Nitrogen-containing condensed ring derivative inhibitors, methods for preparing the same, and use thereof

Abstract

Nitrogen-containing fused ring derivative inhibitors, their preparation methods, and their use. The present invention particularly relates to compounds represented by general formula (I), their preparation methods, pharmaceutical compositions, and their use as NK inhibitors in the treatment of depression, anxiety, schizophrenia, sex hormone-dependent diseases, and other related diseases. The various substituents in general formula (I) have the same definitions as in the specification. JPEG2023537244000280.jpg43170

Description

[Technical Field]

[0001] Field of Invention This invention belongs to the field of drug synthesis and specifically relates to nitrogen-containing condensed ring derivative inhibitors, methods for preparing the same, and the use thereof. [Background technology]

[0002] Background of the Invention Neurokinins (NK) include substance P (SP), neurokinin A, and neurokinin B, and correspond to three types of receptors: neurokinin 1 receptor (NK1R), neurokinin 2 receptor (NK2R), and neurokinin 3 receptor (NK3R). All three of these receptors are G protein-coupled receptors, with NK1R being the most widely distributed. NK1R is mainly distributed in both 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. Currently, NK receptor inhibitors are used to treat menopausal hot flashes, depression, schizophrenia, and other conditions. In particular, NK3R is closely related to hot flashes and other symptoms of menopausal syndrome, and NK3R inhibitors have been shown to have a beneficial effect in alleviating menopausal hot flashes.

[0003] Menopausal hot flashes refer to symptoms such as hot flashes and sweating that frequently occur in menopausal women, and are a prominent feature of menopausal syndrome. Menopausal hot flashes are caused by vasomotor dysfunction due to a decrease in estrogen levels in the body. When estrogen decreases in the body, the brain mistakenly perceives this as a high body temperature. The brain then signals the heart to pump more blood and the sweat glands to release more sweat, resulting in sweating, palpitations, dizziness, etc. More than three-quarters of women experience hot flashes during menopause. These symptoms can last for more than a year in 80% of patients, and in some patients, they can last for about five years after menopause. Currently, the main treatment for menopausal hot flashes is hormone replacement therapy, but this therapy is associated with a relatively high risk of breast cancer, stroke, coronary artery disease, dementia, etc. Paroxetine, an oral medication (belonging to the SSRI class and used to treat depression), is the only small molecule drug approved for treating menopausal hot flashes, but it also has side effects and is only approved in the United States. Therefore, there is a clinical need to develop safer and more effective medicines for treating menopausal symptoms.

[0004] International application WO201415489 reports NK receptor inhibitor compounds. However, most of the compounds in that specification showed Ki greater than 20 nM in in vitro binding experiments to NK1R / NK2R / NK3R, and most did not show IC in cell function experiments. 50 They exhibit inhibitory activity against NK3R at concentrations above 30 nM. In CN103906750, most of the compounds listed in the specification showed Ki values ​​above 20 nM in in vitro binding experiments to NK1R / NK2R / NK3R, and most showed IC50 in cell function experiments. 50It has been reported that inhibitory activity against NK3R is observed at concentrations above 20 nM. In CN105229008B, it has been reported that most of the compounds in its specification show Ki values ​​above 30 nM in in vitro binding experiments with NK3R. In CN102906093B, it has been reported that most of the compounds in its specification show Ki values ​​above 500 nM in in vitro binding experiments with NK1R / NK2R / NK3R. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2014 / 154895 [Patent Document 2] CN103906750 [Patent Document 3] CN105229008B [Patent Document 4] CN102906093B [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] Therefore, there is an urgent need to develop highly active NK receptor inhibitors to alleviate the symptoms of menopausal hot flashes in order to meet the enormous market demand. [Means for solving the problem]

[0007] Summary of the Invention The object of the present invention is to provide a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, the structure of the compound of formula (I) is as follows.

[0008] [ka]

[0009] [In the formula, The A ring is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; R a is hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n -, -(CH2) n R aa -, -(CH2) n OR aa -, -(CH2) n SR aa -, -(CH2) n C(O)R aa -, -(CH2) n C(O)OR aa -, -(CH2) n S(O) m R aa -, -(CH2) n NR aa R bb -, -(CH2) n C(O)NR aa R bb -, -(CH2) n NR aa C(O)R bb , and -(CH2) n NR aa S(O) m R bb selected from the group consisting of, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may optionally be further substituted; R1 is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the above amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be further substituted by optional choice; R2 is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, oxo, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the above amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be further substituted by optional choice; R aa and R bb Each of these is independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and the above amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be further substituted by optional choice; x is 0, 1, 2, 3, 4, 5, or 6; y is 0, 1, 2, 3, 4, or 5; z is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2; and n is 0, 1, or 2.

[0010] In a more preferred embodiment of the present invention, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof contains at least one deuterium atom, except that (R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazole-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone.

[0011] In a more preferred embodiment of the present invention, ring A is C 3~8 Cycloalkyl, 3-12 membered heterocyclyl, C 6~14 Aryl and 5-14 membered heteroaryls; preferably 5-10 membered heteroaryls containing 1-4 atoms selected from the group consisting of N, O, and S; more preferably 5 membered heteroaryls, 5-membered condensed 5-membered heteroaryls, or 5-membered condensed 6-membered heteroaryls containing 1-4 atoms selected from the group consisting of N, O, and S; even more preferably [ka] It is selected from the group consisting of the following.

[0012] In a more preferred embodiment of the present invention, in a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] The group is selected from the following groups. [ka]

[0013] In a more preferred embodiment of the present invention, in a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, [ka] The group is selected from the following groups.

[0014] [ka]

[0015] [ka]

[0016] In a more preferred embodiment of the present invention, R a These are hydrogen, deuterium, halogen, amino, hydroxy, cyano, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3-12 membered heterocyclyl, C 6~14 Aryl, 5-14 member heteroaryl, -(CH2) n -,-(CH2) n R aa ,-(CH2) n Ure aa ,-(CH2) n SR aa ,-(CH2) n C(O)R aa ,-(CH2) n C(O)OR aa ,-(CH2) n S(O) m R aa ,-(CH2) n NR aa R bb ,-(CH2) n C(O)NR aa R bb ,-(CH2) n NR aa C(O)R bb , and -(CH2) n NR aa S(O) mR bb selected from the group consisting of, said C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 deuterated alkyl, C 1~6 haloalkyl, C 1~6 hydroxyalkyl, C 1~6 alkoxy, C 1~6 alkylthio, C 1~6 haloalkoxy, C 3~8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl are each deuterium, halogen, amino, hydroxy, cyano, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 deuterated alkyl, C 1~6 haloalkyl, C 1~6 hydroxyalkyl, C 1~6 alkoxy, C 1~6 alkylthio, C 1~6 haloalkoxy, C 3~8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; [[ID=z48]]preferably hydrogen, deuterium, halogen, cyano, amino, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 deuterated alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 alkylthio, C 1~6 deuterated alkoxy, -(CH2) n1 OR aa 、-(CH2) n1 SR aa 、or -(CH2) n1 NR aa R bb ;<00006More preferably, the substituents may be further substituted with one or more substituents from among hydrogen, deuterium, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, isopropyl, deuterated methyl, ethynyl, -OCH3, -OCD3, -NHCH3, -N(CH3)2, or -SCH3.

[0017] In a more preferred embodiment of the present invention, R1 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3-12 membered heterocyclyl, C 6~14 Selected from the group consisting of aryls and 5-14 member heteroaryls, the above C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3-12 membered heterocyclyl, C 6~14 Aryls and 5-14 member heteroaryls are deuterium, halogen, amino, hydroxy, cyano, and C, respectively. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3-12 membered heterocyclyl, C6~14 Aryls, and 5- to 14-membered heteroaryls; Preferably hydrogen, deuterium, halogen, or 5-6 membered heteroaryl; More preferably, it may be further optionally substituted with one or more substituents from hydrogen, deuterium, fluorine, chlorine, bromine, or thienyl.

[0018] In a more preferred embodiment of the present invention, R2 is hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3-12 membered heterocyclyl, C 6~14 The group is selected from aryls and 5- to 14-membered heteroaryls.

[0019] In a more preferred embodiment of the present invention, R aa and R bb These are, independently, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3-12 membered heterocyclyl, C 6~14 Selected from the group consisting of aryls and 5-14 member heteroaryls, the above C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl deuterated, C1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3-12 membered heterocyclyl, C 6~14 Aryls and 5-14 member heteroaryls are deuterium, halogen, amino, hydroxy, cyano, and C, respectively. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, 3-12 membered heterocyclyl, C 6~14 The molecule may be further optionally substituted with one or more substituents from among aryl and 5- to 14-membered heteroaryl groups.

[0020] In a more preferred embodiment of the present invention, ring A is [ka] Selected from the group consisting of; R a These are hydrogen, deuterium, halogen, cyano, amino, and C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkyl deuterated, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 1~6 Deuterated alkoxy, -(CH2) n1 Ure aa ,-(CH2) n1 SR aa , and -(CH2) n1 NR aa R bb ; Preferably hydrogen, deuterium, fluorine, chlorine, cyano, amino, methyl, deuterated methyl, ethynyl, azetidinyl, tetrahydropyrrolyl, -OCH3, -OCD3, -NHCH3, -N(CH3)2, -SCH3, -N(CD3)2, -N(CH3)CH(CH3)2, [ka] It is selected from the group consisting of the following.

[0021] In a more preferred embodiment of the present invention, ring A is [ka] And, R a The halogen is preferably fluorine, chlorine, or bromine, more preferably chlorine.

[0022] The present invention further provides a compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof, the structure of the compound of formula (II) is as follows: [ka] [In the formula, R1 is selected from the group consisting of hydrogen, deuterium, and halogens; preferably hydrogen, deuterium, fluorine, chlorine, or bromine; R3 is hydrogen, deuterium, halogen, C 1~6 Alkyl, C 1~6 Selected from the group consisting of deuterated alkyls and 3-6 membered heterocyclines; the above C 1~6 Alkyl, C 1~6 Alkyl deuterated compounds and 3- to 6-membered heterocyclines are composed of deuterium and halogens, respectively; Preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, methyl deuteride, azetidinyl, tetrahydropyrrolyl, [ka] The substituents may be further substituted by one or more of the substituents as optional; [y is 1, 2, 3, 4, or 5].

[0023] The present invention further provides a method for preparing a compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the method comprising the following steps: [ka] A step of deprotecting the compound of formula (I-1) to obtain the compound of formula (I-2), or its stereoisomer, and a pharmaceutically acceptable salt thereof; next, subjecting the compound of formula (I-2) and the compound of formula (I-3) to a condensation reaction to obtain the compound of formula (I), or its stereoisomer, or a pharmaceutically acceptable salt thereof; [In the formula, Pg is an amino protecting group; preferably allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethyloxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, or p-methoxyphenyl; more preferably 2,4-dimethoxybenzyl; R is a halogen, hydroxyl, and -C(O)OR A Preferably, fluorine, chlorine, bromine, iodine, or hydroxyl; more preferably, selected from the group consisting of chlorine or hydroxyl; R A is C 1~6 It is alkyl.

[0024] The present invention further provides a method for preparing a compound of formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the method comprising the following steps: [ka] A step of deprotecting the compound of formula (II-1) to obtain the compound of formula (II-2), or its stereoisomer, and a pharmaceutically acceptable salt thereof; next, subjecting the compound of formula (II-2) and the compound of formula (II-3) to a condensation reaction to obtain the compound of formula (II), or its stereoisomer, or a pharmaceutically acceptable salt thereof; [In the formula, Pg is an amino protecting group; preferably allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethyloxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, or p-methoxyphenyl; more preferably 2,4-dimethoxybenzyl; R is a halogen, hydroxyl, and -C(O)OR A Preferably, fluorine, chlorine, bromine, iodine, or hydroxyl; more preferably selected from the group consisting of chlorine or hydroxyl; R A is C 1~6 It is alkyl.

[0025] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of each of the above general formulas, its stereoisomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0026] The present invention also provides preferred embodiments relating to the use of compounds of each of the above general formulas, their stereoisomers, or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions in the preparation of NK inhibitor-related pharmaceuticals, particularly in the preparation of NK3 inhibitor-related pharmaceuticals.

[0027] The present invention also provides preferred embodiments relating to the use of compounds of each of the above general formulas, their stereoisomers, or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions, in the preparation of pharmaceuticals for treating and / or preventing mental disorders, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsions, obesity, inflammatory diseases, vomiting, pre-eclampsia, respiratory tract disorders, reproductive disorders, sex hormone-dependent diseases, or gynecological disorders.

[0028] The present invention also provides preferred embodiments relating to the use of compounds of each of the above general formulas, their stereoisomers, or pharmaceutically acceptable salts thereof, or the above pharmaceutical compositions, in the preparation of pharmaceuticals for treating and / or preventing menopausal syndrome-related disorders, including symptoms such as hot flashes, sweating, palpitations, dizziness, and obesity.

[0029] The present invention further relates to compounds of each of the above general formulas, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, for use as pharmaceuticals to treat and / or prevent mental disorders, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsions, obesity, inflammatory diseases, vomiting, pre-eclampsia, respiratory tract disorders, reproductive disorders, sex hormone-dependent diseases, or gynecological disorders.

[0030] The present invention also relates to methods for treating and / or preventing mental disorders, cognitive impairments, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsions, obesity, inflammatory diseases, vomiting, pre-eclampsia, respiratory tract disorders, reproductive disorders, sex hormone-dependent disorders, or gynecological disorders, the methods comprising the step of administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof to a mammal.

[0031] In some embodiments, the method includes treatments such as treating and / or preventing mental disorders, cognitive impairments, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsions, obesity, inflammatory diseases, vomiting, pre-eclampsia, respiratory tract disorders, reproductive disorders, sex hormone-dependent disorders, or gynecological disorders.

[0032] The treatment methods provided herein include the step of administering a therapeutically effective amount of the compound of the present invention to a subject. In one embodiment, the present invention provides a method for treating related disorders, including menopausal hot flashes, in mammals. The method includes the step of administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof to a mammal. [Modes for carrying out the invention]

[0033] definition Unless otherwise stated, terms used in this specification and in the claims have the meanings set forth below.

[0034] The term "alkyl" refers to a saturated aliphatic hydrocarbon group that is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, and most preferably an alkyl group having 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-methylhexyl, 5-methylhexyl, Examples include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-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, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers.More preferably, the alkyl group is a lower alkyl group having 1 to 6 carbon atoms, and 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, and the like. The alkyl group may be substituted or unsubstituted. If substituted, the substituent may be substituted at any available connection point. The substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl. The alkyl of the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0035] The term "alkylene" means an alkyl group in which one hydrogen atom is further substituted. For example, "methylene" means -CH2-, "ethylene" means -(CH2)2-, "propylene" means -(CH2)3-, and "butylene" means -(CH2)4-. The term "alkenyl" means an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl. The alkenyl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocyclylthio.

[0036] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Polycyclic cycloalkyls include cycloalkyls having a spiro ring, a fused ring, or a crosslinking ring. Cycloalkyls are preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0037] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which individual rings are connected by a single shared carbon atom (called a spiro atom), and the rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Spirocycloalkyls are preferably 6- to 14-membered spirocycloalkyls, more preferably 7- to 10-membered spirocycloalkyls. Depending on the number of spiro atoms shared between the rings, spirocycloalkyls can be classified as mono-spirocycloalkyls, di-spirocycloalkyls, or poly-spirocycloalkyls, and spirocycloalkyls are preferably mono-spirocycloalkyls or di-spirocycloalkyls, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spirocycloalkyls. Non-limiting examples of spirocycloalkyls include: [ka] Spirocycloalkyls include mono-spirocycloalkyls in which cycloalkyls and heterocyclyls share a spiro atom, and non-limiting examples include the following:

[0038] [ka]

[0039] The term "fused cycloalkyl" refers to a 5-20 membered all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with another ring, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Fused cycloalkyls are preferably 6-14 membered fused cycloalkyls, more preferably 7-10 membered fused cycloalkyls. Depending on the number of ring members, fused cycloalkyls can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyls, and fused cycloalkyls are preferably bicyclic or tricyclic fused cycloalkyls, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyls. Non-limiting examples of fused cycloalkyls include the following:

[0040] [ka]

[0041] The term "bridged cycloalkyl" refers to a 5-20 membered all-carbon polycyclic group in which each of the two rings in the system shares two non-adjacent carbon atoms, and the rings may have one or more double bonds, but none of the rings have a fully conjugated π-electron system. Bridged cycloalkyls are preferably 6-14 membered, more preferably 7-10 membered. Depending on the number of ring members, bridged cycloalkyls can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyls, and bridged cycloalkyls are preferably bicyclic, tricyclic, or tetracyclic bridged cycloalkyls, more preferably bicyclic or tricyclic bridged cycloalkyls. Non-limiting examples of bridged cycloalkyls include the following.

[0042] [ka]

[0043] The cycloalkyl ring may be condensed with an aryl ring, a heteroaryl ring, or a heterocyclyl ring, in which case the ring bonded to the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptyl. The cycloalkyl may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0044] The term "heterocyclyl" refers to a ring atom consisting of one or more N, O, and S(O) atoms. mA heteroatom selected from the group consisting of (wherein m is an integer from 0 to 2), where the remaining ring atoms are carbon atoms, except for -OO-, -OS-, or -SS- in the ring, and the remaining ring atoms are carbon atoms, is a 3 to 20 member saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group. Preferably, the heterocyclyl has 3 to 12 ring atoms, 1 to 4 of which are heteroatoms; more preferably 3 to 8 ring atoms; most preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclils include azetidinil, oxetanil, tetrahydropyranil, azepanil, tetrahydropyrrolyl, imidazolidinil, tetrahydrofuranil, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranil, dihydropyrazolyl, dihydropyrrolyl, piperidinil, piperazinil, morpholinil, thiomorpholinil, homopiperazinil, and pyranil, with azetidinil, tetrahydropyrrolyl, oxetanil, tetrahydrofuranil, tetrahydropyranil, azepanil, piperidinil, and piperazinil being preferred. Polycyclic heterocyclils include heterocyclils having a spiro ring, a fused ring, or a bridging ring, which may be connected to other groups through single bonds and may be further condensed to other cycloalkyls, heterocyclils, aryls, and heteroaryls through any two or more atoms in the ring.

[0045] The term "spiroheterocyril" refers to a compound in which individual rings are connected by a single shared atom (called a spiro atom), and one or more ring atoms are composed of N, O, and S(O). mThe term refers to a 5-20 membered polycyclic heterocyclil group, where the heteroatom is selected from the group consisting of (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon atoms, and the ring may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Spiroheterocyclils are preferably 6-14 membered spiroheterocyclils, more preferably 7-10 membered spiroheterocyclils. Depending on the number of spiroatoms shared between the rings, spiroheterocyclils can be divided into mono-spiroheterocyclils, di-spiroheterocyclils, or poly-spiroheterocyclils, where spiroheterocyclils are preferably mono-spiroheterocyclils or di-spiroheterocyclils, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiroheterocyclils. Non-limiting examples of spiroheterocyclils include the following:

[0046] [ka]

[0047] The term "fused heterocyclyl" refers to a compound in which each ring in the system shares a pair of adjacent atoms with another ring, and one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system, and one or more ring atoms are N, O, and S(O). m The formula (wherein m is an integer from 0 to 2) represents a 5-20 member polycyclic heterocyclil group, where the heteroatom is selected from the group and the remaining ring atom is a carbon atom. The condensed heterocyclil is preferably a 6-14 member condensed heterocyclil, more preferably a 7-10 member condensed heterocyclil. Depending on the number of ring members, the condensed heterocyclil can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclils, and the condensed heterocyclil is preferably a bicyclic or tricyclic condensed heterocyclil, more preferably a 5-member / 5-member or 5-member / 6-member bicyclic condensed heterocyclil. Non-limiting examples of condensed heterocyclils include the following:

[0048] [ka]

[0049] The term "bridged heterocyclil" refers to a 5-14 member polycyclic heterocyclil group in which each of the two rings in the system shares two non-adjacent atoms, the rings may have one or more double bonds, but none of the rings have a fully conjugated π-electron system, one or more ring atoms are heteroatoms selected from the group consisting of N, O, and S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon atoms. Bridged heterocyclils are preferably 6-14 member bridged heterocyclils, more preferably 7-10 member bridged heterocyclils. Depending on the number of ring members, bridged heterocyclils can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclils, and bridged heterocyclils are preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclils, more preferably bicyclic or tricyclic bridged heterocyclils. Non-limiting examples of bridged heterocyclils include the following:

[0050] [ka]

[0051] The heterocyclyl ring may be fused to an aryl ring, a heteroaryl ring, or a cycloalkyl ring, in which case the ring bonded to the parent structure is a heterocyclyl. Non-restrictive examples include the following:

[0052] [ka]

[0053] The heterocyclyl may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0054] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring having a conjugated π-electron system (i.e., each ring in the system shares an adjacent pair of carbon atoms with another ring in the system), preferably a 6- to 10-membered aryl, such as phenyl and naphthyl. More preferably, the aryl is phenyl. The aryl ring may be fused to a heteroaryl ring, a heterocyclyl ring, or a cycloalkyl ring, in which case the ring bonded to the parent structure is an aryl ring. Non-limiting examples include the following:

[0055] [ka]

[0056] The aryl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0057] The term "heteroaryl" refers to a 5-14 member heteroaromatic system having 1-4 heteroatoms selected from the group consisting of O, S, and N. Heteroaryls are preferably 5-10 member heteroaryls, more preferably 5- or 6 member heteroaryls, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiadiazolyl, pyrazinyl, oxadiazolyl, etc.; preferably triazolyl, pyridyl, thienyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl, thiadiazolyl; more preferably triazolyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl. The heteroaryl ring may be fused to an aryl ring, a heterocyclyl ring, or a cycloalkyl ring, in which case the ring bonded to the parent structure is a heteroaryl ring. Non-restrictive examples include the following:

[0058] [ka]

[0059] The heteroaryl group may be substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0060] The term "alkoxy" means an -O-(alkyl) group or an -O-(unsubstituted cycloalkyl) group where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0061] "Haloalkyl" means an alkyl group substituted with one or more halogens where alkyl is as defined above.

[0062] "Haloalkoxy" means an alkoxy group substituted with one or more halogens where alkoxy is as defined above.

[0063] "Hydroxyalkyl" means an alkyl group substituted with hydroxy where alkyl is as defined above.

[0064] "Alkenyl" means an alkenyl chain also known as an alkene group, where alkenyl may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0065] "Alkynyl" means (CH≡C-), where alkynyl may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0066] "Hydroxy" refers to the -OH group.

[0067] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0068] "Amino" means -NH2.

[0069] "Cyano" means -CN.

[0070] "Nitro" means -NO2.

[0071] "Carboxylate" means -C(O)OH.

[0072] "THF" stands for tetrahydrofuran.

[0073] "¼" refers to ethyl acetate.

[0074] "MeOH" stands for methanol.

[0075] "DMF" stands for N,N-dimethylformamide.

[0076] "DIPEA" stands for diisopropylethylamine.

[0077] "TFA" stands for trifluoroacetic acid.

[0078] "MeCN" stands for acetonitrile.

[0079] "DMA" means N,N-dimethylacetamide.

[0080] "Et2O" means diethyl ether.

[0081] "DCE" means 1,2-dichloroethane.

[0082] "DIPEA" means N,N-diisopropylethylamine.

[0083] "NBS" means N-bromosuccinimide.

[0084] "NIS" means N-iodosuccinimide.

[0085] "Cbz-Cl" means benzyl chloroformate.

