75(m,1H) , 1.58-1.48 (m, 3H). HRMS (ESI) C 14 H 21 N 2 O 2 + ([M+H] + ) calculated value: 249.1598, measured value: 249.1604.

步骤2：仿照实施例50步骤2的方法，以INT-44和INT-69为原料进行还原胺化反应，制备得到化合物I-83，白色固体(收率67％)。H NMR(800MHz,CD 3OD-d 4)δ7.19–7.17(m,1H),7.06(d,J＝8.3Hz,1H),6.97–6.92(m,2H),6.86(td,J＝7.5,1.1Hz,1H),6.54(dd,J＝8.3,2.5Hz,1H),6.45(d,J＝2.5Hz,1H),3.98(t,J＝6.1Hz,2H),3.86(s,3H),3.19(dd,J＝12.9,6.8Hz,1H),3.13–3.05(m,2H),3.02(dd,J＝12.9,8.0Hz,1H),2.88–2.85(m,2H),2.55–2.49(m,2H),2.17–2.13(m,1H),1.86–1.77(m,4H),1.63–1.58(m,2H),1.25–1.20(m,1H),1.18–1.15(m,1H),1.02–0.98(m,1H).HRMS(ESI)C 25H 33N 2O 3 +([M+H] +) 计算值：409.2486，实测值：409.2492。 Step 2: Following the method of step 2 in Example 50, using INT-44 and INT-69 as raw materials for reductive amination reaction, compound I-83 was prepared as a white solid (yield 67%). H NMR (800MHz, CD 3 OD-d 4 ) δ 7.19–7.17 (m, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.97–6.92 (m, 2H), 6.86 (td, J = 7.5, 1.1 Hz, 1H), 6.54 (dd, J = 8.3, 2.5 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 3.98 (t, J = 6.1 Hz, 2H), 3.86 (s, 3H), 3.19(dd,J=12.9,6.8Hz,1H),3.13-3.05(m,2H),3.02(dd,J=12.9,8.0Hz,1H),2.88-2.85(m,2H),2.55 --2.49(m,2H),2.17–2.13(m,1H),1.86–1.77(m,4H),1.63–1.58(m,2H),1.25–1.20(m,1H),1.18–1.15(m, 1H),1.02–0.98(m,1H).HRMS(ESI)C 25 H 33 N 2 O 3 + ([M+H] + ) Calculated value: 409.2486, measured value: 409.2492.

实施例84：反式(E)-7-((4-(((2-(2-甲氧基苯基)环丙基)甲基)胺基)丁-2-烯-1基)氧基)喹啉-2(1H)-酮(I-84)的制备Example 84: trans (E)-7-((4-(((2-(2-methoxyphenyl)cyclopropyl)methyl)amino)but-2-en-1-yl)oxy Preparation of quinoline-2(1H)-one (I-84)

Figure PCTCN2021076289-appb-000341
Figure PCTCN2021076289-appb-000341

步骤1：仿照实施例44步骤1～3中所述以3,4-二氢-7-羟基-2(1H)-喹啉酮和1,4-二溴丁烷制备中间体INT-42的方法，以7-羟基-2-喹诺酮(CAS:70500-72-0)和反式-1,4-二溴-2-丁烯(CAS:821-06-7)为原料制备中间体INT-70。 1H NMR(800MHz,CD 3OD-d 4)δ7.87(d,J＝9.4Hz,1H),7.56(d,J＝8.7Hz,1H),6.88(dd,J＝8.6,2.4Hz,1H),6.86(d,J＝2.4Hz,1H),6.43(d,J＝9.4Hz,1H),6.03–5.99(m,1H),5.92–5.86(m,1H),4.67–4.60(m,2H),3.31–3.30(m,2H).HRMS(ESI)C 13H 15N 2O 2 +([M+H] +)计算值：231.1128，实测值：231.1127。 Step 1: Follow the steps 1 to 3 in Example 44 to prepare intermediate INT-42 with 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane Method, using 7-hydroxy-2-quinolone (CAS: 70500-72-0) and trans-1,4-dibromo-2-butene (CAS: 821-06-7) as raw materials to prepare intermediate INT- 70. 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 7.87 (d, J = 9.4 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 6.88 (dd, J = 8.6, 2.4 Hz, 1H), 6.86(d,J=2.4Hz,1H), 6.43(d,J=9.4Hz,1H), 6.03-5.99(m,1H), 5.92-5.86(m,1H), 4.67-4.60(m ,2H),3.31–3.30(m,2H).HRMS(ESI)C 13 H 15 N 2 O 2 + ([M+H] + ) Calculated value: 231.1128, measured value: 231.1127.

步骤2：仿照实施例50步骤2的方法，以INT-44和INT-70为原料进行还原胺化反应，制备得到化合物I-84，白色固体(收率44％)。 1H NMR(800MHz,CD 3OD-d 4)δ8.19(d,J＝9.3Hz,1H),7.76(d,J＝8.8Hz,1H),7.18(td,J＝7.8,1.7Hz,1H),7.08(dd,J＝8.8,2.4Hz,1H),7.03(d,J＝2.4Hz,1H),6.95(dd,J＝7.6,1.7Hz,1H),6.93(dd,J＝8.2,1.1Hz,1H),6.86(td,J＝7.4,1.1Hz,1H),6.70(d,J＝9.3Hz,1H),6.32–6.26(m,1H),6.08–6.03(m,1H),4.80(d,J＝5.1Hz,2H),3.84(s,3H),3.81–3.78(m,2H),3.18(dd,J＝12.9,6.9Hz,1H),3.02(dd,J＝12.9,8.0Hz,1H),2.14–2.09(m,1H),1.23–1.19(m,1H),1.17–1.14(m,1H),1.00–0.97(m,1H).HRMS(ESI)C 24H 27N 2O 3 +([M+H] +)计算值：391.2016，实测值：391.2019。 Step 2: Following the method of Step 2 of Example 50, using INT-44 and INT-70 as raw materials for reductive amination reaction, compound I-84 was prepared as a white solid (yield 44%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 8.19 (d, J = 9.3 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.18 (td, J = 7.8, 1.7 Hz, 1H), 7.08 (dd, J = 8.8, 2.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 7.6, 1.7 Hz, 1H), 6.93 (dd, J = 8.2 ,1.1Hz,1H),6.86(td,J=7.4,1.1Hz,1H),6.70(d,J=9.3Hz,1H),6.32–6.26(m,1H),6.08–6.03(m,1H) , 4.80 (d, J = 5.1 Hz, 2H), 3.84 (s, 3H), 3.81–3.78 (m, 2H), 3.18 (dd, J = 12.9, 6.9 Hz, 1H), 3.02 (dd, J = 12.9 ,8.0Hz,1H),2.14-2.09(m,1H),1.23-1.19(m,1H),1.17-1.14(m,1H),1.00-0.97(m,1H).HRMS(ESI)C 24 H 27 N 2 O 3 + ([M+H] + ) Calculated value: 391.2016, measured value: 391.2019.

实施例85：反式(E)-7-((4-(((2-(2-甲氧基苯基)环丙基)甲基)胺基)丁-2-烯-1基)氧基)-3,4-二氢喹啉-2(1H)-酮(I-85)的制备Example 85: trans (E)-7-((4-(((2-(2-methoxyphenyl)cyclopropyl)methyl)amino)but-2-en-1-yl)oxy Yl)-3,4-dihydroquinoline-2(1H)-one (I-85)

Figure PCTCN2021076289-appb-000342
Figure PCTCN2021076289-appb-000342

步骤1：仿照实施例44步骤1～3中所述以3,4-二氢-7-羟基-2(1H)-喹啉酮和1,4-二溴丁烷制备中间体INT-42的方法，以3,4-二氢-7-羟基-2(1H)-喹啉酮和反式-1,4-二溴-2-丁烯(CAS:821-06-7)为原料制备中间体INT-71。 1H NMR(800MHz,CD 3OD-d 4)δ7.05(d,J＝8.3Hz,1H),6.55(dd,J＝8.3,2.5Hz,1H),6.46(d,J＝2.5Hz,1H),5.97–5.93(m,1H),5.86–5.81(m,1H),4.50–4.48(m,2H),3.29–3.27(m,2H),2.88–2.84(m,2H),2.56–2.51(m,2H).HRMS(ESI)C 13H 17N 2O 2 +([M+H] +)计算值：233.1285，实测值：233.1287。 Step 1: Follow the steps 1 to 3 in Example 44 to prepare intermediate INT-42 with 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 1,4-dibromobutane Method, using 3,4-dihydro-7-hydroxy-2(1H)-quinolinone and trans-1,4-dibromo-2-butene (CAS:821-06-7) as raw materials to prepare intermediate Body INT-71. 1 H NMR (800MHz, CD 3 OD-d 4 ) δ7.05 (d, J = 8.3 Hz, 1H), 6.55 (dd, J = 8.3, 2.5 Hz, 1H), 6.46 (d, J = 2.5 Hz, 1H), 5.97--5.93(m,1H), 5.86--5.81(m,1H), 4.50--4.48(m,2H), 3.29--3.27(m,2H), 2.88--2.84(m,2H), 2.56-- 2.51 (m, 2H). HRMS (ESI) C 13 H 17 N 2 O 2 + ([M+H] + ) calculated value: 233.1285, measured value: 233.1287.

步骤2：仿照实施例50步骤2的方法，以INT-44和INT-71为原料进行还原胺化反应，制备得到化合物I-85，白色固体(收率52％)。1H NMR(800MHz,CD 3OD-d 4)δ7.20–7.17(m,1H),7.08(d,J＝8.3Hz,1H),6.96–6.93(m,2H),6.86(td,J＝7.5,0.9Hz,1H),6.58(dd,J＝8.3,2.5Hz,1H),6.49(d,J＝2.5Hz,1H),6.25–6.20(m,1H),5.99–5.91(m,1H),4.64–4.60(m,2H),3.85(s,3H),3.78–3.73(m,2H),3.15(dd,J＝12.9,6.7Hz,1H),2.98(dd,J＝12.9,7.9Hz,1H),2.88–2.84(m,2H),2.54–2.49(m,2H),2.13–2.09(m,1H),1.22–1.18(m,1H),1.18–1.14(m,1H),0.99–0.94(m,1H).HRMS(ESI)C 24H 29N 2O 3 +([M+H] +)计算值：393.2173，实测值：393.2171。 Step 2: Following the method of step 2 of Example 50, using INT-44 and INT-71 as raw materials for reductive amination reaction, compound I-85 was prepared as a white solid (yield 52%). 1H NMR(800MHz, CD 3 OD-d 4 )δ7.20–7.17(m,1H), 7.08(d,J=8.3Hz,1H), 6.96–6.93(m,2H), 6.86(td,J= 7.5, 0.9 Hz, 1H), 6.58 (dd, J = 8.3, 2.5 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H), 6.25-6.20 (m, 1H), 5.99-5.91 (m, 1H) ), 4.64–4.60 (m, 2H), 3.85 (s, 3H), 3.78–3.73 (m, 2H), 3.15 (dd, J = 12.9, 6.7 Hz, 1H), 2.98 (dd, J = 12.9, 7.9 Hz,1H), 2.88–2.84(m,2H), 2.54–2.49(m,2H), 2.13–2.09(m,1H), 1.22–1.18(m,1H), 1.18–1.14(m,1H), 0.99–0.94(m,1H).HRMS(ESI) C 24 H 29 N 2 O 3 + ([M+H] + ) Calculated value: 393.2173, measured value: 393.2171.

实施例86：N-(4-(2-(((2-(2-甲氧基苯基)反式环丙基)甲基)胺基)乙基)反式环己基)吡咯烷-1-甲酰胺(I-86)的制备Example 86: N-(4-(2-(((2-(2-methoxyphenyl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl)pyrrolidine-1 -Preparation of formamide (I-86)

Figure PCTCN2021076289-appb-000343
Figure PCTCN2021076289-appb-000343

步骤1：将中间体INT-72(280mg,1.19mmol)(参考文献WO 2019016828A1制备)和三乙胺(359mg,3.56mmol)溶于无水乙腈(30mL)中，在0℃氮气保护下逐滴滴加入1- 吡咯烷甲酰氯(CAS:1192-63-8,238mg,1.78mmol)，然后室温搅拌过夜。减压蒸干溶剂，残留物用硅胶柱层析分离(乙酸乙酯/石油醚＝2/1)得白色固体中间体INT-73(212mg,yield 51％)。 1H NMR(800MHz,CDCl 3)δ3.97(s,1H),3.67(s,3H),3.64–3.59(m,1H),3.34–3.26(m,4H),3.18(s,3H),2.38–2.28(m,2H),2.04–1.99(m,2H),1.93–1.86(m,4H),1.84–1.78(m,3H),1.17–1.09(m,4H).HRMS(ESI)C 15H 28N 3O 3 +([M+H] +)计算值：298.2125，实测值：298.2127。 Step 1: Intermediate INT-72 (280mg, 1.19mmol) (prepared by reference WO 2019016828A1) and triethylamine (359mg, 3.56mmol) were dissolved in anhydrous acetonitrile (30mL), and the solution was added dropwise at 0°C under nitrogen protection 1-Pyrrolidinecarbonyl chloride (CAS: 1192-63-8, 238 mg, 1.78 mmol) was added dropwise, and then stirred at room temperature overnight. The solvent was evaporated to dryness under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 2/1) to obtain a white solid intermediate INT-73 (212 mg, yield 51%). 1 H NMR(800MHz, CDCl 3 )δ3.97(s,1H), 3.67(s,3H), 3.64-3.59(m,1H), 3.34-3.26(m,4H), 3.18(s,3H), 2.38–2.28(m,2H), 2.04–1.99(m,2H), 1.93–1.86(m,4H), 1.84–1.78(m,3H), 1.17–1.09(m,4H).HRMS(ESI)C 15 H 28 N 3 O 3 + ([M+H] + ) Calculated value: 298.2125, actually measured value: 298.2127.

步骤2：将中间体INT-73(212mg，0.71mmol)溶于干燥四氢呋喃(10mL)，氩气保护，冷却至-78℃。低温下，缓慢滴加1M二异丁基氢化铝四氢呋喃溶液(1.5mL)，反应6小时。加入饱和酒石酸钾钠水溶液淬灭反应，室温下搅拌1小时，过滤。滤液用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得无色油状物INT-74(反式混合物，140mg)，直接用于步骤3。Step 2: Intermediate INT-73 (212 mg, 0.71 mmol) was dissolved in dry tetrahydrofuran (10 mL), protected with argon, and cooled to -78°C. At low temperature, 1M diisobutylaluminum hydride tetrahydrofuran solution (1.5 mL) was slowly added dropwise, and reacted for 6 hours. The reaction was quenched by adding saturated potassium sodium tartrate aqueous solution, stirred at room temperature for 1 hour, and filtered. The filtrate was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oil INT-74 (trans mixture, 140 mg), which was directly used in step 3.

步骤3：仿照实施例50步骤2的方法，以INT-60和INT-74为原料进行还原胺化反应，制备得到化合物I-86，白色固体(收率38％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.22–7.18(m,1H),6.99–6.94(m,2H),6.89(td,J＝7.5,0.8Hz,1H),3.89(s,3H),3.59–3.50(m,1H),3.38–3.34(m,4H),3.22(dd,J＝12.9,6.8Hz,1H),3.14–3.07(m,2H),3.03(dd,J＝12.9,8.1Hz,1H),2.21–2.15(m,1H),1.98–1.92(m,6H),1.89–1.82(m,2H),1.69–1.61(m,2H),1.42–1.33(m,3H),1.28–1.22(m,1H),1.20–1.17(m,1H),1.17–1.10(m,2H),1.04–0.99(m,1H).HRMS(ESI)C 24H 38N 3O 2 +([M+H] +)计算值：400.2959，实测值：400.2956。 Step 3: Following the method of step 2 in Example 50, using INT-60 and INT-74 as raw materials for reductive amination reaction, compound I-86 was prepared as a white solid (yield 38%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ7.22-7.18(m,1H), 6.99-6.94(m,2H), 6.89(td,J=7.5,0.8Hz,1H), 3.89(s ,3H),3.59–3.50(m,1H),3.38–3.34(m,4H),3.22(dd,J=12.9,6.8Hz,1H),3.14–3.07(m,2H),3.03(dd,J =12.9,8.1Hz,1H),2.21–2.15(m,1H),1.98–1.92(m,6H),1.89–1.82(m,2H),1.69–1.61(m,2H),1.42–1.33(m ,3H),1.28–1.22(m,1H),1.20–1.17(m,1H),1.17–1.10(m,2H),1.04–0.99(m,1H).HRMS(ESI)C 24 H 38 N 3 O 2 + ([M+H] + ) calculated value: 400.2959, measured value: 400.2956.

实施例87：N-(4-(2-(((2-(2-甲氧基苯基)反式环丙基)甲基)胺基)乙基)反式环己基)苯甲酰胺(I-87)的制备Example 87: N-(4-(2-(((2-(2-methoxyphenyl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl)benzamide ( I-87) Preparation

Figure PCTCN2021076289-appb-000344
Figure PCTCN2021076289-appb-000344

步骤1：仿照实施例86步骤1中所述以中间体INT-72和1-吡咯烷甲酰氯制备中间体INT-73的方法，以中间体INT-72和苯甲酰氯为原料制备中间体INT-75。白色固体(收率69％)。 1H NMR(800MHz,CDCl 3)δ7.75(d,J＝7.3Hz,2H),7.50–7.46(m,1H),7.42(t,J＝7.6Hz,2H),5.95(d,J＝7.5Hz,1H),4.00–3.89(m,1H),3.69(s,3H),3.19(s,3H),2.42–2.28(m,2H),2.16–2.07(m,2H),1.94–1.84(m,3H),1.33–1.25(m,2H),1.22–1.14(m,2H). Step 1: Following the method of preparing intermediate INT-73 with intermediate INT-72 and 1-pyrrolidinecarbonyl chloride as described in Example 86, step 1, intermediate INT-72 and benzoyl chloride are used as raw materials to prepare intermediate INT -75. White solid (69% yield). 1 H NMR (800MHz, CDCl 3 ) δ 7.75 (d, J = 7.3 Hz, 2H), 7.50-7.46 (m, 1H), 7.42 (t, J = 7.6 Hz, 2H), 5.95 (d, J = 7.5Hz, 1H), 4.00--3.89 (m, 1H), 3.69 (s, 3H), 3.19 (s, 3H), 2.42 - 2.28 (m, 2H), 2.16 - 2.07 (m, 2H), 1.94 - 1.84 (m,3H),1.33-1.25(m,2H),1.22-1.14(m,2H).

步骤2：仿照实施例86步骤2中所述的用二异丁基氢化铝还原中间体INT-73来制备中间体INT-74的方法，将中间体INT-75用二异丁基氢化铝还原为中间体INT-76，并直接用于步骤3。Step 2: Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-75 with diisobutylaluminum hydride It is the intermediate INT-76 and used directly in step 3.

步骤3：仿照实施例50步骤2的方法，以INT-60和INT-76为原料进行还原胺化反应，制备得到化合物I-87，白色固体(收率53％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.81–7.77(m,2H),7.54–7.49(m,1H),7.47–7.41(m,2H),7.15–7.09(m,1H),6.92–6.87(m,2H),6.83(td,J＝7.4,0.7Hz,1H),3.86(s,3H),3.85–3.81(m,1H),2.81(dd,J＝12.2,5.9Hz,1H),2.76–2.64(m,2H),2.48(dd,J＝12.2,8.0Hz,1H),2.01–1.96(m,2H),1.96–1.91(m,1H),1.88–1.81(m,2H),1.53–1.44(m,2H),1.43–1.33(m,3H),1.17–1.08(m,3H),1.01–0.96(m,1H),0.83–0.76(m,1H).HRMS(ESI)C 26H 35N 2O 2 +([M+H] +)计算值：407.2693，实测值：407.2696。 Step 3: Following the method of step 2 of Example 50, using INT-60 and INT-76 as raw materials for reductive amination reaction, compound I-87 was prepared as a white solid (yield 53%). 1 H NMR(800MHz, CD 3 OD-d 4 ) δ7.81-7.77(m,2H), 7.54-7.49(m,1H), 7.47-7.41(m,2H), 7.15-7.09(m,1H) ,6.92-6.87(m,2H),6.83(td,J=7.4,0.7Hz,1H),3.86(s,3H),3.85-3.81(m,1H),2.81(dd,J=12.2,5.9Hz ,1H),2.76–2.64(m,2H), 2.48(dd,J=12.2,8.0Hz,1H),2.01–1.96(m,2H),1.96–1.91(m,1H),1.88–1.81(m ,2H),1.53–1.44(m,2H),1.43–1.33(m,3H),1.17–1.08(m,3H),1.01–0.96(m,1H),0.83–0.76(m,1H).HRMS (ESI) C 26 H 35 N 2 O 2 + ([M+H] + ) calculated value: 407.2693, measured value: 407.2696.

实施例88：N-(4-(2-(((2-(2-甲氧基苯基)反式环丙基)甲基)胺基)乙基)反式环己基)苯磺酰胺(I-88)的制备Example 88: N-(4-(2-(((2-(2-methoxyphenyl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl)benzenesulfonamide ( I-88) Preparation

Figure PCTCN2021076289-appb-000345
Figure PCTCN2021076289-appb-000345

步骤1：仿照实施例86步骤1中所述以中间体INT-72和1-吡咯烷甲酰氯制备中间体INT-73的方法，以中间体INT-72和苯磺酰氯为原料制备中间体INT-77。白色固体(收率63％)。 1H NMR(800MHz,CDCl 3)δ7.88(d,J＝7.9Hz,2H),7.55(t,J＝7.4Hz,1H),7.49(t,J＝7.5Hz,2H),5.03–4.79(m,1H),3.64(s,3H),3.16(s,3H),3.12–3.06(m,1H),2.29–2.22(m,2H),1.81(d,J＝11.6Hz,2H),1.76–1.71(m,3H),1.24–1.17(m,2H),1.02–0.92(m,2H). Step 1: Following the method of preparing intermediate INT-73 with intermediate INT-72 and 1-pyrrolidinecarbonyl chloride as described in step 1 of Example 86, intermediate INT-72 and benzenesulfonyl chloride are used as raw materials to prepare intermediate INT. -77. White solid (63% yield). 1 H NMR(800MHz, CDCl 3 )δ7.88(d,J=7.9Hz,2H), 7.55(t,J=7.4Hz,1H), 7.49(t,J=7.5Hz,2H), 5.03-4.79 (m,1H),3.64(s,3H),3.16(s,3H),3.12–3.06(m,1H),2.29–2.22(m,2H),1.81(d,J=11.6Hz,2H), 1.76–1.71(m,3H), 1.24–1.17(m,2H), 1.02–0.92(m,2H).

