Fused ring compounds, methods for their preparation, pharmaceutical compositions, and uses thereof

Abstract

The present invention relates to fused ring compounds, their preparation methods, pharmaceutical compositions, and uses thereof. The fused ring compounds have the structural features represented by formula (I). These fused ring compounds are somatostatin receptor subtype 4 (SSTR4) agonist compounds with a novel structure, better efficacy, high bioavailability, and better solubility. [C1] TIFF2023526791000180.tif34156

Description

[Technical Field]

[0001] The present invention relates to organic compounds, in particular to fused ring compounds, their preparation methods, pharmaceutical compositions, and their uses. [Background technology]

[0002] Somatostatin receptors (SSTRs) are a family of G protein-coupled receptors that mediate the action of somatostatin and its analogs and exert a variety of biological effects. Their physiological functions and mechanisms have long been of interest. Research has shown that these specific membrane receptors, including SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, play important roles in biological processes such as regulating growth hormone (GH) secretion, inducing cell apoptosis, inhibiting tumor cell proliferation, inhibiting insulin action, and inhibiting cell proliferation via cAMP, PTP, and MAPK signaling pathways, while exhibiting kinetic characteristics similar to those of other G protein-coupled receptors.

[0003] Somatostatin (SST) is a cyclic polypeptide widely distributed in the central nervous system and peripheral tissues. It exists in two forms in vivo: a 14-peptide (SST-14) and a 28-peptide (SST-28) form. Research indicates that SST signaling is mediated by the SST receptor family on the cell membrane. SST exists in only two forms. The complexity of SST's physiological function is reflected by the complexity of its receptor. Therefore, the biological importance of SSTRs is somewhat greater than that of SSTs. SSTRs are structurally similar to other G protein-coupled receptors, possessing seven transmembrane (TM) α-helical structures and possessing N-glycosylation and palmitoylation sites (except for SSTR3) in the N-terminal region. Furthermore, TM7 contains a unique and highly conserved amino acid sequence unique to SSTRs.

[0004] SSTRs are coupled to various cellular effector systems via G proteins and are involved in four important signal transduction pathways: the cyclic adenylate (cAMP) pathway; the voltage-dependent Ca pathway; 2+ The third is the mitogen-activated protein kinase (MAPK) pathway. The fourth is the protein tyrosine phosphatase (PTP) pathway.

[0005] SSTR1 is involved in the inhibition of cell proliferation. SSTR3, in addition to inducing apoptosis, is also involved in the suppression of GH and insulin release, the processing and regulation of sensory signals, and the integration of sensory and visceral functions, olfactory and other sensory functions. SSTR4, on the other hand, inhibits GH and insulin release and coordinates extrapyramidal motor and sensory functions. SSTR2 and SSTR5 play a key role in regulating animal growth, primarily inhibiting GH and insulin release and participating in central integration. They also mediate anti-tumor effects, including anti-proliferative and apoptotic effects, and are the primary subtypes mediating anti-tumor effects. These results reveal a close relationship between endocrinology and immunity.

[0006] Among these five receptors, SSTR4 has come to the forefront as a potential mediator in central nervous system pathology, inflammation, and even pain mechanisms. Targeting SSTR4 has the added advantage of limiting pituitary secretion without inhibiting glucagon, growth hormone, or insulin secretion. In the central nervous system, SSTR4 is expressed at relatively high levels in the hippocampus and neocortex, areas of memory and learning, and in Alzheimer's disease pathology. Recent studies have shown that SSTR4 agonists can improve learning and memory in rodent models of Alzheimer's disease, which corresponds to a reduction in β-amyloid levels. Furthermore, studies have further found that SSTR4 receptor stimulation can enhance cue recall in a dose-dependent manner, potentially possessing direct cognitive-enhancing activity. Other studies have also shown that K+ It has been shown that SSTR4 binding to ion channels can regulate hippocampal excitability. This has important implications for the treatment of certain epilepsies with SSTR4 agonists. Furthermore, SSTR4 agonists are effective in rodent models of pain associated with acute and chronic peripheral antinociceptive and anti-inflammatory activities. Recent data indicate that SRIF released into nociceptors expressed by the capsaicin-sensitive receptor TRPV1 acts on SSTR4 and SSTR2 to produce antinociceptive effects.

[0007] Pain is one of the most common and troublesome symptoms in clinical practice and one of the main reasons patients seek medical treatment. Depending on its duration, pain can be divided into acute and chronic pain. Acute pain includes pain caused by tissue injury or postoperative inflammation. Chronic pain includes nociceptive, neuropathic, visceral, and mixed pain. Currently, the burden of pain treatment remains largely borne by well-known analgesics, including narcotic analgesics (e.g., lidocaine), opioid medications, and nonsteroidal anti-inflammatory drugs (NSAIDs). Drugs with novel mechanisms of action, such as antidepressants and anticonvulsants, are also joining the ranks of analgesics. While many patients benefit from existing analgesics, these drugs can only adequately relieve symptoms in a quarter of patients. Furthermore, existing medications typically suffer from poor tolerance, significant toxicity and side effects, poor long-term safety, potential for drug abuse, and inconvenient use, leaving patients desperate for safer and more effective analgesics. The use of SSTR4 agonists for pain relief has been attracting increasing attention, and the development of novel SSTR4 agonists is highly anticipated as they have broad application prospects.

[0008] CN105473574A disclosed a compound represented by the following formula (I), which is an agonist of SSTR4, applicable to the prevention or treatment of diseases related to SSTR4. However, there is still a wide demand in the art for an SSTR4 agonist with good efficacy, high bioavailability, and good solubility. [ka] Summary of the Invention [Problem to be solved by the invention]

[0009] In view of this, there is a need to provide somatostatin receptor subtype 4 (SSTR4) agonist-based compounds with novel structures, better efficacy, high bioavailability, and better solubility. [Means for solving the problem]

[0010] The present invention relates to a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, [ka] however, R1 is -H and C 1-6 alkyl; L1 is selected from -NH- and -O-; R2 and R3 are each independently -H or C 1-6 Alkyl, and C 3-6 cycloalkyl, where R2 and R3 are not both -H; or R2 and R3 together form a 3-6 membered saturated cyclic group containing 0-1 groups selected from -O-, -NR9-, -SO-, and -SO2-; R4, R5, R6, R7, and R8 are each independently -H, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkoxy C 1-6 Alkyl, -(CH2) m -C 3-10 Carbocyclic group, -(CH2) m -(3- to 10-membered heterocyclic group), -(CH2) m -OC 3-10 Carbocyclic group, -(CH2) m The heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S, and the alkyl, alkoxy, carbocyclic group, phenyl, heteroaryl, or heterocyclic group in R4, R5, R6, R7, and R8 are each independently selected from -H, -F, -Cl, -Br, -I, hydroxy, mercapto group, cyano, amino, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; R9 is -H, C 1-6 Alkyl, C 1-4 Alkoxy C 1-6 Alkyl, halogen, hydroxy, cyano, and C 3-6 cycloalkyl; A is C 6-14 A is selected from the group consisting of aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclic group, and 5- to 14-membered cycloalkyl, and the aryl, heteroaryl, heterocyclic group, and cycloalkyl in A are each selected from the group consisting of 1 to 4 R 10 wherein said heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from the group consisting of N, O, or S; L2 is a single bond, -(CR a R b ) n -and-(CR a R b ) n When R is selected from the group consisting of: 10 are each independently -H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-6 Alkyl, C1-4 Alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl, and -SR 11 and at least one R 10 Ha-SR 11 where R 11 are independently -H, C 1-6 Alkyl, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), C 6-10 aryl, or 5- to 6-membered heteroaryl, wherein said heterocyclic group and heteroaryl contain 1 to 4 heteroatoms selected from N, O, or S, and said alkyl, alkoxy, aryl, heteroaryl, carbocyclic group, or heterocyclic group are each independently selected from -H, halogen, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; L2 is -(CR a R b ) n When R is selected from the group consisting of 10 are each independently -H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3-10 membered heterocyclic group), -O-(CH2) n -C3-10 Carbocyclic group, or -O-(CH2) n -(3- to 10-membered heterocyclic group), and -SR 11 wherein R 11 are independently -H, C 1-6 Alkyl, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), C 6-10 aryl, and 5- to 6-membered heteroaryl, wherein said heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from the group consisting of N, O, or S, and said alkyl, alkoxy, aryl, heteroaryl, carbocyclic group, or heterocyclic group is each independently selected from H, halogen, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; R a and R b are each independently -H and C 1-6 alkyl; m, if present, is independently selected from 0, 1, 2 and 3; If n occurs, it is independently selected from 0, 1, 2 and 3.

[0011] The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of the above-described compound, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0012] The present invention provides the use of the above-mentioned compound, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for the treatment and / or prevention of a disease or condition affected by activation of SSTR4.

[0013] The present invention provides the use of the above compound, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or the above pharmaceutical composition, in the preparation of a medicament for the treatment and / or prevention of pain.

[0014] Compared with the prior art, the present invention has one or more of the following beneficial effects:

[0015] The compounds provided by the present invention incorporate sulfur into specific sites in the core structure, resulting in novel compounds with excellent SSTR4 agonistic effects and / or better selectivity for SSTR4 over other SSTRs, and can be used as SSTR4 agonists to prevent and / or treat diseases or conditions affected by SSTR4 activation (e.g., Alzheimer's disease and other CNS disorders such as epilepsy and depression), as well as to treat pain and / or inflammation of various causes. Experimental studies have also shown that the compounds of the present invention have high metabolic stability and / or excellent pharmacokinetics and / or excellent pharmacodynamic effects. [Brief explanation of the drawings]

[0016] [Figure 1] Figure 1 shows the results of a single-dose pharmacodynamic study in the rat CFA pain model. [Figure 2] FIG. 2 shows the results of a multiple-dose pharmacodynamic study in the rat CFA pain model. DETAILED DESCRIPTION OF THE INVENTION

[0017] The compounds of the present invention, their preparation methods, pharmaceutical compositions, and their use will be described in more detail below with reference to specific examples.The present invention can be implemented in many different forms and is not limited to the embodiments described herein.On the contrary, these embodiments are provided to fully understand the present invention.

[0018] Unless otherwise specified, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the present invention. As used herein, the term "and / or" refers to any and all combinations of one or more associated items.

[0019] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0020] The elements (including carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen) contained in the groups and compounds described in the present invention include all isotopes thereof. Furthermore, the elements carbon, hydrogen, oxygen, sulfur, or nitrogen contained in the groups and compounds described in the present invention may be further substituted with one or more of their corresponding isotopes. Here, the carbon isotope is: 12 C. 13 C, and 14 C, isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and isotopes of oxygen include 16 O. 17 O, and 18 O, and sulfur isotopes are 32 S, 33 S, 34 S, and 36 Contains S, and nitrogen isotopes are 14 N and 15 Contains N, and the fluorine isotope is 19 Contains F, and the chlorine isotopes are 35 Cl, 36Cl, and 37 Contains Cl, and the isotopes of bromine are 79 Br and 81 Contains Br.

