CN113527307A - Triazole group-containing fused ring derivative inhibitor, and preparation method and application thereof - Google Patents

Triazole group-containing fused ring derivative inhibitor, and preparation method and application thereof Download PDF

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CN113527307A
CN113527307A CN202110423859.3A CN202110423859A CN113527307A CN 113527307 A CN113527307 A CN 113527307A CN 202110423859 A CN202110423859 A CN 202110423859A CN 113527307 A CN113527307 A CN 113527307A
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alkyl
radical
cycloalkyl
aryl
alkynyl
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王峰
黄志强
邓海宁
李凯龙
苏熠东
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Shanghai Hansoh Biomedical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Abstract

The invention relates toAnd a fused ring derivative inhibitor containing triazolyl, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method and a pharmaceutical composition thereof, and application of the compound as an NK inhibitor in treating depression, anxiety, schizophrenia, sex hormone dependence and other related diseases, wherein each substituent in the general formula (I) is defined as the specification.

Description

Triazole group-containing fused ring derivative inhibitor, and preparation method and application thereof
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a triazole-containing fused ring derivative inhibitor, and a preparation method and application thereof.
Background
Neurokinin (NK) comprises Substance P (SP), Neurokinin a and Neurokinin B, and its three corresponding receptors are Neurokinin 1 receptor (NK1R), Neurokinin 2 receptor (NK2R) and Neurokinin 3 receptor (NK3R), respectively. The three types of receptors are G protein coupled receptors, wherein NK1R is most widely distributed and distributed in both the central nervous system and the peripheral nervous system, NK2R is mainly distributed in the peripheral nervous system, and NK3R is mainly distributed in the central nervous system. At present, the NK receptor inhibitor is applied to treating diseases such as climacteric hectic fever, depression, schizophrenia and the like, particularly NK3R is closely related to symptoms such as climacteric syndrome hectic fever, and the NK3R inhibitor is proved to have a good effect of improving the climacteric hectic fever.
Climacteric hot flashes (Menopausal hot flashes) refer to symptoms such as hot flashes and sweating that often occur in people in menopause, and are the prominent manifestation of climacteric syndrome. Climacteric hot flashes are caused by vasomotor dysfunction due to decreased estrogen levels in the body. When the estrogen in the body is reduced, the brain can be mistaken for hyperthermia, so the brain can send signals to the heart to require the heart to pump more blood and the sweat glands to release more sweat, and the symptoms of sweating, palpitation, dizziness and the like are accompanied. More than three quarters of women have hot flashes in menopause, and 80% of patients can have the symptoms for more than 1 year, and some can still maintain about 5 years after menopause. At present, the treatment aiming at climacteric hot flashes is mainly hormone replacement therapy, but the therapy is easy to cause diseases such as breast cancer, cerebral apoplexy, coronary heart disease, dementia and the like, and has a large risk coefficient. Oral drugs such as paroxetine (belonging to SSRIs class of drugs for treating depression) are the only approved small molecule drugs for treating climacteric hectic fever, and also have the problem of side effects, and are approved only in the united states, so that there is a clinical need to develop safer and more effective climacteric syndrome treatment drugs.
International application WO2014154895 reports NK receptor inhibitor compounds, but the compounds therein mostly have Ki above 20nM in vitro binding experiments of NK1R/NK2R/NK3R, and mostly have IC50 above 30nM in cell function experiments on NK3R inhibition. CN103906750 reports that most of Ki in-vitro binding experiments of NK1R/NK2R/NK3R are above 20nM, and in cell function experiments, IC (integrated Circuit) has inhibitory effect on NK3R50Most were above 20 nM. CN105229008B reported that the Ki was mostly above 30nM in NK3R binding experiments in vitro. CN102906093B reported that most of Ki's were above 500nM in NK1R/NK2R/NK3R binding experiments in vitro.
Therefore, there is an urgent need to develop NK receptor inhibitors having high activity for improving climacteric hectic fever symptoms to meet the enormous market demand.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
Figure BDA0003028590740000021
wherein:
ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R1selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbbSaid alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted with a substituent selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2)n-、-(CH2)nRcc、-(CH2)nORcc、-(CH2)nSRcc、-(CH2)nC(O)Rcc、-(CH2)nC(O)ORcc、-(CH2)nS(O)mRcc、-(CH2)nNRccRdd、-(CH2)nC(O)NRccRdd、-(CH2)nNRccC(O)RddOr- (CH)2)nNRccS(O)mRddIs substituted with one or more substituents of (1);
R2selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nP(O)RaaRbb、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbb；
Or, any two adjacent or non-adjacent R2Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R3selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, oxo, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbbSaid alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, oxo, nitro, hydroxy, cyano, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
or, any two adjacent or non-adjacent R3Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, oxo, nitro, hydroxy, cyano, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
Raa、Rbb、Rccand RddEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted with one or more substituents selected from the group consisting of alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroarylOne or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
x is 0, 1,2,3, 4, 5 or 6;
y is 0, 1,2,3, 4, 5 or 6;
z is 0, 1,2,3, 4 or 5;
m is 0, 1 or 2; and is
n is 0, 1 or 2.
In a further preferred embodiment of the invention, ring A is selected from C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably C6-10An aryl group; more preferably phenyl.
In a further preferred embodiment of the invention, ring C is selected from C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably 5-6 membered heteroaryl containing 1-3 atoms selected from N, O or S; more preferred is thiadiazolyl or pyridyl.
In a further preferred embodiment of the invention, R1Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
in a further preferred embodiment of the invention, R1Is selected from C1-6Alkyl or C3-6A cycloalkyl group.
In a further preferred embodiment of the invention, R2Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbb；
In a further preferred embodiment of the invention, R2Selected from 3-8 member heterocyclic radical containing 1-3 atoms selected from N, O or S atoms, - (CH)2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nP(O)RaaRbb、-(CH2)nNRaaRbbOr- (CH)2)nC(O)NRaaRbb。
In the inventionIn a preferred embodiment, R2Is selected from- (CH)2)nOCN、-(CH2)nOCH2F、-(CH2)nOCH3、-(CH2)nSCH2F、-(CH2)nSCH3、-(CH2)nS(O)mCH3、(CH2)nNH2、-(CH2)nNHCH3、-(CH2)nN(CH3)2、-(CH2)nC(O)NH2、-(CH2)nC(O)NHCH3、-(CH2)nC(O)N(CH3)2、-(CH2)nC(O)OEt、-(CH2)nP(O)(CH3)2、
Figure BDA0003028590740000041
Figure BDA0003028590740000042
Optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Substituted by one or more substituents of haloalkoxy
In a further preferred embodiment of the invention, R3Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally,further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
In a further preferred embodiment of the invention, R3Is selected from C1-6Alkyl, halogen, C6-10Aryl, 3-8 membered heteroaryl containing 1-3 atoms selected from N, O or S, or- (CH)2)nSRaa(ii) a Said C1-6Alkyl and C6-10Aryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
In a further preferred embodiment of the invention, Raa、Rbb、RccAnd RddEach independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkanesBase, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
In a further preferred embodiment of the present invention, the compound has the structure according to formula (II):
Figure BDA0003028590740000051
wherein:
R1selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably C1-6Alkyl or C3-6A cycloalkyl group;
R2selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1RA1、-(CH2)n1ORA1、-(CH2)n1C(O)RA1、-(CH2)n1C(O)ORA1、-(CH2)n1OC(O)RA1、-(CH2)n1S(O)m1RA1、-(CH2)n1P(O)RA1RA2、-(CH2)n1NRA1RA2、-(CH2)n1NRA1C(O)RA2、-(CH2)n1NRA1C(O)ORA2、-(CH2)n1C(O)NRA1RA2Or- (CH)2)n1NRA1S(O)m1RA2；
Preferably 3-to 8-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S, - (CH)2)n1RA1、-(CH2)n1ORA1、-(CH2)n1SRA1、-(CH2)n1C(O)ORA1、-(CH2)n1S(O)m1RA1、-(CH2)n1P(O)RA1RA2、-(CH2)n1NRA1RA2Or- (CH)2)n1C(O)NRA1RA2；
RA1And RA2Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroAryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
m1 is 0, 1 or 2; and is
n1 is 0, 1,2,3 or 4.