步骤2：仿照实施例86步骤2中所述的用二异丁基氢化铝还原中间体INT-73来制备中间体INT-74的方法，将中间体INT-77用二异丁基氢化铝还原为中间体INT-78，并直接用于步骤3。Step 2: Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride as described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-77 with diisobutylaluminum hydride It is an intermediate INT-78 and used directly in step 3.

步骤3：仿照实施例50步骤2的方法，以INT-60和INT-78为原料进行还原胺化反应，制备得到化合物I-88，白色固体(收率51％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.88–7.84(m,2H),7.63–7.59(m,1H),7.57–7.53(m,2H),7.20–7.15(m,1H),6.95–6.90(m,2H),6.88–6.83(m,1H),3.84(s,3H),3.16(dd,J＝12.9,6.7Hz,1H),3.05–2.93(m,4H),2.16 –2.10(m,1H),1.77–1.68(m,4H),1.58–1.51(m,2H),1.28–1.24(m,1H),1.23–1.17(m,3H),1.17–1.13(m,1H),1.00–0.93(m,3H).HRMS(ESI)C 25H 35N 2O 3S +([M+H] +)计算值：443.2363，实测值：443.2364。 Step 3: Following the method of step 2 of Example 50, using INT-60 and INT-78 as raw materials for reductive amination reaction, compound I-88 was prepared as a white solid (yield 51%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ7.88-7.84 (m, 2H), 7.63-7.59 (m, 1H), 7.57-7.53 (m, 2H), 7.20-7.15 (m, 1H) ,6.95–6.90(m,2H),6.88–6.83(m,1H),3.84(s,3H),3.16(dd,J=12.9,6.7Hz,1H),3.05–2.93(m,4H),2.16 --2.10(m,1H),1.77–1.68(m,4H),1.58–1.51(m,2H),1.28–1.24(m,1H),1.23–1.17(m,3H),1.17–1.13(m, 1H),1.00–0.93(m,3H).HRMS(ESI)C 25 H 35 N 2 O 3 S + ([M+H] + ) Calculated value: 443.2363, measured value: 443.2364.

实施例89：N-(4-(2-(((2-(2-甲氧基苯基)反式环丙基)甲基)胺基)乙基)反式环己基)环己基甲酰胺(I-89)的制备Example 89: N-(4-(2-(((2-(2-methoxyphenyl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl)cyclohexylcarboxamide (I-89) Preparation

Figure PCTCN2021076289-appb-000346
Figure PCTCN2021076289-appb-000346

步骤1：仿照实施例86步骤1中所述以中间体INT-72和1-吡咯烷甲酰氯制备中间体INT-73的方法，以中间体INT-72和环己基甲酰氯为原料制备中间体INT-79。白色固体(收率64％)。 1H NMR(600MHz,CDCl 3)δ3.67(s,3H),3.18(s,3H),2.39–2.25(m,2H),2.06–1.98(m,1H),1.98–1.91(m,2H),1.90–1.71(m,8H),1.70–1.61(m,1H),1.47–1.35(m,2H),1.27–1.09(m,7H).HRMS(ESI)C 17H 31N 2O 3 +([M+H] +)计算值：311.2329，实测值：311.2335。 Step 1: Following the method of preparing intermediate INT-73 with intermediate INT-72 and 1-pyrrolidinecarboxylic acid chloride as described in Example 86, step 1, the intermediate INT-72 and cyclohexylcarboxylic acid chloride are used as raw materials to prepare intermediate INT-79. White solid (yield 64%). 1 H NMR (600MHz, CDCl 3 ) δ 3.67 (s, 3H), 3.18 (s, 3H), 2.39-2.25 (m, 2H), 2.06-1.98 (m, 1H), 1.98-1.91 (m, 2H) ),1.90–1.71(m,8H),1.70–1.61(m,1H),1.47–1.35(m,2H),1.27–1.09(m,7H).HRMS(ESI)C 17 H 31 N 2 O 3 + ([M+H] + ) Calculated value: 311.2329, measured value: 311.2335.

步骤2：仿照实施例86步骤2中所述的用二异丁基氢化铝还原中间体INT-73来制备中间体INT-74的方法，将中间体INT-79用二异丁基氢化铝还原为中间体INT-80，并直接用于步骤3。Step 2: Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-79 with diisobutylaluminum hydride It is an intermediate INT-80 and used directly in step 3.

步骤3：仿照实施例50步骤2的方法，以INT-60和INT-80为原料进行还原胺化反应，制备得到化合物I-89，白色固体(收率52％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.16–7.12(m,1H),6.91(dd,J＝9.2,6.0Hz,2H),6.84(t,J＝7.3Hz,1H),3.85(s,3H),3.58–3.52(m,1H),2.99(dd,J＝12.5,6.3Hz,1H),2.92–2.83(m,2H),2.75(dd,J＝12.4,8.1Hz,1H),2.15–2.08(m,1H),2.07–2.01(m,1H),1.88–1.84(m,2H),1.82–1.75(m,4H),1.74–1.71(m,2H),1.70–1.65(m,1H),1.58–1.50(m,2H),1.43(qd,J＝12.6,3.2Hz,2H),1.32–1.26(m,3H),1.25–1.16(m,4H),1.10–1.04(m,3H),0.92–0.87(m,1H).HRMS(ESI)C 26H 41N 2O 2 +([M+H] +)计算值：413.3163，实测值：413.3158。 Step 3: Following the method of step 2 in Example 50, using INT-60 and INT-80 as raw materials for reductive amination reaction, compound 1-89 was prepared as a white solid (yield 52%). 1 H NMR(800MHz,CD 3 OD-d 4 )δ7.16–7.12(m,1H), 6.91(dd,J=9.2,6.0Hz,2H), 6.84(t,J=7.3Hz,1H), 3.85(s,3H),3.58–3.52(m,1H),2.99(dd,J=12.5,6.3Hz,1H), 2.92–2.83(m,2H), 2.75(dd,J=12.4,8.1Hz, 1H), 2.15--2.08(m,1H), 2.07--2.01(m,1H), 1.88--1.84(m,2H), 1.82--1.75(m,4H), 1.74--1.71(m,2H), 1.70-- 1.65(m,1H),1.58–1.50(m,2H),1.43(qd,J=12.6,3.2Hz,2H),1.32–1.26(m,3H),1.25–1.16(m,4H),1.10– 1.04 (m, 3H), 0.92-0.87 (m, 1H). HRMS (ESI) C 26 H 41 N 2 O 2 + ([M+H] + ) Calculated value: 413.3163, measured value: 413.3158.

实施例90：N-(4-(2-(((2-(2-甲氧基苯基)反式环丙基)甲基)胺基)乙基)反式环己基)哌啶-1-甲酰胺(I-90)的制备Example 90: N-(4-(2-(((2-(2-methoxyphenyl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl)piperidine-1 -Preparation of formamide (I-90)

Figure PCTCN2021076289-appb-000347
Figure PCTCN2021076289-appb-000347

步骤1：仿照实施例86步骤1中所述以中间体INT-72和1-吡咯烷甲酰氯制备中间体INT-73的方法，以中间体INT-72和哌啶-1-甲酰氯(CAS:13939-69-0)为原料制备中间体INT-81。白色固体(收率62％)。 1H NMR(800MHz,CDCl 3)δ4.23(s,1H),3.67(s,3H),3.64–3.56(m,1H),3.31–3.27(m,4H),3.18(s,3H),2.39–2.22(m,2H),2.00(d,J＝11.9Hz,2H),1.88–1.75(m,3H),1.60–1.56(m,2H),1.56–1.52(m,4H),1.14–1.10(m,4H).HRMS(ESI)C 16H 30N 3O 3 +([M+H] +)计算值：312.2282，实测值：312.2286。 Step 1: Following the method of preparing intermediate INT-73 with intermediate INT-72 and 1-pyrrolidinecarboxylic acid chloride in step 1 of Example 86, using intermediate INT-72 and piperidine-1-carboxylic acid chloride (CAS :13939-69-0) as the raw material to prepare intermediate INT-81. White solid (62% yield). 1 H NMR (800MHz, CDCl 3 ) δ 4.23 (s, 1H), 3.67 (s, 3H), 3.64-3.56 (m, 1H), 3.31-3.27 (m, 4H), 3.18 (s, 3H), 2.39–2.22(m,2H),2.00(d,J=11.9Hz,2H),1.88–1.75(m,3H),1.60–1.56(m,2H),1.56–1.52(m,4H),1.14– 1.10 (m, 4H). HRMS (ESI) C 16 H 30 N 3 O 3 + ([M+H] + ) Calculated value: 312.2282, measured value: 312.2286.

步骤2：仿照实施例86步骤2中所述的用二异丁基氢化铝还原中间体INT-73来制备中间体INT-74的方法，将中间体INT-81用二异丁基氢化铝还原为中间体INT-82，并直接用于步骤3。Step 2: Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-81 with diisobutylaluminum hydride It is an intermediate INT-82 and used directly in step 3.

步骤3：仿照实施例50步骤2的方法，以INT-60和INT-82为原料进行还原胺化反应，制备得到化合物I-90，白色固体(收率49％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.16–7.11(m,1H),6.92–6.89(m,2H),6.85–6.82(m,1H),3.85(s,3H),3.51–3.45(m,1H),3.35–3.32(m,4H),2.93(dd,J＝12.4,6.2Hz,1H),2.85–2.77(m,2H),2.65(dd,J＝12.4,8.1Hz,1H),2.02–1.98(m,1H),1.92–1.86(m,2H),1.82–1.77(m,2H),1.64–1.59(m,2H),1.54–1.48(m,6H),1.29–1.21(m,3H),1.16–1.11(m,1H),1.10–1.02(m,3H),0.89–0.83(m,1H).HRMS(ESI)C 25H 40N 3O 2 +([M+H] +)计算值：414.3115，实测值：414.3120。 Step 3: Following the method of step 2 in Example 50, using INT-60 and INT-82 as raw materials for reductive amination reaction, compound I-90 was prepared as a white solid (yield 49%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 7.16-7.11 (m, 1H), 6.92-6.89 (m, 2H), 6.85-6.82 (m, 1H), 3.85 (s, 3H), 3.51 –3.45(m,1H), 3.35–3.32(m,4H), 2.93(dd,J＝12.4,6.2Hz,1H), 2.85–2.77(m,2H), 2.65(dd,J＝12.4,8.1Hz ,1H),2.02–1.98(m,1H),1.92–1.86(m,2H),1.82–1.77(m,2H),1.64–1.59(m,2H),1.54–1.48(m,6H),1.29 –1.21(m,3H),1.16–1.11(m,1H),1.10–1.02(m,3H),0.89–0.83(m,1H).HRMS(ESI)C 25 H 40 N 3 O 2 + ([ M+H] + ) Calculated value: 414.3115, measured value: 414.3120.

实施例91：N-(4-(2-(((2-(2-甲氧基苯基)反式环丙基)甲基)胺基)乙基)反式环己基)-1H-吲哚-2-甲酰胺(I-91)的制备Example 91: N-(4-(2-(((2-(2-methoxyphenyl)transcyclopropyl)methyl)amino)ethyl)transcyclohexyl)-1H-indyl Preparation of indole-2-carboxamide (I-91)

Figure PCTCN2021076289-appb-000348
Figure PCTCN2021076289-appb-000348

步骤1：将2-吲哚甲酸(CAS:1477-50-5,191mg,1.18mmol)和HATU(902mg,2.37mmol)溶于无水DMF(20mL)中，室温搅拌0.5h，再依次加入DIPEA(459mg,3.56mmol)和中间体INT-72(280mg,1.18mmol)，然后室温搅拌过夜。向反应液中加入水(60mL)，用乙酸乙酯萃取三次，合并酯相，减压蒸干溶剂，残留物用硅胶柱层析分离(乙酸乙酯/石油醚＝2/1)得中间体INT-83。 1H NMR(800MHz,CDCl 3)δ9.30(s,1H),7.64(d,J＝8.0Hz,1H),7.43(d,J＝8.2Hz,1H),7.28(t,J＝7.6Hz,1H),7.14(t,J＝7.4Hz,1H),6.84(s,1H),6.09(s,1H),4.01–3.92(m,1H),3.69(s,3H),3.20(s,3H),2.44–2.28(m,2H),2.18–2.09(m,2H),1.92–1.85(m,3H),1.37–1.29(m,2H),1.23–1.14(m,2H). Step 1: Dissolve 2-indolecarboxylic acid (CAS:1477-50-5,191mg, 1.18mmol) and HATU (902mg, 2.37mmol) in anhydrous DMF (20mL), stir at room temperature for 0.5h, and then add DIPEA ( 459mg, 3.56mmol) and intermediate INT-72 (280mg, 1.18mmol), then stirred at room temperature overnight. Water (60 mL) was added to the reaction solution, extracted three times with ethyl acetate, the ester phases were combined, the solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether = 2/1) to obtain an intermediate INT-83. 1 H NMR(800MHz,CDCl 3 )δ9.30(s,1H), 7.64(d,J=8.0Hz,1H), 7.43(d,J=8.2Hz,1H), 7.28(t,J=7.6Hz ,1H),7.14(t,J=7.4Hz,1H),6.84(s,1H),6.09(s,1H),4.01–3.92(m,1H), 3.69(s,3H), 3.20(s, 3H), 2.44-2.28 (m, 2H), 2.18-2.09 (m, 2H), 1.92-1.85 (m, 3H), 1.37-1.29 (m, 2H), 1.23--1.14 (m, 2H).

步骤2：仿照实施例86步骤2中所述的用二异丁基氢化铝还原中间体INT-73来制备中间体INT-74的方法，将中间体INT-83用二异丁基氢化铝还原为中间体INT-84，并直接用于步骤3。Step 2: Following the method of reducing intermediate INT-73 with diisobutylaluminum hydride described in step 2 of Example 86 to prepare intermediate INT-74, reducing intermediate INT-83 with diisobutylaluminum hydride It is the intermediate INT-84 and used directly in step 3.

步骤3：仿照实施例50步骤2的方法，以INT-60和INT-84为原料进行还原胺化反应，制备得到化合物I-91，白色固体(收率52％)。 1H NMR(800MHz,CD 3OD-d 4)δ7.58(d,J＝8.0Hz,1H),7.42(dd,J＝8.3,0.8Hz,1H),7.21–7.18(m,1H),7.17–7.13(m,1H),7.10–7.07(m,1H),7.06–7.02(m,1H),6.95–6.89(m,2H),6.86–6.83(m,1H),3.87(s,3H),3.85–3.82(m,1H),2.99(dd,J＝12.4,6.2Hz,1H),2.93–2.84(m,2H),2.73(dd,J＝12.2,8.2Hz,1H),2.08–1.98(m,3H),1.89–1.83(m,2H),1.62–1.53(m,2H),1.46–1.36(m,3H),1.20–1.12(m,3H),1.09–1.04(m,1H),0.92–0.87(m,1H).HRMS(ESI)C 28H 26N 3O 2 +([M+H] +)计算值：446.2802，实测值：446.2807。 Step 3: Following the method of step 2 of Example 50, using INT-60 and INT-84 as raw materials for reductive amination reaction, compound I-91 was prepared as a white solid (yield 52%). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 7.58 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 8.3, 0.8 Hz, 1H), 7.21-7.18 (m, 1H), 7.17–7.13(m,1H), 7.10–7.07(m,1H), 7.06–7.02(m,1H), 6.95–6.89(m,2H), 6.86–6.83(m,1H), 3.87(s,3H) ), 3.85–3.82 (m, 1H), 2.99 (dd, J = 12.4, 6.2 Hz, 1H), 2.93–2.84 (m, 2H), 2.73 (dd, J = 12.2, 8.2 Hz, 1H), 2.08– 1.98(m,3H),1.89-1.83(m,2H),1.62-1.53(m,2H),1.46-1.36(m,3H),1.20-1.12(m,3H),1.09-1.04(m,1H) ), 0.92-0.87 (m, 1H). HRMS (ESI) C 28 H 26 N 3 O 2 + ([M+H] + ) calculated value: 446.2802, measured value: 446.2807.

实施例92：反式7-(4-(乙基((2-(5-氟-2-甲氧基苯基)环丙基)甲基)胺基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(I-92)的制备Example 92: trans 7-(4-(ethyl((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)amino)butoxy)-3,4- Preparation of dihydroquinoline-2(1H)-one (I-92)

Figure PCTCN2021076289-appb-000349
Figure PCTCN2021076289-appb-000349

仿照实施例2的方法，以I-47和乙醛水溶液为原料进行还原胺化反应，得产物I-92(白色泡沫)。 1H NMR(800MHz,CD 3OD-d 4)δ7.03(d,J＝8.3Hz,1H),6.88–6.83(m,1H),6.81(td,J＝8.5,3.0Hz,1H),6.58(dd,J＝9.6,3.0Hz,1H),6.51(dd,J＝8.3,2.5Hz,1H),6.43(d,J＝2.5Hz,1H),3.94(t,J＝5.8Hz,2H),3.81(s,3H),2.92–2.83(m,6H),2.83–2.78(m,1H),2.73–2.66(m,1H),2.56–2.49(m,2H),2.15–2.08(m,1H),1.80–1.68(m,4H),1.19–1.09(m,4H),1.05–0.98(m,1H),0.92–0.84(m,1H).HRMS(ESI)C 26H 34FN 2O 3 +([M+H] +)计算值：441.2548，实测值：441.2551。 Following the method of Example 2, using I-47 and acetaldehyde aqueous solution as raw materials for reductive amination reaction, the product I-92 (white foam) was obtained. 1 H NMR (800MHz, CD 3 OD-d 4 ) δ7.03 (d, J = 8.3 Hz, 1H), 6.88-6.83 (m, 1H), 6.81 (td, J = 8.5, 3.0 Hz, 1H), 6.58(dd,J=9.6,3.0Hz,1H),6.51(dd,J=8.3,2.5Hz,1H),6.43(d,J=2.5Hz,1H),3.94(t,J=5.8Hz,2H ), 3.81 (s, 3H), 2.92-2.83 (m, 6H), 2.83-2.78 (m, 1H), 2.73-2.66 (m, 1H), 2.56-2.49 (m, 2H), 2.15-2.08 (m ,1H),1.80-1.68(m,4H),1.19-1.09(m,4H),1.05-0.98(m,1H),0.92-0.84(m,1H).HRMS(ESI)C 26 H 34 FN 2 O 3 + ([M+H] + ) calculated value: 441.2548, measured value: 441.2551.

实施例93：反式7-(4-(乙基((2-(5-氟-2-甲氧苯基)环丙基)甲基)胺基)丁氧基)喹啉-2(1H)-酮(I-93)的制备Example 93: trans 7-(4-(ethyl((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)amino)butoxy)quinoline-2(1H Preparation of )-ketone (I-93)

Figure PCTCN2021076289-appb-000350
Figure PCTCN2021076289-appb-000350

仿照实施例2的方法，以I-67和乙醛水溶液为原料进行还原胺化反应，得产物I-93(白色泡沫)。 1H NMR(800MHz,CD 3OD-d 4)δ7.89–7.84(m,1H),7.57–7.51(m,1H),6.87–6.82(m,2H),6.82–6.77(m,2H),6.59(dd,J＝9.5,2.4Hz,1H),6.43(dd,J＝9.4,1.1Hz,1H),4.12–4.04(m,2H),3.81(s,3H),3.06–2.87(m,5H),2.84–2.73(m,1H),2.19–2.10(m,1H),1.91–1.70(m,4H),1.23–1.15(m,4H),1.09–1.00(m,1H),0.95–0.85(m,1H).HRMS(ESI)C 26H 32FN 2O 3 +([M+H] +)计算值：439.2391，实测值：439.2398。 Imitating the method of Example 2, using I-67 and acetaldehyde aqueous solution as raw materials for reductive amination reaction, the product I-93 (white foam) was obtained. 1 H NMR (800MHz, CD 3 OD-d 4 ) δ7.89-7.84(m,1H), 7.57-7.51(m,1H), 6.87-6.82(m,2H), 6.82-6.77(m,2H) ,6.59(dd,J=9.5,2.4Hz,1H), 6.43(dd,J=9.4,1.1Hz,1H), 4.12–4.04(m,2H),3.81(s,3H),3.06–2.87(m ,5H),2.84-2.73(m,1H),2.19--2.10(m,1H),1.91--1.70(m,4H),1.23--1.15(m,4H),1.09-1.00(m,1H),0.95 -0.85(m,1H).HRMS(ESI)C 26 H 32 FN 2 O 3 + ([M+H] + ) Calculated value: 439.2391, measured value: 439.2398.

实施例94：反式7-(3-(((2-(5-氯-2-甲氧基苯基)环丙基)甲基)(乙基)胺基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-94)的制备Example 94: trans 7-(3-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)(ethyl)amino)propoxy)-3, Preparation of 4-dihydroquinoline-2(1H)-one (I-94)

Figure PCTCN2021076289-appb-000351
Figure PCTCN2021076289-appb-000351

仿照实施例2的方法，以I-81和乙醛水溶液为原料进行还原胺化反应，得产物I-94(白色泡沫)。 1H NMR(800MHz,CD 3OD-d 4)δ7.08(dd,J＝8.7,2.6Hz,1H),7.03(d,J＝8.3Hz,1H),6.85(d,J＝8.7Hz,1H),6.80(d,J＝2.6Hz,1H),6.49(dd,J＝8.3,2.5Hz,1H),6.42(d,J＝2.4Hz,1H),4.00–3.95(m,2H),3.79(s,3H),2.98–2.91(m,1H),2.91–2.81(m,6H),2.71–2.66(m,1H),2.55–2.49(m,2H),2.12–2.05(m,1H),2.01–1.96(m,2H),1.16– 1.12(m,4H),1.02–0.98(m,1H),0.88–0.85(m,1H).HRMS(ESI)C 25H 32ClN 2O 3 +([M+H] +)计算值：443.2096，实测值：443.2091。 Imitating the method of Example 2, using I-81 and acetaldehyde aqueous solution as raw materials for reductive amination reaction, the product I-94 (white foam) was obtained. 1 H NMR(800MHz,CD 3 OD-d 4 )δ7.08(dd,J=8.7,2.6Hz,1H), 7.03(d,J=8.3Hz,1H), 6.85(d,J=8.7Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 6.49 (dd, J = 8.3, 2.5 Hz, 1H), 6.42 (d, J = 2.4 Hz, 1H), 4.00–3.95 (m, 2H), 3.79 (s, 3H), 2.98-2.91 (m, 1H), 2.91-2.81 (m, 6H), 2.71-2.66 (m, 1H), 2.55-2.49 (m, 2H), 2.12-2.05 (m, 1H) ),2.01–1.96(m,2H),1.16–1.12(m,4H),1.02–0.98(m,1H),0.88–0.85(m,1H).HRMS(ESI)C 25 H 32 ClN 2 O 3 + ([M+H] + ) Calculated value: 443.2096, measured value: 443.2091.