[0021] The term "alkyl" refers to a saturated straight-chain or branched-chain aliphatic hydrocarbon group, specifically a saturated hydrocarbon containing normal carbon atoms, secondary carbon atoms, tertiary carbon atoms, quaternary carbon atoms, or combinations thereof. Phrases containing this term, such as "C 1-6 "Alkyl" refers to an alkyl containing 1 to 6 carbon atoms, and "C 1-6When "alkyl" is present, each may independently be a C1 alkyl, a C2 alkyl, a C3 alkyl, a C4 alkyl, a C5 alkyl, or a C6 alkyl. In one embodiment, it may include alkyls having 1 to 20 carbon atoms, preferably alkyls having 1 to 10 carbon atoms, and more preferably alkyls having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, 1-propyl, 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-propan-1-yl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-propan-2-yl (t-Bu, tert-butyl, -C(CH3)3). , 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-butan-2-yl (-C(CH3)2CH2CH3), 3-methyl-butan-2-yl (-CH(CH3)CH(CH3)2), 3-methyl-butan-1-yl (-CH2CH2CH(CH3)2), 2-methyl-butan-1-yl (-CH2CH(CH3) CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), hexan-2-yl (-CH(CH3)CH2CH2CH2CH3), hexan-3-yl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-pentan-2-yl (-C(CH3)2CH2CH2CH3), 3-methyl-pentan-2-yl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-pentan-2-yl (-CH(CH3)CH 2CH(CH3)2), 3-methyl-pentan-3-yl (-C(CH3)(CH2CH3)2), 2-methyl-pentan-3-yl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-butan-2-yl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-butan-2-yl (-CH(CH3)C(CH3)3, octyl (-(CH2)7CH3), and n-nonyl, as well as various branched isomers thereof.The alkyl may be substituted or unsubstituted, and if substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from the group consisting of F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0022] "Alkoxy" refers to -O-alkyl, where alkyl is as defined herein above, preferably having 1 to 12 carbon atoms. Phrases containing this term, such as "C 1-4 "Alkoxy" refers to an -O-alkyl in which the alkyl portion contains 1 to 4 carbon atoms. 1-4 If there is "alkoxy", C 1-4 Each alkoxy may be independently C1 alkoxy, C2 alkoxy, C3 alkoxy, or C4 alkoxy. The alkoxy may be substituted or unsubstituted, and non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy. When substituted, the number of substituents is preferably 1 to 5, and the substituents are independently selected from the group consisting of F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0023] "Alkoxyalkyl" refers to an alkyl substituted with an alkoxy as defined above. Phrases containing this term, such as "C 1-4 Alkoxy C 1-6 "Alkyl" means C 1-4 Alkoxy-substituted C 1-6 refers to alkyl, and "C 1-4 Alkoxy C 1-6 When "alkyl" is present, each independently represents a C1 alkoxy C 1-6 Alkyl, C2 alkoxyC 1-6 Alkyl, C3 alkoxyC 1-6 Alkyl, C4 alkoxyC 1-6The alkoxyalkyl may be alkyl. The alkoxyalkyl may be substituted or unsubstituted. Non-limiting examples of alkoxyalkyl include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl, propoxyethyl, isopropoxymethyl, butoxypropyl, tert-butoxyethyl, pentyloxyethyl, hexyloxyethyl, cyclopropoxymethyl, cyclopropoxyethyl, cyclopropoxypropyl, or cyclohexyloxymethyl; if substituted, the number of substituents is preferably 1 to 5, and the substituents are independently selected from the group consisting of F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0024] "Alkenyl" refers to alkyl, as defined herein, containing at least one carbon-carbon double bond. In one embodiment, the alkenyl contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkenyl include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, or 4-decenyl. When substituted, the number of substituents is preferably 1 to 5, and the substituents are independently selected from the group consisting of F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0025] "Alkynyl" refers to alkyl, as defined herein, containing at least one carbon-carbon triple bond. In one embodiment, the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkynyl include substituted or unsubstituted ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 3-butynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, or 4-decynyl. When substituted, the number of substituents is preferably 1 to 5, and the substituents are independently selected from the group consisting of F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0026] "Carbocyclic group" or "cycloalkyl" refers to a saturated or partially unsaturated cyclic carbon-containing group. In one embodiment, a carbocyclic group is a 3-6 membered monocyclic, a 3-8 membered monocyclic, a 3-10 membered monocyclic, a 4-12 membered bicyclic, or a 10-15 membered tricyclic ring system. Carbocyclic rings include bridged rings or spiro rings. Non-limiting examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl, or spiro[3.3]heptyl, and the like. Carbocyclic groups may be substituted. When substituted, the number of substituents is preferably 1 to 5, and the substituents are independently selected from the group consisting of F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0027] The term "heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted, saturated or partially unsaturated cyclic group containing a heteroatom selected from the group consisting of N, O, and S. In one embodiment, the heterocyclic group may be a 3- to 8-membered monocyclic, a 4- to 12-membered bicyclic, or a 10- to 15-membered tricyclic ring system, and is preferably a 3- to 10-membered heterocyclic group containing at least one, preferably 1 to 4, heteroatoms selected from N, O, or S. The N or S heteroatom in the heterocycle may be oxidized to various oxidation states, for example, to form an N-oxide. A heterocycle can be attached to the rest of the molecule through a heteroatom or a carbon atom. A heterocycle includes bridged or spiro rings. Non-limiting examples of heterocycles include ethylene oxide, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxane, 1,3-dioxane, azepanyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiane, dihydrofuran, dihydropyran, dithiolanyl, tetrahydrofuran, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, dihydrobenzofuran, dihydropyridyl, tetrahydrothienyl, sulfur-oxidized tetrahydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and the like; when substituted, the substituents are preferably 1 to 5 and are independently selected from the group consisting of F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0028] "Aryl" refers to a substituted or unsubstituted all-carbon monocyclic or fused polycyclic unsaturated group having a conjugated π-electron system. In one embodiment, the aryl is a 6- to 14-membered aromatic ring, preferably a 6- to 10-membered aromatic ring. Non-limiting examples include phenyl or naphthyl. The aryl can be fused with a heteroaryl, heterocyclic group, or cycloalkyl, and the point of attachment to the rest of the molecule is on the aryl. Non-limiting examples of the aryl include benzofuran, benzocyclopentyl, or benzothiazole. When the aryl is substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from the group consisting of F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0029] "Heteroaryl" refers to a substituted or unsubstituted monocyclic or fused polycyclic unsaturated group containing at least one heteroatom selected from the group consisting of N, O, and S. In one embodiment, heteroaryl is a 5- to 15-membered heteroaryl, a 5- to 14-membered heteroaryl, or preferably a 5- to 10-membered heteroaryl, or more preferably a 5- to 6-membered heteroaryl, wherein the number of heteroatoms is 1 to 4, preferably 1 to 3, and more preferably 1 to 2. Non-limiting examples of heteroaryl include pyridyl, furanyl, thienyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzofuran, benzimidazole, benzopyridine, or pyrrolopyridine. When heteroaryl is substituted, the number of substituents is preferably 1 to 5, and the substituents are independently selected from the group consisting of F, Cl, Br, I, ═O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0030] "Heteroalkyl" refers to a group in which at least one carbon atom of an alkyl has been replaced with a non-carbon atom, where the non-carbon atom may be an N atom, an O atom, and / or an S atom, etc. For example, if a carbon atom of an alkyl attached to a core structure is replaced with a non-carbon atom, the resulting heteroalkyl is an alkoxy (e.g., -OCH), alkylamino (e.g., -NHCH, -N(CH), etc.), or alkylthio (e.g., -SCH), respectively. If a carbon atom of an alkyl attached to a core structure is not replaced with a non-carbon atom, and a heteroatom is embedded within the group, the resulting heteroalkyl group is an alkyloxyalkyl (e.g., -CHCH-O-CH), alkylaminoalkyl (e.g., -CHNHCH, -CHN(CH), etc.), or alkylthioalkyl (e.g., -CH-S-CH), respectively. When the terminal carbon atom of an alkyl is replaced with a non-carbon atom, the resulting heteroalkyl is a hydroxyalkyl (e.g., -CH2CH2-OH), aminoalkyl (e.g., -CH2NH2), or mercaptoalkyl (e.g., -CH2CH2-SH), respectively.

[0031] "Amino" refers to a derivative of ammonia having structural features of the formula -N(X)2 or the formula -NR'R" where each "X", R', and R" is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Non-limiting examples of amino include -NH2, -N(alkyl)2, -NH(alkyl), -N(cycloalkyl)2, -NH(cycloalkyl), -N(heterocyclyl)2, -NH(heterocyclyl), -N(aryl)2, -NH(aryl), -N(alkyl)(aryl), -N(alkyl)(heterocyclyl), -N(cycloalkyl)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), and the like.

[0032] "Halogen" refers to F, Cl, Br, or I. "Halogenated" refers to the replacement of one or more hydrogen atoms of a molecule or group with a halogen selected from F, Cl, Br, or I.

[0033] "Pharmaceutically acceptable salts" refers to pharmaceutically acceptable non-toxic acid or base salts, including salts formed with inorganic acids or bases, or salts formed with organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts formed with Al, Ca, Li, Mg, K, Na, and Zn. Salts derived from organic bases include, but are not limited to, salts formed with primary, secondary, or tertiary amines. The primary, secondary, or tertiary amines include naturally occurring substituted or unsubstituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benethamine penicillin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, or polyamine resins; salts derived from inorganic and organic acids include sulfates, phosphates, nitrates, bromides, and the like. These include, but are not limited to, salts formed with acids such as hydrogen, hydrochloric, formic, acetic, propionic, benzenesulfonic, benzoic, phenylacetic, salicylic, alginic, anthranilic, camphoric, citric, vinylsulfonic, formic, fumaric, furoic, gluconic, glucuronic, glutamic, glycolic, isethionic, lactic, maleic, malic, mandelic, mucic, pamoic, pantothenic, stearic, succinic, sulfanilic, tartaric, p-toluenesulfonic, malonic, 2-hydroxypropionic, oxalic, glycolic, glucuronic, galacturonic, citric, lysine, arginine, aspartic, cinnamic, p-toluenesulfonic, methanesulfonic, ethanesulfonic, or trifluoromethanesulfonic acid.

[0034] "Stereoisomer" refers to isomers with different spatial arrangements of atoms in molecules, including cis-trans isomers, enantiomers, and conformational isomers.

[0035] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds to an organism.

[0036] A "prodrug" refers to a substance that can be converted into a biologically active compound of the present invention under physiological conditions or by degradation. Prodrugs of the present invention are prepared by modifying functional groups in the compound, and the modifications can be removed using conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxy group, an amino group, or a mercapto group in the compounds of the present invention is bonded to any group. When a prodrug of a compound of the present invention is administered to a mammal, the prodrug is cleaved to form a free hydroxy group, a free amino group, or a free mercapto group, respectively. Examples of prodrugs include, but are not limited to, compounds formed by reacting a hydroxy group or an amino group in the compounds of the present invention with formic acid, acetic acid, or benzoic acid.

[0037] "Optionally" or "may" includes when an item or circumstance may or may not occur, meaning that the described item or circumstance may later occur, but does not necessarily occur. For example, "an aryl may be substituted with an alkyl" means that alkyl may be present, but is not necessarily present; the term includes when the aryl is substituted with an alkyl and when the aryl is not substituted with an alkyl.

