Imidazole-containing fused ring derivatives, their preparation method and pharmaceutical applications

Abstract

The present invention relates to a compound of formula (I), its stereoisomer, tautomer, isotopic label, nitrogen oxide, solvate, polycrystalline form, pharma- ceutically acceptable salt or prodrug, and its preparation method and pharmaceutical composition. The compound is an NK-3 receptor antagonist used to prevent and / or treat 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, and menopausal syndrome-related disease. [Formula 1] JPEG2024514007000296.jpg32169

Description

Detailed Description of the Invention

[0001] The present invention claims priority from Chinese Patent Application No. 202110432744.0, entitled "Imidazole-containing fused ring system derivatives, their preparation methods and pharmaceutical applications," filed with the State Intellectual Property Office of the People's Republic of China on April 21, 2021, which is incorporated herein by reference in its entirety.

[0002] [Technical field] The present invention relates to the field of drug synthesis, and specifically to imidazole-containing fused ring system derivatives represented by general formula (I), their preparation methods and pharmaceutical compositions containing said derivatives, their use as therapeutic agents, and their use as selective NK-3 receptor (NK-3R) antagonists for the treatment and / or prevention of a wide range of CNS and peripheral diseases.

[0003] [Background technology] Tachykinin receptors are targets for a family of structurally related peptides, collectively termed "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 various biological activities. Currently, three tachykinin receptors are known: neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3) receptors. Tachykinin receptors belong to the rhodopsin-like seven-transmembrane G protein-coupled receptor family. SP has the highest affinity and is thought 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, NK-2, and NK-3 receptors have been identified in different species. NK-1 and NK-2 receptors are expressed in a variety of peripheral tissues, and NK-1 receptors are also expressed in the CNS, whereas NK-3 receptors are primarily expressed in the CNS.

[0004] Neurokinin receptors mediate a variety of biological effects stimulated by tachykinins, including transmission of excitatory neuronal signals (e.g., pain) in the CNS and periphery, modulation of smooth muscle contractile activity, modulation of immune and inflammatory responses, induction of a blood pressure lowering effect by dilation of the peripheral vascular system, and stimulation of endocrine and exocrine secretions.

[0005] The NK-3 receptor is encoded by the TACR3 gene and is involved in the regulation of the hypothalamus-pituitary-gonadal axis. TACR3 gene knockout or mutant mice are characterized by abnormal reproductive organ development, reduced levels of sex hormones, and severely reduced fertility. TACR3 gene mutations cause abnormal release of gonadotropins in patients, leading to sexual infantility and infertility, and a significant proportion of familial hypogonadism is caused by TACR3 gene mutations.

[0006] Kisspeptin / neurokinin B / dynorphin (KNDy) neurons are involved in the gonadotropin-releasing hormone (GnRH) signaling pathway, promoting estrogen production via the GnRH neuron-pituitary-genital pathway. This signaling pathway is regulated by a negative feedback mechanism, maintaining hormone levels within a reasonable range. At the same time, KNDy neurons are also involved in the thermoregulatory signaling pathway, releasing NKB ligands that bind to NK-3 receptors in the median preoptic nucleus, suppressing shivering and vasoconstriction, promoting sweating and vasodilation, and regulating body temperature within a reasonable range. In menopausal women, the decline in estrogen levels in the body disrupts the negative feedback mechanism, causing overactivation of KNDy neurons, resulting in the release of large amounts of endogenous NKB ligands that bind to NK-3 receptors in the median preoptic nucleus, resulting in sweating, vasodilation, and hot flashes. Therefore, the development of antagonists against NK-3 receptors on KNDy neurons and the median preoptic nucleus is expected to have a positive therapeutic effect on hot flash symptoms.

[0007] In the CNS, NK-3 receptors are expressed in regions including the medial prefrontal cortex, hippocampus, thalamus, and amygdala. Furthermore, NK-3 receptors are expressed on dopaminergic neurons. Activation of NK-3 receptors has been shown to regulate the release of dopamine, acetylcholine, and serotonin, suggesting the therapeutic utility of NK-3 receptor modulators in the treatment of various diseases, including psychotic disorders, anxiety, depression, schizophrenia, and obesity, pain, or inflammation.

[0008] Although much meaningful research has been conducted in this field, there is a need for continued research and development of more effective small molecule NK-3R antagonists. The present invention provides NK-3R antagonists with novel structures, and compounds with such structures have good activity and can effectively treat a range of CNS and peripheral diseases.

[0009] [Summary of the Invention] The present invention provides a compound of formula (I), a stereoisomer, a tautomer, an isotopically labeled compound, a nitrogen oxide, a solvate, a polycrystalline form, a pharmaceutically acceptable salt, or a prodrug thereof.

[0010] [ka]

[0011] (wherein ring A is a heterocyclic group containing at least two N atoms, and n is an integer of 1 to 5; R1 is 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 R23 , -NR 24 S(O) a -R 25 , -SR 26 or unsubstituted or optionally containing one or more R a an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group substituted with R2 is 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 , -SR 26 or unsubstituted or optionally containing one or more R a an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group substituted with R a are the same or different and independently represent H, D (deuterium), oxo, thio, 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 , -NR24 S(O) a -R 25 , -SR 26 or unsubstituted or optionally containing one or more R c an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group substituted with R3 may be the same or different and independently represent H, 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 unsubstituted or optionally containing one or more R d an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group substituted with R' is H, -L-Ar, -LR 10 Selected from R 10 is an alkyl group, an alkenyl group, or an alkynyl group, L is absent or -(CH2) m -CO-, -(CH2) m -CS-, -(CH2) m -SO2-, -(CH2) m -SO- and an alkylene group, and m is 0, 1, 2, or 3; Ar is an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocyclic group, and the aryl group, heteroaryl group, cycloalkyl group, and heterocyclic group may optionally be substituted with one or more R4, or any two adjacent or non-adjacent R4 may be unsubstituted or optionally substituted with one or more R b may be linked to form a cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group substituted with R4, the same or different, independently of each other, is H, oxo, thio, 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 , -SR 26 or unsubstituted or optionally containing one or more R b an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group substituted with 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 and independently represent H, oxo, thio, halogen, —OH, unsubstituted or optionally one or more Rb R is selected from alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, and heterocyclic groups substituted with 15 and R 16 , R 17 and R 18 , R 19 and R 20 , R 22 and R 23 may be ring-formed to form a heterocyclic or heteroaryl group containing at least one N atom (e.g., a heterocyclic or heteroaryl group containing one N atom and optionally one to three further N, O, or S atoms), and the heterocyclic or heteroaryl group may optionally be ring-formed to form a heterocyclic or heteroaryl group containing at least one N atom (e.g., a heterocyclic or heteroaryl group containing one N atom and optionally one to three further N, O, or S atoms), and the heterocyclic or heteroaryl group may optionally be ring-formed to form a heterocyclic or heteroaryl group containing at least one N atom (e.g., a heterocyclic or heteroaryl group containing at least ... b and may be substituted with adjacent or non-adjacent R b may be linked to form a ring to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group may further comprise one or more R d may be substituted with R b , R c are the same or different and independently represent H, D (deuterium), 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 unsubstituted or optionally containing one or more R dan alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group substituted with R d are the same or different and independently represent 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 , an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group; a is 1 or 2, 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 and are each independently selected from H, halogen, —OH, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group. In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by the following formula (I') or formula (I'').

[0012] [ka]

[0013] (Ring A, Ar, L, R 10 , R1, R2, R3, n have the above definitions.) In one embodiment of the present invention, L is -(CH2) m -CO-, -(CH2) m -CS-, -(CH2) m -SO2- or C 1-4 is selected from the alkylene groups

[0014] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (IA) or formula (IB) below.

[0015] [ka]

[0016] (R1, R2, R3, and R' are defined above, and p is 1, 2, or 3.) In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (II) or formula (II') below.

[0017] [ka]

[0018] (Ar, L, R 10 , R1, R2, and R3 are defined above, and p is 1, 2, or 3. In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by the following formula (III-1), formula (III-2), formula (III-3), or formula (III-4).

[0019] [ka]

[0020] (Ar, R 10, R1, R2, and R3 are defined above, and p is 1, 2, or 3. In one embodiment of the present invention, R2 is a substituted or unsubstituted heteroaryl group, for example, a substituted or unsubstituted thiadiazole group, a substituted or unsubstituted thiazole group, a substituted or unsubstituted imidazole group, a substituted or unsubstituted triazole group, a substituted or unsubstituted oxazole group, or a substituted or unsubstituted oxadiazole group. Specifically, R2 is a thiadiazole group substituted with an alkyl group or a haloalkyl group, or a thiazole group substituted with an alkyl group or a haloalkyl group.

[0021] In one embodiment of the present invention, R2 is selected from the following groups:

[0022] [ka]

[0023] (wherein R5 and R6 are the same or different and independently represent H, D (deuterium), oxo, thio, 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 , -SR 26 , unsubstituted or optionally one or more R c wherein each substituent is as defined above. In some embodiments of the invention, R2 is a haloalkyl group, for example, trifluoromethyl, hexafluoroethyl, -CH2-CF3.

[0024] In some embodiments of the invention, R1 is H, D (deuterium), halogen, -CN, alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, -cycloalkyl group-alkyl group, -cycloalkyl group-CO-alkyl group, -CO-alkyl group, -CO-alkenyl group, -CO-alkynyl group, -CO-aryl group, -CO-heteroaryl group, -CO-cycloalkyl group, -CO-heterocyclic group, -COO-alkyl group, -O-CO-alkyl group, -NH2, alkylamino group, dialkylamino group, - CONH2, -CONH-alkyl group, -CO-N(alkyl group)2, -NHCO-alkyl group, -NHCOO-alkyl group, -N(alkyl group)(-CO-alkyl group), -S(O)2-alkyl group, -S(O)2NH2, -S(O)2NH-alkyl group, -S(O)2N(alkyl group)2, -NHS(O)2-alkyl group, -SH, -S-alkyl group, and the alkyl group, alkenyl group, alkynyl group, and cycloalkyl group may be substituted with one or more halogen, oxo, hydroxy group, alkyl group, or alkoxy group.

[0025] In some embodiments of the present invention, R1 is -NR 15 R 16 where R 15 , R 16are the same or different and independently selected from H, alkyl groups, cycloalkyl groups, hydroxy alkyl groups, hydroxy cycloalkyl groups, -alkyl-O-alkyl groups, -alkyl-O-cycloalkyl groups, -CO-alkyl groups, -CO-cycloalkyl groups, -CO-alkenyl groups, -CO-alkynyl groups, -CO-aryl groups, -CO-heteroaryl groups, -CO-heterocyclic groups, -CO-alkyl-O-alkyl groups, -CO-alkyl-NH2, -CO-alkyl-NH-alkyl groups, -CO-alkyl-N(alkyl)2, -CO-O-alkyl groups, -S(O)2-alkyl groups and -S(O)2-cycloalkyl groups, and the alkyl groups, alkenyl groups, alkynyl groups and cycloalkyl groups may be substituted with one or more halogen, oxo or hydroxy groups.

[0026] In some embodiments of the present invention, R1 is -NR 15 R 16 where R 15 , R 16 are linked to form a heterocyclic group containing at least one N atom, and are preferably 4- to 10-membered monocyclic or bicyclic heterocyclic groups containing one N atom and optionally further containing 1 to 3 N, O, or S atoms, and specifically include, for example, a 4-membered ring, such as an azetidinyl group; a 5-membered ring, such as a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, an oxazolidinyl group, an iso- an oxazolidinyl group, a thiazolidinyl group, an isothiazolidinyl group; or a 6-membered ring, such as a piperidinyl group, a tetrahydropyridine group, a dihydropyridine group, a piperazinyl group, a morpholinyl group, an oxazinyl group, or a thiazinyl group; or a 7-membered ring, such as an azepanyl group; or an 8-membered ring, such as an azacyclooctyl group, wherein the N-containing heterocycle is H, D, oxo, thio, halogen, -CN, -NO, -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 unsubstituted or optionally containing one or more R d

[0039] The N-containing heterocycle may be substituted with one or more substituents (e.g., 1 to 5 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups substituted with R. Exemplarily, the N-containing heterocycle may be substituted with 1 to 5 or 1 to 3 substituents selected from the group consisting of H, oxo, thio, 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, and dialkylamino groups. Optionally, adjacent or non-adjacent substituents on the N-containing heterocycle may form a ring to form a substituted or unsubstituted cycloalkyl, heterocyclic, aryl, or heteroaryl group. Exemplarily, R1 is unsubstituted or R d and an indolinyl group, an isoindolinyl group, a dihydroquinolyl group, a tetrahydroquinolyl group, a dihydroisoquinolyl group, a tetrahydroisoquinolyl group, an oxazacyclooctyl group, an azabicyclohexyl group, an azabicycloheptane group, an azabicyclooctane group, an oxazabicyclohexyl group, an oxazabicycloheptane group, or an oxazabicyclooctane group.

[0027] In some embodiments of the present invention, R1 is an aryl group, such as a phenyl group, a naphthyl group, or an anthracenyl group, and the aryl group is selected from the group consisting of H, oxo, thio, halogen, -CN, -NO2, -OR, and the like. 31 , -CO-R 32 , -COO-R 33 , -O-CO-R34 , -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 unsubstituted or optionally containing one or more R d The aryl group may be substituted with one or more substituents (e.g., 1 to 5 substituents) selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group substituted with . Exemplarily, the aryl group may be substituted with 1 to 5 or 1 to 3 substituents selected from the group consisting of H, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, -NH-CO-alkyl group, -CO-NH2, -CO-NH-alkyl group, -CO-N(alkyl group)2, -CO-alkyl group, -O-CO-alkyl group, -CO-O-alkyl group, -NH2, an alkylamino group, and a dialkylamino group.

[0028] In some embodiments of the present invention, R1 is a heteroaryl group, preferably a 4- to 10-membered monocyclic or bicyclic heteroaryl group optionally containing 1 to 5 selected from N, O, and S, specifically, for example, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a quinolyl group, a quinazolinyl group, a cinnolinyl group, a pyrrolyl group, an indolyl group, an imidazolyl group, a benzimidazolyl group, a pyrazolyl group, a benzopyrazolyl group, a thienyl group, a benzothienyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, a benzoxazolyl group, a furyl group, a benzofuryl group, etc., and the heteroaryl group is preferably 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 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 unsubstituted or optionally containing one or more R d The heteroaryl group may be substituted with one or more substituents (e.g., 1 to 5 substituents) selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group substituted with . Exemplarily, the heteroaryl group may be substituted with 1 to 5 or 1 to 3 of H, D, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, -NH-CO-alkyl group, -CO-NH-alkyl group, -CO-alkyl group, -O-CO-alkyl group, -CO-O-alkyl group, -NH2, an alkylamino group, and a dialkylamino group.

[0029] In some embodiments of the present invention, R1 is a heterocyclic group, preferably a 4- to 10-membered monocyclic or bicyclic heterocyclic group optionally containing 1 to 5 selected from N, O, and S, and specifically, for example, a morpholinyl group, piperidinyl group, dihydropyridine group, tetrahydropyridine group, piperazinyl group, dihydropyrrole group, pyrrolidinyl group, 2H-pyranyl group, azetidine group, azepane group, azacyclooctane group, imidazolinyl group, indolinyl group, isoindolinyl group, dihydroquinolinyl group, a tetrahydroquinolyl group, a dihydroisoquinolyl group, a tetrahydroisoquinolyl group, an oxazolidinyl group, an oxazinyl group, an oxazepanyl group, an oxazacyclooctyl group, a thiazolidinyl group, an isothiazolidinyl group, an azabicyclohexyl group, an azabicycloheptyl group, an azabicyclooctyl group, an oxazacyclohexyl group, an oxazepanyl group, or an azabicyclooctyl group, and the heterocyclic group is H, D, oxo, thio, halogen, -CN, -NO, -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 unsubstituted or optionally containing one or more R dThe heterocyclic group may be substituted with one or more substituents (e.g., 1 to 5 substituents) selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group substituted with . Exemplarily, the heterocyclic group may be substituted with 1 to 5 or 1 to 3 substituents selected from the group consisting of H, D, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, -NH-CO-alkyl group, -CO-NH-alkyl group, -CO-alkyl group, -O-CO-alkyl group, -CO-O-alkyl group, -NH2, an alkylamino group, and a dialkylamino group.

[0030] In some embodiments of the present invention, Ar is an aryl group, such as a phenyl group, a naphthyl group, or an anthracenyl group, and the aryl group may be H, oxo, thio, halogen, —CN, —NO, —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 unsubstituted or optionally containing one or more R dThe aryl group may be substituted with one or more substituents (for example, 1 to 5 substituents) selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group substituted with . Exemplarily, the aryl group may be substituted with 1 to 5 or 1 to 3 substituents selected from the group consisting of H, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, -NH-CO-alkyl group, -CO-NH-alkyl group, -CO-alkyl group, -O-CO-alkyl group, -CO-O-alkyl group, -NH2, an alkylamino group, and a dialkylamino group.

[0031] In some embodiments of the present invention, Ar is a heteroaryl group, preferably a 4- to 10-membered monocyclic or bicyclic heteroaryl group optionally containing 1 to 5 selected from N, O, and S, such as a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a quinolyl group, a quinazolinyl group, a cinnolinyl group, a pyrrolyl group, an indolyl group, an imidazolyl group, a benzimidazolyl group, a pyrazolyl group, a benzopyrazolyl group, a thienyl group, a benzothienyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, a benzoxazolyl group, a furyl group, a benzofuryl group, etc., and the heteroaryl group is selected from H, oxo, thio, halogen, —CN, —NO, —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 unsubstituted or optionally containing one or more R dThe heteroaryl group may be substituted with one or more substituents (e.g., 1 to 5 substituents) selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group substituted with . Exemplarily, the heteroaryl group may be substituted with 1 to 5 or 1 to 3 of H, oxo, thio, F, Cl, Br, I, -OH, -CN, -NO2, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, -NH-CO-alkyl group, -CO-NH-alkyl group, -CO-alkyl group, -O-CO-alkyl group, -CO-O-alkyl group, -NH2, an alkylamino group, and a dialkylamino group.

[0032] In some embodiments of the present invention, Ar is a cycloalkyl group, preferably a cycloalkyl group containing 3 to 10 carbon atoms, more preferably a cycloalkyl group containing 3 to 6 carbon atoms, and most preferably a cyclopropyl group.

[0033] In some embodiments of the present invention, R3 are the same or different and are independently selected from H, oxo, thio, halogen, -CN, -NO2, alkyl, alkoxy, haloalkyl, and haloalkoxy groups.

[0034] In some embodiments of the present invention, R 10 is a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, a vinyl group or an ethynyl group.

[0035] In one embodiment of the present invention, the compound of formula (I) is a compound of formula (IV) below:

[0036] [ka]

[0037] (Ar, R1, and R2 are defined above.) In some embodiments of the present invention, the compound of formula (IV) may be a compound of formula (IV-A) or (IV-B) below.

[0038] [ka]

[0039] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by the following formula (V), formula (V'), or formula (V'').

[0040] [ka]

[0041] wherein M is N or CR6; R5 and R6 are the same or different and independently represent 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 , -SR 26 , unsubstituted or optionally one or more R c wherein each substituent is as defined above; Ar, R, R 10 is defined above.) In some embodiments of the present invention, the compound of formula (V) may be a compound of formula (VA) or formula (VB) below.

[0042] [ka]

[0043] In some embodiments of the present invention, the compound of formula (I) may be a compound of formula (VI):

[0044] [ka]

[0045] (M, R1, and R5 are defined above.) In some embodiments of the present invention, the compound of formula (VI) may be a compound of formula (VI-A) or (VI-B) below.

[0046] [ka]

[0047] In some embodiments of the present invention, the compound of formula (I) may be the specific compound below or a pharmaceutically acceptable salt thereof.

[0048] [ka] JPEG0007746406000014.jpg193169JPEG0007746406000015.jpg218169JPEG0007746406000016.jpg212169JPEG0007746406000017.jpg207169JPEG000 7746406000018.jpg174169JPEG0007746406000019.jpg185169JPEG0007746 406000020.jpg181169JPEG0007746406000021.jpg186169JPEG00077464060 00022.jpg186169JPEG0007746406000023.jpg195169JPEG0007746406000024.jpg180169JPEG0007746406000025.jpg175169JPEG0007746406000026.j pg185169JPEG0007746406000027.jpg175169JPEG0007746406000028.jpg211169JPEG0007746406000029.jpg217169JPEG0007746406000030.jpg168169

[0049] In some embodiments of the present invention, the compound of formula (I) may be the specific compound below.

[0050] [ka]

[0051] The present invention further provides a process for preparing the compound of formula (I) as described above, which comprises reacting a compound of formula (X) with a compound of formula (XI) in the presence of a base (e.g., triethylamine) to obtain the compound of formula (I).

[0052] [ka]

[0053] (wherein R1, R2, R3, R', ring A, and n are defined above, and R7 is a halogen (e.g., chlorine, bromine) or a hydroxy group.) In some embodiments of the present invention, compounds of formula (I-4) may be prepared by a process comprising reacting compounds of formula (I-2) with a protected ammonia (e.g., diphenylmethanimine) and removing the protecting group to obtain compounds of formula (I-3), followed by reacting compounds of formula (I-3) with R9-X to obtain compounds of formula (I-4).

[0054] [ka]

[0055] (wherein ring A, R2, R3, R', n are as defined above, X is halogen, and R9 are the same or different and independently represent H, -OH, -CO-R 20 , -S(O) a -R 25 , unsubstituted or optionally one or more R b and is selected from an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group substituted with In some embodiments of the present invention, compounds of formula (I-5) can be prepared by reacting compounds of formula (I-2) with R 1a -H to give the compound of formula (I-5).

[0056] [ka]

[0057] wherein ring A, R2, R3, R', n are as defined above, X is a halogen, and R 1a is -NR 15 R 16 or a heteroaryl group, R 15 and R 16 are ring-formed to form an N-containing heterocyclic or heteroaryl group, said heterocyclic or heteroaryl group optionally containing one or more Rb and may be substituted with adjacent or non-adjacent R b are linked to each other and are unsubstituted or are linked to one or more R d The ring may be formed to form a cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group substituted with According to the present invention, the compound represented by formula (I-2) and R 1a Copper or palladium catalyzed coupling of -H provides compounds of formula (I-5).

[0058] In some embodiments of the present invention, compounds of formula (I-6) can be prepared by reacting compounds of formula (I-2) with R 1b -Y to give a compound of formula (I-6).

[0059] [ka]

[0060] wherein ring A, R2, R3, R', n are as defined above, X is a halogen, and R 1b is a cyano group, an alkyl group, an aryl group, or a heteroaryl group, and Y is -B(OH)2, -Sn(alkyl group)3, or

[0061] [ka]

[0062] etc.) According to an embodiment of the present invention, the compound of formula (I-2) may be prepared by a process comprising reacting a compound of formula (X) with a compound of formula (XI-1) in the presence of a base (e.g., triethylamine) to obtain a compound of formula (I-1), and then reacting with a halogenating reagent to obtain a compound of formula (I-2).

[0063] [ka]

[0064] (wherein R7, R2, R3, R', ring A, n, and X are defined above.) If necessary, any group in the reactants or intermediates in the above embodiments can be protected with a protecting group, and after completion of the reaction, the protecting group can be removed by selecting an appropriate method.

[0065] The reactant materials in the above embodiments can be synthesized by methods reported in the literature or obtained commercially. The starting materials are typically derived from commercial sources such as Aldrich, or can be readily prepared by methods known to those skilled in the art (e.g., SciFinder, Reaxys online databases).

[0066] In the preparation method of the present invention, appropriate reaction conditions and raw materials can be selected according to each case. For example, it is possible to replace only one substituent with another substituent of the present invention in a single reaction step, or to replace multiple substituents with another substituent of the present invention in the same reaction step.

[0067] Each compound that cannot be obtained via the above reaction scheme can be prepared by deriving another compound represented by formula (I) or by routinely modifying the above synthesis scheme.

[0068] The compound represented by formula (I) according to the present invention, its stereoisomer, tautomer, isotope label, nitrogen oxide, solvate, polycrystalline substance, metabolite, pharmaceutically acceptable salt, or prodrug can be synthesized by a method including a method similar to a method well known in the chemical field, and the steps and conditions thereof can be referenced to the steps and conditions of similar reactions in the field, and in particular, can be synthesized according to the description in this specification.

[0069] In the present invention, the compound represented by formula (I) may be modified at its terminals by a method well known in the art to obtain another compound represented by formula (I).

[0070] After the reaction according to the present invention is completed, the reaction product can be treated by a conventional post-treatment method. In the present invention, when the crude product of the compound represented by formula (I) is obtained after the treatment, it can be separated and purified by a general means such as preparative HPLC, preparative TLC, or heavy crystallization.

[0071] The present invention further provides an intermediate having the structure of a compound of formula (XI).

