Imidazole fused ring derivatives, processes for their preparation and their use in medicine

Abstract

The present application relates to a compound as shown in formula (I), stereoisomer, tautomer, isotopically labeled, nitroxide, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof, and preparation method and pharmaceutical composition. The compound is an NK-3 receptor antagonist, which can be used for preventing and / or treating depression, anxiety, psychosis, schizophrenia, psychotic disorder, bipolar disorder, cognitive disorder, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder, pain, convulsion, obesity, inflammatory disease, vomiting, preeclampsia, airway related disease, reproductive disorder, contraception and sex hormone dependent disease, gynecological disease related disease, menopausal syndrome related disease.

Description

[0001] The present application claims priority from the prior application of Patent Application No. 202110432744.0, filed on April 21, 2021, with the State Intellectual Property Office of China, entitled "Imidazole Fused Ring Derivatives, Preparation Methods Thereof and Pharmaceutical Applications Thereof". The prior application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the field of drug synthesis, and specifically relates to imidazole fused ring derivatives represented by general formula (I), preparation methods thereof, and pharmaceutical compositions containing the derivatives as therapeutic agents, and uses thereof as selective NK-3 receptor (NK-3R) antagonists for treating and / or preventing a series of wide-ranging CNS and peripheral diseases. BACKGROUND

[0003] Tachykinin receptors are the targets of a structurally related family of peptides collectively named "tachykinins" including substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). Tachykinins are synthesized in the central nervous system (CNS) and peripheral tissues, where they exert a variety of biological activities. Three tachykinin receptors are currently known, which are named neurokinin-1 (NK-1) receptor, neurokinin-2 (NK-2) receptor and neurokinin-3 (NK-3) receptor. Tachykinin receptors belong to the rhodopsin-like seven-transmembrane G protein-coupled receptors. SP has the highest affinity and is considered to be the endogenous ligand for the NK-1 receptor, NKA is the endogenous ligand for the NK-2 receptor, and NKB is the endogenous ligand for the NK-3 receptor. NK-1 receptor, NK-2 receptor and NK-3 receptor have been identified in different species. NK-1 receptor and NK-2 receptor are expressed in a variety of peripheral tissues and NK-1 receptor is also expressed in the CNS, while NK-3 receptor is mainly expressed in the CNS.

[0004] Neurokinin receptors mediate a variety of biological effects stimulated by tachykinins, including transmission of excitatory neuronal signals in the CNS and periphery (e.g. pain), modulation of smooth muscle contractile activity, modulation of immune and inflammatory responses, induction of hypotensive effects via dilation of the peripheral vasculature, and stimulation of endocrine and exocrine gland secretion.

[0005] NK-3 receptor is encoded by TACR3 gene, which is involved in the regulation of hypothalamic-pituitary-gonadal axis. Both TACR3 gene knockout and mutant mice show abnormal development of reproductive organs, low sex hormone levels, and severely reduced reproductive capacity. Carrying TACR3 gene mutation can cause abnormal gonadotropin release in patients, resulting in patients with sexual infantilism and infertility, and a considerable part of familial hypogonadism is caused by TACR3 gene mutation.

[0006] Kisspeptin / neurokinin B / dynorphin (KNDy) neurons are involved in the gonadotropin-releasing hormone (GnRH) signaling pathway, which promotes the production of estrogen through the GnRH neuron-pituitary-gonad pathway, and this signaling pathway is regulated by a negative feedback mechanism to maintain the hormone level in a certain reasonable range. At the same time, KNDy neurons are also related to the temperature regulation signaling pathway, which regulates the body temperature in a certain range by releasing NKB ligands, combining with NK-3 receptors on the median preoptic nucleus, and inhibiting shivering and vasoconstriction, and promoting sweating and vasodilation. In postmenopausal women, due to the decrease of estrogen level in the body, the negative feedback mechanism is lost, so that the KNDy neurons are over-activated, and a large amount of endogenous NKB ligands are released to combine with the NK-3 receptors on the median preoptic nucleus, resulting in sweating, vasodilation, and hot flashes. Therefore, the development of antagonists targeting KNDy neurons and NK-3 receptors on the median preoptic nucleus is expected to have a positive therapeutic effect on the symptoms of hot flashes.

[0007] In the CNS, NK-3 receptors are expressed in regions including the medial prefrontal cortex, hippocampus, thalamus, and amygdala. In addition, NK-3 receptors are expressed on dopaminergic neurons. It has been demonstrated that activation of NK-3 receptors modulates the release of dopamine, acetylcholine, and serotonin, which suggests a therapeutic utility of NK-3 receptor modulators in the treatment of a variety of conditions, including psychotic disorders, anxiety, depression, schizophrenia, and obesity, pain, or inflammation.

[0008] Although a large number of meaningful researches have been carried out in this field, there is still a need to continue to develop more effective small molecule NK-3R antagonists, and the present application provides a novel structure of NK-3R antagonist, and it is found that the compound with such structure has good activity and can effectively treat a series of CNS and peripheral diseases. SUMMARY

[0009] The present application provides a compound as shown in formula (I), a stereoisomer, a tautomer, an isotopically labeled, a nitroxide, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof,

[0010]

[0011] wherein ring A is a heterocyclic group containing at least two N atoms; n is an integer of 1-5;

[0012] R1is selected from H, halogen, -CN, -NO2, -OR 11 , -CO-R 12 , -CS-R 12 , -COO-R 13-O-CO-R 14 -NR 15 R 16 -CONR 17 R 18 -NR 19 CO-R 20 -S(O) a -R 21 -S(O) a NR 22 R 23 -NR 24 S(O) a -R 25 -S-R 26 , or the following groups, which are unsubstituted or optionally substituted by one or more R a alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0013] R2is selected from halogen, -CN, -NO2, -OR 11 , -CO-R 12 , -CS-R 12 , -COO-R 13 , -O-CO-R 14 , -NR 15 R 16 , -CONR 17 R 18 , -NR 19 CO-R 20 , -S(O) a -R 21 , -S(O) a NR 22 R 23 -NR 24 S(O) a -R 25 -S-R 26 , or the following groups, which are unsubstituted or optionally substituted by one or more R a alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0014] R a are identical or different, independently of one another, selected from H, D (deuterium), oxo, thia, halogen, -CN, -NO2, -OR 11 , -CO-R 12 , -CS-R 12 , -COO-R 13 , -O-CO-R 14 , -NR 15 R 16 , -CONR 17 R18 , -NR 19 CO-R 20 , -S(O) a -R 21 , -S(O) a NR 22 R 23 , -NR 24 S(O) a -R 25 , -S-R 26 , or unsubstituted or optionally substituted by one or more R c alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0015] R3are the same or different, independently of one another, selected from the group consisting of H, oxo, thia, halogen, -CN, -NO2, -OR 31 , -CO-R 32 , -COO-R 33 , -OCO-R 34 , -NR 35 R 36 , -CONR 37 R 38 , -NR 39 CO-R 40 , -S(O) a -R 41 , -S(O) a NR 42 R 43 , -NR 44 S(O) a -R 45 , -S-R 46 , or unsubstituted or optionally substituted by one or more R d alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0016] R' is selected from the group consisting of H, -L-Ar, -L-R 10 ; R 10 is alkyl, alkenyl, alkynyl;

[0017] L is absent or selected from the group consisting of -(CH2) m -CO-, -(CH2) m -CS-, -(CH2) m -SO2-, -(CH2) m -SO-, alkylene; m is 0, 1, 2, 3;

[0018] Ar is aryl, heteroaryl, cycloalkyl or heterocyclyl, which aryl, heteroaryl, cycloalkyl and heterocyclyl groups optionally can be substituted by one or more R4; or, any two adjacent or non-adjacent R4are linked to form an unsubstituted or optionally substituted ring of five or six members, which ring is unsubstituted or optionally substituted by one or more R b substituted cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0019] R4are the same or different, independently of each other, selected from the group consisting of H, oxo, thia, halogen, -OH, the following radicals, which are unsubstituted or optionally substituted by one or more R 11 , -CO-R 12 , -CS-R 12 , -COO-R 13 , -O-CO-R 14 , -NR 15 R 16 , -CONR 17 R 18 , -NR 19 CO-R 20 , -S(O) a -R 21 , -S(O) a NR 22 R 23 , -NR 24 S(O) a -R 25 , -S-R 26 , or unsubstituted or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl; b

[0020] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 are the same or different, independently of each other, selected from the group consisting of H, oxo, thia, halogen, -OH, the following radicals, which are unsubstituted or optionally substituted by one or more R b alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl; R 15 and R 16 , R 17 and R 18 , R 19 ​and R 20 , R 22 and R 23 may form a ring to form a heterocyclyl group or a heteroaryl group containing at least one N atom (e.g. a heterocyclyl group or a heteroaryl group containing one N atom and optionally further containing 1-3 N, O, S); said heterocyclyl group or heteroaryl group can optionally be substituted by one or more R b , and adjacent or non-adjacent R b may be linked to form a ring to form a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, which can be further substituted by one or more R d ;

[0021] R b , R c are the same or different, independently of each other, selected from the group consisting of H, D (deuterium), oxo, thioxo, halogen, -CN, -NO2, -OR 31 , -CO-R 32 , -COO-R 33 , -O-CO-R 34 , -NR 35 R 36 , -CONR 37 R 38 , -NR 39 CO-R 40 , -S(O) a -R 41 , -S(O) a NR 42 R 43 , -NR 44 S(O) a -R 45 , -S-R 46 , or unsubstituted or optionally substituted by one or more R d : alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0022] R d are the same or different, independently of each other, selected from the group consisting of H, oxo, thioxo, halogen, -CN, -NO2, -OR 31 , -CO-R 32 , -COO-R 33 , -O-CO-R 34 , -NR 35 R 36 , -CONR 37 R 38 , -NR 39 CO-R 40 , -S(O) a -R 41 , -S(O)a NR 42 R 43 , -NR 44 S(O) a -R 45 , -S-R 46 , alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0023] a is 1 or 2;

[0024] R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 are the same or different, independently of each other, selected from the group consisting of H, halogen, -OH, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl.

[0025] In one embodiment of the present application, the compound of formula (I) is a compound of formula (I’), (I”) as follows:

[0026]

[0027] ring A, Ar, L, R 10 , R1, R2, R3, n have the definitions described above.

[0028] In one embodiment of the present application, L is selected from -(CH2) m -CO-, -(CH2) m -CS-, -(CH2) m -SO2- or C 1-4 alkylene.

[0029] In one embodiment of the present application, the compound of formula (I) is a compound of formula (IA) or (IB) as follows:

[0030]

[0031] R1, R2, R3, R’ are as defined above; p is 1, 2 or 3.

[0032] In one embodiment of the present application, the compound of formula (I) is a compound of formula (II) or (II’):

[0033]

[0034] Ar, L, R 10 , R1, R2, R3are as defined above; p is 1, 2 or 3.

[0035] In one embodiment of the present application, the compound of formula (I) is a compound of formula (III-1), (III-2), (III-3), (III-4):

[0036] Ar, R 10 , R1, R2, R3are as defined above; p is 1, 2 or 3.

[0037] In one embodiment of the present application, the R2is a substituted or unsubstituted heteroaryl, for example, a substituted or unsubstituted thiadiazole, a substituted or unsubstituted thiazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted triazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted oxadiazole, in particular, the R2is an alkyl- or haloalkyl-substituted thiadiazole, an alkyl- or haloalkyl-substituted thiazole.

[0038] In one embodiment of the present application, the R2is selected from the group consisting of:

[0039]

[0040] wherein R5, R6are the same or different, independently selected from H, D (deuterium), oxo, thioxo, halogen, -CN, -NO2, -OR 11 , -CO-R 12 , -CS-R 12 , -COO-R 13 , -O-CO-R 14 , -NR 15 R 16 , -CONR 17 R 18 , -NR 19 CO-R 20 , -S(O) a -R 21 , -S(O) a NR 22 R 23 , -NR 24 S(O) a -R 25 , -S-R 26, or optionally substituted by one or more R c substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl; wherein each substituent is as defined above.

[0041] In some embodiments of the application, R2is haloalkyl, for example trifluoromethyl, hexafluoroethyl, -CH2-CF3.

[0042] In some embodiments of the application, R1is H, D (deuterium), halogen, -CN, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, -cycloalkyl-alkyl, -cycloalkyl-CO-alkyl, -CO-alkyl, -CO-alkenyl, -CO-alkynyl, -CO-aryl, -CO-heteroaryl, -CO-cycloalkyl, -CO-heterocyclyl, -COO-alkyl, -O-CO-alkyl, -NH2, alkylamino, dialkylamino, -CONH2, -CONH-alkyl, -CO-N(alkyl)2, -NHCO-alkyl, -NHCOO-alkyl, -N(alkyl)(-CO-alkyl), -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, -NHS(O)2-alkyl, -SH, -S-alkyl, the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl groups can be substituted by one or more halogen, oxo, hydroxyl, alkyl, alkoxy.

[0043] In some embodiments of the application, R1is -NR 15 R 16 , R 15 , R 16 are the same or different, independently of each other, selected from H, alkyl, cycloalkyl, hydroxyalkyl, hydroxycycloalkyl, -alkyl-O-alkyl, -alkyl-O-cycloalkyl, -CO-alkyl, -CO-cycloalkyl, -CO-alkenyl, -CO-alkynyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, -CO-alkyl-O-alkyl, -CO-alkyl-NH2, -CO-alkyl-NH-alkyl, -CO-alkyl-N(alkyl)2, -CO-O-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl groups can be substituted by one or more halogen, oxo, hydroxyl.

[0044] In some embodiments of the application, R1is -NR 15 R 16 , R 15 , R 16a heterocyclyl group containing at least one N atom, preferably a 4-10 membered monocyclic or bicyclic heterocyclyl group containing one N atom and optionally 1-3 additional N, O, S atoms; specific examples include a 4 membered ring such as azetidinyl; a 5 membered ring such as pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl; or a 6 membered ring such as piperidinyl, tetrahydropyridinyl, dihydropyridinyl, piperazinyl, morpholinyl, oxazinanyl, thiazinanyl; or a 7 membered ring such as azepanyl; or an 8 membered ring such as azocanyl; said N-containing heterocyclyl group can be substituted with one or more (e.g. 1-5) of the following: H, D, oxo, thioxo, halogen, -CN, -NO2, -OR 31 , -CO-R 32 , -COO-R 33 , -O-CO-R 34 , -NR 35 R 36 , -CONR 37 R 38 , -NR 39 CO-R 40 , -S(O) a -R 41 , -S(O) a NR 42 R 43 , -NR 44 S(O) a -R 45 , -S-R 46 , or the following groups optionally substituted with one or more R d : alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl. Exemplarily, said N-containing heterocyclyl group can be substituted with 1-5 or 1-3 of the following: H, oxo, thioxo, F, Cl, Br, I, -OH, -CN, -NO2, alkyl, alkoxy, haloalkyl, haloalkoxy, -NH-CO-alkyl, -CO-NH-alkyl, -CO-N(alkyl)2, -CO-alkyl, -O-CO-alkyl, -CO-O-alkyl, -NH2, alkylamino, dialkylamino; optionally, adjacent or non-adjacent substituents on said N-containing heterocyclyl group can cyclize to form a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl or heteroaryl group; exemplary R1 is unsubstituted or substituted with R d : indolinyl, isoindolinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, azepanyloxy, azabicyclohexyl, azabicycloheptane, azabicyclooctane, azepanyloxy, azepanyloxy.

[0045] In some embodiments of the present invention, R1 is an aryl group, such as phenyl, naphthyl, or anthracene, and the aryl group may be substituted by one or more of the following substituents (e.g., 1-5 substituents): H, oxo, thio, halogen, -CN, -NO2, -OR. 31 -CO-R 32 -COO-R 33 -O-CO-R 34 -NR 35 R 36 -CONR 37 R 38 -NR 39 CO-R 40 -S(O) a -R 41 -S(O) a NR 42 R 43 -NR 44 S(O) a -R 45 -SR 46 Or without substitution or optionally by one or more R d The following groups may be substituted: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic. Exemplarily, the aryl group may be substituted with 1-5 or 1-3 of the following substituents: H, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, alkyl, alkoxy, haloalkyl, haloalkoxy, -NH-CO-alkyl, -CO-NH2, -CO-NH-alkyl, -CO-N(alkyl)2, -CO-alkyl, -O-CO-alkyl, -CO-O-alkyl, -NH2, alkylamino, dialkylamino.

[0046] In some embodiments of the present invention, R1 is a heteroaryl group, preferably optionally containing 1-5 4-10 member monocyclic or bicyclic heteroaryl groups selected from N, O, and S; specifically, for example, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, quinazolinyl, cyclolinyl, pyrroleyl, indolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzopyrazolyl, thiophene, benzothiophene, thiazolyl, thiadiazolyl, oxazolyl, benzooxazolyl, furanyl, benzofuranyl, etc., wherein the heteroaryl group may be substituted by one or more of the following substituents (e.g., 1-5 substituents): H, D, oxo, thio, halogen, -CN, -NO2, -OR. 31 -CO-R 32 -COO-R 33 -O-CO-R 34 -NR 35 R 36 -CONR 37 R38 -NR 39 CO-R 40 -S(O) a -R 41 -S(O) a NR 42 R 43 -NR 44 S(O) a -R 45 -SR 46 Or without substitution or optionally by one or more R d The following groups may be substituted: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic. Exemplarily, the heteroaryl group may be substituted with 1-5 or 1-3 of the following: H, D, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, alkyl, alkoxy, haloalkyl, haloalkoxy, -NH-CO-alkyl, -CO-NH-alkyl, -CO-alkyl, -O-CO-alkyl, -CO-O-alkyl, -NH2, alkylamino, dialkylamino.

[0047] In some embodiments of the present invention, R1 is a heterocyclic group, preferably, optionally containing 1-5 4-10 member monocyclic or bicyclic heterocyclic groups selected from N, O, and S; specifically, for example, morpholino, piperidinyl, dihydropyridine, tetrahydropyridine, piperazine, dihydropyrrole, pyrrolidinyl, 2H-pyranyl, N-heterocyclic butane, N-heterocyclic heptane, N-heterocyclic octane, imidazolino, indololino, isoindolino, dihydroquinolino, tetrahydroquinolino, dihydroisoquinolino, etc. Tetrahydroisoquinolinyl, oxazolyl, oxazinyl, aziroxetane, aziroxetane, octane, thiazinyl, thiazolyl, isothiazolyl, azirbiscyclohexyl, azirbiscyclohexyl, azirbiscyclohexyl, azirbiscyclohexyl, azirbiscyclohexyl, azirbiscyclohexyl, azirbiscyclohexyl, azirbiscyclohexyl, the heterocyclic group may be substituted with one or more of the following substituents (e.g., 1-5 substituents): H, D, oxo, thio, halogen, -CN, -NO2, -OR 31 -CO-R 32 -COO-R 33 -OCO-R 34 -NR 35 R 36 -CONR 37 R 38 -NR 39 CO-R 40 -S(O) a -R 41 -S(O) a NR 42 R 43 -NR 44 S(O)a -R 45 -SR 46 Or without substitution or optionally by one or more R d The following groups may be substituted: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic. Exemplarily, the heterocyclic group may be substituted with 1-5 or 1-3 of the following substituents: H, D, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, alkyl, alkoxy, haloalkyl, haloalkoxy, -NH-CO-alkyl, -CO-NH-alkyl, -CO-alkyl, -O-CO-alkyl, -CO-O-alkyl, -NH2, alkylamino, dialkylamino.

[0048] In some embodiments of the present invention, Ar is an aryl group, such as phenyl, naphthyl, or anthracene, and the aryl group may be substituted by one or more of the following substituents (e.g., 1-5 substituents): H, oxo, thio, halogen, -CN, -NO2, -OR. 31 -CO-R 32 -COO-R 33 -O-CO-R 34 -NR 35 R 36 -CONR 37 R 38 -NR 39 CO-R 40 -S(O) a -R 41 -S(O) a NR 42 R 43 -NR 44 S(O) a -R 45 -SR 46 Or without substitution or optionally by one or more R d The following groups may be substituted: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic. Exemplarily, the aryl group may be substituted with 1-5 or 1-3 of the following substituents: H, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, alkyl, alkoxy, haloalkyl, haloalkoxy, -NH-CO-alkyl, -CO-NH-alkyl, -CO-alkyl, -O-CO-alkyl, -CO-O-alkyl, -NH2, alkylamino, dialkylamino.

[0049] In some embodiments of the present invention, Ar is a heteroaryl group, preferably optionally containing 1-5 4-10 membered monocyclic or bicyclic heteroaryl groups selected from N, O, and S; for example, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, quinazolinyl, cyclolinyl, pyrroleyl, indolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzopyrazolyl, thiophene, benzothiophene, thiazolyl, thiadiazolyl, oxazolyl, benzooxazolyl, furanyl, benzofuranyl, etc., wherein the heteroaryl group may be substituted by one or more of the following substituents (e.g., 1-5 substituents): H, oxo, thio, halogen, -CN, -NO2, -OR. 31 -CO-R 32 -COO-R 33 -O-CO-R 34 -NR 35 R 36 -CONR 37 R 38 -NR 39 CO-R 40 -S(O) a -R 41 -S(O) a NR 42 R 43 -NR 44 S(O) a -R 45 -SR 46 Or without substitution or optionally by one or more R d The following groups may be substituted: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic. Exemplarily, the heteroaryl group may be substituted with 1-5 or 1-3 of the following: H, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, alkyl, alkoxy, haloalkyl, haloalkoxy, -NH-CO-alkyl, -CO-NH-alkyl, -CO-alkyl, -O-CO-alkyl, -CO-O-alkyl, -NH2, alkylamino, dialkylamino.

[0050] In some embodiments of the present invention, Ar is a cycloalkyl group, preferably a cycloalkyl group containing 3-10 carbon atoms, more preferably a cycloalkyl group containing 3-6 carbon atoms, and most preferably a cyclopropyl group.

[0051] In some embodiments of the present invention, R3 may be the same or different and is independently selected from H, oxo, thio, halogen, -CN, -NO2, alkyl, alkoxy, haloalkyl, haloalkoxy.

[0052] In some embodiments of the present invention, R 10It is a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, or ethynyl.

[0053] In one embodiment of the present invention, the compound represented by formula (I) is the compound represented by formula (IV) as follows:

[0054]

[0055] Ar, R1, and R2 are defined as above.

[0056] In some embodiments of the present invention, the compound of formula (IV) may be a compound of formula (IV-A) or formula (IV-B):

[0057]

[0058] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (V), formula (V'), or formula (V''):

[0059]

[0060] Where M is N or CR6;

[0061] R5 and R6 may be the same or different, and are independently selected from H, halogens, -CN, -NO2, and -OR. 11 -CO-R 12 -CS-R 12 -COO-R 13 -O-CO-R 14 -NR 15 R 16 -CONR 17 R 18 -NR 19 CO-R 20 -S(O) a -R 21 -S(O) a NR 22 R 23 -NR 24 S(O) a -R 25 -SR 26 No substitution or optional use by one or more R c The following groups may be substituted: alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, heterocyclic; wherein each substituent is as defined above;

[0062] Ar, R1, R 10 As defined above.

[0063] In some embodiments of the present invention, the compound of formula (V) can be a compound of formula (VA) or formula (VB):

[0064]

[0065] In some embodiments of the present invention, the compound of formula (I) can be a compound of formula (VI):

[0066]

[0067] M, R1, and R5 are defined as above.

[0068] In some embodiments of the present invention, the compound of formula (VI) can be a compound of formula (VI-A) or formula (VI-B):

[0069]

[0070] In some embodiments of the present invention, the compound of formula (I) can be a specific compound or a pharmaceutically acceptable salt thereof:

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087] In some embodiments of the present invention, the compound of formula (I) can be a specific compound as follows:

[0088]

[0089] The present invention also provides a method for preparing the above-mentioned compound (I), comprising: reacting the compound (X) with the compound (XI) in the presence of a base (e.g., triethylamine) to obtain the compound (I);

[0090]

[0091] Among them, R1, R2, R3, R', ring A, and n are as defined above; R7 is a halogen (e.g., chlorine, bromine) or a hydroxyl group.

[0092] In some embodiments of the present invention, the compound of formula (I-4) can also be prepared by the following method: reacting formula (I-2) with a protecting ammonia (e.g., benzophenone imine), and then removing the protecting group to obtain the compound of formula (I-3); then reacting the compound of formula (I-3) with R9-X to obtain the compound of formula (I-4).

[0093]

[0094] Among them, rings A, R2, R3, R', and n are as defined above, X is a halogen, and R9 may be the same or different, independently selected from H, -OH, and -CO-R. 20 -S(O) a -R 25 No substitution or optional use by one or more R b The following groups can be substituted: alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic.

[0095] In some embodiments of the present invention, compounds of formula (I-5) can also be prepared by the following method, including: reacting formula (I-2) with R 1a The -H reacts to give the compound of formula (I-5).

[0096]

[0097] Among them, rings A, R2, R3, R', and n are as defined above, X is a halogen, and R... 1a For -NR 15 R 16 Or heteroaryl, R 15 and R 16Cycloning to form a heterocyclic or heteroaryl group containing N; the heterocyclic or heteroaryl group may optionally be oxidized by one or more R groups. b Replace, and adjacent or non-adjacent R b They can be connected into a ring to form unsubstituted or R-shaped structures. d The substituted cycloalkyl, heterocyclic, aryl, or heteroaryl groups.

[0098] According to the present invention, the formula (I-2) and R 1a -H is coupled via catalytic coupling with copper or pd to obtain compound (I-5).

[0099] In some embodiments of the present invention, compounds of formula (I-6) can also be prepared by the following method, including: mixing compounds of formula (I-2) with R. 1b -Y reacts to give compound (I-6).

[0100]

[0101] Among them, rings A, R2, R3, R', and n are as defined above, X is a halogen, and R... 1b It is cyano, alkyl, aryl, or heteroaryl, and Y is -B(OH)2, -Sn(alkyl)3, or wait;

[0102] According to an embodiment of the present invention, the compound of formula (I-2) can be prepared by the following method: reacting the compound of formula (X) with the compound of formula (XI-1) in the presence of a base (e.g., triethylamine) to obtain the compound of formula (I-1), and then reacting it with a halogenated reagent to obtain the compound of formula (I-2).

[0103]

[0104] Among them, R7, R2, R3, R', ring A, n, and X are defined as above.

[0105] If necessary, protecting groups can be used to protect any functional groups of the reactants or intermediates in the above scheme. After the reaction is complete, a suitable method can be selected to remove the protecting group.

[0106] The reactants in the above scheme can be synthesized by methods reported in the literature or obtained by purchase. The starting materials are usually from commercial sources, such as Aldrich, or can be easily prepared using methods known to those skilled in the art (obtained through online databases such as SciFinder and Reaxys).

[0107] The preparation method of the present invention allows for the selection of suitable reaction conditions and raw materials according to various circumstances. For example, in a one-step reaction, only one substituent can be replaced with another substituent according to the present invention, or multiple substituents can be replaced with other substituents according to the present invention in the same reaction step.

[0108] If the compounds cannot be obtained via the above route, they can be prepared by deriving other compounds of formula (I) or by conventionally changing the synthetic route.

[0109] The compounds of formula (I) described in this invention, their stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, metabolites, pharmaceutically acceptable salts or prodrugs may be synthesized by means of methods similar to those known in the field of chemistry, with steps and conditions referencing those of similar reactions in the art, particularly as described herein.

[0110] In this invention, the compound shown in formula (I) can also be obtained by peripheral modification of the compound prepared in the above scheme using conventional methods in the art to obtain other compounds shown in formula (I).

[0111] After the reaction of this invention is completed, conventional post-processing methods can be used for further processing. In this invention, if a crude compound as shown in formula (I) is obtained after processing, it can be separated and purified using conventional methods such as preparative HPLC, preparative TLC, or recrystallization.

[0112] The present invention also provides an intermediate having the structure of a compound of formula (XI).

[0113]

[0114] Among them, R1, R2, R3, ring A, and n are defined as above.

[0115] In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XII).

[0116]

[0117] R1, R2, R3, and p are defined as above.

[0118] In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XIII).

[0119]

[0120] R2, R3, and p are defined as above.

[0121] In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XIV).

[0122]

[0123] R5 is defined as above.

[0124] In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XV).

[0125]

[0126] In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XV-A) or formula (XV-B).

[0127]

[0128] The present invention also provides a method for preparing formula (XIII), comprising any of the following methods,

[0129] Method 1, the method includes the following steps:

[0130]

[0131] Wherein, R2, R3, and p are as defined above; R8 is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aralkyl group (e.g., 4-methoxybenzyl, 2,4-dimethoxybenzyl); X is a halogen;

[0132] 1) The compound of formula (XVIII) is reacted with R8-X to give the compound of formula (XVII);

[0133] 2) The compound of formula (XVII) is subjected to hydrogenation in the presence of a reducing agent to obtain the compound of formula (XVI);

[0134] 3) The compound of formula (XVI) is reacted under acidic conditions to obtain the compound of formula (XIII).

[0135] or

[0136] Method 2, the method comprising the following steps: hydrogenating compound (XVIII) in the presence of a catalyst to obtain compound (XIII);

[0137]

[0138] R2, R3, and p are defined as above.

[0139] According to the present invention, the compound of formula (XVIII) can be prepared by the following method, comprising: reacting the compound of formula (XX) with R2COOH to obtain the compound of formula (XIX), and then cyclizing the compound of formula (XIX) to obtain the compound of formula (XVIII);

[0140]

[0141] R2, R3, and p are defined as above.

[0142] The present invention also provides a pharmaceutical composition comprising one, two or more of the following: a compound represented by formula (I) above, its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, pharmaceutically acceptable salts, metabolites, and prodrugs;

[0143] According to the present invention, the pharmaceutical composition may optionally contain at least one pharmaceutically acceptable excipient;

[0144] According to the present invention, the pharmaceutical composition may optionally contain at least one additional active ingredient; specifically, the pharmaceutical composition may also contain one or more active ingredients other than compounds of formula (I), their stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, pharmaceutically acceptable salts, metabolites, and prodrugs.

[0145] In the pharmaceutical composition described herein, the dosage of the compound represented by formula (I), its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, pharmaceutically acceptable salts, metabolites, and prodrugs may be a therapeutically effective amount.

[0146] According to the present invention, the pharmaceutical compositions of the present invention can be formulated into dosage forms suitable for administration by methods known in the art.

[0147] The present invention also provides one, two or more of the following: compounds represented by formula (I), stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, pharmaceutically acceptable salts, metabolites, prodrugs, or the use of the pharmaceutical composition thereof in the preparation of a medicament.

[0148] According to the present invention, the drug is an NK-3 receptor antagonist.

[0149] According to the present invention, the drug is used for the prevention and / or treatment of diseases mediated by NK-3 receptors;

[0150] In some implementations, the drug may be used to prevent and / or treat depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorder, cognitive impairment, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, seizures, obesity, inflammatory diseases, vomiting, preeclampsia, airway-related diseases, reproductive disorders, contraceptive and sex hormone-dependent diseases, or gynecological diseases.