[0038] A "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as, for example, a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the term "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch, potato starch, and substituted or unsubstituted beta-cyclodextrin; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; and (10) propionate. (11) polyhydric alcohols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium and hydrogen hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other compatible non-toxic substances used in the preparation of pharmaceuticals.

[0039] The term "solvate" refers to a solvent-bound compound or salt form thereof, typically formed by solvolysis. This physical association includes hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein can be prepared, for example, as crystalline forms and solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include stoichiometric and non-stoichiometric solvates. In some embodiments, the solvates can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The term "solvate" includes solution-state and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0040] The term "metabolite" refers to substances that include products of in vivo metabolism of compounds of the invention, including intermediate and ultimate metabolites.

[0041] The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate) with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optoelectronic properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0042] The dosage form and administration route of the compound of the present invention or a pharmaceutical composition thereof are not particularly limited.

[0043] Exemplary routes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intraperitoneal, intramuscular, or subcutaneous) injection and / or topical administration.

[0044] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or the following ingredients: The above ingredients are (a) fillers or compatibilizers such as starch, lactose, sucrose, glucose, mannitol, silicic acid, etc.; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, complex silicates, and sodium carbonate; (e) solvents such as paraffin; (f) absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.

[0045] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms can contain inert diluents (e.g., water or other solvents), solubilizers, and emulsifiers commonly used in the art. Specific examples include ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. In addition to the inert diluent, the composition may further contain adjuvants such as wetting agents, suspending agents, sweeteners, flavoring agents, and fragrances. For example, suspensions can contain suspending agents. Specific examples include ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0046] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents, or excipients are selected from water, ethanol, and polyols, or suitable mixtures thereof.

[0047] Dosage forms for topical administration include ointments, powders, patches, sprays, and inhalants, which are prepared under sterile conditions by mixing the active ingredient with a pharmaceutically acceptable carrier, together with preservatives, buffers, and / or propellants as required.

[0048] The present invention relates to the following embodiments.

[0049] In one embodiment, the present invention relates to a compound of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof. [ka]

[0050] however, R1 is -H, and C 1-6 selected from the group consisting of straight or branched chain alkyl; L1 is selected from -NH- and -O-; R2 and R3 are each independently -H or C 1-6 Straight or branched chain alkyl, and C 3-6 cycloalkyl, where R2 and R3 are not both -H; or R2 and R3 together form a 3-6 membered saturated cyclic group containing 0-1 groups selected from -O-, -NR9-, -SO-, and -SO2-; R4, R5, R6, R7, and R8 are each independently -H, C 1-6 Straight or branched chain alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6Alkyl, -(CH2) m -C 3-10 Carbocyclic group, -(CH2) m -(3- to 10-membered heterocyclic group), -(CH2) m -OC 3-10 Carbocyclic group, -(CH2) m The heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S, and the alkyl, alkoxy, carbocyclic group, phenyl, heteroaryl, or heterocyclic group in R4, R5, R6, R7, and R8 are each independently selected from -H, -F, -Cl, -Br, -I, hydroxy, mercapto group, cyano, amino, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; R9 is -H, C 1-6 Straight or branched chain alkyl, C 1-4 Alkoxy C 1-6 Alkyl, halogen, hydroxy, cyano, and C 3-6 cycloalkyl; A is C 6-14 A is selected from the group consisting of aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclic group, and 5- to 14-membered cycloalkyl, and the aryl, heteroaryl, heterocyclic group, and cycloalkyl in A are each selected from the group consisting of 1 to 4 R 10 wherein said heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from the group consisting of N, O, or S; L2 is a single bond, -(CR a R b ) n -and-(CR a R b ) n When R is selected from the group consisting of: 10 are each independently -H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-6 Straight or branched chain alkyl, C 1-4 Alkoxy C1-6 Alkyl, C 3-6 Cycloalkyl, and -SR 11 and at least one R 10 Ha-SR 11 where R 11 are independently -H, C 1-6 Straight or branched chain alkyl, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), C 6-10 aryl, or 5- to 6-membered heteroaryl, wherein said heterocyclic group and heteroaryl contain 1 to 4 heteroatoms selected from N, O, or S, and said alkyl, alkoxy, aryl, heteroaryl, carbocyclic group, or heterocyclic group are each independently selected from -H, halogen, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; L2 is -(CR a R b ) n When R is selected from the group consisting of 10 are each independently -H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3-10 membered heterocyclic group), -O-(CH2) n -C 3-10Carbocyclic group, or -O-(CH2) n -(3- to 10-membered heterocyclic group), and -SR 11 wherein R 11 are independently -H, C 1-6 Straight or branched chain alkyl, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), C 6-10 aryl, and 5- to 6-membered heteroaryl, wherein said heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from the group consisting of N, O, or S, and said alkyl, alkoxy, aryl, heteroaryl, carbocyclic group, or heterocyclic group is each independently selected from H, halogen, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; R a and R b are each independently -H, and C 1-6 selected from the group consisting of straight or branched chain alkyl; m, if present, is independently selected from 0, 1, 2 and 3; If n occurs, it is independently selected from 0, 1, 2 and 3.

[0051] In one embodiment, in the compound represented by the above formula (I) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, L1 is -NH-; and R1 is -H.

[0052] In one embodiment, the present invention provides a compound of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein the compound has the structural feature of formula (VI): [ka]

[0053] however, L1 is selected from -NH- and -O-; L2 is a single bond and -(CR a R b ) n -or- (CR a R b ) n O-; where R a , R b are independently -H, and C 1-6 selected from the group consisting of straight or branched chain alkyl; If n occurs, it is independently selected from 0, 1, 2 and 3.

[0054] In one embodiment, the present invention provides a compound of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein the compound has the structural feature of formula (II). [ka]

[0055] however, L1 is selected from -NH- and -O-; L2 is a single bond, -(CR a R b ) n -and-(CR a R b ) n O-; where R a and R bare each independently -H, and C 1-6 selected from the group consisting of straight or branched chain alkyl; If n occurs, it is independently selected from 0, 1, 2 and 3.

[0056] In one embodiment, in the compound represented by the above formula (II) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, R1 is -H; L1 is -NH-; and L2 is selected from the group consisting of a single bond, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CHO-, and -CH2CHO-.

[0057] In one embodiment, in the compound represented by formula (II) above provided herein, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, R2 and R3 are each independently C 1-6 Straight or branched chain alkyl, and C 3-6 cycloalkyl; or R2 and R3 together form a 3-6 membered saturated cyclic group containing 0-1 groups selected from the group consisting of -O-, -SO-, and -SO2-.

[0058] In one embodiment, the present invention provides a compound of formula (II) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein R 11 are independently -H, C 1-6 Straight or branched chain alkyl, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -alkenyl, -(CH2) n -alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), C 6-10aryl, and 5- to 6-membered heteroaryl, wherein said heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from the group consisting of N, O, or S, and said alkyl, alkoxy, aryl, heteroaryl, carbocyclic group, or heterocyclic group is each independently -H, halogen, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 It may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy.

[0059] In one embodiment, the present invention provides a compound of formula (II) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein R 11 are each independently selected from the group consisting of methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, and pyridyl.

[0060] In one embodiment, the present invention provides a compound represented by formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein the compound has the structural feature of formula (III). [ka]

[0061] R 10 are each independently -H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -alkenyl, -(CH2) n -alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n-(3-10 membered heterocyclic group), -O-(CH2) n -C 3-10 Carbocyclic group, -O-(CH2) n -(3- to 10-membered heterocyclic group), and -SR 11 wherein R 11 are independently -H, C 1-6 Straight or branched chain alkyl, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -alkenyl, -(CH2) n -alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), C 6-10 aryl, and 5- to 6-membered heteroaryl, wherein said heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from the group consisting of N, O, or S, and said alkyl, alkoxy, aryl, heteroaryl, carbocyclic group, or heterocyclic group is each independently -H, halogen, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; R a and R b are each independently -H, and C 1-6 It is selected from the group consisting of straight or branched chain alkyl.

[0062] In one embodiment, the present invention provides a compound of formula (III) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein R 10 are each independently -H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutoxy, tetrahydrofuranyl, and -SR 11 wherein R 11are each independently selected from the group consisting of methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, and pyridyl; R a and R b are each independently selected from the group consisting of —H, methyl, ethyl, and isopropyl.

[0063] In one embodiment, the present invention provides a compound of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein said compound has the structural feature of formula (IV). [ka]

[0064] R4 is C 1-6 Straight or branched chain alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, -(CH2) m -C 3-10 Carbocyclic group, -(CH2) m -(3- to 10-membered heterocyclic group), -(CH2) m -OC 3-10 Carbocyclic group, -(CH2) m -O- (3- to 10-membered heterocyclic group), phenyl, and 5- to 6-membered heteroaryl, wherein the heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from N, O, or S, and the alkyl, alkoxy, carbocyclic group, phenyl, heteroaryl, or heterocyclyl in R4 is each independently -H, -F, -Cl, -Br, -I, hydroxy, mercapto group, cyano, amino, C 1-4 Alkyl, and C 1-4 and m, when present, is independently selected from 0, 1, 2, and 3.

[0065] In one embodiment, the present invention provides a compound of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein the compound has the structural feature of formula (V). [ka]

[0066] R2 and R3 are independently C 1-6 Straight or branched chain alkyl, and C 3-6 cycloalkyl, wherein R2 and R3 are not both -H; or R2 and R3 together form a 3- to 6-membered saturated cycloalkyl;

[0067] R4, R5, R6, and R7 are each independently -H, C 1-6 Straight or branched chain alkyl, C 1-6 Alkoxy, and C 1-6 Alkoxy C 1-6 alkyl, and the alkyl and alkoxy in R4, R5, R6, and R7 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy;

[0068] A is C 6-14 A is selected from the group consisting of aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclic group, and 5- to 14-membered cycloalkyl, and the aryl, heteroaryl, heterocyclic group, and cycloalkyl in A are selected from the group consisting of 1 to 4 R 10 wherein said heteroaryl or heterocyclic group contains 1 to 4 N atoms;

[0069] When L2 is selected from a single bond, R 10are each independently -H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-6 Straight or branched chain alkyl, C 1-4 Alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl, and -SR 11 and at least one R 10 Ha-SR 11 where R 11 are independently -H, C 1-6 Straight or branched chain alkyl, C 1-4 Alkoxy C 1-6 Alkyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group) and 5- to 6-membered heteroaryl, wherein said heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from the group consisting of O, S, or N, and said alkyl, alkoxy, carbocyclic, or heterocyclic group is each independently selected from -H, halogen, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy;

[0070] L2 is -(CR a R b ) n R when selected from S- 10 are each independently -H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, and C 1-4 Alkoxy C 1-6 alkyl, wherein the alkyl and alkoxy are each independently selected from the group consisting of H, halogen, hydroxy, cyano, C 1-4 Alkyl, and C 1-4 may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy;

[0071] R a and Rb are each independently -H, and C 1-6 selected from the group consisting of straight or branched chain alkyl;

[0072] If n occurs, it is independently selected from 0, 1, 2 and 3.