In a further preferred embodiment of the present invention, the compound has the structure according to formula (III):
Figure BDA0003028590740000061
wherein:
R3selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n2RA3、-(CH2)n2ORA3、-(CH2)n2C(O)RA3、-(CH2)n2C(O)ORA3、-(CH2)n2OC(O)RA3、-(CH2)n2S(O)m2RA3、-(CH2)n2P(O)RA3RA4、-(CH2)n2NRA3RA4、-(CH2)n2NRA3C(O)RA4、-(CH2)n2NRA3C(O)ORA4、-(CH2)n2C(O)NRA3RA4Or- (CH)2)n2NRA3S(O)m2RA4；
Preferably contains 1 to 3 members selected from N, O or3-to 8-membered heterocyclic group of S atom, - (CH)2)n2RA3、-(CH2)n2ORA3、-(CH2)n2SRA3、-(CH2)n2C(O)ORA3、-(CH2)n2S(O)m2RA3、-(CH2)n2P(O)RA3RA4、-(CH2)n2NRA3RA4Or- (CH)2)n2C(O)NRA3RA4(ii) a Said 3-8 membered heterocyclyl containing 1-3 atoms selected from N, O or S is optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
RA3and RA4Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
t is 0, 1 or 2;
m2 is 0, 1 or 2; and is
n2 is 0, 1,2,3 or 4.
The invention further comprises an intermediate for preparing the compounds of the general formulas (I) and stereoisomers or pharmaceutically acceptable salts thereof, which are shown in the following general formula (IV):
Figure BDA0003028590740000071
wherein:
R1is selected from C1-6Alkyl or C3-6A cycloalkyl group; preferably a cycloalkyl group;
R3selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n2RA3、-(CH2)n2ORA3、-(CH2)n2C(O)RA3、-(CH2)n2C(O)ORA3、-(CH2)n2OC(O)RA3、-(CH2)n2S(O)m2RA3、-(CH2)n2P(O)RA3RA4、-(CH2)n2NRA3RA4、-(CH2)n2NRA3C(O)RA4、-(CH2)n2NRA3C(O)ORA4、-(CH2)n2C(O)NRA3RA4Or- (CH)2)n2NRA3S(O)m2RA4；
Preferably 3-to 8-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S, - (CH)2)n2RA3、-(CH2)n2ORA3、-(CH2)n2SRA3、-(CH2)n2C(O)ORA3、-(CH2)n2S(O)m2RA3、-(CH2)n2P(O)RA3RA4、-(CH2)n2NRA3RA4Or- (CH)2)n2C(O)NRA3RA4(ii) a Said 3-8 membered heterocyclyl containing 1-3 atoms selected from N, O or S is optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
RA3and RA4Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl; and is
t is 0, 1 or 2.
The present invention further comprises a process for preparing a compound of formula (III), and stereoisomers or pharmaceutically acceptable salts thereof, which process comprises the steps of:
Figure BDA0003028590740000081
the compound of the general formula (IV) and the compound of the general formula (V) are subjected to condensation or coupling reaction to obtain a compound of a general formula (III),
wherein:
R4is hydroxy or halogen; preferably halogen;
the invention also provides a pharmaceutical composition, which comprises a therapeutically effective dose of each compound shown in the general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention also provides a preferable scheme, and also relates to application of the compounds with the general formulas, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in preparation of NK inhibitor related medicines, especially in preparation of NK3 inhibitor related medicines.
The invention also provides a preferable scheme, and also relates to application of the compound shown in the general formula (I) and stereoisomer thereof or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing medicaments for treating and/or preventing psychotic disorders, cognitive disorders, Parkinson's disease, pain, convulsion, obesity, inflammatory diseases, emesis, preeclampsia, airway related diseases, reproductive disorders, sex hormone dependent diseases or gynecological diseases.
The invention also provides a preferable scheme, and also relates to application of the compound shown in the general formula (I) and stereoisomers or pharmaceutically acceptable salts thereof or the pharmaceutical composition in preparation of medicaments for treating and/or preventing diseases related to climacteric syndromes, wherein the climacteric syndromes comprise symptoms such as hot flushes, sweating, palpitation, dizziness, obesity and the like.
The invention further relates to a method for preparing a medicament for treating and/or preventing psychotic disorders, cognitive disorders, Parkinson's disease, pain, convulsions, obesity, inflammatory diseases, emesis, preeclampsia, airway-related diseases, reproductive disorders, sex hormone dependent diseases or gynecological disease-related diseases by using the compound shown in the general formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof.
The present invention also relates to a method of treating and/or preventing psychotic disorders, cognitive disorders, parkinson's disease, pain, convulsions, obesity, inflammatory diseases, emesis, preeclampsia, airway-related diseases, reproductive disorders, sex hormone dependent diseases or gynaecological disease-related diseases, which comprises administering to said mammal a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
In some embodiments, the present methods relate to treatments such as the treatment and/or prevention of psychotic disorders, cognitive disorders, parkinson's disease, pain, convulsions, obesity, inflammatory diseases, emesis, preeclampsia, airway-related diseases, reproductive disorders, sex hormone dependent diseases or gynaecological disease related conditions.
The methods of treatment provided herein comprise administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the invention provides a method of treating a disorder comprising a climacteric hot flash related condition in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2)2-, "propylene" means- (CH)2)3-, "butylene" means- (CH)2)4-and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0003028590740000101
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
Figure BDA0003028590740000102
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0003028590740000111
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure BDA0003028590740000112
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetane, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetane, tetrahydrofuranyl, tetrahydropyranyl, azepanyl, piperidinyl, and piperazinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6To 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0003028590740000121
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0003028590740000122
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure BDA0003028590740000123
Figure BDA0003028590740000131
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0003028590740000132
the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0003028590740000133
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, oxadiazole and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferred are triazolyl, pyrrolyl, thienyl, thiazolyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl and oxadiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0003028590740000141
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" refers to (CH ≡ C-), wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"carboxy" refers to-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et2O "means diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd2(dba)3"refers to tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bisdiphenylphosphinoferrocene.
"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bistrimethylsilyl amide.
"MeLi" refers to methyllithium.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc)3"refers to sodium triacetoxyborohydride.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
The hydrogen described herein may be replaced by deuterium, which is an isotope thereof, and any hydrogen in the compounds of the examples to which the invention relates may also be replaced by deuterium.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more hydrogens, preferably up to 5, more preferably 1 to 3 hydrogens in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000171
The first step is as follows: preparation of ethyl 2- (1- (2, 4-dimethoxybenzyl) -3-carbonylpiperazin-2-yl) acetate
Figure BDA0003028590740000172
Sodium borohydride acetate (16g, 75.8mmol) was added to a solution of 2, 4-dimethoxybenzaldehyde (9g, 54.2mmol) and ethyl 2- (3-carbonylpiperazin-2-yl) acetate (10g, 54.2mmol) in acetonitrile (150ml) under cooling in an ice-water bath, acetic acid (4.9g, 81.2mmol) was added, and the reaction solution was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (200ml), the pH was adjusted to 7 with saturated aqueous sodium bicarbonate, the layers were separated, the aqueous phase was extracted with ethyl acetate (50ml × 2), the organic phases were combined, dried and concentrated. The residue was separated by means of a silica gel column (dichloromethane: methanol ═ 50: 1) to give the product ethyl 2- (1- (2, 4-dimethoxybenzyl) -3-carbonylpiperazin-2-yl) acetate (13g, yield: 72%).
MS m/z(ESI):337.1[M+H]+.
The second step is that: preparation of ethyl 2- (1- (2, 4-dimethoxybenzyl) -3-ethoxy-1, 2,5, 6-tetrahydropyrazin-2-yl) acetate
Figure BDA0003028590740000173
Triethoxytetrafluoroborate (2.8g, 14.8mmol, 5 portions per 15 min) was added to a solution of ethyl 2- (1- (2, 4-dimethoxybenzyl) -3-carbonylpiperazin-2-yl) acetate (2g, 6.0mmol) in dichloromethane (10ml) at 0 ℃ under nitrogen protection, the reaction solution was stirred at room temperature for 5 hours, the reaction solution was added dropwise to a 0 ℃ aqueous sodium hydroxide solution (10ml, 3M), the solution was separated, the aqueous phase was extracted with dichloromethane (50 ml. times.2), the organic phases were combined, washed with water (50 ml. times.2), dried, and concentrated to give crude ethyl 2- (1- (2, 4-dimethoxybenzyl) -3-ethoxy-1, 2,5, 6-tetrahydropyrazin-2-yl) acetate (2.18g), used directly in the next step.
MS m/z(ESI):365.2[M+H]+.
The third step: preparation of ethyl 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetate
Figure BDA0003028590740000181
3-cyclopropyl-1, 2, 4-thiadiazole-5-carboxylic acid hydrazide (0.83g, 4.5mmol) was added to a solution of ethyl 2- (1- (2, 4-dimethoxybenzyl) -3-ethoxy-1, 2,5, 6-tetrahydropyrazin-2-yl) acetate (2.18g, 6.0mmol) in anhydrous methanol (20ml), and the reaction mixture was stirred at 75 ℃ overnight. The reaction mixture was concentrated, and the residue was separated by means of a silica gel column (petroleum ether: ethyl acetate 1: 1) to give ethyl 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetate (1.65g, yield: 57%)
MS m/z(ESI):485.2[M+H]+.
