WO2020211798A1 - Inhibiteur contenant un dérivé d'anneau bicyclique, et son procédé de préparation et ses utilisations - Google Patents

Inhibiteur contenant un dérivé d'anneau bicyclique, et son procédé de préparation et ses utilisations Download PDF

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Publication number
WO2020211798A1
WO2020211798A1 PCT/CN2020/085028 CN2020085028W WO2020211798A1 WO 2020211798 A1 WO2020211798 A1 WO 2020211798A1 CN 2020085028 W CN2020085028 W CN 2020085028W WO 2020211798 A1 WO2020211798 A1 WO 2020211798A1
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alkyl
group
cycloalkyl
aryl
ring
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PCT/CN2020/085028
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English (en)
Chinese (zh)
Inventor
王峰
孙丹妮
苏熠东
蔡家强
包如迪
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上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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Priority to CN202080003245.3A priority Critical patent/CN112272670B/zh
Publication of WO2020211798A1 publication Critical patent/WO2020211798A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to an inhibitor containing a diacyl ring derivative and a preparation method and application thereof.
  • Neurokinin includes substance P (substance P, SP), neurokinin A and neurokinin B.
  • the corresponding three types of receptors are neurokinin 1 receptor (NK1R) and neurokinin. 2 receptor (NK2R) and neurokinin 3 receptor (NK3R).
  • These three types of receptors are all G protein coupled receptors, of which NK1R is the most widely distributed, both in the central and peripheral nervous systems, NK2R is mainly distributed in the peripheral nervous system, and NK3R is mainly distributed in the central nervous system.
  • NK receptor inhibitors have been used to treat menopausal hot flashes, depression, schizophrenia and other diseases.
  • NK3R is closely related to symptoms such as menopausal syndrome hot flashes.
  • NK3R inhibitors have been shown to have a good improvement in menopausal flashes. The effect of heat.
  • Menopausal hot flashes refer to symptoms such as hot flashes, sweating, and obesity that often occur in menopausal people, and are prominent manifestations of menopausal syndrome. Menopausal hot flashes are caused by vasomotor dysfunction caused by decreased estrogen levels in the body. When the estrogen in the body drops, it will cause the brain to mistake it for hyperthermia. Therefore, the brain sends a signal to the heart to pump more blood, and the sweat glands release more sweat, accompanied by sweating, palpitations, and dizziness. Wait.
  • menopausal hot flashes More than three-quarters of women have hot flashes during menopause, and 80% of patients have this symptom for more than one year, and some can last until about 5 years after menopause.
  • the main treatment for menopausal hot flashes is hormone replacement therapy, but this therapy is likely to cause breast cancer, stroke, coronary heart disease, dementia and other diseases, with a high risk factor.
  • Oral drugs, such as paroxetine (a SSRIs drug that treats depression) are the only small molecule drugs approved for the treatment of menopausal hot flashes. They also have side effects and are only approved in the United States, so clinical development is needed A safer and more effective treatment for menopausal syndrome.
  • NK receptor inhibitor compounds reported NK receptor inhibitor compounds, but most of the compounds in the NK1R/NK2R/NK3R in vitro binding experiments have Ki above 20nM. In cell function experiments, the IC50 for NK3R inhibition is mostly 30nM. the above. Vitro CN103906750 reported NK1R / NK2R / NK3R binding experiments 20nM Ki mostly in the above experiments in cell function, most NK3R inhibition IC 50 20nM or more. CN105229008B reported that in the in vitro binding experiment of NK3R, most of Ki was above 30nM. CN102906093B reported that in the in vitro binding experiments of NK1R/NK2R/NK3R, most of Ki were above 500nM.
  • the object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:
  • E and G are each independently selected from N, C or CR aa ;
  • Ring A does not exist or is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • Ring B is selected from cycloalkyl or heterocyclic group
  • Ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl, -(CH 2 ) n -, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n SR aa , -(CH 2 ) n C(O)R aa , -(CH 2 ) n C(O)OR aa , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)NR aa R bb , -(CH 2
  • R 2 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n -, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n SR aa ,- (CH 2 ) n C(O)R aa , -(CH 2 ) n C(O)OR aa , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)NR aa R bb , -(
  • any two adjacent or non-adjacent R 2 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl group, Optionally further selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl , Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group substituted by one or more substituents;
  • R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, oxo, nitro, hydroxyl, cyano, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n -, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n SR aa ,- (CH 2 ) n C(O)R aa , -(CH 2 ) n C(O)OR aa , -(CH 2 ) n S(O) m R aa , -(CH 2 ) n NR aa R bb , -(CH 2 ) n C(O)NR aa R bb , -(
  • any two adjacent or non-adjacent R 3 are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, the cycloalkyl, heterocyclic group, aryl and heteroaryl group, Optionally further selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, oxo, nitro, hydroxyl, cyano, alkenyl, alkynyl , Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group substituted by one or more substituents;
  • R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro, hydroxyl, amino , Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cyano, nitro One or one of group, hydroxy, amino, alkenyl, alkynyl, substituted or unsubstituted cyclo
  • x 0, 1, 2, 3, 4, 5 or 6;
  • y is 0, 1, 2, 3, 4, 5 or 6;
  • z 0, 1, 2, 3, 4 or 5;
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • n1 0, 1, or 2.