[0151] The sex hormone-dependent diseases mentioned include, but are not limited to, benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male pattern baldness, endometriosis, puberty abnormalities, uterine fibroids, uterine fibroids, hormone-dependent cancers, hyperandrogenemia, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysmenorrhea (PMDD), HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN with luteinized theca cells in the ovarian stroma), other manifestations of high intraovarian androgen concentrations (e.g., follicular arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumors (virilizing ovarian tumors or adrenal tumors), menorrhagia, and adenomyosis.

[0152] The airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction, and cough.

[0153] In some implementations, the drug is used to treat and / or prevent menopausal syndrome-related conditions, including symptoms such as hot flashes, sweating, palpitations, dizziness, and obesity.

[0154] The present invention also provides a method for treating and / or preventing NK3 receptor-mediated symptoms or diseases, the method comprising administering to a therapeutically effective amount of one, two or more of the following: a compound of formula (I), its stereoisomers, tautomers, isotope labels, nitrogen oxides, solvates, polymorphs, pharmaceutically acceptable salts, metabolites, and prodrugs;

[0155] According to the present invention, the condition or disease is depression, anxiety, psychosis, schizophrenia, psychotic disorder, bipolar disorder, cognitive impairment, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, seizures, obesity, inflammatory diseases, vomiting, preeclampsia, airway-related diseases, reproductive disorders, contraceptive and sex hormone-dependent diseases or gynecological diseases.

[0156] The sex hormone-dependent diseases mentioned include, but are not limited to, benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male pattern baldness, endometriosis, puberty abnormalities, uterine fibroids, uterine fibroids, hormone-dependent cancers, hyperandrogenemia, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysmenorrhea (PMDD), HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN with luteinized theca cells in the ovarian stroma), other manifestations of high intraovarian androgen concentrations (e.g., follicular arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumors (virilizing ovarian tumors or adrenal tumors), menorrhagia, and adenomyosis.

[0157] The airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction, and cough.

[0158] In some implementations, the condition or disease is a menopausal syndrome-related disease, which includes symptoms such as hot flashes, sweating, palpitations, dizziness, and obesity.

[0159] The method comprises administering to a patient in need a therapeutically effective amount of a compound of formula (I), its stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, polymorphs, pharmaceutically acceptable salts, metabolites, or one, two, or more prodrugs. Preferably, the patient is a warm-blooded animal, more preferably a human.

[0160] Terminology Definition

[0161] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0162] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0163] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0164] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-40" is equivalent to describing each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-40", namely 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40. It should be understood that when describing one or more substituents herein, "a plurality of" should refer to integers ≥2, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0165] The term "halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0166] The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation.

[0167] The term "thiolation" refers to the substitution of a carbon atom in a substituent with a sulfide group (=S) formed by sulfidation.

[0168] Unless otherwise stated, the definitions of terms in this document also apply to groups containing the term; for example, the definition of alkyl also applies to alkyl groups in alkoxy, alkylamino, dialkylamino, haloalkyl, haloalkoxy, etc.

[0169] In the general formula definition of this application, the term "optional" (or "optionally", "optionally") means that it is substituted by 0 or one or more substituents. For example, "optionally substituted by one, two or more R" means that it may not be substituted by R (no substitution) or may be substituted by one, two or more R.

[0170] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions. The substituents mentioned can be, but are not limited to, =O, hydrogen, deuterium, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, carboxyl, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, etc.

[0171] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently selected" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can be independently selected from the same or different specific groups. More specifically, the descriptive phrase "...independently selected" can mean either that the specific options expressed by the same symbol in different groups do not affect each other, or that the specific options expressed by the same symbol in the same group do not affect each other.

[0172] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, the invention includes every independent secondary combination of the various members of these group types and scopes. For example, the term "C..." 1-6 "Alkyl" specifically refers to independently disclosed C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl.

[0173] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0174] The term "alkyl" or "alkylene" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 40 carbon atoms. For example, "C..." 1-10 Alkyl", C 1-6 Alkyl", "C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl or alkylene group contains 1-12 carbon atoms; in other embodiments, the alkyl or alkylene group contains 1-6 carbon atoms; and in still other embodiments, the alkyl or alkylene group contains 1-4 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, etc. sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. Examples of the alkylene group include, but are not limited to, methylene and ethylene.

[0175] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2-40 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp. 2 The double bonds are separable or conjugated. The alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis" and "tans", or the orientation of "E" and "Z", preferably "C". 2-10 "alkenyl", "C" 2-6 "Alkenyl". "C" 2-6 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C"). 2-3(Alkenyl). Examples of the alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pentyl -2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methyl 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)- 1-Methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0176] The term "alkynyl" should be understood to refer to a straight-chain or branched hydrocarbon group containing one or more triple bonds and having 2 to 40 carbon atoms, preferably "C2-C". 10"-Alynyl" and "C2-C6-Alynyl". The term "C2-C6-Alynyl" should be understood to preferably represent a straight-chain or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-Alynyl"). The C2-C6-Alynyl is, for example, ethynyl, propynyl, propynyl-2-Alynyl, butynyl, butynyl-2-Alynyl, butynyl-3-Alynyl, pentynyl, pentynyl-2-Alynyl, pentynyl-3-Alynyl, pentynyl-4-Alynyl, hexynyl, hexynyl-2-Alynyl, hexynyl-3-Alynyl, hexynyl-4-Alynyl, hexynyl-5-Alynyl, 1-methylpropynyl-2-Alynyl, 2-methylbutynyl-3-Alynyl, 1-methylbutynyl-3-Alynyl, 1-methylbutynyl-2-Alynyl, 3- The alkynyl group is methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpentan-4-ynyl, 2-methylpentan-4-ynyl, 1-methylpentan-4-ynyl, 2-methylpentan-3-ynyl, 1-methylpentan-3-ynyl, 4-methylpentan-2-ynyl, 1-methylpentan-2-ynyl, 4-methylpentan-1-ynyl, 3-methylpentan-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylpropan-2-ynyl, 1-isopropylpropan-2-ynyl, 2,2-dimethylbutan-3-ynyl, 1,1-dimethylbutan-3-ynyl, 1,1-dimethylbutan-2-ynyl, or 3,3-dimethylbutan-1-ynyl. In particular, the alkynyl group is ethynyl, propan-1-ynyl, or propan-2-ynyl.

[0177] The term "cycloalkyl" should be understood to refer to saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cycloalkanes having 3 to 40 carbon atoms, preferably "C". 3-10 cycloalkyl. The term "C" 3-10 "Cycloalkyl" should be understood to refer to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cycloalkanes having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decahydronaphthalene ring.

[0178] The term "heterocyclic group" should be understood to refer to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cycloalkanes comprising 1-5 heteroatoms independently selected from N, O, and S, forming a non-aromatic cyclic group with a total ring atom number of 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.), preferably a "3-10 membered heterocyclic group". The term "3-10 membered heterocyclic group" means a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cycloalkanes comprising 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S, for example, 1, 2, or 3 heteroatoms independently selected from N, O, and S. The heterocyclic group can be attached to the remainder of the molecule via any one of the carbon atoms or a nitrogen atom (if present). Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirrobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, tetrahydropyridinyl, 2H-pyranyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl.

[0179] According to the present invention, the heterocyclic group is non-aromatic. When the 3-20 membered heterocyclic group is linked with other groups to form the compound of the present invention, the carbon atom on the 3-20 membered heterocyclic group can be linked with other groups, or the heterocyclic atom on the ring of the 3-20 membered heterocyclic group can be linked with other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be linked with other groups. Or when the 3-20 membered heterocyclic group is selected from piperidinium, the nitrogen atom on the piperidinium ring and the carbon atom at its para position can be linked with other groups.

[0180] The term "aryl" should be understood to refer to a monocyclic, bicyclic, or tricyclic hydrocarbon ring having aromatic or partially aromatic properties with 6 to 20 carbon atoms, preferably "C". 6-14 Aryl. The term "C" 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0181] The term "heteroaryl" should be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems, including aromatic or partially aromatic ones, having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, for example, "5-14-membered heteroaryl". The term "5-14-membered heteroaryl" should also be understood to include monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O, and S, and, in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylonitrileyl, inazinyl, purinyl, and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylonitrileyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, etc. When the 5-20 membered heteroaryl group is linked with other groups to form the compound of the present invention, the carbon atom on the 5-20 membered heteroaryl ring may be linked with other groups, or the heteroatom on the 5-20 membered heteroaryl ring may be linked with other groups. When the 5-20 membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, the hydrogen atom linked to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen atom linked to the heteroatom on the heteroaryl ring may be substituted.

[0182] Unless otherwise stated, heterocyclic, heteroaryl, or heteroaryl groups include all possible isomers, such as their positional isomers. Thus, for some illustrative, non-limiting examples, forms may include those in which one, two, or more of the following positions (if present) are substituted or bonded to other groups, including pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thiophene or thiophene groups include thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0183] The term "alkoxy" should be understood as -O-alkyl, as defined above.

[0184] The term “halogenated alkyl” should be understood as an alkyl group in which the H atom is partially or completely replaced by a halogen, as defined above.

[0185] The term “haloalkoxy” should be understood as -O-haloalkyl, as defined above. The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereo chemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0186] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0187] "Enantiomers" refer to two non-overlapping but mirror-image isomers of a compound.

[0188] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0189] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)- configuration.

[0190] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0191] In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomer separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0192] The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved for the tautomers. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0193] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, etc.

[0194] The term "carrier" refers to a diluent, excipient, excipient, or matrix that is administered together with the compound. These drug carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Aqueous and aqueous solutions, saline solutions, and aqueous glucose and glycerol solutions are preferred as carriers, particularly for injectable solutions. Suitable drug carriers are described in EW Martin's "Remington's Pharmaceutical Sciences".

[0195] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C) esters. 1-24 Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent compound with a hydroxyl group. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series; Edward B. He, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0196] As used in this invention, the term "metabolite" refers to the product obtained in vivo through the metabolism of a specific compound or its salt. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0197] Pharmaceutically acceptable salts can be, for example, acid addition salts of compounds of the present invention that have sufficient basicity, having a nitrogen atom in the chain or ring.

[0198] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0199] The term "nitrogen oxide" in this invention refers to an N-oxide formed by oxidizing one or more nitrogen atoms when the compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen atoms in nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), wherein the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane.

[0200] The term "isotope label" includes, but is not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl)-labeled compounds of the present invention. Isotope-labeled compounds of the present invention can be used for the determination of the tissue distribution of the compounds, their prodrugs, and metabolites; preferred isotopes for such determinations include 3 H and 14C. Furthermore, in some cases, substitution with a heavier isotope (e.g., deuterium (2H or D)) can provide increased metabolic stability, which offers therapeutic advantages such as increased in vivo half-life or reduced dose requirements. The isotopically labeled compounds of the present invention can generally be prepared according to the methods described herein by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0201] As used in this invention, the term "treatment" refers to any disease or condition, and in some embodiments, it means improving the disease or condition (i.e., slowing down or stopping or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" means alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceived by the patient. In still other embodiments, "treatment" means regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters) or both. In still other embodiments, "treatment" means preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0202] The term "effective amount" or "therapeutic effective amount" refers to the amount of the compound of this invention sufficient to achieve the intended application (including, but not limited to, the treatment of diseases as defined below). Therapeutic effective amounts may vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, such as the subject's weight and age, the severity of the disease, and the route of administration, which can be readily determined by those skilled in the art. Specific dosages will vary depending on factors such as the particular compound selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which the drug is administered, and the physical delivery system used.

[0203] Unless otherwise stated, any abbreviations for protecting groups, amino acids and other compounds used in this invention shall be those that are commonly used and recognized, or refer to the IUPAC-IUB Commission on Biological Nomenclature (see Biological. 1972, 11: 942-944).

[0204] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0205] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention. Detailed Implementation

[0206] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0207] Examples

[0208] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0209] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18 150×4.6 mm column).

[0210] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0211] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0212] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0213] Example 1

[0214] Preparation of (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (001)

[0215]

[0216] Step 1: Preparation of 2-(chloromethyl)-3-methylpyrazine

[0217] 2,3-Dimethylpyrazine 001a (10 g, 92.47 mmol) was added to carbon tetrachloride (250 mL) solvent, followed by N-chlorosuccinimide (14.83 g, 110.96 mmol) and benzoyl peroxide (224 mg, 9.25 mmol). The reaction mixture was reacted at 80 °C for 16 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the solvent was evaporated to dryness and water (150 mL) and dichloromethane (3 × 100 mL) were added. The mixture was extracted and separated, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the title product 2-(chloromethyl)-3-methylpyrazine 001b (3.20 g, colorless oil), yield: 22%.

[0218] MS m / z(ESI): 143.2 [M+1] + .

[0219] 1 H NMR (400MHz, CDCl3) δ8.45 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 4.71 (s, 2H), 2.69 (s, 3H).

[0220] Step 2: Preparation of 2-((3-methylpyrazin-2-yl)methyl)isoindololin-1,3-dione

[0221] 2-(chloromethyl)-3-methylpyrazine 001b (3.20 g, 22.44 mmol) was added to N,N-dimethylformamide solvent, and 6.23 g (33.66 mmol) of potassium phthalimide was added. The reaction mixture was reacted at 110 °C for 8 hours under nitrogen protection and monitored by LCMS. After the reaction was completed, the solvent was evaporated to dryness, and water and ethyl acetate were added. The mixture was extracted and separated, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography with petroleum ether / ethyl acetate (1:1) to give the title product 2-3-methylpyrazine-2-ylmethylisoindoline-1,3-dione 001c (3.10 g), a pale yellow solid, yield: 95%.

[0222] MS m / z(ESI): 254.2[M+1]+.

[0223] 1 H NMR (400MHz, CDCl3) δ8.33(d,J=2.4Hz,1H),8.24(d,J=2.4Hz,1H),7.90(dd,J=5.6,3.2Hz,2H),7.75(dd,J=5.6,3.2Hz,2H),5.02(s,2H),2.70(s,3H).

[0224] Step 3: Preparation of 2-(aminomethyl)-3-methylpyrazine

[0225] 2-((3-methylpyrazine-2-yl)methyl)isoindoline-1,3-dione 001c (2.00 g, 7.90 mmol) was added to ethanol (50 mL) solvent, followed by hydrazine hydrate (3.95 g, 79 mmol). The reaction mixture was reacted at 80 °C for 6 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the solvent was evaporated to dryness and water (150 mL) was added. The mixture was extracted with dichloromethane / methanol (1 / 1, V / V, 50 mL), and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 2-(aminomethyl)-3-methylpyrazine 001d (300 mg, yellow oil), yield: 28%.

[0226] MS m / z (ESI): 124.3 [M+1] + .

[0227] 1 H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 8.33 (d, J = 2.4Hz, 1H), 4.02 (s, 2H), 2.54 (s, 3H).

[0228] Step 4: Preparation of 3-methyl-N-((3-methylpyrazin-2-yl)methyl)-1,2,4-thiadiazole-5-carboxamide

[0229] 3-Methyl-1,2,4-thiadiazole-5-carboxylic acid (280 mg, 1.94 mmol) was added to dichloromethane (10 mL) solvent, followed by the addition of 0.5 mL of oxaloyl chloride (0.5 mL) and N,N-dimethylformamide (0.1 mL). The reaction mixture was reacted at 25 °C for 0.5 h. After the reaction was completed as monitored by LCMS, the solvent was evaporated to dryness to obtain the crude product 3-methyl-1,2,4-thiadiazole-5-carbonyl chloride. (3-Methylpyrazine-2-yl)methylamine (200 mg, 1.62 mmol) and triethylamine (246 mg, 2.43 mmol) were added to dichloromethane (10 mL) solvent, and the crude product 3-methyl-1,2,4-thiadiazole-5-carbonyl chloride dissolved in dichloromethane (5 mL) was slowly added dropwise. The reaction mixture was reacted at 25 °C for 0.5 h. After the reaction was monitored by LCMS, water (30 mL) and dichloromethane (3 × 20 mL) were added, the mixture was extracted and separated, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title product 3-methyl-N-((3-methylpyrazin-2-yl)methyl)-1,2,4-thiadiazole-5-carboxamide 001e (170 mg, yellow solid), yield: 40%.

[0230] MS m / z(ESI): 250.2 [M+1] + .

[0231] 1 H NMR (400MHz, CDCl3) δ8.59 (s, 1H), 8.46 (s, 2H), 4.78 (d, J = 4.8Hz, 2H), 2.76 (s, 3H), 2.65 (s, 3H).

[0232] Step 5: Preparation of 3-methyl-5-(8-methylimidazo[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole

[0233] 3-Methyl-N-((3-methylpyrazin-2-yl)methyl)-1,2,4-thiadiazole-5-carboxamide 001e (400 mg, 1.60 mmol) was added to acetonitrile (10 mL), followed by phosphorus oxychloride (0.74 g, 4.80 mmol) and N,N-dimethylformamide (0.2 mL). The reaction mixture was reacted at 85 °C for 48 hours under nitrogen protection. After the reaction was completed, the solvent was evaporated to dryness using LCMS. Add saturated sodium bicarbonate solution (50 mL) and ethyl acetate (3 × 20 mL), extract and separate the contents, wash with saturated sodium chloride solution (50 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title product 3-methyl-5-(8-methylimidazo[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole 001f (250 mg, yellow solid), yield: 60%.

[0234] MS m / z(ESI): 232.2 [M+1] + .

[0235] 1 H NMR (400MHz, CDCl3) δ9.58 (d, J = 3.2Hz, 1H), 8.51 (s, 1H), 7.81 (s, 1H), 3.22 (s, 3H), 2.83 (s, 3H).

[0236] Step 6: Preparation of 7-(4-methoxybenzyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)imidazo[1,5-a]pyrazine-7-onium

[0237] 3-Methyl-5-(8-methylimidazo[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole 001f (1.0 g, 4.3 mmol) was added to acetonitrile (6 mL), followed by potassium iodide (357 mg, 2.15 mmol) and 1-(chloromethyl)-4-methoxybenzyl (1.30 g, 8.60 mmol). The reaction mixture was reacted at 8 °C for 16 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the solvent was evaporated to dryness to give the crude product 7-(4-methoxybenzyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazole-5-yl)imidazo[1,5-a]pyrazin-7-onium 001g (600 mg, yellow solid), yield: 34%.

[0238] MS m / z(ESI): 352.2 [M+1] + .

[0239] Step 7: Preparation of 5-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-methyl-1,2,4-thiadiazole

[0240] 0.01 g (600 mg, 1.7 mmol) of 7-(4-methoxybenzyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)imidazo[1,5-a]pyrazine-7-onium was added to 10 mL of ethanol, followed by 0.1 mL of acetic acid and 320 mg (5.1 mmol) of sodium cyanoborohydride. The reaction mixture was reacted at 0 °C for 0.5 h under nitrogen protection. After the reaction was completed, the solvent was evaporated to dryness by LCMS. Add water (50 mL) and dichloromethane (3 × 20 mL), extract and separate the contents, wash with saturated sodium chloride solution (50 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title product 5-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-methyl-1,2,4-thiadiazole 001h (300 mg, yellow solid), yield: 24%.

[0241] MS m / z(ESI): 356.2 [M+1] + .

[0242] Step 8: Preparation of 3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)1,2,4-thiadiazole

[0243] 5-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-methyl-1,2,4-thiadiazole 001h (200 mg, 0.56 mmol) was added to trifluoroacetic acid (3 mL) solvent. The reaction mixture was reacted at 100 °C for 16 h under nitrogen protection. After the reaction was completed as monitored by LCMS, the reaction mixture was cooled to room temperature. The solvent was evaporated to dryness to obtain the crude product, which was purified by reverse column chromatography (acetonitrile / water = 1:10) to give the title product 3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)1,2,4-thiadiazole 001i (120 mg, white solid), yield: 72%.

[0244] MS m / z(ESI): 236.2 [M+1] + .

[0245] HNMR: 1 H NMR (400MHz, DMSO-) d6)δ9.47(s,1H),7.32(s,1H),4.95-4.88(m,1H),4.70(q,J=6.4Hz,

[0246] 1H),4.45-4.35(m,1H),3.86-3.79(m,1H),3.60-3.51(m,1H),2.66(s,3H),1.63(d,J=6.8Hz,3H).

[0247] Step 9: Preparation of (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone

[0248] 3-Methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)1,2,4-thiadiazole 001i (100 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL), followed by the addition of triethylamine (64 mg, 0.63 mmol) and p-fluorobenzoyl chloride (80 mg, 0.50 mmol). The reaction mixture was reacted at 25 °C for 2 hours. After the reaction was complete, water (20 mL) and dichloromethane (2 × 20 mL) were added, and the mixture was extracted and separated. The extract was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase chromatography (acetonitrile / water = 1:1) to obtain 001 (10.20 mg, white solid), yield: 25%.

[0249] MS m / z(ESI): 358.0 [M+1] + .

[0250] 1 H NMR (400MHz, CDCl3) δ7.47 (dd, J=8.6, 5.3Hz, 2H), 7.16 (t, J=8.6Hz, 2H), 7.07 (s, 1H), 5.71 (br s,1H),5.06(dd,J=13.8,2.4Hz,1H),4.43-4.35(m,1H),4.24-4.17(m,1H),3.54(t,J=12.7Hz,1H),2.68(s,3H),1.61(d,J=6.8Hz,3H).

[0251] Example 2

[0252] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (002) and (S)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (003)

[0253] (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 002a (100 mg) was resolved by perp-SFC (CO2 / MeOH(0.2NH4.OH)) to obtain (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 002a (100 mg). (S)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) ketone (002) (39.20 mg, white solid) and (S)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) ketone (003) (39.20 mg, white solid).

[0254] The data corresponding to 002 is as follows:

[0255] t R =3.62min

[0256] HNMR: 1 H NMR (400MHz, CDCl3) δ7.47 (dd, J=8.6, 5.6Hz, 2H), 7.16 (t, J=8.6Hz, 2H), 7.06 (s, 1H), 5.93-5.52 (m, 1H), 5 .06(dd,J=13.8,2.4Hz,1H),4.54-4.11(m,2H),3.54(t,J=12.4Hz,1H),2.68(s,3H),1.61(d,J=6.8Hz,3H).

[0257] The data corresponding to 003 is as follows:

[0258] t R =1.82min

[0259] MS m / z(ESI): 358.0 [M+1] + .

[0260] HNMR: 1H NMR (400MHz, CDCl3) δ7.51-7.43(m,2H),7.16(t,J=8.6Hz,2H),7.06(s,1H),5.91-5.47(m,1H),5.05( dd,J=13.8,2.4Hz,1H),4.52-4.06(m,2H),3.54(t,J=12.6Hz,1H),2.67(s,3H),1.61(d,J=6.8Hz,3H).

[0261] The conditions for splitting SFC are:

[0262] Column: Daicel CHIRALPAK OZ-H 250mm*20mm ID, 5μm

[0263] Mobile phase: CO2 / MeOH (0.2% NH4·OH) = 70 / 30

[0264] Flow rate: 50 g / min.

[0265] Example 3

[0266] Preparation of (4-fluorophenyl)(1-chloro-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (004)

[0267] (4-Fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (004a) (30 mg, 0.084 mmol) was dissolved in 5 mL of dichloromethane, and NCS (22 mg, 0.17 mmol) was added. The reaction mixture was reacted at room temperature for 30 minutes. After the reaction was completed, 10 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography (43% acetonitrile / water) to give (4-fluorophenyl)(1-chloro-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 004 (2 mg, white solid), yield: 6%.

[0268] MS m / z(ESI): 392.1 [M+1] + .

[0269] 1H NMR (400MHz, CDCl3) δ7.47 (dd, J=6.4, 5.6Hz, 2H), 7.17 (t, J=8.4Hz, 2H), 6.15-5.58 (m, 1H), 5. 04(d,J=13.2Hz,1H),4.40-3.98(m,2H),3.66-3.42(m,1H),2.67(s,3H),1.62(d,J=6.0Hz,3H).

[0270] HPLC: 254nm (95.03%), 214nm (95.95%).

[0271] Example 4

[0272] Preparation of (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (005)

[0273]

[0274] Dissolve (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (005a) (50 mg, 0.11 mmol) in 2 mL of tetrahydrofuran / water (4 / 1), then add pyridineboronic acid (16 mg, 0.12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol), and potassium carbonate (24 mg, 0.17 mmol) in sequence. The reaction mixture was stirred at 80°C for 4 hours under nitrogen protection. The reaction solution was extracted with ethyl acetate, dried over saturated sodium chloride solution and anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (50% acetonitrile / water) to give (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (005) (12.7 mg, white solid), yield: 25%.

[0275] MS: m / z (ESI): 435.2 [M+1] + .

[0276] 1H NMR (400MHz, CDCl3) δ8.78-8.55(m,2H),7.90-7.57(m,2H),7.51(dd,J=8.4,5.2Hz,2H),7.19(t,J=8.4Hz,2H),6.64- 6.29(m,1H),5.13(dd,J=14.0,2.4Hz,1H),4.33-4.07(m,2H),3.79-3.58(m,1H),2.70(s,3H),1.58(d,J=6.8Hz,3H).

[0277] HPLC: 254nm (100%), 214nm (100%).

[0278] Example 5

[0279] Preparation of methyl 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (006)

[0280]

[0281] At room temperature, (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (006a) (50 mg, 0.11 mmol) was dissolved in methanol (5 mL), and potassium acetate (34 mg, 0.34 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol) were added. The reaction was stirred at 80 °C for 2 hours in a carbon monoxide atmosphere. After the reaction was complete, the solvent was evaporated to dryness, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phase was collected, and the solvent was evaporated to dryness to give the crude product. The crude product was purified by reverse-phase column chromatography (acetonitrile / water) to obtain methyl 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (006) (5 mg, white solid), yield: 10%.

[0282] MS m / z (ESI) 416.2 [M+1] + .

[0283] 1H NMRδppm (400MHz, CDCl3):7.49-7.49(m,2H),7.13-7.17(m,2H),6.41(s,1H),5.61(s,1H),5.0 6-5.10(m,2H),4.29(s,1H),3.89(s,3H),3.53-3.68(m,1H),2.69(s,3H),1.69(d,J=6.6Hz,3H)

[0284] 19 F NMR (376MHz, cdcl3) δppm: -108.53, -109.06--109.73.

[0285] Example 6

[0286] Preparation of 7-(4-fluorobenzoyl)-N,8-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (007)

[0287]

[0288] Methyl 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (007a) (20 mg, 0.05 mmol) was dissolved in ethanol (2 mL), and then a 4 M ethanol solution of methylamine (0.5 mL) was added. The mixture was stirred at 90 °C for 3 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure and purified by reverse-phase column chromatography (55% acetonitrile / water) to give 7-(4-fluorobenzoyl)-N,8-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (007) (2.19 mg, white solid), yield: 10%.

[0289] MS.m / z(ESI):415.2[M+1] + .

[0290] 1 H NMR (400MHz, CDCl3) δ7.48 (dd, J=8.4, 5.4Hz, 2H), 7.13 (t, J=8.4Hz, 2H), 7.05 (s, 1H), 5.81-5.54 (m, 1H), 5.16-4.84(m,2H),4.31-4.21(m,1H),3.62-3.40(m,1H),2.94(s,3H),2.71(s,3H),1.75(d,J=6.8Hz,3H).

[0291] HPLC: 254nm (99.4%), 214nm (97.4%).

[0292] Example 7

[0293] Preparation of N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazole[1],5-a]pyrazin-1-yl)acetamide (008)

[0294]

[0295] Step 1: Preparation of [1-[(diphenylmethylene)amino]-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl](4-fluorophenyl)methyl ketone

[0296] Dissolve (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (008a) (100 mg, 0.23 mmol) in N,N-dimethylformamide (4 mL), then add diphenylmethaneimine (50 mg, 0.27 mmol), (±)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (29 mg, 0.046 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one, and palladium (26 mg, 0.046 mmol). The reaction mixture was stirred at 100 °C for 16 hours with 149 mg of cesium carbonate (1 mol) and 149 mg of cesium carbonate (149 mg, 0.46 mmol). The reaction mixture was then added to water (10 mL), extracted with ethyl acetate (20 mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give [1-[(diphenylmethylene)amino]-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl](4-fluorophenyl)methyl ketone 008b (40 mg, yellow solid), yield: 29%.

[0297] MS.m / z(ESI):537.2[M+1] + .

[0298] Step 2: Preparation of (1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone

[0299] [1-[(diphenylmethylene)amino]-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl](4-fluorophenyl) methyl ketone 008b (40 mg, 0.07 mmol) was dissolved in dichloromethane, and hydrochloric acid (3 mg, 0.07 mmol) was added. The reaction mixture was stirred at 25 °C for 0.5 hours. After concentration, the reaction mixture was subjected to reverse-phase column chromatography (acetonitrile / water = 40%) to give (1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 008c (20 mg, pale yellow solid), yield: 69%.

[0300] MS.m / z(ESI):373.1[M+1]+.

[0301] 1H NMR (400MHz, CDCl3) δ7.47 (dd, J=8.4, 5.2Hz, 2H), 7.16 (t, J=8.4Hz, 2H), 5.84 (brs, 1H), 5.00 (d,J=12.4Hz,1H),4.12-3.91(m,2H),3.67-3.30(m,3H),2.64(s,3H),1.55(d,J=4.8Hz,3H).

[0302] Step 3: Preparation of N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazolium[1],5-a]pyrazin-1-yl)acetamide

[0303] (1-Amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 008c (15 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of trimethylamine (6 mg, 0.06 mmol) and acetyl chloride (4 mg, 0.04 mmol). The reaction mixture was stirred at 0 °C for 0.5 hours. Add water (5 mL), extract with dichloromethane (10 mL), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and precipitate the residue by reverse column chromatography (acetonitrile / water = 60%) to give N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazole[1],5-a]pyrazin-1-yl)acetamide 008 (5 mg, white solid), yield: 29%.

[0304] MS.m / z(ESI):415.1[M+1]+ .

[0305] 1 H NMR (400MHz, CDCl3) δ7.62-7.41(m,3H),7.16(t,J=8.6Hz,2H),6.14-5.72(m,1H),5.32-4.73(m, 2H),4.20(t,J=11.2Hz,1H),3.61-3.35(m,1H),2.68(s,3H),2.12(s,3H),1.38(d,J=5.2Hz,3H).

[0306] HPLC: 254nm (99.2%), 214nm (99.6%).

[0307] Example 8

[0308] Preparation of (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (009)

[0309]

[0310] (4-Fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 009a (50 mg, 0.013 mmol) was dissolved in dichloromethane (10 mL), followed by N-bromosuccinimide (25 mg, 0.013 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with dichloromethane (10 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (40% acetonitrile / water) to give (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 009 (16 mg, white solid), yield: 26%.