The fourth step: preparation of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) ethan-1-ol
Figure BDA0003028590740000182
Lithium aluminium hydride (305mg, 8.0mmol) was added portionwise to a solution of ethyl 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetate (1.3g, 2.7mmol) in tetrahydrofuran (30ml) at 0 ℃ under nitrogen and the reaction stirred for 20 min at 0 ℃. Water (280mg, 16mmol) was slowly added to the reaction solution, stirring was continued for 5 minutes, anhydrous sodium sulfate was added, and filtration was performed. The organic phase was evaporated to dryness to give crude 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) ethan-1-ol (650mg, yield: 55%) which was used directly in the next step.
MS m/z(ESI):443.2[M+H]+.
The fifth step: preparation of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) ethyl methanesulfonate
Figure BDA0003028590740000191
Methanesulfonyl chloride (252mg, 2.2mmol) was added dropwise to a solution of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) ethan-1-ol (650mg, 1.5mmol) and triethylamine (445mg, 4.4mmol) in dichloromethane (20ml) at 0 ℃ under nitrogen. After stirring the reaction mixture at 0 ℃ for 30 minutes, it was quenched by addition of saturated brine, extracted with dichloromethane (25 ml. times.2), the organic phases were combined, washed with water (50 ml. times.2), dried over anhydrous sodium sulfate and concentrated to give crude 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) ethylmethanesulfonate (650mg) which was used directly in the next step.
MS m/z(ESI):521.2[M+H]+.
And a sixth step: preparation of 3-cyclopropyl-5- (7- (2, 4-dimethoxybenzyl) -8- (2- (methylsulfonyl) ethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole
Figure BDA0003028590740000192
Sodium methanesulfinate (1.27g, 12.5mmol) and potassium iodide (2.0g, 12.5mmol) were added to a solution of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) ethyl methanesulfonate (650mg, 1.25mmol) in N, N-dimethylformamide (10ml) at room temperature under nitrogen. The reaction is carried out for 1 hour at 110 ℃ by microwave. The reaction mixture was cooled, water (50ml) was added, ethyl acetate (100ml) was extracted, the organic phase was washed with saturated brine (30 ml. times.6), the organic phase was dried, concentrated, and the residue was separated by a silica gel column (dichloromethane: methanol: 100: 3) to give the product, 3-cyclopropyl-5- (7- (2, 4-dimethoxybenzyl) -8- (2- (methylsulfonyl) ethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (400mg, yield: 63%)
MS m/z(ESI):505.2[M+H]+.
The seventh step: preparation of 3-cyclopropyl-5- (8- (2- (methylsulfonyl) ethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole
Figure BDA0003028590740000201
Trifluoroacetic acid (2ml) was added dropwise to a solution of 3-cyclopropyl-5- (7- (2, 4-dimethoxybenzyl) -8- (2- (methylsulfonyl) ethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (400mg, 0.8mmol) in dichloromethane (2ml) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. Water (25ml) was added to the reaction mixture, which was stirred for 15 minutes, then filtered, the filtrate was extracted with dichloromethane (30 ml. times.2), the organic phase was dried and concentrated to give the product 3-cyclopropyl-5- (8- (2- (methylsulfonyl) ethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (150mg, yield: 53%).
MS m/z(ESI):355.1[M+H]+.
Eighth step: preparation of (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000202
P-fluorobenzoyl chloride (54mg, 0.34mmol) was added dropwise to a dichloromethane (10ml) solution of 3-cyclopropyl-5- (8- (2- (methylsulfonyl) ethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (80mg, 0.22mmol) and triethylamine (68mg, 0.68mmol) at 0 ℃ under nitrogen protection, the reaction solution was stirred at room temperature for 30 minutes, then quenched with saturated brine, extracted with dichloromethane (30ml × 2), dried with organic phase, concentrated, and the residue was separated by silica gel column (petroleum ether: ethyl acetate ═ 100: 0 to petroleum ether: ethyl acetate ═ 0: 100) to give the product (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl ) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone (68mg, yield: 63%).
1H NMR(400MHz,Chloroform-d)δ7.57–7.44(m,2H),7.24–7.14(m,2H),6.40–5.63(m,1H),4.97–4.72(m,1H),4.61–3.96(m,2H),3.84–3.50(m,2H),3.47–3.35(m,1H),3.16(s,1H),3.07–2.73(m,2H),2.71–2.48(m,2H),2.50–2.29(m,1H),1.28–0.94(m,4H).
MS m/z(ESI):477.1[M+H]+.
Example 2
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (3, 4-dichlorophenyl) methanone
Figure BDA0003028590740000211
The preparation of example 2 refers to the eighth step of example 1.
1H NMR(400MHz,Chloroform-d)δ7.66–7.54(m,2H),7.38–7.30(m,1H),6.30–5.99(m,1H),4.95–4.76(m,1H),4.36–3.99(m,2H),3.86–3.51(m,2H),3.51–3.27(m,1H),2.99(s,3H),2.71–2.51(m,2H),2.49–2.32(m,1H),1.22–0.98(m,4H).
MS m/z(ESI):527.0[M+H]+.
Example 3
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4- (thiophen-2-yl) phenyl) methanone
Figure BDA0003028590740000212
The preparation of example 3 refers to the eighth step of example 1.
MS m/z(ESI):540.9[M+H]+.
Example 4
(S) - (4-chlorophenyl) (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (methoxymethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000221
The first step is as follows: preparation of methyl O-methyl-D-serine ester hydrochloride
Figure BDA0003028590740000222
O-methyl-D-serine (5.0g, 42mmol) was dissolved in methanol (50mL), cooled to 0 deg.C, thionyl chloride (15g, 0.13mol) was added dropwise, and the reaction was stirred at room temperature overnight. The solvent was spin-dried to give methyl O-methyl-D-serine hydrochloride (5.6g, yield: 100%) as a white solid.
The second step is that: preparation of benzyl (2-carbonylethyl) carbamate
Figure BDA0003028590740000223
Benzyl (2-hydroxyethyl) carbamate (3.0g, 15mmol) was dissolved in ethyl acetate (50mL), 15% sodium bromide solution (5mL, 7.7mmol), 2,2,6, 6-tetramethylpiperidine nitroxide (47mg, 0.3mmol) were added, cooled to 0 deg.C, sodium hypochlorite solution (24g, 16mmol) adjusted to pH-8 with sodium bicarbonate in advance was added dropwise, and the reaction was stirred at 0 deg.C for 4 hours. Water (100mL) was added, extraction was performed with ethyl acetate (100 mL. times. 2), and the organic phase was washed with saturated sodium thiosulfate (100mL), saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give benzyl (2-carbonylethyl) carbamate (3.0g, yield: 100%) as a pale yellow liquid.
The third step: preparation of methyl N- (2- (((benzyloxy) carbonyl) amino) ethyl) -O-methyl-D-serine acid ester
Figure BDA0003028590740000224
Methyl O-methyl-D-serine ester hydrochloride (1.7g,10.1mmol) was dissolved in dichloromethane (100mL), triethylamine (12.5g, 0.12mol) was added, a solution of benzyl (2-carbonylethyl) carbamate (3g, 15.5mmol) in dichloromethane (10mL) was added, stirring was continued for half an hour, cooling was performed to 0 deg.C, sodium triacetoxyborohydride (6.6g, 31mmol) was added, and the reaction was stirred at room temperature overnight. After cooling to 0 ℃, the pH was adjusted to 8 with saturated sodium bicarbonate, the aqueous phase was extracted with dichloromethane (100mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain methyl N- (2- (((benzyloxy) carbonyl) amino) ethyl) -O-methyl-D-serine ester (1.5g, yield: 31%) as a pale yellow liquid.
MS m/z(ESI):311.1[M+H]+.
The fourth step: preparation of (R) -3- (methoxymethyl) piperazin-2-one
Figure BDA0003028590740000231
Methyl N- (2- (((benzyloxy) carbonyl) amino) ethyl) -O-methyl-D-serine acid ester (1.5g, 4.8mmol) was dissolved in methanol (30mL), palladium on carbon (500mg) was added to replace hydrogen three times, and the reaction was stirred under hydrogen (15Psi) at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated to give (R) -3- (methoxymethyl) piperazin-2-one (0.6g, yield: 87%) as a colorless gum.