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I) is a compound represented by the general formula (I-1), its stereoisomers or a pharmaceutically acceptable salt thereof:
  • Ring D is selected from a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 6-10 aryl group, a 5-12 membered heteroaryl group or not present, and the heterocyclic group or heteroaryl group contains 1- 3 heteroatoms, heteroatoms are selected from one or more of N, O, S(O)m; optionally further substituted by H, F, Cl, Br, C 1-8 alkyl, cyano, hydroxyl, Amino, C 1-8 alkylamino, -C(O)-C 1-8 alkyl substituted;
  • z is 1, 2, 3, 4, or 5;
  • Ring A, ring B, ring C, E, G, L, R 1 to R 3 , x, y, and z are as described in the general formula (I).
  • the present invention also provides a preferred solution.
  • the ring D is selected from C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group or not present,
  • the heterocyclic group and heteroaryl group contain 1 to 3 heteroatoms, and the heteroatoms are selected from one or more of N, O, S(O)m; optionally further by H, F, Cl, Br, C 1-6 alkyl, cyano, hydroxyl, amino, C 1-6 alkylamino, -C(O)-C 1-6 alkyl substituted.
  • the ring D may be, for example
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I) is a compound represented by the general formula (I-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • W is selected from C, O or N;
  • o 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • the ring containing W is optionally further substituted by H, F, Cl, Br, C 1-8 alkyl, cyano, hydroxyl, amino, C 1-8 alkylamino, -C (O)-C 1-8 alkyl Replaced by
  • Ring A, ring B, ring C, E, G, L, R 1 to R 3 , x, y, and z are as described in the general formula (I).
  • the present invention also provides a preferred solution.
  • the ring C is selected from the group consisting of C 3-12 cycloalkyl, 3-12 membered heterocycle, C 6-12 aryl and 5-14 membered heteroaryl.
  • the heteroaryl group contains 1-3 heteroatoms, and the heteroatoms are selected from one or more of N, O, and S(O)m.
  • the present invention also provides a preferred solution.
  • the ring C is selected from the group consisting of C 3-10 cycloalkyl, 3-10 membered heterocycle, C 6-10 aryl and 5-10 membered heteroaryl, wherein the heterocycle Or the heteroaryl group contains 1-3 heteroatoms, and the heteroatoms are selected from one or more of N, O, and S(O)m.
  • the present invention also provides a preferred solution, wherein the ring C is selected from the group consisting of C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 6-8 aryl and 5-8 membered heteroaryl, wherein the heterocyclic ring Or the heteroaryl group contains 1-3 heteroatoms, and the heteroatoms are selected from one or more of N, O, and S(O)m.
  • the present invention also provides a preferred solution, wherein the ring C is selected from the following groups:
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I) is a compound represented by the general formula (I-3), the general formula (I-4), and its stereoisomers Or its pharmaceutically acceptable salt:
  • Ring A, ring B, E, G, L, W, R 2 to R 3 , x, y, o, and q are as described in the general formula (I).
  • the present invention also provides a preferred solution, the E and G are different from each other, one of which is N and the other is C.
  • the present invention also provides a preferred solution.
  • the ring B is selected from C 3-12 cycloalkyl or 3-12 membered heterocyclic ring, and the heterocyclic ring contains 1-3 heteroatoms, and the heteroatoms are selected from N, O , One or more of S(O)m.
  • the present invention also provides a preferred solution.
  • the ring B is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclic ring, and the heterocyclic ring contains 1-3 heteroatoms, and the heteroatoms are selected from N, O , One or more of S(O)m.
  • the present invention also provides a preferred solution.
  • the ring B is selected from C 6-8 membered monocycloalkyl, C 8-10 membered spirocycloalkyl, C 6-8 membered bridged cycloalkyl, 6-8 membered Single heterocyclic ring, 8-10 membered spiro heterocyclic ring or 6-8 membered bridged heterocyclic ring, and the heterocyclic ring contains 1-3 heteroatoms, and the heteroatoms are selected from one of N, O, S(O)m or Many kinds.
  • the ring B is selected from
  • the present invention also provides a preferred solution.
  • the compound represented by general formula (I) is a compound represented by general formula (I-5), general formula (I-6), and its stereoisomers Or its pharmaceutically acceptable salt:
  • Rings A, L, W, R 2 to R 3 , x, y, o and q are as described in general formula (I).
  • R aa and R bb are each independently selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, halogen, cyano, amino, C 2-8 alkenyl, C 2 -8alkynyl , C 3-8 cycloalkyl, 5-8 membered heterocyclic group, C 6-10 aryl or 5-8 membered heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group, optionally further substituted by one or more substituents selected from hydrogen, halogen, cyano group and amino group; heterocyclic group or heterocyclic group contains 1-3 Heteroatoms are selected from one or more of N, O, and S(O)m.
  • R aa and R bb are each independently selected from hydrogen, C 1-8 alkyl, halogen, and amino, and said C 1-8 alkyl is optionally further selected from one of hydrogen, halogen, cyano, amino or Replaced by multiple substituents;
  • R aa and R bb are each independently selected from hydrogen, C 1-8 alkyl, F, Cl, Br, I, and the C 1-8 alkyl is optionally further selected from halogen F, Cl, Br, I Is substituted by one or more substituents;
  • the present invention also provides a preferred solution.
  • the ring A is selected from C 3-12 cycloalkyl; 3-12 membered heterocyclic ring, containing 1-3 heteroatoms, and heteroatoms are selected from N, O, S(O )
  • One or more of m, optionally fused with C 6-12 aryl, 5-12 membered heteroaryl; C 6-12 aryl, 5-14 membered heteroaryl, containing 1-3 Heteroatoms are selected from one or more of N, O, and S(O)m.
  • the present invention also provides a preferred solution.