[0311] MS.m / z.(ESI):436.20[M+1] + .

[0312] 1H NMR (400MHz, CDCl3) δ7.49-7.45(m,2H),7.19-7.17(m,2H),6.02-5.81(m,1H),5.13-4 .92(m,2H),4.25-4.13(m,1H),3.68-3.49(m,1H),2.68(s,3H),1.64(d,J=6.4Hz,3H).

[0313] HPLC: 254nm (99.76%), 214nm (99.53%)

[0314] Example 9

[0315] Preparation of N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylacetamide (010)

[0316]

[0317] Step 1: Preparation of N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)acetamide

[0318] Compound 010a (40 mg, 0.11 mmol) and DIEA (42 mg, 0.32 mmol) were dissolved in DCM (3 mL), and then acetyl chloride (13 mg, 0.16 mmol) was added dropwise. The reaction mixture was reacted at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL), washed with water in saturated NaHCO3 solution and saturated NaCl solution, and dried over anhydrous sodium sulfate. After filtration and concentration, compound N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)acetamide 010b (35 mg, yellow oil) was obtained, yield: 70%.

[0319] MS m / z (ESI): 415.2 [M+1] + .

[0320] Step 2: Preparation of N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylacetamide

[0321] Compound 010b (35 mg, 0.08 mmol) was dissolved in 3 mL of anhydrous THF. After cooling to 0 °C, NaH (10 mg, 0.25 mmol, 60%) was added. The reaction solution was stirred at room temperature for 30 min, and then CH3I (18 mg, 0.13 mmol) was added. After reacting at room temperature for 2 h, the solution was poured into 10 mL of water and extracted with ethyl acetate (3 × 10 mL). The solution was then washed with water and saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by pre-HPLC (ACN / H2O (0.1% FA) = 53%) to give compound N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylacetamide 010 (10 mg, white solid), yield: 27%.

[0322] MS m / z(ESI): 429.2 [M+1] + .

[0323] 1 H NMR (400MHz, DMSO-d6) δ7.59-7.55(m,2H),7.34-7.28(m,2H),5.65(s,1H),4.84(d,J=12.0Hz,1H),4 .28(s,1H),3.85(s,1H),3.64(s,1H),3.04(s,3H),2.61(s,3H),1.79(s,3H),1.42(d,J=6.6Hz,3H).

[0324] Example 10

[0325] Preparation of 7-(4-fluorobenzoyl)-N,N,8-trimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (011)

[0326]

[0327] 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid 011a (25 mg, 0.060 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and dimethylamine hydrochloride (8 mg, 0.090 mmol), N,N-diisopropylethylamine (10 mg, 0.07 mmol), and HATU (36 mg, 0.09 mmol) were added sequentially. The reaction solution was reacted at 25 °C for 2 hours. After the reaction was completed by LCMS monitoring, 20 mL of water was added to the reaction solution, and then the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. 7-(4-fluorobenzoyl)-N,N,8-trimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 011 was purified by reversed-phase chromatography (42% acetonitrile / water). (7.50 mg, white solid) Yield: 28%.

[0328] MS m / z(ESI): 429.2 [M+1] + .

[0329] HPLC: 254nm (98.4%), 214nm (98.2%).

[0330] 1 H NMR (400MHz, CDCl3) δ7.48 (dd, J=8.4, 5.6Hz, 2H), 7.13 (t, J=8.8Hz, 2H), 6.04-5.59 (m, 1H), 5.06-4 .89(m,2H),4.37-4.17(m,1H),3.68-3.31(m,4H),3.04(s,3H),2.70(s,3H),1.66(d,J=6.8Hz,3H).

[0331] Example 11

[0332] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methylthione (012)

[0333]

[0334] (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 012a (20 mg, 0.05 mmol) was dissolved in 4 mL of toluene, and then Lawson's reagent (24 mg, 0.06 mmol) was added. After stirring at 110 °C for 3 hours, the reaction solution was concentrated and then gradually diluted with 20 mL of acetic acid. Extracted with ethyl ester, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (60% acetonitrile / water) to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methylthione 012 (1.6 mg, pale yellow solid), yield: 6.8%.

[0335] MS m / z(ESI): 415.1 [M+1] + .

[0336] 1 H NMR (400MHz, CDCl3) δ8.72(d,J=5.2Hz,2H),7.85(d,J=4.8Hz,2H),7.36(dd,J=7.6,4.8Hz,2H),7.14(t,J=8.4Hz,2 H),5.88-5.80(m,1H),5.22-5.14(m,1H),4.38-4.25(m,2H),3.87-3.80(m,1H),2.69(s,3H),1.70(d,J=6.8Hz,3H).

[0337] HPLC: 254nm (97.2%), 214nm (94.3%).

[0338] Example 12

[0339] Preparation of (R-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-3-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (013)

[0340]

[0341] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 013a (30 mg, 0.07 mmol) was dissolved in a mixture of 8 mL tetrahydrofuran and 2 mL water. Pyridine-3-boronic acid (13 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added sequentially. The reaction mixture was heated to 80 °C for 16 hours under nitrogen protection, then cooled to room temperature and 10 mL of water was added. The mixture was then extracted with dichloromethane (3 × 10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography (acetonitrile / water = 51 / 49) to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-3-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 013 (6.9 mg, white solid), yield: 24%.

[0342] MS m / z(ESI): 435.1 [M+1] + .

[0343] 1 HNMR(400MHz, CDCl3)δ9.07(s,1H),8.58(s,1H),8.10(s,1H),7.52-7.49(m,2H),7.40(s,1H),7.21-7.17(m,2 H),6.42(s,1H),5.15-5.12(m,1H),4.31(s,1H),4.11(s,1H),3.68(s,1H),2.70(s,3H),1.53(d,J=6.4Hz,3H).

[0344] 19 FNMR (376MHz, CDCl3) δ -108.76.

[0345] Example 13

[0346] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (014)

[0347]

[0348] To a solution of (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 014a (30 mg, 0.07 mmol) in dioxane (10 mL), 2-(tributyltinyl)pyridine (52 mg, 0.14 mmol) and tetra(triphenylphosphine)palladium (5 mg, 0.007 mmol) were added. Under nitrogen protection, the resulting mixture was stirred in a sealed tube at 100 °C for 6 hours. LC-MS showed that the reaction was complete. Aqueous KF (1M, 5 mL) was added to the reaction solution, and the mixture was diluted with 10 mL of water and extracted with DCM (3 × 10 mL). The combined organic layers were concentrated under reduced pressure and purified by reverse-phase column chromatography (acetonitrile / water = 60 / 40) to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 014 (2.8 mg, white solid, yield: 9.0%).

[0349] MS m / z(ESI): 435.1 [M+1] +

[0350] 1 HNMR(400MHz, CDCl3)δ8.67-8.34(m,1H),8.09(s,1H),7.71(s,1H),7.51(s,2H),7.16-7.13 (m,3H),6.12(s,1H),5.11(s,1H),4.33-4.04(m,2H),3.59(s,1H),2.70(s,3H),1.69(s,3H). 19 FNMR (376MHz, CDCl3) δ -109.43.

[0351] Example 14

[0352] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-phenyl-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone (015)

[0353]

[0354] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone 015a (30 mg, 0.07 mmol) was dissolved in 2 mL of tetrahydrofuran / water (3:1), and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.014 mmol), potassium carbonate (15 mg, 0.11 mmol), and phenylboronic acid (9 mg, 0.07 mmol) were added. The mixture was stirred at 80 °C for 4 hours under nitrogen protection. The reaction solution was extracted with ethyl acetate (20 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (65% acetonitrile / water) to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-phenyl-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone 015 (6.0 mg, white solid), yield: 19%.

[0355] MS.m / z(ESI):434.2[M+1] + .

[0356] 1 H NMR (400MHz, CDCl3) δ7.95-7.61(m,2H),7.54-7.40(m,4H),7.35-7.31(m,1H),7.21-7.14(m,2H),6.56-6.26(m,1H), 5.11(d,J=13.8Hz,1H),4.38-4.21(m,1H),4.18-3.90(m,1H),3.76-3.51(m,1H),2.69(s,3H),1.50(d,J=6.8Hz,3H).

[0357] HPLC: 254nm (99.6%), 214nm (99.9%).

[0358] Example 15

[0359] Preparation of (R)-(4-fluorophenyl)(1-(4-fluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (016)

[0360]

[0361] Add (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 016a (30 mg, 0.070 mmol), (4-fluorophenyl)boronic acid (15 mg, 0.11 mmol), Pd(dppf)Cl2 (10 mg, 0.014 mmol), and potassium carbonate to a 10 mL microwave tube equipped with a stir bar. ( 29 mg (0.21 mmol). Tetrahydrofuran / water solvent (5:1, 1 / 0.2 mL) was then added. The mixture was evacuated, purged with nitrogen, and capped. The mixture was then heated to 80 °C and stirred for 2 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the crude product. The crude product was then purified by reversed-phase chromatography (42% acetonitrile / water) to give (R)-(4-fluorophenyl)(1-(4-fluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone 016 (2.21 mg, yellow solid), yield: 7%.

[0362] MS m / z(ESI): 452.2 [M+1] + .

[0363] 1 H NMR(400MHz, CDCl3)δ7.75(s,2H),7.52-7.48(m,2H),7.21-7.14(m,4H),6.37(s,1H),5.11( d,J=12.8Hz,1H),4.28(s,1H),4.05(s,1H),3.67(s,1H),2.69(s,3H),1.49(d,J=6.4Hz,3H).

[0364] 19 F NMR(376MHz, CDCl3)δ-108.88(s,1H),-114.06(s,1H).

[0365] Example 16

[0366] Preparation of (R)-(1-(4-chlorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (017)

[0367]

[0368] To a 10 mL microwave tube equipped with a stir bar, add (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 017a (30 mg, 0.070 mmol), (4-chlorophenyl)boronic acid (16 mg, 0.11 mmol), Pd(dppf)Cl2 (10 mg, 0.014 mmol), and potassium carbonate (29 mg, 0.21 mmol). Then add the solvent tetrahydrofuran / water (5:1) (1 / 0.2 mL), evacuate, purge with nitrogen, and cap. Seal the tube and heat to 80 °C with stirring for 2 h. After the reaction was monitored by LCMS and TLC, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give crude product, which was then purified by reversed-phase chromatography (41% acetonitrile / water) to give (R)-(1-(4-chlorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 017 (7.36 mg, yellow solid), yield: 22%.

[0369] MS m / z(ESI): 468.0 [M+1] + .

[0370] 1 H NMR (400MHz, CDCl3) δ7.73 (s, 1H), 7.52 (m, 1H), 7.42 (s, 1H), 7.19 (t, J = 8.4Hz, 1H), 6.40 (s, 1H), 5 .11(d,J=13.2Hz,1H),4.28(s,1H),4.07(s,1H),3.67(s,1H),2.69(s,3H),1.50(d,J=6.4Hz,3H).

[0371] 19 F NMR (376MHz, CDCl3) δ-108.83 (s, 1H).

[0372] Example 17

[0373] Preparation of (R)-(4-fluorophenyl)(1-(4-methoxyphenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (018)

[0374]

[0375] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone 018a (30 mg, 0.07 mmol) was dissolved in tetrahydrofuran / water = 4 / 1 (5 mL), followed by the addition of 4-methoxyphenylboronic acid (16 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol), and PdCl2 (dppf) (6 mL). After the addition of 0.007 mmol g, the reaction solution was reacted at 80°C for 2 hours under nitrogen protection. The filtrate was concentrated by filtration, and the residue was purified by reverse-phase column chromatography (55% acetonitrile / water) to obtain (R)-(4-fluorophenyl)(1-(4-methoxyphenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 018 (8.6 mg, white solid), yield: 26%.

[0376] MS m / z(ESI): 464.2 [M+H + ].

[0377] 1 H NMR(400MHz,CDCl3)δ7.71(br s,2H),7.50(dd,J=8.5,5.3Hz,2H),7.18(t,J=8.6Hz,2H),6.99(d,J=8.3Hz,2H),5.11(d,J=14.0Hz,1H), 4.33-4.23(m,1H),4.10-4.02(m,1H),3.85(s,3H),3.71-3.61(m,2H),2.69(s,3H),1.49(d,J=6.5Hz,3H).

[0378] HPLC: 99.25% (214nm), 99.62% (254nm).

[0379] 19 F NMR (376MHz, CDCl3) δ-109.02.

[0380] Example 18

[0381] Preparation of (R)-N-(4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)phenyl)acetamide (019)

[0382]

[0383] Step 1: Preparation of (R)-(1-(4-aminophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone

[0384] To a 10 mL microwave tube equipped with a stir bar, add (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl 019a (30 mg, 0.070 mmol), (4-aminophenyl)boronic acid (14 mg, 0.11 mmol), Pd(dppf)Cl2 (10 mg, 0.014 mmol), and potassium carbonate (29 mg, 0.21 mmol), then add the solvent tetrahydrofuran / water (5:1, 1 / 0.2 mL). Evacuate the tube, purge with nitrogen, and cap. Then, heat to 80 °C and stir for 2 hours. After the reaction was completed by LCMS monitoring, the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give (R)-(1-(4-aminophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 019b (30 mg, yellow solid), yield: 88%.

[0385] MS m / z(ESI): 449.3 [M+1] + .

[0386] Step 2: Preparation of (R)-N-(4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)phenyl)acetamide

[0387] Dissolve (R)-(1-(4-aminophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 019b (35 mg, 0.20 mmol) and triethylamine (21 mg, 0.21 mmol) in 2 mL of dichloromethane, and slowly add acetyl chloride (8 mg, 0.11 mmol) to the solution. The reaction solution was reacted at 25°C for 10 minutes. After the reaction was completed by LCMS monitoring, 20 mL of water was added to the reaction solution, and then extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The solution was purified by reversed-phase chromatography (45% acetonitrile / water) to obtain (R)-N-(4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)phenyl)acetamide 019 (8.02 mg, yellow solid), yield: 22%.

[0388] MS m / z(ESI): 491.2 [M+1] + .

[0389] 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),7.70-7.60(m,6H),7.34(t,J=8.8Hz,2H),6.21(s,1H),4.91(d,J =12.4Hz,1H),4.38(s,1H),3.88(s,1H),3.72(s,1H),2.64(s,3H),2.07(s,3H),1.43(d,J=6.8Hz,3H).

[0390] 19 F NMR(376MHz,DMSO)δ-110.65(s,1H).

[0391] Example 19

[0392] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (020)

[0393]

[0394] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone 020a (35 mg, 0.08 mmol) was dissolved in tetrahydrofuran / water = 4 / 1 (2.5 mL), and 2-thiopheneboronic acid (16 mg, 0.12 mmol), potassium carbonate (34 mg, 0.24 mmol), and PdCl2 (dppf) (6 mg, 0.008 mmol) were added sequentially. After the addition of the feed was complete, the reaction solution was reacted at 80°C for 2 hours under nitrogen protection. After filtration, the filtrate was concentrated, and the residue was purified by reverse-phase column chromatography (55% acetonitrile / water) to obtain (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(thiophen-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 020 (10.4 mg, white solid), yield: 30%.

[0395] MS m / z(ESI): 440.1 [M+1] +

[0396] 1 H NMR (400MHz, CDCl3) δ7.50 (dd, J=8.1, 5.4Hz, 2H), 7.39-7.29 (m, 2H), 7.18 (t, J=8.5Hz, 2H), 7.13-7.05 (m, 1H), 5.14-5.08(m,1H),4.32-4.23(m,1H),4.11-4.02(m,1H),3.77-3.56(m,2H),2.69(s,3H),1.62(d,J=5.6Hz,3H).

[0397] HPLC: 98.60% (214nm), 98.40% (254nm).

[0398] 19 F NMR (376MHz, CDCl3) δ -108.91.

[0399] Example 20

[0400] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(thiazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (021)

[0401]

[0402] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 021a (35 mg, 0.08 mmol) was dissolved in dioxane (5 mL), followed by the sequential addition of 4-(tri-n-butyltin)thiazole (33 mg, 0.088 mmol) and Pd(PPh3)4 (9.3 mg, 0.008 mmol). After the addition was complete, the reaction mixture was incubated at 100 °C for 16 hours under nitrogen protection. After filtration of the reaction solution, the filtrate was concentrated, and the residue was purified by reverse-phase column chromatography (55% acetonitrile / water) to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(thiazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 021 (5.4 mg, white solid), yield: 15%.

[0403] MS obsd.(ESI+):[(M+H) + = 441.0.

[0404] 1 H NMR (400MHz, MeOD) δ9.07 (s, 1H), 7.92-7.86 (m, 1H), 7.59 (br s, 2H), 7.25 (t, J = 8.2Hz, 2H), 6.58 (br s,1H),5.15-5.04(m,1H),4.43-4.33(m,1H),4.01-3.73(m,2H),2.67(s,3H),1.66(d,J=6.6Hz,3H).

[0405] HPLC: 100% (214nm), 99.51% (254nm).

[0406] 19 F NMR (376MHz, MeOD) δ-111.66.

[0407] Example 21

[0408] Preparation of (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(oxazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (022)

[0409]

[0410] Dissolve (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 022a (44 mg, 0.10 mmol) in 3 mL of DMA, and then add 1,3-oxazole (14 mg, 0.20 mmol), potassium acetate (29 mg, 0.30 mmol), and palladium acetate (2 mg, 0.01 mmol) in sequence. Under nitrogen protection, the reaction solution was heated to 135℃ and reacted for 24 hours. After the reaction was completed, it was cooled to room temperature and 30 mL of water was added. Then, it was extracted with ethyl acetate (2 × 40 mL). The organic phases were combined sequentially, dried over anhydrous sodium sulfate and concentrated. The residue was separated by reverse-phase column chromatography (47% acetonitrile / water) and then purified by Prep-HPLC to obtain (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(oxazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 022 (0.9 mg, pale yellow solid), yield: 2%.

[0411] MS m / z(ESI): 425.0 [M+1] + .

[0412] HPLC: 96.85% (214nm), 96.81% (254nm).

[0413] 1 H NMR(400MHz, CDCl3)δ7.71(s,1H),7.50(dd,J=8.6,5.2Hz,2H),7.32-7.29(m,1H),7.16(t,J=8.6Hz,2H),5.1 6-5.08(m,1H),4.35-4.24(m,1H),4.18-4.03(m,1H),3.82-3.52(m,2H),2.70(s,3H),1.74(d,J=6.4Hz,3H).

[0414] Example 22

[0415] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (023)

[0416]

[0417] Dissolve (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 023a (31 mg, 0.07 mmol) in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.8 mL), and then add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrazole-1-carboxylic acid tert-butyl ester (41 mg, 0.14 mmol), potassium carbonate (29 mg, 0.21 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) in sequence. Under nitrogen protection, the reaction solution was heated to 90°C and reacted for 4 hours. The reaction solution was then cooled to room temperature, and 30 mL of water was added. Extraction was performed with ethyl acetate (2 × 40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated using a silica gel column (petroleum ether / ethyl acetate = 1 / 3), and then purified by Prep-HPLC to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 023 (4.5 mg, white solid), yield: 15%.

[0418] MS m / z(ESI): 424.1 [M+1] + .

[0419] HPLC: 98.45% (214nm), 98.68% (254nm).

[0420] 1 H NMR (400MHz, CDCl3) δ7.98 (s, 1H), 7.78-7.62 (m, 1H), 7.49 (dd, J = 8.4, 5.2Hz, 2H), 7.17 (t, J = 8.4Hz, 2H), 6.20 (s,1H),5.15-5.05(m,1H),4.24(br,1H),4.06(br,1H),3.85-3.40(m,2H),2.68(s,3H),1.57(d,J=6.4Hz,3H).

[0421] 19 F NMR (376MHz, CDCl3) δ -108.85.

[0422] Example 23

[0423] Preparation of (R)-(1,8-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (024)

[0424]

[0425] Step 1: Add (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl ketone 024a (60 mg, 0.14 mmol), methylboric acid (25 mg, 0.42 mmol), Pd(dppf)Cl2 (15 mg, 0.032 mmol), and potassium carbonate (58 mg, 0.42 mmol) to a 10 mL microwave tube equipped with a stir bar. Then add the solvent... The reaction mixture was prepared using dioxane / water (5:1,2 / 0.4 mL). A vacuum was created, nitrogen was introduced, and the container was capped. The mixture was then heated to 90°C through a tube seal and stirred for 1 hour. After the reaction was complete, the reaction mixture was concentrated using LCMS. The product was purified by reversed-phase chromatography (40% acetonitrile / water) to obtain (1,8-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 024b (29 mg, white solid).

[0426] The second step involved preparing (R)-(1,8-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 024 (6.63 mg, white solid) by SFC (CO2 / MeOH (0.2% NH4.OH)), yield: 23%.

[0427] MS m / z(ESI): 372.1 [M+1] + .

[0428] 1 H NMR (400MHz, CDCl3) δ7.49-7.45(m,2H),7.19-7.14(m,2H),5.94(s,1H),5.00(d,J=12.8Hz,1H), 4.18-4.13(m,1H),4.02(br,s,1H),3.63(s,1H),2.66(s,3H),2.27(s,3H),1.56(d,J=6.8Hz,3H).

[0429] 19F NMR(376MHz, CDCl3)δ-109.01(s,1H).

[0430] Example 24

[0431] Preparation of (7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyrazin-1-ylcarbamate (025)

[0432]

[0433] (1-Amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 025a (15 mg, 0.04 mmol) was dissolved in 2 mL of dichloromethane, then triethylamine (8 mg, 0.08 mmol) and chloro(ethoxy) methyl ketone (9 mg, 0.08 mol) were added. After stirring at room temperature for 4 hours, the reaction solution was then transferred sequentially... Extracted with 10 mL of dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (50% acetonitrile / water) to give (7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyrazin-1-ylcarbamate (025) (2.39 mg, white solid), yield: 13%).

[0434] MS.m / z(ESI):445.2[M+1] + .

[0435] 1 H NMR (400MHz, CDCl3) δ7.51-7.46(m,2H),7.16(t,J=8.6Hz,2H),6.50-6.36(m,1H),5.08(d,J=13.6Hz,1H ),4.31-3.87(m,4H),3.60-3.40(m,1H),2.67(s,3H),1.47(d,J=4.4Hz,3H),1.25(dd,J=7.6,4.8Hz,3H).

[0436] HPLC: 254nm (96.3%), 214nm (98.6%).

[0437] Example 25

[0438] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (026)

[0439]

[0440] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 026a (50 mg, 0.11 mmol) was dissolved in 2 mL of tetrahydrofuran / water (3:1), and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 0.02 mmol), potassium carbonate (23 mg, 0.17 mmol), and pyridin-4-ylboronic acid (15 mg, 0.12 mmol) were added. Under nitrogen protection, the mixture was stirred at 80°C for 4 hours. The reaction solution was extracted sequentially with 20 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (50% acetonitrile / water) to obtain (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (026) (25 mg, white solid), yield: 50%.

[0441] MS m / z(ESI): 435.1 [M+1] + .

[0442] 1 H NMR (400MHz, CDCl3) δ8.72(d,J=4.4Hz,2H),7.76(d,J=3.6Hz,2H),7.51(dd,J=7.2,5.2Hz,2H),7.19(t,J=8.4Hz,2H),6.56-6. 34(m,1H),5.13(d,J=12.0Hz,1H),4.36-4.23(m,1H),4.19-3.95(m,1H),3.78-3.58(m,1H),2.69(s,3H),1.58(d,J=6.4Hz,3H).

[0443] HPLC: 254nm (96.1%), 214nm (95.2%).

[0444] Example 26

[0445] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyrimidin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (027)

[0446]

[0447] Step 1: Preparation of 4-bromopyrimidine

[0448] 4-Oxypyrimidine 027a (800 mg, 8.33 mmol) was dissolved in 8 mL of acetonitrile, and phosphorus oxybromide (1.53 g, 10.00 mmol) was added. The reaction mixture was heated to 100 °C and reacted for 4 hours. The reaction mixture was then cooled to room temperature, quenched with 20 mL of water, and extracted with ethyl acetate (2 × 40 mL). The organic phases were combined sequentially, dried over anhydrous sodium sulfate, and concentrated to give 4-bromopyrimidine 027b (380 mg, orange oil), yield: 27%.

[0449] 1 H NMR (400MHz, CDCl3) δ8.96 (s, 1H), 8.51 (d, J = 5.2Hz, 1H), 7.56 (dd, J = 5.6, 1.2Hz, 1H).

[0450] Step 2: Preparation of 4-(trimethyltinyl)pyrimidine

[0451] 4-Bromopyrimidine 027b (318 mg, 2.00 mmol) was dissolved in dioxane, and hexamethyldistin (655 mg, 2.00 mmol) and Pd(PPh3)4 (116 mg, 0.10 mmol) were added sequentially. Under nitrogen protection, the reaction solution was heated to 110 °C and reacted for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diatomaceous earth was added, and the solvent was removed by rotary evaporation. The residue obtained was purified by neutral alumina column (6% ethyl acetate / petroleum ether) to obtain 4-(trimethyltinyl)pyrimidine 027c (180 mg, colorless oil), yield: 36%.

[0452] MS m / z(ESI): 245.0 [M+1] + .

[0453] 1 H NMR (400MHz, CDCl3) δ9.24(d,J=1.2Hz,1H),8.50(d,J=4.8Hz,1H),7.48(dd,J=4.8,1.6Hz,1H),0.38(s,9H).

[0454] Step 3: Preparation of 4-[(4R)-5-[(4-fluorophenyl)carbonyl]-4-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-4H,6H,7H-imidazo[1,5-a]pyrazin-3-yl]pyrimidine

[0455] Dissolve (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (35 mg, 0.08 mmol) in dioxane (6 mL), and then add 4-(trimethyltinyl)pyrimidine O27c (39 mg, 0.16 mmol) and Pd(PPh3)4Cl2 (7 mg, 0.008 mmol) in sequence. Under nitrogen protection, the reaction solution was heated to 120°C and reacted for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated. The residue obtained was separated by silica gel column chromatography (65% ethyl acetate / petroleum ether) and then purified by reversed-phase column chromatography (51% acetonitrile / water) to obtain (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyrimidin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 027 (7.2 mg, white solid), yield: 20%.

[0456] MS m / z(ESI): 436.1 [M+1] + .

[0457] HPLC: 99.34% (214nm), 98.34% (254nm).

[0458] 1 H NMR (400MHz, CDCl3) δ9.29-8.87(m,1H),8.71(s,1H),8.05(s,1H),7.50(dd,J=8.4,5.6Hz,2H),7.16(t,J=8.4Hz,2 H),6.74-6.07(m,1H),5.22-5.06(m,1H),4.50-3.95(m,2H),3.85-3.52(m,1H),2.71(s,3H),1.73(d,J=5.2Hz,3H).

[0459] 19 F NMR (376MHz, CDCl3) δ -108.61.

[0460] Example 27

[0461] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridazin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (028)

[0462]

[0463] Compound (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 028a (35 mg, 0.008 mmol) was dissolved in tetrahydrofuran / water = 4 / 1 (2.5 mL). Then, pyridazine-4-borate pinacol ester (20 mg, 0.0096 mmol), potassium carbonate (51 mg, 0.24 mmol), and PdCl2 (dppf) (14.7 mg, 0.016 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at 90 °C for 3 hours under nitrogen protection. The mixture was then filtered, and the filtrate was concentrated. The residue was purified by pre-HPLC (acetonitrile / water) to give compound 028 (9.3 mg, white solid), yield: 26%.

[0464] MS m / z(ESI): 436.1 [M+1] +

[0465] 1 H NMR (400MHz, CDCl3) δ9.73 (s, 1H), 9.23 (s, 1H), 7.84 (s, 1H), 7.51 (dd, J = 8.4, 5.2Hz, 2H), 7.20 (t, J = 8.4Hz, 2H),6.47(br,1H),5.21-5.10(m,1H),4.41-4.03(m,2H),3.73(br,1H),2.71(s,3H),1.63(d,J=6.8Hz,3H).

[0466] Example 28

[0467] Preparation of (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(pyridin-3-ylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (029)

[0468]

[0469] Compound (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 029a (52.4 mg, 0.12 mmol) was dissolved in 2.5 mL of anhydrous dioxane, followed by the addition of 3-aminopyridine (16 mg, 0.12 mmol), cesium carbonate (117 mg, 0.36 mmol), and X-PHOS (11.4 mg, 0.0 mmol). 24 mmol) and tris(dibenzylacetone)palladium (6 mg, 0.008 mmol) were added. After the addition was complete, the reaction solution was stirred at 120 °C for 16 hours under nitrogen protection. The reaction solution was filtered and the filtrate was concentrated. 20 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 10 mL) and washed with saturated brine (3 × 10 mL). The resulting organic layer was concentrated, and the residue was purified by pre-HPLC (acetonitrile / water) to give compound 029 (7 mg, pale yellow solid), yield: 13%.

[0470] MS m / z (ESI): 450.1 [M+1] + .

[0471] HPLC (ENB200026-089-P1-A): 97.94% (214nm), 98.27% (254nm).

[0472] 1 H NMR(400MHz, CDCl3)δ8.32(s,1H),8.07(s,1H),7.51-7.43(m,2H),7.36(br,1H),7.22-7.08(m,3H ),5.85(m,2H),5.13-5.06(m,1H),4.22(br,2H),3.59(br,1H),2.68(s,3H),1.53(d,J=6.6Hz,4H).

[0473] 19F NMR (376MHz, CDCl3) δ-108.70.

[0474] Example 29

[0475] Preparation of (1-(1H-imidazol-1-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (030)

[0476]

[0477] (1-Bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 030a (60 mg, 0.14 mmol) was dissolved in 2.5 mL of dioxane, followed by the addition of 1H imidazole (19 mg, 0.28 mmol), potassium carbonate (88 mg, 0.41 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (6 mg, 0.04 mmol), and cuprous iodide (5 mg, 0.03 mmol). The reaction mixture was heated to 120 °C and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether), and then purified by reversed-phase column chromatography (44% acetonitrile / water) to give (1-(1H-imidazol-1-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 030 (2.7 mg, white solid), yield: 5%.

[0478] MS m / z(ESI): 424.1 [M+1] + .

[0479] 1 H NMR(400MHz,MeOD)δ8.06(s,1H),7.62-7.56(m,2H),7.48(s,1H),7.31-7.24(m,2H),7.23-7.16(m,1H),6.02(s ,1H),5.17-5.06(m,1H),4.61(s,1H),4.34-4.46(m,1H),3.83-3.66(m,1H),2.68(s,3H),1.35(d,J=6.8Hz,3H).

[0480] 19 F NMR (376MHz, CDCl3) δ-111.44.

[0481] Example 30

[0482] Preparation of 4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)benzonitrile (031)

[0483]

[0484] Dissolve (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 031a (40 mg, 0.09 mmol) in 2 mL of a tetrahydrofuran / water (3:1) mixture, then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.02 mmol) and potassium carbonate (19 mg, 0.13 mmol) sequentially. The extracts of 4-cyanobenzyl benzoate (21 mg, 0.09 mmol) and pinacol ester (21 mg, 0.09 mmol) were extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by reverse-phase column chromatography (65% acetonitrile / water) to give 4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)benzonitrile 031 (9.3 mg, yellow solid), yield: 21%.