The fifth step: preparation of (R) -4- (2, 4-dimethoxybenzyl) -3- (methoxymethyl) piperazin-2-one
Figure BDA0003028590740000232
(R) -3- (methoxymethyl) piperazin-2-one (0.6g, 4.2mmol) was dissolved in acetonitrile (20mL), 2, 4-dimethoxybenzaldehyde (0.76g, 4.6mmol) and acetic acid (0.38g, 6.3mmol) were added, cooled to 0 ℃ and stirred for half an hour. Sodium triacetoxyborohydride (1.3g, 6.3mmol) was added and the reaction stirred at room temperature overnight. Cooled to 0 deg.C, pH-8 with saturated sodium bicarbonate, aqueous phase extracted with dichloromethane (30mL x2), organic phase dried over anhydrous sodium sulfate, filtered, concentrated, crude product separated by prep-TLC to give (R) -4- (2, 4-dimethoxybenzyl) -3- (methoxymethyl) piperazin-2-one (0.4g, yield: 33%) as a colorless gum.
MS m/z(ESI):295.2[M+H]+.
And a sixth step: preparation of (R) -1- (2, 4-dimethoxybenzyl) -5-ethoxy-6- (methoxymethyl) -1,2,3, 6-tetrahydropyrazine
Figure BDA0003028590740000233
(R) -4- (2, 4-dimethoxybenzyl) -3- (methoxymethyl) piperazin-2-one (50mg, 0.17mmol) was dissolved in dichloroethane (1mL), sodium carbonate (54mg, 0.51mmol) was added, cooling to 0 ℃ was performed, triethyloxonium tetrafluoroborate (0.68mL, 0.68mmol) was added dropwise, and the reaction was stirred at room temperature for 2 hours. Brine (20mL) was added and the aqueous phase was extracted with dichloromethane (20mL x2), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated to give (R) -1- (2, 4-dimethoxybenzyl) -5-ethoxy-6- (methoxymethyl) -1,2,3, 6-tetrahydropyrazine (50mg, 100% crude) which was used directly in the next step.
The seventh step: preparation of (S) -3-cyclopropyl-5- (7- (2, 4-dimethoxybenzyl) -8- (methoxymethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole
Figure BDA0003028590740000241
(R) -1- (2, 4-dimethoxybenzyl) -5-ethoxy-6- (methoxymethyl) -1,2,3, 6-tetrahydropyrazine (50mg, 0.14mmol) was dissolved in methanol (10mL), 3-cyclopropyl-1, 2, 4-thiadiazole-5-carbohydrazide (17mg, 0.11mmol) was added, and the reaction was stirred at 65 ℃ overnight. The reaction solution was spun dry, and the crude product was separated by prep-TLC to give (S) -3-cyclopropyl-5- (7- (2, 4-dimethoxybenzyl) -8- (methoxymethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (30mg, yield: 49%) as a colorless gum.
MS m/z(ESI):443.2[M+H]+.
Eighth step: preparation of (S) -3-cyclopropyl-5- (8- (methoxymethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole using the same
Figure BDA0003028590740000242
(S) -3-cyclopropyl-5- (7- (2, 4-dimethoxybenzyl) -8- (methoxymethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (30mg, 0.07mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1.5mL) was added, and the reaction was stirred at room temperature for 1 hour. Water (5mL) was added and stirred for half an hour, a solid precipitated, filtered, the pH of the filtrate was adjusted to >14 with 4M sodium hydroxide solution, extracted with dichloromethane (10mLx 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (S) -3-cyclopropyl-5- (8- (methoxymethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (20mg, yield: 100%).
MS m/z(ESI):293.2[M+H]+.
The ninth step: preparation of (S) - (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (methoxymethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000251
(S) -3-cyclopropyl-5- (8- (methoxymethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (20mg, 0.068mmol) was dissolved in dichloromethane (5mL), a saturated aqueous sodium bicarbonate solution (2mL) was added, 4-fluorobenzoyl chloride (13mg, 0.08mmol) was added, and the reaction was stirred at room temperature for half an hour. Water (10mL) was added, extracted with dichloromethane (10mL x2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by high performance liquid chromatography to give (S) - (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (methoxymethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone (7.1mg, yield: 25%) as a white solid.
MS m/z(ESI):415.0[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.54–7.50(m,2H),7.19–7.15(m,2H),6.03–5.95(m,1H),4.87–4.84(m,1H),4.20–3.95(m,5H),3.33(s,3H),2.43–2.39(m,1H),1.14–1.12(m,4H).
Example 5
2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N, N-dimethylacetamide
Figure BDA0003028590740000252
The first step is as follows: preparation of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetic acid
Figure BDA0003028590740000253
Ethyl 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetate (50mg, 0.1mmol) was dissolved in ethanol (5mL), water (0.5mL) was added, sodium hydroxide (21mg, 0.5mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was spin-dried to give the sodium salt of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetic acid (50mg, yield: 100% crude) as a yellow solid.
MS m/z(ESI):457.1[M+H]+.
The second step is that: preparation of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N, N-dimethylacetamide
Figure BDA0003028590740000261
The sodium salt of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetic acid (50mg, 0.1mmol) was dissolved in N, N-dimethylformamide (5mL), 2M dimethylamine/tetrahydrofuran solution (0.11mL,0.22mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (51mg, 0.13mmol) and N, N-diisopropylethylamine (71mg, 0.55mmol) were added and the reaction stirred at room temperature for 2 hours. Water (20mL) was added, the aqueous phase was extracted with dichloromethane (20mL x2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by prep-TLC to give 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N, N-dimethylacetamide (40mg, yield: 75%) as a yellow solid.
MS m/z(ESI):484.1[M+H]+.
The third step: preparation of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N, N-dimethylacetamide
Figure BDA0003028590740000262
2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N, N-dimethylacetamide (40mg,0.08mmol) was dissolved in dichloromethane (8mL), trifluoroacetic acid (2mL) was added, and the reaction was stirred at room temperature for 1 hour. Water (10mL) was added and stirred for half an hour to precipitate a solid, which was filtered, the pH of the filtrate was adjusted to >14 with 4M sodium hydroxide solution, the filtrate was extracted with dichloromethane (20mL x2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N, N-dimethylacetamide (20mg, yield: 72%).
MS m/z(ESI):334.2[M+H]+.
The fourth step: preparation of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N, N-dimethylacetamide
Figure BDA0003028590740000271
2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N, N-dimethylacetamide (20mg, 0.06mmol) was dissolved in dichloromethane (8mL), saturated aqueous sodium bicarbonate (4mL) was added, 4-fluorobenzoyl chloride (14mg, 0.09mmol) was added, and the reaction was stirred at room temperature for half an hour. Water (20mL) was added, extracted with dichloromethane (20mL x2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by high performance liquid chromatography to give 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N, N-dimethylacetamide (16mg, yield: 59%) as a white solid.
MS m/z(ESI):456.2[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.52–7.48(m,2H),7.19–7.15(m,2H),6.20–6.16(m,1H),5.00–4.96(m,1H),4.43–4.39(m,1H),4.15–4.10(m,2H),3.59–3.50(m,2H),3.12(s,3H),2.87(s,3H),2.41–2.37(m,1H),1.12–1.11(m,4H).
Example 6
2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) -N-methylacetamide
Figure BDA0003028590740000272
The preparation of example 6 was carried out in the second to fourth steps of example 5.
MS m/z(ESI):442.2[M+H]+.
Example 7
(4-chlorophenyl) (3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000281
The preparation of example 7 was carried out in the third to eighth steps of example 1.
MS m/z(ESI):467.4[M+H]+.
Example 8
(S) - (4-chlorophenyl) (3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -8- ((methylsulfonyl) methyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000282
The preparation of example 8 refers to example 4.
MS m/z(ESI):453.1[M+H]+.
Example 9
(4-chlorophenyl) (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (oxetan-3-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000291
The preparation of example 9 is as in example 4.
MS m/z(ESI):443.0[M+H]+.
Example 10
(4-chlorophenyl) (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000292
The preparation of example 10 refers to the eighth step of example 1.