  • the ring A is selected from C 3-8 cycloalkyl; 3-10 membered heterocyclic ring, containing 1-3 heteroatoms, and heteroatoms are selected from N, O, S(O ) One or more of m, optionally fused with phenyl; C 6-10 aryl; 5-10 membered heteroaryl, containing 1-3 heteroatoms, heteroatoms selected from N, O , One or more of S(O)m.
  • the present invention also provides a preferred solution.
  • the ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, Cyclohexadienyl, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyridazine, piperazine, 1,4-dioxane, pyran, piperidine, 4hydro-2H-pyran, morpholine, Phenyl, naphthyl, preferably imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole
  • the present invention also provides a preferred solution, the ring A is selected from The present invention also provides a preferred solution, wherein said R 2 is selected from hydrogen, deuterium, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 alkoxy , C 1-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -(CH 2 ) n -, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n SR aa , -(CH 2 ) n C(O)R aa , -(CH 2 ) n C(O)OR
  • any two adjacent or non-adjacent R 2 are linked to form a C 3-8 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, said
  • the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from hydrogen, deuterium, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, C 2-8 alkenyl, C 2-8 alkynyl, substituted or unsubstituted
  • the present invention also provides a preferred solution.
  • the R 2 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy. , C 1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-8 Membered heterocyclic group, C 6-10 aryl group, 5-8 membered heteroaryl group, -(CH 2 ) n -, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n SR aa , -(CH 2 ) n C(O)R aa , -(CH 2 ) n C(O)OR aa , -(CH 2 ) n S
  • any two adjacent or non-adjacent R 2 are linked to form a C 3-6 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, said The cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, C 2-6 alkenyl, C 2-6 alkynyl, substituted or unsubstituted One or more of C 3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-8 aryl group, and substituted or unsubstituted 5-8 membered heteroaryl group Sub
  • R 2 is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, Halogen, amino, nitro, hydroxyl, cyano, oxo, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl or -(CH 2 ) n NR aa R bb ;
  • any two adjacent or non-adjacent R 2 are linked to form a C 5-8 cycloalkyl or 5-8 membered heterocyclic group.
  • the cycloalkyl and heterocyclic groups are optionally further selected from Hydrogen, C 1-4 alkyl, halogen, amino, nitro, hydroxyl, cyano, oxo, C 2-4 alkenyl, C 2-4 alkynyl, substituted or unsubstituted C 3-4 cycloalkane
  • the group is substituted by one or more substituents; wherein, the heterocyclic ring or heteroaryl group contains 1-3 heteroatoms, and the heteroatoms are selected from one or more of N, O, and S(O)m.
  • the present invention also provides a preferred solution.
  • the R 2 is selected from hydrogen, deuterium, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxo, -( CH 2 )-N(CH 3 ) 2 , -(CH 2 )-N(CH 2 CH 3 ) 2 , or any two adjacent or non-adjacent R 2 links to form a 5-8 membered heterocyclic group , Optionally further substituted by one or more substituents of C 1-4 alkyl, halogen and oxo; wherein, the heterocycle or heteroaryl group contains 1-3 heteroatoms, and the heteroatoms are selected from N One or more of, O, S(O)m.
  • R 3 is selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, halogen, oxo, nitro, cyano, C 2-8 alkynyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, -(CH 2 ) n C(O)R aa , -(CH 2 ) n NR aa R bb or -( CH 2 ) n C(O)NR aa R bb , the C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group and C 6-10 aryl group, optionally further selected from one of hydrogen, halogen, amino, oxo, nitro, hydroxyl, cyano, C 2-8 alkenyl, and C 2-8 alkynyl Or
  • any two adjacent or non-adjacent R 3 linkages form a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 6-10 aryl group or a 5-10 membered heteroaryl group.
  • R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, halogen, oxo, nitro, cyano, C 2-6 alkynyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, -(CH 2 ) n C(O)R aa , -(CH 2 ) n NR aa R bb or -( CH 2 ) n C(O)NR aa R bb , the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered hetero Cyclic group and C 6-8 aryl group, optionally further selected from one of hydrogen, halogen, amino, oxo, nitro, hydroxyl, cyano, C 2-6 alkenyl, and C 2-6 alkynyl Or
  • any two adjacent or non-adjacent R 3 are linked to form a C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group, said C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl or 5-8 membered heteroaryl, optionally further selected from hydrogen, C 1-6 alkyl, C 1- 6 is substituted by one or more substituents of haloalkyl, halogen, nitro, cyano, and C 2-6 alkynyl, and the heterocycle or heteroaryl group contains 1-3 heteroatoms, and the heteroatoms are selected from N One or more of, O, S(O)m; R aa and R bb are each independently selected from hydrogen and C 1-6 alkyl.
  • R 3 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, F, Cl, Br, I, oxo, nitro, cyano, C 2-4 alkynyl, C 3-4 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, -(CH 2 ) n C(O)R aa , -(CH 2 ) n NR aa R bb or -(CH 2 ) n C(O)NR aa R bb , said C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 3-4 cycloalkyl , 3-6 membered heterocyclic group and C 6-8 aryl group, optionally further selected from hydrogen, F, Cl, Br, I, amino, oxo, nitro, hydroxyl, cyano, C 2-4 Alkenyl, C 2-4 alky
  • any two adjacent or non-adjacent R 3 are linked to form a C 3-4 cycloalkyl, 3-4 membered heterocyclic group, C 6-8 aryl group or 5-8 membered heteroaryl group, said C 3-4 cycloalkyl, 3-4 membered heterocyclic group, C 6-8 aryl or 5-8 membered heteroaryl, optionally further selected from hydrogen, C 1-4 alkyl, C 1- 4 substituted by one or more substituents of haloalkyl, halogen, nitro, cyano, and C 2-4 alkynyl, and the heterocycle or heteroaryl group contains 1-3 heteroatoms, and the heteroatoms are selected from N One or more of, O, S(O)m; R aa and R bb are each independently selected from hydrogen and C 1-4 alkyl.