[0086] "Pd2(dba)3" means tris(dibenzylideneacetone)dipalladium.

[0087] "Dppf" means 1,1'-bis(diphenylphosphino)ferrocene.

[0088] "HATU" means 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0089] "KHMDS" means potassium hexamethyldisilazide.

[0090] "LiHMDS" means lithium bis(trimethylsilyl)amide.

[0091] "MeLi" means methyllithium.

[0092] "n-BuLi" means n-butyllithium.

[0093] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0094] Various expressions such as "X is selected from the group consisting of A, B, or C," "X is selected from the group consisting of A, B, and C," "X is A, B, or C," and "X is A, B, and C" all express the same meaning; that is, X can be any one or more of A, B, and C.

[0095] Any hydrogen described in this invention may be replaced with its isotope, deuterium, and any hydrogen in the compounds related to the examples of this invention may also be replaced with deuterium.

[0096] "Optional" or "optionally" means that the event or situation described below may occur but is not necessarily to occur, and this statement includes situations in which such event or situation may or may not occur. For example, "optionally substituted heterocyclyl with alkyl" means that alkyl groups may be present but are not necessarily to occur, and this statement includes situations in which the heterocyclyl is substituted with alkyl and situations in which the heterocyclyl is not substituted with alkyl.

[0097] "Substituted" means that one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, are independently replaced by a corresponding number of substituents. Needless to say, substituents exist only in their possible chemical positions. Those skilled in the art can determine, without excessive effort, whether substitution is possible or impossible experimentally or theoretically. For example, amino or hydroxyl combinations having free hydrogen atoms and free carbon atoms with unsaturated bonds (e.g., olefinic) can be unstable.

[0098] "Pharmaceutical composition" means a mixture of one or more compounds of the present invention, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to a living organism, which helps in the absorption of the active ingredient in order to exhibit biological activity.

[0099] "Pharmacologically acceptable salt" means a salt of the compound of the present invention that is safe and effective in mammals and has the desired biological activity.

[0100] Detailed description of the invention The present disclosure will be further described with reference to the following embodiments, which should not be considered to limit the scope of the present disclosure. [Examples]

[0101] The structure of the compound of the present invention was identified by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR shift (δ) was set to 10 -6 The values ​​are shown in ppm. NMR was determined using a Bruker AVANCE-400 spectrometer. The solvent used for determination was deuterated dimethyl sulfoxide (DMSO-). d 6) Deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) were used, with tetramethylsilane (TMS) as the internal standard.

[0102] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity series mass spectrometer. High-performance liquid chromatography (HPLC) was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6mm chromatography column).

[0103] Yantai Huanghai's HSGF254 or Qingdao's GF254 silica gel plates were used as thin-layer silica gel chromatography (TLC) plates. The dimensions of the silica gel plates used in TLC were 0.15 mm to 0.2 mm, and the dimensions of the silica gel plates used in product purification were 0.4 mm to 0.5 mm. Yantai Huanghai's 200-300 mesh silica gel was generally used as a support for column chromatography.

[0104] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized by or in accordance with methods known in the art.

[0105] Unless otherwise specified, all reactions of the present invention were carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, and the solvent used was a dry solvent. Reaction temperatures are expressed in degrees Celsius.

[0106] (Example 1) (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0107] [ka]

[0108] Step 1: Preparation of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine

[0109] [ka]

[0110] (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazine-2-one (0.20 g, 0.38 mmol) was dissolved in dichloroethane (1 mL), cooled to 0°C, and triethyloxidanium tetrafluoroborate (4.5 mL, 4.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Water (10 mL) was added, and the reaction mixture was stirred for half an hour until a solid precipitate formed, then filtered. The aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.2 g), which was used directly in the next step. MS m / z (ESI): 293.2 [M+H] + .

[0111] Step 2: Preparation of benzo[d]thiazole-2-carbozide

[0112] [ka]

[0113] Ethyl benzo[d]thiazole-2-carboxylate (300 mg, 1.45 mmol) was dissolved in anhydrous alcohol (10 mL), and 85% hydrazine hydrate (102 mg, 1.74 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, filtered, and dried to obtain benzo[d]thiazole-2-carbohdrazide (270 mg, yield: 96%). MS m / z (ESI): 194.2 [M+H] + .

[0114] Step 3: Preparation of (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole

[0115] [ka]

[0116] (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (200 mg, 0.68 mmol) was dissolved in ethanol (10 mL), and benzo[d]thiazole-2-carbohdrazide (120 mg, 0.62 mmol) was added. The reaction mixture was stirred overnight at 80°C and subjected to rotary evaporation until dry. The crude product was separated by column chromatography (petroleum ether / ethyl acetate: 5 / 1~1 / 2) to obtain (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (100 mg, yield: 38%). MS m / z (ESI): 422.2 [M+H] + .

[0117] Step 4: Preparation of (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole

[0118] [ka]

[0119] (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (100 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. Water (10 mL) was added, the reaction mixture was stirred for 5 minutes, and filtered. 3 M sodium hydroxide solution was added to the filtrate until the pH of the aqueous phase exceeded 14. The filtrate was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (40 mg, yield: 62%). MS m / z (ESI): 272.2 [M+H] + .

[0120] Step 5: Preparation of (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0121] [ka]

[0122] (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (40 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (23 mg, 0.23 mmol) was added, followed by 4-fluorobenzoyl chloride (28 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 hour, washed with water (10 mL), and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was purified by preparative high-performance liquid chromatography to obtain (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (25 mg, yield: 42%). MS m / z (ESI): 394.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.06 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.57 -7.45 (m, 4H), 7.27 -7.16 (m, 2H), 5.78 (br s, 1H), 5.12 (d, J = 14.6 Hz, 1H), 4.84 -4.55 (m, 1H), 4.42 -4.35 (m, 1H), 3.60 -3.54 (m, 1H), 1.77 (d, J = 6.9 Hz, 3H).

[0123] (Example 2) (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-2,3,5,6-d4)methanone

[0124] [ka]

[0125] Step 1: Preparation of 4-fluoro-2,3,5,6-d4-benzoic acid

[0126] [ka]

[0127] To a solution of p-fluorobenzoic acid (1.8 g, 12.9 mmol) in isopropanol (50 mL) and heavy water (100 mL), 10% Pd / C (0.73 g, 50% w / w water content) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100°C for 3 days, cooled, and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target product, 4-fluoro-2,3,5,6-d4-benzoic acid (1.5 g, yield: 81%). MS m / z (ESI): 143.0 [MH] -

[0128] Step 2: Preparation of (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-2,3,5,6-d4)methanone

[0129] [ka]

[0130] (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (15 mg, 55 μmol), 4-fluoro-2,3,5,6-d4-benzoic acid (10 mg, 68 μmol), and N,N-diisopropylethylamine (22 mg, 169 μmol) were dissolved in N,N-dimethylformamide (1.5 ml) to which 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32 mg, 84 μmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude product was subjected to preparative HPLC separation to obtain product (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-2,3,5,6-d4)methanone (11 mg, yield: 50%). MS m / z (ESI): 398.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.13-7.92 (m, 2H), 7.62-7.43 (m, 2H), 5.91-5.70 (m, 1H), 5.24-5.01 (m, 1H), 4.81-4.52 (m, 1H), 4.50-4.26 (m, 1H), 3.72-3.41 (m, 1H), 1.93-1.82 (m, 3H).

[0131] (Example 3) (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-chlorophenyl)methanone

[0132] [ka]

[0133] The preparation method for Example 3 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 410.2 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.06 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.58-7.40 (m, 6H), 5.93-5.73 (m, 1H), 5.13 (d, J = 13.6 Hz, 1H), 4.74-4.49 (m, 1H), 4.43-4.34 (m, 1H), 3.63-3.52 (m, 1H), 1.78 (d, J = 6.8 Hz, 3H).

[0134] (Example 4) (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(3,4-dichlorophenyl)methanone

[0135] [ka]

[0136] The preparation method for Example 4 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 444.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.07 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.62-7.47 (m, 4H), 7.33 (d, J = 8.2 Hz, 1H), 5.83 (br s, 1H), 5.16 (d, J = 13.6 Hz, 1H), 4.81-4.49 (m, 1H), 4.45-4.35 (m, 1H), 3.66-3.57 (m, 1H), 1.80 (d, J = 6.8 Hz, 3H).

[0137] (Example 5) (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-(thiene-2-yl)phenyl)methanone

[0138] [ka]

[0139] The preparation method for Example 5 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 458.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.61-7.46 (m, 4H), 7.40 (s, 1H), 7.36 (d, J = 5.1 Hz, 1H), 7.13 (s, 1H), 6.02-5.84 (m, 1H), 5.17 (d, J = 13.4 Hz, 1H), 4.78-4.62 (m, 1H), 4.51-4.40 (m, 1H), 3.69-3.56 (m, 1H), 1.86 (d, J = 6.5 Hz (3H).

[0140] (Example 6) (R)-(3-(benzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3a]pyrazine-7(8H)-yl)(phenyl-d5)methanone

[0141] [ka]

[0142] The preparation method for Example 6 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 381.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.04-7.94 (m, 2H), 7.55-7.47 (m, 2H), 5.84-5.79 (m, 1H), 5.13-5.10 (m, 1H), 4.46-4.39 (m, 2H), 3.59-3.55 (m, 1H), 1.80-1.78 (m, 3H).

[0143] (Example 7) (R)-(3-(4-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0144] [ka]

[0145] The preparation method for Example 7 was carried out in reference to Example 1. MS m / z (ESI): 412.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.75-7.73 (m, 1H), 7.52-7.43 (m, 3H), 7.22-7.16 (m, 3H), 5.86-5.80 (m, 1H), 5.15-5.12 (m, 1H), 4.65-4.39 (m, 2H), 3.60-3.55 (m, 1H), 1.78-1.75 (m, 3H).

[0146] (Example 8) (R)-(4-chlorophenyl)(3-(4-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0147] [ka]

[0148] The preparation method for Example 8 was carried out in reference to Example 1. MS m / z (ESI): 428.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.77-7.74 (m, 1H), 7.50-7.40 (m, 4H), 7.25-7.18 (m, 2H), 5.86-5.80 (m, 1H), 5.14-5.11 (m, 1H), 4.61-4.38 (m, 2H), 3.60-3.56 (m, 1H), 1.77 (d, J = 8.0 Hz, 3H).

[0149] (Example 9) (R)-(3-(5-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0150] [ka]

[0151] The preparation method for Example 9 was carried out in reference to Example 1. MS m / z (ESI): 412.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.96-7.84 (m, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.56-7.43 (m, 2H), 7.33-7.29 (m, 1H), 7.20-7.16 (m, 2H), 5.93-5.69 (m, 1H), 5.08 (d, J = 13.7 Hz, 1H), 4.76-4.48 (m, 1H), 4.41-4.30 (m, 1H), 3.66-3.49 (m, 1H), 1.78 (d, J = 6.8 Hz, 3H).

[0152] (Example 10) (R)-(4-chlorophenyl)(3-(5-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0153] [ka]

[0154] The preparation method for Example 10 was carried out in reference to Example 1. MS m / z (ESI): 428.2 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.95-7.87 (m, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.48-7.42 (m, 4H), 7.31-7.29 (m, 1H), 5.95-5.65 (m, 1H), 5.09 (d, J = 14.3 Hz, 1H), 4.73-4.48 (m, 1H), 4.40-4.33 (m, 1H), 3.64-3.48 (m, 1H), 1.78 (d, J = 6.4 Hz, 3H).

[0155] (Example 11) (R)-(3,4-dichlorophenyl)(3-(5-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0156] [ka]

[0157] The preparation method for Example 11 was carried out in reference to Example 1. MS m / z (ESI): 462.0 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.95-7.88 (m, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 9.6 Hz, 2H), 7.36-7.27 (m, 2H), 5.94-5.77 (m, 1H), 5.12 (d, J = 13.7 Hz, 1H), 4.65-4.49 (m, 1H), 4.42-4.33 (m, 1H), 3.67-3.54 (m, 1H), 1.79 (d, J = 6.7 Hz, 3H).

[0158] (Example 12) (R)-(3-(6-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0159] [ka]

[0160] Step 1: Preparation of ethyl 2-((4-fluorophenyl)amino)-2-oxoacetate

[0161] [ka]

[0162] 4-Fluoroaniline (5.0 g, 45 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0°C. Triethylamine (9.1 g, 90 mmol) was added, followed by the dropwise addition of ethyl 2-chloro-2-oxoacetate (7.4 g, 55 mmol). The reaction mixture was stirred at room temperature for 1 hour. Water (200 mL) was added, and the aqueous phase was extracted with dichloromethane (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 2-((4-fluorophenyl)amino)-2-oxoacetate (9 g, crude product 95%), which was used directly in the next step. MS m / z (ESI): 211.2 [M+H] + .

[0163] Step 2: Preparation of ethyl 2-((4-fluorophenyl)amino)-2-thioxoacetate

[0164] [ka]

[0165] Ethyl 2-((4-fluorophenyl)amino)-2-oxoacetate (5.0 g, 24 mmol) was dissolved in toluene (50 mL), and Lawson's reagent (5.74 g, 14 mmol) was added. The reaction mixture was stirred at 70°C for 2 hours. The solvent was dried by rotary evaporation, and the crude product was separated by column chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain ethyl 2-((4-fluorophenyl)amino)-2-thioxoacetate (4.0 g, yield: 100%) as a brown solid. MS m / z (ESI): 228.2 [M+H] + .

[0166] Step 3: Preparation of 6-fluorobenzo[d]thiazole-2-carboxylic acid

[0167] [ka]

[0168] Ethyl 2-((4-fluorophenyl)amino)-2-thioxoacetate (1.0 g, 4.4 mmol) was dissolved in 10 mL of 2 M aqueous sodium hydroxide solution, stirred for half an hour, and cooled to 0°C. Potassium ferricyanate (4.3 g, 13.2 mol) in 10 mL of water was added, and the reaction mixture was stirred at room temperature for 2 hours. 2 M HCl was added to adjust the pH to 1-2, and the solid precipitated. The reaction mixture was filtered, and the solid was dried to obtain a mixture of 6-fluorobenzo[d]thiazole-2-carboxylic acid and the decarboxylation product (0.8 g, yield: 95%) as a white solid. MS m / z (ESI): 196.2 [MH] - .

[0169] Step 4: Preparation of methyl 6-fluorobenzo[d]thiazole-2-carboxylate

[0170] [ka]

[0171] A mixture of 6-fluorobenzo[d]thiazole-2-carboxylic acid and the decarboxylation product (0.8 g, 4.1 mmol) was dissolved in methanol (30 mL) and cooled to 0°C. Thionyl chloride (2.4 g, 20.3 mmol) was added, and the reaction mixture was stirred at 60°C for 2 hours. The solvent was dried by rotary evaporation, and the pH was adjusted to approximately 8 by adding saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE / EA = 100 / 1 to 3 / 1) to obtain methyl 6-fluorobenzo[d]thiazole-2-carboxylate (0.24 g, yield: 28%) as a brown solid. MS m / z (ESI): 212.2 [M+H] + .

[0172] Step 5: Preparation of 6-fluorobenzo[d]thiazole-2-carbozide

[0173] [ka]

[0174] Methyl 6-fluorobenzo[d]thiazole-2-carboxylate (0.24 g, 1.1 mmol) was dissolved in anhydrous methanol (5 mL), and 85% hydrazine hydrate (0.13 g, 2.3 mmol) was added. The reaction mixture was stirred at 60°C for 1 hour until a solid precipitate formed, and then filtered. The solid was dried to obtain 6-fluorobenzo[d]thiazole-2-carbohdrazide (0.17 g, yield: 71%) as a white solid. MS m / z (ESI): 212.2 [M+H] + .

[0175] Step 6: Preparation of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine

[0176] [ka]

[0177] (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazine-2-one (0.3 g, 1.1 mmol) was dissolved in dichloroethane (8 mL) and cooled to 0°C. Triethyloxidanium tetrafluoroborate (0.86 g, 4.6 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. TLC (DCM / MeOH = 10 / 1) indicated that the reaction was complete. The reaction mixture was stopped with 2 M cold sodium hydroxide aqueous solution (30 mL). The aqueous phase was extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.3 g, 100% crude product), which was used directly in the next step.

[0178] Step 7: Preparation of (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-6-fluorobenzo[d]thiazole

[0179] [ka]

[0180] (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-(methoxymethyl)-1,2,3,6-tetrahydropyrazine (300 mg, 1.0 mmol) was dissolved in ethanol (20 mL), and 6-fluorobenzo[d]thiazole-2-carbohdrazide (173 mg, 0.83 mmol) was added. The reaction mixture was stirred overnight at 80°C and subjected to rotary evaporation until dry. The crude product was separated by column chromatography (PE / EA = 10 / 1 to 1 / 3) to obtain (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-6-fluorobenzo[d]thiazole (150 mg, yield: 42%) as a colorless colloid. MS m / z (ESI): 440.2 [M+H] + .

[0181] Step 8: Preparation of (R)-6-fluoro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole

[0182] [ka]

[0183] (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-6-fluorobenzo[d]thiazole (150 mg, 0.3 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and the reaction mixture was stirred for half an hour until a solid precipitate formed, then filtered. 4 M sodium hydroxide solution was added to adjust the pH to over 14, and the filtrate was extracted with dichloromethane (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-6-fluoro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (60 mg, yield: 61%). MS m / z (ESI): 290.2 [M+H] + .

[0184] Step 9: Preparation of (R)-(3-(6-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0185] [ka]

[0186] According to step 5 of Example 1, (R)-(3-(6-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (19.5 mg, yield: 69%) was obtained as a white solid. MS m / z (ESI): 412.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.02-7.98 (m, 1H), 7.66-7.64 (m, 1H), 7.52-7.49 (m, 2H), 7.30-7.26 (m, 1H), 7.20-7.16 (m, 2H), 5.83-5.76 (m, 1H), 5.12-5.04 (m, 1H), 4.61-4.38 (m, 2H), 3.61-3.56 (m, 1H), 1.80-1.76 (m, 3H).

[0187] (Example 13) (R)-(4-chlorophenyl)(3-(6-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0188] [ka]

[0189] The preparation of Example 13 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 428.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.01-7.98 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.48-7.42 (m, 4H), 7.29-7.27 (m, 1H), 5.85-5.76 (m, 1H), 5.08-5.05 (m, 1H), 4.58-4.32 (m, 2H), 3.59-3.55 (m, 1H), 1.76 (d, J = 8.0 Hz, 3H).

[0190] (Example 14) (R)-(3,4-dichlorophenyl)(3-(6-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0191] [ka]

[0192] The preparation of Example 14 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 462.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.99-7.97 (m, 1H), 7.64-7.60 (m, 3H), 7.33-7.27 (m, 2H), 5.82-5.75 (m, 1H), 5.12-5.05 (m, 1H), 4.63-4.36 (m, 2H), 3.62-3.57 (m, 1H), 1.78-1.76 (m, 3H).

[0193] (Example 15) (R)-(3-(4,6-difluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0194] [ka]

[0195] The preparation of Example 15 was carried out in reference to Example 12. MS m / z (ESI): 430.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.52-7.46 (m, 3H), 7.20-7.16 (m, 2H), 7.08-7.04 (m, 1H), 5.85-5.80 (m, 1H), 5.09-5.05 (m, 1H), 4.61-4.37 (m, 2H), 3.62-3.55 (m, 1H), 1.78-1.76 (m, 3H).

[0196] (Example 16) (R)-(4-chlorophenyl)(3-(4,6-difluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0197] [ka]

[0198] The preparation of Example 16 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 446.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.48-7.41 (m, 5H), 7.08-7.04 (m, 1H), 5.84-5.80 (m, 1H), 5.10-5.07 (m, 1H), 4.66-4.36 (m, 2H), 3.61-3.54 (m, 1H), 1.77 (d, J = 4.0 Hz, 3H).

[0199] (Example 17) (R)-(3-(5,6-difluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0200] [ka]

[0201] Step 1: Ethyl 2-oxo-2-((2,4,5-trifluorophenyl)amino)acetate

[0202] [ka]

[0203] 2,4,5-trifluoroaniline (6.6 g, 44.87 mmol) and triethylamine (13.62 g, 134.60 mmol, 18.77 mL) were dissolved in dichloromethane (100 mL), and ethyl 2-chloro-2-oxoacetate (7.35 g, 53.84 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 0°C for 20 minutes. The reaction was stopped with saturated brine (100 mL). The mixture was separated into two phases. The organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product ethyl 2-oxo-2-((2,4,5-trifluorophenyl)amino)acetate (10.4 g, yield: 93.78%) as a bright yellow solid, which was used directly in the next step. MS m / z (ESI): 248.0 [M+H] + .

[0204] Step 2: Ethyl 2-thioxo-2-((2,4,5-trifluorophenyl)amino)acetate

[0205] [ka]

[0206] Ethyl 2-oxo-2-((2,4,5-trifluorophenyl)amino)acetate (10.4 g, 42.08 mmol) was dissolved in xylene (150 mL), and Lawson's reagent (10.21 g, 25.25 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 110 °C for 1 hour. LC-MS showed the formation of the reaction product, and the reaction solution was used directly in the next step. MS m / z (ESI): 264.0 [M+H] + .

[0207] Step 3: Ethyl 5,6-difluorobenzo[d]thiazole-2-carboxylate

[0208] [ka]

[0209] The reaction mixture from the previous step was cooled, and cesium carbonate (24.75 g, 75.98 mmol) was added. The reaction mixture was heated to 160°C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the reaction was stopped with saturated brine (100 mL). Next, ethyl acetate (100 mL) was added, and stirring was continued for 10 minutes. The mixture was filtered, and the liquid phase was extracted with ethyl acetate (75 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution: petroleum ether:ethyl acetate = 5:1) to obtain the target product ethyl 5,6-difluorobenzo[d]thiazole-2-carboxylate (3 g, yield: 32.47%). MS m / z (ESI): 244.0 [M+H] + .

[0210] Step 4: 5,6-Difluorobenzo[d]thiazole-2-carbohdrozide

[0211] [ka]

[0212] Ethyl 5,6-difluorobenzo[d]thiazole-2-carboxylate (0.58 g, 2.38 mmol) was dissolved in ethanol (10 mL), and hydrazine hydrate (210.31 mg, 3.58 mmol, 85% aqueous solution) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was filtered to obtain the solid crude product 5,6-difluorobenzo[d]thiazole-2-carbohradazide (0.375 g, yield: 68.61%), which was used directly in the next step. MS m / z (ESI): 230.0 [M+H] + .

[0213] Step 5: (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine

[0214] [ka]

[0215] (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methylpiperazine-2-one (0.6 g, 2.27 mmol) was dissolved in dichloromethane (7 mL), and triethyloxonium tetrafluoroborate (1.08 g, 5.67 mmol) was added in three portions at 10-minute intervals at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction solution was added to cold sodium hydroxide aqueous solution (2 M, 10 mL). The mixture was separated into two phases, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.65 g) as a colorless oil. This crude product was used directly in the next step. MS m / z (ESI): 293.2 [M+H] + .

[0216] Step 6: (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-5,6-difluorobenzo[d]thiazole

[0217] [ka]

[0218] (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.66 g, 2.26 mmol) and 5,6-difluorobenzo[d]thiazole-2-carbozide (0.375 g, 1.64 mmol) were dissolved in MeOH (2 mL). The mixture was stirred under a nitrogen atmosphere at 80°C for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution:dichloromethane:methanol = 100:0 to 95:5) to obtain the target product (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-5,6-difluorobenzo[d]thiazole (0.46 g, yield: 45%) as a bright yellow solid. MS m / z (ESI): 458.1 [M+H] + .