[0073] In one embodiment, in the compound represented by formula (I) above provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, A is selected from the group consisting of the following structures: [ka]

[0074] In one embodiment, in the compound represented by formula (I) above provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, A is one selected from the group consisting of the following structures: [ka]

[0075] In one embodiment, in the compound represented by formula (I) above provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, A is selected from the group consisting of the following structures: [ka]

[0076] In one embodiment, the present invention provides a compound represented by formula (a), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka]

[0077] however, [ka] represents a single or double bond, where two [ka] Only one of the represents a double bond; X1 is CR 13 or NR 12 and; X2 is CR 13 or NR 12 and; Alternatively, X and its substituents may be adjacent carbon atoms and their substituents R 13 and together form a benzene ring or a 5- or 6-membered heteroaromatic ring, and the benzene ring or the 5- or 6-membered heteroaromatic ring is 13 may be substituted with; R 13 are each independently -H, halogen, cyano, or -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, -(CH2) n -5- to 6-membered heteroaryl, and -SR 11 selected from the group consisting of: R 12 is H, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; R 11 -H, C 1-6Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; R2 and R3 are independently H or C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n - selected from the group consisting of OR; R4 and R5 are independently H or C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n - selected from the group consisting of OR; n is 0, 1, 2 or 3; where at least one R 13 Ga-SR 11 It is a substituent.

[0078] In one embodiment, the present invention provides a compound represented by formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein: X2 is CR 13 and; X1 and its substituents are adjacent carbon atoms and their substituents R13 and together form a benzene ring or a 5- or 6-membered heteroaromatic ring, and the benzene ring or the 5- or 6-membered heteroaromatic ring is 13 is replaced by; R 13 are each independently -H, halogen, cyano, or -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, -(CH2) n -5- to 6-membered heteroaryl, and -SR 11 selected from the group consisting of: R 11 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6alkyl selected from the group consisting of: R2 and R3 are independently H or C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -OR selected from the group consisting of: R4 and R5 are independently H or C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n - selected from the group consisting of OR; n is 0, 1, 2 or 3; where at least one R 13 Ga-SR 11 It is a substituent.

[0079] In one embodiment, the present invention provides a compound represented by formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein: X2 is NR 12 and; X1 and its substituents are adjacent carbon atoms and their substituents R 13 and together form a benzene ring or a 5- or 6-membered heteroaromatic ring, and the benzene ring or the 5- or 6-membered heteroaromatic ring is 13 is replaced by; R 13 are each independently -H, halogen, cyano, or -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, -(CH2) n -5- to 6-membered heteroaryl, and -SR11 selected from the group consisting of: R 11 -H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; R2 and R3 are independently H or C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n - selected from the group consisting of OR; R4 and R5 are independently H or C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n - selected from the group consisting of OR; n is 0, 1, 2 or 3; where at least one R 13 Ga-SR 11 is.

[0080] In one embodiment, the present invention provides a compound represented by formula (b), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka] however, R 13 are each independently H, halogen, cyano, or -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, -(CH2) n -5- to 6-membered heteroaryl, and -SR 11 and at least one R 13 Ha-SR 11 and; R 12 is H, C 1-6 Alkyl or halogenated C 1-6 selected from the group consisting of alkyl; R 11 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; R' and R'' are hydrogen, C1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; n is 0, 1, 2 or 3; p is 1, 2, 3 or 4.

[0081] In one embodiment, the present invention provides a compound represented by formula (b) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein: p is 1, 2 or 3; R 13 are independently H, halogen, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 3-10 Carbocyclic groups, and -SR 11 and at least one R 13 Ha-SR 11 and; R 11 is C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -C 3-6 selected from the group consisting of carbocyclic groups; R 12 is H, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0 or 1.

[0082] In one embodiment, the present invention provides a compound represented by formula (b) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein: p is 1 or 2; R 13 are independently H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -SR11 and at least one R 13 Ha-SR 11 and; R 11 is C 1-4 Alkyl, and -(CH2) n -C 3-4 selected from the group consisting of carbocyclic groups; R 12 is H, C 1-4 Alkyl and halogenated C 1-4 selected from the group consisting of alkyl; n is 0 or 1.

[0083] In one embodiment, the present invention provides a compound represented by formula (b) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein: P is 1; R 13 is -SMe; R 12 is H or C 1-4 It is alkyl.

[0084] In one embodiment, the present invention provides a compound represented by formula (b-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka] however, R 11 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2)n - selected from the group consisting of 5- to 6-membered heteroaryl; R 12 is H, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0, 1, 2, or 3.

[0085] In one embodiment, the compound represented by the above formula (b-1) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, R 11 is C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -C 3-6 selected from the group consisting of carbocyclic groups; R 12 is H, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0 or 1.

[0086] In one embodiment, the compound represented by the above formula (b-1) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, R 11 is C 1-4 Alkyl, and -(CH2) n -C 3-4 selected from the group consisting of carbocyclic groups; R 12 is H, C 1-4 Alkyl and halogenated C 1-4 selected from the group consisting of alkyl; n is 0 or 1.

[0087] In one embodiment, the compound represented by the above formula (b-1) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, R 11 is methyl; R 12 is H or C 1-4 It is alkyl.

[0088] In one embodiment, the present invention provides a compound represented by formula (c), or a stereoisomer thereof represented by formula (c-1) or formula (c-2), an N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof. [ka] however, R 13 are each independently H, halogen, cyano, or -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, -(CH2) n -5- to 6-membered heteroaryl, and -SR 11 and at least one R 13 Ha-SR 11 and; R 11 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C6-10 Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R4 and R5 are independently H or C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n - selected from the group consisting of OR; R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0, 1, 2 or 3; r is 1, 2, 3, 4, or 5.

[0089] In one embodiment, the compound represented by formula (c) provided by the present invention, or its stereoisomer represented by formula (c-1) or formula (c-2), N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, r is 1, 2, or 3; R 13 are independently H, halogen, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 3-10 Carbocyclic groups, and -SR 11 and at least one R 13 Ha-SR 11 and; R 11 is C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -C 3-6 selected from the group consisting of carbocyclic groups; R4 and R5 are independently H and C 1-6selected from the group consisting of alkyl; n is 0 or 1.

[0090] In one embodiment, the compound represented by formula (c) provided by the present invention, or its stereoisomer represented by formula (c-1) or formula (c-2), N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, r is 1 or 2; R 13 are independently H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -SR 11 and at least one R 13 Ha-SR 11 and; R 11 is C 1-4 Alkyl, and -(CH2) n -C 3-4 selected from the group consisting of carbocyclic groups; R4 and R5 are independently H and C 1-6 selected from the group consisting of alkyl; n is 0 or 1.

[0091] In one embodiment, in the compound represented by formula (c) above provided by the present invention, or its stereoisomer represented by formula (c-1) or formula (c-2), N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, r is 2; R 13 One of them is -SMe, the other is H, and C 1-4 alkyl; R4 and R5 are each independently selected from the group consisting of H, and C 1-4 alkyl.

[0092] In one embodiment, in the compound of formula (c) provided herein, or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, or prodrugs thereof, represented by formula (c-1) or formula (c-2), R is 1; R 13 is -SMe; R4 and R5 are each independently H, and C 1-4 alkyl.

[0093] In one embodiment, the present invention provides a compound represented by formula (d), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka] however, R 13 are each independently H, halogen, cyano, or -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, -(CH2) n -5- to 6-membered heteroaryl, and -SR 11 and at least one R 13 Ha-SR 11 and; R 11 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2)n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0, 1, 2 or 3; r is 1, 2, 3, 4, or 5.

[0094] In one embodiment, the present invention provides a compound represented by formula (d) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein r is 1, 2, or 3; R 13 are independently H, halogen, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 3-10 Carbocyclic groups, and -SR 11 and at least one R 13 Ha-SR 11 and;R 11 is C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -C 3-6 carbocyclic groups; n is 0 or 1.

[0095] In one embodiment, the present invention provides a compound represented by formula (d) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein r is 1 or 2; R 13 are independently H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -SR 11 and at least one R 13 Ha-SR 11 and;R 11 is C 1-4 Alkyl, and -(CH2) n -C 3-4 carbocyclic groups; n is 0 or 1.

[0096] In one embodiment, the present invention provides a compound represented by formula (d) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein r is 2; R 13 One of them is -SMe, the other is H, and C 1-4 alkyl.

[0097] In one embodiment, the present invention provides a compound represented by formula (d) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein r is 1; R 13 is -SMe.

[0098] In one embodiment, the present invention provides a compound represented by formula (d-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka] however, R 11 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2)n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R 13 are each independently H, halogen, cyano, or -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, -(CH2) n -5- to 6-membered heteroaryl, and -SR 11 selected from the group consisting of: R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4.

[0099] In one embodiment, the compound represented by the above formula (d-1) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, q is 0, 1 or 2; R 13 are independently H, halogen, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 3-10 Carbocyclic groups, and -SR 11 selected from the group consisting of: R 11 is C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -C 3-6 selected from the group consisting of carbocyclic groups; n is 0 or 1.

[0100] In one embodiment, in the compound represented by the above formula (d-1) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, q is 0 or 1; R 11 is C 1-4 Alkyl, and -(CH2) n -C 3-4 R is selected from the group consisting of carbocyclic groups; 13 is H, C 1-4 Alkyl and halogenated C 1-4 alkyl; and n is 0 or 1.

[0101] In one embodiment, in the compound represented by the above formula (d-1) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, q is 0; R 11 is C 1-4 It is alkyl.

[0102] In one embodiment, the present invention provides a compound represented by formula (d-2), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka] however, R 11 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R 13 are each independently H, halogen, cyano, or -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, -(CH2) n -5- to 6-membered heteroaryl, and -SR 11 selected from the group consisting of: R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4.

[0103] In one embodiment, in the compound represented by the above formula (d-2) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, q is 0, 1, or 2; R 11 is C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -C 3-6 R is selected from the group consisting of carbocyclic groups; 13 are independently H, halogen, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 3-10 Carbocyclic groups, and -SR 11 and n is 0 or 1.

[0104] In one embodiment, in the compound represented by the above formula (d-2) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, q is 0 or 1; R 11 is C 1-4 Alkyl, halogenated C 1-4 Alkyl, and -(CH2) n -C 3-4 R is selected from the group consisting of carbocyclic groups; 13 are independently H, C 1-6 Alkyl and halogenated C 1-6 alkyl; and n is 0 or 1.

[0105] In one embodiment, the present invention provides a compound represented by the above formula (d-2), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein q is 1; R 11 is methyl; R 13 is H or C 1-4 It is alkyl.

[0106] In one embodiment, the present invention provides a compound represented by formula (d-3), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka] however, R 11 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R 13 is H, halogen, cyano, -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10Aryl, -(CH2) n -5- to 6-membered heteroaryl, and -SR 11 selected from the group consisting of: R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0, 1, 2, or 3.

[0107] In one embodiment, in the compound represented by the above formula (d-3) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, R 11 is C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -C 3-6 R is selected from the group consisting of carbocyclic groups; 13 are independently H, halogen, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 3-10 Carbocyclic groups, and -SR 11 and n is 0 or 1.