  • the present invention also provides a preferred solution, wherein the R 3 is independently selected from hydrogen, -C(O)-CH 3 , -C(O)N(CH 3 ) 2 , F, Cl, trifluoromethyl Group, trifluoroethyl, oxo, cyclopropyl, cyclobutyl, acetylene, propyne, butyne, cyano, nitro, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyridazine, Piperazine, 1,4-dioxane, pyran, piperidine, 4hydro-2H-pyran, morpholine, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, Triazolyl, tetrazolyl, pyridyl, pyrimidinyl,
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (I) is a compound represented by the general formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • M is selected from N or CR aa ;
  • s is an integer of 0, 1 or 2;
  • t is an integer of 0, 1 or 2;
  • Ring A, ring C, E, G, L, R 1 to R 3 , x, y, and z are as described in general formula (I).
  • the present invention also provides a preferred solution.
  • the compound represented by general formula (II), its stereoisomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (III), its stereo Isomer or its pharmaceutically acceptable salt:
  • Ring A, ring C, L, M, R 1 to R 3 , x, y, z, s, and t are as described in general formula (II).
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (III), its stereoisomers or pharmaceutically acceptable salts thereof are the general formula (IV) and the general formula (IV-A).
  • Ring A, ring C, L, R 1 to R 3 , x, y, z, s, and t are as described in general formula (III).
  • the present invention also provides a preferred solution.
  • the compound represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (V), its stereo Isomer or its pharmaceutically acceptable salt:
  • Ring A, ring C, L, R 1 to R 3 , x, y, and z are as described in the general formula (I).
  • the present invention also provides a preferred solution.
  • the compound represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (VI), its stereo Isomer or its pharmaceutically acceptable salt:
  • Ring A, ring C, R 1 to R 3 , x, y, and z are as described in the general formula (I).
  • the present invention also provides a preferred solution.
  • the compound represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (VII), its stereo Isomer or its pharmaceutically acceptable salt:
  • Ring A, ring C, R 1 to R 3 , x, y, and z are as described in the general formula (I).
  • the present invention also provides a preferred solution.
  • the compound represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (VIII), its stereo Isomer or its pharmaceutically acceptable salt:
  • R 5 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R aa , -(CH 2 ) n OR aa , -(CH 2 ) n C(O)R aa or -(CH 2 ) n NR aa R bb ;
  • any two adjacent or non-adjacent R 5 groups are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, said cycloalkyl, heterocyclic group, aryl and heteroaryl group, Optionally further selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, oxo, alkenyl, alkynyl , Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group substituted by one or more substituents;
  • p 0, 1 or 2;
  • Ring A, ring C, R 1 , R 3 , y and z are as described in general formula (I).
  • the present invention also provides a preferred solution.
  • the compound represented by the general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof, and its specific structure is as shown in the general formula (VIII-A):
  • the present invention also provides a preferred solution.
  • the compound represented by general formula (VIII), its stereoisomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (IX), its stereo Isomer or its pharmaceutically acceptable salt:
  • R 4 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, oxo, nitro, hydroxyl, cyano, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n R aa , -(CH 2 ) n C(O)R aa , -(CH 2 ) n OR aa or -(CH 2 ) n NR aa R bb , said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl , Optionally further selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alk
  • Ring A, R 3 , R 5 , y and p are as described in general formula (VIII).
  • the present invention also provides a preferred solution.
  • the compound represented by general formula (IX), its stereoisomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (X), its stereo Isomer or its pharmaceutically acceptable salt:
  • R 3 , R 4 , R 5 , y and p are as described in the general formula (IX).
  • the present invention also provides a preferred solution.
  • Ring A is selected from the following groups:
  • Ring B is selected from the following groups:
  • Ring C is selected from the following groups:
  • the present invention also provides a preferred solution.
  • the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that: Selected from the following groups:
  • the present invention also provides a preferred solution.
  • the compound, its stereoisomer or pharmaceutically acceptable salt thereof is characterized in that: Selected from the following groups:
  • the present invention also provides a preferred solution.
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group or -(CH 2 ) n NR aa R bb , the C 1-6 alkyl, C 3-8 cycloalkyl and 3-12 membered heterocyclic group, optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxyl, amino, cyano, oxygen Substituted by one or more substituents in C 3-8 cycloalkyl, 3-12 heterocyclic group and -(CH 2 ) n C(O)R cc ;
  • R 2 is selected from hydrogen, C 1-6 alkyl, oxo, C 3-8 cycloalkyl or -(CH 2 ) n NR aa R bb ;
  • any two adjacent or non-adjacent R 2 are linked to form a C 3-8 cycloalkyl group
  • R 3 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-4 alkynyl, halogen, oxo, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl, -(CH 2 ) n C(O)R aa or -(CH 2 ) n C(O)NR aa R bb , the C 1-6 alkane Group, C 1-6 haloalkyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-12 membered heteroaryl, optionally further Is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxyl, amino, cyano, oxo, C 3-8 cycloalkyl, 3-12 heterocyclyl, C One or more substitu
  • any two adjacent or non-adjacent R 3 linkages form a C 3-8 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-12 membered heteroaryl group.