[0219] Step 7: (R)-5,6-difluoro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole

[0220] [ka]

[0221] (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-5,6-difluorobenzo[d]thiazole (110 mg, 0.24 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was evaporated under reduced pressure until dry, and then water (7 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then filtered to remove the solid. 2N sodium hydroxide aqueous solution was added to the liquid phase to adjust the pH to 13, and then the liquid phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (R)-5,6-difluoro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (46 mg, yield: 62%). MS m / z (ESI): 308.0 [M+H] + .

[0222] Step 8: (R)-(3-(5,6-difluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0223] [ka]

[0224] (R)-5,6-difluoro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (46 mg, 0.15 mmol) and triethylamine (45 mg, 0.45 mmol) were dissolved in dichloromethane (5 mL), and p-fluorobenzoyl chloride solution (36 mg, 0.22 mmol) was added. The mixture was stirred at 25°C for 20 minutes. The reaction mixture was evaporated until dry, and the crude product was separated by preparative HPLC to obtain the product (31 mg, yield: 48%). MS m / z (ESI): 430.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.88-7.79 (m, 1H), 7.79-7.70 (m, 1H), 7.55-7.46 (m, 2H), 7.22-7.13 (m, 2H), 5.94-5.63 (m, 1H), 5.13-4.98 (m, 1H), 4.84-4.44 (m, 1H), 4.44-4.25 (m, 1H), 3.66-3.46 (m, 1H), 1.82-1.71 (m, 3H).

[0225] (Example 18) (R)-(3-(5,7-difluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0226] [ka]

[0227] The preparation of Example 18 was carried out in reference to Example 17. MS m / z (ESI): 429.8 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.62-7.55 (m, 1H), 7.53-7.46 (m, 2H), 7.18 (t, 2H), 7.04 (td, J = 9.1, 2.1 Hz, 1H), 5.96-5.64 (m, 1H), 5.05 (d, J = 13.6 Hz, 1H), 4.80-4.48 (m, 1H), 4.44-4.32 (m, 1H), 3.70-3.52 (m, 1H), 1.79 (d, J = 6.8 Hz, 3H).

[0228] (Example 19) (R)-(3-(6-chlorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0229] [ka]

[0230] Step 1: Preparation of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine

[0231] [ka]

[0232] (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazine-2-one (0.20 g, 0.38 mmol) was dissolved in dichloroethane (1 mL), cooled to 0°C, and triethyloxidanium tetrafluoroborate (4.5 mL, 4.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, and water (10 mL) was added. The reaction mixture was stirred for half an hour until solid precipitate formed, and then filtered. The aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.2 g), which was used directly in the next step. MS m / z (ESI): 293.2 [M+H] + .

[0233] Step 2: Preparation of 6-chlorobenzo[d]thiazole-2-carbonitrile

[0234] [ka]

[0235] 6-chlorobenzo[d]thiazole-2-amine (5 g, 27 mmol) and cuprous cyanide (2.9 g, 32.5 mmol) were added to acetonitrile (60 mL), followed by the addition of isoamyl nitrite (4.8 g, 41 mmol). The reaction mixture was maintained at 60°C for 3 hours, then cooled to room temperature and filtered. The filtration cake was washed with ethyl acetate. The resulting solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain the product 6-chlorobenzo[d]thiazole-2-carbonitrile (1 g, yield: 19%). 1 ¹H NMR (400 MHz, chloroform-d): δ 8.15 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.63 (d, J = 8.9 Hz, 1H).

[0236] Step 3: Preparation of methyl 6-chlorobenzo[d]thiazole-2-carboxylate

[0237] [ka]

[0238] 6-chlorobenzo[d]thiazole-2-carbonitride (1 g, 5.2 mmol) was dissolved in methanol (20 mL), and potassium carbonate (2.2 g, 15.6 mmol) was added. The reaction mixture was kept at room temperature for 16 hours, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain the product, methyl 6-chlorobenzo[d]thiazole-2-carboxylate (380 mg, yield: 32%). 1 ¹H NMR (400 MHz, chloroform-d): δ 8.03 (d, J = 8.9 Hz, 1H), 7.93 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 4.05 (s, 3H).

[0239] Step 4: Preparation of 6-chlorobenzo[d]thiazole-2-carbozide

[0240] [ka]

[0241] Methyl 6-chlorobenzo[d]thiazole-2-carboxylate (380 mg, 1.7 mmol) was dissolved in ethanol (10 mL), and 85% hydrazine hydrate (118 mg, 2 mmol) was added. The reaction mixture was kept at room temperature for 3 hours, filtered, and dried to obtain the product 6-chlorobenzo[d]thiazole-2-carbohdrazide (300 mg, yield: 78%). MS m / z (ESI): 227.8 [M+H] + .

[0242] Step 5: Preparation of (R)-6-chloro-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole

[0243] [ka]

[0244] 6-chlorobenzo[d]thiazole-2-carbohydrazide (150 mg, 0.66 mmol) and (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (200 mg, 0.68 mmol) were added to ethanol (10 mL). The reaction mixture was maintained at 80°C for 16 hours, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 1:1:1:1-1:2-2) to obtain the product (R)-6-chloro-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (150 mg, yield: 48%). MS m / z (ESI): 455.8 [M+H] + .

[0245] Step 6: Preparation of (R)-6-chloro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole

[0246] [ka]

[0247] (R)-6-chloro-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (150 mg, 0.33 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was kept at room temperature for 1 hour, and water (5 mL) was added. The reaction mixture was stirred for 5 minutes and filtered. The pH of the filtrate was adjusted to above 7, and the filtrate was extracted with DCM (5 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (R)-6-chloro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (70 mg, yield: 70%). MS m / z (ESI): 306.2 [M+H] + .

[0248] Step 7: Preparation of (R)-(3-(6-chlorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0249] [ka]

[0250] (R)-6-chloro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (30 mg, 0.1 mmol) was dissolved in dichloromethane (1 mL), and triethylamine (15 mg, 0.15 mmol) and p-fluorobenzoyl chloride (19 mg, 0.12 mmol) were added. The reaction mixture was kept at room temperature for 1 hour, the solvent was removed by rotational evaporation, and the product was purified by preparative HPLC to obtain (R)-(3-(6-chlorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (7.9 mg, yield: 19%). MS m / z (ESI): 427.8 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.99-7.91 (m, 2H), 7.55-7.45 (m, 3H), 7.18 (t, J = 8.0 Hz, 2H), 5.90-5.64 (m, 1H), 5.07 (d, J = 12.3 Hz, 1H), 4.82-4.57 (m, 1H), 4.42-4.31 (m, 1H), 3.61-3.52 (m, 1H), 1.77 (d, J = 6.7 Hz, 3H).

[0251] (Example 20) (R)-(3-(6-chlorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-chlorophenyl)methanone

[0252] [ka]

[0253] The preparation of Example 20 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 444.0 [M+H] + .

[0254] (Example 21) (R)-2-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-6-carbonil

[0255] [ka]

[0256] Step 1: Preparation of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine

[0257] [ka]

[0258] (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazine-2-one (0.5 g, 1.1 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, and triethyloxidanium tetrafluoroborate (1.44 g, 7.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. TLC (DCM / MeOH = 10 / 1) indicated that the reaction was complete. The reaction mixture was stopped with 2 M cold sodium hydroxide aqueous solution (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.5 g, 90% crude product), which was used directly in the next step.

[0259] Step 2: Preparation of 6-bromobenzo[d]thiazole-2-carbozide

[0260] [ka]

[0261] Methyl 6-bromobenzo[d]thiazole-2-carboxylate (0.2 g, 0.7 mmol) was dissolved in anhydrous methanol (5 mL), and 85% hydrazine hydrate (78 mg, 0.8 mmol) was added. The reaction mixture was stirred at 60°C for 1 hour until a solid precipitate formed, and the solvent was removed by rotary evaporation to obtain 6-bromobenzo[d]thiazole-2-carbohdrazide (0.2 g, yield: 100%) as a white solid.

[0262] Step 3: Preparation of (R)-6-bromo-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole

[0263] [ka]

[0264] (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-(methoxymethyl)-1,2,3,6-tetrahydropyrazine (500 mg, 1.7 mmol) was dissolved in methanol (20 mL), and 6-bromobenzo[d]thiazole-2-carbohdrazide (200 mg, 0.74 mmol) was added. The reaction mixture was stirred overnight at 65°C and subjected to rotary evaporation until dry. The crude product was separated by column chromatography (PE / EA = 10 / 1 to 1 / 3) to obtain (R)-6-bromo-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (200 mg, yield: 54%) as a colorless colloid. MS m / z (ESI): 502.2 / 500.2 [M+H] + .

[0265] Step 4: Preparation of (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-6-carbonitrile

[0266] [ka]

[0267] (R)-6-bromo-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole (100 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (3 mL), and zinc cyanide (94 mg, 0.8 mmol) and tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) were added. The reaction system was purged with nitrogen (×3), and the reaction mixture was stirred in a microwave at 100°C for 1 hour. Water (20 mL) was added, and the reaction mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative TLC to obtain (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-6-carbonitrile (90 mg, yield: 99%) as a colorless colloid. MS m / z (ESI): 447.2 [M+H] + .

[0268] Step 5: Preparation of (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-6-carbonitrile

[0269] [ka]

[0270] (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-6-carbonitrile (90 mg, 0.2 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and the reaction mixture was stirred for half an hour until a solid precipitate formed, after which it was filtered. 4 M sodium hydroxide solution was added to adjust the pH of the filtrate to over 14, and the filtrate was extracted with dichloromethane (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-6-carbonitrile (60 mg, yield: 99%). MS m / z (ESI): 297.2 [M+H] + .

[0271] Step 6: Preparation of (R)-2-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-6-carbonitrile

[0272] [ka]

[0273] According to step 5 of Example 1, (R)-2-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-6-carbonitrile (49 mg, yield: 58%) was obtained as a white solid. MS m / z (ESI): 419.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.52-7.48 (m, 2H), 7.20-7.16 (m, 2H), 5.80-5.76 (m, 1H), 5.10-5.06 (m, 1H), 4.64-4.36 (m, 2H), 3.61-3.55 (m, 1H), 1.78 (d, J = 8.0 Hz, 3H).

[0274] (Example 22) (R)-(4-fluorophenyl)(8-methyl-3-(4-methylbenzo[d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0275] [ka]

[0276] The preparation of Example 22 was carried out in reference to Example 17. MS m / z (ESI): 407.8 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.80 (d, J = 7.4 Hz, 1H), 7.56-7.45 (m, 2H), 7.43-7.31 (m, 2H), 7.23-7.13 (m, 2H), 5.75 (br s, 1H), 5.12 (d, J = 12.5 Hz, 1H), 4.80-4.60 (m, 1H), 4.48-4.32 (m, 1H), 3.67-3.48 (m, 1H), 2.76 (s, 3H), 1.78 (s, 3H).

[0277] (Example 23) (R)-(4-chlorophenyl)(8-methyl-3-(4-methylbenzo[d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0278] [ka]

[0279] The preparation of Example 23 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 423.8 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.82 (d, J = 7.3 Hz, 1H), 7.51-7.46 (m, 3H), 7.46-7.40 (m, 2H), 7.39-7.36 (m, 1H), 5.95-5.87 (m, 1H), 5.24-5.17 (m, 1H), 4.74-4.65 (m, 1H), 4.52-4.45 (m, 1H), 3.69-3.63 (m, 1H), 2.77 (s, 3H), 2.12 (m, 3H).

[0280] (Example 24) (R)-(4-fluorophenyl)(8-methyl-3-(6-methylbenzo[d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0281] [ka]

[0282] The preparation of Example 24 was carried out by referring to Example 17. MS m / z (ESI): 408.1[M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ values: 7.99-7.88 (m, 1H), 7.82-7.73 (m, 1H), 7.62-7.42 (m, 2H), 7.40-7.31 (m, 1H), 7.23-7.07 (m, 2H), 5.98-5.61 (m, 1H), 5.27-5.00 (m, 1H), 4.79-4.52 (m, 1H), 4.48-4.29 (m, 1H), 3.74-3.39 (m, 1H), 2.53 (s, 3H), 1.98-1.85 (m, 3H).

[0283] (Example 25) (R)-(4-chlorophenyl)(8-methyl-3-(6-methylbenzo[d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0284] [ka]

[0285] The preparation of Example 25 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 424.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.95-7.86 (m, 1H), 7.79-7.70 (m, 1H), 7.51-7.37 (m, 4H), 7.37-7.29 (m, 1H), 6.01-5.48 (m, 1H), 5.15-5.00 (m, 1H), 4.84-4.44 (m, 1H), 4.44-4.19 (m, 1H), 3.66-3.41 (m, 1H), 2.52 (s, 3H), 1.75 (d, J = 6.8 Hz, 3H).

[0286] (Example 26) (R)-(3,4-dichlorophenyl)(8-methyl-3-(6-methylbenzo[d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0287] [ka]

[0288] The preparation of Example 26 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 458.0[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.96-7.85 (m, 1H), 7.80-7.69 (m, 1H), 7.64-7.51 (m, 2H), 7.41-7.28 (m, 2H), 6.04-5.51 (m, 1H), 5.23-5.00 (m, 1H), 4.84-4.42 (m, 1H), 4.43-4.23 (m, 1H), 3.74-3.44 (m, 1H), 2.52 (s, 3H), 1.82-1.75 (m, 3H).

[0289] (Example 27) (R)-(4-fluorophenyl)(8-methyl-3-(7-methylbenzo[d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0290] [ka]

[0291] The preparation of Example 27 was carried out in reference to Example 17. MS m / z (ESI): 408.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 8.4 Hz, 3H), 7.32 (t, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 5.98-5.66 (br, 1H), 5.19-5.04 (m, 1H), 4.80-4.45 (br, 1H), 4.45-4.31 (m, 1H), 3.66-3.49 (m, 1H), 2.63(s, 3H), 1.78 (d, J = 6.4 Hz, 3H).

[0292] (Example 28) (R)-(4-chlorophenyl)(8-methyl-3-(7-methylbenzo[d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0293] [ka]

[0294] The preparation of Example 28 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 424.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 6.04-5.58 (br, 1H), 5.14-5.08 (m, 1H), 4.92-4.51 (br, 1H), 4.43-4.31 (m, 1H), 3.63-3.48 (br, 1H), 2.53(s, 3H), 1.76 (d, J = 6.4 Hz, 3H).

[0295] (Example 29) (R)-(4-fluorophenyl)(3-(6-methoxybenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0296] [ka]

[0297] The preparation of Example 29 was carried out by referring to Example 12. MS m / z (ESI): 424.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.97-7.87 (m, 1H), 7.58-7.43 (m, 2H), 7.42-7.34 (m, 1H), 7.22-7.06 (m, 3H), 5.92-5.67 (m, 1H), 5.17-4.96 (m, 1H), 4.73-4.47 (m, 1H), 4.46-4.26 (m, 1H), 3.91 (s, 3H), 3.67-3.42 (m, 1H), 1.85-1.70 (m, 3H).

[0298] (Example 30) (R)-(4-chlorophenyl)(3-(6-methoxybenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0299] [ka]

[0300] The preparation of Example 30 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 440.1[M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 7.96-7.85 (m, 1H), 7.53-7.32 (m, 5H), 7.18-7.06 (m, 1H), 5.98-5.60 (m, 1H), 5.14-4.98 (m, 1H), 4.82-4.44 (m, 1H), 4.42-4.25 (m, 1H), 3.91 (s, 3H), 3.66-3.44 (m, 1H), 1.75 (d, J = 6.9 Hz, 3H).

[0301] (Example 31) (R)-(3,4-dichlorophenyl)(3-(6-methoxybenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0302] [ka]

[0303] The preparation of Example 31 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 474.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.95-7.86 (m, 1H), 7.64-7.49 (m, 2H), 7.42-7.36 (m, 1H), 7.35-7.28 (m, 1H), 7.19-7.05 (m, 1H), 5.95-5.60 (m, 1H), 5.20-4.98 (m, 1H), 4.75-4.41 (m, 1H), 4.44-4.19 (m, 1H), 3.99-3.79 (m, 3H), 3.69-3.37 (m, 1H), 1.94-1.80 (m, 3H).

[0304] (Example 32) (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[5,4-b]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0305] [ka]

[0306] The preparation of Example 32 was carried out in reference to Example 17. MS m / z (ESI): 395.0[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (m, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.63-7.60 (m, 1H), 7.55 ( m, 2H), 7.28 (t, J = 8.4 Hz, 2H), 5.84-5.51 (br, 1H), 4.78 (d, J = 12.8 Hz, 1H), 4.37-4.31 (m, 1H), 4.05-3.87 (br, 1H), 3.66-3.58 (m, 1H), 1.57 (d, J = 6.4 Hz, 3H).

[0307] (Example 33) (R)-(4-chlorophenyl)(8-methyl-3-(thiazolo[5,4-b]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0308] [ka]

[0309] The preparation of Example 33 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 411.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.75-8.70 (m, 1H), 8.50 (d, J = 8.4 Hz, 1H), 7.71-7.68 (m, 1H), 7.59 ( s, 4H), 5.93-5.58 (br, 1H), 4.82 (d, J = 14.8 Hz, 1H), 4.48-4.34 (m, 1H), 4.13-3.88 (br, 1H), 3.78-3.68 (br, 1H), 1.65 (d, J = 6.8 Hz, 3H).

[0310] (Example 34) (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[4,5-c]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0311] [ka]

[0312] The preparation of Example 34 was carried out with reference to Example 17. MS m / z (ESI): 395.1 [M+H] + .

[0313] (Example 35) (R)-(4-chlorophenyl)(8-methyl-3-(thiazolo[4,5-c]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0314] [ka]

[0315] The preparation of Example 35 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 411.1[M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 9.39 (s, 1H), 8.72-8.44 (m, 1H), 8.11-7.83 (m, 1H), 7.64-7.33 (m, 4H), 6.01-5.51 (m, 1H), 5.19-4.94 (m, 1H), 4.80-4.43 (m, 1H), 4.45-4.24 (m, 1H), 3.70-3.40 (m, 1H), 1.78 (d, J = 6.9 Hz, 3H).

[0316] (Example 36) (R)-(3,4-dichlorophenyl)(8-methyl-3-(thiazolo[4,5-c]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0317] [ka]

[0318] The preparation of Example 36 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 445.0[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 9.40 (s, 1H), 8.72-8.57 (m, 1H), 8.16-8.01 (m, 1H), 7.68-7.52 (m, 2H), 7.41-7.29 (m, 1H), 6.01-5.51 (m, 1H), 5.19-4.94 (m, 1H), 4.80-4.43 (m, 1H), 4.45-4.24 (m, 1H), 3.70-3.40 (m, 1H), 1.78 (d, J = 6.9 Hz, 3H).

[0319] (Example 37) (R)-(3-(6-chlorothiazolo[4,5-c]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0320] [ka]

[0321] Step 1: Ethyl 2-((4,6-dichloropyridine-3-yl)amino)-2-oxoacetate

[0322] [ka]

[0323] 4,6-Dichloropyridine-3-amine (4.5 g, 27.6 mmol) and triethylamine (7.7 mL, 56.2 mmol) were dissolved in dichloromethane (150 mL), and ethyl 2-chloro-2-oxoacetate (4.5 g, 33.1 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 0°C for 20 minutes, and the reaction was stopped with saturated brine (100 mL). The mixture was then separated into two phases. The organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product, ethyl 2-((4,6-Dichloropyridine-3-yl)amino)-2-oxoacetate (4.5 g, yield: 62%), which was used directly in the next step. MS m / z (ESI): 263.0 [M+H] + .

[0324] Step 2: Ethyl 6-chlorothiazolo[4,5-c]pyridine-2-carboxylate

[0325] [ka]

[0326] Ethyl 2-((4,6-dichloropyridine-3-yl)amino)-2-oxoacetate (2.2 g, 8.4 mmol) was dissolved in toluene (50 mL), and Lawson's reagent (2.2 g, 5.0 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 110 °C for 3 hours, and then the reaction solution was evaporated until dry. The residue was purified by silica gel flash chromatography (elution: petroleum ether:ethyl acetate = 5:1) to obtain the target product, ethyl 6-chlorothiazolo[4,5-c]pyridine-2-carboxylate (1 g, yield: 49%). MS m / z (ESI): 243.0 [M+H] + .

[0327] Step 3: 6-Chlorothiazolo[4,5-c]pyridine-2-carbohydrazide

[0328] [ka]

[0329] Ethyl 6-chlorothiazolo[4,5-c]pyridine-2-carboxylate (0.95 g, 3.9 mmol) was dissolved in ethanol (30 mL), and hydrazine hydrate (346 mg, 5.9 mmol, 85% aqueous solution) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was filtered to obtain the solid crude product 6-chlorothiazolo[4,5-c]pyridine-2-carbozide (0.5 g, yield: 69%), which was used directly in the next step. MS m / z (ESI): 229.0 [M+H] + .

[0330] Step 4: (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine

[0331] [ka]

[0332] (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methylpiperazine-2-one (0.25 g, 0.95 mmol) was dissolved in dichloromethane (3 mL), and triethyloxonium tetrafluoroborate (0.45 g, 2.38 mmol) was added in three portions at 10-minute intervals at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction solution was added to cold sodium hydroxide aqueous solution (2 M, 10 mL). The mixture was separated into two phases, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product, (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.27 g), as a colorless oil. This crude product was used directly in the next step. MS m / z (ESI): 293.2 [M+H] + .

[0333] Step 5: (R)-6-chloro-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazole-3-yl)thiazolo[4,5-c]pyridine

[0334] [ka]

[0335] (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.27 g, 0.95 mmol) and 6-chlorothiazolo[4,5-c]pyridine-2-carbohazide (184 mg, 0.8 mmol) were dissolved in MeOH (2 mL). The mixture was stirred under a nitrogen atmosphere at 80°C for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution: dichloromethane:methanol = 100:0 to 95:5) to obtain the target product, (R)-6-chloro-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)thiazolo[4,5-c]pyridine (0.4 g, yield: 85%), as a bright yellow solid. MS m / z (ESI): 457.1 [M+H] + .

[0336] Step 6: (R)-6-chloro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazole-3-yl)thiazolo[4,5-c]pyridine

[0337] [ka]

[0338] (R)-6-chloro-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)thiazolo[4,5-c]pyridine (0.4 g, 0.88 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (6 mL) was added. The mixture was stirred at 25 °C for 1 hour. After evaporating the reaction mixture under reduced pressure until dry, water (10 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then filtered to remove the solid. The liquid phase was freeze-dried to obtain the product, (R)-6-chloro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazole-3-yl)thiazolo[4,5-c]pyridinetrifluoroacetate (180 mg, yield: 67%). MS m / z (ESI): 307.0 [M+H] + .

[0339] Step 7: (R)-(3-(6-chlorothiazolo[4,5-c]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0340] [ka]

[0341] (R)-6-chloro-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazole-3-yl)thiazolo[4,5-c]pyridinetrifluoroacetate (100 mg, 0.32 mmol) and triethylamine (66 mg, 0.65 mmol) were dissolved in dichloromethane (10 mL), and p-fluorobenzoyl chloride (78 mg, 0.49 mmol) solution was added. The mixture was stirred at 25°C for 20 minutes. The reaction mixture was evaporated until dry. The crude product was separated by preparative HPLC to obtain the product (R)-(3-(6-chlorothiazolo[4,5-c]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (70 mg, yield: 50%). MS m / z (ESI): 429.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 9.11 (s, 1H), 7.95 (s, 1H), 7.55-7.44 (m, 2H), 7.23-7.14 (m, 2H), 6.02-5.63 (m, 1H), 5.12-4.99 (m, 1H), 4.81-4.46 (m, 1H), 4.46-4.32 (m, 1H), 3.68-3.49 (m, 1H), 1.78 (d, J = 6.9 Hz, 3H).