实施例95：反式7-(3-(乙基((2-(5-氟-2-甲氧基苯基)环丙基)甲基)胺基)丙氧基)-3,4-二氢喹啉-2(1H)-酮(I-95)的制备Example 95: trans 7-(3-(ethyl((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)amino)propoxy)-3,4- Preparation of dihydroquinoline-2(1H)-one (I-95)

Figure PCTCN2021076289-appb-000352
Figure PCTCN2021076289-appb-000352

仿照实施例2的方法，以I-79和乙醛水溶液为原料进行还原胺化反应，得产物I-95(白色泡沫)。 1H NMR(800MHz,CD 3OD-d 4)δ7.03(d,J＝8.3Hz,1H),6.86–6.83(m,1H),6.83–6.79(m,1H),6.56(dd,J＝9.7,3.0Hz,1H),6.49(dd,J＝8.3,2.4Hz,1H),6.42(d,J＝2.4Hz,1H),4.00–3.94(m,2H),3.78(s,3H),2.95–2.87(m,1H),2.87–2.83(m,3H),2.83–2.75(m,3H),2.67–2.61(m,1H),2.55–2.48(m,2H),2.14–2.05(m,1H),2.01–1.92(m,2H),1.17–1.08(m,4H),1.01–0.96(m,1H),0.89–0.82(m,1H).HRMS(ESI)C 25H 32FN 2O 3 +([M+H] +)计算值：427.2391，实测值：427.2395。 Imitating the method of Example 2, using I-79 and acetaldehyde aqueous solution as raw materials for reductive amination reaction, the product I-95 (white foam) was obtained. 1 H NMR(800MHz,CD 3 OD-d 4 )δ7.03(d,J=8.3Hz,1H), 6.86–6.83(m,1H), 6.83–6.79(m,1H), 6.56(dd,J ＝9.7,3.0Hz,1H),6.49(dd,J＝8.3,2.4Hz,1H),6.42(d,J＝2.4Hz,1H),4.00–3.94(m,2H),3.78(s,3H) ,2.95–2.87(m,1H), 2.87–2.83(m,3H), 2.83–2.75(m,3H), 2.67–2.61(m,1H), 2.55–2.48(m,2H), 2.14–2.05( m,1H),2.01–1.92(m,2H),1.17–1.08(m,4H),1.01–0.96(m,1H),0.89–0.82(m,1H).HRMS(ESI)C 25 H 32 FN 2 O 3 + ([M+H] + ) Calculated value: 427.2391, measured value: 427.2395.

实施例96：反式7-(4-(((2-(5-氯-2-甲氧苯基)环丙基)甲基)(乙基)氨基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(I-96)的制备Example 96: trans 7-(4-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)(ethyl)amino)butoxy)-3,4- Preparation of dihydroquinoline-2(1H)-one (I-96)

Figure PCTCN2021076289-appb-000353
Figure PCTCN2021076289-appb-000353

仿照实施例2的方法，以I-71和乙醛水溶液为原料进行还原胺化反应，得产物I-96(白色泡沫)。 1H NMR(800MHz,CD 3OD-d 4)δ7.08(dd,J＝8.7,2.5Hz,1H),7.02(d,J＝8.3Hz,1H),6.85(d,J＝8.7Hz,1H),6.81(d,J＝2.5Hz,1H),6.50(dd,J＝8.3,2.4Hz,1H),6.43(d,J＝2.4Hz,1H),3.94(t,J＝5.8Hz,2H),3.81(s,3H),2.90–2.80(m,7H),2.74–2.68(m,1H),2.54–2.48(m,2H),2.11–2.05(m,1H),1.79–1.69(m,4H),1.18–1.13(m,4H),1.06–0.98(m,1H),0.90–0.84(m,1H).HRMS(ESI)C 26H 34ClN 2O 3 +([M+H] +)计算值：457.2252，实测值：457.2248。 Following the method of Example 2, using I-71 and acetaldehyde aqueous solution as raw materials for reductive amination reaction, the product I-96 (white foam) was obtained. 1 H NMR(800MHz,CD 3 OD-d 4 )δ7.08(dd,J=8.7,2.5Hz,1H), 7.02(d,J=8.3Hz,1H), 6.85(d,J=8.7Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 6.50 (dd, J = 8.3, 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 3.94 (t, J = 5.8 Hz, 2H), 3.81 (s, 3H), 2.90 - 2.80 (m, 7H), 2.74 - 2.68 (m, 1H), 2.54 - 2.48 (m, 2H), 2.11 - 2.05 (m, 1H), 1.79 - 1.69 ( m,4H),1.18–1.13(m,4H),1.06–0.98(m,1H),0.90–0.84(m,1H).HRMS(ESI)C 26 H 34 ClN 2 O 3 + ((M+H ] + ) Calculated value: 457.2252, measured value: 457.2248.

实施例97：反式7-(3-(((2-(5-氯-2-甲氧基苯基)环丙基)甲基)(乙基)胺基)丙氧基)喹啉-2(1H)-酮(I-97)的制备Example 97: trans 7-(3-(((2-(5-chloro-2-methoxyphenyl)cyclopropyl)methyl)(ethyl)amino)propoxy)quinoline- Preparation of 2(1H)-ketone (I-97)

Figure PCTCN2021076289-appb-000354
Figure PCTCN2021076289-appb-000354

仿照实施例2的方法，以I-78和乙醛水溶液为原料进行还原胺化反应，得产物I-97(白色泡沫)。 1H NMR(800MHz,CD 3OD-d 4)δ7.85(d,J＝9.3Hz,1H),7.53(d,J＝8.7Hz,1H),7.08(dd,J＝8.7,2.5Hz,1H),6.85(d,J＝8.7Hz,1H),6.82–6.80(m,2H),6.80–6.77(m,1H),6.43(d,J＝9.4Hz,1H),4.18–4.07(m,2H),3.79(s,3H),3.11–3.05(m,1H),3.05–3.00(m,1H),3.00–2.90(m,3H),2.85–2.73(m,1H),2.15–2.01(m,3H),1.23–1.15(m,4H),1.08–0.99(m,1H),0.95–0.85(m,1H).HRMS(ESI)C 25H 30ClN 2O 3 +([M+H] +)计算值：441.1939，实测值：441.1935。 Imitating the method of Example 2, using I-78 and acetaldehyde aqueous solution as raw materials for reductive amination reaction, the product I-97 (white foam) was obtained. 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 7.85 (d, J = 9.3 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 6.85(d,J=8.7Hz,1H), 6.82–6.80(m,2H), 6.80–6.77(m,1H), 6.43(d,J=9.4Hz,1H), 4.18–4.07(m ,2H),3.79(s,3H),3.11-3.05(m,1H),3.05-3.00(m,1H),3.00-2.90(m,3H),2.85-2.73(m,1H),2.15-2.01 (m,3H),1.23–1.15(m,4H),1.08–0.99(m,1H),0.95–0.85(m,1H).HRMS(ESI)C 25 H 30 ClN 2 O 3 + ((M+ H] + ) Calculated value: 441.1939, measured value: 441.1935.

实施例98：反式7-(4-(((2-(5--氯-2-甲氧苯基)环丙基)甲基)(乙基)胺基)丁氧基)喹啉-2(1H)-酮(I-98)的制备Example 98: trans 7-(4-(((2-(5--chloro-2-methoxyphenyl)cyclopropyl)methyl)(ethyl)amino)butoxy)quinoline- Preparation of 2(1H)-ketone (I-98)

Figure PCTCN2021076289-appb-000355
Figure PCTCN2021076289-appb-000355

仿照实施例2的方法，以I-68和乙醛水溶液为原料进行还原胺化反应，得产物I-98(白色泡沫)。 1H NMR(800MHz,CD 3OD-d 4)δ7.86(d,J＝9.3Hz,1H),7.53(d,J＝8.6Hz,1H),7.07(dd,J＝8.7,2.5Hz,1H),6.85(d,J＝8.7Hz,1H),6.84–6.80(m,3H),6.43(d,J＝9.4Hz,1H),4.12–4.05(m,2H),3.83(s,3H),3.16–2.99(m,5H),2.95–2.90(m,1H),2.18–2.12(m,1H),1.91–1.81(m,4H),1.26–1.21(m,4H),1.12–1.06(m,1H),0.99–0.92(m,1H).HRMS(ESI)C 26H 32ClN 2O 3 +([M+H] +)计算值：455.2096，实测值：455.2092。 Imitating the method of Example 2, using I-68 and acetaldehyde aqueous solution as raw materials for reductive amination reaction, the product I-98 (white foam) was obtained. 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 7.86 (d, J = 9.3 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 8.7, 2.5 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.84-6.80 (m, 3H), 6.43 (d, J = 9.4 Hz, 1H), 4.12-4.05 (m, 2H), 3.83 (s, 3H) ), 3.16–2.99(m,5H), 2.95–2.90(m,1H), 2.18–2.12(m,1H), 1.91–1.81(m,4H), 1.26–1.21(m,4H), 1.12–1.06 (m, 1H), 0.99-0.92 (m, 1H). HRMS (ESI) C 26 H 32 ClN 2 O 3 + ([M+H] + ) calculated value: 455.2096, measured value: 455.2096.

实施例99：反式7-(3-(乙基((2-(5-氟-2-甲氧基苯基)环丙基)甲基)胺基)丙氧基)喹啉-2(1H)-酮(I-99)的制备Example 99: trans 7-(3-(ethyl((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)amino)propoxy)quinoline-2( 1H)-Preparation of ketone (I-99)

Figure PCTCN2021076289-appb-000356
Figure PCTCN2021076289-appb-000356

仿照实施例2的方法，以I-76和乙醛水溶液为原料进行还原胺化反应，然后与氯化氢成盐，得产物I-99的盐酸盐(白色泡沫)。 1H NMR(800MHz,CD 3OD-d 4)δ8.09–7.98(m,1H),7.70–7.57(m,1H),6.95–6.85(m,4H),6.75–6.67(m,1H),6.61–6.53(m,1H),4.28–4.19(m,2H),3.86–3.76(m,3H),3.60–3.36(m,5H),3.30–3.26(m,1H),2.37–2.25(m,3H),1.42–1.35(m,4H),1.28–1.21(m,1H),1.13–1.06(m,1H).HRMS(ESI) C 25H 30FN 2O 3 +([M+H] +)计算值：425.2235，实测值：425.2237。 Imitating the method of Example 2, using I-76 and acetaldehyde aqueous solution as raw materials for reductive amination reaction, and then forming a salt with hydrogen chloride to obtain the product I-99 hydrochloride (white foam). 1 H NMR (800MHz, CD 3 OD-d 4 ) δ 8.09-7.98 (m, 1H), 7.70-7.57 (m, 1H), 6.95-6.85 (m, 4H), 6.75-6.67 (m, 1H) ,6.61–6.53(m,1H), 4.28–4.19(m,2H), 3.86–3.76(m,3H), 3.60–3.36(m,5H), 3.30–3.26(m,1H), 2.37–2.25( m,3H),1.42–1.35(m,4H),1.28–1.21(m,1H),1.13–1.06(m,1H).HRMS(ESI) C 25 H 30 FN 2 O 3 + ((M+H ] + ) Calculated value: 425.2235, measured value: 425.2237.

手性拆分和构型确定实施例：Examples of chiral resolution and configuration determination:

手性拆分实施例1：反式N-(4-(((2-(5-氟-2-甲氧苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-19)的手性拆分制备Chiral Resolution Example 1: trans N-(4-(((2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4 -(2'-pyridyl)benzamide (I-19) by chiral resolution

Figure PCTCN2021076289-appb-000357
Figure PCTCN2021076289-appb-000357

将化合物I-19(游离形式)溶于异丙醇，使用YMC，K-prep LAB 300G HPLC仪器制备，制备条件如下：Chiralcel AY-5(25cm×50mm,10μM)，异丙醇/正己烷/二乙胺体积比为30/70/0.1的混合溶剂为流动相，流速为60mL/min，检测波长为254nm。分离得到第一流出组分(保留时间＝5.575min)为I-19a；第二流出组分(保留时间＝7.672min)为I-19b。将各个流出组分收集，减压浓缩后，按照实施例1步骤6中方法将各组分转换成其盐酸盐。Compound I-19 (free form) was dissolved in isopropanol, and prepared with YMC, K-prep LAB 300G HPLC instrument. The preparation conditions are as follows: Chiralcel AY-5 (25cm×50mm, 10μM), isopropanol/n-hexane/ The mixed solvent with a volume ratio of diethylamine of 30/70/0.1 is the mobile phase, the flow rate is 60 mL/min, and the detection wavelength is 254 nm. The first effluent component (retention time = 5.575 min) was separated to be I-19a; the second effluent component (retention time = 7.672 min) was I-19b. The effluent components were collected, and after concentration under reduced pressure, each component was converted into its hydrochloride according to the method in step 6 of Example 1.

N-(4-((((1R,2R)-2-(5-氟-2-甲氧苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-19a)盐酸盐，白色固体，ee：100％；[α] D 20–13.00(c 0.4,MeOH)。 N-(4-((((1R,2R)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2' - pyridinyl) benzamide (I-19a) hydrochloride, as a white solid, ee: 100%; [α ] D 20 -13.00 (c 0.4, MeOH).

N-(4-((((1S,2S)-2-(5-氟-2-甲氧苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-19b)盐酸盐，白色固体，ee：100％；[α] D 20+11.67(c 0.6,MeOH)。 N-(4-((((1S,2S)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2' -Pyridyl)benzamide (I-19b) hydrochloride, white solid, ee: 100%; [α] D 20 + 11.67 (c 0.6, MeOH).

为确定化合物I-19a和I-19b的手性构型，按照如下合成路线进行对照合成：In order to determine the chiral configuration of compounds I-19a and I-19b, a comparative synthesis was carried out according to the following synthetic route:

Figure PCTCN2021076289-appb-000358
Figure PCTCN2021076289-appb-000358

步骤1：中间体rac-INT-5溶于乙醇，使用YMC，K-prep LAB 100S HPLC仪器制备，制备条件如下：Chiralcel OJ-5A(25cm×50mm,10μM)，乙醇/正己烷体积比为1/99的混合溶剂为流动相，流速为60mL/min，检测波长为214nm。分离得到第一流出组分(保 留时间＝9.618min)为(+)-INT-5；第二流出组分(保留时间＝11.026min)为(–)-INT-5。将各个流出组分收集，减压浓缩得产物。对比参考文献[J.Med.Chem.2015,58,1992-2002]所报道类似化合物的旋光信息，确认第一流出组分(+)-INT-5的绝对构型为(R,R)，第二流出组分(–)-INT-5的绝对构型为(S,S)。Step 1: Intermediate rac-INT-5 is dissolved in ethanol and prepared using YMC, K-prep LAB 100S HPLC instrument, the preparation conditions are as follows: Chiralcel OJ-5A (25cm×50mm, 10μM), ethanol/n-hexane volume ratio is 1 The mixed solvent of /99 is the mobile phase, the flow rate is 60mL/min, and the detection wavelength is 214nm. The first eluting component (retention time = 9.618 min) was separated to be (+)-INT-5; the second eluting component (retention time = 11.026 min) was (–)-INT-5. The effluent components were collected and concentrated under reduced pressure to obtain the product. Comparing the optical rotation information of similar compounds reported in references [J.Med.Chem.2015,58,1992-2002], confirm that the absolute configuration of the first eluting component (+)-INT-5 is (R,R), The absolute configuration of the second eluting component (–)-INT-5 is (S, S).

(+)-叔丁基(((1R,2R)-2-(5-氟-2-甲氧苯基)环丙基)甲基)-氨基甲酸酯((+)-INT-5)，无色油状物,ee:98.5％；[α] D 20+10.93(c 0.5,CHCl 3)。 (+)-tert-butyl(((1R,2R)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)-carbamate((+)-INT-5) , Colorless oil, ee: 98.5%; [α] D 20 +10.93 (c 0.5, CHCl 3 ).

(–)-叔丁基(((1S,2S)-2-(5-氟-2-甲氧苯基)环丙基)甲基)-氨基甲酸酯((–)-INT-5)，无色油状物,ee:96.4％；[α] D 20–11.13(c 0.5,CHCl 3)。 (--)-Tert-butyl(((1S,2S)-2-(5-fluoro-2-methoxyphenyl)cyclopropyl)methyl)-carbamate((--)-INT-5) , colorless oil, ee: 96.4%; [α ] D 20 -11.13 (c 0.5, CHCl 3).

步骤2：将原料(+)-INT-5(378mg,1.28mmol)溶于4M盐酸二氧六环溶液(20mL)并于室温下反应过夜。将溶剂减压蒸除，剩余残渣于乙酸乙酯/石油醚(体积比为1/2，10mL)混合溶液悬浮打浆10分钟。抽滤，滤饼用乙酸乙酯(3mL)淋洗，真空干燥得(–)-INT-6，黄色固体(290mg，收率98％)，[α] D 20–14.80(c 0.5,MeOH)。按照同样的制备方法，可将(+)-INT-5制备得(+)-INT-6，黄色固体，[α] D 20+14.20(c 0.5,MeOH)。(–)-INT-6与(+)-INT-6的旋光符号分别与构型一致的相似化合物的旋光符号一致，参考文献[J.Med.Chem.2015,58,1992-2002]。 Step 2: The raw material (+)-INT-5 (378 mg, 1.28 mmol) was dissolved in a 4M hydrochloric acid dioxane solution (20 mL) and reacted overnight at room temperature. The solvent was evaporated under reduced pressure, and the remaining residue was suspended in a mixed solution of ethyl acetate/petroleum ether (volume ratio 1/2, 10 mL) for 10 minutes. Suction filtration, the filter cake was rinsed with ethyl acetate (3mL), and dried under vacuum to obtain (–)-INT-6, a yellow solid (290mg, yield 98%), [α] D 20 –14.80 (c 0.5, MeOH) . According to the same preparation method, (+)-INT-5 can be prepared to obtain (+)-INT-6, a yellow solid, [α] D 20 +14.20 (c 0.5, MeOH). The optical signs of (–)-INT-6 and (+)-INT-6 are the same as those of similar compounds with the same configuration, refer to [J.Med.Chem.2015,58,1992-2002].

步骤3：按照实施例17步骤3所述的方法，将(–)-INT-6转化为(–)-INT-19，[α] D 20–14.60(c 0.5,MeOH)。将(+)-INT-6转化为(+)-INT-19，[α] D 20+16.13(c 0.5,MeOH). Step 3: According to the method described in step 3 of Example 17, (-)-INT-6 was converted into (-)-INT-19, [α] D 20 -14.60 (c 0.5, MeOH). Convert (+)-INT-6 to (+)-INT-19, [α] D 20 +16.13(c 0.5,MeOH).

步骤4：将原料(–)-INT-19(41mg,0.173mmol)和中间体INT-23(46mg,0.173mmol)溶于四氢呋喃(15mL)并室温下反应15分钟。加入三乙酰氧基硼氢化钠(73mg,0.345mmol)，室温下反应过夜。加入水淬灭反应，乙酸乙酯萃取，饱和食盐水洗涤，浓缩有机相，剩余物硅胶柱层析(0–5％甲醇/二氯甲烷)，得无色油状物I-19a(28mg，收率33％)。将I-19a按照实施例1步骤6中方法转换成其盐酸盐，白色固体。[α] D 20–13.00(c 0.5,MeOH)。 Step 4: The raw material (-)-INT-19 (41 mg, 0.173 mmol) and the intermediate INT-23 (46 mg, 0.173 mmol) were dissolved in tetrahydrofuran (15 mL) and reacted at room temperature for 15 minutes. Sodium triacetoxyborohydride (73mg, 0.345mmol) was added and reacted overnight at room temperature. The reaction was quenched by adding water, extracted with ethyl acetate, washed with saturated brine, concentrated the organic phase, and the residue was subjected to silica gel column chromatography (0–5% methanol/dichloromethane) to obtain a colorless oil I-19a (28 mg, yield Rate 33%). I-19a was converted into its hydrochloride salt as a white solid according to the method in step 6 of Example 1. [α] D 20 -13.00 (c 0.5, MeOH).

按照同样的制备方法，可将(+)-INT-19制备得I-19b盐酸盐，白色固体。[α] D 20+11.80(c 0.5,MeOH)。 According to the same preparation method, (+)-INT-19 can be prepared to obtain I-19b hydrochloride, a white solid. [α] D 20 +11.80 (c 0.5, MeOH).

通过比旋光度的对比，按照该手性合成方法制备得到的I-19a盐酸盐与拆分方法所得I-19a盐酸盐比旋光度一致，确定其绝对构型为(R,R)；同理确定I-19b的绝对构型为(S,S)。By comparing the specific rotation, the specific rotation of I-19a hydrochloride prepared according to the chiral synthesis method is consistent with the specific rotation of I-19a hydrochloride obtained by the resolution method, and its absolute configuration is determined to be (R, R); In the same way, the absolute configuration of I-19b is determined as (S, S).