  • C 3-8 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-12 membered heteroaryl optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxy, amino, cyano, oxo, C 3-8 cycloalkyl and 3-12 heterocyclic group substituted by one or more substituents;
  • R 4 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group or -(CH 2 ) n NR aa R bb , wherein the 3-12 membered heterocyclic ring Group, optionally further selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, halogen, hydroxy, amino, cyano, oxo, C 3-8 cycloalkyl, 3-12 One or more substituents in the heterocyclic group and -(CH 2 ) n C(O)R cc ;
  • R 5 is selected from hydrogen, C 1-6 alkyl, oxo, C 3-8 cycloalkyl or -(CH 2 ) n NR aa R bb ;
  • any two adjacent or non-adjacent R 5 links form a C 3-8 cycloalkyl group
  • R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, or cyano.
  • the present invention also provides a preferred solution.
  • R 1 , R 2 or R 3 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl , C 2-6 alkynyl, -(CH 2 ) n C(O)R aa , -(CH 2 ) n C(O)NR aa R bb , -(CH 2 ) n NR aa R bb , C 6- 14 aryl group, C 3-6 cycloalkyl group or 3-8 membered heterocyclic group containing 1-2 nitrogen atoms, oxygen atoms, sulfur atoms, optionally halogen, hydroxyl, amino, cyano, oxo , C 1-6 alkyl, C 1-6 haloalkyl, -(CH 2 ) n C(O)CH 3 , -(CH 2 ) n C(O)CH 2
  • R aa and R bb are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen, or cyano.
  • R 3 is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl,- (CH 2 ) n C(O)R aa , -(CH 2 ) n C(O)NR aa R bb , -(CH 2 ) n NR aa R bb , C 6-14 aryl, C 3-6 ring Alkyl group or 3-8 membered heterocyclic group containing 1-2 nitrogen atoms, oxygen atoms, sulfur atoms, optionally halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, -(CH 2 ) n C(O)CH 3 , -(CH 2 ) n C(O)CH 2 CH 3 , -(CH 2 ) n C
  • R aa and R bb are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, halogen or cyano;
  • R a is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl group, C 3-6 cycloalkyl group or 3-8 membered heterocyclic group containing 1-2 nitrogen atoms, oxygen atoms and sulfur atoms;
  • Ring C is selected from the following groups:
  • the present invention also relates to a method for preparing the compound represented by general formula (VII-A) or its stereoisomer and pharmaceutically acceptable salt thereof, which comprises the following steps:
  • Pg is selected from amino protecting groups; preferably selected from allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, methoxycarbonyl, p-toluenesulfonyl Acyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl or p-methoxyphenyl; preferably 2,4-dimethoxybenzyl;
  • R is selected from halogen, hydroxyl or -C(O)OR 6 , preferably fluorine, chlorine, bromine, iodine or hydroxyl; more preferably chlorine or hydroxyl;
  • R 6 is selected from C 1-6 alkyl.
  • the present invention also relates to a method for preparing the compound represented by general formula (XI) or its stereoisomer and pharmaceutically acceptable salt thereof, which comprises the following steps:
  • General formula (XI-3) is deprotected to obtain the compound represented by general formula (XI-1) or its stereoisomers and pharmaceutically acceptable salts thereof; then, general formula (XI-1) and general formula (XI-2) ) A coupling reaction occurs to obtain the compound represented by the general formula (XI) or its stereoisomers and pharmaceutically acceptable salts thereof;
  • the present invention also relates to a method for preparing the compound represented by general formula (XII) or its stereoisomers and pharmaceutically acceptable salts thereof, which comprises the following steps:
  • the general formula (XII-1) and the general formula (XII-2) undergo a coupling reaction to obtain the compound represented by the general formula (XII) or its stereoisomers and pharmaceutically acceptable salts thereof.
  • the present invention also relates to a method for preparing the compound represented by general formula (XII) or its stereoisomers and pharmaceutically acceptable salts thereof, which comprises the following steps:
  • the general formula (XII-A1) and the general formula (XII-A2) undergo a coupling reaction to obtain the compound represented by the general formula (XII) or its stereoisomers and pharmaceutically acceptable salts thereof.
  • the present invention also provides a pharmaceutical composition, which includes a therapeutically effective dose of the compound of the general formula and its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable Carrier, diluent or excipient.
  • the present invention also provides a preferred solution, and also relates to the compounds of the general formulas, their stereoisomers or their pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of NK inhibitor-related drugs Applications.
  • the present invention also provides a preferred solution, and also relates to the compounds of the general formulas, their stereoisomers or their pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of NK3 inhibitor-related drugs Applications.
  • the present invention also provides a preferred solution, and also relates to the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is prepared for treatment and/ Or prevent psychiatric disorders, cognitive disorders, Parkinson's disease, pain, convulsions, obesity, inflammatory diseases, vomiting, preeclampsia, airway related diseases, reproductive disorders, sex hormone-dependent diseases or gynecological diseases related diseases In the application.
  • the present invention also provides a preferred solution, and also relates to the compound of general formula (I) and its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is prepared for treatment and/ Or the application in the prevention of diseases related to menopausal syndrome, which includes symptoms such as hot flashes, sweating, palpitations, dizziness and obesity.
  • the present invention further relates to the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in preparation for the treatment and/or prevention of psychotic disorders, cognitive disorders, Drug methods for Parkinson's disease, pain, convulsions, obesity, inflammatory diseases, vomiting, preeclampsia, airway related diseases, reproductive disorders, sex hormone dependent diseases, or diseases related to gynecological diseases.
  • the present invention also relates to the treatment and/or prevention of psychotic disorders, cognitive disorders, Parkinson's disease, pain, convulsions, obesity, inflammatory diseases, vomiting, preeclampsia, airway related diseases, reproductive disorders, and sex hormone dependent diseases Or a method for gynecological diseases-related diseases, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the method involves treatment and/or prevention of psychotic disorders, cognitive disorders, Parkinson’s disease, pain, convulsions, obesity, inflammatory diseases, vomiting, preeclampsia, airway related diseases, reproduction Treatment of disorders, sex hormone-dependent diseases or gynecological diseases.