[0342] (Example 38) (R)-(3-(5-chlorothiazolo[5,4-b]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0343] [ka]

[0344] The preparation of Example 38 was carried out with reference to Example 37. MS m / z (ESI): 429.2 [M+H]+ . 1 H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.0 Hz, 1H), 7.51-7.48 (m, 3H), 7.20-7.16 (m, 2H), 5.79-5.75 (m, 1H), 5.06-5.01 (m, 1H), 4.63-4.34 (m, 2H), 3.59-3.53 (m, 1H), 1.77 (d, J = 8.0 Hz, 3H).

[0345] (Example 39) (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[4,5-d]pyridazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0346] [ka]

[0347] Step 1: Preparation of ethyl 2-((5-chloropyridazine-4-yl)amino)-2-oxoacetate

[0348] [ka]

[0349] 4-amino-5-chloropyridazine (0.63 g, 4.86 mmol) was dissolved in dichloromethane (10 mL) in an ice bath. Triethylamine (0.74 g, 7.29 mmol) was then added to the reaction system, followed by the dropwise addition of ethyl oxalyl chloride (0.73 g, 5.35 mmol). The reaction was carried out at room temperature for 3 hours, and LC-MS indicated completion of the reaction. The reaction solution was diluted with dichloromethane (20 mL) and washed with saturated brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry to obtain the crude product ethyl 2-((5-chloropyridazine-4-yl)amino)-2-oxoacetate (1.20 g, yellow solid, crude product). MS m / z (ESI): 230.0 [M+H] +

[0350] Step 2: Preparation of ethyl thiazolo[4,5-d]pyridazine-2-carboxylate

[0351] [ka]

[0352] Ethyl 2-((5-chloropyridazin-4-yl)amino)-2-oxoacetate (1.20 g, yellow solid, crude product) was dissolved in toluene (20 mL) at room temperature, and Lawson's reagent (1.27 g, 3.14 mmol) was added to the reaction system. The reaction mixture was heated to 90°C and held for 3 hours. LC-MS indicated completion of the reaction. The reaction mixture was cooled to room temperature and subjected to rotational evaporation until dry. The crude product was separated by flash column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain ethyl thiazolo[4,5-d]pyridazin-2-carboxylate (0.30 g, yellow solid, yield: 29.4%). MS m / z (ESI): 210.0 [M+H] + . 1H NMR (400 M, CDCl3) δ 9.99 (s, 2H), 4.63 (q, J = 7.2 Hz, 2H), 1.53 (t, J = 7.2 Hz, 3H).

[0353] Step 3: Preparation of thiazolo[4,5-d]pyridazine-2-carbohradide

[0354] [ka]

[0355] Ethyl thiazolo[4,5-d]pyridazine-2-carboxylate (0.30 g, 0.62 mmol) was dissolved in ethanol (5 mL) at room temperature, and then hydrazine hydrate (98%, 0.093 g, 1.86 mmol) was added to the reaction system. The reaction was carried out overnight at room temperature. LC-MS indicated completion of the reaction. The reaction mixture was filtered. The solid was washed with petroleum ether and subjected to rotary evaporation until dry to obtain thiazolo[4,5-d]pyridazine-2-carbohdrazide (0.06 g, yellow solid, yield: 49%). MS m / z (ESI): 196.0 [M+H] + .

[0356] Step 4: Preparation of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine

[0357] [ka]

[0358] (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazine-2-one (0.11 g, 0.42 mmol) was dissolved in dichloromethane (5 mL) in an ice bath, and then triethyloxonium tetrafluoroborate (0.32 g, 1.66 mmol) was added to the reaction system in several portions. The reaction mixture was stirred at room temperature for 3 hours. TLC showed completion of the reaction. The reaction mixture was added dropwise to aqueous sodium hydroxide solution (2 N, 10 mL) in an ice bath. The reaction mixture was stirred in an ice bath for 10 minutes and separated into two phases. The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation at low temperature until dry to obtain the crude product (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.17 g, colorless oil, crude product), which was used directly in the next step. MS m / z (ESI): 293.1 [M+H] + ,311.1[M+18+H] + .

[0359] Step 5: Preparation of (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)thiazolo[4,5-d]pyridazine

[0360] [ka]

[0361] Thiazolo[4,5-d]pyridazine-2-carbohdrazide (0.06 g, 0.31 mmol) was dissolved in methanol (5 mL) at room temperature, and then a methanol solution of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.17 g, 0.581 mmol, 2 mL methanol) was added dropwise to the reaction system. The reaction mixture was heated to 70°C and stirred overnight. LC-MS indicated completion of the reaction. The reaction mixture was subjected to rotary evaporation until dry. The crude product was separated by preparative thin-layer chromatography (dichloromethane:methanol = 15:1) to obtain (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)thiazolo[4,5-d]pyridazine (0.055 g, yellow solid, yield: 42%). MS m / z (ESI): 424.1 [M+H] + .

[0362] Step 6: (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)thiazolo[4,5-d]pyridazine

[0363] [ka]

[0364] (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)thiazolo[4,5-d]pyridazine (0.055 g, 0.13 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and then trifluoroacetic acid (0.5 mL) was added to the reaction system. The reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated completion of the reaction. The reaction mixture was stopped with saturated brine (10 mL), stirred at room temperature for 10 minutes until a white solid precipitated, and then filtered. The solid was washed with water. The pH of the solution was adjusted to 10-12 with aqueous sodium hydroxide solution (3 M). Next, the aqueous phase was extracted with dichloromethane (10 mL x 2) to remove organic impurities, and the resulting aqueous solution was used directly in the next reaction. MS m / z (ESI): 273.8 [M+H] + .

[0365] Step 7: Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[4,5-d]pyridazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0366] [ka]

[0367] After stirring the aqueous solution obtained in the previous step at room temperature, saturated sodium bicarbonate aqueous solution (2 mL) was added, followed by the dropwise addition of 4-fluorobenzoyl chloride (24.7 mg, 0.156 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated completion of the reaction. The reaction mixture was extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry. The residue was separated by preparative high-performance liquid chromatography and freeze-dried to obtain (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)thiazolo[4,5-d]pyridazine (9 mg, white solid, yield: 17.5%). MS m / z (ESI): 396.0[M+H] + . 1 H NMR (400 MHz, MeOD) δ 10.00 (s, 1H), 9.85 (s, 1H), 7.64-7.60 (m, 2H), 7.30-7.26 (m, 2H), 5.99-5.76 (br, 1H), 5.07-5.03 (m, 1H), 4.53-4.45 (m, 1H), 4.40-4.22 (br, 1H), 3.82-3.69 (m, 1H), 1.76 (d, J = 7.2 Hz, 3H).

[0368] (Example 40) (R)-(4-fluorophenyl)(8-methyl-3-(thieno[2,3-d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0369] [ka]

[0370] The preparation of Example 40 was carried out in reference to Example 1. MS m / z (ESI): 400.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.53-7.49 (m, 3H), 7.32-7.31 (m, 1H), 7.19-7.15 (m, 2H), 5.82-5.77 (m, 1H), 5.00-4.97 (m, 1H), 4.56-4.33 (m, 2H), 3.57-3.54 (m, 1H), 1.77-1.75 (m, 3H).

[0371] (Example 41) (R)-(4-chlorophenyl)(8-methyl-3-(thieno[2,3-d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0372] [ka]

[0373] The preparation of Example 41 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 416.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.53-7.41 (m, 5H), 7.32-7.30 (m, 1H), 5.80-5.75 (m, 1H), 5.00-4.96 (m, 1H), 4.60-4.32 (m, 2H), 3.57-3.53 (m, 1H), 1.76 (d, J = 4.0 Hz, 3H).

[0374] (Example 42) (R)-(4-fluorophenyl)(8-methyl-3-(thieno[3,2-d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3a]pyrazine-7(8H)-yl)methanone

[0375] [ka]

[0376] The preparation of Example 42 was carried out in reference to Example 1. MS m / z (ESI): 400.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.53-7.48 (m, 4H), 7.17 (t, J = 8.0 Hz , 2H), 6.03-5.50 (br, 1H), 4.98 (d, J = 12.8 Hz , 1H), 4.69-4.44 (br, 1H), 4.35-4.30 (m, 1H), 3.59-3.52 (m, 1H), 1.76 (d, J = 6.8 Hz, 3H).

[0377] (Example 43) (R)-(4-chlorophenyl)(8-methyl-3-(thieno[3,2-d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3a]pyrazine-7(8H)-yl)methanone

[0378] [ka]

[0379] The preparation of Example 43 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 415.9 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.52 (t, J = 4.8 Hz , 1H), 7.48-7.41 (m, 5H), 6.04-5.51 (br, 1H), 5.01 (d, J = 13.6 Hz , 1H), 4.85-4.44 (br, 1H), 4.35-4.28 (m, 1H), 3.58-3.52 (m, 1H), 1.76 (d, J = 6.4 Hz, 3H).

[0380] (Example 44) (R)-(3,4-dichlorophenyl)(8-methyl-3-(thieno[3,2-d]thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3a]pyrazine-7(8H)-yl)methanone

[0381] [ka]

[0382] The preparation of Example 44 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 449.9 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.59-7.53 (m, 3H), 7.48 (t, J = 4.8 Hz , 1H), 7.31 (t, J = 7.6 Hz , 1H), 6.05-5.61 (br, 1H), 5.03 (d, J = 12.0 Hz , 1H), 4.76-4.44 (br, 1H), 4.36-4.28 (m, 1H), 3.65-3.51 (br, 1H), 1.77 (d, J = 6.0 Hz, 3H).

[0383] (Example 45) (R)-(4-chlorophenyl)(8-methyl-3-(pyrazolo[1,5-a]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0384] [ka]

[0385] The preparation of Example 45 was carried out in reference to Example 1. MS m / z (ESI): 393.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.42 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.47-7.41 (m, 4H), 7.23 (s, 1H), 7.20-7.17 (m, 1H), 6.89-6.81 (m, 1H), 5.86-5.61 (m, 1H), 4.95 (d, J = 13.8 Hz, 1H), 4.78-4.49 (m, 1H), 4.36-4.24 (m, 1H), 3.60-3.48 (m, 1H), 1.75 (d, J = 5.7 Hz, 3H).

[0386] (Example 46) (R)-(3,4-dichlorophenyl)(8-methyl-3-(pyrazolo[1,5-a]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0387] [ka]

[0388] The preparation of Example 46 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 427.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.42 (d, J = 7.1 Hz, 1H), 7.63-7.56 (m, 3H), 7.31 (d, J = 8.3 Hz, 2H), 7.22-7.15 (m, 1H), 6.89-6.81 (m, 1H), 5.75 (br s, 1H), 4.97 (d, J = 14.2 Hz, 1H), 4.86-4.70 (m, 1H), 4.36-4.24 (m, 1H), 3.62-3.50 (m, 1H), 1.76 (d, J = 6.2 Hz, 3H).

[0389] (Example 47) (R)-(4-fluorophenyl)(8-methyl-3-(7-methylpyrazolo[1,5-a]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0390] [ka]

[0391] The preparation of Example 47 was carried out in reference to Example 1. MS m / z (ESI): 391.1 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.55-7.48 (m , 3H), 7.25 (s, 1H), 7.19-7.13 (m, 3H), 6.71 (t, J = 6.4 Hz, 1H), 5.84-5.51 (br, 1H), 5.00 (d, J = 14.0 Hz, 1H), 4.75-4.46 (br, 1H), 4.42-4.28 (m, 1H), 3.61-3.46 (m, 1H),2.75 (s, 3H), 1.77 (d, J = 6.4 Hz, 3H).

[0392] (Example 48) (R)-(4-chlorophenyl)(8-methyl-3-(7-methylpyrazolo[1,5-a]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0393] [ka]

[0394] The preparation of Example 48 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 407.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.8 Hz, 1H), 7.45 (q, J = 8.0 Hz, 4H), 7.31 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 6.4 Hz, 1H), 5.88-5.49 (br, 1H), 5.00 (d, J = 12.4 Hz , 1H), 4.86-4.50 (br, 1H), 4.42-4.27 (m, 1H), 3.63-3.44 (m, 1H) ,2.75 (s, 3H), 1.76 (d, J = 6.4 Hz, 3H).

[0395] (Example 49) (R)-(3,4-dichlorophenyl)(8-methyl-3-(7-methylpyrazolo[1,5-a]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0396] [ka]

[0397] The preparation of Example 49 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 441.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.17 (s, 1H), 6.93 (d, J = 6.4 Hz, 1H), 5.90-5.70 (br, 1H), 4.78 (d, J = 14.4 Hz, 1H), 4.32-4.25 (m, 1H), 3.93-3.79 (br, 1H), 3.70-3.58 (br, 1H), 2.72(s, 3H), 1.62 (d, J = 6.4 Hz, 3H).

[0398] (Example 50) (R)-(4-fluorophenyl-2,3,5,6-d4)(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazole-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3a]pyrazine-7(8H)-yl)methanone

[0399] [ka]

[0400] The preparation of Example 50 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 366.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 5.97-5.56 (m, 1H), 5.11-4.79 (m, 1H), 4.73-4.147 (m, 1H), 4.41-4.12 (m, 1H), 3.73-3.37 (m, 1H), 1.90-1.69 (m, 3H).

[0401] (Example 51) (R)-(4-chlorophenyl)(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazole-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3a]pyrazine-7(8H)-yl)methanone

[0402] [ka]

[0403] The preparation of Example 51 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 378.2 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.50-7.38 (m, 4H), 5.94-5.70 (m, 1H), 4.94 (d, J = 13.6 Hz, 1H), 4.72-4.47 (m, 1H), 4.33-4.20 (m, 1H), 3.63-3.48 (m, 1H), 1.76 (d, J = 6.3 Hz, 3H).

[0404] (Example 52) (R)-(3,4-dichlorophenyl)(8-methyl-3-(3(methyl-d3)-1,2,4-thiadiazole-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3a]pyrazine-7(8H)-yl)methanone

[0405] [ka]

[0406] The preparation of Example 52 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 412.2 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.58 (d, J = 9.3 Hz, 2H), 7.32 (d, J = 8.4 Hz, 1H), 5.81 (br s, 1H), 4.97 (d, J = 13.0 Hz, 1H), 4.65-4.44 (m, 1H), 4.35-4.23 (m, 1H), 3.64-3.50 (m, 1H), 1.79 (d, J = 6.7 Hz, 3H).

[0407] (Example 53) (R)-(8-methyl-3-(3(methyl-d3)-1,2,4-thiadiazole-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-(thien-2-yl)phenyl)methanone

[0408] [ka]

[0409] The preparation of Example 53 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 426.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.71 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.43-7.33 (m, 2H), 7.13 (s, 1H), 5.93 (br s, 1H), 4.96-4.93 (m, 1H), 4.73-4.55 (m, 1H), 4.38-4.25 (m, 1H), 3.65-3.50 (m, 1H), 1.80 (d, J = 6.9 Hz, 3H).

[0410] (Example 54) (R)-(3-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0411] [ka]

[0412] Step 1: 3-Chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole

[0413] [ka]

[0414] 3,5-dichloro-1,2,4-thiadiazole (5 g, 32.26 mmol) and tributyl(1-ethoxyvinyl) stannan (10.48 g, 29.03 mmol) were dissolved in anhydrous DMF (20 ml) and bis(triphenylphosphine)palladium dichloride (1.13 g, 1.61 mmol) was added. The reaction mixture was heated to 75 °C for 14 hours under a nitrogen atmosphere and then cooled. The reaction mixture was stopped with aqueous potassium fluoride (50 ml), and the solid was removed by filtration. The liquid phase was extracted with ethyl acetate (75 ml x 2). The organic phase was washed with saturated brine (20 ml x 6) and evaporated until dry to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 99:1) to obtain the product 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (4.3 g, yield: 70%). 1 ¹H NMR (400 MHz, chloroform-d): δ 5.52 (d, J = 3.1 Hz, 1H), 4.58 (d, J = 3.1 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H).

[0415] Step 2: Ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate

[0416] [ka]

[0417] 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (3.7 g, 19.41 mmol) in a 70 ml dioxane solution was mixed with a 35 ml aqueous solution of sodium periodate (8.30 g, 38.81 mmol). After stirring the reaction mixture for 2 minutes, potassium permanganate (460.05 mg, 2.91 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution: petroleum ether:ethyl acetate = 100:0~95:5) to obtain the target product ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate (1 g, yield: 27.03%). 1 ¹H NMR (400 MHz, chloroform-d): δ 4.54 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H).

[0418] Step 3: 3-Chloro-1,2,4-thiadiazole-5-carbohydrazide

[0419] [ka]

[0420] To a solution of ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate (0.5 g, 2.6 mmol) in ethanol (10 ml), hydrazine hydrate (229 mg, 3.89 mmol, 85% aqueous solution) was added. The reaction mixture was stirred at room temperature for 1 hour and filtered to obtain the solid product 3-chloro-1,2,4-thiadiazole-5-carbohydrazide (440 mg, yield: 95%). MS m / z (ESI): 179.0 [M+H] + .

[0421] Step 4: (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine

[0422] [ka]

[0423] (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methylpiperazine-2-one (0.6 g, 2.27 mmol) was dissolved in dichloromethane (7 mL), and triethyloxonium tetrafluoroborate (1.08 g, 5.67 mmol) was added in three portions at 10-minute intervals at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction solution was added to cold sodium hydroxide aqueous solution (2 M, 10 mL). The mixture was separated into two phases, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product, (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.65 g), as a colorless oil. This crude product was used directly in the next step. MS m / z (ESI): 293.2 [M+H] + .

[0424] Step 5: 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole

[0425] [ka]

[0426] (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.66 g, 2.26 mmol) and 3-chloro-1,2,4-thiadiazole-5-carbohydrazide (322.54 mg, 1.81 mmol) were dissolved in MeOH (2 mL). The mixture was stirred under a nitrogen atmosphere at 80°C for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution:dichloromethane:methanol = 100:0~95:5) to obtain the target product, 3-chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole (0.22 g, yield: 23.95%), as a bright yellow solid. MS m / z (ESI): 406.8 [M+H] + .

[0427] Step 6: 3-Chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole

[0428] [ka]

[0429] 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole (0.22 g, 540.69 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25°C for 1 hour. After evaporating the reaction mixture under reduced pressure until dry, water (7 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then filtered to remove the solid. The liquid phase was freeze-dried to obtain the product 3-chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole trifluoroacetate (0.2 g, yield: 99.77%). MS m / z (ESI): 257.0 [M+H] + .

[0430] Step 7: The preparation of Example 54 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 379.0[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.54-7.43 (m, 2H), 7.23-7.12 (m, 2H), 5.95-5.69 (m, 1H), 4.95-4.80 (m, 1H), 4.73-4.44 (m, 1H), 4.36-4.18 (m, 1H), 3.64-3.45 (m, 1H), 1.76 (d, J = 6.8 Hz, 3H).

[0431] (Example 55) (R)-(3-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-2,3,5,6-d4)methanone

[0432] [ka]

[0433] Step 1: 3-Chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole

[0434] [ka]

[0435] 3,5-dichloro-1,2,4-thiadiazole (5 g, 32.26 mmol) and tributyl(1-ethoxyvinyl) stannan (10.48 g, 29.03 mmol) were dissolved in anhydrous DMF (20 ml) and bis(triphenylphosphine)palladium dichloride (1.13 g, 1.61 mmol) was added. The reaction mixture was heated to 75 °C for 14 hours under a nitrogen atmosphere and then cooled. The reaction mixture was stopped with aqueous potassium fluoride (50 ml), and the solid was removed by filtration. The liquid phase was extracted with ethyl acetate (75 ml x 2). The organic phase was washed with saturated brine (20 ml x 6) and evaporated until dry to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 99:1) to obtain the product 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (4.3 g, yield: 70%). 1 ¹H NMR (400 MHz, chloroform-d): δ 5.52 (d, J = 3.1 Hz, 1H), 4.58 (d, J = 3.1 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H).

[0436] Step 2: Ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate

[0437] [ka]

[0438] 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (3.7 g, 19.41 mmol) in a 70 ml dioxane solution was mixed with a 35 ml aqueous solution of sodium periodate (8.30 g, 38.81 mmol). After stirring the reaction mixture for 2 minutes, potassium permanganate (460.05 mg, 2.91 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution: petroleum ether:ethyl acetate = 100:0~95:5) to obtain the target product, ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate (1 g, yield: 27.03%). 1 ¹H NMR (400 MHz, chloroform-d): δ 4.54 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H).

[0439] Step 3: 3-Chloro-1,2,4-thiadiazole-5-carbohydrazide

[0440] [ka]

[0441] To a solution of ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate (0.5 g, 2.6 mmol) in ethanol (10 ml), hydrazine hydrate (229 mg, 3.89 mmol, 85% aqueous solution) was added. The reaction mixture was stirred at room temperature for 1 hour and filtered to obtain the solid product 3-chloro-1,2,4-thiadiazole-5-carbohydrazide (440 mg, yield: 95%). MS m / z (ESI): 179.0 [M+H] + .

[0442] Step 4: (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine

[0443] [ka]

[0444] (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methylpiperazine-2-one (0.6 g, 2.27 mmol) was dissolved in dichloromethane (7 mL), and triethyloxonium tetrafluoroborate (1.08 g, 5.67 mmol) was added in three portions at 10-minute intervals at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction solution was added to cold sodium hydroxide aqueous solution (2 M, 10 mL). The mixture was separated into two phases, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product, (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.65 g), as a colorless oil. This crude product was used directly in the next step. MS m / z (ESI): 293.2 [M+H] + .

[0445] Step 5: 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole

[0446] [ka]

[0447] (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.66 g, 2.26 mmol) and 3-chloro-1,2,4-thiadiazole-5-carbohydrazide (322.54 mg, 1.81 mmol) were dissolved in MeOH (10 mL). The mixture was stirred under a nitrogen atmosphere at 80°C for 14 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution:dichloromethane:methanol = 100:0~95:5) to obtain the target product, 3-chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole (0.22 g, yield: 23.95%), as a bright yellow solid. MS m / z (ESI): 406.8 [M+H] + .

[0448] Step 6: 3-Chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole

[0449] [ka]

[0450] 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole (0.22 g, 540.69 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25°C for 1 hour. After evaporating the reaction mixture under reduced pressure until dry, water (7 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then filtered to remove the solid. The liquid phase was freeze-dried to obtain the product 3-chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole trifluoroacetate (0.2 g, yield: 99.77%). MS m / z (ESI): 257.0 [M+H] + .