[0485] MS m / z.(ESI): 459.1 [M+1] + .

[0486] 1 H NMR (400MHz, CDCl3) δ7.93 (dd, J=10.8, 4.0Hz, 2H), 7.74 (dd, J=7.6, 4.4Hz, 2H), 7.50 (dd, J=8.4, 5.6Hz, 2H), 7.19 (t, J=8.6Hz, 2H), 6. 55-6.34(m,1H),5.13(d,J=13.2Hz,1H),4.35-4.24(m,1H),4.19-4.01(m,1H),3.75-3.62(m,1H),2.70(s,3H),1.54(d,J=6.8Hz,3H).

[0487] HPLC: 254nm (98.4%), 214nm (99.2%).

[0488] Example 31

[0489] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(1,2,3,6-tetrahydropyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (032)

[0490]

[0491] Step 1: Preparation of (R)-4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0492] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 032a (60 mg, 0.14 mmol) was dissolved in tetrahydrofuran / water = 4 / 1 (5 mL), followed by the addition of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (65 mg, 0.21 mmol), potassium carbonate (58 mg, 0.42 mmol), and PdCl. 2(dppf)(11mg, 0.014mmol), after the addition was complete, the reaction solution was reacted at 80°C for 2 hours under nitrogen protection. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give (R)-4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 032b (70mg, yellow oil), yield: 93%.

[0493] MS m / z ESI+): 539.2 [M+H] + .

[0494] Step 2: Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(1,2,3,6-tetrahydropyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone

[0495] (R)-4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 032b (30 mg, 0.06 mmol) was dissolved in 3 mL of dichloromethane, and then 0.3 mL of trifluoroacetic acid was added. The reaction solution was then heated in a room temperature environment. After stirring at room temperature for 2 hours, the reaction solution was concentrated and purified by reverse-phase column chromatography (55% acetonitrile / water) to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(1,2,3,6-tetrahydropyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 032 (8.2 mg, pale yellow solid), yield: 31%.

[0496] MS m / z(ESI+): 439.1 [M+1] + ].

[0497] 1 H NMR(400MHz,CDCl3)δ9.83(br s,2H),7.56-7.41(m,2H),7.17(t,J=8.6Hz,2H),6.15-6.07(m,2H),5.05-5.02(m,1H),4.29-4.20(m,1H),4.09-3.99(m,1H),3. 93-3.82(m,2H),3.73-3.62(m,1H),3.52-3.34(m,2H),3.16-3.07(m,1H),2.83-2.76(m,1H),2.67(s,3H),1.58(d,J=6.7Hz,3H).

[0498] 19 F NMR(376MHz, CDCl3)δ-75.72,-108.78.

[0499] HPLC: 100% (214nm), 99.33% (254nm).

[0500] Example 32

[0501] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-morpholino-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone (033)

[0502]

[0503] 033a (100 mg, 0.07 mmol), morpholine (60 mg, 0.69 mmol), sodium tert-butoxide (110 mg, 1.15 mmol), RuPhos (22 mg, 0.05 mmol), and Pd2(dba)3 were dissolved in 2.5 mL of 1,4-dioxane. The mixture was reacted in a microwave oven at 100 °C for 1 h. After filtration and concentration of the filtrate, the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain a pale yellow solid. The residue was then purified by prep-HPLC to obtain (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-morpholino-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone 033 (3 mg, white solid), yield: 2.8%.

[0504] MS m / z(ESI): 443.2 [M+1] + .

[0505] 1 H NMR (400MHz, DMSO-d6) δ7.59(dd,J=8.6,5.4Hz,2H),7.32(dd,J=8.6,5.4Hz,2H),5.75(s,1H),4.86(d,J=13.6Hz,1H),4 .29-4.23(m,1H),3.83(s,1H),3.72(s,4H),3.61(s,1H),3.05(s,2H),2.94(s,2H),2.59(s,3H),1.51(d,J=6.4Hz,3H).

[0506] Example 33

[0507] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)acetamide (034)

[0508]

[0509] Compound 034a (230 mg, 0.62 mmol) and DIEA (239 mg, 1.85 mmol) were dissolved in 10 mL of LCM, and then acetyl chloride (73 mg, 0.93 mmol) was added dropwise. After reacting at room temperature for 1 h, the reaction solution was diluted with 10 mL of LCM, washed with water in saturated NaHCO3 solution and saturated NaCl solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by pre-HPLC (ACN / H2O (0.1% FA) = 25%) to give compound (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)acetamide 034 (108 mg, white solid), yield: 41%.

[0510] MS m / z (ESI): 415.3 [M+1] + .

[0511] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),7.58(dd,J=8.8,5.6Hz,2H),7.32(dd,J=8.8,5.6Hz,2H),5.97(s,1 H),4.88(s,1H),4.29(s,1H),3.83(s,1H),3.61(s,1H),2.62(s,3H),2.04(s,3H),1.28(d,J=6.8Hz,3H).

[0512] Example 34

[0513] Preparation of (R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyrazine-1-onitrile (035)

[0514]

[0515] Add (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 035a (30 mg, 0.070 mmol), zinc powder (0.46 mg, 0.0070 mmol), Pd(dppf)Cl2 (10 mg, 0.014 mmol), and zinc cyanide to a 10 mL microwave tube equipped with a stir bar. (8 mg (0.070 mmol) was added, followed by 2 mL of N,N-dimethylformamide solvent. The mixture was evacuated, purged with nitrogen, and capped. The mixture was then heated to 135 °C and stirred for 2 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was cooled to room temperature, and 20 mL of water was added. The mixture was then extracted with ethyl acetate (2 × 30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1), followed by purification by reversed-phase column chromatography (42% acetonitrile / water) to give (R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyrazine-1-onitrile 035 (4.47 mg, yellow solid), yield: 16%.

[0516] MS m / z(ESI): 383.1 [M+1] + .

[0517] 1 H NMR (400MHz, CDCl3) δ7.50-7.47(m,2H),7.21-7.17(m,2H),6.12-5.58(m,1H),5.11-5.07(m,1H), 4.70-4.47(m,1H),4.24(t,J=10.4Hz,1H),3.63-3.44(m,1H),2.71(s,3H),1.74(d,J=6.8Hz,3H).

[0518] 19 F NMR (376MHz, CDCl3) δ -107.96.

[0519] Example 35

[0520] (4-Fluorophenyl)(8-Methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(methylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methyl ketone (036)

[0521]

[0522] Compound 036a (40 mg, 0.11 mmol), paraformaldehyde (97 mg, 1.07 mmol), and anhydrous MgSO4 were dissolved in 5 mL of LCE and stirred at room temperature for 30 min. Then, sodium triacetoxyborohydride (228 mg, 1.07 mmol) and a catalytic amount of AcOH were added, and the mixture was stirred at room temperature for 16 h. After filtration, the filter cake was washed with 20 mL of LCM, and the filtrate was concentrated. The residue was purified by pre-HPLC (ACN / H2O (0.1% FA) = 40%) to give compound (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(methylamino)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 036 (5 mg, yellow solid), yield: 12%.

[0523] MS m / z(ESI): 387.2 [M+1] + .

[0524] 1 H NMR (400MHz, DMSO-d6) δ7.57 (dd, J=8.8, 5.6Hz, 2H), 7.32 (dd, J=8.8, 5.6Hz, 2H), 5.79 (s, 1H), 4. 81(d,J=12.4Hz,1H),4.22(s,2H),3.79(s,2H),2.78(s,3H),2.57(s,3H),1.42(d,J=6.0Hz,3H).

[0525] Example 36

[0526] Preparation of (1-(dimethylamino)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H))-(4-fluorophenyl)methyl ketone (037)

[0527]

[0528] Compound 037a (50 mg, 0.13 mmol), paraformaldehyde (121 mg, 1.34 mmol), and anhydrous MgSO4 were dissolved in 5 mL of LCE and stirred at room temperature for 30 min. Then, sodium triacetoxyborohydride (285 mg, 1.34 mmol) and a catalytic amount of AcOH were added, and the mixture was stirred at room temperature for 16 h. The mixture was filtered, and the filter cake was washed with 20 mL of LCM. The filtrate was concentrated, and the residue was purified by pre-HPLC (ACN / H2O (0.1% FA) = 40%) to give compound (1-(dimethylamino)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H))-(4-fluorophenyl) methyl ketone 037 (10 mg, yellow solid), yield: 18%.

[0529] MS m / z(ESI): 401.1 [M+1] + .

[0530] 1 H NMR (400MHz, DMSO-d6) δ7.55(dd,J=8.8,5.6Hz,2H),7.30(dd,J=8.8,5.6Hz,2H),5.76(s,1H),4.83(d, J=12.4Hz,1H),4.21(s,1H),3.80(s,1H),3.60(s,1H),2.72(s,6H),2.56(s,3H),1.44(d,J=6.0Hz,3H).

[0531] Example 37

[0532] Preparation of 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-sulfonamide (038)

[0533] Step 1: Preparation of (1-(benzylthio)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H))-(4-fluorophenyl)methyl ketone

[0534] (1-Bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 038a (131 mg, 0.30 mmol) was dissolved in dioxane (15 mL), and DIEA (78 mg, 0.60 mmol), Xantphos (35 mg, 0.06 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), and benzyl mercaptan (56 mg, 0.45 mmol) were added sequentially. The reaction solution was heated to 120 °C and reacted for 40 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (33% ethyl acetate / petroleum ether) and then purified by reversed-phase column chromatography (54% acetonitrile / water) to obtain (1-(benzylthio)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H))-(4-fluorophenyl) methyl ketone 038b (85 mg, pale yellow solid), yield: 58%.

[0535] MS m / z(ESI): 480.1 [M+1] + .

[0536] 1 H NMR(400MHz,DMSO-d6)δ7.54(s,2H),7.41-7.15(m,7H),5.43(br,1H),4.81(br,1H),4.27( br,1H),4.18-4.04(m,2H),3.80(br,1H),3.61(br,1H),2.65(s,3H),1.35(d,J=6.8Hz,3H).

[0537] The second step involves preparing 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-sulfonyl chloride.

[0538] 5-[3-(benzylthio)-5-[(4-fluorophenyl)carbonyl]-4-methyl-4H,6H,7H-imidazo[1,5-a]pyrazin-1-yl]-3-methyl-1,2,4-thiadiazole 038b (58 mg, 0.12 mmol) was dissolved in 5 mL of acetonitrile, and water (9 mg, 0.48 mmol) was added. The mixture was then cooled to 0°C in an ice-water bath. Acetic acid (14 mg, 0.24 mmol) and 1,3-dichloro-5,5-dimethylhydantoin (47 mg, 0.24 mmol) were added sequentially, and the reaction mixture was reacted at 0°C for 30 minutes. After the reaction was completed, 20 mL of saturated sodium bicarbonate was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-sulfonyl chloride 038c (55 mg, pale yellow solid) was obtained in 50% yield.

[0539] MS m / z(ESI): 456.0 [M+1] + .

[0540] Step 3: Preparation of 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-sulfonamide

[0541] 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-sulfonyl chloride 038c (55 mg, 0.12 mmol) was dissolved in 5 mL of tetrahydrofuran, followed by the addition of triethylamine (24 mg, 0.24 mmol) and ammonia (8 mg, 0.24 mmol). The reaction mixture was incubated at 25 °C for 20 minutes. After the reaction was complete, 30 mL of saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 40 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether) and then purified by reversed-phase column chromatography (41% acetonitrile / water) to give 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-sulfonamide 038 (18.2 mg, white solid), yield: 35%.

[0542] MS m / z(ESI): 437.0 [M+1] + .

[0543] HPLC: 99.72% (214nm), 99.18% (254nm).

[0544] 1 H NMR (400MHz, CDCl3) δ7.52-7.43(m,2H),7.21-7.11(m,2H),6.35(br,1H),5.61(br,1H),5.1 6(s,2H),5.07-5.03(m,1H),4.26(br,1H),3.61(br,1H),2.71(s,3H),1.74(d,J=6.4Hz,3H).

[0545] 19 F NMR (376MHz, CDCl3) δ-107.80,-108.47.

[0546] Example 38

[0547] Preparation of 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (039)

[0548] Step 1: Preparation of methyl 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate

[0549] Dissolve (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone 039a in 5 mL of methanol, and then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (33.5 mg, 0.045 mmol) and triethylamine (9 mg, 0.09 mmol) in sequence. Under carbon monoxide protection, the mixture was stirred at 80°C for 16 hours. After the reaction was completed, the solvent methanol was concentrated under reduced pressure. The reaction solution was extracted successively with 20 mL of dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title product methyl 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid ester 039b (25 mg, yellow solid), yield: 59%.

[0550] MS m / z.(ESI): 416.1 [M+1] + .

[0551] The second step involves preparing 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid.

[0552] Methyl 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 039b (60 mg, 0.14 mmol) was dissolved in 8 mL of a methanol / water (3:1) mixture. Lithium hydroxide (23 mg, 0.28 mmol) was then added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was then diluted with 2 mol / L water. The pH was adjusted to 5 with hydrochloric acid, and then extracted with 20 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid 039c (50 mg, yellow solid), yield: 78%.

[0553] MS m / z.(ESI): 402.2[M+1] + .

[0554] Step 3: Preparation of 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide

[0555] Dissolve 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid 039c in 2 mL of N,N-dimethylformamide, and then add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (34 mg, 0.06 mmol), N,N-diisopropylethylamine (12 mg, 0.09 mmol), and ammonium chloride (4 mg, 0.06 mmol) in sequence. The mixture was stirred at room temperature for 2 hours, extracted successively with 10 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (acetonitrile / water) to give the title product 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-carboxamide 039 (6.7 mg, white solid), yield: 27%.

[0556] MS m / z.(ESI): 401.1[M+1] +.

[0557] 1 H NMR (400MHz, CDCl3) δ7.48 (dd, J=8.8, 5.6Hz, 2H), 7.14 (t, J=8.8Hz, 2H), 6.92 (s, 1H), 5.80-5.56 (m, 1H), 5.31(s,1H),5.16-4.81(m,2H),4.36-4.21(m,1H),3.65-3.41(m,1H),2.71(s,3H),1.73(d,J=6.8Hz,3H).

[0558] HPLC: 254nm (98.6%), 214nm (98.6%).

[0559] Example 39

[0560] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)methanesulfonamide (040)

[0561]

[0562] Step 1: Preparation of (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone

[0563] (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 040a (150 mg, 0.42 mmol) was added to 5 mL of dichloromethane solvent, followed by N-bromosuccinimide (89 mg, 0.50 mmol). The reaction was carried out at room temperature for 1 hour, and then 20 mL of water and 2 × 20 mL of dichloromethane were added. The alkane was extracted and separated, then washed successively with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 040b (150 mg, yellow oil), yield: 75%.

[0564] MS m / z(ESI): 436.0 [M+1] + .

[0565] Step 2: Preparation of (R)-(1-((diphenylmethylene)amino)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0566] Add (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 040b (150 mg, 0.34 mmol), benzophenone imine (125 mg, 0.69 mmol), Pd(dppf)Cl2 (21 mg, 0.034 mmol), BINAP (21 mg, 0.034 mmol), and cesium carbonate to a 10 mL microwave tube equipped with a stir bar. ( 336 mg (1.03 mmol) was added. Then, 2 mL of N,N-dimethylformamide solvent was added, the mixture was evacuated, purged with nitrogen, and capped. The mixture was then heated to 120 °C and stirred for 16 hours. The reaction was monitored by LCMS. Upon completion, 040C was obtained, requiring no further purification and ready for the next reaction.

[0567] MS m / z(ESI): 537.3 [M+1] + .

[0568] Step 3: Preparation of (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone

[0569] Dissolve (R)-(1-((diphenylmethylene)amino)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 040c (150 mg, 0.28 mmol) in 5 mL of tetrahydrofuran solvent, and then add concentrated hydrochloric acid (12 M, 0.1 mL, 1.40 mmol) to the solution. l), the reaction solution was reacted at 25°C for 1 hour, and tetrahydrofuran was removed by rotary evaporation. The residue was purified by reverse-phase column chromatography (40% acetonitrile / water) to give (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 040d (79 mg, yellow solid), yield: 70%.

[0570] Step 4: Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-N-(methanesulfonyl)methanesulfonamide

[0571] (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 040d (30 mg, 0.081 mmol) was dissolved in dichloromethane (2 mL). After cooling to 0 °C, triethylamine (46 mg, 0.45 mmol) and methanesulfonyl chloride (37 mg, 0.054 mmol) were added sequentially. The reaction mixture was reacted at 25 °C for 1 hour. After the reaction was completed, 20 mL of water and 2 × 20 mL of dichloromethane were added sequentially. The mixture was extracted and separated, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was crude product (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-N-(methanesulfonyl)methanesulfonamide 040e, which did not require further purification and could be directly used for the next reaction.

[0572] MS m / z(ESI): 529.1 [M+1] + .

[0573] Step 5: Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)methanesulfonamide

[0574] (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-N-(methanesulfonyl)methanesulfonamide 040e (30 mg, 0.057 mmol) was dissolved in 2 mL of tetrahydrofuran, and tetrabutylammonium fluoride (1 min THF, 1 mL, 0.28 mmol) was added to the solution. The reaction solution was reacted at 25 °C for 1 hour. After the reaction was complete, 100 mL of ethyl acetate was added for dilution, and the mixture was washed five times with saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reversed-phase column chromatography (45% acetonitrile / water) to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)methanesulfonamide 040 (7.00 mg, yellow solid), yield: 25%.

[0575] MS m / z(ESI): 451.1 [M+1] + .

[0576] 1 H NMR (400MHz, CDCl3) δ7.49-7.45(m,2H),7.17-7.13(m,2H),6.32-5.95(m,2H),5.75-5.47(m ,1H),5.10-5.01(m,1H),4.28-4.4.16(m,1H),3.56-3.42(m,1H),3.18(s,3H),2.70(s,3H).

[0577] 19 F NMR (376MHz, CDCl3) δ -108.66.

[0578] Example 40

[0579] Preparation of (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (041)

[0580]

[0581] Step 1: Preparation of (R)-(1-((diphenylmethylene)amino)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone

[0582] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 041a (400 mg, 0.92 mmol) was dissolved in N,N-dimethylformamide (6 mL), and then tris(dibenzylacetone)palladium (106 mg, 0.18 mmol), (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (114 mg, 0.18 mmol), benzophenone imine (200 mg, 1.1 mmol) and cesium carbonate (600 mg, 1.84 mmol) were added sequentially. After the addition of the reactants, the reaction solution was stirred at 100°C for 16 hours under nitrogen protection. The reaction solution was then extracted with ethyl acetate (20 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title product (R)-(1-((diphenylmethylene)amino)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 041b (80 mg, yellow solid), yield: 14%.

[0583] MS m / z.(ESI): 537.2 [M+1] + .

[0584] Step 2: Preparation of (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0585] (R)-(1-((diphenylmethylene)amino)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) ketone 041b (80 mg, 0.15 mmol) was dissolved in 2 mL of dichloromethane, and then 0.2 mL of concentrated hydrochloric acid was added. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by Prep-HPLC (acetonitrile / water) to give (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) ketone 041 (35 mg, pale yellow solid), yield: 65%.

[0586] MS m / z.(ESI): 373.1 [M+1] + .

[0587] 1 H NMR (400MHz, CDCl3) δ7.51-7.42(m,2H),7.16(t,J=8.8Hz,2H),6.15-5.73(m,1H),4.99(d ,J=13.2Hz,1H),4.22-3.89(m,2H),3.80-3.10(m,3H),2.64(s,3H),1.55(d,J=6.8Hz,3H).

[0588] HPLC: 254nm (90.1%), 214nm (95.4%).

[0589] Example 41

[0590] Preparation of (7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)(morpholinyl) methyl ketone (042)

[0591]

[0592] 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid 042a (20 mg, 0.05 mmol) was dissolved in 4 mL of dichloromethane, followed by the addition of morpholin (6.5 mg, 0.075 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (29 mg, 0.075 mmol), and N,N-diisopropylethylamine (13 mg). The reaction mixture was stirred at room temperature for 2 hours (0.1 mmol), and the solution was extracted sequentially with ethyl acetate (20 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (45% acetonitrile / water) to give (7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)(morpholinyl) methyl ketone 042 (4.3 mg, white solid), yield: 16%.

[0593] MS.m / z.(ESI).471.2[M+1] + .

[0594] 1H NMR (400MHz, CDCl3) δ7.48 (dd, J=8.0, 5.6Hz, 2H), 7.14 (t, J=8.4Hz, 2H), 6.03-5.59 (m, 1H), 5.20-4.77(m,2H),4.41-4.17(m,3H),3.94-3.50(m,7H),2.70(s,3H),1.67(d,J=6.0Hz,3H).

[0595] HPLC: 254nm (91.3%), 214nm (93.6%).

[0596] Example 42

[0597] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(2-methylpyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (043)

[0598]

[0599] Add (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 043a (30 mg, 0.070 mmol), (2-methylpyridin-4-yl)boronic acid (19 mg, 0.14 mmol), Pd(dppf)Cl2 (10 mg, 0.014 mmol), and potassium carbonate to a 10 mL microwave tube equipped with a stir bar. ( 29 mg (0.21 mmol) was added, followed by the addition of tetrahydrofuran / water solvent (5:1, 1 / 0.2 mL). The mixture was evacuated, purged with nitrogen, and capped. The mixture was then heated to 80 °C and stirred for 2 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the crude product. The crude product was then purified by reversed-phase chromatography (38% acetonitrile / water) to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(2-methylpyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 043 (21.73 mg, white solid), yield: 70%.

[0600] MS m / z(ESI): 449.3 [M+1] + .

[0601] 1H NMR(400MHz, CDCl3)δ8.55(s,1H),7.62-7.49(m,4H),7.24-7.17(m,2H),6.46(s,1H),5.16-5.09(m,1H), 4.36-4.24(m,1H),4.16-3.93(m,1H),3.78-3.61(m,1H),2.70(s,3H),2.63(s,3H),1.57(d,J=6.8Hz,3H).

[0602] 19 F NMR (376MHz, CDCl3) δ -108.66.

[0603] Example 43

[0604] Preparation of (R)-(4-fluorophenyl)(1-(2-fluoropyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (044)

[0605]

[0606] Add (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 044a (30 mg, 0.070 mmol), (2-fluoropyridin-4-yl)boronic acid (19 mg, 0.14 mmol), Pd(dppf)Cl2 (10 mg, 0.014 mmol), and K2CO to a 10 mL microwave tube equipped with a stir bar. 3( 29 mg, 0.21 mmol). Tetrahydrofuran / water (5:1, 1 / 0.2 mL) was then added, the mixture was evacuated, purged with nitrogen, and capped. The mixture was then heated to 80 °C and stirred for 2 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the crude product. This crude product was then purified by reversed-phase chromatography (44% acetonitrile / water) to give (R)-(4-fluorophenyl)(1-(2-fluoropyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 044 (15.89 mg, white solid), yield: 51%.

[0607] MS m / z(ESI): 453.2 [M+1] + .

[0608] 1H NMR(400MHz, CDCl3)δ8.27(s,1H),7.60-7.40(m,4H),7.22-7.17(m,2H),6.44(s,1H),5.19-5 .09(m,1H),4.35-4.4.27(m,1H),4.17-4.4.02(m,1H),3.70(m,1H),2.70(s,3H),1.61(s,3H).

[0609] 19 F NMR (376MHz, CDCl3) δ-67.40,-108.52.

[0610] Example 44

[0611] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(3-methylpyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (045)

[0612]

[0613] (R)-1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 045a (40 mg, 0.09 mmol), (3-methylpyridin-4-yl)boric acid (15 mg, 0.11 mmol), Pd(dppf)₂Cl₂ (13 mg, 0.01 mmol), and potassium carbonate (38 mg, 0.28 mmol) were dissolved in THF / H₂O = 5:1 (2 mL). After reacting the reaction solution at 80℃ for 2 h, the reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain a light yellow solid. Then, it was purified by rep-HPLC to obtain the title product (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(3-methylpyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 045 (7.8 mg, white solid), yield: 18.8%.

[0614] MS m / z(ESI): 449.2 [M+1] + .

[0615] 1H NMR (400MHz, DMSO) δ8.54(s,1H),8.48(s,1H),7.59-7.57(m,2H),7.36(d,J=14.6Hz,1H),7.31(t,J=8.8Hz,2H),5.93 (s,1H),4.92(d,J=12.6Hz,1H),4.38(s,1H),3.78(d,J=86.8Hz,2H),2.63(s,3H),2.29(s,3H),1.17(d,J=6.4Hz,3H).

[0616] Example 45

[0617] Preparation of (R)-(4-fluorophenyl)(1-(3-fluoropyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (046)

[0618]

[0619] (R)-1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone 046a (40 mg, 0.09 mmol), 3-fluoro-4-boronate-pyridine (25 mg, 0.10 mmol), Pd(dppf)₂Cl₂ (13 mg, 0.01 mmol), and potassium carbonate (38 mg, 0.28 mmol) were dissolved in tetrahydrofuran / water = 5:1 (2 mL). In L), the reaction solution was reacted at 80℃ for 2 h and then concentrated. The residue obtained was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain a light yellow solid. Then, it was purified by prep-HPLC to obtain the title product (R)-(4-fluorophenyl)(1-(3-fluoropyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 046 (6.3 mg, white solid), yield: 15%.

[0620] MS m / z (ESI): 454.1 [M+1] + .

[0621] 1H NMR (400MHz, DMSO) δ8.72(s,1H),8.52(s,1H),7.74(s,1H),7.60-7.58(m,2H),7.33(t,J=8.7Hz,2H),6.16 (s,1H),4.95(s,1H),4.39(s,1H),3.84(d,J=24.0Hz,1H),3.65(s,1H),2.65(s,3H),1.25(d,J=6.5Hz,3H).

[0622] Example 46

[0623] Preparation of (R)-(1-(2,6-dimethylpyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazolium[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (047)

[0624]

[0625] (R)-1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 047 (30 mg, 0.07 mmol), (2,6-dimethylpyridin-4-yl)boronic acid (15.6 mg, 0.10 mmol), Pd(dppf)₂Cl₂ (10 mg, 0.01 mmol), and potassium carbonate (28.5 mg, 0.20 mmol) were dissolved in THF / H₂O = 5:1. The reaction solution was reacted in 2 mL at 80 °C for 2 h and then concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain a light yellow solid. Then, it was purified by prep-HPLC to obtain the title product (R)-(1-(2,6-dimethylpyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazolium[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 047 (12 mg, white solid), yield: 37.5%.

[0626] MS m / z(ESI): 463.1 [M+1] + .

[0627] 1H NMR (400MHz, DMSO-d6) δ7.84(s,2H),7.60(dd,J=8.8,5.6Hz,2H),7.32(dd,J=8.8,5.6Hz,2H),6.35(s,1H),4.92-4 .87(m,1H),4.42-4.38(m,1H),3.94(s,1H),3.75(d,J=9.8Hz,1H),2.70(s,6H),2.65(s,3H),1.52(d,J=6.8Hz,3H).

[0628] Example 47

[0629] Preparation of (R)-(4-fluorophenyl)(1-hydroxy-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (048)

[0630]

[0631] (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone 048a (30 mg, 0.08 mmol) was dissolved in 63 mg of 25% sulfuric acid in an aqueous solution, and the solution was then cooled to 0°C. Subsequently, NaNO2 (16.68 mg, 0.2418 mmol) dissolved in 1 mL of water was added dropwise, maintaining the temperature between 0°C and -10°C. After the addition was complete, the ice-salt bath was removed, and the solution was stirred continuously until it reached room temperature. The solution was then neutralized with a calculated amount of 40% sodium hydroxide aqueous solution, and the pH was adjusted to 7-8 with sodium bicarbonate. The solution was then evaporated to dryness under vacuum, and the crude product was purified by high performance liquid chromatography to give the title product (R)-(4-fluorophenyl)(1-hydroxy-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]azine-7(8H)-yl) methyl ketone 048 (12 mg, white solid), yield: 39.5%.

[0632] MS m / z(ESI): 374.1 [M+1] + .

[0633] 1 H NMR (400MHz, CDCl3) δ7.90(s,1H),7.58-7.56(m,2H),7.04-7.00(m,2H),5.28-5.17(m,2H),4.00-3.98(m,2H),2.72(s,3H),2.56(s,3H).

[0634] Example 48

[0635] Preparation of (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-4-methoxy-1,5-dihydro-2H-pyrrolo-2-one (049)

[0636]

[0637] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 049a (28.00 mg, 0.064 mmol), cuprous iodide (6.11 mg, 0.032 mmol), cesium carbonate (62.75 mg, 0.193 mmol), and cesium fluoride (1.95 mg, 0.013 mmol) were dissolved in 1,4-dioxane solution (2 mL), and then trans-(1R,2R)N,N'-dimethyl-cyclohexane-1,2-diamine (1.13 mg, 0.013 mmol) and 4-methoxy-1,3-dihydro-2H-pyrrole-2-one (14.52 mg, 0.128 mmol) were added. Under nitrogen protection, the reaction was heated to 120°C for 16 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated to dryness, and the residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 1:9). The crude product was further purified by reversed-phase rapid chromatography (55% acetonitrile / water) to give (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-4-methoxy-1,5-dihydro-2H-pyrrole-2-one 049 (4.30 mg, white solid), yield: 14%. MS m / z (ESI): 469.1 [M+1] + .

[0638] 1 H NMR (400MHz, CDCl3) δ7.52 (s, 2H), 7.18-7.12 (m, 2H), 6.10 (s, 1H), 5.12 (d, J = 12.8Hz, 2H), 4.74 (d, J = 17. 5Hz,1H),4.25-4.17(m,1H),4.06(d,J=17.6Hz,1H),3.85(s,3H),3.44(s,1H),2.69(s,3H),1.36(s,3H).

[0639] 19 F NMR (376MHz, CDCl3) δ-109.02.

[0640] Example 49

[0641] Preparation of (R)-N-(7-(4-fluorobenzofuran-7-carbonyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide (050) and

[0642] (R)-N-acetyl-N-(7-(4-fluorobenzofuran-7-carbonyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide (051)

[0643]

[0644] Step 1: Preparation of (R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester

[0645] (R)-3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole 050a (200 mg, 0.44 mmol) was added to tetrahydrofuran (5 mL), followed by di-tert-butyl dicarbonate (144 mg, 0.66 mmol) and triethylamine (89 mg, 0.88 mmol). The reaction was carried out at room temperature for 3 hours. After the reaction was completed as monitored by LCMS, water (50 mL) was added. Extracted with ethyl acetate (3 × 50 mL), the extract was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:3) to give the title product (R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester 050b (270 mg, white solid), yield: 94%.