[0072] [ka]

[0073] (wherein R1, R2, R3, ring A, and n are defined above.) In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XII):

[0074] [ka]

[0075] (wherein R1, R2, R3, and p are defined above.) In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XIII):

[0076] [ka]

[0077] (wherein R2, R3, and p are defined above). In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XIV):

[0078] [ka]

[0079] (wherein R5 is defined above). In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XV):

[0080] [ka]

[0081] In some embodiments of the present invention, the compound of formula (XI) is a compound of formula (XV-A) or (XV-B):

[0082] [ka]

[0083] The present invention further provides a method for preparing formula (XIII) comprising any one of the following methods:

[0084] Method 1: This method includes the following steps:

[0085] [ka]

[0086] (wherein R2, R3, and p are defined above, R8 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group (e.g., 4-methoxybenzyl, 2,4-dimethoxybenzyl), and X is a halogen.) 1) reacting a compound of formula (XVIII) with R8-X to obtain a compound of formula (XVII); 2) A step of subjecting the compound of formula (XVII) to a hydrogenation reaction in the presence of a reducing agent to obtain a compound of formula (XVI). 3) reacting the compound of formula (XVI) under acidic conditions to obtain the compound of formula (XIII) Or, Method 2: A method comprising the step of subjecting a compound of formula (XVIII) to a hydrogenation reaction in the presence of a catalyst to obtain a compound of formula (XIII).

[0087] [ka]

[0088] (wherein R2, R3, and p are defined above). According to the present invention, the compound of formula (XVIII) may be prepared by a process comprising reacting a compound of formula (XX) with RCOOH to obtain a compound of formula (XIX), and cyclizing the compound of formula (XIX) to obtain a compound of formula (XVIII).

[0089] [ka]

[0090] (wherein R2, R3, and p are defined above). The present invention further provides pharmaceutical compositions comprising one, two or more of the compounds of formula (I) above, their stereoisomers, tautomers, isotopic labels, nitroxides, solvates, polycrystalline forms, pharmaceutically acceptable salts, metabolites and prodrugs.

[0091] According to the present invention, the pharmaceutical composition may optionally further comprise at least one pharmaceutically acceptable adjuvant.

[0092] According to the present invention, the pharmaceutical composition may optionally further comprise at least one other active ingredient. Specifically, the pharmaceutical composition may further comprise one or more active ingredients other than the compound of formula (I), its stereoisomer, tautomer, isotope label, nitroxide, solvate, polycrystalline form, pharmaceutically acceptable salt, metabolite, or prodrug.

[0093] In the pharmaceutical composition, the compound of formula (I), its stereoisomer, tautomer, isotope-labeled form, nitroxide, solvate, polycrystalline form, pharmaceutically acceptable salt, metabolite, or prodrug may be administered in a therapeutically effective amount.

[0094] In accordance with the present invention, the pharmaceutical compositions of the present invention can be made into dosage forms suitable for administration by methods well known in the art.

[0095] The present invention further provides use of one, two or more of the compounds of formula (I) above, their stereoisomers, tautomers, isotopically labeled forms, nitroxides, solvates, polycrystalline forms, pharmaceutically acceptable salts, metabolites, and prodrugs, or said pharmaceutical composition in the preparation of a medicament.

[0096] According to the present invention, the drug is an NK-3 receptor antagonist.

[0097] According to the present invention, the drug is used for preventing and / or treating NK-3 receptor mediated diseases.

[0098] In some embodiments, the drug is used to prevent and / or treat depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorder, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsions, obesity, inflammatory disorders, vomiting, pre-eclampsia, airway-related disorders, reproductive disorders, contraception, and sex hormone-dependent or gynecological-related disorders.

[0099] The sex hormone-dependent diseases 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, pubertal abnormalities, uterine fibrosis, uterine fibroids, hormone-dependent cancers, hyperandrogenemia, hirsutism, virilization, polycystic ovarian syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN associated with hyperplasia of luteinized theca cells in the ovarian stroma), other manifestations of high ovarian androgen levels (e.g., arrested follicular maturation, atresia, anovulation, painful menstruation, dysfunctional uterine bleeding, infertility), androgen-secreting tumors (virilizing ovarian tumors or adrenal tumors), menorrhagia, and adenomyosis.

[0100] The airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction and cough.

[0101] In some embodiments, the medicament is used to treat and / or prevent disorders associated with menopausal syndrome, including symptoms such as hot flashes, sweating, palpitations, dizziness, and obesity.

[0102] The present invention further provides a method for treating and / or preventing an NK3 receptor-mediated disease or disorder, comprising administering to a subject a therapeutically effective amount of one, two or more of a compound of formula (I), its stereoisomers, tautomers, isotopically labeled forms, nitroxides, solvates, polycrystalline forms, pharmaceutically acceptable salts, metabolites, or prodrugs.

[0103] According to the present invention, the disease or disorder is depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorder, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsions, obesity, inflammatory diseases, vomiting, pre-eclampsia, airway-related diseases, reproductive disorders, contraception, and sex hormone-dependent or gynecological-related diseases.

[0104] The sex hormone-dependent diseases 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, pubertal abnormalities, uterine fibrosis, uterine fibroids, hormone-dependent cancers, hyperandrogenemia, hirsutism, virilization, polycystic ovarian syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome (hyperandrogenemia, insulin resistance, and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN associated with hyperplasia of luteinized theca cells in the ovarian stroma), other manifestations of high ovarian androgen levels (e.g., arrested follicular maturation, atresia, anovulation, painful menstruation, dysfunctional uterine bleeding, infertility), androgen-secreting tumors (virilizing ovarian tumors or adrenal tumors), menorrhagia, and adenomyosis.

[0105] The airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction and cough.

[0106] In some embodiments, the disease or disorder is a menopausal syndrome-related disorder, and the menopausal syndrome includes symptoms such as hot flashes, sweating, palpitations, dizziness, and obesity.

[0107] The method comprises administering to a patient in need thereof a therapeutically effective amount of one, two or more of a compound of Formula (I), its stereoisomers, tautomers, isotopically labeled forms, nitroxides, solvates, polycrystalline forms, pharmaceutically acceptable salts, metabolites, or prodrugs. Preferably, the patient is a warm-blooded animal, more preferably, a human.

[0108] Term definition Unless otherwise specified, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. All patents and published publications related to the present invention are incorporated herein by reference in their entirety.

[0109] Unless otherwise specified, the following definitions as used herein shall apply: For purposes of the present invention, the chemical elements are consistent with the CAS version of the Periodic Table of the Elements and the "Manual of Chemistry and Physics," 75th Edition, 1994. General principles of organic chemistry may also 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.

[0110] The term "comprise" is an open expression that includes the content specified by the present invention but does not exclude other elements.

[0111] Unless otherwise specified, the numerical ranges described in the present specification and claims are equivalent to at least describing each specific integer value. For example, the numerical range "1 to 40" is equivalent to describing each integer value in the numerical range "1 to 10," i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, and each integer value in the numerical range "11 to 40," i.e., 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, and 40. It should be understood that "multiple" in the context of one or more when describing a substituent herein refers to an integer of 2 or more, for example, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0112] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0113] The term "oxo" refers to an oxo group (=O) that is formed by oxidizing a carbon, nitrogen, or sulfur atom in a substituent.

[0114] The term "thio" refers to a thio group (=S), which is a substituent formed by sulfurizing a carbon atom in a substituent.

[0115] Unless otherwise specified, the definition of a term in this specification also applies to groups that contain this term. For example, the definition of an alkyl group also applies to the alkyl group in an alkoxy group, an alkylamino group, a dialkylamino group, a haloalkyl group, a haloalkoxy group, etc.

[0116] In the definition of the general formula of the present application, the term "optional" (or "optionally", "optionally") means substituted with zero, one or more substituents. For example, "optionally substituted with one, two or more R" means that it may not be substituted with R (unsubstituted), or may be substituted with one, two or more R.

[0117] In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. Furthermore, when a group is substituted with one or more of the aforementioned substituents, the substituents are independent of each other, i.e., the one or more substituents may be different or the same. Unless otherwise specified, one substituent may be substituted at each substitutable position of the group being substituted. When multiple positions in a given structural formula can be substituted with one or more substituents selected from a specified group, the substituents may be the same or different at each position. Here, the substituents may be, but are not limited to, =0, hydrogen, deuterium, cyano, nitro, halogen, alkyl, haloalkyl, alkoxy, carboxyl, cycloalkyl, cycloalkyloxy, heterocyclic, heterocyclic alkyl, aryl, aryl alkyl, aryloxy, heteroaryl, heteroaryl alkyl, heteroaryloxy, etc.

[0118] In addition, the description format "independently selected from ..." used in the present invention should be interpreted broadly to mean that the described individuals are independent of each other and independently selected from the same or different specific groups unless otherwise specified. More specifically, the description format "independently selected from ..." may mean that specific options represented by the same symbol in different groups do not affect each other, or that specific options represented by the same symbol in the same group do not affect each other.

[0119] In various parts of this specification, substituents of the compounds disclosed in this invention are disclosed according to the type and range of the group. In particular, the present invention is intended to include combinations of the individual moieties of each member within these group types and ranges. For example, the term "C 1~6 "Alkyl group" means specifically an independently disclosed C1 alkyl group, C2 alkyl group, C3 alkyl group, C4 alkyl group, C5 alkyl group, or C6 alkyl group.

[0120] Linking substituents are described in various sections of this invention. When a structure clearly requires a linking group, the Marcush variable listed for that group should be understood as the linking group. For example, when a structure clearly requires a linking group and the definition of the Marcush group for that variable includes an "alkyl group" or an "aryl group," the "alkyl group" or "aryl group" should be understood to represent the linked alkylene or arylene group, respectively.

[0121] The term "alkyl group" or "alkylene group" refers to a straight or branched chain saturated hydrocarbon group having 1 to 40 carbon atoms. For example, "C 1~10 alkyl group," "C 1~6 alkyl group" and "C 1~6 "Alkyl group" refers to straight- and branched-chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl or alkylene group contains 1 to 12 carbon atoms, in some other embodiments, the alkyl or alkylene group contains 1 to 6 carbon atoms, and in some other embodiments, the alkyl or alkylene group contains 1 to 4 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, 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, 1,2-dimethylbutyl, etc., or isomers thereof. Examples of the alkylene group include, but are not limited to, methylene and ethylene.

[0122] The term "alkenyl group" refers to an alkenyl group having at least one site of unsaturation, i.e., one carbon-carbon sp 2 represents a linear or branched hydrocarbon group containing 2 to 40 carbon atoms having double bonds, said double bonds may be separate or conjugated to each other, wherein said alkenyl group may be optionally substituted with one or more substituents as described herein, including "cis" and "tans" positions, or "E" and "Z" positions, and preferably "C" 2~10 alkenyl group," "C 2~6 "C alkenyl group." 2~6 An "alkenyl group" preferably contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms, especially 2 or 3 carbon atoms ("C 2~3The term "alkenyl group" should be understood to represent a straight or branched chain monovalent hydrocarbon group having an alkyl group ("alkenyl group"). Illustrative examples of the alkenyl group include 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)-pent-2-enyl, (E)-pent-1-enyl. nyl group, (Z)-pent-1-enyl group, hex-5-enyl group, (E)-hex-4-enyl group, (Z)-hex-4-enyl group, (E)-hex-3-enyl group, (Z)-hex-3-enyl group, (E)-hex-2-enyl group, (Z)-hex-2-enyl group, (E)-hex-1-enyl group, (Z)-hex-1-enyl group, isopropenyl group, 2-methylprop-2-enyl group, 1-methylprop-2-enyl group , 2-methylprop-1-enyl group, (E)-1-methylprop-1-enyl group, (Z)-1-methylprop-1-enyl group, 3-methylbut-3-enyl group, 2-methylbut-3-enyl group, 1-methylbut-3-enyl group, 3-methylbut-2-enyl group, (E)-2-methylbut-2-enyl group, (Z)-2-methylbut-2-enyl group, (E)-1-methylbut-2-enyl group, (Z)-1-methylbut-2-enyl group Examples of vinyl groups include, but are not limited to, (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, and 1-isopropylvinyl groups.

[0123] The term "alkynyl group" is to be understood as meaning a linear or branched hydrocarbon group containing one or more triple bonds and having 2 to 40 carbon atoms, preferably "C2-C 10The term "C2-C6-alkynyl group" is to be understood as denoting a straight-chain or branched monovalent hydrocarbon group, preferably containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, in particular 2 or 3 carbon atoms ("C2-C3-alkynyl group"). Examples of the C2 to C6 alkynyl group include an ethynyl group, a prop-1-ynyl group, a prop-2-ynyl group, a but-1-ynyl group, a but-2-ynyl group, a but-3-ynyl group, a pent-1-ynyl group, a pent-2-ynyl group, a pent-3-ynyl group, a pent-4-ynyl group, a hex-1-ynyl group, a hex-2-ynyl group, a hex-3-ynyl group, a hex-4-ynyl group, a hex-5-ynyl group, a 1-methylprop-2-ynyl group, a 2-methylbut-3-ynyl group, a 1-methylbut-3-ynyl group, a 1-methylbut-2-ynyl group, a 3-methylbut-1-ynyl group, a 1-ethylprop-2-ynyl group, a 3-methylpent-4-ynyl group, a 2-methylpent-5-ynyl group, a 2-methylpent-6-ynyl group, a 2-methylpent-7-ynyl group, a 2-methylpent-8-ynyl group, a 2-methylpent-9-ynyl group, a 2-methylpent-10-ynyl group, a 2-methylpent-11-ynyl group, a 2-methylpent-12-ynyl group, a 2-methylpent-13-ynyl group, a 2-methylpent-14-ynyl group, a 2-methylpent-15-ynyl group, a 2-methylpent-16-ynyl group, a 2-methylpent-17-ynyl group, a 2-methylpent-18-ynyl group, a 2-methylpent-19 ... 1-methylpent-4-ynyl group, 1-methylpent-4-ynyl group, 2-methylpent-3-ynyl group, 1-methylpent-3-ynyl group, 4-methylpent-2-ynyl group, 1-methylpent-2-ynyl group, 4-methylpent-1-ynyl group, 3-methylpent-1-ynyl group, 2-ethylbut-3-ynyl group, 1-ethylbut-3-ynyl group, 1-ethylbut-2-ynyl group, 1-propylprop-2-ynyl group, 1-isopropylprop-2-ynyl group, 2,2-dimethylbut-3-ynyl group, 1,1-dimethylbut-3-ynyl group, 1,1-dimethylbut-2-ynyl group, or 3,3-dimethylbut-1-ynyl group. In particular, the alkynyl group is an ethynyl group, a prop-1-ynyl group or a prop-2-ynyl group.

[0124] The term "cycloalkyl group" is to be understood as meaning a saturated or partially unsaturated monocyclic, bicyclic hydrocarbon ring or polycyclic cycloalkane group having 3 to 40 carbon atoms, preferably "C 3~10 The term "C" is a cycloalkyl group. 3~10A "cycloalkyl group" should be understood to represent a saturated or partially unsaturated monocyclic, bicyclic hydrocarbon ring or polycyclic cycloalkane group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3~10 The cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, or a cyclodecyl group, or a bicyclic hydrocarbon group such as a decalin ring group.

[0125] The term "heterocyclic group" should be understood to mean a saturated or partially unsaturated monocyclic, bicyclic hydrocarbon ring, or polycyclic cycloalkane group, including a non-aromatic cyclic group having a total of 3 to 20 atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.) forming the ring, containing 1 to 5 heteroatoms independently selected from N, O, and S, preferably a "3- to 10-membered heterocyclic group." The term "3- to 10-membered heterocyclic group" means a saturated or partially unsaturated monocyclic, bicyclic hydrocarbon ring, or polycyclic cycloalkane group containing 1 to 5, preferably 1 to 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 may be linked to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to, a 4-membered ring, such as an azetidinyl group or an oxetanyl group; a 5-membered ring, such as a tetrahydrofuryl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, or a pyrrolinyl group; a 6-membered ring, such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a tetrahydropyridyl group, a 2H-pyranyl group, a piperazinyl group, or a trithianyl group; or a 7-membered ring, such as a diazepanyl group. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as, for example, a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as, for example, a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e., contain one or more double bonds, for example, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or may be benzo-fused, for example, but not limited to, a dihydroisoquinolyl group.

[0126] According to the present invention, the heterocyclic group is non-aromatic. When the 3- to 20-membered heterocyclic group is linked to another group to form the compound according to the present invention, a carbon atom on the 3- to 20-membered heterocyclic group may be linked to the other group, or a heterocyclic atom on the 3- to 20-membered heterocyclic group may be linked to the other group. For example, when the 3- to 20-membered heterocyclic group is selected from a piperazinyl group, a nitrogen atom on the piperazinyl group may be linked to the other group. Alternatively, when the 3- to 20-membered heterocyclic group is selected from a piperidinyl group, a nitrogen atom on the piperidinyl group and a carbon atom at the para-position thereof may be linked to the other group.

[0127] The term "aryl group" is to be understood as meaning an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6~14 The term "C" is an aryl group. 6~14 An "aryl group" is a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") preferably having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6~14 aryl groups"), in particular rings having six carbon atoms ("C6 aryl groups"), such as phenyl groups; biphenyl groups; or rings having nine carbon atoms ("C9 aryl groups"), such as indanyl or indenyl groups; or rings having ten carbon atoms ("C 10 aryl group), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl; or a ring having 13 carbon atoms ("C 13 aryl group), such as a fluorenyl group; or a ring having 14 carbon atoms ("C 14 It should be understood that the C represents an aryl group, such as an anthracenyl group. 6~20 When the aryl group is substituted, it may be singly or multiply substituted, and the substitution site is not particularly limited, and may be, for example, ortho-substituted, para-substituted, or meta-substituted.

[0128] The term "heteroaryl group" should be understood to include mono-, bi- or tricyclic aromatic ring systems which are aromatic or partially aromatic and have 5 to 20 ring atoms and contain 1 to 5 heteroatoms independently selected from N, O and S, e.g., "5- to 14-membered heteroaryl groups". The term "5- to 14-membered heteroaryl groups" should be understood to include monovalent mono-, bi- or tricyclic aromatic ring systems which have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5, 6, 9 or 10 carbon atoms, and contain 1 to 5, preferably 1 to 3 heteroatoms, each independently selected from N, O and S, and which in each case may be benzo-fused. In particular, heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thio-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and the like; Alternatively, the 5- to 20-membered heteroaryl group may be selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolyl, quinazolinyl, and isoquinolyl; azocinyl, indolizinyl, and purinyl, and the like, and their benzo derivatives; and cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl. When the 5- to 20-membered heteroaryl group is linked to another group to form the compound of the present invention, a carbon atom on the 5- to 20-membered heteroaryl ring may be linked to the other group, or a heteroatom on the 5- to 20-membered heteroaryl ring may be linked to the other group. When the 5- to 20-membered heteroaryl group is substituted, it may be single-substituted or multi-substituted. Moreover, the substitution site is not particularly limited, and for example, a hydrogen atom bonded to a carbon atom on the heteroaryl ring may be substituted, or a hydrogen atom bonded to a heteroatom on the heteroaryl ring may be substituted.

[0129] Unless otherwise specified, heterocyclic, heteroaryl or heteroarylene groups include all possible isomeric forms thereof, for example, their positional isomers.Thus, some illustrative and non-limiting examples include those substituted or bonded to other groups at one, two or more positions, such as 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions (if present), and include pyridin-2-yl, pyridin-2-ylidene, pyridin-3-yl, pyridin-3-ylidene, pyridin-4-yl and pyridin-4-ylidene; thienyl or thienylene groups, including thiophen-2-yl, thiophen-2-ylidene, thiophen-3-yl and thiophen-3-ylidene; pyrazole-1 group, pyrazole-3 group, pyrazole-4 group, pyrazole-5 group.

[0130] The term "alkoxy group" is to be understood as an --O-alkyl group, said alkyl group being as defined above.

[0131] The term "haloalkyl group" is to be understood as an alkyl group in which some or all of the H's are replaced by halogen, said alkyl group being as defined above.

[0132] The term "haloalkoxy group" is to be understood as an -O-haloalkyl group, wherein the haloalkyl group is defined above. The definitions and rules of stereochemistry used in the present invention generally follow those in S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0133] "Stereoisomers" refer to compounds that have identical chemical constitution but differ with regard to the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, structural isomers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0134] "Enantiomers" refer to two non-superimposable isomers of a compound which are mirror images of one another.

[0135] "Diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

[0136] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can be present in racemic or enantiomerically enriched form, for example, in the (R)-, (S)-, or (R,S)-configuration. 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.

[0137] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, or diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0138] In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents include optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, appropriately N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic resolution of enantiomers can also be advantageously carried out using optically active resolving agents (e.g., dinitrobenzoylphenylglycine, triacetylcellulose or other carbohydrate derivatives, or chiral derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are solvent mixtures containing water or alcohols, such as hexane / isopropanol / acetonitrile.

[0139] The term "tautomer" refers to structural isomers with different energies that can be interconverted via a low energy barrier. When tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via rearrangement of some bond electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is the tautomerization of phenol and keto. One specific example of tautomerization of a phenol and a keto is the interconversion of the tautomers pyridin-4-ol and pyridin-4(1H)-one. Unless otherwise specified, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0140] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and do not typically cause allergic or similar untoward reactions, such as gastrointestinal upset, dizziness, etc.

[0141] The term "carrier" refers to a diluent, adjuvant, excipient, or base with which the compound is administered. Such pharmaceutical carriers may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Water and aqueous solutions, saline solutions, aqueous glucose and glycerol solutions are preferably used as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin.

[0142] The term "prodrug" as used in the present invention refers to a compound that is converted in vivo to a compound represented by formula (I). Such conversion is affected by hydrolysis of the prodrug in blood or conversion to the parent structure by enzymes in blood or tissue. The prodrug compounds of the present invention may be esters, and examples of esters that can be used as prodrugs in the prior art include phenyl esters, aliphatic (C 1~24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound of the present invention contains a hydroxy group, which can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, e.g., such phosphate ester compounds are obtained by phosphorylating the parent hydroxy group. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, 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 S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0143] The term "metabolite" as used herein refers to a product obtained by metabolism of a particular compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like of an administered compound. Correspondingly, the present invention includes metabolites of a compound, including those produced by contacting a compound of the present invention with a mammal for a substantial period of time.

[0144] Pharmaceutically acceptable salts may be, for example, acid addition salts of sufficiently basic compounds according to the invention which have a nitrogen atom in the chain or ring.

[0145] The term "solvate" according to the present invention refers to an association formed between one or more solvent molecules and the compound according to the present invention. The term "hydrate" refers to an association formed with the solvent molecule water.

[0146] The term "nitrogen oxide" in the present invention means that, when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are tertiary amine N-oxides or N-oxides containing nitrogen atoms of azacyclic rings. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages 1977). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), which involves, for example, reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent, such as dichloromethane.

[0147] The term "isotope labeled" refers 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 Isotopically labeled compounds of the present invention include, but are not limited to, compounds labeled with HCl. Isotopically labeled compounds of the present invention are useful in determining the tissue distribution of the compounds and their prodrugs and metabolites, and the preferred isotope for use in such determinations is 3 H and 14C. Furthermore, in some cases, substitution with heavier isotopes, such as deuterium (H or D), can result in increased metabolic stability, which can confer therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds according to the present invention can generally be prepared according to the methods described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0148] As used herein, the term "treatment" of any disease or condition refers, in some embodiments, to improved disease or condition (i.e., alleviating, preventing, or reducing the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treatment" refers to the alleviation and / or improvement of at least one physical parameter, including physical parameters imperceptible to the patient. In other embodiments, "treatment" refers to modulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treatment" refers to preventing or delaying the onset, development, or worsening of the disease or condition.

[0149] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of the present invention sufficient to achieve the desired application (including, but not limited to, the treatment of diseases as defined below). A therapeutically effective amount may vary depending on factors such as the desired application (in vitro or in vivo), or the subject and disease being treated, such as the subject's weight and age, the severity of the disease, and the method of administration, and is readily determined by one of ordinary skill in the art. Specific doses will vary depending on factors such as the particular compound selected, the administration regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system hosted.

[0150] Abbreviations for any protecting groups, amino acids and other compounds used in the present invention follow commonly used and recognized abbreviations unless otherwise specified, or refer to the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11:942-944).

[0151] In the description herein, references such as "one embodiment," "some embodiments," "examples," "particular examples," or "some examples" mean that the particular feature, structure, material, or characteristic described with reference to that embodiment or example is included in at least one embodiment or example of the present invention. In the description herein, general descriptions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine or combine different embodiments or examples and features of different embodiments or examples described herein, if not inconsistent.

[0152] Although the embodiments of the present invention have been shown and described above, the above embodiments are illustrative and should not be understood as limiting the present invention, and those skilled in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

[0153] [Mode for Carrying Out the Invention] The present invention will be further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0154] Example The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) were expressed in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0155] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer, and 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).

[0156] The silica gel plates used for thin-layer chromatography were Yantai Yellow Sea HSGF254 (China) or Qingdao GF254 (China). The TLC specifications were 0.15mm to 0.20mm, and the thin-layer chromatography specifications used to separate and purify the products were 0.4mm to 0.5mm. Column chromatography typically used 200-300 mesh Yantai Yellow Sea silica gel (China).