手性拆分实施例2：反式N-(4-(((2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-41)的手性拆分制备Chiral Resolution Example 2: trans N-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthalene Chiral resolution preparation of amide (I-41)

Figure PCTCN2021076289-appb-000359
Figure PCTCN2021076289-appb-000359

将化合物I-41(游离形式)溶于异丙醇，制备条件：Chiralcel AY-5(25cm×50mm,10μM)，乙醇/正己烷体积比为15/85的混合溶剂为流动相，流速为60mL/min，检测波长为254nm。分离得到第一流出组分(保留时间＝5.847min)为I-41a；第二流出组分(保留时间＝8.492min)为I-41b。将各个流出组分收集，减压浓缩后，按照实施例1步骤6中方法将各组分转换成其盐酸盐。Compound I-41 (free form) was dissolved in isopropanol, preparation conditions: Chiralcel AY-5 (25cm×50mm, 10μM), a mixed solvent with a volume ratio of ethanol/n-hexane of 15/85 as the mobile phase, and a flow rate of 60mL /min, the detection wavelength is 254nm. The first effluent component (retention time = 5.847 min) was separated to be I-41a; the second effluent component (retention time = 8.492 min) was I-41b. The effluent components were collected, and after concentration under reduced pressure, each component was converted into its hydrochloride according to the method in step 6 of Example 1.

N-(4-((((1R,2R)-2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-41a)盐酸盐，白色固体，ee：95.1％；[α] D 20–2.50(c 0.4,MeOH)。旋光偏转方向与I-19a盐酸盐一致，确定其构型为(1R,2R)。 N-(4-((((1R,2R)-2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthylamide (I- 41a) Hydrochloride, white solid, ee: 95.1%; [α] D 20 -2.50 (c 0.4, MeOH). The direction of optical rotation is consistent with that of I-19a hydrochloride, and its configuration is determined to be (1R, 2R).

N-(4-((((1S,2S)-2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-2-萘酰胺(I-41b)盐酸盐，白色固体，ee：97.3％；[α] D 20+1.94(c 0.6,MeOH)。旋光偏转方向与I-19b盐酸盐一致，确定其构型为(1S,2S)。 N-(4-((((1S,2S)-2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-2-naphthylamide (I- 41b) Hydrochloride, white solid, ee: 97.3%; [α] D 20 +1.94 (c 0.6, MeOH). The direction of optical rotation is consistent with that of I-19b hydrochloride, and its configuration is determined to be (1S, 2S).

手性拆分实施例3：反式N-(4-(((2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-1H-吲哚-2-甲酰胺(I-43)的手性拆分制备Chiral Resolution Example 3: trans N-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1H-indole Chiral resolution preparation of indole-2-carboxamide (I-43)

Figure PCTCN2021076289-appb-000360
Figure PCTCN2021076289-appb-000360

将化合物I-42(游离形式)溶于异丙醇，使用YMC，K-prep LAB 100S HPLC仪器制备，制备条件如下：Chiralcel OJ-5A(25cm×50mm,10μM)，异丙醇/正己烷/二乙胺体积比为1/99/0.1的混合溶剂为流动相，流速为60mL/min，检测波长为220nm。分离得到第一流出组分(保留时间＝19.932min)为I-42a；第二流出组分(保留时间＝23.757min)为I-42b。将各个流出组分收集，减压浓缩后，按照实施例1步骤6中方法将各组分转换成其盐酸盐。Compound I-42 (free form) was dissolved in isopropanol, and prepared with YMC, K-prep LAB 100S HPLC instrument. The preparation conditions are as follows: Chiralcel OJ-5A (25cm×50mm, 10μM), isopropanol/n-hexane/ The mixed solvent with the volume ratio of diethylamine of 1/99/0.1 is the mobile phase, the flow rate is 60 mL/min, and the detection wavelength is 220 nm. The first effluent component (retention time=19.932min) was separated to be I-42a; the second effluent component (retention time=23.757min) was I-42b. The effluent components were collected, and after concentration under reduced pressure, each component was converted into its hydrochloride according to the method in step 6 of Example 1.

N-(4-((((1R,2R)-2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-1H-吲哚-2-甲酰胺(I-42a)盐酸盐，白色固体，ee：98.6％；[α] D 20–0.25(c 0.4,MeOH)。旋光偏转方向与I-19a 盐酸盐一致，确定其构型为(1R,2R)。 N-(4-((((1R,2R)-2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1H-indole-2- Formamide (I-42a) hydrochloride, white solid, ee: 98.6%; [α] D 20 -0.25 (c 0.4, MeOH). The direction of optical rotation is consistent with that of I-19a hydrochloride, and its configuration is determined to be (1R, 2R).

N-(4-((((1S,2S)-2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-1H-吲哚-2-甲酰胺(I-42b)盐酸盐，白色固体，ee：97.4％；[α] D 20+0.17(c 0.6,MeOH)。旋光偏转方向与I-19b盐酸盐一致，确定其构型为(1S,2S)。 N-(4-((((1S,2S)-2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-1H-indole-2- Formamide (I-42b) hydrochloride, white solid, ee: 97.4%; [α] D 20 +0.17 (c 0.6, MeOH). The direction of optical rotation is consistent with that of I-19b hydrochloride, and its configuration is determined to be (1S, 2S).

手性拆分实施例4：反式N-(4-(((2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-41)的手性拆分制备Chiral Resolution Example 4: trans N-(4-(((2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-( Chiral Resolution and Preparation of 2'-pyridyl)benzamide (I-41)

Figure PCTCN2021076289-appb-000361
Figure PCTCN2021076289-appb-000361

将化合物I-43(游离形式)溶于异丙醇，使用YMC，K-prep LAB 100S HPLC仪器制备，制备条件如下：Chiralcel OD-5(25cm×50mm,10μM)，异丙醇/正己烷/二乙胺体积比为20/80/0.1的混合溶剂为流动相，流速为60mL/min，检测波长为254nm。分离得到第一流出组分(保留时间＝9.484min)为I-43a；第二流出组分(保留时间＝13.213min)为I-43b。将各个流出组分收集，减压浓缩后，按照实施例1步骤6中方法将各组分转换成其盐酸盐。Compound I-43 (free form) was dissolved in isopropanol, and prepared using YMC, K-prep LAB 100S HPLC instrument. The preparation conditions are as follows: Chiralcel OD-5 (25cm×50mm, 10μM), isopropanol/n-hexane/ The mixed solvent with a volume ratio of diethylamine of 20/80/0.1 is used as the mobile phase, the flow rate is 60 mL/min, and the detection wavelength is 254 nm. The first effluent component (retention time = 9.484 min) was separated to be I-43a; the second effluent component (retention time = 13.213 min) was I-43b. The effluent components were collected, and after concentration under reduced pressure, each component was converted into its hydrochloride according to the method in step 6 of Example 1.

N-(4-((((1R,2R)-2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-43a)盐酸盐，白色固体，ee：99.4％；[α] D 20–1.58(c 0.4,MeOH)。旋光偏转方向与I-19a盐酸盐一致，确定其构型为(1R,2R)。 N-(4-((((1R,2R)-2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2'-pyridine Benzamide (I-43a) hydrochloride, white solid, ee: 99.4%; [α] D 20 -1.58 (c 0.4, MeOH). The direction of optical rotation is consistent with that of I-19a hydrochloride, and its configuration is determined to be (1R, 2R).

N-(4-((((1S,2S)-2-(2,3-二氯苯基)环丙基)甲基)(丙基)氨)丁基)-4-(2’-吡啶基)苯甲酰胺(I-43b)盐酸盐，白色固体，ee：99.4％；[α] D 20+2.87(c 0.5,MeOH)。旋光偏转方向与I-19b盐酸盐一致，确定其构型为(1S,2S)。 N-(4-((((1S,2S)-2-(2,3-dichlorophenyl)cyclopropyl)methyl)(propyl)amino)butyl)-4-(2'-pyridine Yl)benzamide (I-43b) hydrochloride, white solid, ee: 99.4%; [α] D 20 + 2.87 (c 0.5, MeOH). The direction of optical rotation is consistent with that of I-19b hydrochloride, and its configuration is determined to be (1S, 2S).

生物活性测试部分Biological activity test section

1.部分化合物对于多巴胺受体的亲和力活性测试。1. The affinity activity test of some compounds for dopamine receptors.

亲和力活性采用放射性同位素配体的方法进行测试。Affinity activity is tested using radioisotope ligand method.

1.1化合物对多巴胺D1受体亲和力活性的测定：1.1 Determination of the affinity activity of the compound to the dopamine D1 receptor:

(1)人源多巴胺D1受体细胞膜的准备：将稳定表达人源多巴胺D1受体的瞬时转染HEK-293细胞置于直径15厘米的培养皿中，在含10％胎牛血清(FBS)和1％青霉素钠/链霉素(100U/mL)的标准培养基(DMEM)中培养至90％融合状态。细胞经pH＝7.4的磷酸盐缓冲液(PBS)冲洗，刮入50mL锥形管，离心10分钟(1000rpm，4℃)，再 用裂解液(50mm Tris HCl缓冲液，pH＝7.4，4℃)重新悬浮细胞，进行低渗裂解。细胞悬浮液离心20分钟(21,000rpm，4℃)，除去上清液得细胞膜分离颗粒，将细胞膜颗粒再悬浮配成1mg/mL混悬液(浓度按Bradford实验测定)，于-80℃保存备用。(1) Preparation of human dopamine D1 receptor cell membrane: Place the transiently transfected HEK-293 cells stably expressing human dopamine D1 receptor in a petri dish with a diameter of 15 cm, in a culture dish containing 10% fetal bovine serum (FBS) And 1% penicillin sodium/streptomycin (100U/mL) standard medium (DMEM) cultured to 90% confluence. The cells were washed with phosphate buffered saline (PBS) with pH=7.4, scraped into a 50mL conical tube, centrifuged for 10 minutes (1000rpm, 4℃), and then lysing solution (50mm Tris HCl buffer, pH=7.4, 4℃) Resuspend the cells and perform hypotonic lysis. The cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane separation particles, and the cell membrane particles were resuspended to form a 1mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use .

(2)放射性同位素配体竞争结合实验：竞争结合实验在96孔板中进行，所用的标准缓冲溶液体系为50mM HEPES,50mM NaCl,5mM MgCl 2,0.5mM EDTA,pH＝7.4；标准冲洗液为50mM Tris HCl,pH＝7.4；所用放射性同位素配体为[ 3H]-SCH23390。将待测化合物配成相应10mM浓度的DMSO溶液，然后用缓冲液稀释至10μM,再用缓冲液3倍梯度稀释，得11个浓度点(0.1，0.3，1，3，10，30，100，300，1000，3000，10000nM)。将不同浓度的待测化合物转移到96孔板上，每孔50μL；再依次加入50μL放射性同位素配体[ 3H]-SCH23390(0.6～1.3nM)和50μL人源多巴胺D1受体细胞膜悬浮液，轻轻摇匀，室温下避光孵育90分钟。4℃条件下，使用96孔Packard Filtermate收集器，在聚乙烯亚胺浸泡过的96孔过滤器垫上真空过滤终止孵育反应，并用标准冲洗液冲洗三次。在热板上将闪烁液(scintillation cocktail)融化在微波炉烘干的过滤器表面，用保鲜膜包裹过滤器，使用Microbeta计数器计数，用GraphPad Prism 6处理数据，计算IC 50值，再通过Cheng-Prusoff方程计算得K i。 (2) Radioisotope ligand competition binding experiment: The competition binding experiment was carried out in a 96-well plate, and the standard buffer solution system used was 50mM HEPES, 50mM NaCl, 5mM MgCl 2 , 0.5mM EDTA, pH=7.4; the standard washing solution was 50mM Tris HCl, pH=7.4; the radioisotopic ligand used is [ 3 H]-SCH23390. The compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10μM, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM). Transfer test compounds of different concentrations to a 96-well plate, 50μL per well; then add 50μL of radioisotope ligand [ 3 H]-SCH23390 (0.6～1.3nM) and 50μL of human dopamine D1 receptor cell membrane suspension in sequence, Shake gently and incubate for 90 minutes in the dark at room temperature. At 4°C, using a 96-well Packard Filtermate collector, vacuum filtration on a 96-well filter pad soaked in polyethyleneimine to terminate the incubation reaction, and rinse three times with a standard rinsing solution. Melt the scintillation cocktail on the surface of the microwave-dried filter on the hot plate, wrap the filter with plastic wrap, use a Microbeta counter to count, process the data with GraphPad Prism 6, calculate the IC 50 value, and then pass Cheng-Prusoff The equation is calculated to obtain K i .

1.2化合物对多巴胺D2受体亲和力活性的测定：1.2 Determination of the affinity activity of the compound to the dopamine D2 receptor:

(1)人源多巴胺D2受体细胞膜的准备：将稳定表达人源多巴胺D2受体的纤维原细胞置于直径15厘米的培养皿中，在含10％胎牛血清(FBS)和1％青霉素钠/链霉素(100U/mL)的标准培养基(DMEM)中培养至90％融合状态。细胞经pH＝7.4的磷酸盐缓冲液(PBS)冲洗，刮入50mL锥形管，离心10分钟(1000rpm，4℃)，再用裂解液(50mm Tris HCl缓冲液，pH＝7.4，4℃)重新悬浮细胞，进行低渗裂解。细胞悬浮液离心20分钟(21,000rpm，4℃)，除去上清液得细胞膜颗粒，将细胞膜颗粒再悬浮配成1mg/mL混悬液(浓度按Bradford实验测定)，于-80℃保存备用。(1) Preparation of human dopamine D2 receptor cell membrane: place fibroblasts stably expressing human dopamine D2 receptor in a petri dish with a diameter of 15 cm, in a culture dish containing 10% fetal bovine serum (FBS) and 1% penicillin Sodium/streptomycin (100U/mL) standard medium (DMEM) was cultured to a 90% confluent state. The cells were washed with phosphate buffered saline (PBS) with pH=7.4, scraped into a 50mL conical tube, centrifuged for 10 minutes (1000rpm, 4℃), and then lysing solution (50mm Tris HCl buffer, pH=7.4, 4℃) Resuspend the cells and perform hypotonic lysis. The cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane particles, and the cell membrane particles were resuspended to form a 1 mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use.

(2)放射性同位素配体竞争结合实验：竞争结合实验在96孔板中进行，所用的标准缓冲溶液体系为50mM HEPES,50mM NaCl,5mM MgCl 2,0.5mM EDTA,pH＝7.4；标准冲洗液为50mM Tris HCl,pH＝7.4；所用放射性同位素配体为[ 3H]-N-methylspiperone。将待测化合物配成相应10mM浓度的DMSO溶液，然后用缓冲液稀释至10μM,再用缓冲液3倍梯度稀释，得11个浓度点(0.1，0.3，1，3，10，30，100，300，1000，3000，10000nM)。将不同浓度的待测化合物转移到96孔板上，每孔50μL；再依次加入50μL放射性同位素配体[ 3H]-N-methylspiperone(0.4～1.0nM)和50μL人源多巴胺D2受体细胞膜悬浮液，轻轻摇匀，室温下避光孵育90分钟。4℃条件下，使用96孔Packard Filtermate收集器，在聚乙烯亚胺浸泡过的96孔过滤器垫上真空过滤终止孵育反应，并用标准冲洗液冲洗三次。在热板上将闪烁液(scintillation cocktail)融化在微波炉烘干的过滤器表面，用保鲜膜包裹过滤器，使用Microbeta计数器计数，用GraphPad Prism 6处理数据，计算IC 50值，再通过Cheng-Prusoff方程计算得K i。 (2) Radioisotope ligand competition binding experiment: The competition binding experiment was carried out in a 96-well plate, and the standard buffer solution system used was 50mM HEPES, 50mM NaCl, 5mM MgCl 2 , 0.5mM EDTA, pH=7.4; the standard washing solution was 50mM Tris HCl, pH=7.4; the radioisotopic ligand used is [ 3 H]-N-methylspiperone. The compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10μM, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM). Transfer test compounds of different concentrations to a 96-well plate, 50μL per well; then add 50μL of radioisotope ligand [ 3 H]-N-methylspiperone (0.4～1.0nM) and 50μL of human dopamine D2 receptor cell membrane suspension Shake gently, and incubate for 90 minutes in the dark at room temperature. At 4°C, using a 96-well Packard Filtermate collector, vacuum filtration on a 96-well filter pad soaked in polyethyleneimine to terminate the incubation reaction, and rinse three times with a standard rinsing solution. Melt the scintillation cocktail on the surface of the microwave-dried filter on the hot plate, wrap the filter with plastic wrap, use a Microbeta counter to count, process the data with GraphPad Prism 6, calculate the IC 50 value, and then pass Cheng-Prusoff The equation is calculated to obtain K i .

1.3化合物对多巴胺D3受体亲和力活性的测定：1.3 Determination of the affinity activity of the compound to the dopamine D3 receptor:

(1)人源多巴胺D3受体细胞膜的准备：将稳定表达人源多巴胺D3受体的瞬时转染HEK-293细胞置于直径15厘米的培养皿中，在含10％胎牛血清(FBS)和1％青霉素钠/链霉素(100U/mL)的标准培养基(DMEM)中培养至90％融合状态。细胞经pH＝7.4的磷酸盐缓冲液(PBS)冲洗，刮入50mL锥形管，离心10分钟(1000rpm，4℃)，再用裂解液(50mm Tris HCl缓冲液，pH＝7.4，4℃)重新悬浮，进行低渗裂解。细胞悬浮液离心20分钟(21,000rpm，4℃)，除去上清液得细胞膜颗粒，将细胞膜颗粒再悬浮配成1mg/mL混悬液(浓度按Bradford实验测定)，于-80℃保存备用。(1) Preparation of human dopamine D3 receptor cell membrane: Place the transiently transfected HEK-293 cells stably expressing human dopamine D3 receptor in a petri dish with a diameter of 15 cm, in a culture dish containing 10% fetal bovine serum (FBS) And 1% penicillin sodium/streptomycin (100U/mL) standard medium (DMEM) cultured to 90% confluence. The cells were washed with phosphate buffered saline (PBS) with pH=7.4, scraped into a 50mL conical tube, centrifuged for 10 minutes (1000rpm, 4℃), and then lysing solution (50mm Tris HCl buffer, pH=7.4, 4℃) Resuspend and perform hypotonic lysis. The cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane particles, and the cell membrane particles were resuspended to form a 1 mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use.

(2)放射性同位素配体竞争结合实验：竞争结合实验在96孔板中进行，所用的标准缓冲溶液体系为50mM HEPES,50mM NaCl,5mM MgCl 2,0.5mM EDTA,pH＝7.4；标准冲洗液为50mM Tris HCl,pH＝7.4；所用放射性同位素配体为[ 3H]-N-methylspiperone。将待测化合物配成相应10mM浓度的DMSO溶液，然后用缓冲液稀释至10μM,再用缓冲液3倍梯度稀释，得11个浓度点(0.1，0.3，1，3，10，30，100，300，1000，3000，10000nM)。将不同浓度的待测化合物转移到96孔板上，每孔50μL；再依次加入50μL放射性同位素配体[ 3H]-N-methylspiperone(0.5–1.8nM)和50μL人源多巴胺D3受体细胞膜悬浮液，轻轻摇匀，室温下避光孵育90分钟。4℃条件下，使用96孔Packard Filtermate收集器，在聚乙烯亚胺浸泡过的96孔过滤器垫上真空过滤终止孵育反应，并用标准冲洗液冲洗三次。在热板上将闪烁液(scintillation cocktail)融化在微波炉烘干的过滤器表面，用保鲜膜包裹过滤器，使用Microbeta计数器计数，用GraphPad Prism 6处理数据，计算IC 50值，再通过Cheng-Prusoff方程计算得K i。 (2) Radioisotope ligand competition binding experiment: The competition binding experiment was carried out in a 96-well plate, and the standard buffer solution system used was 50mM HEPES, 50mM NaCl, 5mM MgCl 2 , 0.5mM EDTA, pH=7.4; the standard washing solution was 50mM Tris HCl, pH=7.4; the radioisotopic ligand used is [ 3 H]-N-methylspiperone. The compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10μM, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM). Transfer the test compounds of different concentrations to a 96-well plate, 50μL per well; then add 50μL of radioisotope ligand [ 3 H]-N-methylspiperone (0.5–1.8nM) and 50μL of human dopamine D3 receptor cell membrane suspension Shake gently, and incubate for 90 minutes in the dark at room temperature. At 4°C, using a 96-well Packard Filtermate collector, vacuum filtration on a 96-well filter pad soaked in polyethyleneimine to terminate the incubation reaction, and rinse three times with a standard rinsing solution. Melt the scintillation cocktail on the surface of the microwave-dried filter on the hot plate, wrap the filter with plastic wrap, use a Microbeta counter to count, process the data with GraphPad Prism 6, calculate the IC 50 value, and then pass Cheng-Prusoff The equation is calculated to obtain K i .

1.4化合物对多巴胺D4受体亲和力活性的测定：1.4 Determination of the affinity activity of the compound to the dopamine D4 receptor:

(1)人源多巴胺D4受体细胞膜的准备：将稳定表达人源多巴胺D4受体的HEK-293细胞置于直径15厘米的培养皿中，在含10％含铁小牛血清和1％青霉素钠/链霉素(100U/mL)的标准培养基(DMEM)中培养至90％融合状态。细胞经pH＝7.4的磷酸盐缓冲液(PBS)冲洗，刮入50mL锥形管，离心10分钟(1000rpm，4℃)得细胞微球，再用裂解液(50mm Tris HCl缓冲液，pH＝7.4，4℃)重新悬浮细胞微球，进行低渗裂解。细胞悬浮液离心20分钟(21,000rpm，4℃)，除去上清液得细胞膜分离颗粒，将细胞膜颗粒再悬浮配成1mg/mL混悬液(浓度按Bradford实验测定)，于-80℃保存备用。(1) Preparation of human dopamine D4 receptor cell membrane: place HEK-293 cells stably expressing human dopamine D4 receptor in a petri dish with a diameter of 15 cm. Sodium/streptomycin (100U/mL) standard medium (DMEM) was cultured to a 90% confluent state. The cells were washed with phosphate buffered saline (PBS) with pH=7.4, scraped into a 50mL conical tube, centrifuged for 10 minutes (1000rpm, 4℃) to obtain cell microspheres, and then used lysis buffer (50mm Tris HCl buffer, pH=7.4 , 4℃) Resuspend the cell microspheres for hypotonic lysis. The cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane separation particles, and the cell membrane particles were resuspended to form a 1mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use .