[0646] MS m / z(ESI): 336.2 [M+1] + .

[0647] Step 2: Preparation of (R)-1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester

[0648] (R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester 050b (270 mg, 0.80 mmol) was added to dichloromethane (5 mL) solvent, followed by N-bromosuccinimide (71 mg, 1.20 mmol), and the reaction was carried out at room temperature for 1 hour. After the reaction was monitored by LCMS, water (220 mL) and ethyl acetate (3 × 20 mL) were added for extraction and separation. The mixture was then washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title product (R)-1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester 050c (250 mg, white solid), yield: 68%.

[0649] MS m / z(ESI): 414.1 [M+1] + .

[0650] Step 3: Preparation of (R)-5-(1-bromo-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-methyl-1,2,4-thiadiazole

[0651] (R)-1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylic acid tert-butyl ester 050c (250 mg, 0.60 mmol) was dissolved in 5 mL of dichloromethane, and trifluoroacetic acid (1 mL, 3.00 mmol) was added. The reaction solution was reacted at 25 °C for 1 hour. After the reaction was completed as monitored by LCMS, the dichloromethane was removed by rotary evaporation, and the residue was added to acetonitrile and water and lyophilized to give (R)-5-(1-bromo-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-yl)-3-methyl-1,2,4-thiadiazolium 050d (150 mg, yellow solid), yield: 71%.

[0652] MS m / z(ESI): 314.0 [M+1] + .

[0653] Step 4: Preparation of (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorobenzofuran-7-yl) methyl ketone

[0654] (R)-5-(1-bromo-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-3-methyl-1,2,4-thiadiazole 050d (150 mg, 0.48 mmol) was dissolved in 3 mL of dichloromethane. N,N-diethylpropylethylamine (185 mg, 1.43 mmol) and 4-fluoro-1-benzofuran-7-carbonyl chloride (190 mg, 0.95 mmol) were added sequentially. The reaction mixture was incubated at 25 °C for 1 hour. After the reaction was complete, water (20 mL) and dichloromethane (3 × 20 mL) were added. The mixture was extracted and separated, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorobenzofuran-7-yl) methyl ketone 050e (150 mg, yellow solid), yield: 61%.

[0655] MS m / z(ESI): 476.0 [M+1] + .

[0656] Step 5: Preparation of (R)-(1-(((diphenylmethylene)amino)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazine7(8H)-yl)(4-fluorobenzofuran-7-yl) methyl ketone

[0657] Add (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorobenzofuran-7-yl) methyl ketone 050e (150 mg, 0.34 mmol), benzophenone imine (125 mg, 0.69 mmol), Pd(dppf)Cl2 (21 mg, 0.034 mmol), BINAP (21 mg, 0.034 mmol), and cesium carbonate to a 10 mL microwave tube equipped with a stir bar. ( 336 mg (1.03 mmol) was added, followed by the addition of solvent N,N-dimethylformamide (2 mL). The mixture was evacuated, purged with nitrogen, and capped. The mixture was then heated to 120 °C and stirred for 16 h. After the reaction was completed as monitored by LCMS, 050f was obtained. No further purification was required, and the reaction could proceed directly to the next step.

[0658] MS m / z (ESI): 557.3 [M+1] + .

[0659] Step 6: Preparation of (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorobenzofuran-7-yl) methyl ketone

[0660] Dissolve (R)-(1-(((diphenylmethylene)amino)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazolium[1,5-a]pyrazin 7(8H)-yl)(4-fluorobenzofuran-7-yl) methyl ketone 050f (140 mg, 0.24 mmol) in 5 mL of tetrahydrofuran, and then add concentrated hydrochloric acid (12 M, 0.1 mL, 1.40 mmol) to the solution. The reaction solution was reacted at 25°C for 1 hour. Tetrahydrofuran was removed by rotary evaporation. The residue was purified by reverse-phase column chromatography (40% acetonitrile / water) to give (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorobenzofuran-7-yl) methyl ketone 050 g (50 mg, yellow solid), yield: 47%.

[0661] MS m / z(ESI): 413.2 [M+1] + .

[0662] Step 7: Preparation of (R)-N-(7-(4-fluorobenzofuran-7-carbonyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide and (R)-N-acetyl-N-(7-(4-fluorobenzofuran-7-carbonyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide

[0663] 0.50 g (20 mg, 0.049 mmol) of (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorobenzofuran-7-yl) methyl ketone was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (13 mg, 0.097 mmol) and acetyl chloride (12 mg, 0.015 mmol) were added sequentially. The reaction mixture was reacted at 25 °C for 1 hour. After the reaction was completed, 20 mL of water and 2 × 20 mL of dichloromethane were added, the mixture was extracted and separated, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase chromatography (42% acetonitrile / water) to (R)-N-(7-(4-fluorobenzofuran-7-carbonyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 050 (3.05 mg, yellow solid), yield: 13%; and (R)-N-acetyl-N-(7-(4-fluorobenzofuran-7-carbonyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 051 (7.28 mg, yellow solid), yield: 32%, by reversed-phase chromatography (45% acetonitrile / water).

[0664] Characterization data for 050:

[0665] MS m / z(ESI): 455.2[M+1]+.

[0666] 1 H NMR (400MHz, CDCl3) δ7.42-7.37(m,2H),7.04(t,J=8.8Hz,1H),6.97-6.92(m,1H),6.39-6.25(m,1H), 5.23-5.00(m,2H),4.33-4.19(m,1H),3.70-3.57(m,1H),2.66(s,3H),2.21-2.11(m,3H),1.53(s,3H).

[0667] 19 F NMR (376MHz, CDCl3) δ-115.48.

[0668] Characterization data for 051:

[0669] MS m / z(ESI): 497.1 [M+1] + .

[0670] 1H NMR (400MHz, CDCl3) δ7.68 (s, 1H), 7.41 (s, 1H), 7.05 (t, J = 8.4Hz, 1H), 6.96 (s, 1H), 5.98-5.82 (m, 1H), 5.10-5.0 1(m,1H),4.41-4.26(m,1H),4.00-3.84(m,1H),3.75-3.63(m,1H),2.67(s,3H),2.45-2.10(m,6H),1.54(s,3H).

[0671] 19 F NMR (376MHz, CDCl3) δ-114.80.

[0672] Example 50

[0673] (R)-(4-fluorobenzofuran-7-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl)methyl ketone (052)

[0674]

[0675] Step 1: Preparation of 1-bromo-2-(3,3-diethoxypropoxy)-4-fluorobenzene

[0676] 2-Bromo-5-fluorophenol 052a (5 g, 26.20 mmol) was added to N,N-dimethylformamide (50 mL) solvent, followed by the addition of 2-bromo-1,1-diethoxyethane (7.74 g, 39.30 mmol) and potassium carbonate (89 mg, 0.88 mmol). The reaction mixture was reacted at 120 °C for 16 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, water (100 mL) and ethyl acetate (3 × 80 mL) were added, the mixture was extracted and separated, washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:3) to obtain the title product 1-bromo-2-(3,3-diethoxypropoxy)-4-fluorobenzene 052b (8.40 g, white solid), yield: 96%.

[0677] 1HNMR(400MHz,DMSO)δ7.62-7.58(m,1H),7.15-7.11(m,1H),6.81-6.76(m,1H),4.83(t,J=5.4Hz,1H), 4.05(d,J=5.4Hz,2H),3.74-3.68(m,2H),3.67-3.60(m,2H),3.59-3.45(m,2H),1.14(t,J=7.2Hz,6H).

[0678] Step 2: Preparation of 7-bromo-4-fluorobenzofuran

[0679] 1-Bromo-2-(3,3-diethoxypropoxy)-4-fluorobenzene 052b (8.4 g, 26.25 mmol) was added to toluene (100 mL) solvent, followed by polyphosphoric acid (9 g, 52.5 mmol). The reaction mixture was reacted at 120 °C for 5 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was cooled to 0 °C, and ammonia was slowly added dropwise until the pH of the mixture equaled 10. Water (200 mL) and ethyl acetate (3 × 80 mL) were added, and the mixture was extracted and separated. The extract was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the title product 7-bromo-4-fluorobenzofuran 052c (2 g, white solid), yield: 44%.

[0680] 1 HNMR (400MHz, DMSO) δ8.20 (d, J = 2.2Hz, 1H), 7.61-7.57 (m, 1H), 7.24-7.21 (m, 1H), 7.15-7.11 (m, 1H).

[0681] Step 3: Preparation of 7-methoxycarbonyl-4-fluorobenzofuran

[0682] 7-Bromo-4-fluorobenzofuran 052c (1.00 g, 4.70 mmol) was dissolved in methanol (15 mL), and potassium acetate (1.38 g, 14.1 mmol) and Pd(dppf)Cl2 (340 mg, 0.40 mmol) were added sequentially. The reaction mixture was reacted at 80 °C for 16 hours under a carbon monoxide atmosphere. After the reaction was completed by LCMS monitoring, the methanol was removed by rotary evaporation, and water (200 mL) and ethyl acetate (3 × 80 mL) were added. The mixture was extracted and separated, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9:1) to obtain the title product 7-bromo-4-fluorobenzofuran 052d (700 mg, white solid), yield: 56%.

[0683] MS m / z(ESI): 195.1 [M+1] + .

[0684] Step 4: Preparation of 7-carboxylic acid-4-fluorobenzofuran

[0685] 150 mg (0.77 mol) of 7-methoxycarbonyl-4-fluorobenzofuran 052d was dissolved in tetrahydrofuran / water (5 mL) (v / v = 4 / 1), and lithium hydroxide monohydrate (39 mg, 0.93 mol) was added. The reaction mixture was reacted at 25 °C for 3 hours. The reaction was monitored by LCMS until completion. The reaction solution was directly evaporated to dryness to obtain 7-carboxylic acid-4-fluorobenzofuran 052e, which could be used directly in the next reaction without purification.

[0686] MS m / z(ESI): 181.2 [M+1] + .

[0687] Step 5: Preparation of 7-chlorocarbonyl-4-fluorobenzofuran

[0688] 120 mg (0.67 mmol) of 7-carboxylic acid-4-fluorobenzofuran 052e was dissolved in dichloromethane (5 mL), followed by the addition of oxalyl chloride (396 mg, 3.33 mmol) and N,N-dimethylformamide (0.1 mL). The reaction mixture was incubated at 25 °C for 0.5 h. The reaction was monitored by LCMS until completion. The reaction mixture was directly evaporated to dryness to obtain 7-chlorocarbonyl-4-fluorobenzofuran 052f, which could be used directly in the next reaction without further purification.

[0689] MS m / z (ESI): 181.2 [M-Cl+1] + .

[0690] Step 6: Preparation of (R)-(4-fluorobenzofuran-7-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone

[0691] (R)-3-methyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole 0.52 g (30 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), followed by the addition of N,N-diisopropylethylamine (49 mg, 0.38 mmol) and 7-chlorocarbonyl-4-fluorobenzofuran 0.52 f (25 mg, 0.13 mmol). The reaction mixture was incubated at 25 °C for 0.5 h. After the reaction was completed as monitored by LCMS, water (20 mL) and dichloromethane (2 × 20 mL) were added, followed by extraction and separation. The mixture was then washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase chromatography (45% acetonitrile / water) to give (R)-(4-fluorobenzofuran-7-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone 052 (30.42 mg, white solid), yield: 59%.

[0692] MS m / z(ESI): 398.1 [M+1] + .

[0693] 1 HNMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.42-7.39 (m, 1H), 7.18-7.03 (m, 2H), 6.96 (d, J = 2.4Hz, 1H), 6.20-5.82 (m, 1H), 5.07 (d, J = 12.4Hz, 1H), 4.31-4.20 (m, 1H), 4.03-3.77 (m, 1H), 3.68-3.50 (m, 1H), 2.66 (s, 3H), 1.68 (s, 3H).

[0694] Example 51

[0695] Preparation of (R)-(1-(2,6-difluoropyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (053)

[0696]

[0697] Compound (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 053a (30 mg, 0.067 mmol) was dissolved in tetrahydrofuran / water = 4 / 1 (2.5 mL). Then, (2,6-difluoropyridin-4-yl)pyridineboronic acid (16.5 mg, 0.103 mmol), potassium carbonate (51 mg, 0.24 mmol), and PdCl2 (dppf) (14.7 mg, 0.016 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at 90 °C for 3 hours under nitrogen protection. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by pre-HPLC (acetonitrile / water) to give compound (053) (8.5 mg, white solid), yield: 26%.

[0698] MS m / z(ESI):[M+1] + 471.1

[0699] 1H NMR(400MHz,cdcl3)δ7.50(dd,J=8.5,5.2Hz,2H),7.38-7.26(m,1H),7.19(t,J=8.5Hz,1H),6.39(s,1 H),5.14(d,J=14.5Hz,1H),4.47-3.98(m,2H),3.85-3.54(m,1H),2.70(s,3H),1.62(d,J=6.8Hz,3H).

[0700] Example 52

[0701] Preparation of 2,2,2-trifluoro-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide (054)

[0702]

[0703] Compound 054a (40 mg, 0.11 mmol) and pyridine (17 mg, 0.21 mmol) were dissolved in DCM (4 mL), and then trifluoroacetic anhydride (34 mg, 0.16 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was diluted with DCM (10 mL), washed with saturated NaHCO3 water, and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN / H2O (0.1% FA) = 53%) to give 2,2,2-trifluoro-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 054 (11 mg, white solid), yield: 22%.

[0704] MS m / z(ESI): 469.1 [M+1] + .

[0705] 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),7.58(dd,J=8.8,5.6Hz,2H),7.30(dd,J=8.8,5.6Hz,2H),5. 87(s,1H),4.86(s,1H),4.33(s,1H),3.84(s,1H),3.63(s,1H),2.62(s,3H),1.29(d,J=6.4Hz,3H).

[0706] Example 53

[0707] Preparation of (R)-(5-fluoropyridin-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (055)

[0708]

[0709] Step 1: Preparation of 5-fluoropyridine chloride

[0710] 5-Fluoropyridinecarboxylic acid 055a (80 mg, 0.57 mmol) was dissolved in dichloromethane (3 mL), and then oxalyl chloride (360 mg, 2.84 mmol) was added dropwise, followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness to obtain 055b, which was used directly in the next step of the reaction.

[0711] Step 2: Preparation of (R)-(5-fluoropyridin-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone

[0712] 5-Fluoropyridine chloride (30.5 mg, 0.19 mmol) 055b was dissolved in dichloromethane (2 mL) and added dropwise to a dichloromethane (2 mL) solution of (R)-3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazolium[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole (30 mg, 0.1275 mmol) and triethylamine (32.0 mg, 0.312 mmol). The mixture was stirred at room temperature for 0.5 hours, and the reaction solution was quenched with saturated ammonium chloride (2 mL) and saturated sodium bicarbonate (2 mL). Extracted with ethyl acetate (2 × 10 mL), the organic layers were combined, dried with sodium sulfate, filtered, and the organic phase was concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid, which was then purified by prep-HPLC to give the title product (R)-(5-fluoropyridin-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 055 (2.1 mg, white solid), yield: 5%.

[0713] MS m / z(ESI): 359.1 [M+1] + .

[0714] 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=2.7Hz,1H),7.93-7.90(m,1H),7.83-7.81(m,1H),7.25(s,1H),5.85(d,J=6.4Hz,1 H),4.84-4.82(m,1H),4.30-4.20(m,1H),4.16-4.12(m,1H),3.72-3.59(m,1H),2.50-2.49(m,3H),1.56-1.55(m,3H).

[0715] Example 54

[0716] Preparation of (R)-(6-fluoropyridin-3-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (056)

[0717]

[0718] Step 1: Preparation of 6-fluoronicotinic acid chloride

[0719] 6-Fluoropyridine-3-carboxylic acid 056a (50 mg, 0.35 mmol) was dissolved in dichloromethane (3 mL), and then oxalyl chloride (225 mg, 1.75 mmol) was added dropwise, followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness to obtain 056b, which was used directly in the next reaction step.

[0720] Step 2: Preparation of (R)-(6-fluoropyridin-3-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone

[0721] Dissolve 6-fluoronicotinic acid chloride (30.5 mg, 0.19 mmol) 056b in dichloromethane (2 mL) and add dropwise to a dichloromethane (2 mL) solution of (R)-3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazole[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole (30 mg, 0.1275 mmol) and triethylamine (32.0 mg, 0.312 mmol). Stir at room temperature for 0.5 hours. The reaction solution was quenched with saturated ammonium chloride (2 mL) and saturated sodium bicarbonate (2 mL), extracted with ethyl acetate (2 × 10 mL), and the organic layers were then combined sequentially. The mixture was dried over sodium sulfate, filtered, and the organic phase was concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a pale yellow solid. The solid was then purified by prep-HPLC to give the title product (R)-(6-fluoropyridin-3-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 056 (2.1 mg, white solid), yield: 5%.

[0722] MS m / z(ESI): 359.0 [M+1] + .

[0723] 1 H NMR (400MHz, DMSO) δ8.43-8.41(m,1H),8.19-8.17(m,1H),7.33-7.31(m 1H),7.21(s,1H),5.82-5.60(m,1H),4.84-4.79(m,1H),4.31-4.25(m,1H),3.79-3.49(m,2H),2.56-2.52(m,3H),1.54(d,J=6.7Hz,3H).

[0724] Example 55

[0725] Preparation of (R)-(5-fluorothiophene-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (057)

[0726]

[0727] (R)-3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazole[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole 057a (30 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (2.5 mL), followed by the sequential addition of N,N-diisopropylethylamine (42 mg, 0.33 mmol), HATU (96 mg, 0.26 mmol), and 5-fluorothiophene-2-carboxylic acid (22 mg, 0.15 mmol). The reaction mixture was incubated at 25 °C for 3 hours. After the reaction was complete, the reaction was quenched with brine (40 mL), extracted with ethyl acetate (2 × 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase column chromatography (34% acetonitrile / water) to give (R)-(5-fluorothiophene-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 057 (2.6 mg, white solid), yield: 5%.

[0728] MS m / z(ESI): 364.1 [M+1] + .

[0729] 1 H NMR (400MHz, DMSO) δ7.42-7.37(m,1H),7.20(s,1H),6.84-6.83(m,1H),5.70-5.68(m,1H),4.93-4.90(m ,1H),4.54(d,J=14.1Hz,1H),4.35-4.32(m,1H),3.73-3.72(m,1H),2.64(s,3H),1.56(d,J=6.7Hz,3H).

[0730] Example 56

[0731] Preparation of (R)-(5-fluorofuran-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone (058)

[0732]

[0733] Step 1: Preparation of 5-nitrofuran-2-carboxylic acid benzyl ester

[0734] 5-Nitrofuran-2-carboxylic acid 058a (3.00 g, 19.10 mmol) was added to N,N-dimethylformamide (30 mL), followed by benzyl bromide (4.90 g, 28.60 mmol) and potassium carbonate (7.92 g, 57.30 mmol). The reaction was allowed to proceed at room temperature for 16 hours. After LCMS monitoring, water (50 mL) and ethyl acetate (3 × 50 mL) were added for extraction and separation. The extract was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was achieved using a silica gel column (petroleum ether / ethyl acetate = 10:1) to obtain the title product, benzyl 5-nitrofuran-2-carboxylic acid ester 058b (4.50 g, yellow solid), in 97% yield.

[0735] 1 H NMR (400MHz, CDCl3) δ7.46-7.37(m,5H),7.33(d,J=4.0Hz,1H),7.30(d,J=4.0Hz,1H),5.40(s,2H).

[0736] Step 2: Preparation of 5-fluorofuran-2-carboxylic acid benzyl ester

[0737] 5-Nitrofuran-2-carboxylic acid benzyl ester 058b (2.50 g, 10.01 mmol) was added to sulfolane (30 mL), followed by potassium fluoride (2.93 g, 50.4 mmol) and tetraphenylphosphine bromide (420 mg, 1.0 mmol). The reaction mixture was reacted at 140 °C for 2 hours. After the reaction was completed by LCMS monitoring, the reaction mixture was cooled to room temperature, and water (200 mL) and ethyl acetate (3 × 80 mL) were added for extraction and separation. The mixture was then washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title product, 5-fluorofuran-2-carboxylic acid benzyl ester 058c (400 mg, white solid), yield: 17%.

[0738] MS m / z(ESI): 243.0.(M+23).

[0739] Step 3: Preparation of 5-fluorofuran-2-carboxylic acid

[0740] Benzyl 5-fluorofuran-2-carboxylic acid ester 058c (200 mg, 0.91 mmol) was dissolved in methanol (5 mL), and Pd / C (10 mg, 0.091 mmol) was added. The reaction solution was reacted at 25 °C for half an hour under a hydrogen atmosphere. After the reaction was completed as monitored by LCMS, the catalyst was filtered off, and the methanol was removed by rotary evaporation. The residue was added to acetonitrile and water and lyophilized to give 5-fluorofuran-2-carboxylic acid ester 058d (100 mg, white body), yield: 78%.

[0741] MS m / z(ESI): 131.1 [M+1] + .

[0742] Step 4: Preparation of (R)-(5-fluorofuran-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone

[0743] 5-Fluorofuran-2-carboxylic acid 058d (50 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (2 mL), followed by N,N-diisopropylethylamine (49 mg, 0.38 mmol), (R)-3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole 058e (30 mg, 0.13 mmol), and HATU (73 mg, 0.19 mmol). The reaction mixture was incubated at 25 °C for 1 hour. After the reaction was complete, water (20 mL) and dichloromethane (2 × 20 mL) were added, followed by extraction and separation. The mixture was then washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was prepared by Prep-HPLC to obtain (R)-(5-fluorofuran-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone 058 (3.05 mg, yellow solid), yield: 13%.

[0744] MS m / z(ESI): 348.2 [M+1] + .

[0745] 1 H NMR (400MHz, CDCl3) δ7.15(s,1H),7.09(s,1H),5.88-5.83(m,,1H),5.70-5.67(m,1H),5.14-5.07(m, 1H), 4.86-4.80 (m, 1H), 4.30 (t, J = 10.8Hz, 1H), 3.61-3.51 (m, 1H), 2.70 (s, 3H), 1.67 (d, J = 6.4Hz, 3H).

[0746] 19 F NMR (376MHz, CDCl3) δ -108.67.

[0747] Example 57

[0748] Preparation of (R)-(4-fluorophenyl)(1-(2-fluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone (059)

[0749]

[0750] (1-Bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 059a (30 mg, 0.07 mmol), (2-fluorophenyl)borondiol (10.6 mg, 0.08 mmol), potassium carbonate (19.0 mg, 0.14 mmol), and Pd(dppf)Cl2 (5.3 mg, 0.007 mmol) were dissolved in a tetrahydrofuran / water (5 / 1, 6 mL) mixture. The reaction mixture was purged with nitrogen and reacted at 80 °C for 2 hours. After the reaction was completed, the reaction mixture was concentrated to dryness, and the residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a crude product, which was then purified by reversed-phase chromatography (55% acetonitrile / water) to give (R)-(4-fluorophenyl)(1-(2-fluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazol[1,5-a]pyrazin-7(8H)-yl) methyl ketone 059 (4.33 mg, white solid), yield: 14%.

[0751] MS m / z (ESI): 451.5 [M+1] + .

[0752] 1 H NMR (400MHz, CDCl3) δ7.69-7.65(m,1H),7.52-7.48(m,2H),7.37-7.31(m,1H),7.25-7.13(m,4H),6.30- 5.81(m,1H),5.16(d,J=13.2Hz,1H),4.33-3.97(m,2H),3.72-3.41(m,1H),2.70(s,3H),1.30(br,s,3H).

[0753] Example 58

[0754] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazole[1],5-a]pyrazin-1-yl)-N-methylacetamide (060)

[0755]

[0756] Step 1: Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)acetamide

[0757] Compound 060a (35 mg, 0.09 mmol) and triethylamine (28 mg, 0.28 mmol) were dissolved in dichloromethane (3 mL), and then acetyl chloride (11 mg, 0.14 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate water, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazin-1-yl)acetamide 060b (40 mg, yellow solid), yield: 82%.

[0758] MS m / z(ESI): 415.1 [M+1] + .

[0759] Step 2: Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylacetamide

[0760] Compound 060b (35 mg, 0.08 mmol) was dissolved in anhydrous THF (3 mL), cooled to 0 °C, and then NaH (4 mg, 0.17 mmol, 60%) was added. The mixture was reacted at room temperature for 1 h, followed by the addition of iodomethane (24 mg, 0.17 mmol) and the reaction mixture was reacted at room temperature for 2 h. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (3 × 10 mL), washed with saturated NaCl solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by pre-HPLC (ACN / H2O (0.1% FA) = 36%) to obtain compound (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylacetamide 060 (14.2 mg, white solid), yield: 39%.

[0761] MS m / z(ESI): 429.2 [M+1] + .

[0762] 1 H NMR (400MHz, DMSO-d6) δ7.60-7.57(m,2H),7.34-7.30(m,2H),5.67(s,1H),4.87(d,J=13.0Hz,1H),4 .31(s,1H),3.81(s,1H),3.66(s,1H),3.07(s,3H),2.64(s,3H),1.82(s,3H),1.45(d,J=6.8Hz,3H).

[0763] Example 59

[0764] (R)-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-ylcarbamate (061)

[0765]

[0766] (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 061a (80 mg, 0.21 mmol) was dissolved in dichloromethane (3 mL), and N,N-diethylpropylethylamine (83 mg, 0.64 mmol) and methyl chloroformate (30 mg, 0.32 mmol) were added sequentially. The reaction mixture was reacted at 25 °C for 1 hour. After the reaction was completed, 20 mL of water and 2 × 20 mL of dichloromethane were added, the mixture was extracted and separated, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase chromatography (39% acetonitrile / water) to give (R)-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-ylcarbamate 061 (40.00 mg, yellow solid), yield: 41%.

[0767] MS m / z(ESI): 431.2 [M+1] + .

[0768] 1 HNMR(400MHz, CDCl3)δ7.52-7.48(m,2H),7.19-7.13(m,2H),6.54-6.40(m, 1H),6.07-5.86(m,1H),5.09(d,J=12.8Hz,1H),4.24-4.17(m,1H),3.72(br,

[0769] s,3H),3.56-3.44(m,1H),2.68(s,3H),1.47(s,3H).

[0770] 19 FNMR (376MHz, CDCl3) δ -109.28.

[0771] Example 60

[0772] Preparation of (R)-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)(methyl)carbamate (062)

[0773]

[0774] Add (R)-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyrazin-1-ylcarbamate 061 (30 mg, 0.070 mmol) to 2 mL In N,N-dimethylformamide solvent, the mixture was cooled to 0°C and sodium hydride (6.69 mg, 0.28 mmol, 60% mineral oil) was added. The reaction solution was reacted at 0°C for 10 minutes, then iodomethane (15 mg, 0.10 mmol) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, 20 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 × 20 mL). The extract was then washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (40% acetonitrile / water) to obtain (R)-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)(methyl)carbamate 062 (24.74 mg, yellow oil), yield: 80%.

[0775] MS m / z (ESI): 445.2 [M+1] + .

[0776] 1 H NMR (400MHz, CDCl3) δ7.55-7.45(m,2H),7.22-7.13(m,2H),6.21-5.55m,1H),5.33-4.60(m,1 H),4.27-4.18(s,1H),3.77-3.73(m,1H),3.52(s,3H),3.26(s,3H),2.68(s,3H),1.48(s,3H).

[0777] 19 F NMR (376MHz, CDCl3) δ -108.98.

[0778] Example 61

[0779] Preparation of (R)-(1-(2,6-difluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazolium[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (063)

[0780]

[0781] To a 10 mL microwave tube equipped with a stir bar, add (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 063a (30 mg, 0.070 mmol), (2,6-difluorophenyl)borondiol (33 mg, 0.21 mmol), Pd(dtbpf)Cl2 (9 mg, 0.014 mmol), and potassium phosphate (29 mg, 0.21 mmol), followed by the addition of dioxane / water solvent (2 mL / 0.4 mL). The tube is then evacuated, purged with nitrogen, and capped. The tube is then microwave-heated to 90 °C with stirring for 1 hour. After the reaction is complete, the reaction mixture is concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give crude product, which was then purified by reversed-phase chromatography (38% acetonitrile / water) to give (R)-(1-(2,6-difluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazolium[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 063 (3.45 mg, white solid), yield: 10%.

[0782] MS m / z(ESI): 470.2 [M+1] + .

[0783] 1 H NMR (400MHz, CDCl3) δ7.50-7.45(m,2H),7.39-7.32(m,1H),7.19-7.14(m,2H),7.03-6.94(m,1H),6.09-5 .80(m,1H),5.15-5.11(m,1H),4.37-4.08(m,1H),3.66-3.51(m,1H),2.70(s,2H),1.32(d,J=5.6Hz,2H).

[0784] Example 62

[0785] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylmethanesulfonamide (064)

[0786]

[0787] Step 1: Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-(methylsulfonyl)methanesulfonamide

[0788] Compound 064a (35 mg, 0.09 mmol) and triethylamine (28 mg, 0.28 mmol) were dissolved in dichloromethane (3 mL), and then methanesulfonyl chloride (22 mg, 0.19 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was diluted with DCM (10 mL), washed with saturated sodium bicarbonate solution, and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-(methanesulfonyl)methanesulfonamide 064b (40 mg, yellow solid), yield: 64%.

[0789] MS m / z(ESI): 529.1 [M+1] + .

[0790] Step 2: Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)methanesulfonamide

[0791] Compound 064b (35 mg, 0.07 mmol) was dissolved in THF (3 mL), and then TBAF (69 mg, 0.03 mmol, 1 M in THF) was added dropwise. The reaction was allowed to proceed at room temperature for 1 h. The reaction solution was diluted with saturated NH4Cl solution, extracted with ethyl acetate (3 × 5 mL), and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)methanesulfonamide 064c (25 mg, yellow solid), yield: 84%.

[0792] MS m / z (ESI): 451.2 [M+1] + .

[0793] Step 3: Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylmethanesulfonamide

[0794] Compound 064c (25 mg, 0.06 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and NaH (4.5 mg, 0.12 mmol, 60%) was added under N2. After reacting at room temperature for 1 h, iodomethane (15.8 mg, 0.12 mmol) was added dropwise, and the reaction was continued at room temperature for 2 h. The reaction solution was quenched with saturated NH4Cl (10 mL) solution, extracted with ethyl acetate (3 × 10 mL), and dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by pre-HPLC (ACN / H2O (0.1% FA) = 45%) to give compound (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylmethanesulfonamide 064 (11.4 mg, white solid), yield: 44%.

[0795] MS m / z(ESI): 465.1 [M+1] + .

[0796] 1 H NMR(400MHz,DMSO-d6)δ7.59(d,J=7.2Hz,2H),7.31(d,J=7.2Hz,2H),5.86(s,1H),4.87-4.82(m,1H), 4.33(s,1H),3.85(s,1H),3.58(s,1H),3.17(s,3H),3.10(s,3H),2.64(s,3H),1.52(d,J=6.0Hz,3H).