[0157] The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.

[0158] Unless otherwise specified, all reactions of this invention are carried out under an atmosphere of dry nitrogen or argon gas with continuous magnetic stirring, solvents are dry solvents, and reaction temperatures are in degrees Celsius.

[0159] Example 1 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)methanone (001)

[0160] [ka]

[0161] First step, preparation of 2-(chloromethyl)-3-methylpyrazine 2,3-Dimethylpyrazine 001a (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 heated at 80 °C for 16 hours under nitrogen gas protection. The reaction was monitored by LCMS. Upon completion, the solvent was spin-dried, water (150 mL) was added, and the mixture was extracted with dichloromethane (3 × 100 mL). The extract was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure and purified on a silica gel column (petroleum ether / ethyl acetate = 10:1) to give the title product, 2-(chloromethyl)-3-methylpyrazine 001b (3.20 g, colorless oil). The yield was 22%.

[0162] MS m / z (ESI): 143.2 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 8.45(d,J=2.0Hz,1H), 8.38(d,J=2.0Hz,1H), 4.71(s, 2H), 2.69(s, 3H). Second step, preparation of 2-((3-methylpyrazin-2-yl)methyl)isoindoline-1,3-dione 2-(Chloromethyl)-3-methylpyrazine 001b (3.20 g, 22.44 mmol) was added to N,N-dimethylformamide as a solvent, and potassium phthalimide (6.23 g, 33.66 mmol) was added. The reaction mixture was reacted at 110°C for 8 hours under nitrogen gas protection. The reaction was monitored by LCMS. After the reaction was completed, the solvent was spin-dried, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified on a silica gel column (petroleum ether / ethyl acetate = 1:1) to obtain the title product, 2-3-methylpyrazin-2-ylmethylisoindoline-1,3-dione 001c (3.10 g, pale yellow solid). The yield was 95%.

[0163] MS m / z (ESI): 254.2 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 8.33(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). Third step, preparation of 2-(aminomethyl)-3-methylpyrazine 2-((3-Methylpyrazin-2-yl)methyl)isoindoline-1,3-dione 001c (2.00 g, 7.90 mmol) was added to ethanol (50 mL) and hydrazine hydrate (3.95 g, 79 mmol) was added. The reaction mixture was reacted at 80°C for 6 hours under nitrogen gas protection. The reaction was monitored by LCMS. Upon completion of the reaction, the solvent was spin-dried, water (150 mL) was added, and the mixture was extracted with dichloromethane / methanol (1 / 1, v / v, 50 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure to give the crude product, 2-(aminomethyl)-3-methylpyrazine 001d (300 mg, yellow oil). The yield was 28%.

[0164] MS m / z (ESI): 124.3 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 8.36(s,1H),8.33(d,J=2.4Hz,1H),4.02(s,2H),2.54(s,3H). Fourth step, preparation of 3-methyl-N-((3-methylpyrazin-2-yl)methyl)-1,2,4-thiadiazole-5-formamide 3-Methyl-1,2,4-thiadiazole-5-carboxylic acid (280 mg, 1.94 mmol) was added to dichloromethane (10 mL), followed by 0.5 mL of oxalyl chloride (0.5 mL) and N,N-dimethylformamide (0.1 mL). The reaction mixture was allowed to react at 25 °C for 0.5 h. The reaction was monitored by LCMS. Upon completion, the solvent was spun down to give the crude product, 3-methyl-1,2,4-thiadiazole-5-carbonyl chloride. (3-Methylpyrazin-2-yl)methylamine (200 mg, 1.62 mmol) and triethylamine (246 mg, 2.43 mmol) were added to dichloromethane (10 mL), and the crude product, 3-methyl-1,2,4-thiadiazole-5-carbonyl chloride, dissolved in dichloromethane (5 mL) was added dropwise slowly. The reaction mixture was reacted at 25° C. for 0.5 hours. The reaction was monitored by LCMS. After completion of the reaction, water (30 mL) was added, and the mixture was extracted with dichloromethane (3×20 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column (petroleum ether / ethyl acetate=1:1) to obtain the title product, 3-methyl-N-((3-methylpyrazin-2-yl)methyl)-1,2,4-thiadiazole-5-formamide 001e (170 mg, yellow solid), with a yield of 40%.

[0165] MS m / z (ESI): 250.2 [M+1] + . 1H NMR(400MHz,CDCl3)δ 8.59(s,1H),8.46(s,2H),4.78(d,J=4.8Hz,2H),2.76(s,3H),2.65(s,3H). Fifth step, preparation of 3-methyl-5-(8-methylimidazo[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole 3-Methyl-N-((3-methylpyrazin-2-yl)methyl)-1,2,4-thiadiazole-5-formamide 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 gas protection. The reaction was monitored by LCMS, and upon completion, the solvent was spun off. Saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified on a silica gel column (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), with a yield of 60%.

[0166] MS m / z (ESI): 232.2 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 9.58(d,J=3.2Hz,1H),8.51(s,1H),7.81(s,1H),3.22(s,3H),2.83(s,3H). Step 6: Preparation of 7-(4-methoxybenzyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)imidazo[1,5-a]pyrazin-7-ium 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-methoxybenzene (1.30 g, 8.60 mmol). The reaction mixture was reacted under nitrogen gas protection at 8°C for 16 hours. The reaction was monitored by LCMS. Upon completion, the solvent was spun down to afford the crude product, 7-(4-methoxybenzyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)imidazo[1,5-a]pyrazin-7-ium 001g (600 mg, yellow solid), in a 34% yield.

[0167] MS m / z (ESI): 352.2 [M+1] + . Seventh step, 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 7-(4-Methoxybenzyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)imidazo[1,5-a]pyrazin-7-ium 001g (600 mg, 1.7 mmol) was added to ethanol (10 mL), followed by acetic acid (0.1 mL) and sodium cyanoborohydride (320 mg, 5.1 mmol). The reaction mixture was incubated at 0°C for 0.5 hours under nitrogen gas protection. The reaction was monitored by LCMS, and upon completion, the solvent was spun off. Water (50 mL) was added, and the mixture was extracted with dichloromethane (3 × 20 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified on a silica gel column (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), with a yield of 24%.

[0168] MS m / z (ESI): 356.2 [M+1] + . Step 8: Preparation of 3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)1,2,4-thiadiazole 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) as a solvent. The reaction mixture was reacted at 100°C for 16 hours under nitrogen gas protection. The reaction was monitored by LCMS. Upon completion of the reaction, the reaction mixture was cooled to room temperature. The solvent was spin-dried to obtain a crude product, which was purified using a reverse-phase column (acetonitrile / water = 1:10) to obtain 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). The yield was 72%.

[0169] MS m / z (ESI): 236.2 [M+1] + . HNMR: 1 H NMR (400 MHz, DMSO- d6 )δ 9.47(s,1H),7.32(s,1H),4.95-4.88(m,1H),4.70(q,J=6.4Hz,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). 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)methanone 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), and triethylamine (64 mg, 0.63 mmol) and p-fluorobenzoyl chloride (80 mg, 0.50 mmol) were added, followed by reaction at 25 °C for 2 hours. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with dichloromethane (2 × 20 mL), washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified using a reverse-phase column (acetonitrile / water = 1:1) to give 001 (10.20 mg, white solid), with a yield of 25%.

[0170] MS m / z (ESI): 358.0 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.47(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). Example 2 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)methanone (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)methanone (003)

[0171] [ka]

[0172] (4-Fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 002a (100 mg) was separated by perp-SFC (CO₂ / MeOH (0.2N H₄OH)) 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)methanone 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)methanone (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)methanone (003) (39.20 mg, white solid).

[0173] The data corresponding to 002 was as follows:

[0174] t R =3.62min HNMR: 1 H NMR(400MHz,CDCl3)δ 7.47(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). The data corresponding to 003 was as follows:

[0175] t R =1.82min MS m / z (ESI): 358.0 [M+1] + . HNMR: 1H NMR(400MHz,CDCl3)δ 7.51-7.43(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). SFC division conditions: Column: Daicel CHIRALPAK OZ-H 250mm*20mm ID, 5μm Mobile phase: CO2 / MeOH(0.2%NH4·OH)=70 / 30 Flow rate: 50g / min.

[0176] Example 3 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)methanone (004)

[0177] [ka]

[0178] (4-Fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (004a) (30 mg, 0.084 mmol) was dissolved in 5 mL of dichloromethane, NCS (22 mg, 0.17 mmol) was added, and the reaction mixture was allowed to react at room temperature for 30 minutes. After completion of the reaction, the reaction was quenched by adding 10 mL of water, 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 (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)methanone 004 (2 mg, white solid), yield 6%.

[0179] MS m / z (ESI): 392.1 [M+1] + .

[0180] 1 H NMR(400MHz,CDCl3)δ 7.47(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). HPLC:254nm(95.03%),214nm(95.95%). Example 4 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)methanone (005)

[0181] [ka]

[0182] (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)methanone (005a) (50 mg, 0.11 mmol) was dissolved in 2 mL of tetrahydrofuran / water (4 / 1), and pyridineboronic acid (16 mg, 0.12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (16 mg, 0.02 mmol), and potassium carbonate (24 mg, 0.17 mmol) were added in that order. The mixture was stirred at 80°C for 4 hours under nitrogen gas protection, and the reaction mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified using a reverse phase column (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)methanone (005) (12.7 mg, white solid). The yield was 25%.

[0183] MS: m / z(ESI): 435.2 [M+1] + .

[0184] 1 H NMR(400MHz,CDCl3)δ 8.78-8.55(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). HPLC: 254 nm (100%), 214 nm (100%). Example 5 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-methylformate (006)

[0185] [ka]

[0186] (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)methanone (006a) (50 mg, 0.11 mmol) was dissolved in methanol (5 mL) at room temperature, and potassium acetate (34 mg, 0.34 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol) were added. The reaction was stirred at 80°C for 2 hours under a carbon monoxide atmosphere. After completion of the reaction, the solvent was spun off and extracted with ethyl acetate (3 x 10 mL). The organic phase was collected and the solvent was spun off to give the crude product. The crude product was separated and purified using a reverse phase column (acetonitrile / water) to obtain 7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-methyl formate (006) (5 mg, white solid), with a yield of 10%.

[0187] MS m / z(ESI)416.2[M+1] + . 1 H NMR δ ppm(400MHz,CDCl3):7.49-7.49(m,2H),7.13-7.17(m,2H),6.41(s,1H),5.61(s,1H),5.06- 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) 19 F NMR(376MHz,cdcl3)δ ppm:-108.53,-109.06--109.73.

[0188] Example 6 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-formamide (007)

[0189] [ka]

[0190] 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 (007a) (20 mg, 0.05 mmol) was dissolved in ethanol (2 mL) and 0.5 mL of a 4 M ethanol solution of methylamine was added. The mixture was stirred at 90° C. for 3 hours under nitrogen gas protection. The reaction mixture was concentrated under reduced pressure and purified using a reverse-phase column (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-formamide (007) (2.19 mg, white solid), 10% yield.

[0191] MS.m / z(ESI):415.2[M+1] + .

[0192] 1 H NMR(400MHz,CDCl3)δ 7.48(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). HPLC:254nm(99.4%),214nm(97.4%). Example 7 Preparation of 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 (008)

[0193] [ka]

[0194] First step: 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)methanone (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)methanone (008a) (100 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (4 mL), and the solution was sequentially treated with diphenylmethanimine (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, palladium (26 mg, 0.046 mmol), and cesium carbonate (1 The reaction mixture was stirred at 100°C for 16 hours, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. The residue was purified by 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)methanone 008b (40 mg, yellow solid), yield 29%.

[0195] MS.m / z(ESI):537.2[M+1]+ .

[0196] Second step: 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)methanone [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)methanone 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. The reaction mixture was concentrated and then purified by reverse-phase column chromatography (acetonitrile / water = 40%) to afford (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)methanone 008c (20 mg, pale yellow solid), with a yield of 69%.

[0197] MS.m / z(ESI):373.1[M+1] + .

[0198] 1 H NMR(400MHz,CDCl3)δ 7.47(dd,J=8.4,5.2Hz,2H),7.16(t,J=8.4Hz,2H),5.84(brs,1H),5.00(d,J=12.4 Hz,1H),4.12-3.91(m,2H),3.67-3.30(m,3H),2.64(s,3H),1.55(d,J=4.8Hz,3H). Third step: Preparation of 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 (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)methanone 008c (15 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL), and trimethylamine (6 mg, 0.06 mmol) and acetyl chloride (4 mg, 0.04 mmol) were added in that order. The reaction mixture was stirred at 0°C for 0.5 hours, and water (5 mL) was added to the reaction mixture. The mixture was extracted with chloromethane (10 mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. The residue was purified by reverse phase 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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 008 (5 mg, white solid), yield: 29%.

[0199] MS.m / z(ESI):415.1[M+1] + .

[0200] 1 H NMR(400MHz,CDCl3)δ 7.62-7.41(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). HPLC:254nm(99.2%),214nm(99.6%). Example 8 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)methanone (009)

[0201] [ka]

[0202] (4-Fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 009a (50 mg, 0.013 mmol) was dissolved in dichloromethane (10 mL) and N-bromosuccinimide (25 mg, 0.013 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with dichloromethane (10 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and the resulting 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)methanone 009 (16 mg, white solid). The yield was 26%.

[0203] MS m / z (ESI): 436.20 [M+1] + .

[0204] 1 H NMR(400MHz,CDCl3)δ 7.49-7.45(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). HPLC:254nm(99.76%),214nm(99.53%) Example 9 Preparation of 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-methylacetamide (010)

[0205] [ka]

[0206] First step: Preparation of 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 Compound 010a (40 mg, 0.11 mmol) and DIEA (42 mg, 0.32 mmol) were dissolved in DCM (3 mL), and acetyl chloride (13 mg, 0.16 mmol) was added dropwise. The reaction mixture was allowed to react at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL), washed with saturated NaHCO3 solution and saturated NaCl solution, and dried over anhydrous sodium sulfate. Filtration and concentration afforded compound 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 010b (35 mg, yellow oil) in 70% yield.

[0207] MS m / z(ESI):415.2[M+1] + .

[0208] Second step: Preparation of 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-methylacetamide Compound 010b (35 mg, 0.08 mmol) was dissolved in 3 mL of anhydrous THF and cooled to 0 ° C. NaH (10 mg, 0.25 mmol, 60%) was added, the reaction mixture was stirred at room temperature for 30 min, and CHI (18 mg, 0.13 mmol) was added. After reacting at room temperature for 2 h, the mixture was poured into 10 mL of water, extracted with ethyl acetate (3 × 10 mL), washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by pre-HPLC (ACN / HO (0.1% FA) = 53%) to obtain compound 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-methylacetamide 010 (10 mg, white solid), yield 27%.

[0209] MS m / z (ESI): 429.2 [M+1] + .

[0210] 1 H NMR(400MHz,DMSO-d6)δ 7.59-7.55(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). Example 10 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-carboxylic acid amide (011)

[0211] [ka]

[0212] 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 in that order. The reaction mixture was allowed to react for 2 hours at 25° C. The reaction was monitored by LCMS. After completion of the reaction, 20 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate (2×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Purification by reverse phase column (42% acetonitrile / water) gave 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-carboxylic acid amide 011 (7.50 mg, white solid), yield 28%.

[0213] MS m / z (ESI): 429.2 [M+1] + . HPLC:254nm(98.4%),214nm(98.2%). 1 H NMR(400MHz,CDCl3)δ 7.48(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). Example 11 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)methanethione (012)

[0214] [ka]

[0215] (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)methanone 012a (20 mg, 0.05 mmol) was dissolved in 4 mL of toluene, and Lawesson's reagent (24 mg, 0.06 mmol) was added. After stirring at 110°C for 3 hours, the reaction mixture was concentrated, extracted with 20 mL of ethyl acetate, and then saturated sodium chloride. 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)methanethione 012 (1.6 mg, pale yellow solid). The yield was 6.8%.

[0216] MS m / z(ESI):415.1[M+1] + .

[0217] 1 H NMR(400MHz,CDCl3)δ 8.72(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,2H),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). HPLC:254nm(97.2%),214nm(94.3%). Example 12 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)methanone (013)

[0218] [ka]

[0219] (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)methanone 013a (30 mg, 0.07 mmol) was dissolved in a mixture of 8 mL of tetrahydrofuran and 2 mL of water. Pyridine-3-boronic acid (13 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol) and Pd(dppf)Cl (5 mg, 0.007 mmol) were added in this order. Under nitrogen gas protection, the reaction mixture was heated to 80 °C for 16 hours, and then cooled to room temperature. 10 mL of water was added and extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified using a reverse phase column (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)methanone 013 (6.9 mg, white solid), with a yield of 24%.

[0220] MS m / z(ESI):435.1[M+1] + .

[0221] 1 HNMR(400MHz,CDCl3)δ 9.07(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,2H),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). 19 FNMR (376 MHz, CDCl3) δ -108.76. Example 13 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)methanone (014)

[0222] [ka]

[0223] 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)methanone 014a (30 mg, 0.07 mmol) in dioxane (10 mL) was added 2-(tri-n-butylstannyl)pyridine (52 mg, 0.14 mmol) and tetrakis(triphenylphosphine)palladium (5 mg, 0.007 mmol). Under nitrogen gas protection, the resulting mixture was stirred in a sealed tube at 100 °C for 6 h, and LCMS showed the reaction was complete. Aqueous KF (1M, 5 mL) was added to the reaction mixture, and the mixture was diluted with 10 mL of water and extracted with DCM (3 × 10 mL). The organic layers were combined, 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)methanone 014 (2.8 mg, white solid), yield 9.0%. MS m / z(ESI):435.1[M+1] + 1HNMR(400MHz,CDCl3)δ 8.67-8.34(m,1H),8.09(s,1H),7.71(s,1H),7.51(s,2H),7.16-7.13(m,3H),6.1 2(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 (376 MHz, CDCl3) δ -109.43. Example 14 Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-phenyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (015)

[0224] [ka]

[0225] (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)methanone 015a (30 mg, 0.07 mmol) was dissolved in 2 mL of tetrahydrofuran / water (3:1), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (10 mg, 0.014 mmol), potassium carbonate (15 mg, 0.11 mmol), and benzeneboronic acid (9 mg, 0.07 mmol) were added. The mixture was stirred at 80°C for 4 hours under nitrogen gas protection. The reaction mixture was extracted with ethyl acetate (20 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure, and the resulting residue was purified using a reverse-phase column (65% acetonitrile / water) to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-phenyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 015 (6.0 mg, white solid). The yield was 19%.

[0226] MS.m / z(ESI):434.2[M+1] + .

[0227] 1 H NMR(400MHz,CDCl3)δ 7.95-7.61(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). HPLC:254nm(99.6%),214nm(99.9%). Example 15 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)methanone (016)

[0228] [ka]

[0229] (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)methanone 016a (30 mg, 0.070 mmol), (4-fluorophenyl)boronic acid (15 mg, 0.11 mmol), Pd(dppf)Cl (10 mg, 0.014 mmol), and potassium carbonate (29 mg, 0.21 mmol) were added to a 10 mL microwave tube equipped with a stir bar. Then, tetrahydrofuran / water (5:1, 1 / 0.2 mL) solvent was added. The tube was evacuated, backfilled with nitrogen gas, and capped. The tube was sealed and heated to 80 °C and stirred for 2 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated and the residue was purified by silica gel column (petroleum ether / ethyl acetate=1:1) to obtain the crude product, which was purified by reverse phase column (42% acetonitrile / water) to obtain (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)methanone 016 (2.21 mg, yellow solid), the yield was 7%.

[0230] MS m / z (ESI): 452.2 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.75(s,2H),7.52-7.48(m,2H),7.21-7.14(m,4H),6.37(s,1H),5.11(d,J=12.8H z,1H),4.28(s,1H),4.05(s,1H),3.67(s,1H),2.69(s,3H),1.49(d,J=6.4Hz,3H). 19 F NMR(376MHz,CDCl3)δ -108.88(s,1H),-114.06(s,1H). Example 16 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)methanone (017)

[0231] [ka]

[0232] (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)methanone 017a (30 mg, 0.070 mmol), (4-chlorophenyl)boronic acid (16 mg, 0.11 mmol), Pd(dppf)Cl (10 mg, 0.014 mmol), and potassium carbonate (29 mg, 0.21 mmol) were added to a 10 mL microwave tube equipped with a stir bar. Tetrahydrofuran / water (5:1) (1:0.2 mL) solvent was then added, and the tube was evacuated, filled with nitrogen, and capped. The tube was sealed and heated to 80 °C with stirring for 2 h. The reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was concentrated and the residue was purified by silica gel column (petroleum ether / ethyl acetate=1:1) to obtain the crude product, which was then purified by reverse phase column (41% acetonitrile / water) to obtain (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)methanone 017 (7.36 mg, yellow solid), the yield was 22%.

[0233] MS m / z (ESI): 468.0 [M+1] + . 1H NMR(400MHz,CDCl3)δ 7.73(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=1 3.2Hz,1H),4.28(s,1H),4.07(s,1H),3.67(s,1H),2.69(s,3H),1.50(d,J=6.4Hz,3H). 19 F NMR(376MHz,CDCl3)δ -108.83(s,1H). Example 17 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)methanone (018)

[0234] [ka]

[0235] (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)methanone 018a (30 mg, 0.07 mmol) was dissolved in tetrahydrofuran / water = 4 / 1 (5 mL), and the solution was sequentially treated with 4-methoxybenzeneboronic acid (16 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol), and PdCl(dppf) (6 mg, 0.007 mmol). After the completion of the feed, the reaction mixture was reacted at 80°C for 2 hours under nitrogen gas protection. The filtrate was filtered and concentrated. The resulting residue was purified by reverse phase column chromatography (55% acetonitrile / water) to give (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)methanone 018 (8.6 mg, white solid). The yield was 26%.

[0236] MS m / z(ESI):464.2[M+H + ]. 1 H NMR(400MHz,CDCl3)δ 7.71(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). HPLC:99.25%(214nm),99.62%(254nm). 19 F NMR(376MHz,CDCl3)δ -109.02. Example 18 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)

[0237] [ka]

[0238] First step: 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)methanone A 10 mL microwave tube equipped with a stir bar was charged with (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)methanone 019a (30 mg, 0.070 mmol), (4-aminophenyl)boronic acid (14 mg, 0.11 mmol), Pd(dppf)Cl (10 mg, 0.014 mmol), and potassium carbonate (29 mg, 0.21 mmol), followed by the solvent tetrahydrofuran / water (5:1, 1 / 0.2 mL). The tube was evacuated, filled with nitrogen gas, and capped. The tube was sealed and heated to 80 °C for 2 h with stirring. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column (petroleum ether / ethyl acetate=1:1) to obtain (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)methanone 019b (30 mg, yellow solid). The yield was 88%.

[0239] MS m / z(ESI):449.3[M+1] + . Second Step: 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 (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)methanone 019b (35 mg, 0.20 mmol) and triethylamine (21 mg, 0.21 mmol) were dissolved in 2 mL of dichloromethane, and acetyl chloride (8 mg, 0.11 mmol) was slowly added dropwise to the solution. The reaction mixture was reacted at 25°C for 10 minutes and monitored by LCMS. After completion of the reaction, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase column (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), with a yield of 22%.

[0240] MS m / z (ESI): 491.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 10.08(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). 19 F NMR(376MHz,DMSO)δ -110.65(s,1H). Example 19 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)methanone (020)

[0241] [ka]

[0242] (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)methanone 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 PdCl(dppf) (6 mg, 0.008 mmol) were added in that order. After the feed was completed, the reaction mixture was reacted at 80°C for 2 hours under nitrogen gas protection. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified using a reverse phase column (55% acetonitrile / water) to give (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)methanone 020 (10.4 mg, white solid). The yield was 30%.

[0243] MS m / z (ESI): 440.1 [M+1] + 1 H NMR(400MHz,CDCl3)δ 7.50(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). HPLC:98.60%(214nm),98.40%(254nm). 19 F NMR(376MHz,CDCl3)δ -108.91. Example 20 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)methanone (021)

[0244] [ka]

[0245] (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)methanone 021a (35 mg, 0.08 mmol) was dissolved in dioxane (5 mL), and 4-(tri-n-butylstannyl)thiazole (33 mg, 0.088 mmol) and Pd(PPh3)4 (9.3 mg, 0.008 mmol) were added sequentially. After the feed was completed, the reaction mixture was reacted at 100 °C for 16 h under nitrogen gas protection. The reaction mixture was filtered, and the filtrate was concentrated. 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)methanone 021 (5.4 mg, white solid). The yield was 15%.