  • the treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention.
  • the present invention provides a method of treating diseases including menopausal hot flashes in mammals. The method includes administering to the mammal a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.
  • 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 1 to 6 carbon atoms
  • the alkyl group is 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, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • a lower alkyl group containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted. When substituted, substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate group, the present invention preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl , Deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
  • alkylene means that one hydrogen of an alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, and “propylene” means -(CH 2 ) 3 -, “butylene” refers to -(CH 2 ) 4 -and so on.
  • alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, condensed and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • Non-limiting examples include:
  • fused cycloalkyl 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 rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthi
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include oxetane, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl , Dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl Alkyl, tetrahydrofuranyl, tetrahydropyranyl, azepanyl, piperidinyl and piperazinyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group 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 bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxy, or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, oxadiazole, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl , Thienyl, thiazolyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, thi
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • alkenyl refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), where the alkynyl group 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, Carboxy or carboxylate group.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH 2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH means methanol
  • DMF N, N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN means Otoharu.
  • DMA refers to N,N-dimethylacetamide.
  • Et 2 O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi refers to methyl lithium
  • N-BuLi refers to n-butyl lithium
  • 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
  • other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.
  • the hydrogen described in the present invention can be replaced by its isotope deuterium, and any hydrogen in the embodiment compounds of the present invention can also be replaced by deuterium.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogens in the group, preferably up to 5, more preferably 1 to 3 hydrogens independently of each other replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention. Such salt is safe and effective when used in mammals, and has due biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in units of parts per million (ppm).
  • the NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • the liquid mass spectrometry LC-MS measurement uses an Agilent 1200 Infinity Series mass spectrometer.
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification used for TLC is 0.15mm ⁇ 0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by using or following methods known in the art.
  • the fifth step (R)-cyclopropyl(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1, Preparation of 2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone
  • indole-3-carbaldehyde 500mg, 3.4mmol
  • potassium hydrogen persulfate complex salt 2.12g, 3.4mmol
  • sodium chloride 400mg, 6.8mmol
  • the first step 3-methyl-5-((8R)-8-methyl-7-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-5,6, Preparation of 7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole
  • reaction solution was stirred at room temperature for 16 hours, and then sodium cyanoborohydride (39 mg, 0.62 mmol) and methanol (2 mL) were added. After the reaction solution was stirred at room temperature for 12 hours, it was extracted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate aqueous solution (30 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude product.
  • the first step preparation of (2-((2,4-dimethoxybenzyl)amino)ethyl) t-butyl carbamate
  • Step 2 Preparation of methyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)(2,4-dimethoxybenzyl)amino)-2-cyclopropylacetate
  • the third step Preparation of methyl 2-((2-aminoethyl)(2,4-dimethoxybenzyl)amino)-2-cyclopropylacetate
  • Step 5 Preparation of 6-cyclopropyl-1-(2,4-dimethoxybenzyl)-5-ethoxy-1,2,3,6-tetrahydropyrazine
  • the sixth step 5-(8-cyclopropyl-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
  • 6-cyclopropyl-1-(2,4-dimethoxybenzyl)-5-ethoxy-1,2,3,6-tetrahydropyrazine (Intermediate 5-5, 1.80 g, 5.65mmol) was dissolved in methanol (30mL), and then 3-methyl-1,2,4-thiadiazole-5-carboxhydrazide (Intermediate 1-4, 1.34g, 8.46mmol) was added to the reaction In the system, replace the nitrogen, heat to 65°C, and stir overnight.
  • the seventh step 5-(8-cyclopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3 -Methyl-1,2,4-thiadiazole preparation
  • the eighth step (8-cyclopropyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazole Preparation of and [4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone
  • Step 2 Preparation of 3-cyclopropyl-1,2,4-thiadiazole-5-carboxylic acid ethyl ester
  • Chromatographic column CHIRALPAK AD-H 4.6*250mm, 5 ⁇ m;
  • Chromatographic column CHIRALPAK AD-H 4.6*250mm, 5 ⁇ m;
  • Example 6 can also be obtained by chiral resolution of Example 151.
  • the preparation method refers to Example 2.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to Example 2.
  • the preparation method refers to Example 2.
  • Example 24 was prepared using the above synthetic route.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the second step of Example 2.
  • the preparation method refers to Example 4.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the second step of Example 2.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to the second step of Example 2.
  • Example 39 was obtained from Example 24 through chiral resolution.
  • the preparation method refers to Examples 2 and 1.
  • Example 43 was obtained from Example 24 through chiral resolution.
  • the preparation method refers to the second step of Example 2.
  • the preparation method refers to the fifth step of Example 1.
  • the preparation method refers to Examples 2 and 1.
  • Example 76 For the preparation method of Example 76, refer to the sixth step of Example 6.
  • Example 77 For the preparation method of Example 77, refer to the sixth step of Example 6.
  • Example 78 For the preparation method of Example 78, refer to the sixth step of Example 6.
  • Example 79 For the preparation method of Example 79, refer to the sixth step of Example 6.
  • Example 80 was prepared with (R)-3-cyclopropyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a] Pyrazin-3-yl)-1,2,4-thiadiazole (Intermediate 6-5) and 3,4,5-trifluorobenzoic acid as raw materials. Refer to the sixth step of Example 6.
  • Example 81 For the preparation method of Example 81, refer to the sixth step of Example 6.