[0797] Example 63

[0798] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)ethanesulfonamide (065)

[0799]

[0800] (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 065a (60 mg, 0.14 mmol), N,N-diisopropylethylamine (31.2 mg, 0.242 mmol) and ethylsulfonyl chloride (16 mg, 0.121 mmol) were mixed and dissolved in dichloromethane (4 mL). The mixture was stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether), and then purified by reversed-phase column chromatography (44% acetonitrile / water) to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)ethanesulfonamide 065 (2.7 mg, white solid), yield: 7%.

[0801] MS m / z(ESI): 465.1 [M+1] + .

[0802] 1 H NMR (400MHz, MeOD) δ7.58-7.50(m,2H),7.27-7.22(m,2H),4.31-4.24(m,1H),3.24(s,2H),2.84-2.79(m,4H),2.63(s,3H),1.29(t,J=6.4Hz,6H).

[0803] 19 F NMR (376MHz, MeOD) δ-111.59.

[0804] Example 64

[0805] Preparation of (3-(3-tert-butyl-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (066)

[0806]

[0807] Step 1: Preparation of ethyl 3-tert-butyl-1,2,4-thiadiazole-5-carboxylate

[0808] Trimethylacetamide 066a (2.02 g, 20.00 mmol) and chlorocarbonyl sulfinyl chloride (2.88 g, 22.00 mmol) were dissolved in dry toluene (15 mL). The reaction solution was reacted at 120 °C for 3 hours, then cooled to room temperature and saturated sodium bicarbonate solution (50 mL) was added. The mixture was then extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a reaction intermediate. This intermediate was dissolved in toluene (15 mL), and ethyl cyanoformate (3.96 g, 40.00 mmol) was added. The reaction solution was reacted at 130 °C for 16 hours. After cooling to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give ethyl 3-tert-butyl-1,2,4-thiadiazole-5-carboxylic acid ester 066b (1.24 g, pale yellow oil), yield: 28%.

[0809] MS m / z(ESI): 215.1 [M+1] + .

[0810] 1 H NMR (400MHz, CDCl3) δ4.51 (q, J = 7.2Hz, 2H), 1.49 (s, 9H), 1.45 (t, J = 7.2Hz, 3H).

[0811] Step 2: Preparation of 3-tert-butyl-1,2,4-thiadiazole-5-carboxylic acid

[0812] Ethyl 3-tert-butyl-1,2,4-thiadiazole-5-carboxylic acid 066b (1.24 g, 5.79 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (2.5 mL), and lithium hydroxide monohydrate (291 mg, 6.94 mmol) was added. The reaction mixture was reacted at 25 °C for 1 hour. The tetrahydrofuran was removed by rotary evaporation, and then excess lithium hydroxide was neutralized by adding 1 M hydrochloric acid dropwise to the residue. The mixture was lyophilized to give 3-tert-butyl-1,2,4-thiadiazole-5-carboxylic acid 066c (1.08 g, white solid), yield: 98%.

[0813] MS m / z (ESI): 187.1 [M+1] + .

[0814] 1 H NMR (400MHz, CD3OD) δ1.43 (s, 9H).

[0815] Step 3: Preparation of 3-tert-butyl-N-[(3-methylpyrazin-2-yl)methyl]-1,2,4-thiadiazole-5-carboxamide

[0816] 3-tert-butyl-1,2,4-thiadiazole-5-carboxylic acid 066c (1.08 g, 5.79 mmol) was dissolved in dichloromethane (30 mL), and oxalyl chloride (1.47 g, 11.58 mmol) was added, followed by 3 drops of DMF. The reaction mixture was reacted at 25 °C for 30 minutes. The reaction mixture was concentrated to remove excess oxalyl chloride, and then dissolved in dichloromethane (8 mL). This solution was added dropwise to a dichloromethane (22 mL) solution containing (3-methylpyrazin-2-yl)methylamine 4 (713 mg, 5.79 mmol) and triethylamine (878 mg, 8.68 mmol). The reaction mixture was reacted at 25 °C for 30 minutes. After the reaction was complete, the reaction mixture was washed once each with saturated ammonium chloride (60 mL) and saturated sodium bicarbonate (60 mL). The resulting aqueous phase was extracted with ethyl acetate (2 × 50 mL). All organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 3-tert-butyl-N-[(3-methylpyrazin-2-yl)methyl]-1,2,4-thiadiazole-5-carboxamide 066d (1.28 g, yellow solid), yield: 75%.

[0817] MS m / z(ESI): 292.1 [M+1] + .

[0818] 1 H NMR (400MHz, CDCl3) δ8.55(s,1H),8.45(d,J=2.8Hz,1H),8.44(d,J=2.8Hz,1H),4.78(d,J=4.8Hz,2H),2.63(s,3H),1.48(s,9H).

[0819] Step 4: Preparation of 3-tert-butyl-5-{4-methylimidazolium[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole

[0820] 3-tert-butyl-N-[(3-methylpyrazin-2-yl)methyl]-1,2,4-thiadiazole-5-carboxamide 066d (1.21 g, 4.15 mmol) was dissolved in acetonitrile (24 mL), and DMF (0.2 mL) was added, followed by slow addition of phosphorus oxychloride (3.18 g, 20.76 mmol). The reaction mixture was heated to 90 °C and reacted for 24 hours. The reaction mixture was cooled to room temperature and quenched with water (30 mL), then neutralized with ammonia. The acetonitrile was removed by rotary evaporation, and the residue was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 33 / 1) to obtain 3-tert-butyl-5-{4-methylimidazolium[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole 066e (1.02 g, light brown solid), yield: 88%.

[0821] MS m / z(ESI): 274.1 [M+1] + .

[0822] 1 H NMR (400MHz, CDCl3) δ9.21(d,J=4.8Hz,1H),7.93(d,J=0.8Hz,1H),7.82(d,J=5.2Hz,1H),2.81(s,3H),1.54(s,9H).

[0823] Step 5: Preparation of 1-(3-tert-butyl-1,2,4-thiadiazol-5-yl)-5-[(4-methoxyphenyl)methyl]-4-methylimidazo[1,5-a]pyrazine-quaternary ammonium salt

[0824] 3-tert-butyl-5-{4-methylimidazolium[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole 066e (1.20 g, 4.39 mmol) was dissolved in acetonitrile (20 mL), followed by the sequential addition of potassium iodide (146 mg, 0.88 mmol) and 4-methoxybenzyl chloride (1.38 g, 8.78 mmol). The reaction mixture was heated to 80 °C and reacted for 4 hours. The reaction mixture was cooled to room temperature, the solid was filtered off, and the solution was washed with acetonitrile (10 mL). The filtrate was concentrated to give crude 1-(3-tert-butyl-1,2,4-thiadiazole-5-yl)-5-[(4-methoxyphenyl)methyl]-4-methylimidazo[1,5-a]pyrazin-quaternary ammonium salt 066f (1.73 g, green solid), yield: 60%. This crude product was used directly in the next reaction.

[0825] MS m / z(ESI): 394.1 [M+1] + .

[0826] Step 6: Preparation of 3-tert-butyl-5-{5-[(4-methoxyphenyl)methyl]-4-methyl-4H,6H,7H imidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole

[0827] Crude 1-(3-tert-butyl-1,2,4-thiadiazol-5-yl)-5-[(4-methoxyphenyl)methyl]-4-methylimidazo[1,5-a]pyrazine-quaternary ammonium salt 066f (1.73 g, 4.39 mmol) was dissolved in ethanol (30 mL), cooled to 0 °C, and then acetic acid (5 drops) and sodium cyanoborohydride (551 mg, 8.77 mmol) were added sequentially. The reaction solution was reacted at 0 °C for 30 minutes. After the reaction was completed, the reaction was quenched with water (10 mL), and the ethanol was removed by rotary evaporation. The pH of the residue was adjusted to 8 by adding saturated sodium bicarbonate, and then extracted with dichloromethane (2 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 1 / 9) to give 0.66 g (560 mg, light brown solid) of 3-tert-butyl-5-{5-[(4-methoxyphenyl)methyl]-4-methyl-4H,6H,7H imidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole, yield: 31%.

[0828] MS m / z(ESI): 398.2 [M+1] + .

[0829] 1 H NMR (400MHz, CDCl3) δ7.30(d,J=8.0Hz,2H),7.00(s,1H),6.90(d,J=8.4Hz,2H),4.69-4.58(m,1H),4.29(br,1H),4.08-4.02(m ,1H),3.91-3.84(m,1H),3.82(s,3H),3.40-3.30(m,1H),3.22-3.13(m,1H),2.66(br,1H),1.57(d,J=5.6Hz,3H),1.43(s,9H).

[0830] Step 7: Preparation of 3-tert-butyl-5-{4-methyl-4H,5H,6H,7H imidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole

[0831] 0.66 g (150 mg, 0.03 mmol) of 3-tert-butyl-5-{5-[(4-methoxyphenyl)methyl]-4-methyl-4H,6H,7H-imidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole was dissolved in trifluoroacetic acid (5 mL). The reaction solution was heated to 100 °C and reacted for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and water (10 mL) was added. Then, saturated sodium bicarbonate was slowly added to adjust the pH to 8. The solution was extracted with dichloromethane (3 × 30 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 0.66 h (105 mg, light brown solid) of 3-tert-butyl-5-{4-methyl-4H,5H,6H,7H-imidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole, yield: 98%.

[0832] MS m / z(ESI): 278.1 [M+1] + .

[0833] Step 8: Preparation of (3-(3-tert-butyl-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone

[0834] 3-tert-butyl-5-{4-methyl-4H,5H,6H,7H-imidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole 0.66 h (50 mg, 0.18 mmol) was dissolved in dichloromethane (6 mL), followed by the sequential addition of triethylamine (46 mg, 0.45 mmol) and p-fluorobenzoyl chloride (37 mg, 0.23 mmol). The reaction mixture was incubated at 25 °C for 20 min. After the reaction was complete, the solution was quenched with saturated sodium bicarbonate (20 mL) and extracted with dichloromethane (2 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3), and then purified by reverse-phase column chromatography (55% acetonitrile / water) to give (3-(3-tert-butyl-1,2,4-thiadiazol-5-yl)-8-methyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 066 (30.0 mg, white solid), yield: 40%.

[0835] MS m / z(ESI): 400.1 [M+1] + .

[0836] HPLC: 98.61% (214nm), 97.08% (254nm).

[0837] 1H NMR (400MHz, CDCl3) δ7.52-7.42(m,2H),7.16(t,J=8.8Hz,2H),7.02(s,1H),5.65(br,1H),5.11-5. 00(m,1H),4.43(br,1H),4.28-4.14(m,1H),3.64-3.46(m,1H),1.60(d,J=6.8Hz,3H),1.44(s,9H).

[0838] 19 F NMR (376MHz, CDCl3) δ -108.95.

[0839] Example 65

[0840] Preparation of (R)-1-[7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-ylazacyclobut-2-one (067)

[0841]

[0842] (1-Bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 067a (31 mg, 0.07 mmol) was dissolved in dioxane (2.5 mL), followed by the addition of 2-azacyclobutanone (8 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (2 mg, 0.014 mmol), and cuprous iodide (7 mg, 0.04 mmol). The reaction mixture was heated to 120 °C and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether), and then purified by reversed-phase column chromatography (44% acetonitrile / water) to give (R)-1-[7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl]azacyclobut-2-one 067 (16.1 mg, white solid), yield: 54%.

[0843] MS m / z(ESI): 427.1 [M+1] + .

[0844] HPLC: 99.81% (214nm), 100% (254nm).

[0845] 1H NMR(400MHz, CDCl3)δ7.56-7.43(m,2H),7.15(t,J=8.4Hz,2H),6.04(br,1H),5.25-4.68(m,2H),4 .26-4.13(m,1H),3.90-3.84(m,1H),3.66-3.37(m,2H),3.03(br,2H),2.68(s,3H),1.48(br,3H).

[0846] 19 F NMR (376MHz, CDCl3) δ -108.56.

[0847] Example 66

[0848] Preparation of (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)pyrrolidine-2-one (068)

[0849]

[0850] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone 068a (40 mg, 0.09 mmol) was dissolved in 1,4-dioxane (2 mL), and then pyrrolidone-2-one (100 mg, 0.19 mmol), potassium carbonate (38 mg, 0.28 mmol), cuprous iodide (1 mg, 0.005 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (18 mg, 0.04 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (3 mg, 0.02 mmol) were added sequentially. The reaction was carried out under nitrogen protection and heated at 120°C with stirring for 16 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain a crude product. The crude product was purified by reverse-phase column chromatography (mobile phase: acetonitrile / water = 52 / 48) to give (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)pyrrolidine-2-one 068 (6.53 mg, pale yellow solid), yield: 15%.

[0851] MS m / z(ESI): 441.1 [M+1] + .

[0852] HPLC: 90.94% (214nm), 97.04% (254nm).

[0853] 1 H NMR (400MHz, CDCl3) δ7.56-7.45(m,2H),7.21-7.12(m,2H),5.99(s,1H),5.11(d,J=12.8Hz,1H),5.01-4.72(m ,1H),4.28-4.12(m,2H),3.64(s,1H),3.43(s,1H),2.69(s,3H),2.52(s,2H),2.30-2.12(m,2H),1.36(s,3H).

[0854] Example 67

[0855] Preparation of (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)piperidin-2-one (069)

[0856]

[0857] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 069a (40 mg, 0.09 mmol) was dissolved in dioxane (2.5 mL), followed by the addition of piperidin-2-one (14 mg, 0.14 mmol), potassium carbonate (38 mg, 0.28 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.018 mmol), and cuprous iodide (2 mg, 0.009 mmol). The reaction mixture was heated to 120 °C and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether) and then purified by reversed-phase column chromatography (44% acetonitrile / water) to give (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)piperidin-2-one 069 (2.1 mg, white solid), yield: 6.5%.

[0858] MS m / z (ESI): 455.2 [M+1] + .

[0859] 1 H NMR(400MHz,MeOD)δ7.58-7.56(m,2H),7.25 -7.23(m,2H),5.87-5.71(m,1H),5.09-5.01(m,1H),4.35-4.26(m,1H),4.08-3.90(m,2H),3 .69-3.49(m,2H),2.66(s,3H),2.59-2.43(m,2H),1.91-1.97(m,4H),1.45(d,J=8.0Hz,3H).

[0860] 19 F NMR (376MHz, CDCl3) δ -104.97.

[0861] Example 68

[0862] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)cyclopropaneformamide (070)

[0863]

[0864] (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 070a (30 mg, 0.081 mmol) was dissolved in dichloromethane (3 mL), followed by the addition of N,N-diisopropylethylamine (100 mg, 0.24 mmol) and cyclopropane carbohydrate (17 mg, 0.16 mmol). The reaction mixture was incubated at 25 °C for 1 hour. After the reaction was complete, water (20 mL) and dichloromethane (2 × 20 mL) were added sequentially. The mixture was extracted and separated, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase chromatography (45% acetonitrile / water) to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)cyclopropaneformamide 070 (22.00 mg, yellow solid), yield: 57%.

[0865] MS m / z(ESI): 441.2 [M+1] + .

[0866] 1HNMR (400MHz, CDCl3) δ7.82 (s, 1H), 7.52-7.48 (m, 2H), 7.15 (t, J = 8.8Hz, 2H), 6.21-5.73 (m, 2H), 5.13-5.06 (m, 1H), 4.25-4.15(m,1H),3.56-3.41(m,1H),2.68(s,1H),1.52(s,1H),1.38(s,3H),1.07-0.96(m,2H),0.88-0.76(m,2H).

[0867] 19 FNMR (376MHz, CDCl3) δ -109.38.

[0868] Example 69

[0869] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylcyclopropaneformamide (071)

[0870]

[0871] (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazole[1,5-a]pyrazin-1-yl)cyclopropaneformamide (070) (11 mg, 0.025 mmol) was added to N,N-dimethylformamide (2 mL), cooled to 0 °C, and sodium hydride (60%, 2 mg, 0.054 mmol) was added. The reaction solution was reacted at 0 °C for 10 minutes, and then iodomethane (7 mg, 0.05 mmol) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 × 20 mL). The extract was then washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (42% acetonitrile / water) to obtain (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylcyclopropaneformamide 070 (7.12 mg, white solid), yield: 60%.

[0872] MS m / z (ESI): 455.2 [M+1] + .

[0873] 1H NMR (400MHz, CDCl3) δ7.50-7.46(m,2H),7.20-7.14(m,2H),5.09-5.05(m,1H),4.39-4.09(m,2H),3.71-3 .42(m,2H),3.22(s,3H),2.70(s,3H),1.56(d,J=6.8Hz,2H),1.40(s,1H),1.12-0.82(m,3H),0.59(s,1H).

[0874] Example 70

[0875] Preparation of (R)-4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)morpholin-3-one (072)

[0876]

[0877] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 072a (48 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2 mL), followed by the addition of morpholino-3-one (33 mg, 0.33 mmol), cesium carbonate (107 mg, 0.33 mmol), cuprous iodide (1 mg, 0.005 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (3 mg, 0.02 mmol). The reaction mixture was heated to 110 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain a crude product. The crude product was purified by reverse-phase column chromatography (acetonitrile / water = 30 / 70) to give (R)-4-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)morpholin-3-one (072) (10.9 mg, white solid), yield: 21.18%.

[0878] MS m / z (ESI): 457.2 [M+1] + .

[0879] HPLC: 95.26% (214nm), 97.45% (254nm).

[0880] 1 H NMR (400MHz, CDCl3) δ7.53-7.44(m,2H),7.15(t,J=8.4Hz,2H),5.76(s,1H),5.09(d,J=13.1Hz,2H),4.97 -4.62(m,4H),4.38-4.13(m,2H),4.03(s,1H),3.59(s,1H),3.48-3.39(m,1H),2.68(s,3H),1.38(s,3H).

[0881] Example 71

[0882] Preparation of (R)-(1-(2,3-difluoropyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (074)

[0883]

[0884] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 074a (35 mg, 0.08 mmol), (2,3-difluoropyridin-4-yl)boranediol (14.02 mg, 0.09 mmol), potassium carbonate (22.17 mg, 0.16 mmol), and Pd(dppf)Cl2 (5.87 mg, 0.008 mmol) were dissolved in a tetrahydrofuran / water (1:4, 2.5 mL) mixture. The reaction mixture was purged with nitrogen and heated to 90 °C for 5 hours. After the reaction was completed, the reaction mixture was concentrated to dryness, and the residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 2 / 3) to obtain a crude product, which was further purified by reversed-phase chromatography (69% acetonitrile / water) to give (R)-(1-(2,3-difluoropyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 074 (8.70 mg, white solid), yield: 23%.

[0885] MS m / z (ESI): 471.5 [M+1] + .

[0886] 1 H NMR(400MHz, CDCl3)δ8.01(d,J=4.9Hz,1H),7.63(t,J=4.8Hz,1H),7.52-7.49(m,2H),

[0887] 7.21-7.17(m,2H),6.23(s,1H),5.66(s,1H),5.18(d,J=14.2Hz,1H),4.33(s,1H),3.55(s,1H),2.72(s,3H),1.39(d,J=6.6Hz,3H).

[0888] Example 72

[0889] Preparation of (R)-(1-(3-fluoro-2-methylpyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (075)

[0890]

[0891] Step 1: Preparation of 3-fluoro-2-methyl-4-(trimethyltinyl)pyridine

[0892] 4-Bromo-3-fluoro-2-methylpyridine 075a (57 mg, 0.30 mmol) was dissolved in dioxane (3 mL), followed by the addition of hexamethyldistin (147 mg, 0.45 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol). The reaction mixture was heated to 110 °C for 4 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, diatomaceous earth (1 g) was added, and the organic solvent was removed by rotary evaporation. The residue was purified by neutral alumina column chromatography (5.5% ethyl acetate / petroleum ether) to obtain 3-fluoro-2-methyl-4-(trimethylstanyl)pyridine 075b (59 mg, colorless oil), yield: 68%.

[0893] MS m / z(ESI): 276.0 [M+1] + .

[0894] 1 H NMR (400MHz, CDCl3) δ8.22(dd,J=4.4,2.8Hz,1H),7.16(dd,J=4.0,2.4Hz,1H),2.50(d,J=2.8Hz,4H),0.38(s,9H).

[0895] Step 2: Preparation of (R)-(1-(3-fluoro-2-methylpyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0896] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 075c (35 mg, 0.08 mmol) was dissolved in dioxane (3 mL), followed by the addition of 3-fluoro-2-methyl-4-(trimethyltinyl)pyridine 151b (33 mg, 0.12 mmol), palladium acetate (2 mg, 0.008 mmol), tricyclohexylphosphine (5 mg, 0.02 mmol), and cesium fluoride (37 mg, 0.22 mmol). The reaction mixture was heated to 90 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, quenched with potassium fluoride (1 M, 10 mL), and extracted with ethyl acetate (2 × 15 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was separated by silica gel column chromatography (80% ethyl acetate / petroleum ether) and then further purified by Prep-HPLC to give (R)-(1-(3-fluoro-2-methylpyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 075 (1.02 mg, white solid), yield: 2%.

[0897] MS m / z(ESI): 467.1 [M+1] + .

[0898] HPLC: 90.91% (214nm), 86.82% (254nm).

[0899] 1 H NMR (400MHz, CDCl3) δ8.35 (d, J = 4.4Hz, 1H), 7.56-7.47 (m, 4H), 7.19 (t, J = 8.4Hz, 2H), 5.26-5 .09(m,2H),4.32(br,2H),3.67-3.46(m,2H),2.71(s,3H),2.57(s,3H),1.35(d,J=6.4Hz,3H).

[0900] 19 F NMR (376MHz, CDCl3) δ -108.90.

[0901] Example 73

[0902] Preparation of (R)-(1-(5-fluoro-2-methylpyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (076)

[0903]

[0904] Step 1: Preparation of 5-fluoro-2-methyl-4-(trimethyltinyl)pyridine

[0905] 4-Bromo-5-fluoro-2-methylpyridine 076a (80 mg, 0.42 mmol) was dissolved in dioxane (3 mL), followed by the addition of hexamethyldistin (207 mg, 0.63 mmol) and tetrakis(triphenylphosphine)palladium (49 mg, 0.04 mmol). The reaction mixture was heated to 110 °C for 4 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, diatomaceous earth (1 g) was added, and the organic solvent was removed by rotary evaporation. The residue was purified by neutral alumina column chromatography (4% ethyl acetate / petroleum ether) to obtain 5-fluoro-2-methyl-4-(trimethylstanyl)pyridine 076b (80 mg, colorless oil), yield: 66%.

[0906] MS m / z(ESI): 276.0 [M+1] + .

[0907] 1 H NMR (400MHz, CDCl3) δ8.22 (s, 1H), 7.16 (d, J = 2.8Hz, 1H), 2.52 (s, 3H), 0.38 (s, 9H).

[0908] Step 2: Preparation of (R)-(1-(5-fluoro-2-methylpyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone

[0909] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 076c (35 mg, 0.08 mmol) was dissolved in dioxane (3 mL), followed by the addition of 5-fluoro-2-methyl-4-(trimethyltinyl)pyridine 152b (33 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (9 mg, 0.008 mmol). The reaction mixture was heated to 120 °C for 48 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, quenched with potassium fluoride (1 M, 10 mL), and extracted with ethyl acetate (2 × 15 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was separated by silica gel column chromatography (80% ethyl acetate / petroleum ether) and then further purified by Prep-HPLC to give (R)-(1-(5-fluoro-2-methylpyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 076 (2.86 mg, white solid), yield: 8%.

[0910] MS m / z(ESI): 467.1 [M+1] + .

[0911] HPLC: 99.69% (214nm), 99.56% (254nm).

[0912] 1 H NMR (400MHz, CDCl3) δ8.36(s,1H),7.56(d,J=6.0Hz,1H),7.54-7.46(m,2H),7.19(t,J=8.4Hz,2H),5.94-5.54(m ,1H),5.24-5.12(m,1H),4.38-4.25(m,1H),3.77-3.23(m,2H),2.72(s,3H),2.59(s,3H),1.34(d,J=5.6Hz,3H).

[0913] 19 F NMR (376MHz, CDCl3) δ -108.70.

[0914] Example 74

[0915] (R)-(1-(2,5-difluoropyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone (077)

[0916]

[0917] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 077a (30 mg, 0.07 mmol) was dissolved in a mixture of tetrahydrofuran (2.4 mL) and water (0.6 mL). Then, 2,5-difluoropyridine-4-boronic acid (13 mg, 0.08 mmol), potassium carbonate (29 mg, 0.21 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added sequentially. Under nitrogen protection, the reaction mixture was heated to 90 °C for 3 hours. After the reaction, the mixture was cooled to room temperature. Water (5 mL) and ethyl acetate (2 × 10 mL) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (50% ethyl acetate / petroleum ether), and then purified by reversed-phase column chromatography (51% acetonitrile / water) to give (R)-(1-(2,5-difluoropyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 077 (10.0 mg, white solid), yield: 31%.

[0918] MS m / z(ESI): 471.1 [M+1] + .

[0919] HPLC: 99.76% (214nm), 99.49% (254nm).

[0920] 1 H NMR (400MHz, CDCl3) δ8.08 (s, 1H), 7.55-7.46 (m, 2H), 7.40 (dd, J = 4.4, 2.4Hz, 1H), 7.23-7.14 (m, 2H), 6.32 (b r,1H),5.77(br,1H),5.20-5.16(m,1H),4.37-4.25(m,1H),3.54(br,1H),2.71(s,3H),1.38(d,J=6.4Hz,3H).

[0921] 19 F NMR (376MHz, CDCl3) δ-72.68,-72.74,-108.64.

[0922] Example 75

[0923] Preparation of (R)-(1-(3-fluoro-2-methoxypyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (078)

[0924]

[0925] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 078a (30 mg, 0.069 mmol) was dissolved in 1,4-dioxane / water (4 / 1, 2 mL), followed by the sequential addition of (5-fluoro-6-methoxypyridin-3-yl)borondiol (18 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol). The reaction was carried out under nitrogen protection and heated at 95 °C with stirring for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate (3 × 10 mL), and the organic phases were combined and washed with saturated brine (20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 6) to obtain a crude product. The crude product was purified by reverse column chromatography (acetonitrile / water = 60 / 40) to obtain (R)-(1-(3-fluoro-2-methoxypyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 078 (9.38 mg, white solid), yield: 28.20%.

[0926] MS m / z(ESI): 483.1 [M+1] + .

[0927] HPLC: 99.76% (214nm), 99.78% (254nm).

[0928] 1 H NMR(400MHz, CDCl3) δ7.96(d,J=4.8Hz,1H),7.54-7.46(m,2H),7.28-7.23(m,1H),7.18(t,J=8.6Hz,2H),6.75-6.01(s,1 H),5.94-5.67(m,1H),5.15(d,J=12.8Hz,1H),4.32(s,1H),4.05(s,3H),3.53(s,1H),2.71(s,3H),1.36(d,J=6.4Hz,3H).

[0929] Example 76

[0930] Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(2-(trifluoromethyl)pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (079)

[0931]

[0932] Compound (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 079a (30 mg, 0.0688 mmol) was dissolved in tetrahydrofuran / water = 4 / 1 (2.5 mL). Then, 4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoborane-2-yl)-2-(trifluoromethyl)pyridine (24 mg, 0.089 mmol), potassium carbonate (51 mg, 0.24 mmol), and PdCl2 (dppf) (14.7 mg, 0.016 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at 90 °C for 3 hours under nitrogen protection. After filtration of the reaction solution, the filtrate was concentrated, and the residue was purified by pre-HPLC (acetonitrile / water) to obtain compound (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-(2-(trifluoromethyl)pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 079 (12 mg, white solid), yield: 34%.

[0933] MS m / z(ESI):[M+1] + 503.1

[0934] 1H NMR (400MHz, CDCl3) δ8.78(s,1H),8.20(brs,1H),7.83(brs,1H),7.51(dd,J=8.5,5.2Hz,2H),7.20(t,J=8.5Hz,2H),6.47(brs,1H ),5.15(d,J=13.6Hz,1H),4.32(dd,J=25.1,10.4Hz,1H),4.26-3.96(m,1H),3.86-3.48(m,1H),2.71(s,3H),1.60(d,J=6.8Hz,3H).

[0935] Example 77

[0936] Preparation of (R)-(1-(2-methoxypyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone (080)

[0937]

[0938] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 080a (30 mg, 0.07 mmol) was dissolved in a mixture of tetrahydrofuran (2.4 mL) and water (0.6 mL). Then, 2-methoxypyridine-4-boronic acid (13 mg, 0.08 mmol), potassium carbonate (29 mg, 0.21 mmol), and Pd(dppf)Cl2 (5 mg, 0.007 mmol) were added sequentially. The reaction mixture was heated to 90 °C for 3 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature. Water (5 mL) and ethyl acetate (2 × 10 mL) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (50% ethyl acetate / petroleum ether), and then purified by reversed-phase column chromatography (53% acetonitrile / water) to give (R)-(1-(2-methoxypyridin-4-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 080 (12.0 mg, white solid), yield: 37%.

[0939] MS m / z(ESI): 465.1 [M+1] + .

[0940] HPLC: 99.33% (214nm), 99.50% (254nm).

[0941] 1 H NMR (400MHz, CDCl3) δ8.21(s,1H),7.50(dd,J=8.4,5.6Hz,2H),7.34(br,1H),7.18(t,J=8.4Hz,2H),6.42(s,1H),5.65(br,1 H),5.17-5.05(m,1H),4.35-4.21(m,1H),4.19-4.02(m,1H),3.98(s,3H),3.68(br,1H),2.69(s,3H),1.57(d,J=6.8Hz,3H).

[0942] 19F NMR (376MHz, CDCl3) δ -108.76.

[0943] Example 78

[0944] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)acrylamide (081)

[0945]

[0946] (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 081a (30 mg, 0.081 mmol) and sodium bicarbonate (27 mg, 0.32 mmol) were dissolved in tetrahydrofuran / water (2 mL / 0.4 mL). The reaction solution was placed at -20 °C and acryloyl chloride (22 mg, 0.24 mmol) was slowly added dropwise. The reaction solution was reacted at -20 °C for 10 minutes. After the reaction was completed, 20 mL of water and 2 × 20 mL of dichloromethane were added. The mixture was extracted and separated, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase chromatography (42% acetonitrile / water) to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)acrylamide 081 (15.00 mg, yellow solid), yield: 43%.

[0947] MS m / z(ESI): 427.1 [M+1] + .

[0948] 1 HNMR(400MHz, CDCl3)δ7.56-7.46(m,3H),7.19-7.15(m,2H),6.40-6.31(m,1H),6.26-6.11(m,2H),5.8 0-5.74(m,1H),5.13(d,J=13.6Hz,1H),4.26-4.18(m,1H),3.57-3.37(m,2H),2.69(s,3H),1.37(s,3H).