[0246] MS obsd.(ESI+):[(M+H) + ]=441.0. 1 H NMR(400MHz,MeOD)δ 9.07(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). HPLC:100%(214nm),99.51%(254nm). 19 F NMR (376 MHz, MeOD) δ −111.66. Example 21 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)methanone (022)

[0247] [ka]

[0248] (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)methanone 022a (44 mg, 0.10 mmol) was dissolved in 3 mL of DMA, and 1,3-oxazole (14 mg, 0.20 mmol), potassium acetate (29 mg, 0.30 mmol), and palladium acetate (2 mg, 0.01 mmol) were added in that order. Under nitrogen gas protection, the reaction mixture was heated to 135°C and reacted for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, and 30 mL of water was added. The mixture was extracted with ethyl acetate (2 x 40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated using a reversed-phase column (47% acetonitrile / water) and 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)methanone 022 (0.9 mg, pale yellow solid), with a yield of 2%.

[0249] MS m / z (ESI): 425.0 [M+1] + .

[0250] HPLC:96.85%(214nm),96.81%(254nm). 1H NMR(400MHz,CDCl3)δ 7.71(s,1H),7.50(dd,J=8.6,5.2Hz,2H),7.32-7.29(m,1H),7.16(t,J=8.6Hz,2H),5.16-5.08(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). Example 22 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)methanone (023)

[0251] [ka]

[0252] (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)methanone 023a (31 mg, 0.07 mmol) was dissolved in a mixture of 1,4-dioxane (2.5 mL) and water (0.8 mL), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-formate (41 mg, 0.14 mmol), potassium carbonate (29 mg, 0.21 mmol), and Pd(dppf)Cl (5 mg, 0.007 mmol) were added in this order. The reaction mixture was heated to 90°C under nitrogen gas protection and reacted for 4 hours. The reaction mixture was then cooled to room temperature, and 30 mL of water was added. The mixture was extracted with ethyl acetate (2 x 40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated on a silica gel column (petroleum ether / ethyl acetate = 1 / 3) and 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)methanone 023 (4.5 mg, white solid), yield 15%.

[0253] MS m / z (ESI): 424.1 [M+1] + .

[0254] HPLC:98.45%(214nm),98.68%(254nm). 1 H NMR(400MHz,CDCl3)δ 7.98(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). 19 F NMR(376MHz,CDCl3)δ -108.85. Example 23 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)methanone (024)

[0255] [ka]

[0256] First, in a 10 mL microwave tube equipped with a stir bar, (4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-ylmethanone 024a (60 mg, 0.14 mmol), methylboronic acid (25 mg, 0.42 mmol), Pd(dppf)Cl2 (15 mg, 0.032 mmol), and potassium carbonate (58 mg, 0.42 mmol) were added, and the solvent was dioxane / water (5:1, 2 / 0). 0.4 mL) was added. The tube was evacuated, filled with nitrogen gas, and capped. The tube was sealed and heated to 90 °C and stirred for 1 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated. Purification by reverse phase column (40% acetonitrile / water) gave (1,8-dimethyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 024b (29 mg, white solid).

[0257] In the second step, the resulting racemic product 024b was purified by SFC (CO₂ / MeOH (0.2% NH₄ . OH) to give (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)methanone 024 (6.63 mg, white solid), yield 23%.

[0258] MS m / z (ESI): 372.1 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.49-7.45(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). 19 F NMR(376MHz,CDCl3)δ -109.01(s,1H). Example 24 Preparation of ethyl (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 (025)

[0259] [ka]

[0260] (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)methanone 025a (15 mg, 0.04 mmol) was dissolved in 2 mL of dichloromethane, and triethylamine (8 mg, 0.08 mmol) and chloro(ethoxy)methanone (9 mg, 0.08 mmol) were added. The mixture was stirred at room temperature for 4 hours, and then the reaction solution was sequentially diluted with dichloromethane. The mixture was extracted with 10 mL of ethanol, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified using a reverse-phase column (50% acetonitrile / water) to give ethyl 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 (025) (2.39 mg, white solid). The yield was 13%.

[0261] MS.m / z(ESI):445.2[M+1] + .

[0262] 1 H NMR(400MHz,CDCl3)δ 7.51-7.46(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). HPLC:254nm(96.3%),214nm(98.6%). Example 25 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)methanone (026)

[0263] [ka]

[0264] (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)methanone 026a (50 mg, 0.11 mmol) was dissolved in 2 mL of tetrahydrofuran / water (3:1), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (16 mg, 0.02 mmol), potassium carbonate (23 mg, 0.17 mmol), and pyridin-4-ylboronic acid (15 mg, 0.12 mmol) were added. The mixture was stirred at 80°C for 4 hours under gas protection conditions, and the reaction mixture was extracted with 20 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under suction. The filtrate was concentrated under reduced pressure, and the resulting residue was purified using a reverse-phase column (50% 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)methanone (026) (25 mg, white solid), yield 50%.

[0265] MS m / z(ESI):435.1[M+1] + .

[0266] 1 H NMR(400MHz,CDCl3)δ 8.72(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). HPLC:254nm(96.1%),214nm(95.2%). Example 26 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)methanone (027)

[0267] [ka]

[0268] First step: Preparation of 4-bromopyrimidine 4-Oxopyrimidine 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 for 4 hours. The reaction mixture was cooled to room temperature and quenched by adding 20 mL of water. The mixture was extracted with ethyl acetate (2 x 40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 4-bromopyrimidine 027b (380 mg, orange oil) in a 27% yield.

[0269] 1 H NMR(400MHz,CDCl3)δ 8.96(s,1H),8.51(d,J=5.2Hz,1H),7.56(dd,J=5.6,1.2Hz,1H). Second step: Preparation of 4-(trimethylstannyl)pyrimidine 4-Bromopyrimidine 027b (318 mg, 2.00 mmol) was dissolved in dioxane, and hexamethylditin (655 mg, 2.00 mmol) and Pd(PPh3)4 (116 mg, 0.10 mmol) were added sequentially. The reaction mixture was heated to 110°C under nitrogen gas protection and reacted for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diatomaceous earth was added, and the solvent was removed by rotary evaporation. The resulting residue was purified on a neutral alumina column (6% ethyl acetate / petroleum ether) to give 4-(trimethylstannyl)pyrimidine 027c (180 mg, colorless oil) in a yield of 36%.

[0270] MS m / z (ESI): 245.0 [M+1] + .

[0271] 1 H NMR(400MHz,CDCl3)δ 9.24(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). Third step: 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 (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)methanone (35 mg, 0.08 mmol) was added to dioxane (6 mL), followed by 4-(trimethylstannyl)pyrimidine 027c (39 mg, 0.16 mmol) and Pd(PPh)Cl (7 mg, 0.008 mmol). The reaction mixture was heated to 120°C under nitrogen gas protection and reacted for 5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The resulting residue was separated on a silica gel column (65% ethyl acetate / petroleum ether) and purified on a reverse phase column (51% acetonitrile / water) to give (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)methanone 027 (7.2 mg, white solid), yield 20%.

[0272] MS m / z (ESI): 436.1 [M+1] + .

[0273] HPLC:99.34%(214nm),98.34%(254nm). 1H NMR(400MHz,CDCl3)δ 9.29-8.87(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,2H),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). 19 F NMR(376MHz,CDCl3)δ -108.61. Example 27 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)methanone (028)

[0274] [ka]

[0275] The 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)methanone 028a (35 mg, 0.008 mmol) was dissolved in tetrahydrofuran / water (4 / 1) (2.5 mL), and pyridazine-4-boronic acid pinacol ester (20 mg, 0.0096 mmol), potassium carbonate (51 mg, 0.24 mmol), and PdCl(dppf) (14.7 mg, 0.016 mmol) were added in this order. After the completion of the feed, the reaction mixture was stirred at 90°C for 3 hours under nitrogen gas protection, filtered, and the filtrate was concentrated. The resulting residue was purified by pre-HPLC (acetonitrile / water) to obtain compound 028 (9.3 mg, white solid), with a yield of 26%.

[0276] MS m / z (ESI): 436.1 [M+1] + 1H NMR(400MHz,CDCl3)δ 9.73(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). Example 28 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)methanone (029)

[0277] [ka]

[0278] The 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)methanone 029a (52.4 mg, 0.12 mmol) was dissolved in 2.5 mL of anhydrous dioxane, and the solution was sequentially treated with 3-aminopyridine (16 mg, 0.12 mmol), cesium carbonate (117 mg, 0.36 mmol), X-PHOS (11.4 mg, 0.024 mmol), and tris(dimethanone). After the addition of benzylideneacetone dipalladium (6 mg, 0.008 mmol), the reaction mixture was stirred at 120°C for 16 hours under nitrogen gas protection. The reaction mixture was filtered, and the filtrate was concentrated. 20 mL of water was added, followed by extraction with ethyl acetate (3 x 10 mL) and washing with saturated brine (3 x 10 mL). The resulting organic layer was concentrated, and the residue was purified by pre-HPLC (acetonitrile / water) to obtain compound 029 (7 mg, pale yellow solid). The yield was 13%.

[0279] MS m / z (ESI): 450.1 [M+1] + . HPLC (ENB200026-089-P1-A): 97.94% (214nm), 98.27% (254nm). 1 H NMR(400MHz,CDCl3)δ 8.32(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). 19F NMR(376MHz,CDCl3)δ -108.70. Example 29 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)methanone (030)

[0280] [ka]

[0281] (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)methanone 030a (60 mg, 0.14 mmol) was dissolved in 2.5 mL of dioxane, and 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) were added in that order. The reaction mixture was heated to 120 °C and reacted for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was separated by a silica gel column (70% ethyl acetate / petroleum ether) and purified by a reverse phase column (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)methanone 030 (2.7 mg, white solid), yield 5%.

[0282] MS m / z (ESI): 424.1 [M+1] + .

[0283] 1 H NMR(400MHz,MeOD)δ 8.06(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). 19 F NMR(376MHz,CDCl3)δ -111.44. Example 30 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)

[0284] [ka]

[0285] (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)methanone 031a (40 mg, 0.09 mmol) was dissolved in 2 mL of a tetrahydrofuran / water (3:1) mixed solvent, and the solution was sequentially treated with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (13 mg, 0.02 mmol), potassium carbonate (19 mg, 0.13 mmol), and 4-cyanophenyl The mixture was added with boronic acid pinacol ester (21 mg, 0.09 mmol), extracted with ethyl acetate, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified by reverse phase column (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%.

[0286] MS m / z.(ESI):459.1[M+1] + .

[0287] 1H NMR(400MHz,CDCl3)δ 7.93(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). HPLC:254nm(98.4%),214nm(99.2%). Example 31 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)methanone (032)

[0288] [ka]

[0289] First step: Preparation of (R)-tert-butyl 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)-carboxylate (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)methanone 032a (60 mg, 0.14 mmol) was dissolved in tetrahydrofuran / water = 4 / 1 (5 mL), and the solution was treated with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (65 mg, 0.21 mmol), potassium carbonate (58 mg, 0.42 mmol), and PdCl(dppf) (11 mg, 0.01 mmol) in the presence of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (65 mg, 0.21 mmol), potassium carbonate (58 mg, 0.42 mmol), and PdCl(dppf) (11 mg, 0.01 mmol). After the completion of the feed, the reaction mixture was reacted at 80°C for 2 hours under nitrogen gas protection, then filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain (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)-carboxylate tert-butyl 032b (70 mg, yellow oil), with a yield of 93%.

[0290] MS m / z ESI+): 539.2 [M+H] + . Second Step: 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)methanone (R)-tert-butyl 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)-carboxylate 032b (30 mg, 0.06 mmol) was dissolved in 3 mL of dichloromethane, and 0.3 mL of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 2 hours. After stirring for 1 h, the reaction mixture 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)methanone 032 (8.2 mg, pale yellow solid), yield 31%.

[0291] MS m / z(ESI+):439.1[M+1 + ]. 1 H NMR(400MHz,CDCl3)δ 9.83(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). 19 F NMR(376MHz,CDCl3)δ -75.72,-108.78. HPLC:100%(214nm),99.33%(254nm). Example 32 Preparation of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-morpholino-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (033)

[0292] [ka]

[0293] 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 Pd(dba) were dissolved in 2.5 mL of 1,4-dioxane and reacted at 100 °C in a microwave oven for 1 h. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel column (DCM:MeOH = 20:1) to give a pale yellow solid, which was then purified by prep-HPLC to give (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-1-morpholino-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 033 (3 mg, white solid), yield 2.8%.

[0294] MS m / z (ESI): 443.2 [M+1] + .

[0295] 1 H NMR(400MHz,DMSO-d6)δ 7.59(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). Example 33 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)acetamide (034)

[0296] [ka]

[0297] Compound 034a (230 mg, 0.62 mmol) and DIEA (239 mg, 1.85 mmol) were dissolved in 10 mL of DCM, and acetyl chloride (73 mg, 0.93 mmol) was added dropwise. After reacting at room temperature for 1 h, the reaction mixture was diluted with 10 mL of DCM, washed with 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 / HO (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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 034 (108 mg, white solid) in 41% yield.

[0298] MS m / z(ESI):415.3[M+1] + .

[0299] 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),7.58(dd,J=8.8,5.6Hz,2H),7.32(dd,J=8.8,5.6Hz,2H),5.97(s,1H),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). Example 34 Preparation of (R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-nitrile (035)

[0300] [ka]

[0301] (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)methanone 035a (30 mg, 0.070 mmol), zinc powder (0.46 mg, 0.0070 mmol), Pd(dppf)Cl (10 mg, 0.014 mmol), and zinc cyanide (8 mg, 0.070 mmol) were added to a 10 mL microwave tube equipped with a stir bar, and 2 mL of N,N-dimethylformamide solvent was added. The tube was evacuated, backfilled with nitrogen gas, and capped. The tube was sealed and heated to 135 °C and stirred for 2 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature, 20 mL of water was added, and extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) and then by reverse-phase column (42% acetonitrile / water) to give (R)-7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-nitrile 035 (4.47 mg, yellow solid), yield 16%.

[0302] MS m / z (ESI): 383.1 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.50-7.47(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). 19 F NMR(376MHz,CDCl3)δ -107.96. Example 35 (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)methanone (036)

[0303] [ka]

[0304] Compound 036a (40 mg, 0.11 mmol), paraformaldehyde (97 mg, 1.07 mmol), and anhydrous MgSO4 were dissolved in 5 mL of DCE and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (228 mg, 1.07 mmol) and a catalytic amount of AcOH were added and stirred at room temperature for 16 h. After filtration and rinsing the filter cake with 20 mL of DCM, the filtrate was concentrated and the resulting residue was purified by pre-HPLC (ACN / HO (0.1% FA) = 40%) to give compound 036 (5 mg, yellow solid) in 12% yield.

[0305] MS m / z (ESI): 387.2 [M+1] + .

[0306] 1 H NMR(400MHz,DMSO-d6)δ 7.57(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). Example 36 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)methanone (037)

[0307] [ka]

[0308] Compound 037a (50 mg, 0.13 mmol), paraformaldehyde (121 mg, 1.34 mmol), and anhydrous MgSO4 were dissolved in 5 mL of DCE and stirred at room temperature for 30 min. 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 then filtered and the filter cake was rinsed with 20 mL of DCM. The filtrate was concentrated, and the residue was purified by pre-HPLC (ACN / HO (0.1% FA) = 40%) to give compound 037 (10 mg, yellow solid) in 18% yield.

[0309] MS m / z (ESI): 401.1 [M+1] + .

[0310] 1 H NMR(400MHz,DMSO-d6)δ 7.55(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,1 H),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) Example 37 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)

[0311] [ka]

[0312] First step: 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)methanone (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)methanone 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 benzylthiol (56 mg, 0.45 mmol) were added in this order. The reaction mixture was heated to 120°C under nitrogen gas protection. ℃ The mixture was heated to rt and reacted for 40 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated. The resulting residue was separated on a silica gel column (33% ethyl acetate / petroleum ether) and purified on a reverse phase column (54% acetonitrile / water) to give (1-(benzylthio)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H))-(4-fluorophenyl)methanone 038b (85 mg, pale yellow solid), yield 58%.

[0313] MS m / z (ESI): 480.1 [M+1] + .

[0314] 1H NMR(400MHz,DMSO-d6)δ 7.54(s,2H),7.41-7.15(m,7H),5.43(br,1H),4.81(br,1H),4.27(br,1H),4.1 8-4.04(m,2H),3.80(br,1H),3.61(br,1H),2.65(s,3H),1.35(d,J=6.8Hz,3H). Second step: 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-sulfonyl chloride 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, water (9 mg, 0.48 mmol) was added, and the mixture was 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, and the reaction mixture was allowed to react at 0 °C for 30 minutes. After completion of the reaction, the mixture was quenched by adding 20 mL of saturated sodium bicarbonate, extracted with ethyl acetate (2 × 30 mL), and 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, and the yield was 50%.

[0315] MS m / z (ESI): 456.0 [M+1] + .

[0316] Third step: 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 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, and triethylamine (24 mg, 0.24 mmol) and aqueous ammonia (8 mg, 0.24 mmol) were added in that order, and the reaction mixture was reacted for 20 minutes at 25° C. After completion of the reaction, the mixture was quenched by adding 30 mL of saturated ammonium chloride, extracted with ethyl acetate (2×40 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated on a silica gel column (70% ethyl acetate / petroleum ether) and purified on a reverse phase column (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%.

[0317] MS m / z (ESI): 437.0 [M+1] + .

[0318] HPLC:99.72%(214nm),99.18%(254nm). 1 H NMR(400MHz,CDCl3)δ 7.52-7.43(m,2H),7.21-7.11(m,2H),6.35(br,1H),5.61(br,1H),5.16(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). 19 F NMR(376MHz,CDCl3)δ -107.80,-108.47. Example 38 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-formamide (039)

[0319] [ka]

[0320] First step: 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 (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)methanone 039a was dissolved in 5 mL of methanol, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (33.5 mg, 0.045 mmol) and triethylamine (9 mg, 0.09 mmol) were added in that order. Under the protection of carbon monoxide, the mixture was stirred at 80°C for 16 hours. After the reaction was completed, the solvent methanol was concentrated under reduced pressure, and the reaction mixture was extracted with 20 mL of dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under suction. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 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-carboxylate 039b (25 mg, yellow solid). The yield was 59%.

[0321] MS m / z.(ESI):416.1[M+1] + .

[0322] Second step: 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-carboxylic acid 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) mixed solvent, and lithium hydroxide (23 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 16 hours, and the reaction solution was adjusted to pH 5 with 2 M of hydrochloric acid. The mixture was adjusted, extracted with 20 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain 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), with a yield of 78%.

[0323] MS m / z.(ESI):402.2[M+1] + .

[0324] Third step: 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-formamide 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 was dissolved in 2 mL of N,N-dimethylformamide, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (34 mg, 0.06 mmol), N,N-diisopropylethylamine (12 mg, 0.09 mmol), and ammonium chloride (4 mg, 0.06 mmol) were added in that order. The mixture was stirred at room temperature for 2 hours, extracted with 10 mL of ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under suction. The filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (acetonitrile / water) to obtain 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-formamide 039 (6.7 mg, white solid). The yield was 27%.

[0325] MS m / z.(ESI):401.1[M+1] + .

[0326] 1 H NMR(400MHz,CDCl3)δ 7.48(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). HPLC:254nm(98.6%),214nm(98.6%). Example 39 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)

[0327] [ka]

[0328] First step: 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)methanone (R)-(4-Fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 040a (150 mg, 0.42 mmol) was dissolved in 5 mL of dichloromethane, and N-bromosuccinimide (89 mg, 0.50 mmol) was added. The mixture was allowed to react at room temperature for 1 hour, and then 20 mL of water was added. The mixture was extracted with 20 mL of dichloromethane. The residue was purified by silica gel column chromatography to obtain (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)methanone 040b (150 mg, yellow oil), yield 75%.

[0329] MS m / z (ESI): 436.0 [M+1] + . Second step, 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)methanone (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)methanone 040b (150 mg, 0.34 mmol), benzophenone imine (125 mg, 0.69 mmol), Pd(dppf)Cl (21 mg, 0.034 mmol), BINAP (21 mg, 0.034 mmol), and cesium carbonate (336 mg, 1.03 mmol) were added to a 10 mL microwave tube equipped with a stir bar. 2 mL of N,N-dimethylformamide was added, and the tube was evacuated, backfilled with nitrogen, and capped. The tube was then sealed and heated to 120 °C and stirred for 16 h. The reaction was monitored by LCMS, and after the reaction was completed, 040c was obtained, which was used directly in the next reaction without further purification.

[0330] MS m / z (ESI): 537.3 [M+1] + . Third step: 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)methanone (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)methanone 040c (150 mg, 0.28 mmol) was dissolved in 5 mL of tetrahydrofuran as a solvent, and concentrated hydrochloric acid (12 M, 0.1 mL, 1.40 mmol) was added. The reaction mixture was heated at 25°C. The reaction was allowed to proceed for 1 hour, and the tetrahydrofuran was removed by rotary evaporation. The resulting 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)methanone 040d (79 mg, yellow solid), with a yield of 70%.

[0331] Fourth Step: 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-(methylsulfonyl)methanesulfonamide (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)methanone 040d (30 mg, 0.081 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0° C. Triethylamine (46 mg, 0.45 mmol) and methanesulfonyl chloride (37 mg, 0.054 mmol) were added in this order, and the reaction mixture was reacted at 25° C. for 1 hour. After the reaction was completed, 20 mL of water was added, followed by extraction with 20 mL of dichloromethane (2×20 mL), followed by washing with 20 mL of saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration. The resulting residue was crude (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-(methylsulfonyl)methanesulfonamide 040e, which was used directly in the next reaction without further purification.

[0332] MS m / z (ESI): 529.1 [M+1] + . Fifth Step: 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 (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-(methylsulfonyl)methanesulfonamide 040e (30 mg, 0.057 mmol) was dissolved in 2 mL of tetrahydrofuran, and tetrabutylammonium fluoride (1 M in THF, 1 mL, 0.28 mmol) was added. The reaction mixture was reacted at 25° C. for 1 hour. After the reaction was completed, the mixture was diluted with 100 mL of ethyl acetate and washed five times with saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by reverse phase column (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%.

[0333] MS m / z (ESI): 451.1 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.49-7.45(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). 19 F NMR(376MHz,CDCl3)δ -108.66. Example 40 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)methanone (041)

[0334] [ka]

[0335] First step: 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)methanone (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)methanone 041a (400 mg, 0.92 mmol) was dissolved in N,N-dimethylformamide (6 mL), and tris(dibenzylideneacetone)dipalladium (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 in that order. After the feed was completed, the reaction solution was stirred at 100°C for 16 hours under nitrogen gas protection. The reaction solution was then extracted with ethyl acetate (20 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain 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)methanone 041b (80 mg, yellow solid). The yield was 14%.

[0336] MS m / z.(ESI):537.2[M+1] + .

[0337] Second step: 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)methanone (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)methanone 041b (80 mg, 0.15 mmol) was dissolved in 2 mL of dichloromethane, and 0.2 mL of concentrated hydrochloric acid was added. After the feed was completed, the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting 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)methanone 041 (35 mg, pale yellow solid), with a yield of 65%.

[0338] MS m / z.(ESI):373.1[M+1] + .

[0339] 1 H NMR(400MHz,CDCl3)δ 7.51-7.42(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). HPLC:254nm(90.1%),214nm(95.4%). Example 41 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)methanone (042)

[0340] [ka]

[0341] 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 and sequentially added with morpholine (6.5 mg, 0.075 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (29 mg, 0.075 mmol), and N,N-diisopropylethylamine (13 mg, 0.1 mmol). mol) was added and stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate (20 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure. The resulting 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)methanone 042 (4.3 mg, white solid), yield 16%.

[0342] MS m / z (ESI) 471.2 [M+1] + .

[0343] 1 H NMR(400MHz,CDCl3)δ 7.48(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). HPLC:254nm(91.3%),214nm(93.6%). Example 42 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)methanone (043)

[0344] [ka]

[0345] (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)methanone 043a (30 mg, 0.070 mmol), (2-methylpyridin-4-yl)boronic acid (19 mg, 0.14 mmol), Pd(dppf)Cl (10 mg, 0.014 mmol), and potassium carbonate (29 mg, 0.21 mmol) were added to a 10 mL microwave tube equipped with a stir bar, and the solvent tetrahydrofuran / water (5:1, 1 / 0.2 mL) was added. The tube was evacuated, backfilled with nitrogen gas, and capped. The tube was sealed and heated to 80 °C and stirred for 2 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated and the residue was purified by silica gel column (petroleum ether / ethyl acetate=1:1) to obtain the crude product, which was then purified by reverse phase column (38% acetonitrile / water) to obtain (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)methanone 043 (21.73 mg, white solid), the yield was 70%.

[0346] MS m / z(ESI):449.3[M+1] + . 1 H NMR(400MHz,CDCl3)δ 8.55(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). 19F NMR(376MHz,CDCl3)δ -108.66. Example 43 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)methanone (044)

[0347] [ka]

[0348] (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)methanone 044a (30 mg, 0.070 mmol), (2-fluoropyridin-4-yl)boronic acid (19 mg, 0.14 mmol), Pd(dppf)Cl (10 mg, 0.014 mmol), and KCO (29 mg, 0.21 mmol) were added to a 10 mL microwave tube equipped with a stir bar, and tetrahydrofuran / water (5:1, 1 / 0.2 mL) solvent was added. The tube was evacuated, backfilled with nitrogen, and capped. The tube was sealed and heated to 80 °C and stirred for 2 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated to dryness, and the residue was purified by silica gel column (petroleum ether / ethyl acetate=1:1) to obtain the crude product, which was then purified by reverse phase column (44% acetonitrile / water) to obtain (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)methanone 044 (15.89 mg, white solid), the yield was 51%.