  • Example 82 refers to the sixth step of Example 6.
  • Example 83 For the preparation method of Example 83, refer to the sixth step of Example 6.
  • Example 84 For the preparation method of Example 84, refer to the sixth step of Example 6.
  • the first step (R)-(3-chloro-4,5-difluorophenyl)(3-(3-cyclopropyl-1,2,4-thiadiazol-5-yl)-8-methyl Preparation of yl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone
  • Example 87 was prepared with (R)-3-cyclopropyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a] Pyrazin-3-yl)-1,2,4-thiadiazole (Intermediate 6-5) and p-chlorobenzoic acid as raw materials. Refer to the sixth step of Example 6.
  • Chromatographic column CHIRALPAK AD-H 4.6*250mm, 5 ⁇ m;
  • Example 88 For the preparation method of Example 88, refer to the sixth step of Example 6.
  • Chromatographic column CHIRALPAK AD-H 4.6*250mm, 5 ⁇ m;
  • Example 89 refers to the sixth step of Example 6.
  • Example 90 refers to the sixth step of Example 6.
  • Example 91 For the preparation method of Example 91, refer to the sixth step of Example 6.
  • Example 92 For the preparation method of Example 92, refer to the sixth step of Example 6.
  • Example 93 For the preparation method of Example 93, refer to the sixth step of Example 6.
  • Example 94 For the preparation method of Example 94, refer to the sixth step of Example 6.
  • Example 95 refers to the sixth step of Example 6.
  • Example 96 For the preparation method of Example 96, refer to the sixth step of Example 6.
  • Example 98 For the preparation method of Example 98, refer to the fifth step of the preparation method of Example 60.
  • the preparation method of Example 99 refers to the fifth step of the preparation method of Example 60.
  • Example 103 For the preparation method of Example 103, refer to the fifth step of the preparation method of Example 102.
  • Example 104 For the preparation method of Example 104, refer to the fifth step of the preparation method of Example 102.
  • Example 105 For the preparation method of Example 105, refer to the fifth step of the preparation method of Example 102.

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Abstract

L'invention concerne un composé représenté par la formule générale (I), un procédé se préparation, des compositions pharmaceutiques de celui-ci, et des utilisations de celui-ci en tant qu'inhibiteurs de NK dans le traitement de la dépression, de l'anxiété, de la schizophrénie, de maladies dépendant des hormones sexuelles et d'autres états apparentés. Les substituants dans la formule générale (I) sont tels que définis dans la description.
PCT/CN2020/085028 2019-04-16 2020-04-16 Inhibiteur contenant un dérivé d'anneau bicyclique, et son procédé de préparation et ses utilisations WO2020211798A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022022680A1 (fr) * 2020-07-30 2022-02-03 上海翰森生物医药科技有限公司 Dérivé à cycle fusionné azoté comme inhibiteur, son procédé de préparation et son utilisation
US11505546B2 (en) 2020-03-26 2022-11-22 Janssen Pharmaceutica Nv Azaspirocycles as monoacylglycerol lipase modulators
US11512059B2 (en) 2020-03-26 2022-11-29 Janssen Pharmaceutica Nv Aminocyclobutanes as monoacylglycerol lipase modulators
US11597728B2 (en) 2018-09-28 2023-03-07 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
US11708359B2 (en) 2020-02-10 2023-07-25 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
WO2023138681A1 (fr) * 2022-01-24 2023-07-27 上海翰森生物医药科技有限公司 Sel d'acide ou forme cristalline d'inhibiteur de dérivé à cycle condensé contenant de l'azote, son procédé de préparation et son utilisation
US11787798B2 (en) 2020-03-26 2023-10-17 Janssen Pharmaceutica Nv Aryl piperidines as monoacylglycerol lipase modulators
US11820766B2 (en) 2018-09-28 2023-11-21 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
US11839663B2 (en) 2019-09-30 2023-12-12 Janssen Pharmaceutica Nv Radiolabelled MGL pet ligands
US11891387B2 (en) 2020-03-26 2024-02-06 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators

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CN113549074A (zh) * 2020-04-26 2021-10-26 上海翰森生物医药科技有限公司 含三唑基的并环类衍生物抑制剂、其制备方法和应用
CN115260180B (zh) * 2021-04-30 2024-05-28 长春金赛药业有限责任公司 含三氮唑稠环类衍生物、药物组合物及其制备方法和应用
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009095253A1 (fr) * 2008-02-01 2009-08-06 Merz Pharma Gmbh & Co. Kgaa 6-halo-pyrazolo[1,5-a]pyridines, leur méthode de préparation et leur utilisation comme modulateurs des récepteurs métabotropiques du glutamate (mglur)
WO2010125102A1 (fr) * 2009-04-29 2010-11-04 Glaxo Group Limited Dérivés de 5,6,7,8-tétrahydro[1,2,4]triazolo[4,3-a]pyrazine comme modulateurs de p2x7
