WO2021164661A1 - Dérivé de 2-phénylcyclopropylméthylamine, son procédé de préparation et son utilisation - Google Patents

Dérivé de 2-phénylcyclopropylméthylamine, son procédé de préparation et son utilisation Download PDF

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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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Chinese (zh)
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程建军
汪胜
闫文仲
樊鲁玉
余竞
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上海科技大学
中国科学院分子细胞科学卓越创新中心
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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

L'invention concerne un dérivé de 2-phénylcyclopropylméthylamine tel que représenté par la formule I ci-dessous, ayant une activité d'affinité vis-à-vis des récepteurs de la dopamine et/ou des récepteurs de la 5-hydroxytryptamine, et utilisé pour le traitement de maladies mentales.
PCT/CN2021/076289 2020-02-20 2021-02-09 Dérivé de 2-phénylcyclopropylméthylamine, son procédé de préparation et son utilisation WO2021164661A1 (fr)

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Citations (3)

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WO2007025144A1 (fr) * 2005-08-24 2007-03-01 University Of Illinois - Chicago Agonistes de recepteur 5-ht2c utilises en tant qu'agents anorexigenes
WO2012037258A1 (fr) * 2010-09-16 2012-03-22 Abbott Laboratories Procédés de préparation de dérivés cyclopropyliques substitués en 1,2

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US6284761B1 (en) * 1999-01-08 2001-09-04 Neurogen Corporation 1-phenyl-4-(1-[2-aryl]cyclopropyl)methylpiperazines: dopamine receptor ligands
RU2396265C2 (ru) * 2006-02-17 2010-08-10 Ф. Хоффманн-Ля Рош Аг Производные бензоилпиперидина в качестве модуляторов рецепторов 5ht2 и d3
US8492591B2 (en) * 2010-02-04 2013-07-23 The Board Of Trustees Of The University Of Illinois Highly selective 5-HT(2C) receptor agonists that show anti-psychotic effects with antagonist activity at the 5-HT(2B) receptor
WO2016123164A1 (fr) * 2015-01-29 2016-08-04 The Board Of Trustees Of The University Of Illinois Cyclopropylméthanamines utilisées comme agonistes sélectifs des récepteurs 5-ht(2c)

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WO2002079152A1 (fr) * 2001-03-29 2002-10-10 Bristol-Myers Squibb Company Derives de cyclopropylindole utilises en tant qu'inhibiteurs selectifs de recaptage de la serotonine
WO2007025144A1 (fr) * 2005-08-24 2007-03-01 University Of Illinois - Chicago Agonistes de recepteur 5-ht2c utilises en tant qu'agents anorexigenes
WO2012037258A1 (fr) * 2010-09-16 2012-03-22 Abbott Laboratories Procédés de préparation de dérivés cyclopropyliques substitués en 1,2

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