[0349] MS m / z (ESI): 453.2 [M+1] + .

[0350] 1 H NMR(400MHz,CDCl3)δ 8.27(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). 19 F NMR(376MHz,CDCl3)δ -67.40,-108.52. Example 44 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)methanone (045)

[0351] [ka]

[0352] (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)methanone 045a (40 mg, 0.09 mmol), (3-methylpyridin-4-yl)boronic acid (15 mg, 0.11 mmol), Pd(dppf)Cl (13 mg, 0.01 mmol), and potassium carbonate (38 mg, 0.28 mmol) were dissolved in THF / HO=5:1 (2 mL), and the reaction mixture was heated at 80°C. After reacting for 2 hours, the reaction mixture was concentrated, and the resulting residue was purified by silica gel column (DCM:MeOH=20:1) to give a pale yellow solid, which was then purified by rep-HPLC to give 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)methanone 045 (7.8 mg, white solid), with a yield of 18.8%.

[0353] MS m / z (ESI): 449.2 [M+1] + .

[0354] 1 H NMR(400MHz,DMSO)δ 8.54(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). Example 45 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)methanone (046)

[0355] [ka]

[0356] (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)methanone 046a (40 mg, 0.09 mmol), 3-fluoro-4-borate-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), and the reaction solution was cooled to 80°C. After reacting at °C for 2 hours, the mixture was concentrated, and the resulting residue was purified by silica gel column (dichloromethane:methanol=20:1) to give a pale yellow solid, which was then purified by prep-HPLC to give 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)methanone 046 (6.3 mg, white solid), with a yield of 15%.

[0357] MS m / z (ESI): 454.1 [M+1] + .

[0358] 1 H NMR(400MHz,DMSO)δ 8.72(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). Example 46 Preparation of (R)-(1-(2,6-dimethylpyridin-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)methanone (047)

[0359] [ka]

[0360] (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)methanone 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 / HO = 5:1 (2 mL), and the reaction mixture was The mixture was reacted at 80°C for 2 hours and then concentrated. The resulting residue was purified by silica gel column (DCM:MeOH = 20:1) to give a pale yellow solid, which was then purified by prep-HPLC to give the title product, (R)-(1-(2,6-dimethylpyridin-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)methanone 047 (12 mg, white solid), with a yield of 37.5%.

[0361] MS m / z (ESI): 463.1 [M+1] + .

[0362] 1 H NMR(400MHz,DMSO-d6)δ 7.84(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). Example 47 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)methanone (048)

[0363] [ka]

[0364] (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)methanone 048a (30 mg, 0.08 mmol) was dissolved in 63 mg of 25% aqueous sulfuric acid, and the solution was cooled to 0 °C. NaNO (16.68 mg, 0.2418 mmol) dissolved in 1 mL of water was added dropwise to maintain the temperature between 0 °C and -10 °C. After the addition was complete, the ice-salt bath was removed, and the solution was stirred until it reached room temperature. The solution was then neutralized with a calculated amount of 40% aqueous sodium hydroxide solution, and the pH was adjusted to 7-8 using sodium bicarbonate. The solution was then evaporated to dryness in vacuo, and the crude product was purified by high performance liquid chromatography to obtain 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]pyrazin-7(8H)-yl)methanone 048 (12 mg, white solid), with a yield of 39.5%.

[0365] MS m / z (ESI): 374.1 [M+1] + .

[0366] 1 H NMR(400MHz,CDCl3)δ 7.90(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). Example 48 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-methoxy-1,5-dihydro-2H-pyrrol-2-one (049)

[0367] [ka]

[0368] (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)methanone 049a (28.00 mg, 0.064 mmol), cuprous iodide (6.11 mg, 0.032 mmol), and cesium carbonate (62.75 mg, 0.193 mmol). To a solution of trans-(1R,2R)N,N'-dimethylcyclohexane-1,2-diamine (1.13 mg, 0.013 mmol) and cesium fluoride (1.95 mg, 0.013 mmol) in 1,4-dioxane (2 mL), trans-(1R,2R)N,N'-dimethylcyclohexane-1,2-diamine (1.13 mg, 0.013 mmol) and 4-methoxy-1,3-dihydro-2H-pyrrol-2-one (14.52 mg, 0.128 mmol) were added. The mixture was heated to 120 °C under nitrogen gas protection and reacted for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 1:9). The crude product was further purified by reverse-phase flash 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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-4-methoxy-1,5-dihydro-2H-pyrrol-2-one 049 (4.30 mg, white solid), 14% yield. MS m / z (ESI): 469.1 [M+1] + .

[0369] 1H NMR(400MHz,CDCl3)δ 7.52(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). 19 F NMR(376MHz,CDCl3)δ -109.02. Example 49 (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), Preparation of (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)

[0370] [ka]

[0371] First step: Preparation of tert-butyl (R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (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), and di-tert-butyl dicarbonate (144 mg, 0.66 mmol) and triethylamine (89 mg, 0.88 mmol) were added in that order. The reaction was allowed to proceed at room temperature for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, water (50 mL) was added, and ethyl acetate was added. The mixture was extracted with ethanol (3 × 50 mL), washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure and purified on a silica gel column (petroleum ether / ethyl acetate = 2:3) to obtain the title product, tert-butyl (R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate 050b (270 mg, white solid). The yield was 94%.

[0372] MS m / z (ESI): 336.2 [M+1] + . Second step: Preparation of tert-butyl (R)-1-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (R)-8-Methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate tert-butyl 050b (270 mg, 0.80 mmol) was added to dichloromethane (5 mL) as a solvent, and N-bromosuccinimide (71 mg, 1.20 mmol) was added and reacted at room temperature for 1 hour. The reaction was monitored by LCMS. After completion of the reaction, water (220 mL) was added, extracted with ethyl acetate (3 × 20 mL), and washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column (petroleum ether / ethyl acetate = 1:1) to obtain 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)-carboxylate tert-butyl 050c (250 mg, white solid). The yield was 68%.

[0373] MS m / z(ESI):414.1[M+1] + . Third step: 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 (R)-1-Bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate tert-butyl 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 mixture was reacted at 25 °C for 1 hour. The reaction was monitored by LCMS. Upon completion, the dichloromethane was removed by rotary evaporation. Acetonitrile and water were added to the resulting residue, which was then lyophilized to give (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, yellow solid), yield 71%.

[0374] MS m / z (ESI): 314.0 [M+1] + . Fourth step, 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)methanone (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, and N,N-diisopropylethylamine (185 mg, 1.43 mmol) and 4-fluoro-1-benzofuran-7-carbonyl chloride (190 mg, 0.95 mmol) were added in that order, and the reaction mixture was reacted at 25° C. for 1 hour. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with dichloromethane (3×20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column (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)methanone 050e (150 mg, yellow solid), yield 61%.

[0375] MS m / z (ESI): 476.0 [M+1] + . Fifth Step, 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-fluorobenzofuran-7-yl)methanone To a 10 mL microwave tube equipped with a stir bar was added (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)methanone 050e (150 mg, 0.34 mmol), benzophenone imine (125 mg, 0.69 mmol), Pd(dppf)Cl (21 mg, 0.034 mmol), BINAP (21 mg, 0.034 mmol), and cesium carbonate (336 mg, 1.03 mmol), and the solvent N,N-dimethylformamide (2 mL) was added. The tube was evacuated, filled with nitrogen gas, and capped, and heated to 120°C with stirring for 16 h. The reaction was monitored by LCMS, and after completion of the reaction, 050f was obtained, which was used directly in the next reaction without further purification.

[0376] MS m / z (ESI): 557.3 [M+1] + . Sixth step, 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)methanone (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-fluorobenzofuran-7-yl)methanone 050f (140 mg, 0.24 mmol) was dissolved in 5 mL of tetrahydrofuran, and concentrated hydrochloric acid (12 M, 0.1 mL, 1.40 mmol) was added to the solution. The reaction mixture was stirred at 25°C. The reaction was allowed to proceed for 1 hour, and the tetrahydrofuran was removed by rotary evaporation. The resulting 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)methanone (50 mg, yellow solid), a yield of 47%.

[0377] MS m / z(ESI):413.2[M+1] + . Seventh step: 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 (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)methanone 050g (20 mg, 0.049 mmol) was dissolved in dichloromethane (3 mL), N,N-diisopropylethylamine (13 mg, 0.097 mmol) and acetyl chloride (12 mg, 0.015 mmol) were added in that order, and the reaction mixture was reacted at 25°C for 1 hour. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with 2 x 20 mL of dichloromethane, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse phase column (42% acetonitrile / water) to give (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%. The residue was purified by reverse phase column chromatography (45% acetonitrile / water) to give (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%.

[0378] 050 characteristic data: MS m / z(ESI):455.2[M+1]+. 1 H NMR(400MHz,CDCl3)δ 7.42-7.37(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). 19 F NMR(376MHz,CDCl3)δ -115.48. 051 characteristic data: MS m / z (ESI): 497.1 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.68(s,1H),7.41(s,1H),7.05(t,J=8.4Hz,1H),6.96(s,1H),5.98-5.82(m,1H),5.10-5.01(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). 19 F NMR(376MHz,CDCl3)δ -114.80. Example 50 (R)-(4-Fluorobenzofuran-7-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (052)

[0379] [ka]

[0380] First step: Preparation of 1-bromo-2-(3,3-diethoxypropoxy)-4-fluorobenzene 2-Bromo-5-fluorophenol 052a (5 g, 26.20 mmol) was added to N,N-dimethylformamide (50 mL), followed by 2-bromo-1,1-diethoxyethane (7.74 g, 39.30 mmol) and potassium carbonate (89 mg, 0.88 mmol). The reaction mixture was reacted under nitrogen gas protection at 120°C for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, water (100 mL), ethyl acetate (3×80 mL) were added, the extract was separated, and washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column (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), and the yield was 96%.

[0381] 1 HNMR(400MHz,DMSO)δ 7.62-7.58(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). Second step, preparation of 7-bromo-4-fluorobenzofuran 1-Bromo-2-(3,3-diethoxypropoxy)-4-fluorobenzene 052b (8.4 g, 26.25 mmol) was added to toluene (100 mL) and polyphosphoric acid (9 g, 52.5 mmol) was added. The reaction mixture was heated at 120 °C for 5 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was cooled to 0 °C and aqueous ammonia was slowly added dropwise until the pH of the mixture reached 10. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (3 × 80 mL). The mixture was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure and purified using a silica gel column (petroleum ether / ethyl acetate = 10:1) to give the title product, 7-bromo-4-fluorobenzofuran 052c (2 g, white solid). The yield was 44%.

[0382] 1 HNMR(400MHz,DMSO)δ 8.20(d,J=2.2Hz,1H),7.61-7.57(m,1H),7.24-7.21(m,1H),7.15-7.11(m,1H). Third step: Preparation of 7-methoxycarbonyl-4-fluorobenzofuran 7-Bromo-4-fluorobenzofuran 052c (1.00 g, 4.70 mmol) was dissolved in methanol (15 mL), followed by the addition of potassium acetate (1.38 g, 14.1 mmol) and Pd(dppf)Cl (340 mg, 0.40 mmol). The reaction mixture was stirred at 80 °C for 16 hours under a carbon monoxide atmosphere. The reaction was monitored by LCMS. After completion of the reaction, the methanol was removed by rotary evaporation, water (200 mL) was added, and the mixture was extracted with ethyl acetate (3 × 80 mL). The extract was washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure. The product was purified using a silica gel column (petroleum ether / ethyl acetate = 9:1) to give the title product 7-bromo-4-fluorobenzofuran 052d (700 mg, white solid). The yield was 56%.

[0383] MS m / z (ESI): 195.1 [M+1] +. Fourth step, preparation of 7-carboxylic acid-4-fluorobenzofuran 7-Methoxycarbonyl-4-fluorobenzofuran 052d (150 mg, 0.77 mol) was dissolved in tetrahydrofuran / water (5 mL) (v / v=4 / 1), and lithium hydroxide monohydrate (39 mg, 0.93 mol) was added, and the reaction mixture was reacted at 25° C. for 3 hours. The reaction was monitored by LCMS, and after completion, the reaction mixture was directly spun dry to give 7-carboxylic acid-4-fluorobenzofuran 052e, which was used directly in the next reaction without purification.

[0384] MS m / z (ESI): 181.2 [M+1] + . Step 5: Preparation of 7-chlorocarbonyl-4-fluorobenzofuran 7-Carboxylic acid-4-fluorobenzofuran 052e (120 mg, 0.67 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (396 mg, 3.33 mmol) and N,N-dimethylformamide (0.1 mL) were added sequentially. The reaction mixture was allowed to react at 25 °C for 0.5 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was spun down to give 7-chlorocarbonyl-4-fluorobenzofuran 052f, which was used directly in the next reaction without further purification.

[0385] MS m / z(ESI):181.2[M-Cl+1] + . Sixth step: Preparation of (R)-(4-fluorobenzofuran-7-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (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 052g (30 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (49 mg, 0.38 mmol) and 7-chlorocarbonyl-4-fluorobenzofuran 052f (25 mg, 0.13 mmol) were added, sequentially. The reaction mixture was allowed to react at 25°C for 0.5 hours. The reaction was monitored by LCMS. After completion of the reaction, water (20 mL) was added, extracted with dichloromethane (2 x 20 mL), washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse phase column (45% acetonitrile / water) to give (R)-(4-fluorobenzofuran-7-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 052 (30.42 mg, white solid), yield 59%.

[0386] MS m / z (ESI): 398.1 [M+1] + . 1 HNMR(400MHz,CDCl3)δ 7.66(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). Example 51 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)methanone (053)

[0387] [ka]

[0388] The 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)methanone 053a (30 mg, 0.067 g) was dissolved in tetrahydrofuran / water (2.5 mL) (4 / 1), and (2,6-difluoropyridin-4-yl)pyridineboronic acid (16.5 mg, 0.103 mmol), potassium carbonate (51 mg, 0.24 mmol), and PdCl(dppf) (14.7 mg, 0.016 mmol) were added in that order. After the feed was completed, the reaction mixture was stirred at 90 °C under nitrogen gas protection for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by pre-HPLC (acetonitrile / water) to obtain compound (053) (8.5 mg, white solid), with a yield of 26%.

[0389] MS m / z(ESI):[M+1] + :471.1 1H NMR(400MHz,cdcl3)δ 7.50(dd,J=8.5,5.2Hz,2H),7.38-7.26(m,1H),7.19(t,J=8.5Hz,1H),6.39(s,1H),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). Example 52 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)

[0390] [ka]

[0391] Compound 054a (40 mg, 0.11 mmol) and pyridine (17 mg, 0.21 mmol) were dissolved in DCM (4 mL), and trifluoroacetic anhydride (34 mg, 0.16 mmol) was added dropwise. After reacting at room temperature for 1 h, the reaction mixture was diluted with DCM (10 mL), washed with saturated aqueous NaHCO3, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by prep-HPLC (ACN / HO (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) in 22% yield.

[0392] MS m / z (ESI): 469.1 [M+1] + .

[0393] 1 H NMR(400MHz,DMSO-d6)δ 11.76(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). Example 53 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)methanone (055)

[0394] [ka]

[0395] Step 1: Preparation of 5-fluoropicolinic acid chloride 5-Fluoropicolinic acid 055a (80 mg, 0.57 mmol) was dissolved in dichloromethane (3 mL), and 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 mixture was concentrated to dryness to give 055b, which was used directly in the next reaction.

[0396] Second step, 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)methanone 5-Fluoropicolinic acid chloride (30.5 mg, 0.19 mmol) 055b was dissolved in dichloromethane (2 mL) and added dropwise to a solution of (R)-3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole (30 mg, 0.1275 mmol) and triethylamine (32.0 mg, 0.312 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 0.5 hours, and the reaction mixture was quenched with saturated ammonium chloride (2 mL) and saturated sodium bicarbonate (2 mL). Acetic acid was added to the resulting solution. The organic layers were combined, dried over sodium sulfate, filtered, and the organic phase was concentrated. The resulting residue was purified by silica gel column (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)methanone 055 (2.1 mg, white solid), yield: 5%.

[0397] MS m / z (ESI): 359.1 [M+1] + .

[0398] 1H NMR(400MHz,DMSO-d6)δ 8.67(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,1H),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). Example 54 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)methanone (056)

[0399] [ka]

[0400] First step: Preparation of 6-fluoronicotinyl chloride 6-Fluoropyridine-3-carboxylic acid 056a (50 mg, 0.35 mmol) was dissolved in dichloromethane (3 mL), and oxalyl chloride (225 mg, 1.75 mmol) and one drop of N,N-dimethylformamide were added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness to give 056b, which was used directly in the next reaction.

[0401] Second step: 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)methanone 6-Fluoronicotinyl chloride (30.5 mg, 0.19 mmol) 056b was dissolved in dichloromethane (2 mL) and added dropwise to a solution of (R)-3-methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-1,2,4-thiadiazole (30 mg, 0.1275 mmol) and triethylamine (32.0 mg, 0.312 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture 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 combined, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column (dichloromethane:methanol = 20:1) to give a pale yellow solid, which 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)methanone 056 (2.1 mg, white solid), in a yield of 5%.

[0402] MS m / z (ESI): 359.0 [M+1] + .

[0403] 1 H NMR(400MHz,DMSO)δ 8.43-8.41(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). Example 55 Preparation of (R)-(5-fluorothiophen-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (057)

[0404] [ka]

[0405] (R)-3-Methyl-5-(8-methyl-5,6,7,8-tetrahydroimidazo[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), and 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) were added in that order, and the reaction mixture was reacted at 25° C. for 3 hours. After completion of the reaction, the reaction was quenched with brine (40 mL) and extracted with ethyl acetate (2×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified using a reverse phase column (34% acetonitrile / water) to give (R)-(5-fluorothiophen-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 057 (2.6 mg, white solid), yield 5%.

[0406] MS m / z (ESI): 364.1 [M+1] + .

[0407] 1 H NMR(400MHz,DMSO)δ 7.42-7.37(m,1H),7.20(s,1H),6.84-6.83(m,1H),5.70-5.68(m,1H),4.93-4.90(m,1H),4.5 4(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). Example 56 Preparation of (R)-(5-fluorofuran-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (058)

[0408] [ka]

[0409] Step 1: Preparation of benzyl 5-nitrofuran-2-carboxylate 5-Nitrofuran-2-carboxylic acid 058a (3.00 g, 19.10 mmol) was added to N,N-dimethylformamide (30 mL), followed by the addition of benzyl bromide (4.90 g, 28.60 mmol) and potassium carbonate (7.92 g, 57.30 mmol). The reaction was monitored by LCMS for 16 hours at room temperature. After completion of the reaction, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 × 50 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure and purified using a silica gel column (petroleum ether / ethyl acetate = 10:1) to give the title product, benzyl 5-nitrofuran-2-carboxylate 058b (4.50 g, yellow solid). The yield was 97%.

[0410] 1 H NMR(400MHz,CDCl3)δ 7.46-7.37(m,5H),7.33(d,J=4.0Hz,1H),7.30(d,J=4.0Hz,1H),5.40(s,2H). Second step: Preparation of benzyl 5-fluorofuran-2-carboxylate Benzyl 5-nitrofuran-2-carboxylate 058b (2.50 g, 10.01 mmol) was added to sulfolane (30 mL), followed by potassium fluoride (2.93 g, 50.4 mmol) and tetraphenylphosphonium bromide (420 mg, 1.0 mmol), and the reaction mixture was heated at 140 °C for 2 hours. The reaction was monitored by LCMS. After completion of the reaction, the mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (3 × 80 mL). The mixture was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure and purified using a silica gel column (petroleum ether / ethyl acetate = 5:1) to give the title product, benzyl 5-fluorofuran-2-carboxylate 058c (400 mg, white solid). The yield was 17%.

[0411] MS m / z(ESI):243.0.(M+23). Third step, preparation of 5-fluorofuran-2-carboxylic acid Benzyl 5-fluorofuran-2-carboxylate 058c (200 mg, 0.91 mmol) was dissolved in methanol (5 mL), and Pd / C (10 mg, 0.091 mmol) was added thereto. The reaction mixture was placed under a hydrogen gas atmosphere and reacted at 25°C for 0.5 hours. The reaction was monitored by LCMS. Upon completion, the catalyst was removed by filtration, and the methanol was removed by evaporation. Acetonitrile and water were added to the resulting residue, which was then lyophilized to give 5-fluorofuran-2-carboxylic acid 058d (100 mg, white solid), in a yield of 78%.

[0412] MS m / z (ESI): 131.1 [M+1] + . Fourth step, preparation of (R)-(5-fluorofuran-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 5-Fluorofuran-2-carboxylic acid 058d (50 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 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) were added in that order. The reaction mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with dichloromethane (2 x 20 mL), washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by prep-HPLC to give (R)-(5-fluorofuran-2-yl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 058 (3.05 mg, yellow solid), yield 13%.

[0413] MS m / z (ESI): 348.2 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.15(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). 19 F NMR(376MHz,CDCl3)δ -108.67. Example 57 Preparation of (R)-(4-fluorophenyl)(1-(2-fluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (059)

[0414] [ka]

[0415] (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)methanone 059a (30 mg, 0.07 mmol), (2-fluorophenyl)boronic acid (10.6 mg, 0.08 mmol), potassium carbonate (19.0 mg, 0.14 mmol), and Pd(dppf)Cl (5.3 mg, 0.007 mmol) were dissolved in a tetrahydrofuran / water (5 / 1.6 mL) mixed solvent. The reaction mixture was protected with nitrogen gas 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 flash column chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain the crude product, which was then purified by reverse phase chromatography (55% acetonitrile / water) to obtain (R)-(4-fluorophenyl)(1-(2-fluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 059 (4.33 mg, white solid), yield 14%.

[0416] MS m / z (ESI): 451.5 [M+1] + .

[0417] 1 H NMR(400MHz,CDCl3)δ 7.69-7.65(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). Example 58 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-methylacetamide (060)

[0418] [ka]

[0419] First step: 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)acetamide Compound 060a (35 mg, 0.09 mmol) and triethylamine (28 mg, 0.28 mmol) were dissolved in dichloromethane (3 mL), and acetyl chloride (11 mg, 0.14 mmol) was added dropwise. The reaction mixture was allowed to react at room temperature for 1 h. The reaction mixture was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The filtrate 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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acetamide 060b (40 mg, yellow solid), yield 82%.

[0420] MS m / z(ESI):415.1[M+1] + . Second step: 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-methylacetamide Compound 060b (35 mg, 0.08 mmol) was dissolved in anhydrous THF (3 mL) and cooled to 0 °C. NaH (4 mg, 0.17 mmol, 60%) was added and the mixture was stirred at room temperature for 1 h. Iodomethane (24 mg, 0.17 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture 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 resulting residue was purified by pre-HPLC (ACN / HO (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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-N-methylacetamide 060 (14.2 mg, white solid), with a yield of 39%.

[0421] MS m / z (ESI): 429.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 7.60-7.57(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). Example 59 (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 methyl ester (061)

[0422] [ka]

[0423] (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)methanone 061a (80 mg, 0.21 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (83 mg, 0.64 mmol) and methyl chloroformate (30 mg, 0.32 mmol) were added, and the reaction mixture was reacted at 25° C. for 1 hour. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with 20 mL of dichloromethane, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse phase column 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-tetrahydroimidazo[1,5-a]pyrazin-1-ylcarbamate methyl 061 (40.00 mg, yellow solid), yield 41%.

[0424] MS m / z (ESI): 431.2 [M+1] + . 1 HNMR(400MHz,CDCl3)δ 7.52-7.48(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, s,3H),3.56-3.44(m,1H),2.68(s,3H),1.47(s,3H). 19 FNMR (376 MHz, CDCl3) δ -109.28. Example 60 Preparation of (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)(methyl)carbamate (062)

[0425] [ka]

[0426] Methyl (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 (30 mg, 0.070 mmol) was added to 2 mL of N,N-dimethylformamide solvent, cooled to 0°C, and sodium hydride (6.69 mg, 0.28 mmol, 60% in mineral oil) was added. The reaction mixture was reacted at 0°C for 10 minutes, and then iodomethane (15 mg, 0.10 mmol) was added and reacted at room temperature for 1 hour. After the reaction was completed, The mixture was quenched by adding 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, suction filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (40% acetonitrile / water) to give methyl (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)(methyl)carbamate 062 (24.74 mg, yellow oil), yield 80%.