[0451] Step 7: 4-Fluoro-2,3,5,6-d4-benzoic acid

[0452] [ka]

[0453] To a solution of p-fluorobenzoic acid (1.8 g, 12.9 mmol) in isopropanol (50 mL) and heavy water (100 mL), 10% Pd / C (0.73 g, containing 50% w / w water) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100°C for 3 days, cooled, and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target product, 4-fluoro-2,3,5,6-d4-benzoic acid (1.5 g, yield: 81%). MS m / z (ESI): 143.0 [MH] -

[0454] Step 8: (R)-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-2,3,5,6-d4)methanone

[0455] [ka]

[0456] 3-chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole trifluoroacetate (20 mg, 56 μmol), 4-fluoro-2,3,5,6-d4-benzoic acid (10 mg, 68 μmol), and N,N-diisopropylethylamine (22 mg, 169 μmol) were dissolved in N,N-dimethylformamide (1.5 ml) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (32 mg, 84 μmol). The reaction mixture was stirred at room temperature for 16 hours. The crude product was directly separated by preparative HPLC to obtain the product (R)-(3-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-2,3,5,6-d4)methanone (10 mg, yield: 46%). MS m / z (ESI): 383.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 5.97-5.68 (m, 1H), 4.94-4.81 (m, 1H), 4.74-4.39 (m, 1H), 4.37-4.20 (m, 1H), 3.64-3.46 (m, 1H), 1.76 (d, J = 6.8 Hz, 3H).

[0457] (Example 56) (R)-(3-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0458] [ka]

[0459] Synthesis of the intermediate 3-chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole:

[0460] Step 1: 3-Chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole

[0461] [ka]

[0462] 3,5-Dichloro-1,2,4-thiadiazole (5 g, 32.26 mmol) and tributyl(1-ethoxyvinyl) stannane (10.48 g, 29.03 mmol) were dissolved in anhydrous DMF (20 ml) to which bis(triphenylphosphine)palladium dichloride (1.13 g, 1.61 mmol) was added. The reaction mixture was heated to 75 °C, held under a nitrogen atmosphere for 14 hours, and then cooled. The reaction mixture was stopped with aqueous potassium fluoride solution (50 ml), and the solid was removed by filtration. The liquid phase was extracted with ethyl acetate (75 ml x 2). The organic phase was washed with saturated brine (20 ml x 6) and subjected to rotary evaporation until dry to obtain the crude product. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 99:1) to obtain the product 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (4.3 g, yield: 70%). 1¹H NMR (400 MHz, chloroform-d): δ 5.52 (d, J = 3.1 Hz, 1H), 4.58 (d, J = 3.1 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H).

[0463] Step 2: Ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate

[0464] [ka]

[0465] 3-chloro-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (3.7 g, 19.41 mmol) was dissolved in dioxane (70 ml) and sodium periodate (8.30 g, 38.81 mmol) was added in water (10 mL). After stirring the reaction mixture for 2 minutes, potassium permanganate (460.05 mg, 2.91 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution: petroleum ether:ethyl acetate = 100:0~95:5) to obtain the target product, ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate (1 g, yield: 27.03%). 1 ¹H NMR (400 MHz, chloroform-d): δ 4.54 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H).

[0466] Step 3: 3-Chloro-1,2,4-thiadiazole-5-carbohydrazide

[0467] [ka]

[0468] To a solution of ethyl 3-chloro-1,2,4-thiadiazole-5-carboxylate (0.5 g, 2.6 mmol) in ethanol (10 ml), hydrazine hydrate (229 mg, 3.89 mmol, 85% aqueous solution) was added. The reaction mixture was stirred at room temperature for 1 hour and filtered to obtain the solid product 3-chloro-1,2,4-thiadiazole-5-carbohydrazide (440 mg, yield: 95%). MS m / z (ESI): 179.0 [M+H] + .

[0469] Step 4: (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine

[0470] [ka]

[0471] (3R)-4-[(2,4-dimethoxyphenyl)methyl]-3-methylpiperazine-2-one (0.6 g, 2.27 mmol) was dissolved in dichloromethane (7 mL), and triethyloxonium tetrafluoroborate (1.08 g, 5.67 mmol) was added in three portions at 10-minute intervals at 0°C. The mixture was stirred at 25°C for 3 hours. The reaction solution was added to cold sodium hydroxide aqueous solution (2 M, 10 mL). The mixture was separated into two phases, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product, (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.65 g), as a colorless oil. This crude product was used directly in the next step. MS m / z (ESI): 293.2 [M+H] + .

[0472] Step 5: 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole

[0473] [ka]

[0474] (5R)-4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2H-pyrazine (0.66 g, 2.26 mmol) and 3-chloro-1,2,4-thiadiazole-5-carbohydrazide (322.54 mg, 1.81 mmol) were dissolved in MeOH (2 mL). The mixture was stirred under a nitrogen atmosphere at 80°C for 14 hours and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution:dichloromethane:methanol = 100:0~95:5) to obtain the target product, 3-chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole (0.22 g, yield: 23.95%), as a bright yellow solid. MS m / z (ESI): 406.8 [M+H] + .

[0475] Step 6: 3-Chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole

[0476] [ka]

[0477] 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole (0.22 g, 540.69 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25°C for 1 hour. After evaporating the reaction mixture under reduced pressure until dry, water (7 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then filtered to remove the solid. The liquid phase was freeze-dried to obtain the product 3-chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole trifluoroacetate (0.2 g, yield: 99.77%). MS m / z (ESI): 257.0 [M+H] + .

[0478] Synthesis of the intermediate 3-deuterium-4-fluorobenzoyl chloride:

[0479] Step 1: Preparation of 3-deuterium-4-fluorobenzoic acid

[0480] [ka]

[0481] 3-Bromo-4-fluorobenzoic acid (5 g, 22.83 mmol) was dissolved in sodium deuterium hydroxide solution (30 mL, 2 M in D2O), and zinc powder (5.97 g, 91.32 mmol) was added. The mixture was stirred at 25°C for 24 hours. The reaction solution was filtered to remove the solid. The pH of the aqueous phase was adjusted to 1 with 1N HCl, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product, 3-deuterium-4-fluorobenzoic acid (3 g, yield: 93.12%). MS m / z (ESI): 139.8 [MH] -

[0482] Step 2: Preparation of 3-deuterium-4-fluorobenzoyl chloride

[0483] [ka]

[0484] 3-Deuterium-4-fluorobenzoic acid (200 mg, 1.42 mmol) was dissolved in dichloromethane (5 mL), oxalyl chloride (359.77 mg, 2.83 mmol) was added, and then N,N-dimethylformamide (0.05 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue, 3-Deuterium-4-fluorobenzoyl chloride (0.22 g), was used directly in the next step.

[0485] Synthesis of the target product (R)-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone:

[0486] [ka]

[0487] 3-Chloro-5-[(8R)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole trifluoroacetate (0.35 g, 0.94 mmol) and triethylamine (286.59 mg, 2.83 mmol) were dissolved in dichloromethane (5 mL), and 3-deuterium-4-fluorobenzoyl chloride (210.89 mg, 1.32 mmol) was added. The mixture was stirred at 25°C for 20 minutes. The reaction was stopped with saturated brine (5 mL), and the mixture was separated into two phases. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography to obtain the product (R)-(3-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone (66 mg, 172.03 μmol, yield: 18.22%) as a white solid. MS m / z (ESI): 379.8 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.58-7.40 (m, 2H), 7.22-7.10 (m, 1H), 5.99-5.61 (m, 1H), 5.01-4.80 (m, 1H), 4.80-4.43 (m, 1H), 4.38-4.16 (m, 1H), 3.68-3.45 (m, 1H), 1.88-1.68 (m, 3H).

[0488] (Example 57) (R)-(3-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-chlorophenyl)methanone

[0489] [ka]

[0490] The preparation of Example 57 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 395.0[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.50-7.44 (m, 2H), 7.44-7.37 (m, 2H), 5.97-5.60 (m, 1H), 4.92-4.81 (m, 1H), 4.76-4.40 (m, 1H), 4.36-4.20 (m, 1H), 3.63-3.42 (m, 1H), 1.76 (d, J = 6.8 Hz, 3H).

[0491] (Example 58) (R)-(3-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(3,4,5-trifluorophenyl)methanone

[0492] [ka]

[0493] The preparation of Example 58 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 415.0[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.21-7.08 (m, 2H), 5.98-5.50 (m, 1H), 5.00-4.82 (m, 1H), 4.70-4.36 (m, 1H), 4.36-4.20 (m, 1H), 3.68-3.45 (m, 1H), 1.77 (d, J = 6.8 Hz, 3H).

[0494] (Example 59) (R)-(4-fluorophenyl)(3-(3-(methoxy-d3)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3a]pyrazine-7(8H)-yl)methanone

[0495] [ka]

[0496] The preparation of Example 59 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 377.8 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.56-7.41 (m, 2H), 7.22-7.11 (m, 2H), 5.97-5.65 (m, 1H), 4.95-4.78 (m, 1H), 4.65-4.41 (m, 1H), 4.34-4.21 (m, 1H), 3.62-3.43 (m, 1H), 1.76 (s, 3H).

[0497] (Example 60) (R)-(3-(3-(dimethylamino)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0498] [ka]

[0499] The preparation of Example 60 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 388.1[M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 7.55-7.42 (m, 2H), 7.23-7.09 (m, 2H), 5.97-5.50 (m, 1H), 4.99-4.80 (m, 1H), 4.80-4.48 (m, 1H), 4.40-4.10 (m, 1H), 3.64-3.42 (m, 1H), 3.24 (s, 6H), 1.76 (d, J = 6.6 Hz, 3H).

[0500] (Example 61) (R)-(3-(6-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0501] [ka]

[0502] The preparation of Example 61 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 412.9[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.55-7.42, 7.52-7.50 (m, 2H), 7.30-7.28 (m, 1H), 7.19-7.18 (m, 1H), 5.72-5.68 (m, 1H), 5.18-5.12 (m, 1H), 4.64-4.60 (m, 1H), 4.34-4.30 (m, 1H), 3.58-3.55 (m, 1H), 1.84-1.80 (m, 3H).

[0503] (Example 62) (R)-(3-(5,6-difluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0504] [ka]

[0505] The preparation of Example 62 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 431.0[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.93-7.78 (m, 1H), 7.78-7.66 (m, 1H), 7.60-7.38 (m, 2H), 7.24-7.08 (m, 1H), 6.14-5.42 (m, 1H), 5.30-4.88 (m, 1H), 4.88-4.13 (m, 2H), 3.92-3.16 (m, 1H), 1.70-1.85 (m, 3H).

[0506] (Example 63) (R)-6-fluoro-2-(7-(4-fluorobenzoyl-3-d)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-5-carbonitrile

[0507] [ka]

[0508] Step 1: Preparation of 5-amino-2,4-difluorobenzonitrile

[0509] [ka]

[0510] 2,4-difluoro-5-nitrobenzonitrile (5 g, 27.16 mmol) was dissolved in ethanol (30 mL) and water (10 mL), and iron powder (7.58 g, 135.80 mmol) and ammonium chloride (7.26 g, 135.80 mmol) were added. The reaction was carried out at 80°C for 2 hours. The reaction mixture was filtered and extracted with EA (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution:PE:EA = 10:1 to 5:1) to obtain the product 5-amino-2,4-difluorobenzonitrile (3 g, yield: 71.67%) as a yellow solid. MS m / z (ESI): 155.0 [M+H] + .

[0511] Steps 2-8 were carried out with reference to Example 37. MS m / z (ESI): 437.9 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.31 (d, J = 5.4 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.50 (s, 2H), 7.22-7.15 (m, 1H), 5.91-5.68 (m, 1H), 5.11-4.99 (m, 1H), 4.76-4.58 (m, 1H), 4.43-4.31 (m, 1H), 3.66-3.52 (m, 1H), 1.79 (s, 3H).

[0512] (Example 64) (R)-6-chloro-2-(7-(4-fluorobenzoyl-3-d)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzo[d]thiazole-5-carbonitrile

[0513] [ka]

[0514] The preparation of Example 64 was carried out with reference to Example 17. MS m / z (ESI): 454.0 [M+H] + .

[0515] (Example 65) (R)-(3-(6-aminobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0516] [ka]

[0517] The preparation of Example 65 was carried out by referring to Example 21. MS m / z (ESI): 409.8 [M+H] + .

[0518] (Example 66) (R)-(3-(6-dimethylaminobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0519] [ka]

[0520] The preparation of Example 66 was carried out in reference to Example 21. MS m / z (ESI): 437.1 [M+H] + .

[0521] (Example 67) (R)-(3-(6-aminothiazolo[4,5-c]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0522] [ka]

[0523] The preparation of Example 67 was carried out by referring to Example 21. MS m / z (ESI): 410.0 [M+H] + .

[0524] (Example 68) (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[5,4-d]pyrimidine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0525] [ka]

[0526] Step 1: Preparation of ethyl 2-((4-chloropyrimidine-5-yl)amino)-2-oxoacetate

[0527] [ka]

[0528] 4-Chloropyrimidine-5-amine (5.0 g, 38.6 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0°C. After adding triethylamine (9.8 g, 96.5 mmol), ethyl 2-chloro-2-oxoacetate (6.3 g, 46 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, water (100 mL) was added, and the aqueous phase was extracted with dichloromethane (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain ethyl 2-((4-chloropyrimidine-5-yl)amino)-2-oxoacetate (3.5 g, 39%), which was used directly in the next step. MS m / z (ESI): 230.2 [M+H] + .

[0529] Step 2: Preparation of ethyl thiazolo[5,4-d]pyrimidine-2-carboxylate

[0530] [ka]

[0531] Ethyl 2-((4-chloropyrimidine-5-yl)amino)-2-oxoacetate (3.5 g, 15 mmol) was dissolved in toluene (30 mL), and Lawson's reagent (6.2 g, 15 mmol) was added. The reaction mixture was stirred at 100 °C for 18 hours, and the solvent was removed by rotary evaporation. EA (50 mL) was added. The organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (PE / EA = 10 / 1 to 3 / 1) to obtain ethyl thiazolo[5,4-d]pyrimidine-2-carboxylate (1.8 g, yield: 54%) as an orange solid. MS m / z (ESI): 210.2 [M+H] + .

[0532] Step 3: Preparation of thiazolo[5,4-d]pyrimidine-2-carbozide

[0533] [ka]

[0534] Ethyl thiazolo[5,4-d]pyrimidine-2-carboxylate (1.8 g, 8.6 mmol) was dissolved in anhydrous methanol (10 mL), and 85% hydrazine hydrate (0.5 g, 10 mmol) was added. The reaction mixture was stirred at 25°C for 2 hours until a solid precipitate formed, and then filtered. The solid was dried to obtain thiazolo[5,4-d]pyrimidine-2-carbohradide (0.9 g, yield: 54%) as a white solid. MS m / z (ESI): 196.2 [M+H] + .

[0535] Step 4: Preparation of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine

[0536] [ka]

[0537] (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazine-2-one (0.5 g, 1.1 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, and triethyloxidanium tetrafluoroborate (1.44 g, 7.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. TLC (DCM / MeOH = 10 / 1) indicated completion of the reaction. The reaction mixture was stopped with 2 M cold sodium hydroxide aqueous solution (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.5 g, 90% crude product), which was used directly in the next step.

[0538] Step 5: Preparation of (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazole-3-yl)thiazolo[5,4-d]pyrimidine

[0539] [ka]

[0540] (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-(methoxymethyl)-1,2,3,6-tetrahydropyrazine (500 mg, 1.7 mmol) was dissolved in methanol (20 mL), and thiazolo[5,4-d]pyrimidine-2-carbohradazide (154 mg, 0.78 mmol) was added. The reaction mixture was stirred overnight at 65°C and subjected to rotary evaporation until dry. The residue was separated by column chromatography (PE / EA = 10 / 1 to 3 / 1) to obtain (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazole-3-yl)thiazolo[5,4-d]pyrimidine (240 mg, yield: 72%) as a colorless colloid. MS m / z (ESI): 424.2 [M+H] + .

[0541] Step 6: Preparation of (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazole-3-yl)thiazolo[5,4-d]pyrimidine

[0542] [ka]

[0543] (R)-2-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)thiazolo[5,4-d]pyrimidine (240 mg, 0.6 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, water (10 mL) was added, and the reaction mixture was stirred for half an hour until a solid precipitate formed, after which it was filtered. The pH of the filtrate was adjusted to above 14 with 4 M sodium hydroxide solution, and the filtrate was extracted with dichloromethane (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (R)-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazole-3-yl)thiazolo[5,4-d]pyrimidine (110 mg, yield: 71%). MS m / z (ESI): 274.2 [M+H] + .

[0544] Step 7: Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[5,4-d]pyrimidine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0545] [ka]

[0546] According to step 5 of Example 1, (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[5,4-d]pyrimidine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone (79 mg, yield: 50%) was obtained as a white solid. MS m / z (ESI): 396.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 9.20 (s, 1H), 7.52-7.49 (m, 2H), 7.21-7.16 (m, 2H), 5.83-5.79 (m, 1H), 5.07-5.04 (m, 1H), 4.66-4.37 (m, 2H), 3.62-3.56 (m, 1H), 1.79 (d, J = 4.0 Hz, 3H).

[0547] (Example 69) (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[4,5-d]pyrimidine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0548] [ka]

[0549] The preparation of Example 69 was carried out in reference to Example 17. MS m / z (ESI): 396.2 [M+H] + .

[0550] (Example 70) (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[4,5-b]pyrazine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0551] [ka]

[0552] The preparation of Example 70 was carried out with reference to Example 68. MS m / z (ESI): 396.1 [M+H] + .

[0553] (Example 71) (R)-(4-fluorophenyl)(8-methyl-3-(thiazolo[5,4-c]pyridazin-6-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0554] [ka]

[0555] The preparation of Example 71 was carried out with reference to Example 68. MS m / z (ESI): 396.1 [M+H] + .

[0556] (Example 72) (R)-(4-fluorophenyl)(8-methyl-3-(2-methyl-2H-pyrazolo[4,3-d]thiazole-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0557] [ka]

[0558] The preparation of Example 72 was carried out with reference to Example 17. MS m / z (ESI): 398.0 [M+H] + .

[0559] (Example 73) (R)-(3-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-chlorophenyl-3-d)methanone

[0560] [ka]

[0561] Step 1: Preparation of 3-deuterium-4-chlorobenzoic acid

[0562] [ka]

[0563] 3-Bromo-4-chlorobenzoic acid (5 g, 21.23 mmol) was dissolved in 2 M NaOD / D2O solution (15 mL), and zinc powder (5.55 g, 84.94 mmol) was added. The mixture was stirred at 25°C for 96 hours. The reaction solution was filtered to remove the solid. The pH of the aqueous phase was adjusted to 1 with 1 N HCl, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography to obtain the product, 3-deuterium-4-chlorobenzoic acid (1.3 g, yield: 38.85%). MS m / z (ESI): 156.0 [MH] -

[0564] Step 2: Preparation of 3-deuterium-4-chlorobenzoyl chloride

[0565] [ka]

[0566] 3-Deuterium-4-chlorobenzoic acid (0.1 g, 634.63 μmol) was dissolved in DCM (5 mL), oxalyl chloride (161.10 mg, 1.27 mmol) was added, and then DMF (0.05 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the residue of 3-Deuterium-4-chlorobenzoyl chloride (110 mg), which was used directly in the next step.

[0567] Step 3: The preparation of Example 73 was carried out with reference to Example 56. MS m / z (ESI): 395.9 [M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 7.51-7.44 (m, 1H), 7.44-7.36 (m, 2H), 6.12-5.57 (m, 1H), 4.99-4.79 (m, 1H), 4.78-4.35 (m, 1H), 4.35-4.15 (m, 1H), 3.67-3.42 (m, 1H), 1.76 (d, J = 6.9 Hz, 3H).

[0568] (Example 74) (R)-(3-(3-fluoro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0569] [ka]

[0570] The preparation of Example 74 was carried out with reference to Example 56. MS m / z (ESI): 364.1 [M+H] + .

[0571] (Example 75) (R)-(4-fluorophenyl)(3-(3-methoxy-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0572] [ka]

[0573] Step 1: Preparation of (R)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-3-methoxy-1,2,4-thiadiazole

[0574] [ka]

[0575] (R)-3-chloro-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (100 mg, 0.25 mmol) was dissolved in methanol (5 mL), and anhydrous potassium carbonate (104 mg, 0.75 mmol) was added. The reaction was carried out at 65 °C for 16 hours, and water (10 mL) was added. The reaction mixture was extracted with EA (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA=1:1) to obtain the product (R)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-3-methoxy-1,2,4-thiadiazole (70 mg, yield: 71%). MS m / z (ESI): 402.8 [M+H] + .

[0576] Step 2: Preparation of (R)-3-methoxy-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole

[0577] [ka]

[0578] (R)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-3-methoxy-1,2,4-thiadiazole (70 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour, and water (5 mL) was added. The reaction mixture was stirred for 5 minutes and filtered. The pH of the filtrate was adjusted to above 7, and the filtrate was extracted with DCM (5 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product (R)-3-methoxy-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (30 mg, yield: 70%). MS m / z (ESI): 253.0 [M+H] + .

[0579] Step 3: Preparation of (R)-(4-fluorophenyl)(3-(3-methoxy-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0580] [ka]

[0581] (R)-3-methoxy-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (30 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), and triethylamine (18 mg, 0.18 mmol) and p-fluorobenzoyl chloride (23 mg, 0.14 mmol) were added. The reaction was carried out at room temperature for 1 hour. The reaction mixture was subjected to rotary evaporation to remove the solvent, and the product was purified by preparative HPLC to obtain (R)-(4-fluorophenyl)(3-(3-methoxy-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone (26 mg, yield: 58%). MS m / z (ESI): 374.8 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.52-7.43 (m, 2H), 7.21-7.12 (m, 2H), 5.95-5.67 (m, 1H), 4.86 (dd, J = 13.6, 3.8 Hz, 1H), 4.67-4.39 (m, 1H), 4.27 (td, J = 12.9, 4.4 Hz, 1H), 4.17 (s, 3H), 3.60-3.45 (m, 1H), 1.75 (d, J = 6.9 Hz, 3H).

[0582] (Example 76) (R)-(3-(3-amino-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0583] [ka]

[0584] Step 1: Preparation of 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole

[0585] [ka]

[0586] 3-Bromo-5-chloro-1,2,4-thiadiazole (4.0 g, 19.65 mmol) and tributyl(1-ethoxyvinyl) stannan (6.39 g, 17.69 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL) at room temperature, and then bis(triphenylphosphine)palladium dichloride (0.70 mg, 0.98 mmol) was added. The reaction system was purged with nitrogen, and the reaction mixture was heated to 80°C and held for 14 hours. LC-MS indicated completion of the reaction. The reaction mixture was cooled to room temperature, and the reaction was stopped with saturated potassium fluoride solution (40 mL). The reaction mixture was stirred at room temperature for 10 minutes and filtered. The solid was washed with ethyl acetate solution (40 mL x 3). The organic phase was washed with saturated brine (20 mL x 5), dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry. The residue was purified by silica gel flash chromatography (elution: petroleum ether: ethyl acetate = 100:0 to 98:2) to obtain 3-bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (2.64 g, white solid, yield: 57%). 1 H NMR (400 M, CDCl3) δ 5.53 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 3.2 Hz, 1H), 4.02 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H).

[0587] Step 2: Preparation of ethyl 3-bromo-1,2,4-thiadiazole-5-carboxylate

[0588] [ka]

[0589] 3-Bromo-5-(1-ethoxyvinyl)-1,2,4-thiadiazole (1.10 g, 4.68 mmol) was dissolved in 1,4-dioxane (15 mL) in an ice bath. Then, a solution of sodium periodate (3.00 g, 14.04 mmol) in water (7.5 mL) (subjected to ultrasonic vibration to ensure complete dissolution of sodium periodate in water) was added, followed by potassium permanganate (295.77 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 14 hours. LC-MS indicated that the reaction was not complete, so additional sodium periodate (1.50 g, 7.02 mmol) and potassium permanganate (295.77 mg, 1.87 mmol) were added. The reaction was continued for 14 hours, and LC-MS indicated completion of the reaction. The reaction mixture was filtered, and the solid was washed with ethyl acetate (20 mL x 3). The organic phases were combined and sequentially washed with saturated sodium sulfite solution (30 mL x 3) and saturated brine (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry. The crude product was separated by silica gel flash chromatography (elution: PE:EA = 100:0~98:2) to obtain ethyl 3-bromo-1,2,4-thiadiazole-5-carboxylate (0.28 g, colorless oil, yield: 25.24%). 1 H NMR (400 MHz, CDCl3) δ 4.53 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H).