(2)放射性同位素配体竞争结合实验：竞争结合实验在96孔板中进行，所用的标准缓冲溶液体系为50mM HEPES,50mM NaCl,5mM MgCl 2,0.5mM EDTA,pH＝7.4；标准冲洗液为50mM Tris HCl,pH＝7.4；所用放射性同位素配体为[ 3H]-N-methylspiperone。将待测化合物配成相应10mM浓度的DMSO溶液，然后用缓冲液稀释至10μM,再用缓冲液3倍梯度稀释，得11个浓度点(0.1，0.3，1，3，10，30，100，300，1000，3000，10000nM)。将不同浓度的待测化合物转移到96孔板上，每孔50μL；再依次加入50μL 放射性同位素配体[ 3H]-N-methylspiperone(0.6–1.7nM)和50μL人源多巴胺D4受体细胞膜悬浮液，轻轻摇匀，室温下避光孵育90分钟。4℃条件下，使用96-well Packard Filtermate收集器，在聚乙烯亚胺浸泡过的96孔过滤器垫上真空过滤终止孵育反应，并用标准冲洗液冲洗三次。在热板上将闪烁液(scintillation cocktail)融化在微波炉烘干的过滤器表面，用保鲜膜包裹过滤器，使用Microbeta计数器计数，用GraphPad Prism 6处理数据，计算IC 50值，再通过Cheng-Prusoff方程计算得K i。 (2) Radioisotope ligand competition binding experiment: The competition binding experiment was carried out in a 96-well plate, and the standard buffer solution system used was 50mM HEPES, 50mM NaCl, 5mM MgCl 2 , 0.5mM EDTA, pH=7.4; the standard washing solution was 50mM Tris HCl, pH=7.4; the radioisotopic ligand used is [ 3 H]-N-methylspiperone. The compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10μM, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM). Transfer the test compounds of different concentrations to a 96-well plate, 50μL per well; then add 50μL of radioisotope ligand [ 3 H]-N-methylspiperone (0.6–1.7nM) and 50μL of human dopamine D4 receptor cell membrane suspension Shake gently, and incubate for 90 minutes in the dark at room temperature. At 4°C, use a 96-well Packard Filtermate collector to vacuum filter on a 96-hole filter pad soaked in polyethyleneimine to terminate the incubation reaction, and rinse three times with a standard washing solution. Melt the scintillation cocktail on the surface of the microwave-dried filter on the hot plate, wrap the filter with plastic wrap, use a Microbeta counter to count, process the data with GraphPad Prism 6, calculate the IC 50 value, and then pass Cheng-Prusoff The equation is calculated to obtain K i .

1.5化合物对多巴胺D5受体亲和力活性的测定：化合物对多巴胺D5受体结合活性的测试采用基于放射性同位素配体竞争结合实验来进行。具体操作方法如下：1.5 Determination of the affinity activity of the compound to the dopamine D5 receptor: The test of the compound's binding activity to the dopamine D5 receptor was carried out based on a radioisotope ligand competition binding experiment. The specific operation method is as follows:

(1)人源多巴胺D5受体细胞膜的准备：将稳定表达人源多巴胺D5受体的瞬时转染HEK-293细胞置于直径15厘米的培养皿中，在含10％胎牛血清(FBS)和1％青霉素钠/链霉素(100U/mL)的标准培养基(DMEM)中培养至90％融合状态。细胞经pH＝7.4的磷酸盐缓冲液(PBS)冲洗，刮入50mL锥形管，离心10分钟(1000rpm，4℃)得细胞微球，再用裂解液(50mm Tris HCl缓冲液，pH＝7.4，4℃)重新悬浮细胞微球，进行低渗裂解。细胞悬浮液离心20分钟(21,000rpm，4℃)，除去上清液得细胞膜分离颗粒，将细胞膜颗粒再悬浮配成1mg/mL混悬液(浓度按Bradford实验测定)，于-80℃保存备用。(1) Preparation of human dopamine D5 receptor cell membrane: Place the transiently transfected HEK-293 cells stably expressing human dopamine D5 receptor in a petri dish with a diameter of 15 cm, in a culture dish containing 10% fetal bovine serum (FBS) And 1% penicillin sodium/streptomycin (100U/mL) standard medium (DMEM) cultured to 90% confluence. The cells were washed with phosphate buffered saline (PBS) with pH=7.4, scraped into a 50mL conical tube, centrifuged for 10 minutes (1000rpm, 4℃) to obtain cell microspheres, and then used lysis buffer (50mm Tris HCl buffer, pH=7.4 , 4℃) Resuspend the cell microspheres for hypotonic lysis. The cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane separation particles, and the cell membrane particles were resuspended to form a 1mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use .

(2)放射性同位素配体竞争结合实验：竞争结合实验在96孔板中进行，所用的标准缓冲溶液体系为50mM HEPES,50mM NaCl,5mM MgCl 2,0.5mM EDTA,pH＝7.4；标准冲洗液为50mM Tris HCl,pH＝7.4；所用放射性同位素配体为[ 3H]-SCH23390。将待测化合物配成相应10mM浓度的DMSO溶液，然后用缓冲液稀释至10μM,再用缓冲液3倍梯度稀释，得11个浓度点(0.1，0.3，1，3，10，30，100，300，1000，3000，10000nM)。将不同浓度的待测化合物转移到96孔板上，每孔50μL；再依次加入50μL放射性同位素配体[ 3H]-SCH23390(0.6–1.3nM)和50μL人源多巴胺D5受体细胞膜悬浮液，轻轻摇匀，室温下避光孵育90分钟。4℃条件下，使用96孔Packard Filtermate收集器，在聚乙烯亚胺浸泡过的96孔过滤器垫上真空过滤终止孵育反应，并用标准冲洗液冲洗三次。在热板上将闪烁液(scintillation cocktail)融化在微波炉烘干的过滤器表面，用保鲜膜包裹过滤器，使用Microbeta计数器计数，用GraphPad Prism 6处理数据，计算IC 50值，再通过Cheng-Prusoff方程计算得K i。 (2) Radioisotope ligand competition binding experiment: The competition binding experiment was carried out in a 96-well plate, and the standard buffer solution system used was 50mM HEPES, 50mM NaCl, 5mM MgCl 2 , 0.5mM EDTA, pH=7.4; the standard washing solution was 50mM Tris HCl, pH=7.4; the radioisotopic ligand used is [ 3 H]-SCH23390. The compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10μM, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM). Transfer the test compounds of different concentrations to a 96-well plate, 50μL per well; then add 50μL of radioisotope ligand [ 3 H]-SCH23390 (0.6-1.3nM) and 50μL of human dopamine D5 receptor cell membrane suspension in sequence, Shake gently and incubate for 90 minutes in the dark at room temperature. At 4°C, using a 96-well Packard Filtermate collector, vacuum filtration on a 96-well filter pad soaked in polyethyleneimine to terminate the incubation reaction, and rinse three times with a standard rinsing solution. Melt the scintillation cocktail on the surface of the microwave-dried filter on the hot plate, wrap the filter with plastic wrap, use a Microbeta counter to count, process the data with GraphPad Prism 6, calculate the IC 50 value, and then pass Cheng-Prusoff The equation is calculated to obtain K i .

本发明部分化合物对于多巴胺受体的亲和力数据如表1所示。Table 1 shows the affinity data of some compounds of the present invention for dopamine receptors.

表1：部分通式I化合物对于多巴胺受体D1-D5的亲和力数据。Table 1: Affinity data of some compounds of general formula I for dopamine receptors D1-D5.

Figure PCTCN2021076289-appb-000362
Figure PCTCN2021076289-appb-000362

Figure PCTCN2021076289-appb-000363
Figure PCTCN2021076289-appb-000363

Figure PCTCN2021076289-appb-000364
Figure PCTCN2021076289-appb-000364

Figure PCTCN2021076289-appb-000365
Figure PCTCN2021076289-appb-000365

从上表数据可以看出，部分通式I化合物对多巴胺D3受体表现出较强的亲和力，同时对于其他多巴胺受体的亲和力较差，表现出较好的D3受体选择性。部分化合物同一对对映异构体对于多巴胺受体的亲和活性差异不大。部分化合物，如I-68,I-76,I-79等，对于D2受体表现出较好的亲和力。From the data in the above table, it can be seen that some of the compounds of general formula I have a strong affinity for dopamine D3 receptors, and at the same time have poor affinity for other dopamine receptors, and show better D3 receptor selectivity. Some compounds have little difference in the affinity activity of the same pair of enantiomers for dopamine receptors. Some compounds, such as I-68, I-76, I-79, etc., show good affinity for D2 receptors.

2.部分通式I化合物对于多巴胺D3受体的功能活性测试。2. The functional activity test of some compounds of general formula I on dopamine D3 receptors.

化合物对于多巴胺D3受体的活性检测采用GloSensor cAMP方法进行。采用HEK-293T细胞转染人源多巴胺D 3受体GloSensor cAMP质粒(Promega品牌)，(4μg受体DNA+4μg GloSensor cAMP reporter DNA，10-cm培养皿)，DMEM+10％FBS培养基孵育过夜。细胞铺板：多聚L-Lys预涂的384孔板，15,000–20,000细胞每孔(40μL溶媒)。6-24小时后倾掉溶媒，每孔加入25μL化合物溶液(化合物溶媒1×HBSS,20mM HEPES,pH 7.4,0.1％BSA)，15分钟后每孔加入10μL 2mM荧光素与100nM异丙肾上腺素。对于拮抗剂测试，10分钟后加入10nM多巴胺。孵育20分钟后测试荧光强度。处理数据计算EC 50或IC 50值。 The activity of the compound on the dopamine D3 receptor was detected using the GloSensor cAMP method. Transfect human dopamine D 3 receptor GloSensor cAMP plasmid (Promega brand) with HEK-293T cells, (4μg receptor DNA+4μg GloSensor cAMP reporter DNA, 10-cm petri dish), and incubate in DMEM+10% FBS medium overnight . Cell plating: 384-well plate pre-coated with poly-L-Lys, 15,000-20,000 cells per well (40μL solvent). After 6-24 hours, the solvent was poured out, and 25 μL of compound solution (compound solvent 1×HBSS, 20 mM HEPES, pH 7.4, 0.1% BSA) was added to each well. After 15 minutes, 10 μL of 2 mM fluorescein and 100 nM isoproterenol were added to each well. For the antagonist test, 10 nM dopamine was added after 10 minutes. Test the fluorescence intensity after incubating for 20 minutes. Process the data to calculate the EC 50 or IC 50 value.

表2：部分通式(I)化合物对于多巴胺D3受体的功能活性。Table 2: Functional activities of some compounds of general formula (I) on dopamine D3 receptors.

化合物Compound 多巴胺D3受体功能活性Dopamine D3 receptor functional activity I-19a盐酸盐I-19a hydrochloride 激动剂，EC 50＝3.58nM(E max＝77.9％) Agonist, EC 50 =3.58nM (E max =77.9%) I-19b盐酸盐I-19b hydrochloride 拮抗剂，K i＝16.7nM Antagonist, K i =16.7nM I-41a盐酸盐I-41a hydrochloride 激动剂，EC 50＝177.5nM(E max＝71.7％) Agonist, EC 50 =177.5nM (E max =71.7%) I-41b盐酸盐I-41b hydrochloride 激动剂，EC 50＝99.2nM(E max＝83.4％) Agonist, EC 50 =99.2nM (E max =83.4%) I-42a盐酸盐I-42a hydrochloride 激动剂，EC 50＝87.0nM(E max＝40.7％) Agonist, EC 50 =87.0nM (E max =40.7%) I-42b盐酸盐I-42b hydrochloride 激动剂，EC 50＝142.8nM(E max＝63.4％) Agonist, EC 50 =142.8nM (E max =63.4%) I-43a盐酸盐I-43a hydrochloride 激动剂，EC 50＝12.5nM(E max＝68.1％) Agonist, EC 50 =12.5nM (E max ＝68.1%) I-43b盐酸盐I-43b hydrochloride 激动剂，EC 50＝29.6nM(E max＝96.2％) Agonist, EC 50 =29.6nM (E max =96.2%)

从表2可以看出，化合物I-19a,I-41a,I-41b,I-42a,I-42b,I-43a,I-43b等对于多巴胺D3受体具有激动剂或部分激动剂的活性，而I-19b对于多巴胺D3受体具有比较强的拮抗剂活性。结合表1的数据，这些化合物是选择性的多巴胺D3受体激动剂或拮抗剂。同时可以看出，通式(I)化合物的不同光学异构体具有不同的活性强度，甚至相反的内在活性。It can be seen from Table 2 that compounds I-19a, I-41a, I-41b, I-42a, I-42b, I-43a, I-43b, etc. have agonist or partial agonist activity for dopamine D3 receptors , And I-19b has relatively strong antagonist activity on dopamine D3 receptors. Combined with the data in Table 1, these compounds are selective dopamine D3 receptor agonists or antagonists. At the same time, it can be seen that the different optical isomers of the compound of general formula (I) have different activity intensities and even opposite intrinsic activities.

3.部分通式I化合物对多巴胺D2受体的功能活性测试。3. The functional activity test of some compounds of general formula I on dopamine D2 receptors.

采用BRET方法检测检测多巴胺D 2受体介导的下游G蛋白信号通路活性。第一天，采用HEK-293T细胞，6厘米培养皿以1μg多巴胺D 2受体、1μg含有C端海藻荧光素酶的Gα i1(Gα i1-Rluc)、1μg G β3、1μg含有C端绿色荧光蛋白的Gγ 9(Gγ 9-GFP)和16μL PEI进行转染。同时，为了检测多巴胺D 2受体介导的下游β-arrestin2信号通路，第一天，6厘米培养皿以500μg含有C端海藻荧光素酶的多巴胺D 2受体(D 2-Rluc)、500μg G蛋白偶联受体激酶2(GRK2)、2500μg含有N端绿色荧光蛋白的β-arrestin2(GFP2- ARRB2)和14μL PEI进行转染。第二天，消化长满的细胞，以一个长满细胞的6厘米培养皿细胞量铺一个96孔板，每孔100μL培液。第三天，加药检测。从细胞房中拿出96孔板去除培液，每孔加入40μL底物腔肠素400a(终浓度5μM)，紧接着从左到右依次加入20μL不同的药物，保证药物终浓度由下到上梯度递减，每种处理两个重复，最后，上机检测。机器读值反应胞内β-arrestin2上膜情况以及G蛋白三聚体解离情况，前者表征多巴胺D 2受体下游β-arrestin2信号通路激活程度后者表征多巴胺D 2受体下游G蛋白信号通路激活程度，由此，各种化合物对多巴胺D 2受体的激动作用可被揭示。结果如表3所示。 The BRET method was used to detect the activity of the downstream G protein signal pathway mediated by dopamine D 2 receptor. On the first day, use HEK-293T cells, 6 cm culture dish with 1 μg dopamine D 2 receptor, 1 μg Gα i1 (Gα i1 -Rluc) containing C-terminal seaweed luciferase, 1 μg G β3 , and 1 μg containing C-terminal green fluorescence Protein Gγ 9 (Gγ 9 -GFP) and 16 μL PEI were transfected. At the same time, in order to detect the downstream β-arrestin2 signaling pathway mediated by the dopamine D 2 receptor, on the first day, 500 μg of dopamine D 2 receptor (D 2 -Rluc) containing C-terminal seaweed luciferase in a 6 cm petri dish, 500 μg G protein-coupled receptor kinase 2 (GRK2), 2500μg β-arrestin2 (GFP2-ARRB2) containing N-terminal green fluorescent protein and 14μL PEI were transfected. On the second day, digest the overgrown cells and spread a 96-well plate with 100 μL culture medium per well with the amount of cells in a 6 cm culture dish full of cells. On the third day, dosing and testing. Take out the 96-well plate from the cell chamber to remove the culture solution, add 40 μL of substrate coelenterazine 400a (final concentration 5 μM) to each well, and then add 20 μL of different drugs from left to right to ensure that the final concentration of the drug is from bottom to top The gradient is decreasing, two repetitions of each treatment, and finally, the machine is tested. Β-arrestin2 the film as well as G protein trimer reaction solution within the machine reading from the cell, the former characterized dopamine D 2 receptor β-arrestin2 downstream pathway activation signals which characterize the degree of dopamine D 2 receptor G protein signaling pathway downstream The degree of activation, thus, the agonistic effects of various compounds on dopamine D 2 receptors can be revealed. The results are shown in Table 3.

表3：部分化合物对多巴胺D2受体的功能活性。Table 3: Functional activities of some compounds on dopamine D2 receptors.

化合物Compound Gαi1BRET,EC 50(Emax％) Gαi1BRET,EC 50 (Emax%) β-arrestin2BRET,EC 50(Emax％) β-arrestin2BRET,EC 50 (Emax%) I-44盐酸盐I-44 hydrochloride EC 50＝34.7nM(E max＝51％) EC 50 ＝34.7nM (E max ＝51%) EC 50＝94.0nM(E max＝39％) EC 50 ＝94.0nM (E max ＝39%) I-46盐酸盐I-46 hydrochloride EC 50＝53.5nM(E max＝66％) EC 50 ＝53.5nM (E max ＝66%) EC 50＝97.1nM(E max＝14％) EC 50 ＝97.1nM (E max ＝14%) I-47盐酸盐I-47 hydrochloride EC 50＝4.22nM(E max＝69％) EC 50 ＝4.22nM (E max ＝69%) EC 50＝5.80nM(E max＝12％) EC 50 ＝5.80nM (E max ＝12%) I-50盐酸盐I-50 hydrochloride EC 50＝48.98nM(E max＝25％) EC 50 ＝48.98nM (E max ＝25%) EC 50＝67.6nM(E max＝30％) EC 50 ＝67.6nM (E max ＝30%) I-51盐酸盐I-51 hydrochloride EC 50＝26.30nM(E max＝52％) EC 50 ＝26.30nM (E max ＝52%) EC 50＝32.4nM(E max＝53％) EC 50 ＝32.4nM (E max ＝53%) I-53盐酸盐I-53 hydrochloride EC 50＝18.88nM(E max＝27％) EC 50 ＝18.88nM (E max ＝27%) EC 50＝35.7nM(E max＝12％) EC 50 ＝35.7nM (E max ＝12%) I-54盐酸盐I-54 hydrochloride EC 50＝2.88nM(E max＝28％) EC 50 ＝2.88nM (E max ＝28%) EC 50＝7.43nM(E max＝14％) EC 50 ＝7.43nM (E max ＝14%) I-61盐酸盐I-61 hydrochloride EC 50＝407.38nM(E max＝21％) EC 50 ＝407.38nM (E max ＝21%) EC 50＝128nM(E max＝9％) EC 50 ＝128nM (E max ＝9%) I-64盐酸盐I-64 hydrochloride EC 50＝14.73nM(E max＝66％) EC 50 ＝14.73nM (E max ＝66%) EC 50＝27.6nM(E max＝33％) EC 50 ＝27.6nM (E max ＝33%) I-65盐酸盐I-65 hydrochloride EC 50＝26.3nM(E max＝62％) EC 50 ＝26.3nM (E max ＝62%) EC 50＝23.4nM(E max＝63％) EC 50 ＝23.4nM (E max ＝63%) I-66盐酸盐I-66 hydrochloride EC 50＝169.82nM(E max＝28％) EC 50 ＝169.82nM (E max ＝28%) EC 50＝120nM(E max＝30％) EC 50 ＝120nM (E max ＝30%) I-67盐酸盐I-67 hydrochloride EC 50＝10.87nM(E max＝65％) EC 50 ＝10.87nM (E max ＝65%) EC 50＝2.02nM(E max＝14％) EC 50 ＝2.02nM (E max ＝14%) I-68盐酸盐I-68 hydrochloride EC 50＝7.82nM(E max＝61％) EC 50 ＝7.82nM (E max ＝61%) EC 50＝4.47nM(E max＝15％) EC 50 ＝4.47nM (E max ＝15%) I-69盐酸盐I-69 hydrochloride EC 50＝95.50nM(E max＝31％) EC 50 ＝95.50nM (E max ＝31%) EC 50＝61.7nM(E max＝32％) EC 50 ＝61.7nM (E max ＝32%) I-70盐酸盐I-70 hydrochloride EC 50＝660.70nM(E max＝30％) EC 50 ＝660.70nM (E max ＝30%) EC 50＝338.8nM(E max＝32％) EC 50 ＝338.8nM (E max ＝32%) I-71盐酸盐I-71 hydrochloride EC 50＝6.8nM(E max＝76％) EC 50 ＝6.8nM (E max ＝76%) EC 50＝10.9nM(E max＝22％) EC 50 =10.9nM (E max ＝22%) I-76盐酸盐I-76 hydrochloride EC 50＝4.21nM(E max＝81％) EC 50 ＝4.21nM (E max ＝81%) EC 50＝6.75nM(E max＝40％) EC 50 ＝6.75nM (E max ＝40%) I-77盐酸盐I-77 hydrochloride EC 50＝11.22nM(E max＝65％) EC 50 ＝11.22nM (E max ＝65%) EC 50＝7.08nM(E max＝60％) EC 50 ＝7.08nM (E max ＝60%) I-78盐酸盐I-78 hydrochloride EC 50＝2.63nM(E max＝73％) EC 50 ＝2.63nM (E max ＝73%) EC 50＝15.0nM(E max＝49％) EC 50 =15.0nM (E max ＝49%) I-79盐酸盐I-79 hydrochloride EC 50＝3.47nM(E max＝71％) EC 50 ＝3.47nM (E max ＝71%) EC 50＝14.9nM(E max＝26％) EC 50 =14.9nM (E max ＝26%) I-80盐酸盐I-80 hydrochloride EC 50＝9.3nM(E max＝58％) EC 50 ＝9.3nM (E max ＝58%) EC 50＝10.0nM(E max＝52％) EC 50 =10.0nM (E max ＝52%) I-81盐酸盐I-81 hydrochloride EC 50＝4.15nM(E max＝75％) EC 50 ＝4.15nM (E max ＝75%) EC 50＝18.8nM(E max＝46％) EC 50 =18.8nM (E max ＝46%) I-82盐酸盐I-82 hydrochloride EC 50＝77.62nM(E max＝18％) EC 50 ＝77.62nM (E max ＝18%) EC 50＝191nM(E max＝19％) EC 50 ＝191nM (E max ＝19%) I-83盐酸盐I-83 hydrochloride EC 50＝891.25nM(E max＝12％) EC 50 ＝891.25nM (E max ＝12%) EC 50＝417nM(E max＝14％) EC 50 ＝417nM (E max ＝14%) I-84盐酸盐I-84 hydrochloride EC 50＝17.78nM(E max＝42％) EC 50 ＝17.78nM (E max ＝42%) EC 50＝39.5nM(E max＝34％) EC 50 ＝39.5nM (E max ＝34%) I-85盐酸盐I-85 hydrochloride EC 50＝22.91nM(E max＝22％) EC 50 ＝22.91nM (E max ＝22%) EC 50＝61.3nM(E max＝16％) EC 50 ＝61.3nM (E max ＝16%)

I-88盐酸盐I-88 hydrochloride EC 50＝8.45nM(E max＝68％) EC 50 ＝8.45nM (E max ＝68%) EC 50＝9.49nM(E max＝16％) EC 50 ＝9.49nM (E max ＝16%) I-94盐酸盐I-94 hydrochloride EC 50＝49.55nM(E max＝27％) EC 50 ＝49.55nM (E max ＝27%) EC 50＝13.1nM(E max＝24％) EC 50 =13.1nM (E max ＝24%) I-95盐酸盐I-95 hydrochloride EC 50＝16.66nM(E max＝27％) EC 50 ＝16.66nM (E max ＝27%) EC 50＝4.06nM(E max＝22％) EC 50 ＝4.06nM (E max ＝22%)

从表3可以看出，化合物I-47,I-54,I-68,I-71,I-76,I-78,I-79,I-80,I-81,I-88等对D2受体具有较强的激动剂或部分激动剂活性。It can be seen from Table 3 that the compounds I-47, I-54, I-68, I-71, I-76, I-78, I-79, I-80, I-81, I-88, etc. The receptor has strong agonist or partial agonist activity.