[0108] In one embodiment, in the compound represented by the above formula (d-3) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, R 11 is C 1-4 Alkyl, halogenated C 1-4 Alkyl, and -(CH2) n -C 3-4 R is selected from the group consisting of carbocyclic groups; 13 is H, C 1-4 Alkyl and halogenated C1-4 alkyl; and n is 0 or 1.

[0109] In one embodiment, in the compound represented by the above formula (d-3) provided by the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, R 11 is methyl; R 13 is H or C 1-4 It is alkyl.

[0110] In one embodiment, the present invention provides a compound represented by formula (e), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka] however, R 13 is H, halogen, cyano, -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 3-6 Cycloalkyl, and -SR 11 and at least one R 13 Ha-SR 11 and; R 11 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10 Aryl, and -(CH2) n- selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0, 1, 2 or 3; t is 1, 2, 3, 4, or 5.

[0111] In one embodiment, the present invention provides a compound represented by formula (e) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein t is 1, 2, or 3; R 13 are independently H, halogen, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 3-10 Carbocyclic groups, and -SR 11 and at least one R 13 Ha-SR 11 and;R 11 is C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -C 3-6 carbocyclic groups; n is 0 or 1.

[0112] In one embodiment, the present invention provides a compound represented by formula (e) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein t is 1 or 2; R 13 are independently H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -SR 11 and at least one R13 Ha-SR 11 and;R 11 is C 1-4 Alkyl, and -(CH2) n -C 3-4 carbocyclic groups; n is 0 or 1.

[0113] In one embodiment, the present invention provides a compound represented by formula (e) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein t is 1; R 11 is C 1-4 It is alkyl.

[0114] In one embodiment, the present invention provides a compound represented by formula (e-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof: [ka] however, R 13 is H, halogen, cyano, -(CH2) n -NR'R'', C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 3-6 Cycloalkyl, and -SR 11 is selected from the group consisting of R 11 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -OR, -(CH2) n -C 2-6 Alkenyl, -(CH2) n -C 2-6 Alkynyl, -(CH2) n -C 3-10 Carbocyclic group, -(CH2) n -(3- to 10-membered heterocyclic group), -(CH2) n -C 6-10Aryl, and -(CH2) n - selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C 1-6 Alkyl and halogenated C 1-6 selected from the group consisting of alkyl; n is 0, 1, 2 or 3; s is 0, 1, 2, 3 or 4.

[0115] In one embodiment, the present invention provides a compound represented by the above formula (e-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein s is 0, 1, or 2; R 13 are independently H, halogen, or C 1-6 Alkyl, halogenated C 1-6 Alkyl, -(CH2) n -C 3-10 Carbocyclic groups, and -SR 11 selected from the group consisting of: R 11 is C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -(CH2) n -C 3-6 carbocyclic groups; n is 0 or 1.

[0116] In one embodiment, in the compound represented by the above formula (e-1) provided herein, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, s is 0 or 1; R 13 are independently H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, and -SR 11 selected from the group consisting of: R 11 is C1-4 Alkyl, and -(CH2) n -C 3-4 carbocyclic groups; n is 0 or 1.

[0117] In one embodiment, the present invention provides a compound represented by the above formula (e-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, wherein s is 0; R 11 is C 1-4 It is alkyl.

[0118] In one specific embodiment, the compound is selected from the group consisting of the following structures: [ka]

[0119] In one specific embodiment, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, and trifluoromethanesulfonate, or a combination thereof.

[0120] Preferred pharmaceutically acceptable salts are selected from the group consisting of hydrochloride, sulfate, phosphate, acetate, maleate, succinate, fumarate, malate, oxalate, tartrate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, and trifluoromethanesulfonate salts, or combinations thereof.

[0121] An embodiment of the present invention provides a method for preparing the aforementioned compounds, comprising the steps of: [ka]

[0122] A condensation reaction is carried out between compound 1 and compound 2, where Q represents a nitrogen protecting group.

[0123] The nitrogen protecting group Q is removed from the product of the above condensation reaction.

[0124] Embodiments of the present invention also provide pharmaceutical compositions, wherein said pharmaceutical composition comprises a therapeutically effective amount of said compound, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0125] Embodiments of the present invention also provide the use of the above-mentioned compound, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for the treatment and / or prevention of a disease or condition affected by activation of SSTR4.

[0126] In one specific embodiment, said disease or condition affected by activation of SSTR4 is pain.

[0127] Embodiments of the present invention also provide the use of the compound, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or the pharmaceutical composition, in the preparation of a medicament for the treatment and / or prevention of pain.

[0128] In one embodiment, the present invention provides a compound of the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, or a pharmaceutical composition of the present invention, for the treatment and / or prevention of a disease or condition affected by activation of SSTR4. In one embodiment, the compound or composition is used to treat and / or prevent pain.

[0129] In one embodiment, the present invention provides a method for treating a disease or condition affected by activation of SSTR4, comprising administering the compound of the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, or prodrug thereof, or the pharmaceutical composition of the present invention. In one embodiment, the present invention provides a method for treating pain, comprising administering the compound or pharmaceutical composition of the present invention.

[0130] In one specific embodiment, the pain is neuralgia.

[0131] In one specific embodiment, the pain is back pain, chronic back pain, trigeminal neuralgia, complex regional pain syndrome type I, complex regional pain syndrome type II, irritable bowel syndrome, diabetic neuropathy, osteoarthritis pain, cancer pain, or fibromyalgia.

[0132] The implementation process and beneficial effects of the present invention will be described in detail below through specific examples. The above examples are intended to help better understand the essence and characteristics of the present invention, and are not intended to limit the scope of the present invention.

[0133] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR chemical shifts (δ) are 10 -6The NMR measurements were performed using a Bruker Avance III 400 and a Bruker Avance 300 nuclear magnetic resonance instrument, with deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), and deuterated methanol (CD3OD) as solvents, and tetramethylsilane (TMS) as an internal standard.

[0134] MS measurements are performed using Agilent 6120B (ESI) and Agilent 6120B (APCI).

[0135] The HPLC measurements were carried out using an Agilent 1260DAD high performance liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).

[0136] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used for thin-layer chromatography. The size of the silica gel plates used for thin-layer chromatography (TLC) was 0.15 mm to 0.20 mm, and the size of the silica gel plates used for product separation and purification by thin-layer chromatography was 0.4 mm to 0.5 mm.

[0137] Column chromatography generally uses Yantai Huanghai Silicagel 200-300 mesh silica gel as the carrier.

[0138] Known starting materials of the present invention can be prepared using methods known in the art or purchased from Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, and other companies.

[0139] Nitrogen atmosphere means that the reaction flask is connected to an approximately 1 L balloon of nitrogen.

[0140] By hydrogen atmosphere, it is meant that the reaction flask is connected to an approximately 1 L balloon of hydrogen.

[0141] In the hydrogenation reaction, the flask is usually evacuated and filled with hydrogen gas, and this procedure is repeated three times.

[0142] In the examples, reactions are carried out under a nitrogen atmosphere unless otherwise stated.

[0143] In the examples, unless otherwise specified, solutions refer to aqueous solutions.

[0144] In the examples, unless otherwise specified, the reaction temperature is room temperature.

[0145] The optimum reaction temperature is room temperature, ranging from 20°C to 30°C.

[0146] Abbreviations related to chemical synthesis: Bn: Benzyl Boc: tert-butoxycarbonyl Bz: benzoyl DIPEA: Diisopropylethylamine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DCM: dichloromethane DIEA: N,N-diisopropylethylamine EA: Ethyl acetate Et: Ethyl Me: Methyl Ts: p-toluenesulfonyl HATU: 2-(7-aza1H-benzotriazol-1-yl)-1,1,3,3-tetramethyloronium hexafluorophosphate HPLC: High-performance liquid chromatography LiHMDS: Lithium hexamethyldisilazide MeLi: Methyl lithium NIS: N-iodosuccinimide NMP: N-methylpyrrolidone Raney-Ni: Raney Nickel NEt3: Triethylamine THF: tetrahydrofuran TLC: Thin Layer Chromatography TFA: Trifluoroacetic acid TBAF: tetra-n-butylammonium fluoride SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride Burgess' reagent: Burgess' reagent, CAS No.: 29684-56-8 RT: room temperature

[0147] Example 1 (1R,5S,6r)-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (Compound 1) [ka]

[0148] Step 1: 2-cyano-3-methylthiopyridine (1B) [ka] 2-Cyano-3-fluoropyridine (2.0 g, 16.38 mol) and sodium methanethiolate (1.2 g, 18.02 mmol) were added to dimethyl sulfoxide (10 mL), and the mixture was stirred at room temperature for 5 h. Ethyl acetate (120 mL) was added, washed with water and saturated brine, and the organic phase was evaporated under vacuum. The solvent was evaporated, and the residue was purified on a silica gel column (petroleum ether / ethyl acetate = 3 / 1) to give 2-cyano-3-methylthiopyridine 1B (900 mg, yield: 36.6%) as a white solid.

[0149] Step 2: (3-(methylthio)pyridin-2-yl)methanamine dihydrochloride (1C) [ka] 2-Cyano-3-methylthiopyridine 1B (800 mg, 5.33 mmol) was dissolved in ethanol (20 mL), 10% palladium on carbon (520 mg, 0.53 mmol) and 6 M hydrochloric acid (5 mL) were added, and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 days. After filtration, the filtrate was evaporated to dryness in vacuo to give (3-(methylthio)pyridin-2-yl)methanamine dihydrochloride 1C (1.1 g, crude, unpurified) as a white solid. MS (ESI): m / z = 227.1 [M+H] +

[0150] Step 3: tert-Butyl (2-methyl-1-(((3-(methylthio)pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (1D) [ka] (3-(methylthio)pyridin-2-yl)methanamine dihydrochloride 1C (1.1 g, 4.84 mmol), N-tert-butoxycarbonyl-2-methylalanine (985 mg, 4.84 mmol), HATU (2.6 g, 7.26 mmol), and triethylamine (1.7 g, 16.94 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 16 h. Ethyl acetate (100 mL) was added, and the organic phase was washed with water and saturated brine, followed by rotary evaporation under vacuum. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 3 / 2) to give a white solid (2-methyl-1-(((3-(methylthio)pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate 1D) (860 mg, yield: 53.7%). MS (ESI): m / z = 340.2 [M+H] +

[0151] Step 4: 2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine dihydrochloride (1E) [ka] Tert-butyl (2-methyl-1-(((3-(methylthio)pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate 1D (360 mg, 1.06 mmol) and Burgess' reagent (378 mg, 1.53 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 16 hours. Ethyl acetate (100 mL) was added, and the organic phase was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. Rotary evaporation in vacuo afforded a pale yellow oil. 4 M hydrochloric acid in methanol (5 mL) was added to this oil at 0°C, and the mixture was stirred for 2 hours. The solvent was removed in vacuo to afford a white solid, identified as 2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine dihydrochloride 1E (220 mg, crude product, unpurified). MS (ESI): m / z = 222.1 [M+H] +