[0590] Step 3: Preparation of 3-bromo-1,2,4-thiadiazole-5-carbohydrazide

[0591] [ka]

[0592] Ethyl 3-bromo-1,2,4-thiadiazole-5-carboxylate (0.62 g, 2.62 mmol) was dissolved in ethanol (8 mL) at room temperature, and then hydrazine hydrate (146.95 mg, 2.88 mmol, purity 98%) was added dropwise. The reaction mixture was stirred overnight at room temperature, and LC-MS indicated completion of the reaction. The reaction mixture was subjected to rotary evaporation until dry to obtain 3-bromo-1,2,4-thiadiazole-5-carbohydrazide (0.55 g, bright yellow solid, yield: 94%).

[0593] Step 4: Preparation of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine

[0594] [ka]

[0595] (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazine-2-one (1.0 g, 3.78 mmol) was dissolved in dichloromethane (10 mL) in an ice bath, and triethyloxonium tetrafluoroborate (2.16 g, 11.35 mmol) was added to the reaction system in several portions. The reaction mixture was stirred at room temperature for 3 hours, and TLC showed completion of the reaction. The reaction mixture was added to aqueous sodium hydroxide solution (2 N, 10 mL) in an ice bath, stirred in an ice bath for 10 minutes, and separated into two phases. The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation at low temperature until dry to obtain the crude product (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (1.36 g, colorless oil, crude product), which was used directly in the next step. MS m / z (ESI): 293.1 [M+H] + ,311.1[M+18+H] +

[0596] Step 5: Preparation of (R)-3-bromo-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole

[0597] [ka]

[0598] 3-Bromo-1,2,4-thiadiazole-5-carbohydrazide (550 mg, 2.47 mmol) was dissolved in methanol (10 mL) at room temperature, and then a methanol (3 mL) solution of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (1.36 g, 4.65 mmol) was added dropwise. The reaction mixture was heated to 70°C and held for 14 hours, then cooled to room temperature. LC-MS indicated completion of the reaction. The reaction mixture was subjected to rotary evaporation until dry, and the residue was purified by silica gel flash chromatography (elution:dichloromethane:methanol = 100:0~98:2) to obtain (R)-3-bromo-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (0.60 g, yellow solid, yield: 53.9%). MS m / z (ESI): 450.9, 453.0 [M+H] + .

[0599] Step 6: Preparation of (R)-3-bromo-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole

[0600] [ka]

[0601] (R)-3-bromo-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (0.41 g, 0.91 mmol) was dissolved in dichloromethane (4 mL) at room temperature, and trifluoroacetic acid (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours. LC-MS indicated completion of the reaction. The reaction mixture was stopped with saturated brine. The reaction mixture was stirred at room temperature for 10 minutes until a solid precipitate formed, and then filtered. The solid was washed with water. The reaction mixture was neutralized with aqueous sodium hydroxide solution (2 N) to adjust the pH to 10-12, and then the reaction mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry to obtain (R)-3-bromo-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (0.225 g, yellow solid, yield): 82%). MS m / z (ESI): 300.9, 302.9 [M+H] + .

[0602] Step 7: Preparation of (R)-(3-bromo-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0603] [ka]

[0604] (R)-3-bromo-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (0.225 g, 0.747 mmol) was dissolved in dichloromethane (6 mL) at room temperature, then saturated sodium bicarbonate aqueous solution (2 mL) was added, followed by the dropwise addition of 4-fluorobenzoyl chloride (0.14 g, 0.897 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated completion of the reaction. The reaction mixture was diluted with dichloromethane (10 mL) and then sequentially washed with saturated sodium bicarbonate solution (10 mL x 2) and saturated brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry. The residue was separated by preparative thin-layer chromatography (PE:EA=1:1) to obtain (R)-(3-bromo-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (0.25 g, yellow solid, yield: 79%). MS m / z (ESI): 422.9, 424.9 [M+H] + .

[0605] Step 8: Preparation of tert-butyl (R)-(5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole-3-yl)carbamate

[0606] [ka]

[0607] (R)-(3-(3-bromo-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (0.075g, 0.177mmol), tert-butylcarbamate (0.042g, 0.354mmol), tris(dibenzylideneacetone)dipalladium (0.032g, 0.035mmol), sodium tert-butoxide (0.034g, 0.354mmol), and (1-diphenylphosphanyl-3,4-dimethyl-9H-xanthenyl-2-yl)-diphenylphosphan (0.041g, 0.071mmol) were dissolved in toluene (4mL). The reaction system was purged with nitrogen, the reaction mixture was heated to 100°C and maintained overnight, then cooled to room temperature. LC-MS indicated completion of the reaction. The reaction mixture was subjected to rotational evaporation until dry. The residue was dissolved in ethyl acetate (25 mL) and washed with saturated brine (15 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and subjected to rotational evaporation until dry. The residue was separated by preparative thin-layer chromatography (CH2Cl2:MeOH = 15:1) to obtain tert-butyl (R)-(5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole-3-yl)carbamate (30 mg, yellow solid, yield: 38%). MS m / z (ESI): 460.1 [M+H] + .

[0608] Step 9: Preparation of (R)-(3-(3-amino-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0609] [ka]

[0610] 30 mg, 0.067 mmol of tert-butyl (R)-(5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole-3-yl)carbamate was dissolved in 2 mL of dichloromethane at room temperature, and then 0.5 mL of trifluoroacetic acid was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. LC-MS indicated completion of the reaction. The reaction mixture was subjected to rotary evaporation until dry. The residue was dissolved in 20 mL of ethyl acetate and washed with saturated sodium bicarbonate solution (10 mL x 2) and saturated brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry. The residue was separated by preparative high-performance liquid chromatography and freeze-dried to obtain (R)-(3-(3-amino-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (15 mg, white solid, yield: 61.8%). MS m / z (ESI): 360.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.88-5.65 (br, 1H), 5.20-5.15 (br, 2H), 4.94-4.87 ( m, 1H), 4.83-4.72 (br, 1H), 4.27-4.21 (m, 1H), 3.55-3.48 (m, 1H), 1.75 (d, J = 6.8 Hz, 3H).

[0611] (Example 77) (R)-(4-fluorophenyl)(8-methyl-3-(3-(methylamino)-1,2,4-thiadiazole-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0612] [ka]

[0613] The preparation of Example 77 was carried out with reference to Example 76. MS m / z (ESI): 373.9 [M+H] + .

[0614] (Example 78) (R)-(4-fluorophenyl)(8-methyl-3-(3-(methylthio)-1,2,4-thiadiazole-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0615] [ka]

[0616] The preparation of Example 78 was carried out with reference to Example 75. MS m / z (ESI): 390.0 [M+H] + .

[0617] (Example 79) (R)-(3-ethinyl-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0618] [ka]

[0619] Step 1: Preparation of (E)-5-(2-chlorovinyl)-1,3,4-oxathiazol-2-one

[0620] [ka]

[0621] Propionylamide (1.0 g, 14.48 mmol) was dissolved in 1,2-dichloroethane (20 mL) at room temperature, and then carbonochloride thioanhydride hypochlorite (2.28 g, 17.38 mmol) was added. The reaction mixture was heated to 85°C and kept overnight, then cooled to room temperature. TLC showed completion of the reaction. The solvent was removed by rotary evaporation of the reaction mixture to obtain the crude product (E)-5-(2-chlorovinyl)-1,3,4-oxathiazole-2-one (2.0 g, yellow solid), which was used directly in the next step.

[0622] Step 2: Preparation of ethyl (E)-3-(2-chlorovinyl)-1,2,4-thiadiazole-5-carboxylate

[0623] [ka]

[0624] (E)-5-(2-chlorovinyl)-1,3,4-oxathiazol-2-one (2.0 g, yellow oily substance) was dissolved in xylene (20 mL) at room temperature, and then ethyl cyanoformate (3.63 g, 36.68 mmol) was added. The reaction mixture was heated at 140°C for 4 hours. LC-MS indicated that the reaction was not complete. The reaction mixture was cooled to room temperature, and an additional ethyl cyanoformate (1.82 g, 18.34 mmol) was added. The reaction mixture was then heated at 140°C for 14 hours and cooled to room temperature. LC-MS indicated that the reaction was complete. Xylene was removed by vacuum evacuation with an oil pump, and the residue was purified by silica gel flash chromatography (elution: petroleum ether: ethyl acetate = 100:0~97:3) to obtain the target product, ethyl (E)-3-(2-chlorovinyl)-1,2,4-thiadiazole-5-carboxylate (1.30 g, yellow solid, total yield of 2 steps: 41%). MS m / z (ESI): 218.8 [M+H] + . 1¹H NMR (400 MHz, chloroform-d): δ 7.60 (d, J = 13.6 Hz, 1H), 7.06 (d, J = 13.6 Hz, 1H), 4.50 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H).

[0625] Step 3: Preparation of (E)-3-(2-chlorovinyl)-1,2,4-thiadiazole-5-carbohydrazide

[0626] [ka]

[0627] Ethyl (E)-3-(2-chlorovinyl)-1,2,4-thiadiazole-5-carboxylate (0.22 g, 1.01 mmol) was dissolved in ethanol (5 mL) at room temperature, and then hydrazine hydrate (0.06 g, 1.21 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. LC-MS indicated completion of the reaction. The solid was precipitated, and the reaction mixture was filtered to collect the solid. The solid was dried to obtain (E)-3-(2-chlorovinyl)-1,2,4-thiadiazole-5-carbohydrazide (0.19 g, yellow solid, yield: 92%).

[0628] Step 4: Preparation of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine

[0629] [ka]

[0630] (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazine-2-one (0.38 g, 1.44 mmol) was dissolved in dichloromethane (5 mL) in an ice bath, and triethyloxonium tetrafluoroborate (0.68 g, 3.59 mmol) was added to the reaction system in several portions. The reaction mixture was stirred at room temperature for 3 hours. TLC showed completion of the reaction. The reaction mixture was added to aqueous sodium hydroxide solution (2 N, 10 mL) in an ice bath, stirred in an ice bath for 10 minutes, and separated into two phases. The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation at low temperature until dry to obtain the crude product (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.45 g, colorless oil, crude product), which was used directly in the next step. MS m / z (ESI): 293.1 [M+H] + , 311.1[M+18+H] +

[0631] Step 5: Preparation of (R,E)-3-(2-chlorovinyl)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole

[0632] [ka]

[0633] (E)-3-(2-chlorovinyl)-1,2,4-thiadiazole-5-carbohydrazide (0.19 g, 0.93 mmol) was dissolved in methanol (10 mL) at room temperature, and then a methanol (2 mL) solution of (R)-1-(2,4-dimethoxybenzyl)-5-ethoxy-6-methyl-1,2,3,6-tetrahydropyrazine (0.45 g, 1.54 mmol) was added. The reaction mixture was heated to 65 °C and maintained overnight, then cooled to room temperature. LC-MS indicated completion of the reaction. The reaction mixture was subjected to rotary evaporation until dry. The residue was separated by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to obtain (R,E)-3-(2-chlorovinyl)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (0.29 g, yellow solid, yield: 72.5%). MS m / z (ESI): 433.1 [M+H] +

[0634] Step 6: Preparation of (R)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-3-ethinyl-1,2,4-thiadiazole

[0635] [ka]

[0636] (R,E)-3-(2-chlorovinyl)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (0.13 g, 0.3 mmol) was dissolved in tetrahydrofuran (5 mL), and the reaction system was purged with nitrogen. Sodium hexamethyldisilazide (1.0 M in THF, 0.9 mL, 0.9 mmol) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. LC-MS showed the formation of the target product. The reaction mixture was stopped with saturated ammonium chloride solution (15 mL), and the solid was precipitated. The reaction mixture was filtered, the solid was washed with ethyl acetate (20 mL), and the mixture was separated into two phases. The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry to obtain (R)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-3-ethynyl-1,2,4-thiadiazole (0.09 g, brown oily substance, crude product). This crude product was used directly in the next step. MS m / z (ESI): 397.0 [M+H] + .

[0637] Step 7: Preparation of (R)-3-ethinyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole

[0638] [ka]

[0639] (R)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-3-ethynyl-1,2,4-thiadiazole (0.09 g, 0.23 mmol) was dissolved in dichloromethane (5 mL) in an ice bath, and then trifluoroacetic acid (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated completion of the reaction. The reaction mixture was stopped with saturated brine. The reaction mixture was stirred at room temperature for 10 minutes until a solid precipitate formed, and then filtered. The solid was washed with water. The reaction mixture was neutralized with aqueous sodium hydroxide solution (2 N) to adjust the pH to 10-12, and then the reaction mixture was extracted with dichloromethane (15 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry to obtain (R)-3-ethynyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (0.025 g, yellow oily substance, crude product). This crude product was used directly in the next step. MS m / z (ESI): 247.0 [M+H] +

[0640] Step 8: (R)-(3-ethinyl-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0641] [ka]

[0642] (R)-3-ethynyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (0.025 g, 0.101 mmol) was dissolved in dichloromethane (5 mL) at room temperature, then saturated sodium bicarbonate aqueous solution (2 mL) was added, followed by dropwise addition of a solution of 4-fluorobenzoyl chloride (0.019 g, 0.121 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated completion of the reaction. The reaction mixture was diluted with methylene chloride (10 mL), washed with saturated sodium bicarbonate solution (10 mL x 2), and then washed with saturated brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and subjected to rotary evaporation until dry. The residue was separated by preparative high-performance liquid chromatography and freeze-dried to obtain (R)-(3-ethynyl-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (4 mg, white solid, total yield of 3 steps: 3.6%). MS m / z (ESI): 369.1 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d): δ 7.46-7.50 (m, 2H), 7.17 (t, J = 8.4 Hz, 2H), 5.59-5.98 (br, 1H), 4.90-4.94 (m, 1H), 4.35-4.78 (br, 1H), 4.26-4.30 (m, 1H), 3.50-3.70 (m, 1H), 3.22 (s, 1H), 1.77 (d, J = 6.8 Hz, 3H).

[0643] (Example 80) (R)-(3-(5-fluoro-4-methylthiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0644] [ka]

[0645] The preparation of Example 80 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 377.0 [M+H] + .

[0646] (Example 81) (R)-(4-fluorophenyl)(3-(4-methoxythiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0647] [ka]

[0648] The preparation of Example 81 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 373.8 [M+H] + .

[0649] (Example 82) (R)-(3-(5-fluoro-4-methoxythiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0650] [ka]

[0651] The preparation of Example 82 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 392.1 [M+H] + .

[0652] (Example 83) (R)-(3-(4-dimethylamino)thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0653] [ka]

[0654] The preparation of Example 83 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 386.9 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d): δ 7.45-7.52 (m, 2H), 7.14-7.18 (m, 2H), 5.84 (s, 1H), 5.32-5.40 (m, 2H), 4.88-4.93 (m, 1H), 4.20-4.31 (m, 1H), 3.45-3.56 (m, 1H), 3.00 (s, 6H), 1.74 (d, J = 6.8 Hz, 3H).

[0655] (Example 84) (R)-(4-fluorophenyl)(8-methyl-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0656] [ka]

[0657] The preparation of Example 84 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 413.0 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 6.0 Hz, 2H), 7.16 (t, J = 8.0 Hz, 2H), 5.84-5.63 (br, 1H), 4.88 (d, J = 14.4 Hz, 1H), 4.65-4.45 ( br, 1H), 4.22 (m, 1H), 3.97-3.81 (br, 2H), 3.55-3.45 (m, 1H), 3.13-2.93 (br, 4H), 2.65 (s, 3H), 1.73 (d, J = 6.4 Hz, 3H).

[0658] (Example 85) (R)-(4-chlorophenyl)(8-methyl-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0659] [ka]

[0660] The preparation of Example 85 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 429.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.94-5.53 (br, 1H), 4.88 (d, J = 12.4 Hz, 1H), 4.58-4.48 ( m, 1H), 4.24-4.18 (m, 1H), 3.90-3.80 (m, 2H), 3.54-3.48 (m, 1H), 3.01-2.95 (m, 4H), 2.62 (s, 3H), 1.72 (d, J = 6.4 Hz, 3H).

[0661] (Example 86) (R)-(4-fluorophenyl)(3-(imidazo[2,1-b]thiazole-6-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0662] [ka]

[0663] The preparation of Example 86 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 383.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.54 (d, J = 4.0 Hz, 1H), 7.51-7.47 (m , 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 4.0 Hz, 1H),5.94-5.63 (br, 1H), 4.98 (d, J = 12.8 Hz, 1H), 4.69-4.40 (br, 1H), 4.32-4.25 (m, 1H), 3.58-3.51 (m, 1H), 1.73 (d, J = 6.8 Hz, 3H).

[0664] (Example 87) (R)-(4-chlorophenyl)(3-(6,7-dihydro-4H-pyrano[4,3-d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0665] [ka]

[0666] The preparation of Example 87 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 416.2 [M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 7.46-7.40 (m, 4H), 5.89-5.63 (m, 1H), 4.95-4.90 (m, 3H), 4.70-4.38 (m, 1H), 4.30-4.19 (m, 1H), 4.08-4.06 (m, 2H), 3.61-3.45 (m, 1H), 2.95 (s, 2H), 1.75 (d, J = 6.8 Hz, 3H).

[0667] (Example 88) (R)-(4-fluorophenyl)(8-methyl-3-(pyrazolo[1,5-a]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0668] [ka]

[0669] The preparation of Example 88 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 377.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.42 (d, J = 6.8 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.56-7.43 (m, 2H), 7.26-7.14 (m, 4H), 6.86-6.82 (m, 1H), 5.75 (br s, 1H), 4.94 (d, J = 15.1 Hz, 1H), 4.76-4.50 (m, 1H), 4.38-4.24 (m, 1H), 3.62-3.47 (m, 1H), 1.75 (d, J = 6.9 Hz, 3H).

[0670] (Example 89) (R)-(3-(1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0671] [ka]

[0672] The preparation of Example 89 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 411.2 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.65-7.58 (m, 1H), 7.58-7.49 (m, 2H), 7.20-7.15 (m, 2H), 5.80-5.66 (m, 1H), 4.71-4.57 (m, 1H), 4.47-4.34 (m, 2H), 3.92 (s, 3H), 3.79-3.71 (m, 1H), 2.43 (s, 3H), 1.82 (d, J = 6.8 Hz, 3H).

[0673] (Example 90) (R)-(4-chlorophenyl)(3-(1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0674] [ka]

[0675] The preparation of Example 90 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 427.2 [M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 7.52-7.43 (m, 4H), 7.39-7.34 (m, 1H), 5.64 (br s, 1H), 4.78-4.60 (m, 1H), 4.39-4.26 (m, 2H), 3.93 (s, 3H), 3.68-3.56 (m, 1H), 2.45 (s, 3H), 1.77 (d, J = 6.8 Hz, 3H).

[0676] (Example 91) (R)-(3,4-dichlorophenyl)(3-(1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0677] [ka]

[0678] The preparation of Example 91 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 461.2 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.62 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.43-7.33 (m, 2H), 5.67 (br s, 1H), 4.73-4.57 (m, 1H), 4.39-4.28 (m, 2H), 3.93 (s, 3H), 3.71-3.59 (m, 1H), 2.44 (s, 3H), 1.78 (d, J = 6.5 Hz, 3H).

[0679] (Example 92) (R)-(4-fluorophenyl)(3-(3-fluoropyrazolo[1,5-a]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0680] [ka]

[0681] The preparation of Example 92 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 394.8 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.28 (d, J = 7.1 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.55-7.45 (m, 2H), 7.22-7.11 (m, 3H), 6.88-6.86 (m, 1H), 5.88-5.66 (m, 1H), 4.87-4.78 (m, 1H), 4.70-4.50 (m, 1H), 4.38-4.26 (m, 1H), 3.55 (s, 1H), 1.80 (d, J = 5.2 Hz, 3H).

[0682] (Example 93) (R)-(4-fluorophenyl)(3-(imidazo[1,2-a]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0683] [ka]

[0684] The preparation of Example 93 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 377.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.64-8.62 (m, 1H), 8.28-8.26 (m, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.52-7.49 (m, 2H), 7.34-7.32 (m, 1H), 7.19-7.15 (m, 2H), 6.96-6.94 (m, 1H), 5.85-5.80 (m, 1H), 5.20-5.15 (m, 1H), 4.54-4.40 (m, 2H), 3.63-3.57 (m, 1H), 1.75-1.74 (m, 3H).

[0685] (Example 94) (R)-(4-chlorophenyl)(3-(imidazo[1,2-a]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0686] [ka]

[0687] The preparation of Example 94 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 393.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.45-8.42 (m, 1H), 8.25-8.23 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.47-7.43 (m, 3H), 7.31-7.28 (m, 2H), 6.95-6.90 (m, 1H), 5.79-5.72 (m, 1H), 5.15-5.08 (m, 1H), 4.56-4.34 (m, 2H), 3.58-3.54 (m, 1H), 1.75 (d, J = 4.0 Hz, 3H).

[0688] (Example 95) (R)-(3-(4,5-dimethylthiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0689] [ka]

[0690] The preparation of Example 95 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 372.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.50-7.45 (m, 2H), 7.18-7.15 (m, 2H), 5.78-5.75 (m, 1H), 4.96-4.92 (m, 1H), 4.57-4.25 (m, 2H), 3.55-3.50 (m, 1H), 2.43 (s, 3H), 2.37 (s, 3H), 1.77-1.75 (m, 3H).

[0691] (Example 96) (R)-(4-fluorophenyl)(8-methyl-3-(5-methylthiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0692] [ka]

[0693] The preparation of Example 96 was carried out by referring to step 5 of Example 1. MS m / z (ESI): 358.1[M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 7.55 (s, 1H), 7.52-7.42 (m, 2H), 7.21-7.09 (m, 2H), 5.87-5.58 (m, 1H), 4.98-4.82 (m, 1H), 4.71-4.35 (m, 1H), 4.32-4.13 (m, 1H), 3.59-3.42 (m, 1H), 2.55 (s, 3H), 1.74 (d, J = 6.7 Hz, 3H).

[0694] (Example 97) (R)-(4-chlorophenyl)(3-(6-chlorothiazolo[4,5-c]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0695] [ka]

[0696] The preparation of Example 97 was carried out by referring to step 7 of Example 37. MS m / z (ESI): 444.9 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.55 (s, 1H), 7.52-7.42 (m, 2H), 7.21-7.05.85-5.80 (m, 1H), 5.07-5.05 (m, 1H), 4.66-4.39 (m, 2H), 3.61-3.57 (m, 1H), 1.80-1.77 (m, 3H).

[0697] (Example 98) (R)-(3-(3-bromo-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0698] [ka]

[0699] The preparation of Example 98 was carried out by referring to step 7 of Example 76. MS m / z (ESI): 422.9, 424.9 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.44-7.53 (m, 2H), 7.16-7.20 (m, 2H), 5.78-5.98 (br, 1H), 4.82-4.95 (br, 1H), 4.48-4.67 ( br, 1H), 4.20-4.38 (br, 1H), 3.47-3.65 (br, 1H), 1.75 (d, J = 5.6 Hz, 3H).