CN102906093A (zh) * 2010-04-02 2013-01-30 欧洲筛选有限公司 新型nk-3受体选择性拮抗剂化合物、药物组合物以及在nk-3受体介导的疾病中的使用方法
CN103906750A (zh) * 2011-10-03 2014-07-02 欧洲筛选有限公司 作为选择性NK-3受体拮抗剂的新型手性N-酰基-5,6,7,(8-取代的)-四氢-[1,2,4]三唑并[4,3-a]吡嗪、药物组合物、用于NK-3受体介导的疾病中的方法及其手性合成
WO2014154896A1 (fr) * 2013-03-29 2014-10-02 Euroscreen Sa Nouvelles n-acyl-(3-substitués)-5,6,7,8-tétrahydro[1,2,4]triazolo[4,3-a]pyrazines utilisées en tant qu'antagonistes sélectifs des récepteurs nk-3, composition pharmaceutique, méthodes destinées à être utilisés dans des troubles médiés par le récepteur nk-3
WO2014154897A1 (fr) * 2013-03-29 2014-10-02 Euroscreen Sa Nouvelles n-acyl-(3-substitués)-(8-méthyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines utilisées en tant qu'antagonistes sélectifs des récepteurs nk-3, composition pharmaceutique, méthodes d'utilisation dans le traitement de troubles médiés par les récepteurs nk-3
CN105229008A (zh) * 2013-03-29 2016-01-06 欧洲筛选有限公司 作为选择性NK-3受体拮抗剂的新型N-酰基-(3-取代)-(8-取代)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪、药物组合物、用于NK-3受体介导的病症的方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20231661T1 (hr) * 2015-03-16 2024-03-15 Ogeda N.V. Antagonisti nk-3 receptora za terapijsko ili kozmetičko liječenje viška tjelesne masti

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009095253A1 (fr) * 2008-02-01 2009-08-06 Merz Pharma Gmbh & Co. Kgaa 6-halo-pyrazolo[1,5-a]pyridines, leur méthode de préparation et leur utilisation comme modulateurs des récepteurs métabotropiques du glutamate (mglur)
WO2010125102A1 (fr) * 2009-04-29 2010-11-04 Glaxo Group Limited Dérivés de 5,6,7,8-tétrahydro[1,2,4]triazolo[4,3-a]pyrazine comme modulateurs de p2x7
CN102906093A (zh) * 2010-04-02 2013-01-30 欧洲筛选有限公司 新型nk-3受体选择性拮抗剂化合物、药物组合物以及在nk-3受体介导的疾病中的使用方法
CN103906750A (zh) * 2011-10-03 2014-07-02 欧洲筛选有限公司 作为选择性NK-3受体拮抗剂的新型手性N-酰基-5,6,7,(8-取代的)-四氢-[1,2,4]三唑并[4,3-a]吡嗪、药物组合物、用于NK-3受体介导的疾病中的方法及其手性合成
WO2014154896A1 (fr) * 2013-03-29 2014-10-02 Euroscreen Sa Nouvelles n-acyl-(3-substitués)-5,6,7,8-tétrahydro[1,2,4]triazolo[4,3-a]pyrazines utilisées en tant qu'antagonistes sélectifs des récepteurs nk-3, composition pharmaceutique, méthodes destinées à être utilisés dans des troubles médiés par le récepteur nk-3
WO2014154897A1 (fr) * 2013-03-29 2014-10-02 Euroscreen Sa Nouvelles n-acyl-(3-substitués)-(8-méthyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines utilisées en tant qu'antagonistes sélectifs des récepteurs nk-3, composition pharmaceutique, méthodes d'utilisation dans le traitement de troubles médiés par les récepteurs nk-3
CN105229008A (zh) * 2013-03-29 2016-01-06 欧洲筛选有限公司 作为选择性NK-3受体拮抗剂的新型N-酰基-(3-取代)-(8-取代)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪、药物组合物、用于NK-3受体介导的病症的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
STN COLUMNBUS: "Registry-1", REGISTRY, 21 July 2016 (2016-07-21), DOI: 20200703132457 *
STN COLUMNBUS: "Registry-2", REGISTRY, 18 November 2018 (2018-11-18), DOI: 20200703133238X *

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US11993601B2 (en) 2018-09-28 2024-05-28 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
US11597728B2 (en) 2018-09-28 2023-03-07 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
US11820766B2 (en) 2018-09-28 2023-11-21 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
US11839663B2 (en) 2019-09-30 2023-12-12 Janssen Pharmaceutica Nv Radiolabelled MGL pet ligands
US11708359B2 (en) 2020-02-10 2023-07-25 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
US11897872B2 (en) 2020-03-26 2024-02-13 Janssen Pharmaceutica Nv Azaspirocycles as monoacylglycerol lipase modulators
US11505546B2 (en) 2020-03-26 2022-11-22 Janssen Pharmaceutica Nv Azaspirocycles as monoacylglycerol lipase modulators
US11512059B2 (en) 2020-03-26 2022-11-29 Janssen Pharmaceutica Nv Aminocyclobutanes as monoacylglycerol lipase modulators
US11919870B2 (en) 2020-03-26 2024-03-05 Janssen Pharmaceutica Nv Aminocyclobutanes as monoacylglycerol lipase modulators
US11787798B2 (en) 2020-03-26 2023-10-17 Janssen Pharmaceutica Nv Aryl piperidines as monoacylglycerol lipase modulators
US11891387B2 (en) 2020-03-26 2024-02-06 Janssen Pharmaceutica Nv Monoacylglycerol lipase modulators
CN115427412A (zh) * 2020-07-30 2022-12-02 上海翰森生物医药科技有限公司 含氮并环类衍生物抑制剂、其制备方法和应用
CN115427412B (zh) * 2020-07-30 2024-02-20 上海翰森生物医药科技有限公司 含氮并环类衍生物抑制剂、其制备方法和应用
WO2022022680A1 (fr) * 2020-07-30 2022-02-03 上海翰森生物医药科技有限公司 Dérivé à cycle fusionné azoté comme inhibiteur, son procédé de préparation et son utilisation
WO2023138681A1 (fr) * 2022-01-24 2023-07-27 上海翰森生物医药科技有限公司 Sel d'acide ou forme cristalline d'inhibiteur de dérivé à cycle condensé contenant de l'azote, son procédé de préparation et son utilisation

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