[0152] Step 5: (1R,5S,6r)-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (Compound 1) [ka] 2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine dihydrochloride 1E (60 mg, 0.20 mmol), compound 1F (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (CAS No.: 927679-54-7) (46 mg, 0.20 mmol), HATU (115 mg, 0.30 mmol), diisopropylethylamine (90 mg, 0.70 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC to give a white solid (25 mg). A solution of hydrochloric acid in ethyl acetate (3 M, 4 mL) was added to this, and the mixture was stirred for 2 hours. The mixture was filtered and the solvent was removed to give compound 1, a white solid (1R,5S,6r)-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (12 mg, yield: 17.9%). 1 H NMR(400MHz,CD3OD) δ 9.28(d,1H),8.39(t,1H),8.02(s,1H),7.13(t,1H),7.03(d,1H),3.52-3.42(M,4H),2.66(s,3H),1.97-1.92(M,3H),1.89(s,6H). MS (ESI): m / z = 331.1 [M+H] +

[0153] (1R,5S,6r)-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 1a) [ka] Compound 1 (30 g, 81.7 mmol) was synthesized on an expanded scale using the synthesis method of Example 1. This compound was dissolved in MeOH (210 mL), and a previously prepared solution of potassium tert-butoxide (20.8 g, 185.4 mmol) in methanol (120 mL) was slowly added dropwise in an ice-water bath. The pH of the reaction solution was monitored during this process, and the addition was stopped when the pH exceeded 9. The mixture was stirred for an additional 10 minutes, filtered, and the filtrate was concentrated and dried to obtain a viscous oily crude product. The crude product was purified using a silica gel column (dichloromethane / methanol = 15 / 1) to obtain an off-white solid. This solid was further slurried and purified in ethanol to obtain pure compound 1a (15 g, yield: 55.5%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 8.38(s,1H),8.11(d,1H),7.19(s,1H),6.61(t,1H),6.54(d,1H),2.87( d,2H),2.67(d,2H),2.54(s,3H),1.64(s,6H),1.56(t,1H),1.47(M,2H). MS (ESI): m / z = 331.2 [M+H] +

[0154] Example 2 (1R,5S,6r)-N-(2-methyl-1-((2-(trifluoromethyl)phenyl)thio)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide formate (Compound 2) [ka]

[0155] Step 1: 4-Toluenesulfonic acid 2-methyl-2-nitropropyl ester (2B) [ka] 2-Methyl-2-nitropropan-1-ol 2A (1.19 g, 10.00 mmol) and triethylamine (2.02 g, 20.00 mmol) were mixed and dissolved in dichloromethane (50 mL). The mixture was cooled to 0-5 °C, and 4-methylbenzenesulfonyl chloride (2.86 g, 15.00 mmol) was added. The mixture was stirred at room temperature for 18 h. TLC showed the formation of a new spot. The mixture was diluted with dichloromethane (100 mL) and washed with 1 M hydrochloric acid (100 mL) and saturated sodium bicarbonate solution (100 mL), followed by saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and purified using a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to give 4-toluenesulfonic acid 2-methyl-2-nitropropyl ester 2B as an off-white solid (2.46 g, yield: 90%). 1 H NMR(400MHz,CDCl3) δ 7.77(d,2H),7.37(d,2H),4.28(s,2H),2.47(s,3H),1.60(s,6H).

[0156] Step 2: (2-methyl-2-nitropropyl)(2-(trifluoromethyl)phenyl)sulfane (2D) [ka] 4-Toluenesulfonic acid 2-methyl-2-nitropropyl ester 2B (500 mg, 1.83 mmol), compound 2-(trifluoromethyl)thiophenol 2C (326 mg, 1.83 mmol), and K2CO3 (757 mg, 0.45 mmol) were dissolved in N-methylpyrrolidone (10 mL) and stirred at 80 °C under nitrogen protection for 16 h. After adding 50 mL of water, the reaction mixture was extracted three times with ethyl acetate (50 × 3). The organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated, and the crude product was purified on a silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give the product (2-methyl-2-nitropropyl)(2-(trifluoromethyl)phenyl)sulfane 2D) as a yellow oil (350 mg, yield: 68.6%).

[0157] Step 3: 2-methyl-1-((2-(trifluoromethyl)phenyl)thio)propan-2-amine (2E) [ka] (2-Methyl-2-nitropropyl)(2-(trifluoromethyl)phenyl)sulfane 2D (350 mg, 1.5 mmol) was dissolved in methanol (10 mL), and Raney nickel (50 mg) was added. A hydrogen balloon was installed and replaced three times, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The Raney nickel was removed by filtration, and the filtrate was dried to obtain the product 2-methyl-1-((2-(trifluoromethyl)phenyl)thio)propan-2-amine 2E (312 mg, yield: 100%) as a yellow oil. This was used in the next step without further purification.

[0158] Step 4: (1R,5S,6r)-6-((2-methyl-1-((2-(trifluoromethyl)phenyl)thio)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2F) [ka] 2-Methyl-1-((2-(trifluoromethyl)phenyl)thio)propan-2-amine 2E (100 mg, 0.40 mmol), (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (91 mg, 0.4 mmol), HATU (190 mg, 0.5 mmol), and triethylamine (101 mg, 1 mmol) were dissolved in N,N-dimethylformamide (1 mL) and stirred at room temperature for 16 hours. Water (2 mL) was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a white solid (1R,5S,6r)-6-((2-methyl-1-((2-(trifluoromethyl)phenyl)sulfonyl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester) 2F (110 mg, yield: 60.1%).

[0159] Step 5: (1R,5S,6r)-N-(2-methyl-1-((2-(trifluoromethyl)phenyl)thio)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide formate [ka] (1R,5S,6r)-6-((2-methyl-1-((2-(trifluoromethyl)phenyl)thio)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 2F (110 mg, 0.30 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was dried, and aqueous ammonia (1 mL) was added. The mixture was extracted with dichloromethane (5 mL × 3) to obtain the crude product as an organic phase. The crude product was purified by preparative HPLC to give a white solid (1R,5S,6r)-N-(2-methyl-1-((2-(trifluoromethyl)phenyl)thio)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide formate (compound 2) (25 mg, yield: 22.2%). 1 H NMR(400MHz,DMSO-d6) δ 8.83(s,1H),7.93(s,1H),7.69(d,1H),7.65-7.55(M,2H),7.37(t,1H),3.52(s,2H),3.23(M,4H),1.87(M,2H),1.58(M,1H),1.32(s,6H). MS (ESI): m / z = 359.2 [M+H] +

[0160] Example 3 (1R,5S,6r)-N-(2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 3) [ka]

[0161] Step 1: 3-(Cyclopentylthio)pyridine-2-carbonitrile (3A) [ka] Cyclopentanethiol (918 mg, 9.0 mmol) was dissolved in N,N-dimethylformamide (40 mL). Sodium hydride (60%, 540 mg, 13.5 mmol) was slowly added at 0 °C and the mixture was allowed to react for 30 minutes. 3-Fluoropyridine-2-carbonitrile 1A (1.1 g, 9.0 mmol) was added, and the mixture was slowly warmed to room temperature and stirred overnight at room temperature. LCMS monitoring indicated the reaction was complete. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and rotary evaporated in vacuo to give 3-(cyclopentylthio)pyridine-2-carbonitrile 3A (770 mg, yellow oil). The crude product was used directly in the next step. MS (ESI): m / z = 205.1 [M+H] +

[0162] Step 2: (3-(cyclopentylthio)pyridin-2-yl)methanamine (3B) [ka] 3-(Cyclopentylthio)pyridine-2-carbonitrile 3A was dissolved in methanol (30 mL), and aqueous ammonia (6 mL) was added, followed by the addition of Raney nickel (catalytic amount). The atmosphere was purged with hydrogen gas three times and the mixture was stirred at room temperature overnight. The reaction mixture was filtered under suction to give (3-(cyclopentylthio)pyridin-2-yl)methanamine 3B (800 mg, crude product). This was used directly in the next step. MS (ESI): m / z = 209.1 [M+H] +

[0163] Step 3: (1-(((3-(cyclopentylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester (3C) [ka] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (933.8 mg, 4.6 mmol) and HATU (1.7 g, 4.6 mmol) were dissolved in N,N-dimethylformamide (30 mL) and reacted at room temperature for 0.5 hours. Then, (3-(cyclopentylthio)pyridin-2-yl)methanamine 3B (800 mg, 3.8 mmol) and DIEA (2.1 mL) were added and stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give (1-(((3-(cyclopentylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 3C (600 mg, pale yellow oil). MS (ESI): m / z = 394.1 [M+H] +

[0164] Step 4: tert-Butyl (2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (3D) [ka] (1-(((3-(cyclopentylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 3C (600 mg, 1.53 mmol) was dissolved in dichloromethane (20 mL), Burgess reagent (1.46 g, 6.1 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give (2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate tert-butyl ester 3D (260 mg, yield: 45%, yellow oil). MS (ESI): m / z = 376.1 [M+H] +

[0165] Step 5: 2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (3E) [ka] Tert-butyl (2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 3D (260 mg, 0.69 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature overnight. The reaction solution was rotary evaporated in vacuo to give 2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 3E hydrochloride (180 mg, crude product). This was used in the next step as is. MS (ESI): m / z = 276.1 [M+H] +

[0166] Step 6: (1R,5S,6r)-6-((2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]-3-carboxylic acid tert-butyl ester (3F) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (182 mg, 0.8 mmol) and HATU (304 mg, 0.8 mmol) were dissolved in DMF (10 mL) and reacted at room temperature for 0.5 h. Then, 2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 3E (180 mg, 0.65 mmol) and DIEA (0.5 mL) were added and stirred overnight at room temperature. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give (1R,5S,6r)-6-((2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]-3-carboxylic acid tert-butyl ester 3F (200 mg, yield: 63.5%, yellow oil). MS (ESI): m / z = 485.1 [M+H] +

[0167] Step 7: (1R,5S,6r)-N-(2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 3) [ka] (1R,5S,6r)-6-((2-(8-(cyclopentylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]-3-carboxylic acid tert-butyl ester 3F (200 mg, 0.41 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature for 3 hours. The reaction mixture was spun under vacuum, and the solvent was removed to obtain the crude product. The crude product was purified by preparative HPLC to obtain the pure product (compound 3) (47 mg, yield: 29.8%) as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.40(s,1H),8.14(d,1H),7.20(s,1H),6.68(d,1H),6.61(t,1H),3.85(M,1H),2.92(M,2 H),2.76(M,2H),2.12(M,2H),1.73(M,2H),1.64(s,6H),1.62-1.57(M,5H),1.52(M,2H). MS (ESI): m / z = 385.1 [M+H] +

[0168] Example 4 (1R,5S,6r)-N-(2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 4) [ka]

[0169] Step 1: 3-(thiazol-2-ylsulfanyl)pyridine-2-carbonitrile (4A) [ka] Thiazole-2-thiol (1.44 g, 12.30 mmol), KCO 3( The resulting mixture (3.39 g, 24.59 mmol) was dissolved in DMF (30 mL) and stirred for 5 min. Then, 3-fluoropyridine-2-carbonitrile 1A (1 g, 8.19 mmol) was added and reacted for 2 h. After completion of the reaction, the mixture was quenched with 50 mL of water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, concentrated in vacuo, and the resulting residue was purified using a silica gel column (petroleum ether / ethyl acetate = 2 / 1) to give 3-(thiazol-2-ylsulfanyl)pyridine-2-carbonitrile 4A (1.6 g, yield: 89%). MS (ESI): m / z = 220.1 [M+H] +