MS m/z(ESI):493.1[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.52–7.47(m,2H),7.47–7.38(m,2H),6.45–5.77(m,1H),4.96–4.74(m,1H),4.42–3.96(m,2H),3.87–3.52(m,2H),3.52–3.25(m,1H),2.99(s,3H),2.72–2.50(m,2H),2.48–2.27(m,1H),1.20–0.98(m,4H)。
Example 11
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2-methoxyethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000293
The first step is as follows: preparation of 3-cyclopropyl-5- (7- (2, 4-dimethoxybenzyl) -8- (2-methoxyethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole
Figure BDA0003028590740000301
Sodium hydride (22mg, 0.54mmol, 60% w/w) was added to a solution of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) ethan-1-ol (160mg, 0.36mmol) in tetrahydrofuran (10ml) at 0 ℃ under nitrogen, the reaction was stirred for 10 minutes at 0 ℃ under nitrogen, iodomethane (103mg, 0.72mmol) was added, and the reaction was stirred overnight at room temperature. Quenching with saturated saline solution. Ethyl acetate (25ml x2) was extracted, washed with water, the organic phase was dried to dryness to give a crude product, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate 1: 9) to give the product 3-cyclopropyl-5- (7- (2, 4-dimethoxybenzyl) -8- (2-methoxyethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (90mg, yield: 54%)
MS m/z(ESI):457.2[M+H]+.
The second step is that: preparation of 3-cyclopropyl-5- (8- (2-methoxyethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole
Figure BDA0003028590740000302
The seventh step of example 1.
MS m/z(ESI):307.1[M+H]+.
The third step: preparation of (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2-methoxyethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000311
The same procedure as in the eighth step of example 1.
1H NMR(400MHz,Chloroform-d)δ7.57–7.43(m,2H),7.23–7.07(m,2H),6.59–6.08(m,1H),4.94–4.74(m,1H),4.37–4.10(m,2H),3.81–3.46(m,3H),3.28(s,3H),2.51–2.26(m,3H),1.20–1.00(m,4H).
MS m/z(ESI):429.1[M+H]+.
Example 12
(4-chloro-3-fluorophenyl) (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2-methoxyethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000312
Example 12 was prepared according to the third step of example 11.
1H NMR(400MHz,Chloroform-d)δ7.61–7.43(m,1H),7.36–7.28(m,1H),7.24–7.10(m,1H),6.59–6.08(m,1H),4.93–4.71(m,1H),4.51–3.90(m,2H),3.88–3.36(m,3H),3.30(s,3H),2.64–1.94(m,3H),1.22–0.79(m,4H).
MS m/z(ESI):463.1[M+H]+.
Example 13
2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetic acid ethyl ester
Figure BDA0003028590740000313
The first step is as follows: preparation of Ethyl 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetate
Figure BDA0003028590740000321
The seventh step of example 1.
MS m/z(ESI):335.1[M+H]+.
The second step is that: preparation of Ethyl 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetate
Figure BDA0003028590740000322
The same procedure as in the eighth step of example 1.
1H NMR(400MHz,Chloroform-d)δ7.53–7.42(m,2H),7.22–7.11(m,2H),6.30–6.09(m,1H),5.00–4.81(m,1H),4.46–4.21(m,1H),4.21–4.00(m,2H),4.04–3.83(m,1H),3.81–3.62(m,2H),3.41–3.15(m,1H),2.55–2.27(m,1H),1.25(t,J＝7.1Hz,3H),1.19–0.94(m,4H).
MS m/z(ESI):457.1[M+H]+.
Example 14
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylthio) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4- (methylthio) phenyl) methanone
Figure BDA0003028590740000323
The preparation of example 14 refers to the sixth to eighth steps of example 1.
MS m/z(ESI):473.2[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.43–7.35(m,2H),7.35–7.29(m,2H),6.21–5.88(m,1H),4.93–4.72(m,1H),4.32–4.04(m,1H),3.80–3.44(m,2H),2.89–2.67(m,2H),2.53(s,3H),2.50–2.34(m,2H),2.13(s,3H),2.07–1.96(m,1H),1.20–0.98(m,4H).
Example 15
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) propionitrile
Figure BDA0003028590740000331
The first step is as follows: preparation of 3- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) propionitrile
Figure BDA0003028590740000332
Sodium cyanide (21mg, 0.43mmol) was added to a solution of 2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) ethyl methanesulfonate (75mg, 0.14mmol) in N, N-dimethylformamide (1 ml). The reaction was heated for 2 hours at 95 ℃ under nitrogen. The reaction mixture was cooled, water (50ml) was added, dichloromethane (10ml) was extracted, the organic phase was washed with saturated brine (30ml x 6), the organic phase was dried and evaporated to dryness, and crude 3- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) propionitrile (65mg) was used directly in the next step.
MS m/z(ESI):452.2[M+H]+.
The second step is that: preparation of 3- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) propionitrile
Figure BDA0003028590740000341
The seventh step of example 1.
MS m/z(ESI):302.1[M+H]+.
The third step: preparation of 3- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) propionitrile
Figure BDA0003028590740000342
The same procedure as in the eighth step of example 1.
1H NMR(400MHz,Chloroform-d)δ8.29–8.16(m,2H),7.17–7.04(m,2H),5.23–5.06(m,2H),5.06–4.92(m,1H),4.47–4.27(m,1H),3.61–3.46(m,1H),3.46–3.32(m,1H),3.32–3.15(m,1H),3.05–2.88(m,1H),2.53–2.24(m,2H),1.24–1.00(m,4H).
MS m/z(ESI):424.1[M+H]+.
Example 16
(3, 4-dichlorophenyl) (8- (2- (3, 3-difluoropyrrolidin-1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000343
The first step is as follows: preparation of 5- (8- (2- (3, 3-difluoropyrrolidin-1-yl) ethyl) -7- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -3-methyl-1, 2, 4-thiadiazole
Figure BDA0003028590740000351
Same as the first step of example 15.
MS m/z(ESI):506.2[M+H]+.
The second step is that: preparation of 5- (8- (2- (3, 3-difluoropyrrolidin-1-yl) ethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -3-methyl-1, 2, 4-thiadiazole
Figure BDA0003028590740000352
The seventh step of example 1.
MS m/z(ESI):356.1[M+H]+.
The third step: preparation of (3, 4-dichlorophenyl) (8- (2- (3, 3-difluoropyrrolidin-1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000353
The same procedure as in the eighth step of example 1.
1H NMR(400MHz,Chloroform-d)δ7.67–7.49(m,2H),7.41–7.28(m,1H),6.39–5.99(m,1H),4.99–4.79(m,1H),4.47–3.96(m,2H),3.95–3.45(m,1H),3.30–2.76(m,4H),2.73(s,3H),2.52–2.02(m,4H),1.90–1.43(m,2H).
MS m/z(ESI):528.1[M+H]+.
Example 17
2- (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -7- (4-fluorobenzoyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-8-yl) acetamide
Figure BDA0003028590740000361
The procedure for the preparation of example 17 is as in example 5.
MS m/z(ESI):428.0[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.54–7.50(m,2H),7.17–7.13(m,2H),6.48–6.27(m,2H),5.68–5.64(m,1H),4.93–4.89(m,1H),4.18–4.10(m,3H),3.35–3.30(m,2H),2.41–2.37(m,1H),1.14–1.10(m,4H).
Example 18
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2-methoxyethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (3, 4-dichlorophenyl) methanone
Figure BDA0003028590740000362
Example 18 was prepared according to the third step of example 11.
1H NMR(400MHz,Chloroform-d)δ7.69–7.48(m,2H),7.35–7.28(m,1H),6.58–6.07(m,1H),5.22–4.64(m,1H),4.50–3.92(m,2H),3.91–3.39(m,3H),3.31(s,3H),2.57–2.00(m,3H),1.22–0.89(m,4H).
MS m/z(ESI):479.1[M+H]+.
Example 19
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2-methoxyethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4- (thiophen-2-yl) phenyl) methanone
Figure BDA0003028590740000371
Example 19 was prepared according to the third step of example 11.
1H NMR(400MHz,Chloroform-d)δ7.76–7.64(m,2H),7.54–7.44(m,2H),7.42–7.32(m,2H),7.17–7.07(m,1H),6.55–6.01(m,1H),4.90–4.70(m,1H),4.49–3.90(m,2H),3.90–3.43(m,3H),3.31(s,3H),2.55–2.01(m,3H),1.21–0.92(m,4H).
MS m/z(ESI):493.1[M+H]+.
Example 20
[1,1' -Biphenyl ] -4-yl (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000372
The preparation of example 20 was carried out in accordance with the eighth step of example 1.
1H NMR(400MHz,Chloroform-d)δ8.12–7.29(m,9H),6.33–6.08(m,1H),4.97–4.73(m,1H),4.59–3.98(m,2H),3.92–3.50(m,2H),3.54–3.22(m,1H),2.99(s,3H),2.75–2.50(m,2H),2.50–2.29(m,1H),1.27–0.93(m,4H).
MS m/z(ESI):535.1[M+H]+.
Example 21
(3, 4-dichlorophenyl) (3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000381
The preparation of example 21 is as in example 7.