[0700] (Example 99) (R)-(4-chlorophenyl-3-d)(3-(5,6-difluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0701] [ka]

[0702] The preparation of Example 99 was carried out by referring to step 8 of Example 17. MS m / z (ESI): 447.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ values: 7.92-7.78 (m, 1H), 7.78-7.66 (m, 1H), 7.58-7.32 (m, 3H), 6.10-5.51 (m, 1H), 5.25-4.91 (m, 1H), 4.83-4.14 (m, 2H), 3.77-3.20 (m, 1H), 1.65-1.85 (m, 3H).

[0703] (Example 100) (R)-(3-(6-chlorothiazolo[4,5-b]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0704] [ka]

[0705] The preparation of Example 100 was carried out with reference to Example 37. MS m / z (ESI): 429.0 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.72 (d, J = 2.4 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 7.47-7.51 (m, 2H), 7.16-7.20 (m, 2H), 5.77-6.02 (m, 1H), 5.10-5.15 (m, 1H), 4.48-4.48 (m, 2H), 3.54-3.62 (m, 1H), 1.77 (d, J = 6.8 Hz, 3H).

[0706] (Example 101) (R)-(4-chlorophenyl-3-d)(3-(6-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0707] [ka]

[0708] The preparation of Example 101 was carried out by referring to step 9 of Example 12. MS m / z (ESI): 429.0 [M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 8.01-7.98 (m, 1H), 7.66-7.63 (m, 1H), 7.48-7.43 (m, 3H), 7.30-7.25 (m, 1H), 5.81-5.77 (m, 1H), 5.08-5.05 (m, 1H), 4.59-4.35 (m, 2H), 3.58-3.56 (m, 1H), 1.76 (d, J = 8.0 Hz, 3H).

[0709] (Example 102) (R)-(3-(6-chlorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-chlorophenyl-3-d)methanone

[0710] [ka]

[0711] The preparation of Example 102 was carried out by referring to Example 17. MS m / z (ESI): 445.0 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.01-7.92 (m, 2H), 7.55-7.39 (m, 4H), 5.90-5.75 (m, 1H), 5.13-5.05 (m, 1H), 4.68-4.54 (m, 1H), 4.42-4.34 (m, 1H), 3.63-3.54 (m, 1H), 1.79 (d, J = 6.7 Hz, 3H).

[0712] (Example 103) (R)-(3-(6-chlorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0713] [ka]

[0714] The preparation of Example 103 was carried out with reference to Example 17. MS m / z (ESI): 428.8 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.00-7.91 (m, 2H), 7.55-7.45 (m, 3H), 7.21-7.12 (m, 1H), 5.79 (s, 1H), 5.07 (dd, J = 13.6, 3.8 Hz, 1H), 4.73-4.52 (m, 1H), 4.43-4.31 (m, 1H), 3.65-3.50 (m, 1H), 1.77 (d, J = 6.9 Hz, 3H).

[0715] (Example 104) (R)-(4-fluorophenyl)(3-(6-fluorothiazolo[4,5-b]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0716] [ka]

[0717] The preparation of Example 104 was carried out with reference to Example 17. MS m / z (ESI): 413.1 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.65 (s, 1H), 8.06 (d, J = 7.1 Hz, 1H), 7.55-7.44 (m, 2H), 7.22-7.13 (m, 2H), 5.87 (s, 1H), 5.19-5.07 (m, 1H), 4.60-4.35 (m, 2H), 3.65-3.51 (m, 1H), 1.78 (br, 3H).

[0718] (Example 105) (R)-(3-(5-chloro-6-fluorobenzo[d]thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0719] [ka]

[0720] The preparation of Example 105 was carried out with reference to Example 17. MS m / z (ESI): 447.1 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.11 (d, J = 6.5 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.53-7.46 (m, 2H), 7.21-7.15 (m, 1H), 5.81 (s, 1H), 5.09-5.01 (m, 1H), 4.69-4.57 (m, 1H), 4.41-4.33 (m, 1H), 3.63-3.54 (m, 1H), 1.78 (d, J = 6.9 Hz, 3H).

[0721] (Example 106) (R)-(3-(3-(bis(methyl-d3)amino)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0722] [ka]

[0723] Step 1: Preparation of (R)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-N,N-bis(methyl-d3)-1,2,4-thiadiazole-3-amine 3-Chloro-5-[(8R)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-3-yl]-1,2,4-thiadiazole (250 mg, 614.42 μmol) was dissolved in DMF (5 mL), and triethylamine (248.69 mg, 2.46 mmol, 342.79 μL) and bis(methyl-d3)amine hydrochloride (161.44 mg, 1.84 mmol) were added. The reaction mixture was maintained at 100°C in a microwave for 1 hour, concentrated under reduced pressure, and then purified by silica gel flash chromatography (elution:PE:EA = 1:1 to 1:4) to obtain the product (R)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-N,N-bis(methyl-d3)-1,2,4-thiadiazole-3-amine (200 mg, 474.44 μmol, yield: 77.22%) as a bright yellow solid. MS m / z (ESI): 422.0 [M+H] + .

[0724] Steps 2-3 were carried out by referring to steps 4-5 of Example 1. MS m / z (ESI): 394.0 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.53-7.44 (m, 2H), 7.21-7.13 (m, 2H), 5.71 (s, 1H), 4.86 (dd, J = 13.5, 3.8 Hz, 1H), 4.76-4.47 (m, 1H), 4.33-4.19 (m, 1H), 3.60-3.45 (m, 1H), 1.75 (d, J = 6.9 Hz, 3H).

[0725] (Example 107) (R)-(3-(3-(bis(methyl-d3)amino)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-chlorophenyl)methanone

[0726] [ka]

[0727] The preparation of Example 107 was carried out by referring to Example 106. MS m / z (ESI): 410.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.49-7.37 (m, 4H), 5.71 (s, 1H), 4.86 (dd, J = 13.5, 3.8 Hz, 1H), 4.77-4.44 (m, 1H), 4.32-4.14 (m, 1H), 3.60-3.44 (m, 1H), 1.74 (d, J = 6.9 Hz, 3H).

[0728] (Example 108) (R)-(4-fluorophenyl)(3-(6-fluorothiazolo[4,5-c]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0729] [ka]

[0730] Step 1: 4,6-difluoro-3-aminopyridine

[0731] [ka]

[0732] 2,4-difluoro-5-nitropyridine (1 g, 6.25 mmol) was dissolved in ethyl acetate (30 mL), and 10% palladium-carbon (0.1 g, 50% water content) was added under a nitrogen atmosphere. The mixture was hydrogenated at room temperature (1 atm) for 14 hours. The reaction solution was filtered to obtain an organic phase containing 4,6-difluoro-3-aminopyridine (0.81 g, 6.23 mmol) as the crude product. This organic phase was used directly in the next step. MS m / z (ESI): 131.0 [M+H] + .

[0733] Step 2: Ethyl 2-((4,6-difluoropyridine-3-yl)amino)-2-oxoacetate

[0734] [ka]

[0735] Ethyl oxalyl chloride (1.28 g, 9.34 mmol) was added to a solution of 4,6-difluoro-3-aminopyridine (0.81 g, 6.23 mmol) and triethylamine (2.6 mL, 18.7 mmol) in ethyl acetate (30 mL) under a nitrogen atmosphere at 0°C. The mixture was stirred at 0°C for 30 minutes. The reaction was stopped with saturated brine (100 mL). The mixture was separated into two phases, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product, ethyl 2-((4,6-difluoropyridine-3-yl)amino)-2-oxoacetate (1.16 g, 5.04 mmol, yield: 80.94%), as a colorless oil. MS m / z (ESI): 231.0 [M+H] + .

[0736] Step 3: Ethyl 6-fluorothiazolo[4,5-c]pyridine-2-carboxylate

[0737] [ka]

[0738] Ethyl 2-((4,6-difluoropyridine-3-yl)amino)-2-oxoacetate (1.16 g, 5.04 mmol) was dissolved in toluene (30 mL), and Lawson's reagent (1.22 g, 3.02 mmol) was added under a nitrogen atmosphere. The mixture was stirred at 110 °C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (elution: petroleum ether:ethyl acetate = 5:1) to obtain the target product, ethyl 6-fluorothiazolo[4,5-c]pyridine-2-carboxylate (0.43 g, 1.90 mmol, yield: 37.71%), as a white solid. MS m / z (ESI): 227.0 [M+H] + .

[0739] Step 4: 6-Fluorothiazolo[4,5-c]pyridine-2-carbohydrazide

[0740] [ka]

[0741] Ethyl 6-fluorothiazolo[4,5-c]pyridine-2-carboxylate (0.43 g, 1.90 mmol) was dissolved in ethanol (15 mL), and a solution of 85% hydrazine hydrate (167.64 mg, 2.85 mmol) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was filtered to obtain the solid product 6-fluorothiazolo[4,5-c]pyridine-2-carbozide (0.33 g, 1.56 mmol, yield: 81.82%) as a bright yellow solid. MS m / z (ESI): 213.0 [M+H] + .

[0742] The subsequent steps were carried out with reference to the corresponding steps in Example 1 to obtain (R)-(4-fluorophenyl)(3-(6-fluorothiazolo[4,5-c]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone.

[0743] [ka]

[0744] MS m / z (ESI): 413.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 8.95 (s, 1H), 7.56-7.44 (m, 3H), 7.24-7.09 (m, 2H), 6.07-5.58 (m, 1H), 5.19-4.94 (m, 1H), 4.80-4.46 (m, 1H), 4.46-4.26 (m, 1H), 3.78-3.35 (m, 1H), 1.78 (d, J = 6.9 Hz, 3H).

[0745] (Example 109) (R)-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole-3-carbonitrile

[0746] [ka]

[0747] (R)-(3-bromo-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (Example 98, 0.05 g, 0.118 mmol), tris(dibenzylideneacetone)dipalladium (0.011 g, 0.012 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.014 g, 0.024 mmol), zinc cyanide (0.042 g, 0.35 mmol), and zinc powder (0.015 g, 0.24 mmol) were dissolved in N,N-dimethylformamide (4 mL). The reaction system was purged with nitrogen, the reaction solution was heated to 100 °C and held overnight, and then cooled to room temperature. LC-MS indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate (25 mL), filtered, and the solid was washed with ethyl acetate. The organic phases were combined, washed with saturated brine (10 mL x 5), dried over anhydrous sodium sulfate, filtered, and subjected to rotational evaporation until dry. The residue was separated by preparative thin-layer chromatography (dichloromethane:methanol = 20:1). The crude product was then separated by preparative high-performance liquid chromatography and freeze-dried to obtain (R)-5-(7-(4-fluorobenzoyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole-3-carbonitrile (4 mg, white solid, yield: 9.2%). MS m / z (ESI): 370.0 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d): δ 7.47-7.51 (m, 2H), 7.16-7.21 (m, 2H), 5.76-5.97 (br, 1H), 4.86-4.90 (m, 1H), 4.53-4.69 (br, 1H), 4.28-4.53 (m, 1H), 3.53-3.61 (m, 1H), 1.77 (d, J = 6.8 Hz, 3H).

[0748] (Example 110) (R)-(3-(6-chlorothiazolo[5,4-c]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0749] [ka]

[0750] The preparation of Example 110 was carried out with reference to Example 37. MS m / z (ESI): 429.0 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 9.07 (s, 1H), 7.98 (s, 1H), 7.52-7.49 (m, 2H), 7.21-7.13 (m, 2H), 5.86-5.82 (m, 1H), 5.07-5.04 (m, 1H), 4.63-4.39 (m, 2H), 3.60-3.57 (m, 1H), 1.80-1.79 (m, 3H).

[0751] (Example 111) (R)-(4-fluorophenyl)(8-methyl-3-(6-methylthiazolo[4,5-c]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0752] [ka]

[0753] The preparation of Example 111 was carried out with reference to Example 37. MS m / z (ESI): 409.0 [M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 9.27 (s, 1H), 7.85 (s, 1H), 7.51-7.49 (m, 2H), 7.18-7.16 (m, 2H), 5.84-5.81 (m, 1H), 5.09-5.06 (m, 1H), 4.62-4.39 (m, 2H), 3.60-3.58 (m, 1H), 2.81 (s, 3H), 1.78 (d, J = 8.0 Hz, 3H).

[0754] (Example 112) (R)-(4-fluorophenyl)(3-(3-(isopropyl(methyl)amino)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0755] [ka]

[0756] The preparation of Example 112 was carried out with reference to Example 106. MS m / z (ESI): 416.0 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.52-7.45 (m, 2H), 7.21-7.14 (m, 2H), 5.71 (s, 1H), 4.89-4.82 (m, 1H), 4.78-4.60 (m, 2H), 4.34-4.21 (m, 1H), 3.58-3.48 (m, 1H), 3.06 (s, 3H), 1.77 (d, J = 6.9 Hz, 3H), 1.24 (d, J = 6.7 Hz, 6H).

[0757] (Example 113) (R)-(3-(3-(3,3-difluoroazetidine-1-yl)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0758] [ka]

[0759] Step 1: (R)-3-(3,3-difluoroazetidine-1-yl)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole

[0760] [ka]

[0761] (R)-3-chloro-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (75 mg, 184.33 μmol), 3,3-difluoroazetidine hydrochloride (238.77 mg, 1.84 mmol), and N,N-diisopropylethylamine (476.46 mg, 3.69 mmol, 642.12 μL) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (180.17 mg, 552.98 μmol) was added. The mixture was maintained in a microwave at 110°C for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (dichloromethane:methanol = 20:1) to obtain the target product, (R)-3-(3,3-difluoroazetidine-1-yl)-5-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)-1,2,4-thiadiazole (60 mg, 129.45 μmol, yield: 70.23%). MS m / z (ESI): 464.2 [M+H] + .

[0762] The subsequent steps were carried out with reference to the corresponding steps in Example 1 to obtain (R)-(3-(3-(3,3-difluoroazetidine-1-yl)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone.

[0763] [ka]

[0764] MS m / z (ESI): 437.1[M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 7.55-7.41 (m, 2H), 7.23-7.11 (m, 1H), 5.97-5.51 (m, 1H), 4.90-4.76 (m, 1H), 4.71-4.44 (m, 5H), 4.35-4.12 (m, 1H), 3.62-3.38 (m, 1H), 1.75 (d, J = 6.9 Hz, 3H).

[0765] (Example 114) (R)-(4-fluorophenyl-3-d)(8-methyl-3-(3-(pyrroridine-1-yl)-1,2,4-thiadiazole-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3a]pyrazine-7(8H)-yl)methanone

[0766] [ka]

[0767] The preparation of Example 114 was carried out with reference to Example 113. MS m / z (ESI): 415.2[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.55-7.42 (m, 2H), 7.21-7.10 (m, 1H), 5.91-5.47 (m, 1H), 4.97-4.79 (m, 1H), 4.79-4.34 (m, 1H), 4.33-4.13 (m, 1H), 3.74-3.58 (m, 4H), 3.58-3.42 (m, 1H), 2.13-1.95 (m, 4H), 1.75 (d, J = 6.9 Hz, 3H).

[0768] (Example 115) (R)-(3-(3-(cyclopropyl(methyl)amino)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0769] [ka]

[0770] The preparation of Example 115 was carried out with reference to Example 106. MS m / z (ESI): 414.0 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.53-7.42 (m, 2H), 7.19-7.15 (m, 2H), 5.70 (s, 1H), 4.90 (dd, J = 13.6, 3.8 Hz, 1H), 4.81-4.49 (m, 1H), 4.32-4.19 (m, 1H), 3.59-3.45 (m, 1H), 3.22 (s, 3H), 2.82-2.74 (m, 1H), 1.75 (d, J = 6.9 Hz, 3H), 0.91-0.84 (m, 2H), 0.79-0.71 (m, 2H).

[0771] (Example 116) (R)-(4-fluorophenyl-3-d)(8-methyl-3-(4-(pyrroridine-1-yl)thiazole-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0772] [ka]

[0773] The preparation of Example 116 was carried out with reference to Example 60. MS m / z (ESI): 414.1 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ7.44-7.52 (m, 2H), 7.17 (t, J = 6.8 Hz, 1H), 6.60-6.81 (br, 1H), 5.63-5.80 (br, 1H), 4.85-4.89 (m, 1H), 4.54-4.76 (br, 1H), 4.21-4.38 (m, 1H), 3.45-3.61 (br, 5H), 2.10-2.21 (br, 4H), 1.77 (d, J = 6.8 Hz, 3H).

[0774] (Example 117) (R)-(3-(4-(3-fluoroazetidine-1-yl)thiazole-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0775] [ka]

[0776] The preparation of Example 117 was carried out with reference to Example 60. MS m / z (ESI): 418.0 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d): δ 7.43-7.52 (m, 2H), 7.14-7.19 (m, 1H), 6.01 (s, 1H), 5.66-5.83 (br, 1H), 5.33-5.54 (m, 1H), 4.85-4.89 (m, 1H), 4.50-4.70 (br, 1H), 4.19-4.36 (m, 3H), 4.04-4.13 (m, 2H), 3.43-3.59 (m, 1H), 1.77 (d, J = 6.8 Hz, 3H).

[0777] (Example 118) (R)-(3-(3-fluoroazetidine-1-yl)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0778] [ka]

[0779] The preparation of Example 118 was carried out by referring to Example 113. MS m / z (ESI): 419.1[M+H] + . 1 ¹H NMR (400 MHz, chloroform-d) δ 7.58-7.39 (m, 2H), 7.23-7.12 (m, 1H), 5.92-5.62 (m, 1H), 5.58-5.33 (m, 1H), 4.90-4.76 (m, 1H), 4.72-4.03 (m, 6H), 3.63-3.40 (m, 1H), 1.75 (d, J = 6.9 Hz, 3H).

[0780] (Example 119) (R)-(3-(3-(azidin-1-yl)-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-3-d)methanone

[0781] [ka]

[0782] The preparation of Example 119 was carried out with reference to Example 113. MS m / z (ESI): 401.1 [M+H] + . 1¹H NMR (400 MHz, chloroform-d) δ 7.55-7.40 (m, 2H), 7.23-7.12 (m, 1H), 5.85-5.62 (m, 1H), 4.91-4.78 (m, 1H), 4.75-4.52 (m, 1H), 4.35-4.12 (m, 4H), 3.74-3.59 (m, 1H), 3.59-3.43 (m, 1H), 2.54-2.38 (m, 2H), 1.75 (d, J = 6.9 Hz, 3H).

[0783] (Example 120) (R)-(4-fluorophenyl)(8-methyl-3-(6-methylthiazolo[5,4-c]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone

[0784] [ka]

[0785] (R)-(3-(6-chlorothiazolo[5,4-c]pyridine-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (20 mg, 46.63 μmol), dimethylzinc (1.0 M, 233.17 μL), and Pd(dppf)Cl2 (6.82 mg, 9.33 μmol) were dissolved in 1,4-dioxane (3 mL). The reaction system was purged with nitrogen, and the reaction mixture was stirred at 100 °C for 5 hours. LC-MS showed product formation. The reaction mixture was stopped with saturated brine (5 mL), and the aqueous phase was extracted with DCM (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain (R)-(4-fluorophenyl)(8-methyl-3-(6-methylthiazolo[5,4-c]pyridine-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)methanone (1.2 mg, 2.94 μmol, yield: 6.30%) as a bright pink solid. MS m / z (ESI): 409.0 [M+H] + .

[0786] (Example 121) (R)-(3-(4-chlorothiazol-2-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone

[0787] [ka]

[0788] The preparation of Example 121 was carried out with reference to Example 55. MS m / z (ESI): 379.0 [M+H] + . 1 ¹H NMR (400 MHz, chloroform-d): δ 7.45-7.52 (m, 2H), 7.24 (s, 1H), 7.17 (t, J = 8.4 Hz, 1H), 5.69-5.99 (br, 1H), 4.89-4.92 (m, 1H), 4.52-4.70 (br, 1H), 4.19-4.37 (br, 1H), 3.45-3.67 (m, 1H), 1.77 (d, J = 6.0 Hz, 3H).

[0789] (Example 122) (R)-(3-(3-chloro-1,2,4-thiadiazole-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)(4-fluorophenyl-2-d)methanone

[0790] [ka]

[0791] The preparation of Example 122 was carried out with reference to Example 56. MS m / z (ESI): 380.0 [M+H] + .

[0792] Biological assays and evaluations The present invention will be further described with reference to the following test examples, but these test examples should not be considered to limit the scope of the present invention.

[0793] I. Cell Function Experiments (Test Example 1) Determination of the effects of the compounds of the present invention on calcium ion fluidity in cells exhibiting stable expression of the NK3 receptor.

[0794] Objective of the experiment: The purpose of this study was to determine the inhibitory effect of this compound on the NK3 receptor.

[0795] Experimental equipment: 384-well plate (Corning, 3712); Pipette (Axygen); FLIPR (Molecular Devices).

[0796] Experimental reagents: 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 Company, 354230); DMSO (Sigma, D2650); HBSS (Invitrogen, 14065); HEPES (Invitrogen, 15630080); Probenecid (Sigma, P8761); BSA (Renview Corporation, FA016); Trypsin (HDB Corporation, 0458).

[0797] Experimental method: 1. Preparation of buffer solution: 1×HBSS, 20mM HEPES, 2.5mM probenecid (probenecid was prepared as a 400mM stock solution in 1M NaOH), 0.1% BSA. Probenecid and BSA were added fresh on the first day of the experiment. The experimental buffer solution included dye buffer, compound dilution buffer, etc. 2. After digesting the cells with trypsin, place 1 x 10 cells in a 384-well plate. 4 Seeds were seeded at a density of one seed per well and incubated for 16–24 hours (at least overnight). 3. Discard the culture medium and add 20 μL of dye. Incubate the cells in the dark at 37°C for 60 minutes, then read the calcium signal. 4. The antagonist was prepared before the experiment. 5 μL / well of the 5-fold antagonist compound was added to a 384-well plate, and the cells were incubated in the dark at room temperature for 15 minutes. The plate was transferred to FLIPR, and 5 μL / well of the 6-fold agonist compound was added. Values ​​were read and data saved using FLIPR. The total assay volume was 30 μL, containing 20 μL / well of dye buffer, 5 μL / well of the 5-fold experimental compound, and 5 μL / well of the 6-fold agonist compound.

[0798] Experimental data processing procedure: Calcium signal values ​​were read using FLIPR. The results at each sample collection point during the experiment were calculated as the ratio of the signal at wavelengths 340 / 510 nm to the signal at wavelengths 380 / 510 nm. The maximum minus minimum value was calculated from the signal ratio curve. The IC of the compound was obtained by fitting the inhibition percentage data and 10 concentrations to a parametric nonlinear logistic equation using GraphPad's Prism. 50 The value was calculated.

[0799] Experimental results:

[0800] [Table 1]

[0801] [Table 2]

[0802] Conclusion of the experiment: The data in the table shows that the compounds of the examples of the present invention exhibited good inhibitory activity in experiments concerning calcium flow in cells that exhibit stable NK3 expression.

[0803] (Test Example 2) Determination of the effects of the compounds of the present invention on calcium ion fluidity in cells exhibiting stable expression of NK1 / NK2 receptors.

[0804] Objective of the experiment: The purpose of this study was to determine the inhibitory effect of this compound on NK1 / NK2 receptors.

[0805] Experimental equipment: 384-well plate (Corning, 3712); Pipette (Axygen); FLIPR (Molecular Devices).