[0170] Step 2: (3-(thiazol-2-ylsulfanyl)pyridin-2-yl)methanamine (4B) [ka] 3-(Thiazol-2-ylsulfanyl)pyridine-2-carbonitrile 4A (1.6 g, 7.17 mmol) was dissolved in MeOH (50 mL), palladium on carbon (200 mg) was added, and the mixture was purged with hydrogen gas three times and reacted overnight. After completion of the reaction, the mixture was filtered, and the organic phase of the filtrate was dried to give crude (3-(thiazol-2-ylsulfanyl)pyridin-2-yl)methanamine 4B (1.8 g) as an off-white solid. MS (ESI): m / z = 224.1 [M+H] +

[0171] Step 3: tert-Butyl (2-methyl-1-oxo-1-(((3-(thiazol-2-ylsulfanyl)pyridin-2-yl)methyl)amino)propan-2-yl)carbamate (4C) [ka] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (1.75 g, 8.61 mmol) and HATU (3.60 g, 9.47 mmol) were dissolved in DMF (30 mL) at room temperature, and then (3-(thiazol-2-ylsulfanyl)pyridin-2-yl)methanamine 4B (1.8 g, crude product) and DIEA (2.78 g, 21.52 mmol) were added. After reacting for 1 h, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The organic phase was washed once with 50 mL of saturated aqueous NaCl solution. The organic phase was dried over anhydrous sodium sulfate, suction filtered, and the organic phase was dried. The resulting residue was purified by silica gel column (petroleum ether / ethyl acetate=2 / 1) to give a white solid (2-methyl-1-oxo-1-(((3-(thiazol-2-ylsulfanyl)pyridin-2-yl)methyl)amino)propan-2-yl)tert-butylcarbamate 4C (1.1 g, yield: 37.0%). MS (ESI): m / z = 409.1 [M+H] +

[0172] Step 4: tert-Butyl (2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (4D) [ka] Tert-butyl (2-methyl-1-oxo-1-(((3-(thiazol-2-ylsulfanyl)pyridin-2-yl)methyl)amino)propan-2-yl)carbamate 4C (1.1 g, 2.70 mmol) was dissolved in dry DCM (10 mL), Burgess reagent (3.30 g, 13.48 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed once with 50 mL of saturated aqueous NaCl solution. The organic phase was dried over anhydrous sodium sulfate, suction filtered, and the organic phase was dried. The resulting residue was purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1) to give a white solid (2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)tert-butylcarbamate 4D (200 mg, yield: 19.0%). MS (ESI): m / z = 391.1 [M+H] +

[0173] Step 5: 2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (4E) [ka] To tert-butyl (2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 4D (200 mg, 0.51 mmol), 4 M hydrochloric acid in 1,4-dioxane (5 mL) was added and stirred at room temperature for 30 min. After completion of the reaction, the mixture was evaporated to dryness under vacuum to give crude 2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 4E (120 mg) as an oil. MS (ESI): m / z = 291.1 [M+H] +

[0174] Step 6: (1R,5S,6r)-6-((2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (4F) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (139 mg, 0.61 mmol) and HATU (252 mg, 0.66 mmol) were dissolved in DMF (5 mL). The crude oil product, 2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 4E (120 mg) and DIEA (197 mg, 1.53 mmol), were added and the mixture was stirred at room temperature for 1 h. The mixture was then quenched with water (10 mL). The mixture was then extracted with ethyl acetate (5 mL × 3). The organic phase was washed once with 20 mL of saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and filtered under vacuum. The organic phase was dried and the resulting residue was purified by preparative plate (petroleum ether:ethyl acetate=2:1) ​​to give a white solid (1R,5S,6r)-6-((2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 4F (110 mg, yield: 43.2%). MS (ESI): m / z = 500.1 [M+H] +

[0175] Step 7: (1R,5S,6r)-N-(2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 4) [ka] (1R,5S,6r)-6-((2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 4F (110 mg, 0.22 mmol) was added to 4M / L hydrochloric acid in 1,4-dioxane (3 mL) and stirred at room temperature for 30 min. After completion of the reaction, the mixture was dried in a vacuum oven and purified by pre-HPLC to give (1R,5S,6r)-N-(2-(8-(thiazol-2-ylsulfanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 4) (38 mg, yield: 43.2%). 1 HNMR(400MHz,DMSO-d6) δ 8.40(s,1H),8.37(d,1H),7.82(d,1H),7.77(d,1H),7.19(s,1H),7.07(d,1H), 6.71(dd,1H),2.88(d,2H),2.70(d,2H),1.65(s,6H),1.57(M,1H),1.50(M,2H). MS (ESI): m / z = 400.1 [M+H] +

[0176] Example 5 1-Methyl-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 5-P1 and Compound 5-P2) [ka]

[0177] Step 1: 1-methyl-6-((2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (5A) [ka] 3-(tert-Butoxycarbonyl)-1-methyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (racemic, 200 mg, 0.83 mmol) was dissolved in DMF (2 mL), and 2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 1E, DIEA (321 mg, 2.49 mmol), and HATU (473 mg, 1.24 mmol) were added. The mixture was allowed to react at room temperature for 6 hours. Ethyl acetate (20 mL) was added to the reaction mixture, which was then washed with saturated brine (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1 to 1 / 5) to obtain a yellow solid compound 1-methyl-6-((2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 5A (162 mg, yield: 43.7%). MS (ESI): m / z = 445.1 [M+H] + 5A was subjected to chiral resolution to give 5A-P1 (65 mg, a compound with a short retention time) and 5A-P2 (63 mg, a compound with a long retention time). The chiral resolution conditions are shown in the table below. [Table 1]

[0178] Step 2: 1-methyl-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 5) [ka] 1-Methyl-6-((2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 5A-P1 (65 mg, 0.146 mmol) was dissolved in a hydrochloric acid-dioxane solution (5 mL) and reacted at room temperature for 1 hour. The reaction solution was rotary evaporated in vacuo to remove the solvent. The residue was dissolved in DCM, neutralized with saturated NaHCO3, and purified by prep-TLC (DCM / MeOH) to give the target compound 1-methyl-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 5-P1) (11 mg, yield: 22%). 1 H NMR(400MHz,DMSO-d6) δ 8.41(s,1H),8.09(d,1H),7.20(s,1H),6.59(t,1H),6.53(d,1H),2.95-2.80(M,3H), 2.67(d,1H),2.54(s,3H),2.05-1.95(M,2H),1.68(s,3H),1.62(s,3H),0.96(s,3H). MS (ESI): m / z = 345.1 [M+H] +

[0179] 5A-P2 (63 mg, 0.142 mmol) was deprotected with hydrochloric acid according to the same method as above to give compound 1-methyl-N-(2-(8-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 5-P2) (9 mg, yield: 18%). 1 H NMR(400MHz,DMSO-d6) δ 8.43(s,1H),8.09(d,1H),7.20(s,1H),6.61(t,1H),6.53(d,1H),2.99-2.87(M,3 H),2.73(d,1H),2.54(s,3H),2.01(M,2H),1.68(s,3H),1.62(s,3H),0.97(s,3H). MS (ESI): m / z = 345.1 [M+H] +

[0180] Example 6 (1R,5S,6r)-N-(2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (Compound 6) [ka]

[0181] Step 1: 3-Mercaptopyridine-2-carbonitrile (6B) [ka] 3-Chloro-2-cyanopyridine 6A (2.0 g, 14.4 mmol) and sodium sulfide nonahydrate (3.8 g, 15.8 mmol) were dissolved in N,N-dimethylformamide (60 mL) and stirred at room temperature overnight. LCMS monitoring indicated the reaction was complete. The reaction mixture was used directly in the next step without further treatment.

[0182] Step 2: 3-(ethylthio)pyridine-2-carbonitrile (6C) [ka] To the reaction mixture obtained in Step 1, iodoethane (2.75 g, 17.6 mmol) and potassium carbonate (6.1 g, 44.1 mmol) were added and stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and rotary evaporated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain 3-(ethylthio)pyridine-2-carbonitrile 6C (1.2 g, yield: 49.8%, yellow oil). MS (ESI): m / z = 165.1 [M+H] +

[0183] Step 3: (3-(ethylthio)pyridin-2-yl)methanamine (6D) [ka] 3-(Ethylthio)pyridine-2-carbonitrile 6C (1.1 g, 6.1 mmol) was dissolved in methanol (30 mL), and 10% palladium-carbon (catalytic amount) was added. The mixture was reacted at room temperature for 2 days (during which time, new palladium-carbon replacement was required). The reaction mixture was filtered under suction to give (3-(ethylthio)pyridin-2-yl)methanamine 6D (1.2 g, crude product). MS (ESI): m / z = 169.1 [M+H] +

[0184] Step 4: (1-(((3-(ethylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester (6E) [ka] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (1.45 g, 7.13 mmol) and HATU (2.99 g, 7.86 mmol) were dissolved in N,N-dimethylformamide (30 mL) and reacted at room temperature for 0.5 hours. Next, (3-(ethylthio)pyridin-2-yl)methanamine 6D (1.2 g, 7.14 mmol) and DIEA (2.37 mL) were added and stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give (1-(((3-(ethylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 6E (1.6 g, yield: 63.5%, pale yellow oil). MS (ESI): m / z = 354.1 [M+H] +

[0185] Step 5: tert-Butyl (2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (6F) [ka] (1-(((3-(ethylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 6E (1.5 g, 4.24 mmol) was dissolved in dichloromethane (20 mL), Burgess reagent (2.02 g, 8.48 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give tert-butyl (2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 6F (570 mg, yield: 40.1%, pale yellow oil). MS (ESI): m / z = 336.1 [M+H] +

[0186] Step 6: 2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (6G) [ka] Tert-butyl (2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 6F (570 mg, 1.7 mmol) was dissolved in a hydrochloric acid-methanol solution (20 mL) and reacted at room temperature overnight. The reaction solution was rotary evaporated in vacuo to give 2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 6G (510 mg, crude product). This was used in the next step as is. MS (ESI): m / z = 236.1 [M+H] +

[0187] Step 7: (1R,5S,6r)-6-((2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-carboxylic acid tert-butyl ester (6H) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (300 mg, 1.32 mmol) and HATU (501 mg, 1.32 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 0.5 h. Next, 2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 6G (260 mg, 1.1 mmol) and DIEA (0.5 mL) were added and stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=15 / 1) to give (1R,5S,6r)-6-((2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-carboxylic acid tert-butyl ester 6H (410 mg, yield: 83.7%, yellow oil). MS (ESI): m / z = 445.2 [M+H] +

[0188] Step 8: (1R,5S,6r)-N-(2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (compound 6) [ka] (1R,5S,6r)-6-((2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid tert-butyl ester 6H (410 mg, 0.922 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature for 3 hours. The reaction mixture was rotary evaporated under vacuum to remove the solvent, and then lyophilized to give the target compound (1R,5S,6r)-N-(2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (compound 6) (240 mg, yield: 68.4%) as a yellowish solid. 1 H NMR(400MHz,DMSO-d6) δ 9.16(s,1H),8.32(t,1H),7.89(s,1H),6.98(d,2H),3.27(M,4H),3.16(q,2H),1.91(M,1H),1.80(M,2H),1.75(s,6H),1.32(t,3H). MS (ESI): m / z = 345.1 [M+H] +