[0427] MS m / z(ESI):445.2[M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.55-7.45(m,2H),7.22-7.13(m,2H),6.21-5.55m,1H),5.33-4.60(m,1H),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). 19 F NMR(376MHz,CDCl3)δ -108.98. Example 61 Preparation of (R)-(1-(2,6-difluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone (063)

[0428] [ka]

[0429] (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)methanone 063a (30 mg, 0.070 mmol), (2,6-difluorophenyl)boronic acid (33 mg, 0.21 mmol), Pd(dtbpf)Cl (9 mg, 0.014 mmol), and potassium phosphate (29 mg, 0.21 mmol) were added to a 10 mL microwave tube equipped with a stir bar, and dioxane / water (2 mL / 0.4 mL) solvent was added. The tube was evacuated, filled with nitrogen gas, and capped. The tube was sealed and heated to 90 °C in a microwave oven for 1 hour with stirring. After completion of the reaction, the reaction mixture was concentrated. The residue was purified by silica gel column (petroleum ether / ethyl acetate=1:1) to give the crude product, which was then purified by reverse phase column (38% acetonitrile / water) to give (R)-(1-(2,6-difluorophenyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 063 (3.45 mg, white solid), yield 10%.

[0430] MS m / z (ESI): 470.2 [M+1] + . 1H NMR(400MHz,CDCl3)δ 7.50-7.45(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). Example 62 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-methylmethanesulfonamide (064)

[0431] [ka]

[0432] First step: 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-(methylsulfonyl)methanesulfonamide Compound 064a (35 mg, 0.09 mmol) and triethylamine (28 mg, 0.28 mmol) were dissolved in dichloromethane (3 mL), and methanesulfonyl chloride (22 mg, 0.19 mmol) was added dropwise. After reacting at room temperature for 1 h, the reaction mixture was diluted with DCM (10 mL), washed with saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. After filtration, 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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-N-(methylsulfonyl)methanesulfonamide 064b (40 mg, yellow solid) in 64% yield.

[0433] MS m / z (ESI): 529.1 [M+1] + . Second Step: 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 Compound 064b (35 mg, 0.07 mmol) was dissolved in THF (3 mL), and TBAF (69 mg, 0.03 mmol, 1 M in THF) was added dropwise. After reacting at room temperature for 1 h, the reaction mixture was diluted with saturated NH4Cl solution, extracted with ethyl acetate (3 × 5 mL), and dried over anhydrous sodium sulfate. After filtration, 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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)methanesulfonamide 064c (25 mg, yellow solid) in 84% yield.

[0434] MS m / z (ESI): 451.2 [M+1] + . Third Step: 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-methylmethanesulfonamide 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 mixture was quenched with saturated NH4Cl (10 mL) solution, extracted with ethyl acetate (3 × 10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by pre-HPLC (ACN / HO (0.1% FA) = 45%) to obtain compound (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-methylmethanesulfonamide 064 (11.4 mg, white solid), with a yield of 44%.

[0435] MS m / z (ESI): 465.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 7.59(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). Example 63 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)ethylsulfonamide (065)

[0436] [ka]

[0437] (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)methanone 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), and the mixture was stirred for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated. The resulting residue was separated by a silica gel column (70% ethyl acetate / petroleum ether) and purified by a reverse phase column (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)ethylsulfonamide 065 (2.7 mg, white solid), yield 7%.

[0438] MS m / z (ESI): 465.1 [M+1] + .

[0439] 1 H NMR(400MHz,MeOD)δ 7.58-7.50(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). 19 F NMR (376 MHz, MeOD) δ −111.59. Example 64 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)methanone (066)

[0440] [ka]

[0441] Step 1: Preparation of ethyl 3-tert-butyl-1,2,4-thiadiazole-5-carboxylate Trimethylacetamide 066a (2.02 g, 20.00 mmol) and chlorocarbonylsulfinyl chloride (2.88 g, 22.00 mmol) were dissolved in dry toluene (15 mL), and the reaction mixture was reacted at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the reaction intermediate. The intermediate was dissolved in toluene (15 mL), and ethyl cyanoformate (3.96 g, 40.00 mmol) was added to the mixture. The reaction mixture was reacted at 130° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether / ethyl acetate=5 / 1) to obtain ethyl 3-tert-butyl-1,2,4-thiadiazole-5-carboxylate 066b (1.24 g, pale yellow oil), with a yield of 28%.

[0442] MS m / z (ESI): 215.1 [M+1] + .

[0443] 1 H NMR(400MHz,CDCl3)δ 4.51(q,J=7.2Hz,2H),1.49(s,9H),1.45(t,J=7.2Hz,3H). Second step: Preparation of 3-tert-butyl-1,2,4-thiadiazole-5-carboxylic acid Ethyl 3-tert-butyl-1,2,4-thiadiazole-5-carboxylate 066b (1.24 g, 5.79 mmol) was dissolved in a mixture 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. Tetrahydrofuran was removed by rotary evaporation, and excess lithium hydroxide was neutralized by the dropwise addition of 1 M hydrochloric acid 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) in 98% yield.

[0444] MS m / z (ESI): 187.1 [M+1] + .

[0445] 1 H NMR(400MHz,CD3OD)δ 1.43(s,9H). Third step: Preparation of 3-tert-butyl-N-[(3-methylpyrazin-2-yl)methyl]-1,2,4-thiadiazole-5-formamide 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) and three drops of DMF were added. The reaction mixture was reacted at 25 °C for 30 min. The reaction mixture was concentrated to remove excess oxalyl chloride and dissolved in dichloromethane (8 mL). The mixture 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 min. After completion of the reaction, the reaction mixture was washed once with saturated ammonium chloride (60 mL) and once with saturated sodium bicarbonate (60 mL). The resulting aqueous phase was further extracted with ethyl acetate (2 × 50 mL). The organic phases were all combined, dried over anhydrous sodium sulfate, and concentrated. The resulting 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-formamide 066d (1.28 g, yellow solid), with a yield of 75%.

[0446] MS m / z (ESI): 292.1 [M+1] + .

[0447] 1 H NMR(400MHz,CDCl3)δ 8.55(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). Fourth step: Preparation of 3-tert-butyl-5-{4-methylimidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole 3-tert-Butyl-N-[(3-methylpyrazin-2-yl)methyl]-1,2,4-thiadiazole-5-formamide 066d (1.21 g, 4.15 mmol) was dissolved in acetonitrile (24 mL), DMF (0.2 mL) was added, and phosphorus oxychloride (3.18 g, 20.76 mmol) was slowly added. 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), and the acid therein was neutralized with aqueous ammonia. The acetonitrile therein was removed by rotary evaporation, and the residue was extracted with dichloromethane (3 x 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated and purified using a silica gel column (dichloromethane / methanol = 33 / 1) to obtain 3-tert-butyl-5-{4-methylimidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole 066e (1.02 g, light brown solid), with a yield of 88%.

[0448] MS m / z (ESI): 274.1 [M+1] + .

[0449] 1 H NMR(400MHz,CDCl3)δ 9.21(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). Fifth step: 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 3-tert-Butyl-5-{4-methylimidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole 066e (1.20 g, 4.39 mmol) was dissolved in acetonitrile (20 mL), and potassium iodide (146 mg, 0.88 mmol) and 4-methoxybenzyl chloride (1.38 g, 8.78 mmol) were added sequentially. The reaction mixture was heated to 80° C. and reacted for 4 hours. The reaction mixture was cooled to room temperature, filtered to remove solids, and washed with acetonitrile (10 mL). The filtrate was concentrated to give 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, green solid), yield 60%, which was used directly in the next reaction.

[0450] MS m / z (ESI): 394.1 [M+1] + .

[0451] 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 The 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) and cooled to 0 °C. Acetic acid (5 drops) and sodium cyanoborohydride (551 mg, 8.77 mmol) were added sequentially. The reaction mixture was allowed to react at 0 °C for 30 minutes. After completion of the reaction, the mixture was quenched with water (10 mL) and the ethanol was removed by rotary evaporation. The residual solution was adjusted to pH 8 with saturated sodium bicarbonate and extracted with dichloromethane (2 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated and purified using a silica gel column (petroleum ether / ethyl acetate=11 / 9) to obtain 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, with a yield of 31%.

[0452] MS m / z (ESI): 398.2 [M+1] + .

[0453] 1 H NMR(400MHz,CDCl3)δ 7.30(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). Seventh step: Preparation of 3-tert-butyl-5-{4-methyl-4H,5H,6H,7H-imidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole 066 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 5 mL of trifluoroacetic acid. The reaction mixture was heated to 100°C and reacted for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and water (10 mL) was added thereto. Saturated sodium bicarbonate was slowly added to adjust the pH to 8. Extraction with dichloromethane (3×30 mL) was carried out, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 3-tert-butyl-5-{4-methyl-4H,5H,6H,7H-imidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole 066h (105 mg, light brown solid), yield 98%.

[0454] MS m / z (ESI): 278.1 [M+1] + .

[0455] Eighth step, 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)methanone 3-tert-Butyl-5-{4-methyl-4H,5H,6H,7H-imidazo[1,5-a]pyrazin-1-yl}-1,2,4-thiadiazole 066h (50 mg, 0.18 mmol) was dissolved in dichloromethane (6 mL), and triethylamine (46 mg, 0.45 mmol) and p-fluorobenzoyl chloride (37 mg, 0.23 mmol) were added, in that order. The reaction mixture was reacted at 25 °C for 20 minutes. After completion of the reaction, the mixture 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 resulting residue was separated and purified using a silica gel column (petroleum ether / ethyl acetate = 2 / 3) and further purified using a reverse phase column (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)methanone 066 (30.0 mg, white solid), yield 40%.

[0456] MS m / z (ESI): 400.1 [M+1] + .

[0457] HPLC:98.61%(214nm),97.08%(254nm). 1 H NMR(400MHz,CDCl3)δ 7.52-7.42(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). 19 F NMR(376MHz,CDCl3)δ -108.95. Example 65 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-ylazetidin-2-one (067)

[0458] [ka]

[0459] (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)methanone 067a (31 mg, 0.07 mmol) was dissolved in dioxane (2.5 mL), and 2-azetidinone (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) were added in this order. The reaction mixture was heated to 120°C and reacted for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was separated by a silica gel column (70% ethyl acetate / petroleum ether) and purified by a reverse phase column (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]azetidin-2-one 067 (16.1 mg, white solid), yield 54%.

[0460] MS m / z (ESI): 427.1 [M+1] + .

[0461] HPLC:99.81%(214nm),100%(254nm). 1H NMR(400MHz,CDCl3)δ 7.56-7.43(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). 19 F NMR(376MHz,CDCl3)δ -108.56. Example 66 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)pyrrolidin-2-one (068)

[0462] [ka]

[0463] (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)methanone 068a (40 mg, 0.09 mmol) was dissolved in 1,4-dioxane (2 mL), and pyrrolidin-2-one (100 mg, 0.19 mmol), potassium carbonate (38 mg, 0.28 mmol), cuprous iodide (1 mg, 0.005 mmol), 2-dicyclohexylphosphonium-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 in that order. The reaction was heated and stirred at 120°C for 16 hours under nitrogen gas protection. After completion of the reaction, the mixture was quenched by adding water, extracted with ethyl acetate (3 x 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 resulting residue was purified by 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 obtain (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)pyrrolidin-2-one 068 (6.53 mg, pale yellow solid), yield 15%.

[0464] MS m / z (ESI): 441.1 [M+1] + .

[0465] HPLC:90.94%(214nm),97.04%(254nm). 1H NMR(400MHz,CDCl3)δ 7.56-7.45(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). Example 67 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)

[0466] [ka]

[0467] (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)methanone 069a (40 mg, 0.09 mmol) was dissolved in dioxane (2.5 mL), and 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) were added in this order. The reaction mixture was heated to 120 °C and reacted for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was separated by a silica gel column (70% ethyl acetate / petroleum ether) and purified by a reverse phase column (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%.

[0468] MS m / z (ESI): 455.2 [M+1] + .

[0469] 1 H NMR(400MHz,MeOD)δ 7.58-7.56(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). 19 F NMR(376MHz,CDCl3)δ -104.97. Example 68 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)cyclopropanecarboxamide (070)

[0470] [ka]

[0471] (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)methanone 070a (30 mg, 0.081 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (100 mg, 0.24 mmol) and cyclopropanecarbonyl chloride (17 mg, 0.16 mmol) were added in that order, and the reaction mixture was reacted at 25° C. for 1 hour. After the reaction was completed, water (20 mL) was added in that order, and the mixture was extracted with dichloromethane (2×20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse 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)cyclopropanecarboxamide 070 (22.00 mg, yellow solid), yield 57%.

[0472] MS m / z (ESI): 441.2 [M+1] + . 1 HNMR(400MHz,CDCl3)δ 7.82(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). 19 FNMR (376 MHz, CDCl3) δ -109.38. Example 69 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-methylcyclopropanecarboxamide (071)

[0473] [ka]

[0474] (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)cyclopropanecarboxamide (070) (11 mg, 0.025 mmol) was added to N,N-dimethylformamide (2 mL), which was cooled to 0° C., and sodium hydride (60%, 2 mg, 0.054 mmol) was added. The reaction mixture was reacted at 0° C. for 10 minutes, and iodomethane (7 mg, 0.05 mmol) was added and reacted at room temperature for 1 hour. After the reaction was completed, the mixture was quenched by adding water (20 mL), extracted with ethyl acetate (2 × 20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column (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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-N-methylcyclopropanecarboxamide 071 (7.12 mg, white solid), yield: 60%.

[0475] MS m / z (ESI): 455.2 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.50-7.46(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). Example 70 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)

[0476] [ka]

[0477] (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)methanone 072a (48 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2 mL), and morpholin-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) were added. The reaction mixture was heated to 110 °C under nitrogen gas protection and reacted for 16 h. After completion of the reaction, 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 resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to obtain a crude product, which was then purified by reverse-phase column chromatography (acetonitrile / water = 30 / 70) to obtain (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%.

[0478] MS m / z (ESI): 457.2 [M+1] + .

[0479] HPLC: 95.26% (214nm), 97.45% (254nm).

[0480] 1 H NMR(400MHz,CDCl3)δ 7.53-7.44(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,4 H),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). Example 71 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)methanone (074)

[0481] [ka]

[0482] (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)methanone 074a (35 mg, 0.08 mmol), (2,3-difluoropyridin-4-yl)boronic acid (14.02 mg, 0.09 mmol), potassium carbonate (22.17 mg, 0.16 mmol), and Pd(dppf)Cl (5.87 mg, 0.008 mmol) were dissolved in a tetrahydrofuran / water (1:4, 2.5 mL) mixed solvent. The reaction mixture was protected with nitrogen gas, heated to 90 °C, and reacted for 5 hours. After the reaction was completed, the reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate=2 / 3) to obtain the crude product, which was further purified by reverse phase chromatography (69% acetonitrile / water) to obtain (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)methanone 074 (8.70 mg, white solid), yield: 23%.

[0483] MS m / z (ESI): 471.5 [M+1] + .

[0484] 1 H NMR(400MHz,CDCl3)δ 8.01(d,J=4.9Hz,1H),7.63(t,J=4.8Hz,1H),7.52-7.49(m,2H),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). Example 72 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)methanone (075)

[0485] [ka]

[0486] First step: Preparation of 3-fluoro-2-methyl-4-(trimethylstannyl)pyridine 4-Bromo-3-fluoro-2-methylpyridine 075a (57 mg, 0.30 mmol) was dissolved in dioxane (3 mL), and hexamethylditin (147 mg, 0.45 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) were added, in that order. Under nitrogen gas protection, the reaction mixture was heated to 110 °C and reacted for 4 hours. After the reaction was completed, the reaction 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 give 3-fluoro-2-methyl-4-(trimethylstannyl)pyridine 075b (59 mg, colorless oil) in 68% yield.

[0487] MS m / z (ESI): 276.0 [M+1] + .

[0488] 1 H NMR(400MHz,CDCl3)δ 8.22(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). Second Step: 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)methanone (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)methanone 075c (35 mg, 0.08 mmol) was dissolved in dioxane (3 mL), and 3-fluoro-2-methyl-4-(trimethylstannyl)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) were added in this order. The reaction mixture was heated to 90 °C under nitrogen gas protection and reacted for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched by adding potassium fluoride (1M, 10 mL), and extracted with ethyl acetate (2 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by a silica gel column (80% ethyl acetate / petroleum ether) and 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)methanone 075 (1.02 mg, white solid), yield 2%.

[0489] MS m / z (ESI): 467.1 [M+1] + .

[0490] HPLC:90.91%(214nm),86.82%(254nm). 1 H NMR(400MHz,CDCl3)δ 8.35(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). 19 F NMR(376MHz,CDCl3)δ -108.90. Example 73 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)methanone (076)

[0491] [ka]

[0492] First step: Preparation of 5-fluoro-2-methyl-4-(trimethylstannyl)pyridine 4-Bromo-5-fluoro-2-methylpyridine 076a (80 mg, 0.42 mmol) was dissolved in dioxane (3 mL), and hexamethylditin (207 mg, 0.63 mmol) and tetrakis(triphenylphosphine)palladium (49 mg, 0.04 mmol) were added, in that order. Under nitrogen gas protection, the reaction mixture was heated to 110 °C and reacted for 4 hours. After the reaction was completed, the reaction 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 give 5-fluoro-2-methyl-4-(trimethylstannyl)pyridine 076b (80 mg, colorless oil) in 66% yield.

[0493] MS m / z (ESI): 276.0 [M+1] + .

[0494] 1 H NMR(400MHz,CDCl3)δ 8.22(s,1H),7.16(d,J=2.8Hz,1H),2.52(s,3H),0.38(s,9H). Second Step: 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)methanone (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)methanone 076c (35 mg, 0.08 mmol) was dissolved in dioxane (3 mL), followed by 5-fluoro-2-methyl-4-(trimethylstannyl)pyridine 152b (33 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (9 mg, 0.008 mmol). The reaction mixture was heated to 120 °C under nitrogen gas protection and reacted for 48 h. After completion of the reaction, the mixture was cooled to room temperature and quenched by the addition of potassium fluoride (1 M, 10 mL) and extracted with ethyl acetate (2 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column (80% ethyl acetate / petroleum ether) and 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)methanone 076 (2.86 mg, white solid), yield 8%.

[0495] MS m / z (ESI): 467.1 [M+1] + .

[0496] HPLC:99.69%(214nm),99.56%(254nm). 1 H NMR(400MHz,CDCl3)δ 8.36(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). 19 F NMR(376MHz,CDCl3)δ -108.70. Example 74 (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)methanone (077)

[0497] [ka]

[0498] (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)methanone 077a (30 mg, 0.07 mmol) was dissolved in a mixture of tetrahydrofuran (2.4 mL) and water (0.6 mL), followed by the addition of 2,5-difluoropyridine-4-boronic acid (13 mg, 0.08 mmol), potassium carbonate (29 mg, 0.21 mmol), and Pd(dppf)Cl (5 mg, 0.007 mmol). Under nitrogen gas protection, the reaction mixture was heated to 90 °C and reacted for 3 hours. After completion of the reaction, the mixture was cooled to room temperature. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated on a silica gel column (50% ethyl acetate / petroleum ether) and purified on a reverse-phase column (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)methanone 077 (10.0 mg, white solid), yield 31%.

[0499] MS m / z (ESI): 471.1 [M+1] + .

[0500] HPLC:99.76%(214nm),99.49%(254nm). 1H NMR(400MHz,CDCl3)δ 8.08(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(br,1H),5.7 7(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). 19 F NMR(376MHz,CDCl3)δ -72.68,-72.74,-108.64. Example 75 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)methanone (078)

[0501] [ka]

[0502] (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)methanone 078a (30 mg, 0.069 mmol) was dissolved in 1,4-dioxane / water (4 / 1, 2 mL) and (5-fluoro-6-methoxypyridin-3-yl)boronic acid (18 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol), and Pd(dppf)Cl (5 mg, 0.007 mmol) were added in that order. The reaction mixture was heated and stirred at 95 °C for 2 hours under nitrogen gas protection. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 6) to obtain a crude product, which was then purified by reverse phase column separation (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)methanone 078 (9.38 mg, white solid), yield 28.20%.

[0503] MS m / z (ESI): 483.1 [M+1] + .

[0504] HPLC:99.76%(214nm),99.78%(254nm). 1 H NMR(400MHz,CDCl3)δ 7.96(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,1H),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). Example 76 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)methanone (079)

[0505] [ka]

[0506] The 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)methanone 079a (30 mg, 0.0688 mmol) was dissolved in tetrahydrofuran / water (4 / 1) (2.5 mL), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (24 mg, 0.089 mmol), potassium carbonate (51 mg, 0.24 mmol), and PdCl(dppf) (14.7 mg, 0.016 mmol) were added in this order. After the feed was completed, the reaction mixture was stirred at 90 °C for 3 hours under nitrogen gas protection. The reaction mixture was filtered, and the filtrate was concentrated. The resulting 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)methanone 079 (12 mg, white solid). The yield was 34%.

[0507] MS m / z(ESI):[M+1] + :503.1 1H NMR(400MHz,CDCl3)δ 8.78(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). Example 77 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)methanone (080)

[0508] [ka]

[0509] (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)methanone 080a (30 mg, 0.07 mmol) was dissolved in a mixture of tetrahydrofuran (2.4 mL) and water (0.6 mL), and 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 in that order. The reaction mixture was heated to 90 °C under nitrogen gas protection and reacted for 3 hours. After completion of the reaction, the mixture was cooled to room temperature. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was separated on a silica gel column (50% ethyl acetate / petroleum ether) and purified on a reverse-phase column (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)methanone 080 (12.0 mg, white solid), yield 37%.

[0510] MS m / z (ESI): 465.1 [M+1] + .

[0511] HPLC:99.33%(214nm),99.50%(254nm). 1 H NMR(400MHz,CDCl3)δ 8.21(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,1H),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). 19 F NMR(376MHz,CDCl3)δ -108.76. Example 78 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)acrylamide (081)

[0512] [ka]

[0513] (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)methanone 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 mixture was placed at -20°C, and acryloyl chloride (22 mg, 0.24 mmol) was added dropwise slowly. The reaction mixture was reacted at -20°C for 10 minutes. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with 20 mL of dichloromethane, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse phase column (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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)acrylamide 081 (15.00 mg, yellow solid), yield 43%.

[0514] MS m / z (ESI): 427.1 [M+1] + . 1HNMR(400MHz,CDCl3)δ 7.56-7.46(m,3H),7.19-7.15(m,2H),6.40-6.31(m,1H),6.26-6.11(m,2H),5.80-5.74(m,1 H),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). 19 FNMR (376 MHz, CDCl3) δ -109.26. Example 79 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-methylacrylamide (082)

[0515] [ka]

[0516] (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-methylacrylamide 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 mixture was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was quenched by adding 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, suction filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse 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)-N-methylacrylamide 082 (5.71 mg, white solid), yield 69%.

[0517] MS m / z (ESI): 441.1 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.46-7.43(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). Example 80 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)

[0518] [ka]

[0519] Pyridine-4-carbonyl chloride hydrochloride (17 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL) and potassium carbonate (17 mg, 0.12 mmol) was added under ice bath. 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)methanone 083a (15 mg, 0.04 mmol) was added. Under nitrogen gas protection, the reaction was stirred at 0 °C for 1 hour. After completion of the reaction, the mixture was quenched by adding water and 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 resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=40 / 60) to obtain a crude product, which was then purified by reverse phase 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%.

[0520] MS m / z (ESI): 478.2 [M+1] + .

[0521] HPLC:99.00%(214nm),99.64%(254nm). 1H NMR(400MHz,CDCl3)δ 8.81(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,2H),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). Example 81 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)

[0522] [ka]

[0523] (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)methanone 084a (20 mg, 0.045 mmol) was dissolved in dioxane (2.5 mL), and 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) were added in this order. The reaction mixture was heated to 120 °C and reacted for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was separated on a silica gel column (10% methanol / dichloromethane) and 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 4.3%.

[0524] MS m / z (ESI): 470.1 [M+1] + .

[0525] 1H NMR(400MHz,CDCl3)δ 7.49-7.42(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). Example 82 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)isoindolin-1-one (085)

[0526] [ka]

[0527] (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)methanone 085a (20 mg, 0.045 mmol) was dissolved in dioxane (2.5 mL), and 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) were added in that order. The reaction mixture was heated to 80°C and reacted for 6 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was separated on a silica gel column (70% ethyl acetate / petroleum ether) and purified on a reverse phase column (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)isoindolin-1-one 085 (8.2 mg, white solid), yield 35%.

[0528] MS m / z (ESI): 489.1 [M+1] + .

[0529] HPLC:98.67%(214nm),98.99%(254nm). 1H NMR(400MHz,CDCl3)δ 7.96-7.82(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). 19F NMR(376MHz,CDCl3)δ -109.22. Example 83 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-dihydroisoquinolin-1(2H)-one (086)

[0530] [ka]

[0531] (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)methanone 086a (20 mg, 0.045 mmol) was dissolved in dioxane (2.5 mL), and 3,4,4a,8a-tetrahydro-2H-isoquinolin-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) were added in this order. The reaction mixture was heated to 80°C and reacted for 6 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was separated using a silica gel column (70% ethyl acetate / petroleum ether) and purified using a reverse phase column (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-dihydroisoquinolin-1(2H)-one 086 (11.2 mg, white solid), yield 45%.