[0949] 19 FNMR (376MHz, CDCl3) δ -109.26.

[0950] Example 79

[0951] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylacrylamide (082)

[0952]

[0953] (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methacrylamide 081 (8 mg, 0.019 mmol) was added to N,N-dimethylformamide (2 mL), cooled to 0 °C, and sodium hydride (60%, 2 mg, 0.040 mmol) was added. The reaction mixture was reacted at 0 °C for 10 minutes, and then iodomethane (8 mg, 0.056 mmol) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, 20 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 20 mL), washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (45% acetonitrile / water) to obtain (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methylacrylamide 082 (5.71 mg, white solid), yield: 69%.

[0954] MS m / z(ESI): 441.1 [M+1] + .

[0955] 1 H NMR (400MHz, CDCl3) δ7.46-7.43(m,2H),7.19-7.12(m,2H),6.50-5.96(m,2H),5.53-5.31(m,2H),5.08(dd, J=14.0,3.2Hz,1H),4.30-4.18(m,1H),3.59-3.45(m,1H),3.27(s,3H),2.70(s,3H),1.47(d,J=6.8Hz,3H).

[0956] Example 80

[0957] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)isonicotinamide (083)

[0958]

[0959] Pyridine-4-carbonyl chloride hydrochloride (17 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL), and then potassium carbonate (17 mg, 0.12 mmol) was added under ice bath conditions. After stirring for 5 minutes, (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone 083a (15 mg, 0.04 mmol) was added. The reaction was carried out under nitrogen protection and stirred at 0 °C for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product. The crude product was purified by reverse column chromatography (acetonitrile / water = 60 / 40) to obtain (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)isonicotinamide 083 (11.23 mg, yellow solid), yield: 28.46%.

[0960] MS m / z(ESI): 478.2 [M+1] + .

[0961] HPLC: 99.00% (214nm), 99.64% (254nm).

[0962] 1 H NMR (400MHz, CDCl3) δ8.81(d,J=4.8Hz,2H),8.43(s,1H),7.72(s,2H),7.54(d,J=5.2Hz,2H),7.20(t,J=8.8Hz,2 H),6.14(s,1H),5.17(d,J=13.6Hz,1H),5.08-4.74(m,1H),4.26(s,1H),3.52(s,1H),2.71(s,3H),1.41(s,3H).

[0963] Example 81

[0964] Preparation of (R)-1-[7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)]-4-methylpiperazin-2-one (084)

[0965]

[0966] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 084a (20 mg, 0.045 mmol) was dissolved in dioxane (2.5 mL), followed by the addition of 4-methylpiperazin-2-one (15 mg, 0.13 mmol), cesium carbonate (19 mg, 0.14 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (2 mg, 0.014 mmol), and cuprous iodide (7 mg, 0.04 mmol). The reaction mixture was heated to 120 °C and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (10% methanol / dichloromethane), and then purified by prep-HPLC (44% acetonitrile / water) to give (R)-1-[7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)]-4-methylpiperazin-2-one 084 (1.4 mg, white solid), yield:

[0967] 4.3%.

[0968] MS m / z(ESI): 470.1 [M+1] + .

[0969] 1H NMR (400MHz, CDCl3) δ7.49-7.42(m,2H),7.16-7.12(m,2H),5.35(bs,1H),5.17-4.97(m,1H),4.33-3.99(m, 2H),3.37-3.30(m,3H),3.01-2.78(m,1H),2.68(s,3H),2.45-2.40(m,2H),2.31-1.90(m,1H),1.40(s,3H).

[0970] Example 82

[0971] Preparation of (R)-2-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)isoindoline-1-one (085)

[0972]

[0973] (1-Bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 085a (20 mg, 0.045 mmol) was dissolved in dioxane (2.5 mL), followed by the addition of isoindole (24 mg, 0.18 mmol), cesium carbonate (19 mg, 0.14 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (2 mg, 0.014 mmol), and cuprous iodide (7 mg, 0.04 mmol). The reaction mixture was heated to 80 °C and reacted for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether), and then purified by reversed-phase column chromatography (44% acetonitrile / water) to give (R)-2-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)isoindoline-1-one 085 (8.2 mg, white solid), yield: 35%.

[0974] MS m / z(ESI): 489.1 [M+1] + .

[0975] HPLC: 98.67% (214nm), 98.99% (254nm).

[0976] 1H NMR (400MHz, CDCl3) δ7.96-7.82(m,1H),7.66-7.44(m,6H),7.19(t,J=8.3Hz,2H),6.27(s,1H),5.29(d,J=17.1Hz, 1H), 5.17 (d, J = 13.3Hz, 1H), 4.62 (d, J = 16.8Hz, 1H), 4.27 (t, J = 11.4Hz, 1H), 3.49 (s, 1H), 2.70 (s, 3H), 1.36 (s, 3H).

[0977] 19F NMR (376MHz, CDCl3) δ-109.22.

[0978] Example 83

[0979] Preparation of (R)-2-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-3,4-dihydroisoquinoline-1(2H)-one (086)

[0980]

[0981] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 086a (20 mg, 0.045 mmol) was dissolved in dioxane (2.5 mL), followed by the addition of 3,4,4a,8a-tetrahydro-2H-isoquinoline-1-one (10 mg, 0.068 mmol), cesium carbonate (19 mg, 0.14 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (2 mg, 0.014 mmol), and cuprous iodide (7 mg, 0.04 mmol). The reaction mixture was heated to 80 °C and reacted for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether), and then purified by reversed-phase column chromatography (44% acetonitrile / water) to give (R)-2-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-3,4-dihydroisoquinoline-1(2H)-one 086 (11.2 mg, white solid), yield: 45%.

[0982] MS m / z(ESI): 503.1 [M+1] + .

[0983] 1H NMR (400MHz, CDCl3) δ8.07(s,1H),7.49-7.45(m,3H),7.37-3.30(m,1H),7.23(s,1H),7.17-7.12(m,2H),6.01-5.72(m,1H),5.13(d,J=15.6Hz, 1H),4.90(dd,J=16.7,7.6Hz,1H),4.32-4.17(m,2H),3.87-3.82(m,1H) ,3.54-3.38(m,1H),3.14-3.05(m,2H),2.69(s,3H),1.35-1.20(m,3H).

[0984] Example 84

[0985] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)cyclopropanesulfonamide (087)

[0986]

[0987] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 087a (30.00 mg, 0.069 mmol), cuprous iodide (1.31 mg, 0.007 mmol), and potassium carbonate (11.41 mg, 0.083 mmol) were dissolved in 1,4-dioxane solution (5 mL), and then trans-(1R,2R)N,N'-dimethyl-cyclohexane-1,2-diamine (0.98 mg, 0.007 mmol) and cyclopropanesulfonamide (12.50 mg, 0.103 mol) were added. The reaction was carried out under nitrogen protection and heated to 120 °C for 16 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated to dryness, and the residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 10:1). The crude product was further purified by Prep-HPLC to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)cyclopropanesulfonamide 087 (2.01 mg, white solid), yield: 6%.

[0988] MS m / z(ESI): 477.1 [M+1] + .

[0989] 1 H NMR (400MHz, CDCl3) δ7.52-7.41(m,2H),7.20-7.08(m,2H),5.99(s,1H),5.05(d,J=1 4.1Hz,1H),4.24(s,1H),3.49(bs,2H),2.69(s,3H),1.60(s,4H),1.27-1.02(m,4H).

[0990] 19 F NMR (376MHz, cdcl3) δ -108.71.

[0991] Example 85

[0992] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)pyridine amide (088)

[0993]

[0994] Pyridine-2-carbonyl chloride hydrochloride (16 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL), and then potassium carbonate (2 mg, 0.01 mmol) was added under ice bath conditions. After stirring for 5 minutes, (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methyl ketone 088a (28 mg, 0.08 mmol) was added. The reaction was carried out under nitrogen protection and stirred at 0 °C for 1 hour. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to obtain a crude product. The crude product was purified by reverse column chromatography (acetonitrile / water = 60 / 40) to obtain (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)pyridine amide 088 (10.77 mg, white solid), yield: 28.46%.

[0995] MS m / z(ESI): 478.1 [M+1] + .

[0996] HPLC: 94.73% (214nm), 99.57% (254nm).

[0997] 1 H NMR(400MHz, CDCl3)δ9.94(s,1H),8.61(d,J=4.0Hz,1H),8.19(s,1H),7.89(t,J=7.6Hz,1H),7.54(s,2H),7.51-7.46(m,1H),7.1 9(t,J=8.6Hz,2H),6.45-5.95(m,1H),5.70-4.75(m,2H),4.25(t,J=13.6Hz,1H),3.52(s,1H),2.70(s,3H),1.39(d,J=4.4Hz,3H).

[0998] Example 86

[0999] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-2-methoxyacetamide (089)

[1000]

[1001] (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 089a (50 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), followed by the addition of N,N-diisopropylethylamine (52 mg, 0.40 mmol) and 2-methoxyacetyl chloride (29 mg, 0.27 mmol). The reaction mixture was incubated at 25 °C for 1 hour. After the reaction was complete, 20 mL of water and 2 × 20 mL of dichloromethane were added, the mixture was extracted and separated, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase chromatography (45% acetonitrile / water) to give (R)-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazolium[1,5-a]pyrazin-1-ylcarbamate 089 (25.00 mg, yellow solid), yield: 41%.

[1002] MS m / z (ESI): 445.2 [M+1] + .

[1003] 1 HNMR(400MHz, CDCl3)δ8.33(s,1H),7.53-7.48(m,2H),7.18-7.14(m,2H),6.20-5.85(m,1H),5.12(d,J= 12.8Hz,1H),5.00-4.86(m,1H),4.24-4.17(m,1H),3.98(s,2H),3.48(s,3H),2.69(s,3H),1.38(s,3H).

[1004] Example 87

[1005] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-2-methoxy-N-methylacetamide (090)

[1006]

[1007] (R)-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazole[1,5-a]pyrazin-1-ylcarbamate 089 (12 mg, 0.027 mmol) was added to N,N-dimethylformamide (2 mL), cooled to 0 °C, and sodium hydride (2 mg, 0.054 mmol, 60% mineral oil) was added. The reaction solution was reacted at 0 °C for 10 minutes, then iodomethane (12 mg, 0.081 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The solution was then quenched with 20 mL of water, extracted with ethyl acetate (2 × 20 mL), washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (42% acetonitrile / water) to obtain (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-2-methoxy-N-methylacetamide 090 (5.19 mg, white solid), yield: 41%.

[1008] MS m / z(ESI): 459.2 [M+1] + .

[1009] 1 H NMR (400MHz, CDCl3) δ7.49-7.46(m,2H),7.20-7.15(m,2H),5.80-5.56(m,1H),5.09-5.05(m,1H),4.29-4.20(m,1H),4 .03-3.94(m,1H),3.85-3.77(m,1H),3.62-3.54(m,1H),3.34(s,3H),3.22(s,3H),2.69(s,3H),1.55(d,J=6.8Hz,3H).

[1010] Example 88

[1011] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methyl-2-(methylamino)acetamide (091)

[1012]

[1013] Step 1: Preparation of (R)-(2-((7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)amino)-2-oxoethyl(methyl)carbamate tert-butyl

[1014] (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol-[1,5-a]pyrazin-1-yl)-2-(methylamino)acetamide 109 (22 mg, 0.05 mmol) was dissolved in dichloromethane (6 mL), followed by the addition of triethylamine (15 mg, 0.15 mmol) and di-tert-butyl dicarbonate (22 mg, 0.10 mmol). The reaction mixture was incubated at 25 °C for 1 hour. After the reaction was complete, saturated ammonium chloride (35 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (2 × 40 mL). The combined organic phases were washed with saturated sodium bicarbonate (30 mL), dried over anhydrous sodium sulfate, and concentrated. (R)-(2-((7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)amino)-2-oxoethyl(methyl)carbamate tert-butyl ester 091a (27 mg, pale yellow oil) was obtained in 94% yield.

[1015] MS m / z (ESI): 544.2 [M+1] + .

[1016] Step 2: Preparation of (R)-(2-((7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol-[1,5-a]pyrazin-1-yl)(methyl)amino)-2-oxoethyl(methyl)carbamate tert-butyl

[1017] (R)-(2-((7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazole-5-)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)amino)-2-oxoethyl(methyl)carbamate tert-butyl ester 091a (25 mg, 0.05 mmol) was dissolved in DMF (3 mL). After cooling to 0 °C in an ice bath, potassium carbonate (32 mg, 0.23 mmol) and iodomethane (13 mg, 0.09 mmol) were added sequentially. The reaction solution was reacted at room temperature for 6 hours. After the reaction was completed, water (15 mL) was added. The reaction was quenched, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, washed with saturated brine (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (80% ethyl acetate / petroleum ether) to give (R)-(2-((7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)(methyl)amino)-2-oxoethyl(methyl)carbamate tert-butyl ester 091b (23 mg, colorless oil), yield: 85%.

[1018] MS m / z (ESI): 558.2 [M+1] + .

[1019] Step 3: Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol-[1,5-a]pyrazin-1-yl)-N-methyl-2-(methylamino)acetamide

[1020] (R)-(2-((7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)(methyl)amino)-2-oxoethyl(methyl)carbamate tert-butyl ester 091b (20 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The reaction solution was reacted at 25 °C for 1 hour. After the reaction was completed, saturated sodium bicarbonate (40 mL) was added. Trifluoroacetic acid in the neutralization reaction solution was extracted with dichloromethane (2 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Prep-HPLC to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-N-methyl-2-(methylamino)acetamide 091 (9.3 mg, pale yellow solid), yield: 56%.

[1021] MS m / z(ESI): 458.1 [M+1] + .

[1022] HPLC: 98.84% (214nm), 98.40% (254nm).

[1023] 1 H NMR (400MHz, CD3OD) δ7.63-7.53(m,2H),7.26(t,J=8.4Hz,2H),5.81(br,1H),5.08-4.99(m,1H),4.39-4.27(m,1H),4.11(b r,1H),3.92-3.48(m,2H),3.36(br,1H),3.22(br,2H),3.14-3.06(m,1H),2.67(s,3H),2.30(s,3H),1.57(d,J=6.8Hz,3H).

[1024] 19 F NMR (376MHz, CD3OD) δ-111.34.

[1025] Example 89

[1026] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[15-a]pyrazin-1-yl)-3-methoxypropionamide (092)

[1027]

[1028] (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 092a (30 mg, 0.081 mmol) was dissolved in dichloromethane (3 mL), and N,N-diethylpropylethylamine (31 mg, 0.16 mmol) and 3-methoxyacetyl chloride (20 mg, 0.16 mmol) were added sequentially. The reaction mixture was reacted at 25 °C for 1 hour. After the reaction was completed, 20 mL of water and 2 × 20 mL of dichloromethane were added, the mixture was extracted and separated, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase chromatography (45% acetonitrile / water) to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-3-methoxypropionamide 092 (15.00 mg, yellow solid), yield: 39%.

[1029] MS m / z(ESI): 459.2 [M+1] + .

[1030] 1 HNMR(400MHz, CDCl3)δ8.13(s,1H),7.53-7.48(m,2H),7.18-7.14(m,2H),6.22-5.72(m,2H),5.19-4 .87(m,2H),4.19(t,J=11.6Hz,1H),3.69(s,2H),3.41(s,3H),2.68(s,3H),2.59(s,2H),1.37(s,3H).

[1031] Example 90

[1032] (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-3-methoxy-N-methylpropionamide (093)

[1033]

[1034] (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-3-methoxypropionamide 092 (10 mg, 0.022 mmol) was added to N,N-dimethylformamide (2 mL), cooled to 0 °C, and sodium hydride (60%, 2 mg, 0.054 mmol) was added. The reaction solution was reacted at 0 °C for 10 minutes, and then iodomethane (9 mg, 0.065 mmol) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, 20 mL of water was added to quench the liquid, followed by extraction with ethyl acetate (2 × 20 mL), washing with 20 mL of saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure. The residue was purified by reversed-phase chromatography (42% acetonitrile / water) to obtain (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)-3-methoxy-N-methylpropionamide 093 (4.78 mg, white solid), yield: 46%.

[1035] MS m / z(ESI): 473.2 [M+1] + .

[1036] 1H NMR (400MHz, CDCl3) δ7.48-7.43(m,2H),7.19-7.13(m,2H),6.41-6.03(m,1H),5.61-5.31(m,1H),5.10-5.03(m,1H),4.25 -4.18(m,1H),3.78-3.48(m,3H),3.29(d,J=10.4Hz,3H),3.20(s,2H),2.70(s,3H),2.53-2.33(m,2H),1.54-1.46(m,3H).

[1037] Example 91

[1038] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)benzamide (094)

[1039]

[1040] Compound (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 094a (20.00 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of benzoyl chloride (15.10 mg, 0.11 mmol) and N,N-diisopropylethylamine (34.70 mg, 0.27 mmol). The reaction mixture was purged with nitrogen and reacted at room temperature for 20 minutes. After the reaction was completed, the reaction mixture was concentrated to dryness, and the filter cake was purified by rapid column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the crude product, which was then purified by reversed-phase chromatography (65% acetonitrile / water) to give (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazol[1,5-a]pyrazin-1-yl)benzamide 094 (4.00 mg, white solid), yield: 16%.

[1041] MS m / z(ESI): 477.2 [M+1] + .

[1042] 1H NMR (400MHz, CDCl3) δ8.38 (s, 1H), 7.87 (s, 2H), 7.55-7.45 (m, 5H), 7.18 (t, J = 8.5Hz, 2H), 6. 11(s,1H),5.17-4.80(m,2H),4.24(t,J=11.2Hz,1H),3.49(s,1H),2.69(s,3H),1.39(s,3H).

[1043] Example 92

[1044] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-N-methylbenzamide (095)

[1045]

[1046] (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazole[1,5-a]pyrazin-1-yl)benzamide 094 (8.00 mg, 0.017 mmol) and sodium hydride (60%, 2.02 mg, 0.084 mmol) were dissolved in DMF (3 mL), and the reaction was carried out at 0 °C for 10 minutes; then iodomethane (4.77 mg, 0.034 mmol) was added, and the reaction was continued at room temperature for 15 minutes. After the reaction was completed, the mixture was quenched with water, extracted twice with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to dryness. Prep-HPLC was then used to prepare (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazole[1,5-a]pyrazin-1-yl)-N-methylbenzamide 095 (3.10 mg, white solid), yield: 36%.

[1047] MS m / z(ESI): 491.1 [M+1] + .

[1048] 1 H NMR (400MHz, CDCl3) δ7.64-7.31(m,3H),7.18-7.00(m,6H),4.90(s,2H),4.08(s,2H),3.41(s,3H),3.30(s,1H),2.69(s,3H),1.42(d,J=8.0,3H).

[1049] Example 93

[1050] Preparation of (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-1,5-dihydro-2H-pyrrolo-2-one (096)

[1051]

[1052] Step 1: Preparation of (S)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-5-oxopyrrolidine-3-methylsulfonate

[1053] Dissolve (S)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-4-hydroxypyrrolidone-2-one 104 (9 mg, 0.02 mmol) in dichloromethane (3 mL), then add triethylamine (10 mg, 0.10 mmol) and methanesulfonyl chloride (5 mg, 0.04 mmol) sequentially. The reaction solution is reacted at room temperature for 2 hours. After the reaction is completed, saturated sodium bicarbonate (15 mL) is added to quench the reaction, and the solution is extracted with dichloromethane (2 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give (S)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-5-oxopyrrolidine-3-methylsulfonate 096a (13 mg, yellow oil), yield: 96%.

[1054] MS m / z (ESI): 535.1 [M+1] + .

[1055] Step 2: Preparation of (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-1,5-dihydroH-2H-pyrrolo-2-one

[1056] (S)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-5-oxopyrrolidine-3-methylsulfonate 096a (11 mg, 0.02 mmol) and triethylamine (10 mg, 0.1 mmol) were dissolved in tetrahydrofuran (3 mL). The reaction mixture was heated to 60 °C and reacted for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride (30 mL), and extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated ammonium chloride (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography [42% acetonitrile / water (0.05% ammonium bicarbonate)] to give (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-1,5-dihydroH-2H-pyrrole-2-one 096 (5.67 mg, pale yellow solid), yield: 61%.

[1057] MS m / z(ESI): 439.1 [M+1] + .

[1058] HPLC: 98.05% (214nm), 96.63% (254nm).

[1059] 1 H NMR (400MHz, CD3OD) δ7.62-7.55(m,2H),7.55-7.45(m,1H),7.25(t,J=8.8Hz,2H),6.22(br,1H),5.16-5.04(m,1H),4.9 4-4.88(m,1H),4.85-4.78(m,1H),4.41-4.24(m,2H),4.15-3.85(m,1H),3.75-3.55(m,1H),2.66(s,3H),1.36(br,3H).

[1060] 19 F NMR (376MHz, CD3OD) δ -111.64.

[1061] Example 94

[1062] Preparation of (4-fluorophenyl)(8-methyl-3-(4-(trifluoromethyl)thiazo-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (097)

[1063]

[1064] Step 1: Preparation of ethyl 4-(trifluoromethyl)thiazole-2-carboxylate

[1065] Compound 097a (5.86 g, 44 mmol) was dissolved in ethanol (70 mL), and then 3-bromo-1,1,1-trifluoroacetone (7 g, 36.7 mmol) was added. The reaction mixture was reacted at 80 °C for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL), washed with water in saturated NaCl solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EtOAc = 10:1) to give ethyl 4-(trifluoromethyl)thiazolium-2-carboxylate 097b (5 g, colorless oily liquid), yield: 60%.

[1066] MS m / z(ESI): 226.1 [M+1] + .

[1067] Step 2: Preparation of 4-(trifluoromethyl)thiazole-2-carboxylic acid

[1068] Compound 097b (5 g, 22.2 mmol) was dissolved in ethanol (100 mL), and then an aqueous sodium hydroxide solution (60 mL, 1 M) was added. The reaction was carried out at 50 °C for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water. The pH was adjusted to 5 with dilute HCl (1 M). The reaction solution was concentrated under reduced pressure, and the resulting solid was dissolved in a mixed solution of DCM / MeOH = 10:1 (200 mL). The solution was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4-(trifluoromethyl)thiazol-2-carboxylic acid 097c (1.3 g, light brown solid), yield: 28%.

[1069] MS m / z(ESI): 198.1 [M+1] + .

[1070] Step 3: Preparation of N-((3-methylpyrazin-2-yl)methyl)-4-(trifluoromethyl)thiazole-2-carboxamide

[1071] Compound 097c (1 g, 5.1 mmol) was dissolved in dry DCM (30 mL), followed by the addition of oxalyl chloride (1.29 g, 10.2 mmol) and 5 drops of DMF. The reaction mixture was reacted at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (30 mL). Then, (3-methylpyrazin-2-yl)methylamine (560 mg, 4.547 mmol) and triethylamine (1.38 g, 13.7 mmol) were added, and the reaction mixture was reacted at room temperature for 2 h. The reaction mixture was poured into a saturated NaHCO3 solution, extracted with DCM, washed with saturated NaCl solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give N-((3-methylpyrazin-2-yl)methyl)-4-(trifluoromethyl)thiazol-2-carboxylic acid 097d (1 g, yellow solid), yield: 65.7%.

[1072] MS m / z(ESI): 303.1 [M+1] + .

[1073] Step 4: Preparation of 2-(8-methylimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole

[1074] Compound 097d (1 g, 3.3 mmol) was dissolved in acetonitrile (30 mL), and then P℃l3 (2.53 g, 16.5 mmol) was added. The reaction mixture was reacted at 90 °C for 36 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water in saturated NaHCO3 solution and NaCl solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:PE = 1:1) to give 2-(8-methylimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole 097e (0.51 g, yellow solid), yield: 54.4%.

[1075] MS m / z(ESI): 285.1 [M+1] + .

[1076] Step 5: Preparation of 7-(4-methoxybenzyl)-3-(4-(trifluoromethyl)thiazo-2-yl)imidazo[1,5-a]pyrazine-7-onium salt

[1077] Compound 097e (150 mg, 0.53 mmol) was dissolved in acetonitrile (10 mL), followed by the addition of KI (87 mg, 0.53 mmol) and PMBCl (165 mg, 1.05 mmol). The reaction was carried out at 90 °C for 6 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 7-(4-methoxybenzyl)-3-(4-(trifluoromethyl)thiazo-2-yl)imidazo[1,5-a]pyrazine-7-onium salt 097f (200 mg, reddish-brown oily liquid), yield: 65%.

[1078] MS m / z (ESI): 405.2 [M+1] + .

[1079] Step 6: Preparation of 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole

[1080] Compound 097f (200 mg, 0.49 mmol) was dissolved in ethanol (5 mL), and then sodium cyanoborohydride (93 mg, 1.48 mmol) and a catalytic amount of AcOH were added at 0 °C. The reaction mixture was reacted at 0 °C for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water in saturated NaHCO3 and NaCl solutions, and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:PE = 1:1) to give 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole 097 g (80 mg, yellow solid), yield: 36%.

[1081] MS m / z(ESI): 409.1 [M+1] + .

[1082] Step 7: Preparation of 2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole

[1083] Compound 0.97 g (330 mg, 0.81 mmol) was dissolved in TFA (10 mL) and reacted at 90 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (ACN:H2O (0.1% FA) = 10%) to give 2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole 0.97 h (100 mg, white solid), yield: 39%.

[1084] MS m / z(ESI): 289.2 [M+1] + .

[1085] Step 8: Preparation of (4-fluorophenyl)(8-methyl-3-(4-(trifluoromethyl)thiazo-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone

[1086] Compound 097h (100 mg, 0.35 mmol) was dissolved in DCM (10 mL), followed by the addition of TEA (105 mg, 1.04 mmol) and 4-fluorobenzoyl chloride (82 mg, 0.52 mmol). The reaction mixture was reacted at room temperature for 1 h. The reaction solution was poured into a saturated NaHCO3 solution, extracted with DCM, washed with saturated NaCl solution, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:PE = 60%) to (4-fluorophenyl)(8-methyl-3-(4-(trifluoromethyl)thiazo-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 097 (70 mg, white solid), yield: 44%.

[1087] MS m / z(ESI): 411.1 [M+1] + .

[1088] 1 H NMR(400MHz, CDCl3)δ7.72(s,1H),7.50-7.45(m,2H),7.19-7.14(m,2H),7.02(s,1H),5.83-5.65(m,1 H),5.06-5.02(m,1H),4.42-4.30(m,1H),4.28-4.18(m,1H),3.60-3.53(m,1H),1.61(d,J=6.8Hz,3H).

[1089] 19 F NMR(376MHz, CDCl3)δ-64.15(s,3H),-108.96(s,1H).

[1090] Example 95

[1091] Preparation of (4-fluorophenyl)(8-methyl-3-(4-methylthiazolyl-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (098)

[1092]

[1093] Step 1: Preparation of 4-methylthiazole-2-carbonyl chloride

[1094] 1.67 g (11.60 mmol) of 4-methylthiazol-2-carboxylic acid 098a was added to 10 mL of dichloromethane, followed by 4 mL of oxaloyl chloride and 0.3 mL of N,N-dimethylformamide. The reaction mixture was reacted at 25 °C for 2 hours. After the reaction was completed as monitored by LCMS, the solvent was evaporated to dryness to obtain the crude product 4-methylthiazol-2-carbonyl chloride 098b.

[1095] Step 2: Preparation of 4-methyl-N-((3-methylpyrazin-2-yl)methyl)thiazole-2-carboxamide

[1096] (3-methylpyrazin-2-yl)methylamine (1.30 g, 0.011 mmol) and triethylamine (3.20 g, 0.032 mmol) were added to dichloromethane (30 mL). Crude 4-methylthiazol-2-carbonyl chloride 098b dissolved in dichloromethane (10 mL) was slowly added dropwise. The reaction mixture was reacted at 25 °C for 1 hour. After the reaction was completed, water (30 mL) was added, followed by extraction with dichloromethane (3 × 20 mL). The extract was then washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title product 4-methyl-N-((3-methylpyrazin-2-yl)methyl)thiazol-2-carboxamide 098c (1.76 g, yellow solid), yield: 67%.

[1097] MS m / z(ESI): 249.1 [M+1] + .

[1098] Step 3: Preparation of 4-methyl-2-(8-methylimidazo[1,5-a]pyrazin-3-yl)thiazole

[1099] 4-Methyl-N-((3-methylpyrazin-2-yl)methyl)thiazol-2-carboxamide 098c (1.76 mg, 7.1 mmol) was added to acetonitrile (20 mL), followed by phosphorus oxychloride (1.68 mg, 21.3 mmol) and N,N-dimethylformamide (0.2 mL). The reaction mixture was reacted at 85 °C for 48 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the solvent was evaporated to dryness. Saturated sodium bicarbonate solution (50 mL) was added, followed by extraction with ethyl acetate (3 × 80 mL). The extract was then washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title product 4-methyl-2-(8-methylimidazo[1,5-a]pyrazin-3-yl)thiazolamide 098d (1.23 g, yellow solid), yield: 69%.

[1100] MS m / z(ESI): 231.1 [M+1] + .

[1101] Step 4: Preparation of 7-(4-methoxybenzyl)-8-methyl-3-(4-methylthiazolyl-2-yl)imidazo[1,5-a]pyrazine-7-onium

[1102] 3-Methyl-5-(8-methylimidazo[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole 098d (1.23 g, 5.30 mmol) was added to acetonitrile (10 mL), followed by potassium iodide (422 mg, 2.6 mmol) and 1-(chloromethyl)-4-methoxybenzyl (1.62 g, 10.60 mmol). The reaction mixture was reacted at 85 °C for 16 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the solvent was evaporated to dryness to give the crude product 7-(4-methoxybenzyl)-8-methyl-3-(4-methylthiazo-2-yl)imidazo[1,5-a]pyrazin-7-onium 098e (1 g, yellow solid), yield: 49%.

[1103] MS m / z(ESI): 351.1 (M).

[1104] Step 5: Preparation of 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-methylthiazole

[1105] 7-(4-methoxybenzyl)-8-methyl-3-(4-methylthiazo-2-yl)imidazo[1,5-a]pyrazine-7-onium 098e (1.00 g, 2.80 mmol) was added to ethanol (20 mL), followed by acetic acid (0.5 mL) and sodium cyanoborohydride (530 mg, 8.40 mmol). The reaction mixture was reacted at 0 °C for 0.5 h under nitrogen protection. After the reaction was completed, the solvent was evaporated to dryness by LCMS. Add water (50 mL), extract and separate the contents with dichloromethane (3 × 20 mL), wash with saturated sodium chloride solution (50 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title product 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-methylthiazole 098f (800 mg, yellow solid), yield: 73%.

[1106] MS m / z (ESI): 355.2 [M+1] + .