4.部分通式I化合物对5-HT 2C受体的亲和力测试。 4. The affinity test of some compounds of general formula I to 5-HT 2C receptor.

(1)人源5-HT 2C受体细胞膜的准备：将稳定表达人源5-HT 2C受体的HEK-293细胞置于直径15厘米的培养皿中，在含10％胎牛血清(FBS)和1％青霉素钠/链霉素(100U/mL)的标准培养基(DMEM)中培养至90％融合状态。细胞经pH＝7.4的磷酸盐缓冲液(PBS)冲洗，刮入50mL锥形管，离心10分钟(1000rpm，4℃)得细胞微球，再用裂解液(50mm Tris HCl缓冲液，pH＝7.4，4℃)重新悬浮细胞微球，进行低渗裂解。细胞悬浮液离心20分钟(21,000rpm，4℃)，除去上清液得细胞膜分离颗粒，将细胞膜颗粒再悬浮配成1mg/mL混悬液(浓度按Bradford实验测定)，于-80℃保存备用。 (1) Preparation of human 5-HT 2C receptor cell membrane: HEK-293 cells stably expressing human 5-HT 2C receptor were placed in a petri dish with a diameter of 15 cm. ) And 1% penicillin sodium/streptomycin (100U/mL) standard medium (DMEM) to 90% confluence. The cells were washed with pH=7.4 phosphate buffered saline (PBS), scraped into a 50mL conical tube, centrifuged for 10 minutes (1000rpm, 4℃) to obtain cell microspheres, and then used lysis buffer (50mm Tris HCl buffer, pH=7.4 , 4℃) Resuspend the cell microspheres for hypotonic lysis. The cell suspension was centrifuged for 20 minutes (21,000 rpm, 4°C), the supernatant was removed to obtain cell membrane separation particles, and the cell membrane particles were resuspended to form a 1mg/mL suspension (concentration determined by Bradford experiment), and stored at -80°C for later use .

(2)放射性同位素配体竞争结合实验：竞争结合实验在96孔板中进行，所用的标准缓冲溶液体系为50mM HEPES,50mM NaCl,5mM MgCl 2,0.5mM EDTA,pH＝7.4；标准冲洗液为50mM Tris HCl,pH＝7.4；所用放射性同位素配体为[ 3H]-Mesulergine。将待测化合物配成相应10mM浓度的DMSO溶液，然后用缓冲液稀释至10μM,再用缓冲液3倍梯度稀释，得11个浓度点(0.1，0.3，1，3，10，30，100，300，1000，3000，10000nM)。将不同浓度的待测化合物转移到96孔板上，每孔50μL；再依次加入50μL放射性同位素配体[ 3H]-Mesulergine(1–3nM)和50μL人源5-HT 2C受体细胞膜悬浮液，轻轻摇匀，室温下避光孵育90分钟。4℃条件下，使用96孔Packard Filtermate收集器，在聚乙烯亚胺浸泡过的96孔过滤器垫上真空过滤终止孵育反应，并用标准冲洗液冲洗三次。在热板上将闪烁液(scintillation cocktail)融化在微波炉烘干的过滤器表面，用保鲜膜包裹过滤器，使用Microbeta计数器计数，用GraphPad Prism 7处理数据，计算IC 50值，再通过Cheng-Prusoff方程计算得K i。 (2) Radioisotope ligand competition binding experiment: The competition binding experiment was carried out in a 96-well plate, and the standard buffer solution system used was 50mM HEPES, 50mM NaCl, 5mM MgCl 2 , 0.5mM EDTA, pH=7.4; the standard washing solution was 50mM Tris HCl, pH=7.4; the radioisotopic ligand used is [ 3 H]-Mesulergine. The compound to be tested was prepared into the corresponding 10mM DMSO solution, then diluted with buffer to 10μM, and then diluted with buffer 3 times in a gradient to obtain 11 concentration points (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000, 10000nM). Transfer test compounds of different concentrations to a 96-well plate, 50μL per well; then add 50μL of radioisotope ligand [ 3 H]-Mesulergine (1–3nM) and 50μL of human 5-HT 2C receptor cell membrane suspension in sequence , Shake gently, and incubate for 90 minutes in the dark at room temperature. At 4°C, using a 96-well Packard Filtermate collector, vacuum filtration on a 96-well filter pad soaked in polyethyleneimine to terminate the incubation reaction, and rinse three times with a standard rinsing solution. Melt the scintillation cocktail on the surface of the microwave-dried filter on the hot plate, wrap the filter with plastic wrap, count with a Microbeta counter, process the data with GraphPad Prism 7, calculate the IC 50 value, and pass Cheng-Prusoff The equation is calculated to obtain K i .

表4：部分通式I化合物对5-HT 2C受体的亲和力 Table 4: Affinity of some compounds of general formula I to 5-HT 2C receptor

化合物Compound 5-HT 2C受体亲和力 5-HT 2C receptor affinity I-19a盐酸盐I-19a hydrochloride K i＝1122nM K i ＝1122nM I-19b盐酸盐I-19b hydrochloride K i＝50.1nM K i ＝50.1nM I-41a盐酸盐I-41a hydrochloride K i＝427nM K i =427nM I-41b盐酸盐I-41b hydrochloride K i＝138nM K i ＝138nM I-42a盐酸盐I-42a hydrochloride K i＝513nM K i ＝513nM

I-42b盐酸盐I-42b hydrochloride K i＝61.7nM K i ＝61.7nM I-43a盐酸盐I-43a hydrochloride K i＝417nM K i =417nM I-43b盐酸盐I-43b hydrochloride K i＝44.7nM K i ＝44.7nM

从表4可以看出，通式I化合物对5-HT 2C受体具有不同程度的亲和力。 It can be seen from Table 4 that the compounds of general formula I have different degrees of affinity for 5-HT 2C receptors.

5.部分通式I化合物对5-HT 2C受体的功能活性测试。 5. The functional activity test of some compounds of general formula I on 5-HT 2C receptor.

通式I化合物对5-HT 2C受体的功能活性采用钙流实验方法测定。采用稳定高表达5-HT 2C受体的HEK-293细胞，利用FLIPR TETRA(Molecular Dynamics)高通量荧光成像分析仪进行检测。具体地，以10,000细胞/孔的数量进行多聚赖氨酸预处理的384孔板的铺板；次日加入Fluo-4Direct染料(Invitrogen，20μL/孔)，并加入缓冲液(1×HBSS，2.5mM丙磺舒，20mM HEPES，pH 7.4)孵育1小时(37℃，5％CO 2)。待测化合物以相同缓冲液为溶剂按终浓度进行3倍等梯度稀释，每孔加入10μL，之后在FLIPR仪器上测试钙流强度300秒。化合物的测试浓度为1pM至10μM，但对于活性较弱的化合物最高浓度提高至100μM。5-羟色胺的活性强度标准化为100％，剂量-效应曲线采用GraphPad Prism7.0进行拟合。对于拮抗剂的测定，细胞板预先加入10μL的5-HT(终浓度1nM)，孵育15分钟，之后加待测化合物进行数据读取。所有化合物的数据独立测试3次取平均值。 The functional activity of compounds of general formula I on 5-HT 2C receptors was determined by the calcium flux test method. Using HEK-293 cells stably and highly expressing 5-HT 2C receptors, FLIPR TETRA (Molecular Dynamics) high-throughput fluorescence imaging analyzer was used for detection. Specifically, 384-well plates pretreated with polylysine were plated at a quantity of 10,000 cells/well; Fluo-4Direct dye (Invitrogen, 20μL/well) was added the next day, and buffer (1×HBSS, 2.5 mM probenecid, 20mM HEPES, pH 7.4) were incubated for 1 hour (37°C, 5% CO 2 ). The compound to be tested was diluted with the same buffer as the solvent and the final concentration was 3 times isocratically diluted, 10 μL was added to each well, and then the calcium current intensity was tested on the FLIPR instrument for 300 seconds. The tested concentration of the compound is 1 pM to 10 μM, but the highest concentration for the less active compound is increased to 100 μM. The activity intensity of serotonin was standardized to 100%, and the dose-response curve was fitted with GraphPad Prism7.0. For the determination of antagonists, 10 μL of 5-HT (final concentration 1 nM) was added to the cell plate in advance, incubated for 15 minutes, and then the test compound was added for data reading. The data of all compounds were independently tested 3 times and averaged.

表5：部分通式I化合物对5-HT 2C受体的功能活性测试。 Table 5: Functional activity test of some compounds of general formula I on 5-HT 2C receptor.

化合物Compound 5-HT 2C受体功能活性(钙流实验) 5-HT 2C receptor functional activity (calcium flux test) I-19a盐酸盐I-19a hydrochloride 拮抗剂，IC 50＝14.5μM Antagonist, IC 50 =14.5μM I-19b盐酸盐I-19b hydrochloride 拮抗剂，IC 50＝0.86μM Antagonist, IC 50 =0.86μM I-41a盐酸盐I-41a hydrochloride 拮抗剂，IC 50＝16.1μM Antagonist, IC 50 = 16.1μM I-41b盐酸盐I-41b hydrochloride 激动剂，EC 50＝3.5μM(E max＝30.3％) Agonist, EC 50 =3.5μM (E max =30.3%) I-42a盐酸盐I-42a hydrochloride 拮抗剂，IC 50>30μM Antagonist, IC 50 >30μM I-42b盐酸盐I-42b hydrochloride 激动剂，EC 50＝2.5μM(E max＝44.2％) Agonist, EC 50 =2.5μM (E max =44.2%) I-43a盐酸盐I-43a hydrochloride 拮抗剂，IC 50＝10.1μM Antagonist, IC 50 =10.1μM I-43b盐酸盐I-43b hydrochloride 激动剂，EC 50＝0.74μM(E max＝51.9％) Agonist, EC 50 =0.74μM (E max =51.9%)

从表5可以看出，化合物对于5-HT 2C受体的功能活性(激动或拮抗)中等或较弱，显著弱于它们对于多巴胺D3受体的功能活性。 It can be seen from Table 5 that the functional activity (agonistic or antagonistic) of the compounds on the 5-HT 2C receptor is moderate or weak, which is significantly weaker than their functional activity on the dopamine D3 receptor.

6.部分通式I化合物的药代动力学性质和透过血脑屏障的性质6. The pharmacokinetic properties of some compounds of general formula I and the properties of penetrating the blood-brain barrier

化合物在ICR小鼠体内单剂量静脉和灌胃给药后，于不同时间点采集血样和脑组织，LC-MS/MS测定小鼠血浆和脑组织中化合物的浓度并计算相关药代参数，考察化合物在小鼠药代特征、生物利用度和脑组织中暴露情况。After single-dose intravenous and intragastric administration of the compound in ICR mice, blood samples and brain tissue were collected at different time points. LC-MS/MS measured the concentration of the compound in mouse plasma and brain tissue and calculated related pharmacokinetic parameters. The compound's pharmacokinetic characteristics, bioavailability and exposure in brain tissues of mice.

化合物I-19a、I-41a、I-42a和I-43a(均为盐酸盐)溶解于生理盐水，给药剂量为静脉注射(iv)5mg/kg、灌胃给药(po)10mg/kg。每组9只小鼠。给药前及给药后异氟烷麻醉经眼眶取血0.06mL，置于EDTAK2离心管中并放置冰浴上。5000rpm，4℃离心10min，收集血浆。动物放血后安乐死取脑组织同时生理盐水清洗干净，准确称量加50％冰甲醇按照1:3(m/v)进行组织匀浆，分析检测前，所有血浆和脑组织样品存于-80℃。Compounds I-19a, I-41a, I-42a and I-43a (all hydrochloride) were dissolved in physiological saline, and the dosage was 5 mg/kg for intravenous injection (iv) and 10 mg/kg for intragastric administration (po). kg. Each group has 9 mice. Before and after administration, 0.06 mL of blood was taken from the orbit with isoflurane anesthesia, placed in an EDTAK2 centrifuge tube and placed on an ice bath. Centrifuge at 5000 rpm, 4°C for 10 min, and collect plasma. After bloodletting, the animals were euthanized and the brain tissue was taken and the brain tissue was cleaned with saline. It was accurately weighed and added 50% ice methanol to homogenize the tissue according to 1:3 (m/v). Before analysis and testing, all plasma and brain tissue samples were stored at -80°C .

IV采集时间点：0,5,15,30分钟,1,2,4,6,8,24小时，PO采集时间点：0,15,30分钟,1,2,4,6,8,24小时。脑组织样品采集时间点：0.5和2小时。IV collection time point: 0,5,15,30 minutes,1,2,4,6,8,24 hours, PO collection time point: 0,15,30 minutes,1,2,4,6,8,24 Hour. Brain tissue sample collection time points: 0.5 and 2 hours.

组织样品中药物浓度以LCMS/MS的方法进行分析。数据采集及控制系统软件为Analyst1.5.1软件(Applied Biosystem)。图谱样品峰积分方式为自动积分；采用样品峰面积和内标峰面积的比值作为指标，和样品的浓度进行回归。回归方式：线性回归，权重系数为1/X 2。药代动力学参数用WinNonlin Professional v6.3(Pharsight,USA)用非房室模型分析处理。C max为实测的最大血药浓度，血药浓度-时间曲线下面积AUC (0→t)由梯形法计算得到，T max为给药后血药浓度达峰时间。 The drug concentration in the tissue samples was analyzed by LCMS/MS method. The data acquisition and control system software is Analyst 1.5.1 software (Applied Biosystem). The peak integration method of the spectrum sample is automatic integration; the ratio of the peak area of the sample to the peak area of the internal standard is used as an index, and the concentration of the sample is regressed. Regression method: linear regression, the weight coefficient is 1/X 2 . The pharmacokinetic parameters were analyzed and processed with WinNonlin Professional v6.3 (Pharsight, USA) with a non-compartmental model. C max is the measured maximum plasma concentration, the area under the plasma concentration-time curve AUC (0→t) is calculated by the trapezoid method, and T max is the peak time after the administration of the plasma concentration.

表6:部分化合物的药代动力学性质Table 6: Pharmacokinetic properties of some compounds

Figure PCTCN2021076289-appb-000366
Figure PCTCN2021076289-appb-000366

从表6可以看出，化合物I-42a具有良好的生物利用度和药物代谢性质。It can be seen from Table 6 that compound I-42a has good bioavailability and drug metabolism properties.

表7:部分化合物透过血脑屏障的性质Table 7: Properties of some compounds penetrating the blood-brain barrier

Figure PCTCN2021076289-appb-000367
Figure PCTCN2021076289-appb-000367

从表7可以看出，化合物I-19a、I-41a、I-42a和I-43a具有良好的血脑屏障透过性质。It can be seen from Table 7 that compounds I-19a, I-41a, I-42a and I-43a have good blood-brain barrier permeability.

Claims (20)