[0532] MS m / z (ESI): 503.1 [M+1] + .

[0533] 1H NMR(400MHz,CDCl3)δ 8.07(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). Example 84 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)

[0534] [ka]

[0535] (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)methanone 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 (5 mL), and 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 mixture was heated to 120 °C under nitrogen gas protection and reacted for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated to dryness, and the residue was purified by flash 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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)cyclopropanesulfonamide 087 (2.01 mg, white solid), yield: 6%.

[0536] MS m / z (ESI): 477.1 [M+1] + .

[0537] 1 H NMR(400MHz,CDCl3)δ 7.52-7.41(m,2H),7.20-7.08(m,2H),5.99(s,1H),5.05(d,J=14.1Hz,1H) ,4.24(s,1H),3.49(bs,2H),2.69(s,3H),1.60(s,4H),1.27-1.02(m,4H). 19 F NMR(376MHz,cdcl3)δ -108.71. Example 85 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)pyridineamide (088)

[0538] [ka]

[0539] Pyridine-2-carbonyl chloride hydrochloride (16 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL) and potassium carbonate (2 mg, 0.01 mmol) was added in an ice bath. 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)methanone 088a (28 mg, 0.08 mmol) was added. Under nitrogen gas protection, the reaction was stirred at 0 °C for 1 hour. After completion of the reaction, the mixture was quenched by adding water and 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 resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=40 / 60) to obtain a crude product, which was then purified by reverse phase 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)pyridineamide 088 (10.77 mg, white solid), yield 28.46%.

[0540] MS m / z (ESI): 478.1 [M+1] + .

[0541] HPLC:94.73%(214nm),99.57%(254nm). 1H NMR(400MHz,CDCl3)δ 9.94(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),7.19(t,J=8.6 Hz,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). Example 86 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-methoxyacetamide (089)

[0542] [ka]

[0543] (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)methanone 089a (50 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (52 mg, 0.40 mmol) and 2-methoxyacetyl chloride (29 mg, 0.27 mmol) were added, in that order. The reaction mixture was reacted at 25°C for 1 hour. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with 2 x 20 mL of dichloromethane, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse phase column (45% acetonitrile / water) to give (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 089 (25.00 mg, yellow solid), yield 41%.

[0544] MS m / z(ESI):445.2[M+1] + . 1 HNMR(400MHz,CDCl3)δ 8.33(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). Example 87 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-methoxy-N-methylacetamide (090)

[0545] [ka]

[0546] (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 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% in mineral oil) was added. The reaction mixture was reacted at 0°C for 10 minutes, and iodomethane (12 mg, 0.081 mmol) was added. The mixture was reacted at room temperature for 1 hour. After the reaction was completed, 20 mL of water was added. The mixture was quenched with ethyl acetate (2 × 20 mL), extracted with ethyl acetate, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using a reverse-phase column (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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-2-methoxy-N-methylacetamide 090 (5.19 mg, white solid), yield 41%.

[0547] MS m / z(ESI):459.2[M+1] + . 1 H NMR(400MHz,CDCl3)δ 7.49-7.46(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). Example 88 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-methyl-2-(methylamino)acetamide (091)

[0548] [ka]

[0549] First step: 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)amino)-2-oxyethyl(methyl)carbamate-tert-butyl (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 (22 mg, 0.05 mmol) was dissolved in dichloromethane (6 mL), and triethylamine (15 mg, 0.15 mmol) and di-tert-butyl dicarbonate (22 mg, 0.10 mmol) were added sequentially. The reaction mixture was reacted at 25° C. for 1 hour. After completion of the reaction, the reaction was quenched by adding saturated ammonium chloride (35 mL) and extracted with dichloromethane (2×40 mL). The organic phases were combined, 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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)amino)-2-oxyethyl(methyl)carbamate-tert-butyl 091a (27 mg, pale yellow oil) was obtained, with a yield of 94%.

[0550] MS m / z (ESI): 544.2 [M+1] + .

[0551] Second step: 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)(methyl)amino)-2-oxyethyl(methyl)carbamate-tert-butyl The obtained (R)-(2-((7-(4-fluorobenzoyl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl)amino)-2-oxyethyl(methyl)carbamate-tert-butyl ester 091a (25 mg, 0.05 mmol) was dissolved in DMF (3 mL). The mixture was cooled to 0°C in an ice bath, and potassium carbonate (32 mg, 0.23 mmol) and iodomethane (13 mg, 0.09 mmol) were added in this order. The reaction mixture was reacted at room temperature for 6 hours. After completion of the reaction, water (15 mL) was added to quench the reaction. The mixture was filtered and 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 (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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)(methyl)amino)-2-oxyethyl(methyl)carbamate-tert-butyl 091b (23 mg, colorless oil), yield 85%.

[0552] MS m / z (ESI): 558.2 [M+1] + .

[0553] Third step: 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-methyl-2-(methylamino)acetamide (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)(methyl)amino)-2-oxyethyl(methyl)carbamate-tert-butyl 091b (20 mg, 0.04 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was reacted at 25° C. for 1 hour. After the reaction was completed, saturated sodium bicarbonate (40 mL) was added to obtain a 100% ethyl acetate solution. The trifluoroacetic acid in the reaction mixture was neutralized and 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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-N-methyl-2-(methylamino)acetamide 091 (9.3 mg, pale yellow solid), with a yield of 56%.

[0554] MS m / z (ESI): 458.1 [M+1] + .

[0555] HPLC:98.84%(214nm),98.40%(254nm). 1 H NMR(400MHz,CD3OD)δ 7.63-7.53(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(br,1H),3.9 2-3.48(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). 19 F NMR(376MHz,CD3OD)δ -111.34. Example 89 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-methoxypropionic acid amide (092)

[0556] [ka]

[0557] (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)methanone 092a (30 mg, 0.081 mmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (31 mg, 0.16 mmol) and 3-methoxyacetyl chloride (20 mg, 0.16 mmol) were added in that order, and the reaction mixture was reacted at 25° C. for 1 hour. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with 20 mL of dichloromethane, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse phase column (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)-3-methoxypropionic acid amide 092 (15.00 mg, yellow solid), yield 39%.

[0558] MS m / z(ESI):459.2[M+1] + . 1 HNMR(400MHz,CDCl3)δ 8.13(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). Example 90 (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-methylpropionic acid amide (093)

[0559] [ka]

[0560] (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-methoxypropionic acid amide 092 (10 mg, 0.022 mmol) was added to N,N-dimethylformamide (2 mL), the mixture was cooled to 0° C., and sodium hydride (60%, 2 mg, 0.054 mmol) was added. The reaction mixture was cooled to 0° C. and reacted for 10 minutes. Iodomethane (9 mg, 0.065 mmol) was then added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was quenched by adding 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, suction filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column (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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-3-methoxy-N-methylpropionic acid amide 093 (4.78 mg, white solid), yield 46%.

[0561] MS m / z (ESI): 473.2 [M+1] + . 1H NMR(400MHz,CDCl3)δ 7.48-7.43(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,1 H),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). Example 91 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)benzoylamine (094)

[0562] [ka]

[0563] The 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)methanone 094a (20.00 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), and benzoyl chloride (15.10 mg, 0.11 mmol) and N,N-diisopropylethylamine (34.70 mg, 0.27 mmol) were added. The reaction mixture was protected with nitrogen gas 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 flash column chromatography (petroleum ether / ethyl acetate=4 / 1) to obtain the crude product, which was then purified by reverse phase chromatography (65% acetonitrile / water) 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)benzoylamine 094 (4.00 mg, white solid), yield: 16%.

[0564] MS m / z (ESI): 477.2 [M+1] + .

[0565] 1 H NMR(400MHz,CDCl3)δ 8.38(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). Example 92 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-methylbenzoylamine (095)

[0566] [ka]

[0567] (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)benzoylamine 094 (8.00 mg, 0.017 mmol), sodium hydride (60%, 2.02 mg, 0.084 mmol) were dissolved in DMF (3 mL) and reacted at 0° C. for 10 minutes. Iodomethane (4.77 mg, 0.034 mmol) was then added, and the reaction was continued at room temperature for 15 minutes. After the reaction was completed, it was quenched by adding water, extracted twice with dichloromethane, and dried over anhydrous sodium sulfate. The reaction solution was concentrated to dryness and 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-tetrahydroimidazo[1,5-a]pyrazin-1-yl)-N-methylbenzoylamine 095 (3.10 mg, white solid), yield: 36%.

[0568] MS m / z (ESI): 491.1 [M+1] + .

[0569] 1 H NMR(400MHz,CDCl3)δ 7.64-7.31(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). Example 93 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-pyrrol-2-one (096)

[0570] [ka]

[0571] First step: 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 (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-hydroxypyrrolidin-2-one 104 (9 mg, 0.02 mmol) was dissolved in dichloromethane (3 mL), triethylamine (10 mg, 0.10 mmol) and methanesulfonyl chloride (5 mg, 0.04 mmol) were added in that order, and the reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was quenched by adding saturated sodium bicarbonate (15 mL) and 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), with a yield of 96%.

[0572] MS m / z (ESI): 535.1 [M+1] + .

[0573] Second step, 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-pyrrol-2-one (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 completion of the reaction, the reaction mixture was cooled to room temperature and quenched by the addition of saturated ammonium chloride (30 mL) and extracted with ethyl acetate (2 x 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 [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-pyrrol-2-one 096 (5.67 mg, pale yellow solid), yield 61%.

[0574] MS m / z (ESI): 439.1 [M+1] + .

[0575] HPLC:98.05%(214nm),96.63%(254nm). 1 H NMR(400MHz,CD3OD)δ 7.62-7.55(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),4.94-4.88(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). 19 F NMR(376MHz,CD3OD)δ -111.64. Example 94 Preparation of (4-fluorophenyl)(8-methyl-3-(4-(trifluoromethyl)thiazol-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (097)

[0576] [ka]

[0577] First step: Preparation of ethyl 4-(trifluoromethyl)thiazole-2-carboxylate Compound 097a (5.86 g, 44 mmol) was dissolved in ethanol (70 mL), and 3-bromo-1,1,1-trifluoroacetone (7 g, 36.7 mmol) was added. The mixture was reacted at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (100 mL), washed with saturated NaCl solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (PE: EtOAc = 10:1) to give ethyl 4-(trifluoromethyl)thiazole-2-carboxylate 097b (5 g, colorless oily liquid) in 60% yield.

[0578] MS m / z (ESI): 226.1 [M+1] + . Second step, preparation of 4-(trifluoromethyl)thiazole-2-carboxylic acid Compound 097b (5 g, 22.2 mmol) was dissolved in ethanol (100 mL), and aqueous sodium hydroxide solution (60 mL, 1 M) was added. The mixture was reacted at 50°C for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in water and adjusted to pH 5 with dilute HCl (1 M). The reaction mixture was concentrated under reduced pressure, and the resulting solid was dissolved in a 10:1 DCM / MeOH (200 mL) mixture and stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 4-(trifluoromethyl)thiazole-2-carboxylic acid 097c (1.3 g, pale brown solid), with a yield of 28%.

[0579] MS m / z (ESI): 198.1 [M+1] + . Third step: Preparation of N-((3-methylpyrazin-2-yl)methyl)-4-(trifluoromethyl)thiazole-2-carboxylic acid amide Compound 097c (1 g, 5.1 mmol) was dissolved in dry DCM (30 mL), and oxalyl chloride (1.29 g, 10.2 mmol) and 5 drops of DMF were added. The mixture was allowed to react at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in DCM (30 mL). (3-Methylpyrazin-2-yl)methylamine (560 mg, 4.547 mmol) and triethylamine (1.38 g, 13.7 mmol) were added, and the mixture was allowed to react at room temperature for 2 h. The reaction mixture was poured into 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)thiazole-2-carboxylic acid amide 097d (1 g, yellow solid) in 65.7% yield.

[0580] MS m / z (ESI): 303.1 [M+1] + . Fourth step, preparation of 2-(8-methylimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole Compound 097d (1 g, 3.3 mmol) was dissolved in acetonitrile (30 mL), and PCl3 (2.53 g, 16.5 mmol) was added. The mixture was reacted at 90 °C for 36 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution and NaCl solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting 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) in 54.4% yield.

[0581] MS m / z (ESI): 285.1 [M+1] + . Fifth step, preparation of 7-(4-methoxybenzyl)-3-(4-(trifluoromethyl)thiazol-2-yl)imidazo[1,5-a]pyrazin-7-ium salt Compound 097e (150 mg, 0.53 mmol) was dissolved in acetonitrile (10 mL), and KI (87 mg, 0.53 mmol) and PMBCl (165 mg, 1.05 mmol) were added. The mixture was reacted at 90 °C for 6 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 7-(4-methoxybenzyl)-3-(4-(trifluoromethyl)thiazol-2-yl)imidazo[1,5-a]pyrazin-7-ium salt 097f (200 mg, reddish-brown oily liquid) in 65% yield.

[0582] MS m / z(ESI):405.2[M+1] + . Sixth step, preparation of 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole Compound 097f (200 mg, 0.49 mmol) was dissolved in ethanol (5 mL) and added with sodium cyanoborohydride (93 mg, 1.48 mmol) and a catalytic amount of AcOH at 0°C. The mixture was allowed to react at 0°C for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed with saturated NaHCO3 and NaCl solutions, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting 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 097g (80 mg, yellow solid) in a yield of 36%.

[0583] MS m / z(ESI):409.1[M+1] + . Seventh step, preparation of 2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole Compound 097g (330 mg, 0.81 mmol) was dissolved in TFA (10 mL) and reacted at 90° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (ACN:HO (0.1% FA) = 10%) to give 2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-(trifluoromethyl)thiazole 097h (100 mg, white solid), with a yield of 39%.

[0584] MS m / z (ESI): 289.2 [M+1] + . Eighth step, preparation of (4-fluorophenyl)(8-methyl-3-(4-(trifluoromethyl)thiazol-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone Compound 097h (100 mg, 0.35 mmol) was dissolved in DCM (10 mL), and TEA (105 mg, 1.04 mmol) and 4-fluorobenzoyl chloride (82 mg, 0.52 mmol) were added. The mixture was allowed to react at room temperature for 1 h. The reaction mixture was poured into saturated NaHCO3 solution, extracted with DCM, washed with saturated NaCl solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:PE=60%) to give (4-fluorophenyl)(8-methyl-3-(4-(trifluoromethyl)thiazol-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 097 (70 mg, white solid) in 44% yield.

[0585] MS m / z(ESI):411.1[M+1] + . 1H NMR(400MHz,CDCl3)δ 7.72(s,1H),7.50-7.45(m,2H),7.19-7.14(m,2H),7.02(s,1H),5.83-5.65(m,1H),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). 19 F NMR(376MHz,CDCl3)δ -64.15(s,3H),-108.96(s,1H). Example 95 Preparation of (4-fluorophenyl)(8-methyl-3-(4-methylthiazol-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (098)

[0586] [ka]

[0587] First step: Preparation of 4-methylthiazole-2-carbonyl chloride 4-Methylthiazole-2-carboxylic acid 098a (1.67 g, 11.60 mmol) was added to dichloromethane (10 mL), followed by oxalyl chloride (4 mL) and N,N-dimethylformamide (0.3 mL). The reaction mixture was allowed to react at 25 °C for 2 h. The reaction was monitored by LCMS. Upon completion, the solvent was spun down to give crude 4-methylthiazole-2-carbonyl chloride 098b.

[0588] Second step, preparation of 4-methyl-N-((3-methylpyrazin-2-yl)methyl)thiazole-2-carboxylic acid amide (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), and crude 4-methylthiazole-2-carbonyl chloride 098b dissolved in dichloromethane (10 mL) was slowly added dropwise thereto. The reaction mixture was reacted at 25° C. for 1 hour. The reaction was monitored by LCMS. After the reaction was completed, water (30 mL) was added. The mixture was added to a 100 ml column, extracted with dichloromethane (3×20 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column (petroleum ether / ethyl acetate=5:1) to obtain the title product, 4-methyl-N-((3-methylpyrazin-2-yl)methyl)thiazole-2-carboxylic acid amide 098c (1.76 g, yellow solid), with a yield of 67%.

[0589] MS m / z (ESI): 249.1 [M+1] + . Third step: Preparation of 4-methyl-2-(8-methylimidazo[1,5-a]pyrazin-3-yl)thiazole 4-Methyl-N-((3-methylpyrazin-2-yl)methyl)thiazole-2-carboxylic acid amide 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 gas protection. The reaction was monitored by LCMS, and upon completion, the solvent was spun off. Saturated sodium bicarbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (3 × 80 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column (petroleum ether / ethyl acetate = 5:1) to obtain the title product 4-methyl-2-(8-methylimidazo[1,5-a]pyrazin-3-yl)thiazole 098d (1.23 g, yellow solid), with a yield of 69%.

[0590] MS m / z (ESI): 231.1 [M+1] + . Fourth step: Preparation of 7-(4-methoxybenzyl)-8-methyl-3-(4-methylthiazol-2-yl)imidazo[1,5-a]pyrazin-7-ium 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-methoxybenzene (1.62 g, 10.60 mmol). The reaction mixture was reacted at 85 °C for 16 hours under nitrogen gas protection. The reaction was monitored by LCMS. Upon completion, the solvent was spun down to give the crude product, 7-(4-methoxybenzyl)-8-methyl-3-(4-methylthiazol-2-yl)imidazo[1,5-a]pyrazin-7-ium 098e (1 g, yellow solid), in a 49% yield.

[0591] MS m / z(ESI):351.1.(M). Fifth step, preparation of 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-4-methylthiazole 7-(4-Methoxybenzyl)-8-methyl-3-(4-methylthiazol-2-yl)imidazo[1,5-a]pyrazin-7-ium 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 incubated at 0°C for 0.5 hours under nitrogen gas protection. The reaction was monitored by LCMS, and upon completion, the solvent was spun off. Water (50 mL) was added, and the mixture was extracted with dichloromethane (3 × 20 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column (petroleum ether / ethyl acetate = 5:1) to obtain 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), with a yield of 73%.

[0592] MS m / z (ESI): 355.2 [M+1] + . Sixth step, preparation of methyl-2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole 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 gas protection. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was cooled to room temperature. The solvent was spin-dried to obtain a crude product, which was purified by reverse phase column (acetonitrile / water = 1:10) and lyophilized to obtain 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). The yield was 70%.

[0593] MS m / z (ESI): 235.1 [M+1]+ . Seventh step, preparation of (4-fluorophenyl)(8-methyl-3-(4-methylthiazol-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 4-Methyl-2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole (098g, 30 mg, 0.128 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (25 mg, 0.25 mmol) and 4-fluorobenzoyl chloride (30 mg, 0.192 mmol) were added. The reaction mixture was allowed to react at room temperature for 2 hours. The reaction was monitored by LCMS. After completion of the reaction, the solvent was spun to dryness to obtain the crude product, which was purified by reverse phase column (acetonitrile / water=1:10) and lyophilized to obtain the title product (4-fluorophenyl)(8-methyl-3-(4-methylthiazol-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 098 (18 mg, white solid), with a yield of 38%.

[0594] MS m / z (ESI): 357.1 [M+1] + . 1H NMR(400MHz,CDCl3)δ 7.47(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). Example 96 Preparation of ((4-fluorophenyl)(8-methyl-3-(5-methylthiazol-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (099)

[0595] [ka]

[0596] First step, preparation of 2-(chloromethyl)-3-methylpyrazine 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), and the reaction mixture was incubated at 80 °C for 16 h under nitrogen gas protection. The reaction was monitored by LCMS. Upon completion of the reaction, the solvent was spin-dried, water (150 mL) was added, and the mixture was extracted with dichloromethane (3 × 100 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered under reduced pressure. The filtrate was concentrated under reduced pressure and purified using a silica gel column (petroleum ether / ethyl acetate = 50:1) to give the title product, 2-(chloromethyl)-3-methylpyrazine 099b (3.20 g, colorless oil) in a 22% yield.

[0597] MS m / z (ESI): 143.2 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 8.45(d,J=2.0Hz,1H),8.38(d,J=2.0Hz,1H),4.71(s,2H),2.69(s,3H). Second step, preparation of 2-((3-methylpyrazin-2-yl)methyl)isoindoline-1,3-dione 2-(Chloromethyl)-3-methylpyrazine 099b (3.20 g, 22.44 mmol) was added to N,N-dimethylformamide (40 mL), and potassium phthalimide (6.23 g, 33.66 mmol) was added. The reaction mixture was reacted at 110 °C for 8 hours under nitrogen gas protection. The reaction was monitored by LCMS. After the reaction was completed, the solvent was spin-dried, water (150 mL) was added, and the mixture was extracted with ethyl acetate (3 × 100 mL). The extract was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure and purified using a silica gel column (petroleum ether / ethyl acetate = 1:1) to give the title product, 2-((3-methylpyrazin-2-yl)methyl)isoindoline-1,3-dione 099c (3.10 g, pale yellow solid). The yield was 95%.

[0598] MS m / z (ESI): 254.2 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 8.33(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). Third step: Preparation of (3-methylpyrazin-2-yl)methylamine 2-((3-Methylpyrazin-2-yl)methyl)isoindoline-1,3-dione 099c (2.00 g, 7.90 mmol) was added to ethanol (50 mL), and hydrazine hydrate (3.95 g, 79 mmol) was added. The reaction mixture was reacted at 80°C for 6 hours under nitrogen gas protection. The reaction was monitored by LCMS. Upon completion of the reaction, the solvent was spin-dried, water (150 mL) was added, and the mixture was extracted with dichloromethane / methanol (1 / 1, v / v, 50 mL). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure to give crude (3-methylpyrazin-2-yl)methylamine 099d (300 mg, yellow oil). The yield was 28%.

[0599] MS m / z (ESI): 124.3 [M+1] + . 1 H NMR(400MHz,CDCl3)δ 8.36(s,1H),8.33(d,J=2.4Hz,1H),4.02(s,2H),2.54(s,3H). Fourth step, preparation of 5-methyl-N-((3-methylpyrazin-2-yl)methyl)thiazole-2-carboxylic acid amide 5-Methylthiazole-2-carboxylic acid (280 mg, 1.94 mmol) was added to dichloromethane (10 mL), followed by oxalyl chloride (0.5 mL) and N,N-dimethylformamide (0.1 mL). The reaction mixture was allowed to react at room temperature for 0.5 hours. The reaction was monitored by LCMS. Upon completion, the solvent was spun down to give the crude product, 5-methylthiazole-2-carbonyl chloride.

[0600] (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-methylthiazole-2-carbonyl chloride dissolved in dichloromethane (5 mL) was slowly added dropwise to the mixture. The reaction mixture was allowed to react at room temperature for 0.5 hours. The reaction was monitored by LCMS. After the reaction was completed, water (30 mL) was added, the mixture was extracted with dichloromethane (3 × 20 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure and purified using a silica gel column (petroleum ether / ethyl acetate = 1:1) to give the title product, 5-methyl-N-((3-methylpyrazin-2-yl)methyl)thiazole-2-carboxylic acid amide 099e (170 mg, yellow solid). The yield was 40%.

[0601] MS m / z (ESI): 249.1 [M+1] + . Fifth step, preparation of 5-methyl-2-(8-methylimidazo[1,5-a]pyrazin-3-yl)thiazole 5-Methyl-N-(((3-methylpyrazin-2-yl)methyl)thiazole-2-carboxylic acid amide 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 gas protection. The reaction was monitored by LCMS. Upon completion of the reaction, the solvent was spun off. Sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 30 mL), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column (petroleum ether / ethyl acetate = 1:1) to obtain the title product, 5-methyl-2-(8-methylimidazo[1,5-a]pyrazin-3-yl)thiazole 099f (1.57 g, yellow solid), with a yield of 53%.

[0602] MS m / z (ESI): 231.0 [M+1] + . Step 6: Preparation of 7-(4-methoxybenzyl)-8-methyl-3-(5-methylthiazol-2-yl)imidazo[1,5-a]pyrazin-7-ium 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-methoxybenzene (1.75 g, 11.2 mmol). The reaction mixture was reacted at 85 °C for 6 hours under nitrogen gas protection. The reaction was monitored by LCMS. Upon completion, the solvent was spun down to afford the crude product, 7-(4-methoxybenzyl)-8-methyl-3-(5-methylthiazol-2-yl)imidazo[1,5-a]pyrazin-7-ium 099g (3.88 g, yellow oil), in a 98% yield.

[0603] MS m / z (ESI): 352.1 [M+1] + . Seventh step, preparation of 2-(7-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)-5-methylthiazole 7-(4-Methoxybenzyl)-8-methyl-3-(5-methylthiazol-2-yl)imidazo[1,5-a]pyrazin-7-ium 099g (3.88g, 0.011mol) was added to ethanol (10mL), followed by acetic acid (0.1mL) and sodium cyanoborohydride (2.07g, 0.033mmol). The reaction mixture was reacted under nitrogen gas protection at 0°C for 0.5 hours. The reaction was monitored by LCMS, and after completion, the solvent was spun off. Water (50 mL) was added, and the mixture was extracted with dichloromethane (3 × 20 mL), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure and purified on a silica gel column (petroleum ether / ethyl acetate = 1:1) to obtain 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), with a yield of 13%.