MS m/z(ESI):501.0[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.60–7.58(m,2H),7.34–7.33(m,1H),6.17–6.23(m,1H),4.95–4.91(m,1H),4.22–4.18(m,2H),3.73–3.63(m,2H),3.47–3.43(m,1H),3.00(s,3H),2.73(s,3H),2.62–2.60(m,2H).
Example 22
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4 '-fluoro- [1,1' -biphenyl ] -4-yl) methanone
Figure BDA0003028590740000382
The first step is as follows: preparation of (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4 '-fluoro- [1,1' -biphenyl ] -4-yl) methanone
Figure BDA0003028590740000383
2- (7-Benzotolyltriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (24.5mg, 65. mu. mol) was added to a solution of 3-cyclopropyl-5- (8- (2- (methylsulfonyl) ethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (15mg, 43. mu. mol), 4- (4-fluorophenyl) benzoic acid (11mg, 51. mu. mol) and N, N-diisopropylethylamine (16mg, 126. mu. mol) in N, N-dimethylformamide (1.5ml), and the reaction mixture was stirred at room temperature for 16 hours. The crude product was directly isolated by Prep-HPLC to give the product (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4 '-fluoro- [1,1' -biphenyl ] -4-yl) methanone (8mg, yield: 34%).
1H NMR(400MHz,Chloroform-d)δ7.74–7.63(m,2H),7.63–7.47(m,4H),7.22–7.08(m,2H),6.32–6.06(m,1H),4.95–4.75(m,1H),4.56–4.02(m,2H),3.88–3.52(m,2H),3.52–3.28(m,1H),2.99(s,3H),2.72–2.51(m,2H),2.48–2.32(m,1H),1.24–0.93(m,4H).
MS m/z(ESI):553.1[M+H]+.
Example 23
(4-fluorophenyl) (3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000391
The preparation of example 23 is as in example 7.
MS m/z(ESI):451.4[M+H]+.
Example 24
(S) - (4-chlorophenyl) (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000392
Example 24 was prepared from example 10 via chiral resolution.
1H NMR(400MHz,Chloroform-d)δ7.54–7.46(m,2H),7.46–7.37(m,2H),6.41–5.78(m,1H),4.94–4.69(m,1H),4.45–3.97(m,2H),3.86–3.51(m,2H),3.51–3.27(m,1H),2.98(s,3H),2.68–2.46(m,2H),2.46–2.28(m,1H),1.20–0.97(m,4H).
MS m/z(ESI):493.1[M+H]+.
Example 25
(R) - (4-chlorophenyl) (3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (methylsulfonyl) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000401
Example 25 was prepared from example 10 via chiral resolution.
1H NMR(400MHz,Chloroform-d)δ7.54–7.46(m,2H),7.46–7.37(m,2H),6.41–5.78(m,1H),4.94–4.69(m,1H),4.45–3.97(m,2H),3.86–3.51(m,2H),3.51–3.27(m,1H),2.98(s,3H),2.68–2.46(m,2H),2.46–2.28(m,1H),1.20–0.97(m,4H).
MS m/z(ESI):493.1[M+H]+.
Example 26
(3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -8- (2- (dimethylamino) ethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000402
The procedure for the preparation of example 26 is as in example 16.
MS m/z(ESI):442.1[M+H]+.
Example 27
(4-chlorophenyl) (8- (2- (fluoromethoxy) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000403
The procedure for the preparation of example 27 is as in example 11.
MS m/z(ESI):437.1[M+H]+.
Example 28
(8- (2- (fluoromethoxy) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000411
Example 28 the procedure was as in example 11.
MS m/z(ESI):421.2[M+H]+.
Example 29
(3, 4-dichlorophenyl) (8- (2- (fluoromethoxy) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000412
The procedure for the preparation of example 29 is as in example 11.
MS m/z(ESI):471.1[M+H]+.
Example 30
(4-chlorophenyl) (8- (2- (3-fluoromethylazetidin-1 yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000413
The procedure for the preparation of example 30 is as in example 16.
MS m/z(ESI):462.1[M+H]+.
1H NMR (400MHz, Chloroform-d) Δ 7.52-7.37 (m,4H), 6.27-6.03 (m,1H), 5.34-4.98 (m,2H), 4.93-4.84 (m,1H), 4.27-3.95 (m,3H), 3.78-3.43 (m,3H), 3.23-2.97 (m,2H),2.72(s,3H), 2.34-2.15 (m,2H) -example 31
(3, 4-dichlorophenyl) (3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -8- (2-morpholinylethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000421
The procedure for the preparation of example 31 is as in example 16.
MS m/z(ESI):508.1[M+H]+.
Example 32
(8- (2- (2-oxa-6-azaspiro [3.3] heptan-6-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (3, 4-dichlorophenyl) methanone
Figure BDA0003028590740000422
The procedure for the preparation of example 32 is as in example 16.
MS m/z(ESI):520.0[M+H]+.
Example 33
(4-chlorophenyl) (8- (2- (2-fluoroethoxy) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000431
The procedure for the preparation of example 33 is as in example 11.
MS m/z(ESI):451.0[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.48–7.42(m,4H),6.35–6.30(m,1H),4.93–4.89(m,1H),4.50–4.23(m,4H),3.83–3.61(m,5H),2.73(s,3H),2.46–2.42(m,2H).
Example 34
(8- (2- (2-fluoroethoxy) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000432
The procedure for the preparation of example 34 is as in example 11.
MS m/z(ESI):435.1[M+H]+.
Example 35
(3, 4-dichlorophenyl) (8- (2- (2-fluoroethoxy) ethyl) -3- (3-cyclopropyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000433
The procedure for the preparation of example 35 is as in example 11.
MS m/z(ESI):485.1[M+H]+.
Example 36
(3, 4-dichlorophenyl) (8- (2- (dimethylphosphonyl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000441
The preparation of example 36 was carried out in the sixth to eighth steps of example 1.
MS m/z(ESI):499.0[M+H]+.
Example 37
(3, 4-dichlorophenyl) (8- (2- (dimethylphosphonyl) ethyl) -3- (6-methylpyridin-2-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000442
The preparation of example 37 was carried out in the third to eighth steps of example 1.
MS m/z(ESI):492.2[M+H]+.
Example 38
(8- (2- (3, 3-difluoropyrrolidin-1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000443
The procedure for the preparation of example 38 is as in example 16.
MS m/z(ESI):478.1[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.58–7.39(m,2H),7.22–7.11(m,2H),6.30–5.90(m,1H),5.07–4.76(m,1H),4.50–4.01(m,2H),3.91–3.41(m,1H),3.26–2.77(m,6H),2.73(s,3H),2.46–2.06(m,4H).
Example 39
(4-chlorophenyl) (8- (2- (3, 3-difluoropyrrolidin-1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000451
The procedure for the preparation of example 39 is as in example 16.
MS m/z(ESI):494.1[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.53–7.43(m,2H),7.43–7.37(m,2H),6.40–6.03(m,1H),5.03–4.74(m,1H),4.42–3.94(m,2H),3.85–3.41(m,1H),3.15–2.50(m,9H),2.46–2.01(m,4H).
Example 40
(8- (2- (3, 3-difluoroazetidin-1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000452
The procedure for the preparation of example 40 is as in example 16.
MS m/z(ESI):464.1[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.54–7.44(m,2H),7.23–7.13(m,2H),6.33–5.97(m,1H),4.97–4.77(m,1H),4.41–3.98(m,2H),3.97–3.24(m,5H),3.23–2.79(m,2H),2.72(s,3H),2.39–2.09(m,2H).
EXAMPLE 41
(4-chlorophenyl) (8- (2- (3, 3-difluoroazetidin-1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000461
The procedure for the preparation of example 41 is as in example 16.
MS m/z(ESI):480.1[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.51–7.45(m,2H),7.45–7.37(m,2H),6.33–5.97(m,1H),4.97–4.77(m,1H),4.41–3.98(m,2H),3.97–3.24(m,5H),3.23–2.79(m,2H),2.72(s,3H),2.39–2.09(m,2H).
Example 42
(4-chlorophenyl) (8- (2- (2, 2-difluoroethoxy) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000462
The procedure for the preparation of example 42 is as in example 11.
MS m/z(ESI):469.2[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.49–7.42(m,4H),6.38–6.32(m,1H),5.92-5.65(m,1H),4.94–4.90(m,1H),4.26–4.22(m,2H),3.95–3.65(m,5H),2.73(s,3H),2.43–2.39(m,2H).
Example 43
(4-fluorophenyl) (8- (2- (3-fluoroazetidin 1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000471
The procedure for the preparation of example 43 is as in example 16.