[0806] Experimental reagents: 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 Company, 354230); DMSO (Sigma, D2650); HBSS (Invitrogen, 14065); HEPES (Invitrogen, 15630080); Probenecid (Sigma, P8761); BSA (Renview Corporation, FA016); Trypsin (HDB Corporation, 0458).

[0807] Experimental method: 1. Preparation of buffer solution: 1×HBSS, 20mM HEPES, 2.5mM probenecid (probenecid was prepared as a 400mM stock solution in 1M NaOH), 0.1% BSA. Probenecid and BSA were added fresh on the first day of the experiment. The experimental buffer solution included dye buffer, compound dilution buffer, etc. 2. After digesting the cells with trypsin, place 1 x 10 cells in a 384-well plate. 4 Seeds were seeded at a density of one seed per well and incubated for 16–24 hours (at least overnight). 3. Discard the culture medium and add 20 μL of dye. Incubate the cells in the dark at 37°C for 60 minutes, then read the calcium signal. 4. The antagonist was prepared before the experiment. Antagonist preparation: 5 μL / well of the 5-fold concentration antagonist compound was added to a 384-well plate, and the cells were incubated in the dark at room temperature for 15 minutes. The plate was transferred to FLIPR, and 5 μL / well of the 6-fold concentration agonist compound was added. Values ​​were read and data saved using FLIPR. The total assay volume was 30 μL, containing 20 μL / well of dye buffer, 5 μL / well of the 5-fold concentration experimental compound, and 5 μL / well of the 6-fold concentration agonist compound.

[0808] Experimental data processing procedure: Calcium signal values ​​were read using FLIPR. The results at each sample collection point during the experiment were calculated as the ratio of the signal at wavelengths 340 / 510 nm to the signal at wavelengths 380 / 510 nm. The maximum minus minimum value was calculated from the signal ratio curve. The IC of the compound was obtained by fitting the inhibition percentage data and 10 concentrations to a parametric nonlinear logistic equation using GraphPad's Prism. 50 The value was calculated.

[0809] Experimental results: The compounds in the examples of the present invention all exhibit calcium ion fluidity in cells showing stable expression of NK1 / NK2 receptors, with a total NK1R IC score exceeding 10,000. 50 (nM) value and NK2R IC 50 The (nM) value is shown.

[0810] Conclusion of the experiment: The compounds of the present invention demonstrated good selectivity in experiments concerning calcium flow in cells exhibiting stable expression of NK3 receptors and NK1 / NK2 receptors.

[0811] (Test Example 3) Determination of the action of the compound of the present invention on IP1 in HEK293 cells exhibiting stable NK3 expression.

[0812] 1. Objective of the experiment: The purpose of this study was to determine the antagonistic effect of this compound on the activity of HEK293-NK3 cells.

[0813] 2. Laboratory equipment and reagents: 2.1 Laboratory equipment and consumables: 384-well cell culture plate (Corning, 3824); 384-well Echo compound plate (Labcyte, LP-0200); Bravo Tips (Agilent, 10734-202); EnVision Multi-Label Reader (PE Corporation, 2104-0010); Bravo (Agilent) and ECHO 550 (LABCYTE) pipetting stations; Liquid dispenser (Multidrop Combi). 2.2 Experimental Reagents: DMEM, high glucose (Gibco, 12100); Fetal bovine serum (Biosera, FB-1058 / 500); P / S (Biosera, XC-A4122); 5X Matrigel (Corning, 354230); IP-ONE Gq Kit (Cisbio, 62IPAPEJ); Agonist Senctide (MCE Corporation, HY-P0187); Positive control compound: tarnetant (MCE, HY-14552); Complete medium: DMEM + 10% FBS + 1×P / S; 1× Matrigel: 5× Matrigel diluted with DMEM; Cell line: HDB HEK293-NK3, ​​HD Biosciences (Shanghai) Co., Ltd.

[0814] 3. Experimental method: A 1.150 mm Petri dish was coated with 1 x Matrigel at room temperature for 10 minutes. 2. HEK293-NK3 cell lines were cultured in complete medium and seeded in coated dishes at 37°C and 5% CO2 until 70%–90% confluence was reached. 3. Preparation of positive control compounds and compounds to be tested 1) The compounds were diluted to 11 different concentrations using a Bravo instrument on a 384-well Echo compound plate (LABCYTE, LP-0200). 2) Next, 10 nL of the compound per well (e.g., 10 mM at the compound's storage concentration, the highest concentration point) was transferred to a 384-well cell culture plate (Corning, 3824) using an ECHO instrument, and the plate was kept at room temperature for use. 4. The cells were digested, resuspended in 1× Stimulation Buffer (IP-ONE Gq Kit), and seeded at a rate of 5,000 cells / well / 5μL in a 384-well cell culture plate (containing the compound to be tested) using Multidrop Combi. The culture plate was centrifuged at 300 rpm for 60 seconds at room temperature, and then incubated at 37°C and 5% CO2 for 15 minutes. 5. Remove the cell culture plate from the CO2 incubator. 2×EC 805 μL (to achieve a final concentration of 3 nM) was added using a Multidrop Combi. The culture plate was centrifuged at 300 rpm at room temperature for 60 seconds, and then incubated at 37°C in 5% CO2 for 2 hours. 6. Remove the cell culture plate from the CO2 incubator. 5 μL of IP1 d2 reagent, followed by 5 μL of IP1 Tb cryptotate antibody reagent, were added using a Multidrop Combi. The culture plate was centrifuged at 300 rpm for 60 seconds at room temperature and allowed to stand at room temperature for 1 hour. 7. The plates were read using the EnVision multi-label reader, and data was collected simultaneously.

[0815] Experimental data processing procedure: The fluorescence signal ratio (Ratio) was read and collected using an EnVision multi-label reader. The competitive percentage data was calculated using the formula {Competitive % = (Ratio of sample - Ratio of low control) / (Ratio of high control - Ratio of low control) × 100}, according to the readings for the low control (DMSO control) and high control (positive compound) experimental groups. The concentrations of the 11 compounds to be tested after 3-fold dilution in the reaction system ranged from 10 μM to 0.17 nM. The IC of the compounds was calculated by fitting the competitive percentage data and the 11 concentrations to a parametric nonlinear logistic equation using XLFit. 50 The value was calculated.

[0816] 4. Experimental results:

[0817] [Table 3]

[0818] [Table 4]

[0819] 5. Conclusion of the experiment: The data in the table shows that the compounds of the examples of the present invention exhibited good antagonistic activity in experiments on IP1 in cells that stably express NK3.

[0820] (Test example 4) Pharmacokinetic assay in SD rats

[0821] 1. Objective of the experiment: SD rats were used as test animals. The in vivo (plasma and brain tissue) pharmacokinetic behavior of the compound of the present invention was investigated by oral administration of the compound at a dose of 5 mg / kg to rats.

[0822] 2. Experimental protocol: 2.1 Experimental drugs: Compounds of the present invention prepared by the inventors. 2.2 Laboratory animals: Male SD rats (21 animals per group) purchased from Shanghai JieSiJie Laboratory Animal Co.,Ltd. under animal production license number SCXK(Shanghai)2013-0006 No.311620400001794. 2.3 Preparation of formulations: The experimental reagent was dissolved in 0.5% CMC-Na (1% Tween 80) by sonication to prepare a clear solution or a homogeneous suspension. 2.4 Drug administration: After fasting overnight, male SD rats (21 animals per group) were orally administered the experimental drug at a dose of 5 mg / kg and a volume of 10 mL / kg. 2.5 Sample collection: Rats were sacrificed with CO2 at 0, 0.5, 1, 2, 4, 8, and 24 hours before and after drug administration. 8 mL of blood was collected by cardiac puncture, placed in an EDTA-K2 tube, and centrifuged at 6,000 rpm at 4°C for 6 minutes. Plasma was separated and stored at -80°C. Whole brain tissue was excised, weighed, placed in a 2 mL centrifuge tube, and stored at -80°C. 2.6 Sample preparation: 1) 160 μL of acetonitrile was added to 40 μL of plasma sample for precipitation. After mixing, the sample was centrifuged at 3500 × g for 5 to 20 minutes. 2) 90 μL of acetonitrile containing an internal standard (100 ng / mL) was added to 30 μL of plasma or brain homogenate sample for precipitation. After mixing, the sample was centrifuged at 13,000 rpm for 8 minutes. 3) 70 μL of water was added to 70 μL of the supernatant and mixed by vortex for 10 minutes. Next, 20 μL of the sample was analyzed by LC / MS / MS to determine the concentration of the compound to be tested. The LC / MS / MS instrument used for the analysis was an AB Sciex API 4000 Qtrap. 2.7 Liquid Chromatography Analysis: • Liquid chromatography conditions: Shimadzu LC-20AD pump • Chromatography column: Agilent ZORBAX XDB-C18 (50 × 2.1 mm, 3.5 μm). Mobile phase: Eluent A was a 0.1% formic acid aqueous solution, and eluent B was acetonitrile. ·Flow rate: 0.4mL / min • Elution time: 0-4.0 minutes, the eluate is as follows:

[0823] [Table 5]

[0824] 3. Experimental Results and Analysis Key pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of pharmacokinetic experiments in rats are shown in Table 3 below.

[0825] [Table 6]

[0826] 4. Conclusion of the experiment: The experimental results of pharmacokinetic assays in rats shown in the table indicate that the compounds of the present invention exhibited favorable metabolic characteristics, with high exposure AUC and high maximum plasma concentration C. maxIt can be seen that the results were favorable.

[0827] (Test Example 5) Effect of the compound of the present invention on the progesterone (LH) content in the plasma of bilateral ovariectomized (OVX) rats

[0828] 1. Objective of the experiment: The purpose of this study was to determine the effect of this compound on progesterone (LH) in the plasma of bilateral ovariectomized (OVX) rats.

[0829] 2. Laboratory equipment and reagents: 2.1 Experimental equipment: Balance (PR2202ZH / E, OHAUS); Centrifuge (5424R, Eppendorf); Microplate reader (BioTek Synergy H1); Plate washer (Thermo Scientific); Pipette (Eppendorf & Rainin); Pure water system (Thermo Scientific); 2.2 Experimental Reagents: CMCNa (30036365, Sinopharm Chemical Reagent); Tween 80 (30189828, Sinopharm Chemical Reagent); The Rat LH ELISA kit (Type S) was purchased from Shibayagi Corporation in Japan, catalog number AKRLH-010S. The kit contained assay buffer C, sample dilution buffer G, wash buffer, biotinylated anti-LHα antibody, HRP-conjugated streptavidin, and chromophor (TMB). 2.3 Laboratory animals: We purchased 10-week-old female bilateral ovariectomized SD rats from Beijing Vital River Laboratory Animal Technology Co., Ltd. The animals were housed in an SPF-grade animal facility with 5 SD rats per cage. Cages, bedding, feed, and water were disinfected at high temperatures before use. All animals had free access to food and water.

[0830] 3. Experimental method: Drug administration by group: Ten-week-old female SD rats were subjected to bilateral ovariectomy and used in the experiment three weeks later. Each SD rat was fasted overnight before the experiment and then randomly divided into groups (3 rats per group) before drug administration. Different test compounds were orally administered to each drug administration group at a dose of 30 mg / kg and a volume of 10 mL / kg. Sample collection: Whole blood samples of 0.2–0.3 mL from SD rats in each group were collected 0, 0.5, 1, 2, 4, and 8 hours before and after drug administration, and placed in EDTA-K2 tubes. The tubes were inverted, thoroughly mixed, and centrifuged at 5,000 rpm at 4°C for 5 minutes. The plasma was then separated and stored in a cryogenic freezer (-80±10°C). Sample detection: All reagents, samples, and ELISA plates were equilibrated at room temperature (20-25°C) for at least 30 minutes. Samples were thawed, vortexed, and centrifuged for use. Standard curves were prepared using assay buffer C according to the concentration order of 10, 5, 2.5, 1.25, 0.625, 0.313, and 0. Samples were diluted 2-fold with sample dilution buffer G and allowed to stand at room temperature for 10 minutes. Next, the samples from the previous step were diluted 2.5-fold with assay buffer C and allowed to stand at room temperature for use. 1× wash buffer was added to a 96-well plate at a rate of 300 μL / well for plate washing, and this process was repeated four times. 50 μL of the corresponding standard substance and sample were added to each well according to the settings for the standard curve wells and sample wells, and mixed well. The plate was sealed and incubated at 20-25°C for 2 hours. 50 μL of 1× biotinylated anti-LHα antibody was added per well and mixed well. The plate was sealed and incubated at 20-25°C for 1 hour. 1× Wash Buffer was added at 300 μL / well for plate washing, and this process was repeated four times. Prepared 1× HRP-conjugated streptavidin was added at 50 μL per well and mixed thoroughly. The plate was sealed and incubated at 20-25°C for 0.5 hours. 1× Wash Buffer was added at 300 μL / well for plate washing, and this process was repeated four times. Chromophores (TMB) were added at 50 μL per well and mixed thoroughly. The plate was incubated at 20-25°C for 20 minutes. Stop solution (1M H2SO4) was added at 50 μL per well and mixed thoroughly. The OD value of each well was read at a wavelength of 450 nm using a microplate reader.

[0831] Experimental data processing procedure: The standard curve was plotted using Graphpad, and the sample concentration was calculated. If the sample was diluted during measurement, the actual sample concentration should be obtained by multiplying the value by the corresponding dilution factor in the final calculation.

[0832] 5. Experimental results:

[0833] [Table 7]

[0834] 6. Conclusion of the experiment: The data in the table shows that the compounds of the present invention were able to significantly reduce the LH content in the plasma of ovariectomized (OVX) rats.

[0835] (Test Example 6) Pharmacokinetic study of test compounds on tail skin temperature in a sencutide-induced bilateral ovariectomy rat model

[0836] 1. Objective of the experiment: To evaluate the effect of the test compound on tail skin temperature in sencutide-induced bilateral ovariectomized rats.

[0837] 2. Laboratory equipment and reagents: 2.1.Equipment: Balance (BSA2202s-CW, Sartorius); Thermometer (BAT-10, Physitemp); Probe (SST-1, Physitemp). 2.2. Reagents Senktide (106128-89-6, MCE Corporation); NaCl (10019318, Sinopharm Chemical Reagent); DMSO (D2650-100ML, Sigma Corporation); CMCNa (30036365, Sinopharm Chemical Reagent); Tween 80 (30189828, Sinopharm Chemical Reagent). 2.3. Laboratory Animals We purchased 10-week-old female bilateral ovariectomized SD rats from Beijing Vital River Laboratory Animal Technology Co., Ltd. The animals were housed in an SPF-grade animal facility with 5 SD rats per cage. Cages, bedding, feed, and water were disinfected at high temperatures before use. All animals had free access to food and water. 2.4. Test compound: Compounds of the present invention prepared by the inventors.

[0838] 3. Experimental procedure: Ten-week-old female SD rats underwent bilateral ovariectomy and, after two weeks of recovery, were randomly divided into a negative control group, a model group, and a drug administration group (8 rats per group) based on body weight. Probes were attached to the dorsal side of the rat's tail using medical tape, 1-2 cm away from the tail ridge.

[0839] The medium was orally administered to the negative control group and the model group, and different test compounds were orally administered to each drug administration group at a dose of 30 mg / kg and a volume of 10 mL / kg.

[0840] Thirty minutes after oral administration of the medium or test compound, the negative control group was subcutaneously injected with physiological saline (5 mL / kg), and the model group and each drug administration group were subcutaneously injected with 0.2 mg / mL of sencutide (5 mL / kg) to induce hot flash-like symptoms. Tail skin temperature (TST) was measured and recorded for a total of 75 minutes, 0 minutes before injection and every 5 minutes after injection.

[0841] 4. Data Processing The change in tail skin temperature (ΔTST) at each time point relative to zero is calculated, and the ΔTST-time curve of the change in tail skin temperature is plotted, with the area under the curve (AUC) calculated. ΔTST ) was calculated. ΔTST = TST n -TST0, where TST0 is the tail skin temperature 0 minutes before subcutaneous injection of physiological saline or sencutide; TST n This is the skin temperature of the tail n minutes after subcutaneous injection.

[0842]

number

[0843] 5. Experimental results:

[0844] [Table 8]

[0845] 6. Conclusion of the experiment: The data in the table shows that the compounds of the present invention's examples were able to effectively inhibit the symptoms of sencutide-induced hot flashes in ovariectomized rats.

Claims

1. Compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof: 【Chemistry 1】 [In the formula, Ring A is 【Chemistry 2】 And, R ａ These include halogens, cyanosides, 3- to 12-membered heterocyclines, and -NR ａａ R ｂｂ Selected from the group consisting of; R １ is selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ deuterated alkyl, C １～６ haloalkyl, C １～６ hydroxyalkyl, C １～６ alkoxy, C １～６ alkylthio, C １～６ haloalkoxy, C ３～６ cycloalkyl, 3- to 12-membered heterocyclyl, C ６～１４ aryl, and 5- to 14-membered heteroaryl Here, the aforementioned C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～６ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Aryl and 5-14 member heteroaryls can be optionally selected to contain deuterium, halogen, amino, hydroxy, cyano, or C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～６ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ They may be further substituted with one or more substituents from aryl and 5- to 14-membered heteroaryl groups; R ２ hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～６ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Selected from the group consisting of aryls and 5- to 14-membered heteroaryls; R ａａ and R ｂｂ These are, independently, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Selected from the group consisting of aryls and 5- to 14-membered heteroaryls, Here, the aforementioned C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Aryl and 5- to 14-membered heteroaryls are deuterium, halogen, amino, hydroxy, cyano, and C, respectively. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ The substituents may be further optionally substituted with aryls and one or more substituents from among 5- to 14-membered heteroaryls; x is 0, 1, 2, 3, 4, 5, or 6; y is 0, 1, 2, 3, 4, or 5; z is 0, 1, 2, 3, 4, or 5.

2. Compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof: 【Transformation 3】 [In the formula, Ring A is 【Chemistry 4】 And; R ａ is selected from the group consisting of halogen, amino, nitro, hydroxy, cyano, C ２～６ alkenyl, C ２～６ alkynyl, C ３～８ cycloalkyl, 3- to 12-membered heterocyclyl, C ６～１４ aryl, 5- to 14-membered heteroaryl, -(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 ) ｎ NR ａａ C(O)R ｂｂ , and -(CH ２ ) ｎ NR ａａ S(O) ｍ R ｂｂ ; Here, the aforementioned C ２～６ Alkenil, C ２～６ Alkinyl, C ３～８ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Aryls and 5- to 14-membered heteroaryls are deuterium, halogen, amino, hydroxy, cyano, and C, respectively. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ They may be further substituted with one or more substituents from aryl and 5- to 14-membered heteroaryl groups; R １ Hydrogen, deuterium, halogen, amino, hydroxy, cyano, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Selected from the group consisting of aryls and 5- to 14-membered heteroaryls, Here, the aforementioned C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～６ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Aryl and 5-14 member heteroaryls can be optionally selected to contain deuterium, halogen, amino, hydroxy, cyano, or C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～６ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ They may be further substituted with one or more substituents from aryl and 5- to 14-membered heteroaryl groups; R ２ hydrogen, deuterium, halogen, amino, hydroxy, cyano, oxo, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～６ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Selected from the group consisting of aryls and 5- to 14-membered heteroaryls; R ａａ and R ｂｂ These are, independently, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Selected from the group consisting of aryls and 5- to 14-membered heteroaryls, Here, the aforementioned C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ Aryls and 5- to 14-membered heteroaryls are deuterium, halogen, amino, hydroxy, cyano, and C, respectively. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkyl deuterated, C １～６ Haloalkyl, C １～６ Hydroxyalkyl, C １～６ Alkoxy, C １～６ Alkylthio, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１４ The substituents may be further optionally substituted with aryls and one or more substituents from among 5- to 14-membered heteroaryls; x is 0, 1, 2, 3, 4, 5, or 6; y is 0, 1, 2, 3, 4, or 5; z is 0, 1, 2, 3, 4, or 5; m is 0, 1, or 2; and n is 0, 1, or 2.

3. At least one deuterium atom is R １ A compound of formula (I) according to claim 1 or 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized by being present in [a specific location].

4. R ａ A compound of formula (I) according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is a halogen.

5. R ａ However, fluorine, chlorine, bromine, -NHCH ３ , or -N(CH ３ ) ２ A compound of formula (I) according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is such.

6. R １ A compound of formula (I) according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that the compound is hydrogen, deuterium, halogen, or a 5-6 membered heteroaryl.

7. R １ A compound of formula (I) according to any one of claims 1 to 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that the compound is hydrogen, deuterium, fluorine, chlorine, bromine, or thienyl.

8. Ring A 【Transformation 5】 And; R ａ However, fluorine, chlorine, -NHCH ３ , or -N(CH ３ ) ２ A compound of formula (I) according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

9. Compounds of the following formula (II), their stereoisomers, or pharmaceutically acceptable salts thereof: 【Transformation 6】 [In the formula, R １ It is selected from the group consisting of hydrogen, deuterium, and halogens; R ３ is hydrogen, deuterium, halogen, C １～６ Alkyl, C １～６ Selected from the group consisting of deuterated alkyls and 3- to 6-membered heterocyclines; the above C １～６ Alkyl, C １～６ The deuterated alkyl and the 3- to 6-membered heterocyclyl may each be further optionally substituted with one or more substituents from deuterium and halogens; y is 1, 2, 3, 4, or 5.

10. R １ It is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, or bromine; R ３ This includes hydrogen, deuterium, fluorine, chlorine, bromine, methyl, methyl deuteride, azetidinyl, tetrahydropyrrolyl, 【Transformation 7】 A compound of formula (II) according to claim 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

11. A compound characterized by having the following specific structure, its stereoisomer, or a pharmaceutically acceptable salt thereof: 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 。

12. A method for preparing a compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, comprising the following steps: 【Chemistry 13】 A step of obtaining the compound of formula (II-2), or its stereoisomer, and a pharmaceutically acceptable salt thereof by deprotecting the compound of formula (II-1); next, a step of obtaining the compound of formula (II), or its stereoisomer, or a pharmaceutically acceptable salt thereof by subjecting the compound of formula (II-2) and the compound of formula (II-3) to a condensation reaction. [In the formula, Pg is an amino protecting group; R represents halogen, hydroxyl, and -C(O)OR Ａ Selected from the group consisting of; R Ａ is C １～６ It is alkyl; R1 is selected from the group consisting of hydrogen, deuterium, and halogens; R3 is selected from the group consisting of hydrogen, deuterium, halogens, C1-6 alkyl groups, C1-6 deuterated alkyl groups, and 3-6 membered heterocyclines; the C1-6 alkyl groups, C1-6 deuterated alkyl groups, and 3-6 membered heterocyclines may each be further optionally substituted with one or more substituents from deuterium and halogens; y is 1, 2, 3, 4, or 5.

13. Pg is allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, triphenylmethyl, fluorenylmethyloxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, or p-methoxyphenyl; A method for preparing a compound of formula (II) according to claim 12, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of fluorine, chlorine, bromine, iodine, or hydroxyl.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

15. Use of a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the preparation of an NK inhibitor-related pharmaceutical.

16. Use of a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the preparation of an NK3 inhibitor-related pharmaceutical.

17. Use of a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the preparation of a pharmaceutical for treating and / or preventing mental disorders, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsions, obesity, inflammatory diseases, vomiting, pre-eclampsia, respiratory tract disorders, reproductive disorders, sex hormone-dependent diseases, or gynecological disorders.

18. The use of a compound according to any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the preparation of a pharmaceutical for treating and / or preventing menopausal syndrome-related disorders, wherein the menopausal syndrome includes symptoms of hot flashes, sweating, palpitations, dizziness, and obesity.

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