一种如式I所示的化合物：A compound represented by formula I:
Figure PCTCN2021076289-appb-100001
Figure PCTCN2021076289-appb-100001
 或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物；Or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing; 其中，R 1为氢、卤素、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、-OR a、-SR b、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 1a取代； Wherein, R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group mean that the C 1 -C 4 alkyl group and the C 3 -C 6 cycloalkyl group are each independently Replaced by 1, 2, 3 or 4 R 1a; R 2为氢、卤素、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、-OR a、-SR b、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 2a取代； R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN , Wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group mean that the C 1 -C 4 alkyl group and the C 3 -C 6 cycloalkyl group are each independently covered by 1 , 2, 3 or 4 R 2a substitutions; R 3为氢、卤素、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、-OR a、-SR b、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 3a取代； R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN , Wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group mean that the C 1 -C 4 alkyl group and the C 3 -C 6 cycloalkyl group are each independently covered by 1 , 2, 3 or 4 R 3a substitutions; R 4为氢、卤素、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、-OR a、-SR b、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 4a取代； R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN , Wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group mean that the C 1 -C 4 alkyl group and the C 3 -C 6 cycloalkyl group are each independently covered by 1 , 2, 3 or 4 R 4a substitutions; R 5为氢、卤素、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、-OR a、-SR b、-NR cR d或-CN，其中所述的取代的C 1-C 4烷基和取代的C 3-C 6环烷基是指所述C 1-C 4烷基和C 3-C 6环烷基各自独立地被1、2、3或4个R 5a取代； R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, -OR a , -SR b , -NR c R d or -CN , Wherein the substituted C 1 -C 4 alkyl group and the substituted C 3 -C 6 cycloalkyl group mean that the C 1 -C 4 alkyl group and the C 3 -C 6 cycloalkyl group are each independently covered by 1 , 2, 3 or 4 R 5a substitutions; 或者，“R 1和R 2”、“R 2和R 3”、“R 3和R 4”、或“R 4和R 5”，以及连接它们的相邻的两个碳原子一起共同形成取代或未取代的C 5-C 6环烷基、取代或未取代的5-6元杂环烷基、取代或未取代的苯基或取代或未取代的5-6元杂芳基，所述的取代的C 5-C 6环烷基、取代的5-6元杂环烷基、取代的苯基和取代的5-6元杂芳基是指所述C 5-C 6环烷基、5-6元杂环烷基、苯基和5-6元杂芳基各自独立地被1、2、3或4个R 5b取代； Or, "R 1 and R 2 ", "R 2 and R 3 ", "R 3 and R 4 ", or "R 4 and R 5 ", and two adjacent carbon atoms connecting them together form a substitution Or unsubstituted C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted 5-6 membered heteroaryl, said The substituted C 5 -C 6 cycloalkyl group, the substituted 5-6 membered heterocycloalkyl group, the substituted phenyl group and the substituted 5-6 membered heteroaryl group refer to the C 5 -C 6 cycloalkyl group, 5-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each independently substituted with 1, 2, 3 or 4 R 5b ; 每个R 1a、R 2a、R 3a、R 4a和R 5a各自独立地为卤素、C 1-C 4烷基、C 3-C 6环烷基、-OR e、-SR f或-NR gR h； Each of R 1a , R 2a , R 3a , R 4a and R 5a is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, -OR e , -SR f or -NR g R h ; 每个R 5b独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基； Each R 5b is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; R 6为氢、C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 6环烷基或-(C 1-C 4亚烷基)-(C 3-C 6环烷基)； R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkane base); L为-(CR 8R 9) t-或
Figure PCTCN2021076289-appb-100002
L is -(CR 8 R 9 ) t -or
Figure PCTCN2021076289-appb-100002
 t为2、3、4、5、6、7或8；t is 2, 3, 4, 5, 6, 7 or 8; m为1、2或3；m is 1, 2 or 3; n为1、2或3；n is 1, 2 or 3; 每个R 8和R 9各自独立地为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 8a取代；前提是连接于同一个碳原子上的R 8和R 9不同时为-OR a； Each of R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl refers to the C The 1- C 4 alkyl group is substituted with 1, 2, 3 or 4 R 8a ; provided that R 8 and R 9 attached to the same carbon atom are not at the same time -OR a ; 或者，一个R 8和一个R 9以及连接它们的一个或多个碳原子一起共同形成一个取代或未取代的单环C 3-C 6环烷基，所述的取代的单环C 3-C 6环烷基是指所述单环C 3-C 6环烷基被1、2、3或4个R 8a取代； Alternatively, one R 8 and one R 9 and one or more carbon atoms connecting them together form a substituted or unsubstituted monocyclic C 3 -C 6 cycloalkyl, and the substituted monocyclic C 3 -C 6 -cycloalkyl means that the monocyclic C 3 -C 6 cycloalkyl is substituted with 1, 2, 3 or 4 R 8a ; 每个R 8a独立地为卤素、C 1-C 4烷基、C 3-C 6环烷基或-OR e； Each R 8a is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or -OR e ; A为
Figure PCTCN2021076289-appb-100003
或-X-Y； A is
Figure PCTCN2021076289-appb-100003
Or -XY; R 10为氢或C 1-C 4烷基； R 10 is hydrogen or C 1 -C 4 alkyl; R 11为取代或未取代的C 3-C 8环烷基、取代或未取代的3-8元杂环烷基、-NR 11aR 11b、取代或未取代的C 6-C 14芳基或取代或未取代的5-14元杂芳基，其中所述的取代的C 3-C 8环烷基、取代的3-8元杂环烷基、取代的C 6-C 14芳基和取代的5-14元杂芳基是指所述C 3-C 8环烷基、3-8元杂环烷基、C 6-C 14芳基和5-14元杂芳基各自独立地被1、2、3或4个R 11c取代； R 11 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, -NR 11a R 11b , substituted or unsubstituted C 6 -C 14 aryl or The substituted or unsubstituted 5-14 membered heteroaryl group, wherein the substituted C 3 -C 8 cycloalkyl group, the substituted 3-8 membered heterocycloalkyl group, the substituted C 6 -C 14 aryl group and the substituted The 5-14 membered heteroaryl group means that the C 3 -C 8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 14 aryl group and 5-14 membered heteroaryl group are each independently covered by 1 , 2, 3 or 4 R 11c substitutions; R 11a为氢或C 1-C 4烷基； R 11a is hydrogen or C 1 -C 4 alkyl; R 11b为氢或C 1-C 4烷基； R 11b is hydrogen or C 1 -C 4 alkyl; 或者，R 11a和R 11b以及连接它们的氮原子一起共同形成取代或未取代的4-8元杂环烷基，所述的取代的4-8元杂环烷基是指所述4-8元杂环烷基被1、2、3或4个R 11d取代； Alternatively, R 11a and R 11b and the nitrogen atom connecting them together form a substituted or unsubstituted 4-8 membered heterocycloalkyl, and the substituted 4-8 membered heterocycloalkyl refers to the 4-8 The membered heterocycloalkyl group is substituted with 1, 2, 3 or 4 R 11d ; 每个R 11c独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基、-OR a、-SR b、-NR cR d或-CN； Each R 11c is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN; 每个R 11d独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基、-OR a、-SR b、-NR cR d或-CN； Each R 11d is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN; R 12为氢或C 1-C 4烷基； R 12 is hydrogen or C 1 -C 4 alkyl; R 13为取代或未取代的C 3-C 8环烷基、取代或未取代的3-8元杂环烷基、取代或未取代的C 6-C 14芳基或取代或未取代的5-14元杂芳基，其中所述的取代的C 3-C 8环烷基、取代的3-8元杂环烷基、取代的C 6-C 14芳基和取代的5-14元杂芳基是指所述C 3-C 8环烷基、3-8元杂环烷基、C 6-C 14芳基和5-14元杂芳基各自独立地任选被1、2、3或4个R 13a取代； R 13 is a substituted or unsubstituted C 3 -C 8 cycloalkyl group, a substituted or unsubstituted 3-8 membered heterocycloalkyl group, a substituted or unsubstituted C 6 -C 14 aryl group, or a substituted or unsubstituted 5 -14 membered heteroaryl group, wherein the substituted C 3 -C 8 cycloalkyl group, the substituted 3-8 membered heterocycloalkyl group, the substituted C 6 -C 14 aryl group and the substituted 5-14 membered hetero Aryl refers to the C 3 -C 8 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 14 aryl group and 5-14 membered heteroaryl group each independently optionally by 1, 2, 3 Or 4 R 13a substitutions; 每个R 13a独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基、-OR a、-SR b、-NR cR d或-CN； Each R 13a is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN; X为
Figure PCTCN2021076289-appb-100004
-O-或-S-； X is
Figure PCTCN2021076289-appb-100004
-O- or -S-; R 14和R 15各自独立地为氢或C 1-C 4烷基； R 14 and R 15 are each independently hydrogen or C 1 -C 4 alkyl; Y为取代或未取代的C 6-C 14芳基或取代或未取代的5-14元杂芳基，所述的取代的C 6-C 14芳基和取代的5-14元杂芳基是指所述C 6-C 14芳基和5-14元杂芳基各自独立地被1、2、3或4个R 30取代； Y is a substituted or unsubstituted C 6 -C 14 aryl group or a substituted or unsubstituted 5-14 membered heteroaryl group, the substituted C 6 -C 14 aryl group and the substituted 5-14 membered heteroaryl group Means that the C 6 -C 14 aryl group and the 5-14 membered heteroaryl group are each independently substituted with 1, 2, 3 or 4 R 30 ; 每个R 30独立地为卤素、氧代、取代或未取代的C 1-C 4烷基、取代或未取代的C 3-C 6环烷基、取代或未取代的4-6元杂环烷基、取代或未取代的苯基、取代或未取代的5-6元杂芳基、-OR a、-SR b、-NR cR d或-CN，其中所述取代的C 1-C 4烷基、取代的C 3-C 6环烷基、取代的4-6元杂环烷基、取代的苯基和取代的5-6元杂芳基是指所述C 1-C 4烷基、C 3-C 6环烷基、4-6元杂环烷基、苯基和5-6元杂芳基各自独立地被1、2、3或4个R 40取代； Each R 30 is independently halogen, oxo, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycle Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, -OR a , -SR b , -NR c R d or -CN, wherein the substituted C 1 -C 4- alkyl, substituted C 3 -C 6 cycloalkyl, substituted 4-6 membered heterocycloalkyl, substituted phenyl and substituted 5-6 membered heteroaryl refer to the C 1 -C 4 alkane , C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each independently substituted with 1, 2, 3 or 4 R 40 ; 每个R 40独立地为卤素、氧代、C 1-C 4烷基、C 1-C 4卤代烷基、-OR a、-SR b、-NR cR d或-CN； Each R 40 is independently halogen, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OR a , -SR b , -NR c R d or -CN; 每个R a、R b、R c、R d、R e、R f和R g各自独立地为氢、C 1-C 4烷基、C 3-C 6环烷基或C 1-C 4卤代烷基； Each R a, R b, R c , R d, R e, R f and R g are each independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 4 Haloalkyl *标记的碳原子为S构型、R构型或者两者的混合；*The marked carbon atom is S configuration, R configuration or a mixture of the two; #标记的碳原子为S构型、R构型或者两者的混合；# The carbon atom marked with S configuration, R configuration or a mixture of the two; 所述杂环烷基和杂芳基中的杂原子的个数独立地为1、2、3或4个，每个杂原子独立地为N、O或S。The number of heteroatoms in the heterocycloalkyl group and heteroaryl group is independently 1, 2, 3, or 4, and each heteroatom is independently N, O, or S. 如权利要求1所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，在所述的R 1、R 2、R 3、R 4、R 5、R 1a、R 2a、R 3a、R 4a、R 5a、R 5b、R 8、R 9、R 8a、R 11c、R 11d、R 13a、R 30和R 40的定义中，所述的卤素独立地为氟、氯、溴或碘； The compound of formula I according to claim 1, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, or any one of the foregoing Crystal form or solvate, characterized in that, in the R 1 , R 2 , R 3 , R 4 , R 5 , R 1a , R 2a , R 3a , R 4a , R 5a , R 5b , R 8 , In the definitions of R 9 , R 8a , R 11c , R 11d , R 13a , R 30 and R 40 , the halogen is independently fluorine, chlorine, bromine or iodine; 和/或，在所述的R 1、R 2、R 3、R 4、R 5、R 1a、R 2a、R 3a、R 4a、R 5a、R 5b、R 8、R 9、R 8a、R 10、R 11a、R 11b、R 11c、R 11d、R 12、R 13a、R 14、R 15、R 30、R 40、R a、R b、R c、R d、R e、R f和R g的定义中，所述的C 1-C 4烷基各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, in the R 1 , R 2 , R 3 , R 4 , R 5 , R 1a , R 2a , R 3a , R 4a , R 5a , R 5b , R 8 , R 9 , R 8a , R 10, R 11a, R 11b , R 11c, R 11d, R 12, R 13a, R 14, R 15, R 30, R 40, R a, R b, R c, R d, R e, R f In the definition of R g , the C 1 -C 4 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. ； 和/或，在所述的R 5b、R 11c、R 11d、R 13a、R 40、R a、R b、R c、R d、R e、R f和R g的定义中，所述的C 1-C 4卤代烷基中的卤素独立地为氟、氯、溴或碘； And / or, in the definition of R 5b, R 11c, R 11d , R 13a, R 40, R a, R b, R c, R d, R e, R f and R g are, the said The halogen in the C 1 -C 4 haloalkyl is independently fluorine, chlorine, bromine or iodine; 和/或，在所述的R 5b、R 11c、R 11d、R 13a、R 40、R a、R b、R c、R d、R e、R f和R g的定义中，所述的C 1-C 4卤代烷基中的C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And / or, in the definition of R 5b, R 11c, R 11d , R 13a, R 40, R a, R b, R c, R d, R e, R f and R g are, the said The C 1 -C 4 alkyl group in the C 1 -C 4 haloalkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; 和/或，在所述的R 1、R 2、R 3、R 4、R 5、R 1a、R 2a、R 3a、R 4a、R 5a、R 5b、R 6、R 8、R 9、R 8a、R 30、R a、R b、R c、R d、R e、R f和R g的定义中，所述的C 3-C 6环烷基独立地为环丙基、环丁基、环戊基或环己基； And/or, in the R 1 , R 2 , R 3 , R 4 , R 5 , R 1a , R 2a , R 3a , R 4a , R 5a , R 5b , R 6 , R 8 , R 9 , R 8a, R 30,,, R c, R d, R e, R f R a R b is defined and R g are, the said C 3 -C 6 cycloalkyl group are independently cyclopropyl, cyclobutyloxy Group, cyclopentyl or cyclohexyl; 和/或，在所述的R 6的定义中，所述的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, in the definition of R 6 , the C 1 -C 6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl; 和/或，在所述的R 6的定义中，所述的C 1-C 6卤代烷基中的C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, in the definition of R 6 , the C 1 -C 6 alkyl group in the C 1 -C 6 haloalkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, sec-butyl or tert-butyl; 和/或，在所述的R 6的定义中，所述的C 1-C 6卤代烷基中的卤素为氟、氯、溴或碘； And/or, in the definition of R 6 , the halogen in the C 1 -C 6 haloalkyl group is fluorine, chlorine, bromine or iodine; 和/或，在所述的R 6的定义中，所述的-(C 1-C 4亚烷基)-(C 3-C 6环烷基)中的C 1-C 4亚烷基为-CH 2-、-(CH 2) 2-、-(CH 2) 3-或-(CH 2) 4-； And / or, in the definition of R 6 of said - (C 1 -C 4 alkylene) - (C 3 -C 6 cycloalkyl) C 1 -C 4 in the alkylene group is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -or -(CH 2 ) 4 -; 和/或，在所述的R 6的定义中，所述的-(C 1-C 4亚烷基)-(C 3-C 6环烷基)中的C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基； And / or, in the definition of R 6 of said - (C 1 -C 4 alkylene) - (C 3 -C 6 cycloalkyl) the C 3 -C 6 cycloalkyl is Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; 和/或，在所述的R 11和R 13的定义中，所述的C 3-C 8环烷基独立地为环丙基、环丁基、环戊基或环己基； And/or, in the definition of R 11 and R 13 , the C 3 -C 8 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; 和/或，在所述的R 11和R 13的定义中，所述的3-8元杂环烷基独立地为3、4、5或6元杂环烷基； And/or, in the definitions of R 11 and R 13 , the 3-8 membered heterocycloalkyl is independently a 3, 4, 5 or 6 membered heterocycloalkyl; 和/或，在所述的R 30的定义中，所述的4-6元杂环烷基为4、5或6元杂环烷基； And/or, in the definition of R 30 , the 4-6 membered heterocycloalkyl group is a 4, 5 or 6 membered heterocycloalkyl group; 和/或，在所述的R 5b的定义中，所述的C 1-C 4烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。 And/or, in the definition of R 5b , the C 1 -C 4 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , Isobutoxy, sec-butoxy or tert-butoxy. 如权利要求1或2所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，当R 1为卤素时，所述的卤素为氟或氯； The compound of formula I according to claim 1 or 2, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or any of the foregoing The crystalline form or solvate of the above, characterized in that, when R 1 is halogen, the halogen is fluorine or chlorine; 和/或，当R 1为-OR a时，所述的-OR a为甲氧基； And/or, when R 1 is -OR a , said -OR a is methoxy; 和/或，当R 1为-SR b时，所述的-SR b为甲硫基； And/or, when R 1 is -SR b , said -SR b is methylthio; 和/或，当R 2为卤素时，所述的卤素为氟或氯； And/or, when R 2 is halogen, the halogen is fluorine or chlorine; 和/或，当R 3为卤素时，所述的卤素为氟或氯； And/or, when R 3 is halogen, the halogen is fluorine or chlorine; 和/或，当R 3为取代或未取代的C 1-C 4烷基时，所述的取代或未取代的C 1-C 4烷基为三氟甲基； And/or, when R 3 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is a trifluoromethyl group; 和/或，当R 4为卤素时，所述的卤素为氟或氯； And/or, when R 4 is halogen, the halogen is fluorine or chlorine; 和/或，当R 5为-OR a时，所述的-OR a为甲氧基、乙氧基或2-氟乙氧基； And/or, when R 5 is -OR a , said -OR a is methoxy, ethoxy or 2-fluoroethoxy; 和/或，当“R 1和R 2”、“R 2和R 3”、“R 3和R 4”、或“R 4和R 5”，以及连接它们的相邻的两个碳原子一起共同形成取代或未取代的5-6元杂环烷基时，所述的5-6元杂环烷基为
Figure PCTCN2021076289-appb-100005
And/or, when "R 1 and R 2 ", "R 2 and R 3 ", "R 3 and R 4 ", or "R 4 and R 5 ", and the two adjacent carbon atoms connecting them together When jointly forming a substituted or unsubstituted 5-6 membered heterocycloalkyl group, the 5-6 membered heterocycloalkyl group is
Figure PCTCN2021076289-appb-100005
 和/或，当R 1a、R 2a、R 3a、R 4a和R 5a独立地为卤素时，所述的卤素为氟； And/or, when R 1a , R 2a , R 3a , R 4a and R 5a are independently halogen, the halogen is fluorine; 和/或，当R 5b为卤素时，所述的卤素为氟； And/or, when R 5b is halogen, the halogen is fluorine; 和/或，当R 6为C 1-C 6烷基时，所述的C 1-C 6烷基为甲基、乙基、正丙基或异丙基； And/or, when R 6 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl or isopropyl; 和/或，当R 6为-(C 1-C 4亚烷基)-(C 3-C 6环烷基)时，所述的-(C 1-C 4亚烷基)-(C 3-C 6环烷 基)为环丙基甲基； And/or, when R 6 is -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl), said -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl) is cyclopropylmethyl; 和/或，t为3、4、5或6；And/or, t is 3, 4, 5 or 6; 和/或，当一个R 8和一个R 9以及连接它们的一个或多个碳原子一起共同形成一个取代或未取代的单环C 3-C 6环烷基时，L为
Figure PCTCN2021076289-appb-100006
其中k为0、1、2或3； And/or, when one R 8 and one R 9 and one or more carbon atoms connecting them together form a substituted or unsubstituted monocyclic C 3 -C 6 cycloalkyl group, L is
Figure PCTCN2021076289-appb-100006
Where k is 0, 1, 2 or 3; 和/或，m为1；And/or, m is 1; 和/或，n为1；And/or, n is 1; 和/或，当R 11为取代或未取代的C 3-C 8环烷基时，所述的C 3-C 8环烷基为环己基； And/or, when R 11 is a substituted or unsubstituted C 3 -C 8 cycloalkyl group, the C 3 -C 8 cycloalkyl group is a cyclohexyl group; 和/或，当R 11为取代或未取代的C 6-C 14芳基时，所述的C 6-C 14芳基为苯基； And/or, when R 11 is a substituted or unsubstituted C 6 -C 14 aryl group, the C 6 -C 14 aryl group is a phenyl group; 和/或，当R 11为取代或未取代的5-14元杂芳基时，所述的5-14元杂芳基为吲哚基； And/or, when R 11 is a substituted or unsubstituted 5-14 membered heteroaryl group, the 5-14 membered heteroaryl group is an indolyl group; 和/或，当R 11a为C 1-C 4烷基时，所述的C 1-C 4烷基为甲基； And/or, when R 11a is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is a methyl group; 和/或，当R 11b为C 1-C 4烷基时，所述的C 1-C 4烷基为甲基； And/or, when R 11b is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is a methyl group; 和/或，当R 11a和R 11b以及连接它们的氮原子一起共同形成取代或未取代的4-8元杂环烷基时，所述的4-8元杂环烷基为
Figure PCTCN2021076289-appb-100007
And/or, when R 11a and R 11b and the nitrogen atom connecting them together form a substituted or unsubstituted 4-8 membered heterocycloalkyl group, the 4-8 membered heterocycloalkyl group is
Figure PCTCN2021076289-appb-100007
 和/或，当R 13为取代或未取代的C 6-C 14芳基时，所述的C 6-C 14芳基为苯基； And/or, when R 13 is a substituted or unsubstituted C 6 -C 14 aryl group, the C 6 -C 14 aryl group is a phenyl group; 和/或，当Y为取代或未取代的C 6-C 14芳基时，所述的取代或未取代的C 6-C 14芳基为
Figure PCTCN2021076289-appb-100008
其中环A为苯基或5-6元杂芳基，每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； And/or, when Y is a substituted or unsubstituted C 6 -C 14 aryl group, the substituted or unsubstituted C 6 -C 14 aryl group is
Figure PCTCN2021076289-appb-100008
Wherein ring A is phenyl or 5-6 membered heteroaryl, each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; 和/或，当Y为取代或未取代的5-14元杂芳基时，所述的取代或未取代的5-14元杂芳基为
Figure PCTCN2021076289-appb-100009
其中环B为5-6元杂芳基或8-10元双环杂芳基，环C为5-6元杂芳基，环D为苯基或5-6元杂芳基，每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； And/or, when Y is a substituted or unsubstituted 5-14 membered heteroaryl group, the substituted or unsubstituted 5-14 membered heteroaryl group is
Figure PCTCN2021076289-appb-100009
Wherein ring B is 5-6 membered heteroaryl or 8-10 membered bicyclic heteroaryl, ring C is 5-6 membered heteroaryl, ring D is phenyl or 5-6 membered heteroaryl, each p is independent The ground is 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; 和/或，每个R 30独立地为卤素、氧代、羟基、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基； And/or, each R 30 is independently halogen, oxo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; 和/或，每个R 40独立地为卤素、氧代、羟基、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基； And/or, each R 40 is independently halogen, oxo, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; 和/或，当每个R a、R b、R c、R d、R e、R f和R g各自独立地为C 1-C 4卤代烷基时，所述的C 1-C 4卤代烷基独立地为C 1-C 4氟代烷基； And / or, when each of R a, R b, R c , R d, R e, R f and R g are each independently is C 1 -C 4 haloalkyl, said C 1 -C 4 haloalkyl, Independently C 1 -C 4 fluoroalkyl; 和/或，*和#标记的碳原子形成的三元环的结构为
Figure PCTCN2021076289-appb-100010
或两者的混合。 And/or, the structure of the three-membered ring formed by the carbon atoms marked with * and # is
Figure PCTCN2021076289-appb-100010
Or a mixture of the two. 如权利要求1-3中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，当R 11为取代或未取代的5-14元杂芳基时，所述的5-14元杂芳基为
Figure PCTCN2021076289-appb-100011
The compound of Formula I according to any one of claims 1 to 3, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, Or a crystal form or solvate of any one of the foregoing, characterized in that, when R 11 is a substituted or unsubstituted 5-14 membered heteroaryl group, the 5-14 membered heteroaryl group is
Figure PCTCN2021076289-appb-100011
 和/或，当Y为取代或未取代的C 6-C 14芳基时，所述的取代或未取代的C 6-C 14芳基为
Figure PCTCN2021076289-appb-100012
Figure PCTCN2021076289-appb-100013
其中每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； And/or, when Y is a substituted or unsubstituted C 6 -C 14 aryl group, the substituted or unsubstituted C 6 -C 14 aryl group is
Figure PCTCN2021076289-appb-100012
Figure PCTCN2021076289-appb-100013
Where each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; 和/或，当Y为取代或未取代的5-14元杂芳基时，所述的取代或未取代的5-14元杂芳基为
Figure PCTCN2021076289-appb-100014
Figure PCTCN2021076289-appb-100015
Figure PCTCN2021076289-appb-100016
Figure PCTCN2021076289-appb-100017
其中每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； And/or, when Y is a substituted or unsubstituted 5-14 membered heteroaryl group, the substituted or unsubstituted 5-14 membered heteroaryl group is
Figure PCTCN2021076289-appb-100014
Figure PCTCN2021076289-appb-100015
Figure PCTCN2021076289-appb-100016
Figure PCTCN2021076289-appb-100017