MS m/z(ESI):446.2[M+H]+.
1H NMR(400 MHz,Chloroform-d)δ7.54–7.45(m,2H),7.22–7.14(m,2H),6.22–5.97(m,1H),5.31–4.99(m,2H),4.93–4.86(m,1H),4.27–4.15(m,1H),3.94–3.62(m,3H),3.47–3.27(m,2H),3.09–2.88(m,2H),2.72(s,3H),2.31–2.15(m,2H).
Example 44
(4-fluorophenyl) (8- (2- ((R) -3-fluoropyrrolidin-1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000472
The procedure for the preparation of example 44 is as in example 16.
MS m/z(ESI):460.2[M+H]+.
1H NMR(400 MHz,Chloroform-d)δ7.51–7.49(m,2H),7.19–7.15(m,2H),6.23–6.18(m,1H),5.22–5.09(m,1H),4.90–4.87(m,1H),4.23–4.18(m,1H),3.80–3.76(m,1H),2.96–2.70(m,8H),2.38–2.34(m,2H),2.22–1.85(m,4H).
Example 45
(4-chlorophenyl) (8- (2- ((R) -3-fluoropyrrolidin-1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000481
The procedure for the preparation of example 45 is as in example 16.
MS m/z(ESI):476.2[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.48–7.43(m,4H),7.26–7.22(m,1H),5.23–5.08(m,1H),4.90–4.87(m,1H),4.18–4.15(m,1H),3.80–3.75(m,1H),2.95–2.70(m,7H),2.43–2.02(m,5H),1.90–1.72(m,2H).
Example 46
(4-fluorophenyl) (8- (2- ((S) -3-fluoropyrrolidin-1-yl) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) methanone
Figure BDA0003028590740000482
The procedure for the preparation of example 46 is as in example 16.
MS m/z(ESI):460.2[M+H]+.
Example 47
(8- (2- ((2, 2-difluoroethyl) (methyl) amino) ethyl) -3- (3-methyl-1, 2, 4-thiadiazol-5-yl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) (4-fluorophenyl) methanone
Figure BDA0003028590740000483
Example 47 was prepared according to example 16.
MS m/z(ESI):466.0[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.53–7.44(m,2H),7.22–7.13(m,2H),6.12–5.71(m,2H),4.94–4.84(m,1H),4.45–4.10(m,2H),3.75–3.55(m,1H),3.02–2.77(m,4H),2.72(s,3H),2.51–2.20(m,5H).
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
First, cell function experiment
Test example 1, assay of the effect of the compounds of the invention on the calcium flux in cells stably expressing NK3 receptor for experimental purposes: the purpose of this test example was to measure the inhibitory effect of compounds on the NK3 receptor.
An experimental instrument:
384 well-test plate (Corning; 3712)
Pipette (Axygen)
FLIPR(Molecular Devices)
Experimental reagent:
DMEM(Invitrogen；11965)
fetal bovine serum (Biowest; S1810-500)
Dialyzed serum (S-FBS-AU-065; Serana)
Penicillin and streptomycin (Biowest; L0022-100)
Hygromycin B (CABIOCHEM, 400052)
Matrigel(BD；354230)
DMSO(Sigma；D2650)
HBSS(Invitrogen；14065)
HEPES(Invitrogen；15630080)
Probenecid(Sigma；P8761)
BSA(renview；FA016)
Trypsin (HDB; 0458)
The experimental method comprises the following steps:
1. preparing a buffer solution: 1 XHBSS, 20mM HEPES, 2.5mM probenecid (400 mM stock in 1M NaOH), 0.1% BSA; probe and BSA were added fresh on the day of the experiment; the experimental buffer comprises a dye buffer, a compound dilution buffer and the like.
2. Cells were trypsinized and then treated at 1X 104The density of individual cells/well was seeded to 384 well-assay plates and incubated for 16-24 hours (at least overnight).
3. Discard the broth and add 20 μ L of dye; incubate at 37 ℃ in the dark for 60min, read the calcium signal.
4. Preparing an antagonist before an experiment; 5uL/well concentration 5x antagonist compound was added to 384 well-assay plates and incubated at room temperature for 15min in the dark; transfer the assay plate to a FLIPR and add 5uL/well6X concentration of agonist compound; reading the value and storing the data by using FLIPR; the total assay volume was 30uL, including 20uL/well dye buffer, 5uL/well 5X concentration of the test compound and 5uL/well6X concentration of the agonist compound.
The experimental data processing method comprises the following steps:
reading the calcium signal value through FLIPR, wherein the calculated output result of each sampling time point in the experiment is the ratio of 340/510nm to 380/510nm wavelength signals, and the calculation of subtracting the minimum value from the maximum value is derived from a ratio signal curve; IC of compound was calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to parametric nonlinear logistic formula50The value is obtained.
The experimental results are as follows:
table 1: IC of compound in stable expression of capability of NK3 receptor cell on calcium ion flow50Value of
Figure BDA0003028590740000501
And (4) experimental conclusion:
as can be seen from the data in the table, the compounds of the examples of the present invention showed good inhibitory activity in the experiment of calcium flux of cells stably expressing NK 3.
Test example 2, assay of the effect of the compounds of the invention on the calcium flux in cells stably expressing NK1/NK2 receptor for experimental purposes: the purpose of this test example was to measure the inhibitory effect of compounds on NK1/NK2 receptors.
An experimental instrument:
384 well-test plate (Corning; 3712)
Pipette (Axygen)
FLIPR(Molecular Devices)
Experimental reagent:
DMEM(Invitrogen；11965)
fetal bovine serum (Biowest; S1810-500)
Dialyzed serum (S-FBS-AU-065; Serana)
Penicillin and streptomycin (Biowest; L0022-100)
Hygromycin B (CABIOCHEM, 400052)
Matrigel(BD；354230)
DMSO(Sigma；D2650)
HBSS(Invitrogen；14065)
HEPES(Invitrogen；15630080)
Probenecid(Sigma；P8761)
BSA(renview；FA016)
Trypsin (HDB; 0458)
The experimental method comprises the following steps:
1. preparing a buffer solution: 1 XHBSS, 20mM HEPES, 2.5mM probenecid (400 mM stock in 1M NaOH), 0.1% BSA. Probenecid and BSA were added fresh the day of the experiment. The experimental buffer comprises a dye buffer, a compound dilution buffer and the like.
2. Cells were trypsinized and then treated at 1X 104The density of individual cells/well was seeded to 384 well-assay plates and incubated for 16-24 hours (at least overnight).
3. The broth was discarded and 20 μ L of dye was added. Incubate at 37 ℃ in the dark for 60min, read the calcium signal.
4. Antagonists were prepared prior to the experiment. Antagonist mode: 5uL/well concentration 5 Xantagonist compound was added to 384 well-assay plates and incubated at room temperature for 15min in the dark. The assay plates were transferred to a FLIPR and agonist compounds were added at a concentration of 5uL/well 6X. Values are read and data saved using FLIPR. The total assay volume was 30uL, including 20uL/well dye buffer, 5uL/well 5X concentration of test compound and 5uL/well6x concentration of agonist compound.
The experimental data processing method comprises the following steps:
calcium signal values were read by FLIPR. The calculated output for each sampling time point in the experiment is the ratio of the 340/510nm to 380/510nm wavelength signals. The maximum minus the minimum is calculated from the ratio signal curve. IC of compound was calculated using GraphPad prism to fit the percent inhibition and ten-point concentration data to parametric nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
it was concluded from the above protocol that the compounds of the present invention showed about 0.1nM to 10. mu.M (IC) in the cell functional calcium flux assay50) The biological activity of (1).
In some embodiments, the IC of the compounds of the invention for NK1 receptor inhibitory activity50Less than about 10. mu.M, preferably less than about 1. mu.M, more preferably less than about 100nM, even more preferably less than about 10nM, and most preferably less than 1nM or even less than about 0.1nM of the compounds listed in the present invention.