[0604] MS m / z (ESI): 355.2 [M+1] + . Step 8: Preparation of 5-methyl-2-(8-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole 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 heated at 90°C for 1 hour under nitrogen gas protection. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to room temperature. The solvent was spun off to obtain a filter cake. The filter cake was quenched with water (5 mL) and extracted with dichloromethane (2 x 5 mL). The organic phase was collected and spun off 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 used directly in the next step.

[0605] MS m / z (ESI): 235.1 [M+1] + . Step 9: Preparation of (4-fluorophenyl)(8-methyl-3-(5-methylthiazol-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 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), and triethylamine (151.79 mg, 1.50 mmol) and p-fluorobenzoyl chloride (238.52 mg, 1.50 mmol) were added, sequentially. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with dichloromethane (2 × 20 mL), washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by reverse-phase column (acetonitrile / water = 1:1) and further purified by Prep-HPLC to give (4-fluorophenyl)(8-methyl-3-(5-methylthiazol-2-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 099 (5.33 mg, white solid), the yield was 1.44%.

[0606] MS m / z (ESI): 357.1 [M+1] + . HNMR: 1 H NMR(400MHz,CDCl3)δ 7.49-7.44(m,3H),7.18-7.12(m,2H),6.95(s,1H),5.71(s,1H),4.99(dd,J=12.8,2.4Hz,1 H),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). 19 F NMR(376MHz,CDCl3)δ -109.14. Example 97 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-dihydroisoquinolin-3(2H)-one (100)

[0607] [ka]

[0608] (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)methanone 100a (50 mg, 0.114 mmol) was dissolved in dioxane (2.5 mL), and 3,4,4a,8a-tetrahydro-2H-isoquinolin-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) were added in this order. The reaction mixture was heated to 120 °C and reacted for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was separated on a silica gel column (70% ethyl acetate / petroleum ether) and purified on a reverse phase column (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-dihydroisoquinolin-3(2H)-one 100 (4.5 mg, pale yellow solid), yield 7.4%.

[0609] MS m / z (ESI): 503.1 [M+1] + .

[0610] 1H NMR(400MHz,CDCl3)δ 7.51-7.43(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). Example 98 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)

[0611] [ka]

[0612] (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)methanone 101a (20 mg, 0.04 mmol) was dissolved in dioxane (2.5 mL), and 1,3-oxazolidin-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) were added in that order. The reaction mixture was heated to 120 °C and reacted for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was separated on a silica gel column (70% ethyl acetate / petroleum ether) and purified on a reverse phase column (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%.

[0613] MS m / z (ESI): 443.1 [M+1] + .

[0614] 1H NMR(400MHz,CDCl3)δ 7.57-7.44(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). Example 99 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)

[0615] [ka]

[0616] (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)methanone 102a (20 mg, 0.046 mmol) was dissolved in dioxane (2.5 mL), and 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) were added in that order. The reaction mixture was heated to 120°C and reacted for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated. The resulting residue was separated using a silica gel column (70% ethyl acetate / petroleum ether) and purified using a reverse phase column (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)imidazolin-2-one 102 (4.2 mg, white solid), yield 20%.

[0617] MS m / z (ESI): 442.1 [M+1] + .

[0618] 1H NMR(400MHz,CDCl3)δ 7.65-7.36(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). Example 100 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-hydroxypyrrolidin-2-one (103)

[0619] [ka]

[0620] (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)methanone 103a (20 mg, 0.05 mmol) was dissolved in dioxane (3 mL), and (4R)-4-hydroxypyrrolidin-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) were added in that order. The reaction mixture was heated to 80 °C under nitrogen gas protection and reacted for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column (70% ethyl acetate / petroleum ether) and further purified by reverse phase column (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-hydroxypyrrolidin-2-one 103 (2.1 mg, white solid), yield 9.6%.

[0621] MS m / z (ESI): 457.1 [M+1] + .

[0622] HPLC:98.01%(214nm),93.64%(254nm). 1 H NMR(400MHz,MeOD)δ 7.57(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). 19F NMR(376MHz,MeOD)δ -111.71. Example 101 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-hydroxypyrrolidin-2-one (104)

[0623] [ka]

[0624] (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)methanone 104a (35 mg, 0.08 mmol) was dissolved in dioxane (3 mL), and (4S)-4-hydroxypyrrolidin-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) were added in that order. The reaction mixture was heated to 80 °C under nitrogen gas protection and reacted for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The residue was separated by silica gel column (70% ethyl acetate / petroleum ether) and further purified by reverse phase column (34% ACN / HO) 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-hydroxypyrrolidin-2-one 104 (21 mg, white solid), yield 55%.

[0625] MS m / z (ESI): 457.1 [M+1] + .

[0626] HPLC:98.94%(214nm),96.67%(254nm). 1H NMR(400MHz,CDCl3)δ 7.51(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). 19 F NMR(376MHz,CDCl3)δ -108.87. Example 102 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)

[0627] [ka]

[0628] (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-pyrrol-2-one 049 (4.20 mg, 0.009 mmol) was dissolved in acetonitrile (0.5 mL), and hydrogen chloride solution (1 mL, 1 M) was added. The mixture was heated to 65°C under nitrogen gas protection and reacted for 6 hours. The reaction was monitored by LCMS. After completion of the reaction, 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%.

[0629] MS m / z (ESI): 454.5 [M+1] + .

[0630] 1 H NMR(400MHz,CDCl3)δ 7.53-7.50 m,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). 19 F NMR(376MHz,CDCl3)δ -108.66. Example 103 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]pyrrolidin-2-one (106)

[0631] [ka]

[0632] (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-hydroxypyrrolidin-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 (diethylamino)sulfur trifluoride (7 mg, 0.04 mmol) was added. The reaction mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, saturated sodium bicarbonate (15 mL) was added to the mixture, followed by extraction with dichloromethane (2 × 20 mL). The organic phases were combined, washed sequentially 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]pyrrolidin-2-one 106 (2.24 mg, white solid), yield 21%.

[0633] MS m / z (ESI): 459.1 [M+1] + .

[0634] HPLC:96.57%(214nm),95.23%(254nm). 1 H NMR(400MHz,CD3OD)δ 7.61-7.53(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,2 H),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). 19 F NMR(376MHz,CD3OD)δ -111.72,-176.01. Example 104 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]pyrrolidin-2-one (107)

[0635] [ka]

[0636] (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-hydroxypyrrolidin-2-one 104 (9 mg, 0.02 mmol) was dissolved in dichloromethane (3 mL) and cooled to −78 °C in a dry ice / ethanol bath. Diethylaminosulfur trifluoride (7 mg, 0.04 mmol) was added. The reaction mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, saturated sodium bicarbonate (15 mL) was added to the mixture, which was then extracted with dichloromethane (2 × 20 mL). The organic phases were combined, washed sequentially 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-thiadiazol-5-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]pyrrolidin-2-one 107 (2.82 mg, white solid), 30% yield.

[0637] MS m / z (ESI): 459.1 [M+1] + .

[0638] HPLC:97.24%(214nm),97.61%(254nm). 1H NMR(400MHz,CD3OD)δ 7.57(dd,J=8.8,5.2Hz,2H),7.24(t,J=8.8Hz,2H),6.07(br,1H),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). 19 F NMR(376MHz,CD3OD)δ -111.65,-175.01. Example 105 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)

[0639] [ka]

[0640] (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 a 2 M solution of dimethylamine in tetrahydrofuran (2 mL) was added. 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 concentrated. The residue was purified using a reverse phase column [23% acetonitrile / water (0.05% formic acid)] to give (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), with a yield of 35%.

[0641] MS obsd.(ESI+):[(M+H) + ]458.1. HPLC:98.52%(214nm),99.15%(254nm). 1 H NMR(400MHz,CD3OD)δ 7.62-7.52(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). 19 F NMR(376MHz,CD3OD)δ -111.63. Example 106 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)

[0642] [ka]

[0643] First step: 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 (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)methanone 109a (112 mg, 0.30 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (76 mg, 0.75 mmol) and 2-chloroacetyl chloride (51 mg, 0.45 mmol) were added, sequentially. The reaction mixture was reacted at 25° C. for 20 minutes. After completion of the reaction, the reaction was quenched by adding saturated ammonium chloride (35 mL) and 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 (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%.

[0644] MS m / z (ESI): 449.1 [M+1] + .

[0645] Second step: 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 (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 a solution of methylamine in ethanol (33%, 1.5 mL) was added. The reaction mixture was heated to 60°C and reacted for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The residue was purified by reverse phase column chromatography [23% acetonitrile / water (0.05% formic acid)] 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)-2-(methylamino)acetamide 109 (23.4 mg, pale yellow solid), yield 52%.

[0646] MS m / z (ESI): 444.1 [M+1] + .

[0647] HPLC:99.55%(214nm),98.98%(254nm). 1 H NMR(400MHz,CD3OD)δ 8.52(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). 19 F NMR(376MHz,CD3OD)δ -111.61. Example 107 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-methylpyrrolidin-2-one (110)

[0648] [ka]

[0649] (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)methanone 110a (20 mg, 0.046 mmol) was dissol...

Claims

1. A compound of formula (I), a stereoisomer, tautomer, isotopically labeled compound, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof. 【Chemical 1】 The compound represented by formula (I) is a compound represented by formula (V) below: 【Chemistry 2】 (wherein M is N or CR ６ and R ５ , R ６ are the same or different and independently represent H, D (deuterium), halogen, -OR １１ , unsubstituted or optionally one or more R ｃ and selected from alkyl and cycloalkyl groups substituted with R １ is halogen, -CN, -NO ２ , -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 unsubstituted or optionally substituted with one or more R ａ an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group substituted with oxo, thio, halogen, —CN, or —NO ２ , -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 , unsubstituted or optionally one or more R ｃ substituted with one or more groups selected from alkyl groups substituted with one or more groups selected from cycloalkyl groups substituted with R ａ are the same or different and independently represent H, D, oxo, thio, halogen, —CN, —NO ２ , -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 unsubstituted or optionally substituted with one or more R ｃ and selected from alkyl groups substituted with Ar is an aryl group or a heteroaryl group, and the aryl group or heteroaryl group may optionally be one or more R ４ or optionally two adjacent or non-adjacent R ４ is unsubstituted or optionally substituted with one or more R ｂ may be linked to form a heteroaryl group substituted with R ４ are the same or different and independently represent H, halogen, —CN, —NO ２ , -OR １１ , -CO-R １２ , -CS-R １２ , -COO-R １３ , —O—CO—R １４ or unsubstituted or optionally substituted with one or more R ｂ and selected from alkyl and cycloalkyl groups substituted with 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 and independently represent H, halogen, —OH, unsubstituted or one or more R ｂ an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, or a heterocyclic group substituted with R １５ and R １６ , R １７ and R １８ , R １９ and R ２０ , R ２２ and R ２３ may be ring-formed to form a heterocyclic or heteroaryl group containing at least one N atom, said heterocyclic or heteroaryl group optionally being joined by one or more R ｂ and may be substituted with adjacent or non-adjacent R ｂ may be linked to form a ring to form a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, or the heteroaryl group may further be joined to form one or more R ｄ may be substituted with R ｂ , R ｃ are the same or different and independently represent H, D, oxo, thio, halogen, —CN, —NO ２ , -OR ３１ , -NR ３５ R ３６ or unsubstituted or optionally substituted with one or more R ｄ and selected from alkyl groups substituted with R ｄ are the same or different and independently represent H, oxo, thio, halogen, —CN, —NO ２ , -OR ３１ , -NR ３５ R ３６ , alkyl groups, a is 1 or 2; R ３１ , R ３５ , R ３６ are the same or different and are independently selected from H and alkyl groups, The "alkyl group" is C １－１０ The "alkenyl group" is a C ２－１０ The "alkynyl group" is an alkenyl group, and the "alkynyl group" is C ２－１０ The "cycloalkyl group" is an alkynyl group, and ３－１０ The "aryl group" is a C ６－１４ The "heteroaryl group" is a 5- to 14-membered heteroaryl group, and the "heterocyclic group" is a 3- to 10-membered heterocyclic group.

2. The R １ is a halogen, —CN, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a -cycloalkyl group-alkyl group, a -cycloalkyl group-CO-alkyl group, a —CO-alkyl group, a —CO-alkenyl group, a —CO-alkynyl group, a —CO-aryl group, a —CO-heteroaryl group, a —CO-cycloalkyl group, a —CO-heterocyclic group, a —COO-alkyl group, a —O—CO-alkyl group, —NH ２ , alkylamino group, dialkylamino group, -CONH ２ , —CONH-alkyl group, —CO—N(alkyl group) ２ , —NHCO-alkyl group, —NHCOO-alkyl group, —N(alkyl group)(—CO-alkyl group), —S(O) ２ -alkyl group, -S(O) ２ NH ２ , -S(O) ２ NH-alkyl group, —S(O) ２ N (alkyl group) ２ , -NHS(O) ２ -alkyl group, -SH, -S-alkyl group, wherein the alkyl group, alkenyl group, alkynyl group, and cycloalkyl group may be substituted with one or more halogen, oxo, hydroxy group, alkyl group, and alkoxy group; Alternatively, the R １ is -NR １５ R １６ where R １５ , R １６ are the same or different and are independently selected from H, an alkyl group, a cycloalkyl group, a hydroxy alkyl group, a hydroxy cycloalkyl group, and an -alkyl-O-alkyl group, wherein the alkyl group and cycloalkyl group may be substituted with one or more halogen, oxo, or hydroxy groups; Alternatively, the R １ is -NR １５ R １６ where R １５ , R １６ are linked to form a heterocyclic group containing at least one N atom, which is a 4- to 10-membered monocyclic or bicyclic heterocyclic group containing one N atom and optionally further containing 1 to 3 N, O, or S, and the N-containing heterocycle is selected from the group consisting of H, D, oxo, thio, halogen, —CN, —NO ２ , -OR ３１ , -NR ３５ R ３６ or unsubstituted or optionally substituted with one or more R ｄ and optionally adjacent or non-adjacent substituents on said N-containing heterocycle may form a ring to form a substituted or unsubstituted cycloalkyl group, heterocyclic group, aryl group or heteroaryl group; 2. A compound of formula (I) according to claim 1, its stereoisomer, tautomer, isotopically labeled form, nitrogen oxide, solvate or pharmaceutically acceptable salt.

3. The R １ is an aryl group, the aryl group being a phenyl group, a naphthyl group, an anthracenyl group, the aryl group being one or more R a may be substituted with Alternatively, the R １ is a heteroaryl group, and the heteroaryl group is a 4- to 10-membered monocyclic or bicyclic heteroaryl group optionally containing 1 to 5 atoms selected from N, O, and S, and the heteroaryl group is ａ may be substituted with Alternatively, the R １ is a heterocyclic group, and the heterocyclic group is a 4- to 10-membered monocyclic or bicyclic heterocyclic group optionally containing 1 to 5 atoms selected from N, O, and S, and the heterocyclic group is one or more R ａ may be substituted with, 10. A compound of formula (I) according to claim 1, a stereoisomer, a tautomer, an isotopically labeled compound, a nitrogen oxide, a solvate, or a pharmaceutically acceptable salt thereof.

4. The R １ is -NR １５ R １６ where R １５ , R １６ are linked to form an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolidinyl group, a pyrazolinyl group, an oxazolidinyl group, an isoxazolidinyl group, a thiazolidinyl group, an isothiazolidinyl group, a piperidinyl group, a tetrahydropyridine, a dihydropyridine, a piperazinyl group, a morpholinyl group, an oxazinyl group, a thiazinanyl group, an azepanyl group, or an azacyclooctyl group, and the heterocycle is selected from the group consisting of H, oxo, thio, F, Cl, Br, I, —OH, —CN, and —NO ２ , alkyl group, alkoxy group, haloalkyl group, —NH ２ , alkylamino groups, dialkylamino groups, or the adjacent or non-adjacent substituents on the heterocycle may be unsubstituted or ｄ a ring may be formed to form an indolinyl group, an isoindolinyl group, a dihydroquinolyl group, a tetrahydroquinolyl group, a dihydroisoquinolyl group, a tetrahydroisoquinolyl group, an oxazacyclooctyl group, an azabicyclohexyl group, an azabicycloheptane group, an azabicyclooctane group, an oxazabicyclohexyl group, an oxazabicycloheptane group, or an oxazabicyclooctane group, 10. A compound of formula (I) according to claim 1, a stereoisomer, a tautomer, an isotopically labeled compound, a nitrogen oxide, a solvate, or a pharmaceutically acceptable salt thereof.

5. R １ is an aryl group, the aryl group being a phenyl group, a naphthyl group, or an anthracenyl group, the aryl group being H, oxo, thio, F, Cl, Br, I, —OH, —CN, or —NO ２ , alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, —NH—CO-alkyl group, —CO—NH ２ , —CO—NH-alkyl group, —CO—N(alkyl group) ２ , —CO-alkyl group, —O—CO-alkyl group, —CO—O-alkyl group, —NH ２ , alkylamino groups, and dialkylamino groups; Or, R １ is a heteroaryl group, and the heteroaryl group is a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a quinolyl group, a quinazolinyl group, a cinnolinyl group, a pyrrolyl group, an indolyl group, an imidazolyl group, a benzimidazolyl group, a pyrazolyl group, a benzopyrazolyl group, a thienyl group, a benzothienyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, a benzoxazolyl group, a furyl group, or a benzofuryl group, and the heteroaryl group is H, D, oxo, thio, F, Cl, Br, I, —OH, —CN, —NO ２ , alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, —NH—CO-alkyl group, —CO—NH-alkyl group, —CO-alkyl group, —O—CO-alkyl group, —CO—O-alkyl group, —NH ２ , alkylamino groups, and dialkylamino groups; Or, R １ is a heterocyclic group, and the heterocyclic group is a morpholinyl group, a piperidinyl group, a dihydropyridine group, a tetrahydropyridine group, a piperazinyl group, a dihydropyrrole group, a pyrrolidinyl group, a 2H-pyranyl group, an azetidine group, an azepane group, an azacyclooctane group, an imidazolinyl group, an indolinyl group, an isoindolinyl group, a dihydroquinolyl group, a tetrahydroquinolyl group, a dihydroisoquinolyl group, a tetra ... The heterocyclic group is selected from the group consisting of H, D, oxo, thio, F, Cl, Br, I, —OH, —CN, and —NO. ２ , alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, —NH—CO-alkyl group, —CO—NH-alkyl group, —CO-alkyl group, —O—CO-alkyl group, —CO—O-alkyl group, —NH ２ , optionally substituted with 1 to 5 substituents selected from the group consisting of alkylamino groups and dialkylamino groups; 10. A compound of formula (I) according to claim 1, a stereoisomer, a tautomer, an isotopically labeled compound, a nitrogen oxide, a solvate, or a pharmaceutically acceptable salt thereof.

6. Ar is an aryl group, and the aryl group is a phenyl group, a naphthyl group, an anthracenyl group, and the aryl group is one or more R ４ may be substituted with Alternatively, Ar is a heteroaryl group, the heteroaryl group being a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, a quinolyl group, a quinazolinyl group, a cinnolinyl group, a pyrrolyl group, an indolyl group, an imidazolyl group, a benzimidazolyl group, a pyrazolyl group, a benzopyrazolyl group, a thienyl group, a benzothienyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, a benzoxazolyl group, a furyl group, a benzofuryl group, the heteroaryl group being selected from the group consisting of one or more R ４ may be substituted with, 10. A compound of formula (I) according to claim 1, a stereoisomer, a tautomer, an isotopically labeled compound, a nitrogen oxide, a solvate, or a pharmaceutically acceptable salt thereof.

7. The aryl group may be H, F, Cl, Br, I, —OH, —CN, or —NO ２ , alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, —CO-alkyl groups, —O—CO-alkyl groups, —CO—O-alkyl groups, The heteroaryl group may be H, F, Cl, Br, I, —OH, —CN, or —NO ２ , optionally substituted by 1 to 5 substituents selected from alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, —CO-alkyl groups, —O—CO-alkyl groups, and —CO—O-alkyl groups; 7. A compound of formula (I) according to claim 6, a stereoisomer, a tautomer, an isotopically labeled compound, a nitrogen oxide, a solvate, or a pharmaceutically acceptable salt thereof.

8. The compound represented by formula (I) is a compound represented by the following formula (VA) or formula (VB): 【Chemistry 3】 Ar, R １ , R ５ , M is defined in claim 1; 10. A compound of formula (I) according to claim 1, a stereoisomer, a tautomer, an isotopically labeled compound, a nitrogen oxide, a solvate, or a pharmaceutically acceptable salt thereof.

9. The compound of formula (I) may be a compound of formula (VI): 【Chemistry 4】 Alternatively, it may be a compound of formula (VI-A) or formula (VI-B) below: 【Chemistry 5】 (where R １ , R ５ , M is as defined in claim 1.

10. A compound of formula (I) according to claim 1, a stereoisomer, a tautomer, an isotopically labeled compound, a nitrogen oxide, a solvate, or a pharmaceutically acceptable salt thereof.

10. The following specific compounds, their stereoisomers, tautomers, isotopically labeled compounds, nitrogen oxides, solvates, or pharmaceutically acceptable salts: 【Chemistry 6】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

11. 2. A process for preparing a compound of claim 1, which comprises reacting a compound of formula (X) with a compound of formula (XI) in the presence of a base to obtain a compound of formula (I). 【Chemistry 7】 (where R １ , R ２ , R ３ , R′, ring A, and n are defined in claim 1 ; ７ is a halogen or hydroxy group.

12. A process for preparing the compound of claim 1, comprising: The compound of formula (I-4) can be prepared by reacting the compound of formula (I-2) with ammonia having a protecting group, and then removing the protecting group to obtain the compound of formula (I-3). ９ -X to obtain a compound of formula (I-4), 【Chemistry 8】 (wherein ring A, R ２ , R ３ , R′, n are as defined in claim 1, X is halogen, R ９ are the same or different and independently represent H, —OH, unsubstituted or optionally one or more R ｂ is selected from an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heteroaryl group, and a heterocyclic group substituted with Or, The compound of formula (I-5) is a compound of formula (I-2) and R １ａ -H to obtain a compound of formula (I-5), 【Chemistry 9】 (wherein ring A, R ２ , R ３ , R′, n are as defined in claim 1, X is halogen, R １ａ is -NR １５ R １６ or a heteroaryl group, R １５ and R １６ are ring-formed to form an N-containing heterocyclic or heteroaryl group, said heterocyclic or heteroaryl group optionally containing one or more R ｂ and may be substituted with adjacent or non-adjacent R ｂ are linked to each other and are unsubstituted or are linked to one or more R ｄ A ring may be formed to form a cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group substituted with Or, The compound of formula (I-6) is a compound of formula (I-2) and R １ｂ -Y to obtain a compound of formula (I-6), 【Chemistry 10】 (wherein ring A, R ２ , R ３ , R′, n are as defined in claim 1, X is halogen, R １ｂ is a cyano group, an alkyl group, an aryl group, or a heteroaryl group, and Y is —B(OH) ２ , -Sn(alkyl group) ３ , or 【Chemistry 11】 It is.) Preparation method.

13. An intermediate having the structure of formula (XIV): 【Chemistry 12】 (where R ５ is defined in claim 1. Intermediate.

14. The intermediate is a compound of formula (XV): 【Chemistry 13】 Alternatively, it is a compound of the following formula (XV-A) or formula (XV-B): 【Chemistry 14】 14. The intermediate of claim 13.

15. One, two or more of the compound of formula (I) of claim 1, its stereoisomer, tautomer, isotopically labeled form, nitroxide, solvate, or pharmaceutically acceptable salt; at least one pharmaceutically acceptable adjuvant; 10. A pharmaceutical composition comprising:

16. Use of one, two or more of the compound of formula (I) according to claim 1, its stereoisomer, tautomer, isotopically labeled form, nitroxide, solvate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, in the preparation of a medicament, wherein the medicament is used for preventing and / or treating an NK-3 receptor mediated disease.

17. Use of one, two or more of the compound of formula (I) as defined in claim 1, its stereoisomer, tautomer, isotopically labeled form, nitroxide, solvate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition as defined in claim 15, in the preparation of a medicament for preventing and / or treating depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorder, cognitive impairment, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsions, obesity, inflammatory diseases, vomiting, pre-eclampsia, airway-related diseases, reproductive disorders, contraception and sex hormone-dependent diseases, gynecological diseases, and menopausal syndrome-related diseases.

18. The sex hormone-dependent diseases 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, abnormal puberty, uterine fibrosis, uterine fibroma, hormone-dependent cancer, hyperandrogenemia, hirsutism, virilization, polycystic ovarian syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome, ovarian theca cell hyperplasia, other manifestations of high ovarian androgen levels, androgen-secreting tumors, menorrhagia, and adenomyosis; The airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction, and cough; 18. The use according to claim 17, wherein the menopausal symptoms include hot flashes, sweating, palpitations, dizziness and obesity.

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