[1107] Step 6: Preparation of methyl-2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole

[1108] 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-methylthiazole 098f (200 mg, 0.44 mmol) was added to trifluoroacetic acid (3 mL). The reaction mixture was reacted at 100 °C for 16 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the reaction mixture was cooled to room temperature. The solvent was evaporated to dryness to obtain the crude product, which was purified by reverse column chromatography (acetonitrile / water = 1:10) and lyophilized to give the title product 4-methyl-2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole 098g (800 mg, white solid), yield: 70%.

[1109] MS m / z(ESI): 235.1 [M+1] + .

[1110] Step 7: Preparation of (4-fluorophenyl)(8-methyl-3-(4-methylthiazolyl-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone

[1111] 0.98 g (30 mg, 0.128 mmol) of 4-methyl-2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole was dissolved in 5 mL of dichloromethane, and triethylamine (25 mg, 0.25 mmol) and 4-fluorobenzoyl chloride (30 mg, 0.192 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was completed as monitored by LCMS, the solvent was evaporated to dryness to obtain the crude product, which was purified by reverse column chromatography (acetonitrile / water = 1:10) and lyophilized to obtain the title product (4-fluorophenyl)(8-methyl-3-(4-methylthiazo-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 0.98 (18 mg, white solid), yield: 38%.

[1112] MS m / z(ESI): 357.1 [M+1] + .

[1113] 1H NMR (400MHz, CDCl3) δ7.47 (dd, J=8.4, 5.4Hz, 2H), 7.16 (t, J=8.5Hz, 2H), 6.98 (s, 1H), 6.89 (s, 1H), 6.06-5.38 (m, 1H) ,5.08(d,J=13.4Hz,1H),4.50-4.26(m,1H),4.22-4.18(m,1H),3.75-3.31(m,1H),2.46(s,3H),1.60(d,J=6.7Hz,3H).

[1114] Example 96

[1115] Preparation of ((4-fluorophenyl)(8-methyl-3-(5-methylthiazolyl-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone (099)

[1116]

[1117] Step 1: Preparation of 2-(chloromethyl)-3-methylpyrazine

[1118] 2,3-Dimethylpyrazine 099a (10 g, 92.47 mmol) was added to carbon tetrachloride (250 mL), followed by N-chlorosuccinimide (14.83 g, 110.96 mmol) and benzoyl peroxide (224 mg, 9.25 mmol). The reaction mixture was reacted at 80 °C for 16 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the solvent was evaporated to dryness and water (150 mL) and dichloromethane (3 × 100 mL) were added. The mixture was extracted and separated, then washed successively with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the title product 2-(chloromethyl)-3-methylpyrazine 099b (3.20 g, colorless oil), yield: 22%.

[1119] MS m / z(ESI): 143.2 [M+1] + .

[1120] 1 H NMR (400MHz, CDCl3) δ8.45(d,J=2.0Hz,1H),8.38(d,J=2.0Hz,1H),4.71(s,2H),2.69(s,3H).

[1121] Step 2: Preparation of 2-((3-methylpyrazin-2-yl)methyl)isoindololin-1,3-dione

[1122] 2-(chloromethyl)-3-methylpyrazine 099b (3.20 g, 22.44 mmol) was added to N,N-dimethylformamide (40 mL), followed by potassium phthalimide (6.23 g, 33.66 mmol). The reaction mixture was reacted at 110 °C for 8 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the solvent was evaporated to dryness and water (150 mL) and ethyl acetate (3 × 100 mL) were added. The mixture was extracted and separated, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title product 2-((3-methylpyrazine-2-yl)methyl)isoindoline-1,3-dione 099c (3.10 g, pale yellow solid), yield: 95%.

[1123] MS m / z(ESI): 254.2 [M+1] + .

[1124] 1 H NMR (400MHz, CDCl3) δ8.33(d,J=2.4Hz,1H),8.24(d,J=2.4Hz,1H),7.90(dd,J=5.6,3.2Hz,2H),7.75(dd,J=5.6,3.2Hz,2H),5.02(s,2H),2.70(s,3H).

[1125] Step 3: Preparation of (3-methylpyrazin-2-yl)methylamine

[1126] 2-((3-methylpyrazin-2-yl)methyl)isoindoline-1,3-dione 099c (2.00 g, 7.90 mmol) was added to ethanol (50 mL), followed by hydrazine hydrate (3.95 g, 79 mmol). The reaction mixture was reacted at 80 °C for 6 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the solvent was evaporated to dryness and water (150 mL) was added. The mixture was then extracted with dichloromethane / methanol (1 / 1, V / V, 50 mL), and the organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product (3-methylpyrazin-2-yl)methylamine 099d (300 mg, yellow oil), yield: 28%.

[1127] MS m / z (ESI): 124.3 [M+1] + .

[1128] 1 H NMR (400MHz, CDCl3) δ8.36 (s, 1H), 8.33 (d, J = 2.4Hz, 1H), 4.02 (s, 2H), 2.54 (s, 3H).

[1129] Step 4: Preparation of 5-methyl-N-((3-methylpyrazin-2-yl)methyl)thiazole-2-carboxamide

[1130] 280 mg (1.94 mmol) of 5-methylthiazol-2-carboxylic acid was added to 10 mL of dichloromethane, followed by 0.5 mL of oxaloyl chloride and 0.1 mL of N,N-dimethylformamide. The reaction mixture was allowed to react at room temperature for 0.5 hours. After the reaction was completed as monitored by LCMS, the solvent was evaporated to dryness to obtain the crude product 5-methylthiazol-2-carbonyl chloride.

[1131] (3-methylpyrazin-2-yl)methylamine 099d (200 mg, 1.62 mmol) and triethylamine (246 mg, 2.43 mmol) were added to dichloromethane (10 mL), and crude 5-methylthiazolium-2-carbonyl chloride dissolved in dichloromethane (5 mL) was slowly added dropwise. The reaction mixture was allowed to react at room temperature for 0.5 hours. After the reaction was completed by LCMS monitoring, water (30 mL) and dichloromethane (3 × 20 mL) were added, the mixture was extracted and separated, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title product 5-methyl-N-((3-methylpyrazin-2-yl)methyl)thiazolium-2-carboxamide 099e (170 mg, yellow solid), yield: 40%.

[1132] MS m / z(ESI): 249.1 [M+1] + .

[1133] Step 5: Preparation of 5-methyl-2-(8-methylimidazo[1,5-a]pyrazin-3-yl)thiazole

[1134] 5-Methyl-N-(((3-methylpyrazin-2-yl)methyl)thiazol-2-carboxamide 099e (2.30 g, 9.26 mmol) was added to acetonitrile (30 mL), followed by phosphorus oxychloride (4.86 mL, 46.31 mmol) and N,N-dimethylformamide (1.00 mL). The reaction mixture was reacted at 85 °C for 48 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the solvent was evaporated to dryness. Saturated sodium bicarbonate solution (30 mL) and ethyl acetate (3 × 30 mL) were added, and the mixture was extracted and separated. The extract was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title product 5-methyl-2-(8-methylimidazo[1,5-a]pyrazin-3-yl)thiazolamide 099f (1.57 g, yellow solid), yield: 53%.

[1135] MS m / z(ESI): 231.0 [M+1] + .

[1136] Step 6: Preparation of 7-(4-methoxybenzyl)-8-methyl-3-(5-methylthiazolyl-2-yl)imidazo[1,5-a]pyrazine-7-onium

[1137] 5-Methyl-2-(8-methylimidazo[1,5-a]pyrazin-3-yl)thiazole 099f (1.3 g, 5.6 mmol) was added to acetonitrile (20 mL), followed by potassium iodide (0.93 g, 5.6 mmol) and 1-(chloromethyl)-4-methoxybenzyl (1.75 g, 11.2 mmol). The reaction mixture was reacted at 85 °C for 6 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the solvent was evaporated to dryness to give the crude product 7-(4-methoxybenzyl)-8-methyl-3-(5-methylthiazo-2-yl)imidazo[1,5-a]pyrazin-7-onthium 099g (3.88 g, yellow oil), yield: 98%.

[1138] MS m / z(ESI): 352.1 [M+1] + .

[1139] Step 7: Preparation of 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-5-methylthiazole

[1140] 0.99 g (3.88 g, 0.011 mol) of 7-(4-methoxybenzyl)-8-methyl-3-(5-methylthiazo-2-yl)imidazo[1,5-a]pyrazine-7-onium was added to 10 mL of ethanol, followed by 0.1 mL of acetic acid and 2.07 g (0.033 mmol) of sodium cyanoborohydride. The reaction mixture was reacted at 0 °C for 0.5 h under nitrogen protection. After the reaction was completed, the solvent was evaporated to dryness by LCMS. Add water (50 mL) and dichloromethane (3 × 20 mL), extract and separate the contents, wash with saturated sodium chloride solution (50 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title product 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-5-methylthiazole 099h (800 mg, yellow solid), yield: 13%.

[1141] MS m / z (ESI): 355.2 [M+1] + .

[1142] Step 8: Preparation of 5-methyl-2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole

[1143] 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-5-methylthiazole 099h (235 mg, 0.66 mmol) was added to trifluoroacetic acid (2 mL). The reaction mixture was reacted at 90 °C for 1 hour under nitrogen protection. After the reaction was completed as monitored by LCMS, the reaction mixture was cooled to room temperature. The solvent was evaporated to dryness to obtain a filter cake, which was quenched with water (5 mL). The filter cake was extracted with dichloromethane (2 × 5 mL), and the organic phase was collected and evaporated to dryness to obtain the crude product 5-methyl-2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole 099i, which was directly used in the next step.

[1144] MS m / z(ESI): 235.1 [M+1] + .

[1145] Step 9: Preparation of (4-fluorophenyl)(8-methyl-3-(5-methylthiazolyl-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone

[1146] 5-Methyl-2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole 099i (235.00 mg, 1.00 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (151.79 mg, 1.50 mmol) and p-fluorobenzoyl chloride (238.52 mg, 1.50 mmol). The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, water (20 mL) and dichloromethane (2 × 20 mL) were added, followed by extraction and separation. The mixture was then washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reversed-phase chromatography (acetonitrile / water = 1:1) and further purified by Prep-HPLC to obtain (4-fluorophenyl)(8-methyl-3-(5-methylthiazolyl-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) methyl ketone 099 (5.33 mg, white solid), yield: 1.44%.

[1147] MS m / z(ESI): 357.1 [M+1] + .

[1148] HNMR: 1H NMR (400MHz, CDCl3) δ7.49-7.44(m,3H),7.18-7.12(m,2H),6.95(s,1H),5.71(s,1H),4.99(dd,J=12. 8, 2.4Hz, 1H), 4.49-4.06 (m, 2H), 3.52 (t, J = 12.0Hz, 1H), 2.51 (d, J = 0.8Hz, 3H), 1.59 (d, J = 6.8Hz, 3H).

[1149] 19 F NMR (376MHz, CDCl3) δ-109.14.

[1150] Example 97

[1151] Preparation of (R)-2-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-1,4-dihydroisoquinoline-3(2H)-one (100)

[1152]

[1153] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 100a (50 mg, 0.114 mmol) was dissolved in dioxane (2.5 mL), followed by the addition of 3,4,4a,8a-tetrahydro-2H-isoquinoline-1-one (34 mg, 0.006 mmol), cesium carbonate (47 mg, 0.021 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.018 mmol), and cuprous iodide (2 mg, 0.009 mmol). The reaction mixture was heated to 120 °C and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether) and then purified by reversed-phase column chromatography (44% acetonitrile / water) to give (R)-2-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-1,4-dihydroisoquinoline-3(2H)-one 100 (4.5 mg, pale yellow solid), yield: 7.4%.

[1154] MS m / z(ESI): 503.1 [M+1] + .

[1155] 1H NMR (400MHz, CDCl3) δ7.51-7.43(m,2H),7.30-7.25(m,2H),7.23-7.20(m,2H),7.15(t,J=8.6Hz,2H),5.95-5.55(m,1H),5.26(d,J=15.7Hz,1H ),5.12(d,J=14.7Hz,1H),4.73(d,J=15.0Hz,2H),4.27(t,J=15.1Hz,1H),3.76(s,2H),3.50-3.40(m,1H),2.71(s,3H),1.27(d,J=11.6Hz,3H).

[1156] Example 98

[1157] Preparation of (R)-3-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)oxazolidin-2-one (101)

[1158]

[1159] (1-Bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 101a (20 mg, 0.04 mmol) was dissolved in dioxane (2.5 mL), followed by the addition of 1,3-oxazolidinyl-2-one (20 mg, 0.04 mmol), cesium carbonate (19 mg, 0.13 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.018 mmol), and cuprous iodide (2 mg, 0.009 mmol). The reaction mixture was heated to 120 °C and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether), and then purified by reversed-phase column chromatography (44% acetonitrile / water) to give (R)-3-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)oxazolidin-2-one 101 (4.5 mg, white solid), yield: 21%.

[1160] MS m / z(ESI): 443.1 [M+1] + .

[1161] 1H NMR (400MHz, CDCl3) δ7.57-7.44(m,2H),7.22-7.10(m,2H),6.31-5.75(m,1H),5.23-5.05(m,1H),4.84-4.82(m,1H),4.62-4 .45(m,2H),4.43-4.32(m,1H),4.28-4.14(m,1H),3.98-3.74(m,1H),3.61-3.23(m,1H),2.69(d,J=3.5Hz,3H),1.44(s,3H).

[1162] Example 99

[1163] Preparation of (R)-3-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)imidazolin-2-one (102)

[1164]

[1165] Dissolve (1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 102a (20 mg, 0.046 mmol) in dioxane (2.5 mL), then add imidazolin-2-one (20 mg, 0.23 mmol), cesium carbonate (19 mg, 0.14 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.092 mmol), and cuprous iodide (2 mg, 0.009 mmol) in sequence. The reaction solution was heated to 120°C and reacted for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated. The residue obtained was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether), and then purified by reversed-phase column chromatography (44% acetonitrile / water) to obtain (R)-3-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)imidazolin-2-one 102 (4.2 mg, white solid), yield: 20%.

[1166] MS m / z(ESI): 442.1 [M+1] + .

[1167] 1H NMR (400MHz, CDCl3) δ7.65-7.36(m,2H),7.14(d,J=14.2Hz,2H),6.24-5.77(m,1H),5.24-5.20(m,1H),5.13-4.86(m,1H), 4.49-4.10(m,2H),3.92-3.70(m,1H),3.61-3.58(m,2H),3.52-3.34(m,1H),3.28-3.05(m,1H),2.68(s,3H),1.43(s,3H).

[1168] Example 100

[1169] Preparation of (R)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-4-hydroxypyrrolidone-2-one (103)

[1170]

[1171] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 103a (20 mg, 0.05 mmol) was dissolved in dioxane (3 mL), followed by the addition of (4R)-4-hydroxypyrrolidone-2-one (7 mg, 0.07 mmol), cesium carbonate (37 mg, 0.115 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (1.5 mg, 0.0092 mmol), and cuprous iodide (1 mg, 0.005 mmol). The reaction mixture was heated to 80 °C and reacted for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether) and then further purified by reversed-phase column chromatography (34% acetonitrile / water) to give (R)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-4-hydroxypyrrolidone-2-one 103 (2.1 mg, white solid), yield: 9.6%.

[1172] MS m / z(ESI): 457.1 [M+1] + .

[1173] HPLC: 98.01% (214nm), 93.64% (254nm).

[1174] 1 H NMR (400MHz, MeOD) δ7.57 (dd, J=8.6, 5.3Hz, 2H), 7.24 (t, J=8.7Hz, 2H), 6.14-6.02 (m, 1H), 5.12-5.04 (m, 1H), 4.68-4. 46(m,2H),4.35-4.27(m,1H),4.01-3.71(m,4H),2.95-2.85(m,1H),2.66(s,3H),2.45-2.36(m,1H),1.39-1.36(m,3H).

[1175] 19F NMR(376MHz,MeOD)δ-111.71.

[1176] Example 102

[1177] Preparation of (S)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-4-hydroxypyrrolidone-2-one (104)

[1178]

[1179] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 104a (35 mg, 0.08 mmol) was dissolved in dioxane (3 mL), followed by the addition of (4S)-4-hydroxypyrrolidone-2-one (12 mg, 0.12 mmol), cesium carbonate (78 mg, 0.24 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (2 mg, 0.02 mmol), and cuprous iodide (8 mg, 0.04 mmol). The reaction mixture was heated to 80 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether) and then further purified by reversed-phase column chromatography (34% ACN / H2O) to give (S)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-4-hydroxypyrrolidone-2-one 104 (21 mg, white solid), yield: 55%.

[1180] MS m / z(ESI): 457.1 [M+1] + .

[1181] HPLC: 98.94% (214nm), 96.67% (254nm).

[1182] 1 H NMR(400MHz, CDCl3)δ7.51(br,2H),7.16(t,J=7.6Hz,2H),6.29-5.71(m,2H),5.19-5.05(m,1H),4.67(br,1H),4.45-4.33 (m,1H),4.28-4.14(m,1H),3.61-3.50(m,1H),3.42(br,1H),2.88-2.75(m,1H),2.68(s,3H),2.48(br,1H),1.38(br,3H).

[1183] 19 F NMR (376MHz, CDCl3) δ -108.87.

[1184] Example 102

[1185] Preparation of (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)pyrrolidine-2,4-dione (105)

[1186]

[1187] (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-4-methoxy-1,5-dihydro-2H-pyrrole-2-one 049 (4.20 mg, 0.009 mmol) was dissolved in acetonitrile (0.5 mL), and then hydrogen chloride solution (1 mL, 1 M) was added. The mixture was heated to 65 °C for 6 hours under nitrogen protection. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated to dryness, and the residue was purified by Prep-HPLC to give (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)pyrrolidine-2,4-dione 105 (1.32 mg, white solid), yield: 31.1%. MS m / z (ESI): 454.5 [M+1] + .

[1188] 1H NMR(400MHz, CDCl3)δ7.53-7.50m,2H),7.19-7.15(m,2H),6.03(s,1H),5.14(d,J=13.4Hz,1H),4.78( d,J=18.2Hz,1H),4.29-4.12(m,2H),3.46(s,1H),3.22(s,2H),2.70(s,3H),1.39(s,3H),1.32(s,1H).

[1189] 19 F NMR (376MHz, CDCl3) δ -108.66.

[1190] Example 103

[1191] Preparation of (S)-4-fluoro-1-[(R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]pyrrolidine-2-one (106)

[1192]

[1193] (R)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-4-hydroxypyrrolidine-2-one 103 (10 mg, 0.022 mmol) was dissolved in dichloromethane (3 mL), cooled to -78 °C in a dry ice / ethanol bath, and diethylaminotrifluoride (7 mg, 0.04 mmol) was added. The reaction mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, saturated sodium bicarbonate (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 × 20 mL). The combined organic phases were washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Prep-HPLC to give (S)-4-fluoro-1-[(R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]pyrrolidone-2-one 106 (2.24 mg, white solid), yield: 21%.

[1194] MS m / z(ESI): 459.1 [M+1] + .

[1195] HPLC: 96.57% (214nm), 95.23% (254nm).

[1196] 1H NMR (400MHz, CD3OD) δ7.61-7.53(m,2H),7.27-7.21(m,2H),6.30-6.08(m,1H),5.50-5.35(m,1H),5.13-5.06(m,1H),4.63 -4.36(m,2H),4.34-4.25(m,1H),3.90-3.64(m,2H),2.80-2.68(m,1H),2.66(s,3H),2.52-2.47(m,1H),1.50-1.35(m,3H).

[1197] 19F NMR (376MHz, CD3OD) δ-111.72,-176.01.

[1198] Example 104

[1199] Preparation of (R)-4-fluoro-1-[(R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]pyrrolidine-2-one (107)

[1200]

[1201] (S)-1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-4-hydroxypyrrolidine-2-one 104 (9 mg, 0.02 mmol) was dissolved in dichloromethane (3 mL), cooled to -78 °C in a dry ice / ethanol bath, and diethylaminotrifluoride (7 mg, 0.04 mmol) was added. The reaction mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, saturated sodium bicarbonate (15 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 × 20 mL). The combined organic phases were washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Prep-HPLC to give (R)-4-fluoro-1-[(R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazole-5-]

[1202] 107 (2.82 mg, white solid) of pyrazin-1-yl[1,5-a]pyrrolidine-2-one (30%), yield: 30%.

[1203] MS m / z(ESI): 459.1 [M+1] + .

[1204] HPLC: 97.24% (214nm), 97.61% (254nm).

[1205] 1 H NMR (400MHz, CD3OD) δ7.57 (dd, J=8.8, 5.2Hz, 2H), 7.24 (t, J=8.8Hz, 2H), 6.07 (br, 1H),

[1206] 5.53-5.30(m,1H),5.17-5.00(m,1H),4.40-4.24(m,2H),4.16-3.93(m, 2H),3.65(br,1H),3.10-2.91(m,1H),2.79-5.54(m,4H),1.39(br,3H).

[1207] 19 F NMR(376MHz,CD3OD)δ-111.65,-175.01.

[1208] Example 105

[1209] Preparation of (R)-2-(dimethylamino)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide (108)

[1210]

[1211] (R)-2-chloro-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 108a (45 mg, 0.10 mmol) was dissolved in methanol (0.5 mL), and then dimethylaminetetrahydrofuran solution (2 M, 2 mL) was added. The reaction solution was heated to 60 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated. The residue was purified by reverse-phase column chromatography [23% acetonitrile / water (0.05% formic acid)] to obtain (R)-2-(dimethylamino)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 108 (16 mg, pale yellow solid), yield: 35%.

[1212] MS obsd.(ESI+):[(M+H) + 458.1.

[1213] HPLC: 98.52% (214nm), 99.15% (254nm).

[1214] 1 H NMR (400MHz, CD3OD) δ7.62-7.52(m,2H),7.25(t,J=8.8Hz,2H),6.08(br,1H),5.13-5.00(m, 1H),4.36-4.23(m,1H),4.01(br,1H),3.69(br,1H),3.59-3.37(m,2H),2.65(s,3H),2.56(br s,6H),1.44(br,3H).

[1215] 19 F NMR (376MHz, CD3OD) δ -111.63.

[1216] Example 106

[1217] Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-2-(methylamino)acetamide (109)

[1218]

[1219] Step 1: Preparation of (R)-2-chloro-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide

[1220] (R)-(1-amino-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 109a (112 mg, 0.30 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (76 mg, 0.75 mmol) and 2-chloroacetyl chloride (51 mg, 0.45 mmol). The reaction mixture was incubated at 25 °C for 20 min. After the reaction was complete, saturated ammonium chloride (35 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (2 × 40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (70% ethyl acetate / petroleum ether) to give (R)-2-chloro-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 109b (94 mg, yellow oil), yield: 66%.

[1221] MS m / z(ESI): 449.1 [M+1] + .

[1222] Step 2: Preparation of (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-2-(dimethylamino)acetamide

[1223] (R)-2-chloro-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 109b (45 mg, 0.10 mmol) was dissolved in methanol (0.5 mL), and methylamine ethanol solution (33%, 1.5 mL) was added. The reaction solution was heated to 60 °C and reacted for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated. The residue was purified by reverse-phase column chromatography [23% acetonitrile / water (0.05% formic acid)] to obtain (R)-N-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 109b.

[1224] 2-(methylamino)acetamide 109 (23.4 mg, pale yellow solid), yield: 52%.

[1225] MS m / z(ESI): 444.1 [M+1] + .

[1226] HPLC: 99.55% (214nm), 98.98% (254nm).

[1227] 1 H NMR(400MHz,CD3OD)δ8.52(s,1H),7.63-7.52(m,2H),7.25(t,J=8.8Hz,2H),6.09(br,1H),5.12- 5.01(m,1H),4.35-4.24(m,1H),4.20-3.92(m,1H),3.91-.354(m,3H),2.65(s,6H),1.45(br,3H).

[1228] 19 F NMR (376MHz, CD3OD) δ-111.61.

[1229] Example 107

[1230] Preparation of 1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-3-methylpyrrolidone-2-one (110)

[1231]

[1232] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 110a (20 mg, 0.046 mmol) was dissolved in 1,4-dioxane (1 mL), and 3-methylpyrrolidone-2-one (9 mg, 0.092 mmol), (1R,2R)-N,N'-dimethyl1,2-cyclohexanediamine (7 mg, 0.046 mmol), cuprous iodide (9 mg, 0.046 mmol), cesium fluoride (7 mg, 0.046 mmol), and cesium carbonate (45 mg, 0.14 mmol) were added sequentially. After the addition of the feed was complete, the reaction solution was reacted at 120°C for 16 hours under nitrogen protection. The reaction solution was filtered and the filtrate was concentrated. The residue obtained was purified by reverse-phase column chromatography (55% acetonitrile / water) to give 1-((R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-3-methylpyrrolidone-2-one (110) (6.23 mg, white solid), yield: 30%.

[1233] MS m / z(ESI): 455.1 [M+1] + .

[1234] 1H NMR (400MHz, CDCl3) δ7.52-7.50(m,2H),7.16(t,J=8.6Hz,2H),5.11-5.08(m,1H),4.24-4.18(m,1H),4.10-4 .04(m,1H),3.59-3.55(m,1H),3.50-3.38(m,1H),2.68(s,3H),2.45-2.34(m,1H),1.91-1.74(m,1H),1.57(br s,4H),1.34-1.25(m,5H).

[1235] HPLC: 99.61% (214nm), 99.28% (254nm).

[1236] 19 F NMR (376MHz, CDCl3) δ-109.28.

[1237] Example 108

[1238] Preparation of (R)-1-[7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]-3,3-dimethylpyrrolidone-2-one (111)

[1239]

[1240] (R)-(1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl) methyl ketone 111a (30 mg, 0.07 mmol) was dissolved in dioxane (3 mL), followed by the addition of 3,3-dimethylpyrrolidone-2-one (16 mg, 0.14 mmol), cesium carbonate (67 mg, 0.21 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (2 mg, 0.014 mmol), and cuprous iodide (1 mg, 0.007 mmol). The reaction mixture was heated to 80 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column chromatography (70% ethyl acetate / petroleum ether) and then further purified by reversed-phase column chromatography (45% ACN / H2O) to give (R)-1-(7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-]-3,3-dimethylpyrrolidone-2-one 111 (2.2 mg, white solid), yield: 6.5%.

[1241] MS m / z(ESI): 469.3 [M+1] + .

[1242] HPLC: 100% (214nm), 98.8% (254nm).

[1243] 1H NMR (400MHz, CDCl3) δ7.63-7.51(m,2H),7.25-7.20(m,2H),6.21-6.03(m,1H),5.07(d,J=14.5Hz,1H),4.35-4.27( m,1H),4.04-4.00(m,2H),3.62-3.60(m,2H),2.66(s,3H),2...

Claims

1. A compound as shown in formula (V) or a pharmaceutically acceptable salt thereof, in, M is either N or CH; R5 is selected from alkyl groups or halogen-substituted alkyl groups; R1 is selected from heterocyclic groups; the heterocyclic group is optionally a 4-10 member monocyclic heterocyclic group containing 1-5 N, O, or S; the heterocyclic group is optionally surrounded by one or more R1 groups. a Replaced; R a They may be the same or different, and are independently selected from D, oxo, thio, F, Cl, Br, I, -OH, -CN, alkyl, alkoxy, haloalkyl, -NH-CO-alkyl, -CO-alkyl, -O-CO-alkyl, -NH2, alkylamino, dialkylamino; Ar is a phenyl group; the phenyl group may optionally be substituted with 1 to 5 of the following substituents: F, Cl, Br, I, alkyl, alkoxy, haloalkyl; The term "alkoxy" refers to "alkyloxy". The "alkyl" group defined above is C 1-3 alkyl.

2. The compound of formula (V) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is a heterocyclic group selected from: morpholino, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, piperazine, dihydropyrrole, pyrrolidinyl, 2H-pyranyl, N-heterocyclic butyl, N-heterocyclic heptyl, N-heterocyclic octyl, imidazolinyl, indololinyl, isoindololinyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, oxazolidinyl, oxazinyl, nitroheptyl, nitroheptyl, thiazinyl, thiazolinyl, isothiazolidinyl, nitrohexyl, nitroheptyl, nitroheptyl, thiazolinyl, thiazolinyl, nitrohexyl, nitroheptyl, optionally substituted by 1-5 of the following substituents: D, oxo, thio, F, Cl, Br, I, -OH, -CN, alkyl, alkoxy, haloalkyl, -NH-CO-alkyl, -CO-alkyl, -O-CO-alkyl, -NH2, alkylamino, dialkylamino.

3. The compound of formula (V) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (V) is a compound of formula (VA) or formula (VB): Ar, R1, R5 and M are as defined in claim 1.

4. The compound of formula (V) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein, Compound (V) is the same as compound (VI): Alternatively, it can be a compound of the following formula (VI-A) or formula (VI-B): in, R1, R5, and M are as described in claim 1.

5. The following compounds or their pharmaceutically acceptable salts:

6. The following compounds or their pharmaceutically acceptable salts, 7. A compound selected from the following compounds:

8. A compound selected from the following compounds:

9. A pharmaceutical composition comprising one, two or more of the compounds of any one of claims 1-6 or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipient.

10. Use of one, two or more of the compounds of any one of claims 1-6 or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for the prevention and / or treatment of diseases mediated by NK-3 receptors.

11. Use of one, two or more of the compounds of any one of claims 1-6 or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical composition of claim 9 in the preparation of a medicament for the prevention and / or treatment of psychosis, benign prostatic hyperplasia, or Hair-AN syndrome.

12. The use according to claim 11, wherein the HAIR-AN syndrome is selected from hyperandrogenemia, insulin resistance, and acanthosis nigricans.

13. The use according to claim 10, wherein the disease is selected from: depression, anxiety disorder, schizophrenia, psychotic disorders, bipolar disorder, cognitive impairment, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, seizures, obesity, inflammatory diseases, vomiting, preeclampsia, airway-related diseases, reproductive disorders, contraceptive and sex hormone-dependent diseases, gynecological diseases, and menopausal syndrome-related diseases.

14. The use according to claim 13, wherein the sex hormone-dependent disease is selected from: benign prostatic hyperplasia (BPH), metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male pattern baldness, endometriosis, puberty abnormalities, uterine fibroids, uterine fibroids, hormone-dependent cancers, hyperandrogenemia, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysmenorrhea (PMDD), ovarian theca cell hyperplasia, other manifestations of high intraovarian androgen concentrations, androgen-producing tumors, menorrhagia, and adenomyosis; The airway-related diseases are selected from: chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction, and cough; The menopausal syndrome described includes hot flashes, sweating, palpitations, dizziness, and obesity.

15. The use according to claim 14, wherein the ovarian theca cell hyperplasia is HAIR-AN with luteinized theca cell hyperplasia in the ovarian stroma; Other manifestations of high intraovarian androgen concentrations include: follicular arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, and infertility. The androgen-producing tumors are selected from: masculinizing ovarian tumors or adrenal tumors.

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