Claims (16)

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0003028590730000011
wherein:
ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R1selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbbSaid alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted with a substituent selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH)2)n-、-(CH2)nRcc、-(CH2)nORcc、-(CH2)nSRcc、-(CH2)nC(O)Rcc、-(CH2)nC(O)ORcc、-(CH2)nS(O)mRcc、-(CH2)nNRccRdd、-(CH2)nC(O)NRccRdd、-(CH2)nNRccC(O)RddOr- (CH)2)nNRccS(O)mRddIs substituted with one or more substituents of (1);
R2selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nP(O)RaaRbb、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbb；
Or, any two adjacent or non-adjacent R2Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R3selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, oxo, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbbSaid alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, oxo, nitro, hydroxy, cyano, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
or, any two adjacent or non-adjacent R3Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, oxo, nitro, hydroxy, cyano, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
Raa、Rbb、Rccand RddEach independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted or unsubstituted cycloalkyl, substituted or unsubstituted with one or more substituents selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, substituted or unsubstituted cycloalkyl, and optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted aryl, substituted or unsubstituted or substituted or unsubstituted or substituted or unsubstituted or substituted with one or more substituents selected from the groupSubstituted with one or more substituents selected from the group consisting of unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group;
x is 0, 1,2,3, 4, 5 or 6;
y is 0, 1,2,3, 4, 5 or 6;
z is 0, 1,2,3, 4 or 5;
m is 0, 1 or 2; and is
n is 0, 1 or 2.
2. A compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that ring a is selected from C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably C6-10An aryl group; more preferably phenyl.
3. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that ring C is selected from C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably 5-6 membered heteroaryl containing 1-3 atoms selected from N, O or S; more preferred is thiadiazolyl or pyridyl.
4. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is1Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxyRadical, cyano radical, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably C1-6Alkyl or C3-6A cycloalkyl group.
5. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is2Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nP(O)RaaRbb、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbb；
Preferably 3-to 8-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S, - (CH)2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nP(O)RaaRbb、-(CH2)nNRaaRbbOr- (CH)2)nC(O)NRaaRbb；
Preferably- (CH)2)nOCN、-(CH2)nOCH2F、-(CH2)nOCH3、-(CH2)nSCH2F、-(CH2)nSCH3、-(CH2)nS(O)mCH3、(CH2)nNH2、-(CH2)nNHCH3、-(CH2)nN(CH3)2、-(CH2)nC(O)NH2、-(CH2)nC(O)NHCH3、-(CH2)nC(O)N(CH3)2、-(CH2)nC(O)OEt、-(CH2)nP(O)(CH3)2、
Figure FDA0003028590730000031
Optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy is substituted with one or more substituents.
6. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is3Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbbSaid C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably C1-6Alkyl, halogen, C6-10Aryl, 3-8 membered heteroaryl containing 1-3 atoms selected from N, O or S, or- (CH)2)nSRaa(ii) a Said C1-6Alkyl, heteroaryl and C6-10Aryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
7. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R isaa、Rbb、RccAnd RddEach independently selected from hydrogen, deuterium,Halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
8. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein formula (I) is further represented by formula (II):
Figure FDA0003028590730000041
wherein:
R1selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably C1-6Alkyl or C3-6A cycloalkyl group;
R2selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n1RA1、-(CH2)n1ORA1、-(CH2)n1C(O)RA1、-(CH2)n1C(O)ORA1、-(CH2)n1OC(O)RA1、-(CH2)n1S(O)m1RA1、-(CH2)n1P(O)RA1RA2、-(CH2)n1NRA1RA2、-(CH2)n1NRA1C(O)RA2、-(CH2)n1NRA1C(O)ORA2、-(CH2)n1C(O)NRA1RA2Or- (CH)2)n1NRA1S(O)m1RA2；
Preferably 3-to 8-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S, - (CH)2)n1RA1、-(CH2)n1ORA1、-(CH2)n1SRA1、-(CH2)n1C(O)ORA1、-(CH2)n1S(O)m1RA1、-(CH2)n1P(O)RA1RA2、-(CH2)n1NRA1RA2Or- (CH)2)n1C(O)NRA1RA2；
RA1And RA2Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
m1 is 0, 1 or 2; and is
n1 is 0, 1,2,3 or 4.
9. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein formula (I) is further represented by formula (III):
Figure FDA0003028590730000051
wherein:
R1is selected from C1-6Alkyl or C3-6A cycloalkyl group; preferably a cycloalkyl group;
R3selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n-、-(CH2)nRaa、-(CH2)nORaa、-(CH2)nSRaa、-(CH2)nC(O)Raa、-(CH2)nC(O)ORaa、-(CH2)nS(O)mRaa、-(CH2)nNRaaRbb、-(CH2)nC(O)NRaaRbb、-(CH2)nNRaaC(O)RbbOr- (CH)2)nNRaaS(O)mRbbSaid C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
preferably C1-6Alkyl, halogen, C6-10Aryl, 3-8 membered heteroaryl containing 1-3 atoms selected from N, O or S, or- (CH)2)nSRaa(ii) a Said C1-6Alkyl, heteroaryl and C6-10Aryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl.
R3Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n2RA3、-(CH2)n2ORA3、-(CH2)n2C(O)RA3、-(CH2)n2C(O)ORA3、-(CH2)n2OC(O)RA3、-(CH2)n2S(O)m2RA3、-(CH2)n2P(O)RA3RA4、-(CH2)n2NRA3RA4、-(CH2)n2NRA3C(O)RA4、-(CH2)n2NRA3C(O)ORA4、-(CH2)n2C(O)NRA3RA4Or- (CH)2)n2NRA3S(O)m2RA4；
Preferably 3-to 8-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S, - (CH)2)n2RA3、-(CH2)n2ORA3、-(CH2)n2SRA3、-(CH2)n2C(O)ORA3、-(CH2)n2S(O)m2RA3、-(CH2)n2P(O)RA3RA4、-(CH2)n2NRA3RA4Or- (CH)2)n2C(O)NRA3RA4(ii) a Said 3-8 membered heterocyclyl containing 1-3 atoms selected from N, O or S is optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
RA3and RA4Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
y is 0, 1,2,3, 4, 5 or 6;
t is 0, 1 or 2;
m is 0, 1 or 2;
n is 0, 1,2,3 or 4;
m2 is 0, 1 or 2; and is
n2 is 0, 1,2,3 or 4.
10. The compound of any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, represented by each formula, which is selected from the group consisting of:
Figure FDA0003028590730000071
Figure FDA0003028590730000081
11. an intermediate for the preparation of compounds of each of the general formulae according to any one of claims 1 to 10, and stereoisomers or pharmaceutically acceptable salts thereof, represented by the following general formula (IV):
Figure FDA0003028590730000082
wherein:
R1is selected from C1-6Alkyl or C3-6A cycloalkyl group; preferably a cycloalkyl group;
R3selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n2RA3、-(CH2)n2ORA3、-(CH2)n2C(O)RA3、-(CH2)n2C(O)ORA3、-(CH2)n2OC(O)RA3、-(CH2)n2S(O)m2RA3、-(CH2)n2P(O)RA3RA4、-(CH2)n2NRA3RA4、-(CH2)n2NRA3C(O)RA4、-(CH2)n2NRA3C(O)ORA4、-(CH2)n2C(O)NRA3RA4Or- (CH)2)n2NRA3S(O)m2RA4；
Preferably 3-to 8-membered heterocyclic group containing 1 to 3 atoms selected from N, O or S, - (CH)2)n2RA3、-(CH2)n2ORA3、-(CH2)n2SRA3、-(CH2)n2C(O)ORA3、-(CH2)n2S(O)m2RA3、-(CH2)n2P(O)RA3RA4、-(CH2)n2NRA3RA4Or- (CH)2)n2C(O)NRA3RA4(ii) a Said 3-8 membered heterocyclyl containing 1-3 atoms selected from N, O or S is optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl;
RA3and RA4Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl; and is
t is 0, 1 or 2.
12. A process for preparing a compound of formula (III), and stereoisomers or pharmaceutically acceptable salts thereof, which process comprises the steps of:
Figure FDA0003028590730000091
the compound of the general formula (IV) and the compound of the general formula (V) are subjected to condensation or coupling reaction to obtain a compound of a general formula (III),
wherein:
R4is hydroxy or halogen; preferably halogen;
the other groups are represented by the compounds of the general formula (III) according to claim 9.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of each of the general formulae shown in claims 1 to 10 and stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
14. The use of compounds of each general formula according to any one of claims 1 to 10, and stereoisomers or pharmaceutically acceptable salts thereof, or the use of a pharmaceutical composition according to claim 13 for the preparation of NK inhibitor-related medicaments, in particular NK3 inhibitor-related medicaments.
15. Use of a compound according to any one of claims 1 to 10, and stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment and/or prevention of psychotic disorders, cognitive disorders, parkinson's disease, pain, convulsions, obesity, inflammatory diseases, emesis, preeclampsia, airway-related diseases, reproductive disorders, sex hormone dependent diseases or gynaecological diseases related diseases.
16. Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 for the preparation of a medicament for the treatment and/or prevention of a disease associated with a climacteric syndrome, wherein the climacteric syndrome comprises symptoms such as hot flashes, sweating, palpitation, vertigo and obesity.
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