Where each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; 和/或，每个R 30独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基； And/or, each R 30 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; 和/或，每个R 40独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基。 And/or, each R 40 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy. 如权利要求1-4中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，R 1为氢、卤素、取代或未取代的C 1-C 4烷基、-OR a或-SR b；和/或，R 2为氢、卤素、取代或未取代的C 1-C 4烷基、-OR a或-SR b；和/或，R 1和R 2以及连接它们的相邻的两个碳原子一起共同形成取代或未取代的苯基或者取代或未取代的5-6元杂环烷基； The compound of formula I according to any one of claims 1 to 4, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, Or a crystal form or solvate of any of the foregoing, characterized in that R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; and/or, R 2 Is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; and/or, R 1 and R 2 and two adjacent carbon atoms connecting them together form a substitution Or unsubstituted phenyl or substituted or unsubstituted 5-6 membered heterocycloalkyl; 和/或，每个R 1a独立地为卤素或-OR e； And/or, each R 1a is independently halogen or -OR e ; 和/或，每个R 2a独立地为卤素或-OR e； And/or, each R 2a is independently halogen or -OR e ; 和/或，R 3为氢、卤素、取代或未取代的C 1-C 4烷基、-OR a或-SR b； And/or, R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; 和/或，每个R 3a独立地为卤素或-OR e； And/or, each R 3a is independently halogen or -OR e ; 和/或，R 4为氢、卤素、取代或未取代的C 1-C 4烷基、-OR a或-SR b； And/or, R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; 和/或，每个R 4a独立地为卤素或-OR e； And/or, each R 4a is independently halogen or -OR e ; 和/或，R 5为氢、卤素、取代或未取代的C 1-C 4烷基、-OR a或-SR b； And/or, R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -OR a or -SR b ; 和/或，每个R 5a独立地为卤素或-OR e； And/or, each R 5a is independently halogen or -OR e ; 和/或，每个R 5b独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基； And/or, each R 5b is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; 和/或，R 6为氢、C 1-C 6烷基或-(C 1-C 4亚烷基)-(C 3-C 6环烷基)； And/or, R 6 is hydrogen, C 1 -C 6 alkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl); 和/或，L为-(CR 8R 9) 3-、-(CR 8R 9) 4-、-(CR 8R 9) 5-、
Figure PCTCN2021076289-appb-100018
其中k为0、1、2或3； And/or, L is -(CR 8 R 9 ) 3 -, -(CR 8 R 9 ) 4 -, -(CR 8 R 9 ) 5 -,
Figure PCTCN2021076289-appb-100018
Where k is 0, 1, 2 or 3; 和/或，每个R 8和R 9各自独立地为氢或C 1-C 4烷基； And/or, each of R 8 and R 9 is independently hydrogen or C 1 -C 4 alkyl; 和/或，每个R 8a独立地为C 1-C 4烷基； And/or, each R 8a is independently a C 1 -C 4 alkyl group; 和/或，当A为
Figure PCTCN2021076289-appb-100019
时，所述的
Figure PCTCN2021076289-appb-100020
为
Figure PCTCN2021076289-appb-100021
Figure PCTCN2021076289-appb-100022
Figure PCTCN2021076289-appb-100023
其中每个p独立地为0、1、2或3； And/or, when A is
Figure PCTCN2021076289-appb-100019
When the said
Figure PCTCN2021076289-appb-100020
for
Figure PCTCN2021076289-appb-100021
Figure PCTCN2021076289-appb-100022
Figure PCTCN2021076289-appb-100023
Where each p is independently 0, 1, 2 or 3; 和/或，每个R 10独立地为氢； And/or, each R 10 is independently hydrogen; 和/或，R 11a为C 1-C 4烷基； And/or, R 11a is a C 1 -C 4 alkyl group; 和/或，R 11b为C 1-C 4烷基； And/or, R 11b is a C 1 -C 4 alkyl group; 和/或，每个R 11c独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基； And/or, each R 11c is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; 和/或，每个R 11d独立地为卤素、C 1-C 4烷基、C 1-C 4卤代烷基或C 1-C 4烷氧基； And/or, each R 11d is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; 和/或，当A为
Figure PCTCN2021076289-appb-100024
时，所述的
Figure PCTCN2021076289-appb-100025
为
Figure PCTCN2021076289-appb-100026
其中p为0、1、2或3； And/or, when A is
Figure PCTCN2021076289-appb-100024
When the said
Figure PCTCN2021076289-appb-100025
for
Figure PCTCN2021076289-appb-100026
Where p is 0, 1, 2 or 3; 和/或，R 12为氢或C 1-C 4烷基； And/or, R 12 is hydrogen or C 1 -C 4 alkyl; 和/或，当Y为取代或未取代的C 6-C 14芳基时，所述的取代或未取代的C 6-C 14芳基为
Figure PCTCN2021076289-appb-100027
Figure PCTCN2021076289-appb-100028
其中每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； And/or, when Y is a substituted or unsubstituted C 6 -C 14 aryl group, the substituted or unsubstituted C 6 -C 14 aryl group is
Figure PCTCN2021076289-appb-100027
Figure PCTCN2021076289-appb-100028
Where each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; 和/或，当Y为取代或未取代的5-14元杂芳基时，所述的取代或未取代的5-14元杂芳基为
Figure PCTCN2021076289-appb-100029
Figure PCTCN2021076289-appb-100030
Figure PCTCN2021076289-appb-100031
其中每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； And/or, when Y is a substituted or unsubstituted 5-14 membered heteroaryl group, the substituted or unsubstituted 5-14 membered heteroaryl group is
Figure PCTCN2021076289-appb-100029
Figure PCTCN2021076289-appb-100030
Figure PCTCN2021076289-appb-100031
Where each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; 和/或，X为-O-或-S-；And/or, X is -O- or -S-; 和/或，每个R 30独立地为C 1-C 4烷基； And/or, each R 30 is independently a C 1 -C 4 alkyl group; 和/或，每个R 40独立地为C 1-C 4烷基； And/or, each R 40 is independently a C 1 -C 4 alkyl group; 和/或，每个R a、R b、R c、R d、R e、R f和R g各自独立地为C 1-C 4烷基或C 1-C 4卤代烷基。 And / or, each of R a, R b, R c , R d, R e, R f and R g are each independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl. 如权利要求1-5中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，-L-A选自以下任一组定义：The compound of formula I according to any one of claims 1 to 5, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, Or a crystal form or solvate of any one of the foregoing, characterized in that -LA is selected from any one of the following group definitions: (i)L为-(CR 8R 9) 3-，A为-X-Y，X为-S-，Y为
Figure PCTCN2021076289-appb-100032
Figure PCTCN2021076289-appb-100033
每个p独立地为0或1，每个q独立地为0、1、2或3； (i) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is
Figure PCTCN2021076289-appb-100032
Figure PCTCN2021076289-appb-100033
Each p is independently 0 or 1, and each q is independently 0, 1, 2 or 3; (ii)L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为
Figure PCTCN2021076289-appb-100034
Figure PCTCN2021076289-appb-100035
Figure PCTCN2021076289-appb-100036
每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； (ii) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is
Figure PCTCN2021076289-appb-100034
Figure PCTCN2021076289-appb-100035
Figure PCTCN2021076289-appb-100036
Each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; (iii)L为-(CR 8R 9) 3-、-(CR 8R 9) 4-、-(CR 8R 9) 5-或
Figure PCTCN2021076289-appb-100037
A为-X-Y，X为-O-，Y为
Figure PCTCN2021076289-appb-100038
Figure PCTCN2021076289-appb-100039
每个p独立地为0、1、2或3；或 (iii) L is-(CR 8 R 9 ) 3 -,-(CR 8 R 9 ) 4 -,-(CR 8 R 9 ) 5 -or
Figure PCTCN2021076289-appb-100037
A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-100038
Figure PCTCN2021076289-appb-100039
Each p is independently 0, 1, 2 or 3; or (iv)L为
Figure PCTCN2021076289-appb-100040
A为
Figure PCTCN2021076289-appb-100041
Figure PCTCN2021076289-appb-100042
Figure PCTCN2021076289-appb-100043
k为0、1、2或3；每个p独立地为0、1、2或3； (iv) L is
Figure PCTCN2021076289-appb-100040
A is
Figure PCTCN2021076289-appb-100041
Figure PCTCN2021076289-appb-100042
Figure PCTCN2021076289-appb-100043
k is 0, 1, 2 or 3; each p is independently 0, 1, 2 or 3; 和/或，
Figure PCTCN2021076289-appb-100044
部分为
Figure PCTCN2021076289-appb-100045
Figure PCTCN2021076289-appb-100046
Figure PCTCN2021076289-appb-100047
例如
Figure PCTCN2021076289-appb-100048
部分为
Figure PCTCN2021076289-appb-100049
Figure PCTCN2021076289-appb-100050
and / or,
Figure PCTCN2021076289-appb-100044
Partly
Figure PCTCN2021076289-appb-100045
Figure PCTCN2021076289-appb-100046
Figure PCTCN2021076289-appb-100047
E.g
Figure PCTCN2021076289-appb-100048
Partly
Figure PCTCN2021076289-appb-100049
Figure PCTCN2021076289-appb-100050
 如权利要求1-6中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，R 1为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a； The compound of formula I according to any one of claims 1 to 6, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, Or a crystalline form or solvate of any one of the foregoing, characterized in that R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; 和/或，R 2为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a； And/or, R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; 和/或，R 3为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a； And/or, R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; 和/或，R 4为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a； And/or, R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; 和/或，R 5为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a； And/or, R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a ; 和/或，每个R 1a、R 2a、R 3a、R 4a和R 5a各自独立地为卤素； And/or, each of R 1a , R 2a , R 3a , R 4a and R 5a is independently halogen; 和/或，R 6为氢、C 1-C 6烷基或-(C 1-C 4亚烷基)-(C 3-C 6环烷基)； And/or, R 6 is hydrogen, C 1 -C 6 alkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl); 和/或，L为-(CR 8R 9) 3-、-(CR 8R 9) 4-或
Figure PCTCN2021076289-appb-100051
k为0、1、2或3； And/or, L is -(CR 8 R 9 ) 3 -, -(CR 8 R 9 ) 4 -or
Figure PCTCN2021076289-appb-100051
k is 0, 1, 2 or 3; 和/或，A为
Figure PCTCN2021076289-appb-100052
或-X-Y； And/or, A is
Figure PCTCN2021076289-appb-100052
Or -XY; 和/或，每个R 8和R 9各自独立地为氢或C 1-C 4烷基； And/or, each of R 8 and R 9 is independently hydrogen or C 1 -C 4 alkyl; 和/或，R 10为氢； And/or, R 10 is hydrogen; 和/或，R 11a为氢或C 1-C 4烷基； And/or, R 11a is hydrogen or C 1 -C 4 alkyl; 和/或，R 11b为氢或C 1-C 4烷基； And/or, R 11b is hydrogen or C 1 -C 4 alkyl; 和/或，X为-O-或-S-；And/or, X is -O- or -S-; 和/或，Y为
Figure PCTCN2021076289-appb-100053
Figure PCTCN2021076289-appb-100054
每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； And/or, Y is
Figure PCTCN2021076289-appb-100053
Figure PCTCN2021076289-appb-100054
Each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; 和/或，每个R 30独立地为卤素、C 1-C 4烷基、C 1-C 4烷氧基或C 1-C 4卤代烷基； And/or, each R 30 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkyl; 和/或，每个R 40独立地为卤素、C 1-C 4烷基、C 1-C 4烷氧基或C 1-C 4卤代烷基； And/or, each R 40 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl; 和/或，每个R a独立地为C 1-C 4烷基或C 1-C 4卤代烷基。 And / or each R a is independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl. 如权利要求1-7中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，R 1为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 1a取代； The compound of Formula I according to any one of claims 1-7, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, Or a crystal form or solvate of any one of the foregoing, characterized in that R 1 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is substituted with 1, 2, 3 or 4 R 1a ; R 2为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 2a取代； R 2 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 2a substitutions; R 3为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 3a取代； R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 3a substitutions; R 4为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 4a取代； R 4 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is 1 , 2, 3 or 4 R 4a substitutions; R 5为氢、卤素、取代或未取代的C 1-C 4烷基或-OR a，其中所述的取代的C 1-C 4烷基是指所述C 1-C 4烷基被1、2、3或4个R 5a取代； R 5 is hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl or -OR a , wherein the substituted C 1 -C 4 alkyl means that the C 1 -C 4 alkyl group is covered by 1 , 2, 3 or 4 R 5a substitutions; 每个R 1a、R 2a、R 3a、R 4a和R 5a各自独立地为卤素； Each of R 1a , R 2a , R 3a , R 4a and R 5a is independently halogen; R 6为氢、C 1-C 6烷基或-(C 1-C 4亚烷基)-(C 3-C 6环烷基)； R 6 is hydrogen, C 1 -C 6 alkyl or -(C 1 -C 4 alkylene)-(C 3 -C 6 cycloalkyl); -L-A选自以下任一组定义：-L-A is selected from any of the following group definitions: (i)L为-(CR 8R 9) 3-，A为-X-Y，X为-S-，Y为
Figure PCTCN2021076289-appb-100055
p为0或1，q为0、1、2或3； (i) L is -(CR 8 R 9 ) 3 -, A is -XY, X is -S-, Y is
Figure PCTCN2021076289-appb-100055
p is 0 or 1, q is 0, 1, 2 or 3; (ii)L为-(CR 8R 9) 4-，A为-X-Y，X为-NHC(O)-，Y为
Figure PCTCN2021076289-appb-100056
Figure PCTCN2021076289-appb-100057
每个p独立地为0、1、2或3，每个q独立地为0、1、2或3； (ii) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -NHC(O)-, Y is
Figure PCTCN2021076289-appb-100056
Figure PCTCN2021076289-appb-100057
Each p is independently 0, 1, 2 or 3, and each q is independently 0, 1, 2 or 3; (iii)L为-(CR 8R 9) 4-，A为-X-Y，X为-O-，Y为
Figure PCTCN2021076289-appb-100058
p为0、1、2或3；或 (iii) L is -(CR 8 R 9 ) 4 -, A is -XY, X is -O-, Y is
Figure PCTCN2021076289-appb-100058
p is 0, 1, 2 or 3; or (iv)L为
Figure PCTCN2021076289-appb-100059
A为
Figure PCTCN2021076289-appb-100060
k为0、1、2或3； (iv) L is
Figure PCTCN2021076289-appb-100059
A is
Figure PCTCN2021076289-appb-100060
k is 0, 1, 2 or 3; 每个R 8和R 9各自独立地为氢或C 1-C 4烷基； Each of R 8 and R 9 is independently hydrogen or C 1 -C 4 alkyl; 每个R 8a独立地为C 1-C 4烷基； Each R 8a is independently a C 1 -C 4 alkyl group; R 10为氢或C 1-C 4烷基； R 10 is hydrogen or C 1 -C 4 alkyl; R 11a为氢或C 1-C 4烷基； R 11a is hydrogen or C 1 -C 4 alkyl; R 11b为氢或C 1-C 4烷基； R 11b is hydrogen or C 1 -C 4 alkyl; 每个R 30独立地为卤素、C 1-C 4烷基、C 1-C 4烷氧基或C 1-C 4卤代烷基； Each R 30 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl; 每个R 40独立地为卤素、C 1-C 4烷基、C 1-C 4烷氧基或C 1-C 4卤代烷基； Each R 40 is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or C 1 -C 4 haloalkyl; 每个R a独立地为C 1-C 4烷基或C 1-C 4卤代烷基。 Each R a is independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl. 如权利要求1-8中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化 物，其特征在于，A为-X-Y，Y为
Figure PCTCN2021076289-appb-100061
Figure PCTCN2021076289-appb-100062
The compound of formula I according to any one of claims 1-8, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, Or a crystal form or solvate of any one of the foregoing, characterized in that A is -XY and Y is
Figure PCTCN2021076289-appb-100061
Figure PCTCN2021076289-appb-100062
 如权利要求1-9中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，R 8和R 9均为氢； The compound of formula I according to any one of claims 1-9, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, Or a crystal form or solvate of any one of the foregoing, characterized in that R 8 and R 9 are both hydrogen; 和/或，R 10为氢； And/or, R 10 is hydrogen; 和/或，R 11a为C 1-C 4烷基； And/or, R 11a is a C 1 -C 4 alkyl group; 和/或，R 11b为C 1-C 4烷基； And/or, R 11b is a C 1 -C 4 alkyl group; 和/或，每个p独立地为0或1；And/or, each p is independently 0 or 1; 和/或，每个q独立地为0或1；And/or, each q is independently 0 or 1; 和/或，k为0；And/or, k is 0; 和/或，每个R 30独立地为C 1-C 4烷基； And/or, each R 30 is independently a C 1 -C 4 alkyl group; 和/或，每个R 40独立地为C 1-C 4烷基。 And/or, each R 40 is independently a C 1 -C 4 alkyl group. 如权利要求1所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，所述的如式I所示的化合物选自以下任一结构：The compound of formula I according to claim 1, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, or any one of the foregoing Crystal form or solvate, characterized in that the compound represented by formula I is selected from any of the following structures:
Figure PCTCN2021076289-appb-100063
Figure PCTCN2021076289-appb-100063
Figure PCTCN2021076289-appb-100064
Figure PCTCN2021076289-appb-100064
Figure PCTCN2021076289-appb-100065
Figure PCTCN2021076289-appb-100065
Figure PCTCN2021076289-appb-100066
Figure PCTCN2021076289-appb-100066
Figure PCTCN2021076289-appb-100067
Figure PCTCN2021076289-appb-100067
Figure PCTCN2021076289-appb-100068
Figure PCTCN2021076289-appb-100068
Figure PCTCN2021076289-appb-100069
Figure PCTCN2021076289-appb-100069
Figure PCTCN2021076289-appb-100070
Figure PCTCN2021076289-appb-100070
 其中，*和#的定义如权利要求1或3中所述。Wherein, * and # are defined as described in claim 1 or 3. 如权利要求1-11中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂 化物，其特征在于，*和#标记的碳原子形成的三元环的结构为
Figure PCTCN2021076289-appb-100071
The compound of formula I according to any one of claims 1-11, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, Or a crystal form or solvate of any one of the foregoing, characterized in that the structure of the three-membered ring formed by the carbon atoms marked with * and # is
Figure PCTCN2021076289-appb-100071
 如权利要求1-11中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，*和#标记的碳原子形成的三元环的结构为
Figure PCTCN2021076289-appb-100072
The compound of formula I according to any one of claims 1-11, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, Or a crystal form or solvate of any one of the foregoing, characterized in that the structure of the three-membered ring formed by the carbon atoms marked with * and # is
Figure PCTCN2021076289-appb-100072
 如权利要求1-13中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，其特征在于，所述的药学上可接受的盐为盐酸盐。The compound of formula I according to any one of claims 1-13, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of any one of the foregoing, Or a crystal form or solvate of any one of the foregoing, characterized in that the pharmaceutically acceptable salt is hydrochloride. 一种如权利要求1所述的如式I所示的化合物的制备方法，其选自如下任一方案：A method for preparing the compound of formula I according to claim 1, which is selected from any of the following schemes: 方案1：plan 1: 方案1包括如下步骤：在溶剂中，将如式II-1所示的化合物在还原剂的存在下进行如下所示的还原反应，得到所述的如式I所示化合物即可；其中，-CH 2-L 1-即-L-；R 1、R 2、R 3、R 4、R 5、R 6、L、A、*和#的定义如权利要求1-14中任一项所述； Scheme 1 includes the following steps: in a solvent, the compound represented by formula II-1 is subjected to the reduction reaction shown below in the presence of a reducing agent to obtain the compound represented by formula I; wherein,- CH 2 -L 1 -that is -L-; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, A, * and # are defined in any one of claims 1-14 ；
Figure PCTCN2021076289-appb-100073
Figure PCTCN2021076289-appb-100073
 方案2：Scenario 2: 方案2包括如下步骤：在溶剂中，将如式II-2所示的化合物和R 6a-CHO或
Figure PCTCN2021076289-appb-100074
在还原剂的存在下进行如下所示的还原胺化反应，得到所述的如式I所示化合物即可；其中，R 6a-CH 2-或
Figure PCTCN2021076289-appb-100075
即R 6；R 1、R 2、R 3、R 4、R 5、R 6、L、A、*和#的定义如权利要求1-14中任一项所述； Scheme 2 includes the following steps: in a solvent, the compound represented by formula II-2 and R 6a -CHO or
Figure PCTCN2021076289-appb-100074
Carry out the reductive amination reaction shown below in the presence of a reducing agent to obtain the compound shown in formula I; wherein, R 6a -CH 2 -or
Figure PCTCN2021076289-appb-100075
That is, R 6 ; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, A, *, and # are as defined in any one of claims 1-14;
Figure PCTCN2021076289-appb-100076
Figure PCTCN2021076289-appb-100076
 方案3：Option 3: 方案3包括如下步骤：在溶剂中，将如式II-3所示的化合物和A-L 2-CHO在还原剂 的存在下进行如下所示的还原胺化反应，得到所述的如式I所示化合物即可；其中，-CH 2-L 2-即-L-；R 1、R 2、R 3、R 4、R 5、R 6、L、A、*和#的定义如权利要求1-14中任一项所述； Scheme 3 includes the following steps: in a solvent, the compound shown in formula II-3 and AL 2 -CHO are subjected to the reductive amination reaction shown below in the presence of a reducing agent to obtain the compound shown in formula I Compounds are sufficient; wherein, -CH 2 -L 2 -is -L-; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, A, * and # are as defined in claim 1- As mentioned in any one of 14;
Figure PCTCN2021076289-appb-100077
Figure PCTCN2021076289-appb-100077
 方案4：Option 4: 方案4包括如下步骤：在溶剂中，将如式II-4所示的化合物和
Figure PCTCN2021076289-appb-100078
在还原剂的存在下进行如下所示的还原胺化反应，得到所述的如式I所示化合物即可；其中R 1、R 2、R 3、R 4、R 5、R 6、L、A、*和#的定义如权利要求1-14中任一项所述； Scheme 4 includes the following steps: in a solvent, the compound represented by formula II-4 and
Figure PCTCN2021076289-appb-100078
Carry out the reductive amination reaction shown below in the presence of a reducing agent to obtain the compound shown in formula I; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, The definitions of A, * and # are as described in any one of claims 1-14;
Figure PCTCN2021076289-appb-100079
Figure PCTCN2021076289-appb-100079
 一种化合物，其具有如下结构：A compound having the following structure:
Figure PCTCN2021076289-appb-100080
Figure PCTCN2021076289-appb-100080
 其中R 1、R 2、R 3、R 4、R 5、R 6、L 1、A、*和#的定义权利要求15所述。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , A, * and # are defined in claim 15. 一种药物组合物，其包含如权利要求1-14中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，以及至少一种药用辅料。A pharmaceutical composition comprising the compound of formula I according to any one of claims 1-14, or a tautomer, stereoisomer or isotopic derivative thereof, or any one of the foregoing A pharmaceutically acceptable salt of, or a crystal form or solvate of any of the foregoing, and at least one pharmaceutical excipient. 一种如权利要求1-14中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或溶剂化物，或者如权利要求17所述的药物组合物在制备药物中的应用。A compound of formula I according to any one of claims 1-14, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable compound of any one of the foregoing A salt, or a crystal form or solvate of any of the foregoing, or the use of the pharmaceutical composition according to claim 17 in the preparation of a medicine. 如权利要求18所述的应用，其特征在于，所述药物为用于治疗和/或预防多巴胺能信号通路异常和/或5-羟色胺信号通路异常相关的疾病的药物，例如帕金森氏症、精神分裂症、双相情感障碍、躁狂症、抑郁症、焦虑症、药物成瘾或阿尔茨海默症。The application according to claim 18, wherein the drug is a drug used to treat and/or prevent abnormalities in the dopaminergic signaling pathway and/or diseases related to abnormalities in the serotonin signaling pathway, such as Parkinson's disease, Schizophrenia, bipolar disorder, mania, depression, anxiety, drug addiction, or Alzheimer's disease. 一种如权利要求1-14中任一项所述的如式I所示的化合物或其互变异构体、立体异构体或同位素衍生物，或前述任一者的药学上可接受的盐，或前述任一者的晶型或 溶剂化物在制备多巴胺受体调节剂和/或5-羟色胺受体调节剂中的应用。A compound of formula I according to any one of claims 1-14, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable compound of any one of the foregoing The use of a salt, or a crystal form or solvate of any one of the foregoing, in the preparation of a dopamine receptor modulator and/or a serotonin receptor modulator.
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