[0189] Example 7 (1R,5S,6r)-N-(2-(8-(isopropylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 7) [ka]

[0190] Step 1: 3-(Isopropylthio)pyridine-2-carbonitrile (7A) [ka] After preparing 6B as described above, 2-bromopropane (0.97 g, 7.9 mmol) and potassium carbonate (1.83 g, 13.2 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and rotary evaporated in vacuo to give 3-(isopropylthio)pyridine-2-carbonitrile 7A (crude product). The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(isopropylthio)pyridine-2-carbonitrile 7A (680 mg, yield: 52.7%, yellow oil). MS (ESI): m / z = 179.1 [M+H] +

[0191] Step 2: (3-(isopropylthio)pyridin-2-yl)methanamine hydrochloride (7B) [ka] 3-(Isopropylthio)pyridine-2-carbonitrile 7A (0.68 g, 3.8 mmol) was dissolved in methanol (15 mL), 1 mL of concentrated hydrochloric acid was added, and then 10% palladium on carbon (catalytic amount) was added and the mixture was allowed to react at room temperature overnight. The reaction mixture was suction filtered through Celite to give (3-(isopropylthio)pyridin-2-yl)methanamine hydrochloride 7B (0.6 g, crude product), which was used directly in the next step. MS (ESI): m / z = 183.1 [M+H] +

[0192] Step 3: tert-Butyl (1-(((3-(isopropylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate (7C) [ka] 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (0.80 g, 3.96 mmol) and HATU (1.50 g, 3.96 mmol) were dissolved in DMF (15 mL) and reacted at room temperature for 20 min. After that, (3-(isopropylthio)pyridin-2-yl)methanamine 7B (0.60 g, 3.29 mmol) and DIEA (1.27 g, 9.87 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give crude tert-butyl (1-(((3-(isopropylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 7C. Purification by silica gel column chromatography (petroleum ether / ethyl acetate=2 / 1) gave tert-butyl (1-(((3-(isopropylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 7C (740 mg, yield: 61.1%, pale yellow oil). MS (ESI): m / z = 368.1 [M+H] +

[0193] Step 4: tert-Butyl (2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (7D) [ka] tert-Butyl (1-(((3-(isopropylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 7C (0.74 g, 2.02 mmol) was dissolved in dichloromethane (10 mL), Burgess reagent (1.92 g, 8.08 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated in vacuo to give crude tert-butyl (2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 7D. Purification by silica gel column chromatography (petroleum ether / ethyl acetate=2 / 1) gave tert-butyl (2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 7D (400 mg, yield: 56.9%, pale yellow oil). MS (ESI): m / z = 350.1 [M+H] +

[0194] Step 5: 2-(8-(isopropylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (7E) [ka] Tert-butyl (2-(8-(ethylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 7D (100 mg, 0.29 mmol) was dissolved in a hydrochloric acid-dioxane solution (8 mL) and reacted at room temperature for 2 hours. The reaction solution was rotary evaporated in vacuo to give 2-(8-(isopropylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 7E (70 mg, crude product). This was used in the next step as is. MS (ESI): m / z = 250.1 [M+H] +

[0195] Step 6: (1R,5S,6r)-6-((2-(8-(isopropylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]-3-carboxylic acid tert-butyl ester (7F) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (109.4 mg, 0.48 mmol) and HATU (183.1 mg, 0.48 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 0.5 h. Next, 2-(8-(isopropylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 7E (70 mg, 0.28 mmol) and DIEA (108.8 mg, 0.84 mmol) were added and stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated in vacuo to give the crude product (1R,5S,6r)-6-((2-(8-(isopropylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]-3-carboxylic acid tert-butyl ester 7F (150 mg, crude product). MS (ESI): m / z = 459.1 [M+H] +

[0196] Step 7: (1R,5S,6r)-N-(2-(8-(isopropylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 7) [ka] (1R,5S,6r)-6-((2-(8-(isopropylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]-3-carboxylic acid tert-butyl ester 7F (150 mg) was dissolved in a hydrochloric acid-dioxane solution (5 mL) and reacted at room temperature for 1 hour. The reaction mixture was rotary evaporated to remove the solvent, yielding a crude product. The crude product was purified by preparative HPLC to obtain the target compound (1R,5S,6r)-N-(2-(8-(isopropylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 7) (60 mg, yield: 76.9%, white solid). 1 H NMR(400MHz,DMSO-d6) δ 8.38(s,1H),8.17(d,1H),7.23(s,1H),6.72(d,1H),6.60(t,1H),3.67(M,1H), 2.87(d,2H),2.68(d,2H),1.64(s,6H),1.57(t,1H),1.47(M,2H),1.31(d,6H). MS (ESI): m / z = 359.1 [M+H] +

[0197] Example 8 (1R,5S,6r)-N-(2-(8-((cyclopropylmethyl)thio))thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 8) [ka]

[0198] Step 1: 3-((cyclopropylmethyl)thio)pyridine-2-carbonitrile (8A) [ka] After preparing 6B as described above, (bromomethyl)cyclopropane (964 mg, 7.2 mmol) and potassium carbonate (2.98 g, 21.6 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and rotary evaporated in vacuo to give 3-((cyclopropylmethyl)thio)pyridine-2-carbonitrile 8A (crude product) (1.1 g, yield: 80.3%, yellow oil). MS (ESI): m / z = 191.0 [M+H] +

[0199] Step 2: (3-((cyclopropylmethyl)thio)pyridin-2-yl)methanamine (8B) [ka] 3-((cyclopropylmethyl)thio)pyridine-2-carbonitrile 8A (1.1 g, 5.7 mmol) was dissolved in methanol (30 mL), and then Raney nickel (catalytic amount) and aqueous ammonia (3 mL) were added. The reaction mixture was reacted at room temperature for 18 hours. The reaction mixture was filtered under suction to give (3-((cyclopropylmethyl)thio)pyridin-2-yl)methanamine 8B (crude product) (1.0 g, yield: 89.3%) as a yellow oil. MS (ESI): m / z = 195.0 [M+H] +

[0200] Step 3: (1-(((3-((cyclopropylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester (8C) [ka] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (1.04 g, 5.15 mmol) and HATU (2.54 g, 6.69 mmol) were dissolved in N,N-dimethylformamide (15 mL) and reacted at room temperature for 0.5 h. Next, (3-((cyclopropylmethyl)thio)pyridin-2-yl)methanamine 8B (1.0 g, 5.15 mmol) and triethylamine (1.56 g, 15.45 mmol) were added and stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product, (1-(((3-((cyclopropylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 8C, was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give (1-(((3-((cyclopropylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 8C (900 mg, yield: 46.1%, pale yellow oil). MS (ESI): m / z = 380.2 [M+H] +

[0201] Step 4: tert-Butyl (2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (8D) [ka] (1-(((3-((cyclopropylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 8C (900 mg, 4.24 mmol) was dissolved in dichloromethane (10 mL), Burgess reagent (1.51 g, 6.36 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated in vacuo to give the crude product (2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate tert-butyl ester. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to give tert-butyl (2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 8D (600 mg, yield: 70.0%, pale yellow oil). MS (ESI): m / z = 362.2 [M+H] +

[0202] Step 5: 2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (8E) [ka] Tert-butyl (2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 8D (600 mg, 1.7 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature for 2 hours. The reaction solution was rotary evaporated in vacuo to give 2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 8E (500 mg, crude product). This was used in the next step as is. MS (ESI): m / z = 262.1 [M+H] +

[0203] Step 6: (1R,5S,6r)-6-((2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (8F) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (60.8 mg, 0.27 mmol) and HATU (133 mg, 0.35 mmol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at room temperature for 0.5 h. Next, 2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 8E (70 mg, 0.27 mmol) and triethylamine (81.8 mg, 0.81 mmol) were added and stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product, (1R,5S,6r)-6-((2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 8F, was purified by silica gel column chromatography (dichloromethane / methanol=20 / 1) to give (1R,5S,6r)-6-((2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 8F (60 mg, yield: 47.6%, yellow oil). MS (ESI): m / z = 471.2 [M+H] +

[0204] Step 7: (1R,5S,6r)-N-(2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 8) [ka] (1R,5S,6r)-6-((2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 8F (60 mg, 0.127 mmol) was dissolved in a hydrochloric acid-methanol solution (5 mL) and reacted at room temperature for 3 hours. The reaction mixture was rotary evaporated in vacuo to remove the solvent, yielding a crude product. The crude product was purified by preparative HPLC to yield (1R,5S,6r)-N-(2-(8-((cyclopropylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 8) (20 mg, yield: 42.5%, white solid). 1 H NMR(400MHz,CD3OD) δ 8.50(s,1H),8.13(d,1H),7.34(s,1H),6.74(d,1H),6.61(t,1H),3.35(s,2H),3.28-3.25(M,2H ),2.98(d,2H),1.92(M,2H),1.78(s,6H),1.66(M,1H),1.09(M,1H),0.59(dd,2H),0.29(dd,2H). MS (ESI): m / z = 371.2 [M+H] +

[0205] Example 9 (1R,5S,6r)-N-(2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 9) [ka]

[0206] Step 1: 3-(benzylthio)pyridine-2-carbonitrile (9A) [ka] After preparing 6B as described above, (bromomethyl)benzene (1.5 g, 8.8 mmol) and potassium carbonate (4.1 g, 29.4 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and rotary evaporated in vacuo to give 3-(benzylthio)pyridine-2-carbonitrile 9A (1.3 g, yellow oil). The crude product was used directly in the next step. MS (ESI): m / z = 227.1 [M+H] +

[0207] Step 2: (3-(benzylthio)pyridin-2-yl)methanamine hydrochloride (9B) [ka] 3-(Benzylthio)pyridine-2-carbonitrile 9A (1.3 g, 5.75 mmol) was dissolved in methanol (30 mL), hydrochloric acid (2 mL) was added, and 10% palladium-carbon (catalytic amount) was added. The mixture was reacted at room temperature for 3 days (during this time, it was necessary to replace the palladium-carbon with new palladium-carbon). The reaction solution was filtered under suction to give (3-(benzylthio)pyridin-2-yl)methanamine hydrochloride 9B (1.2 g, crude product). This was used directly in the next step. MS (ESI): m / z = 231.1 [M+H] +

[0208] Step 3: (1-(((3-(benzylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester (9C) [ka] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (1.06 g, 5.2 mmol) and HATU (2.15 g, 5.65 mmol) were dissolved in N,N-dimethylformamide (30 mL) and reacted at room temperature for 0.5 h. Next, (3-(benzylthio)pyridin-2-yl)methanamine 9B (1.20 g, 5.2 mmol) and DIEA (2.1 mL) were added and stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give crude product 9C. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give (1-(((3-(benzylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 9C (600 mg, yield: 27.9%, pale yellow oil). MS (ESI): m / z = 416.1 [M+H] +

[0209] Step 4: tert-Butyl (2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (9D) [ka] (1-(((3-(benzylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 9C (600 mg, 1.45 mmol) was dissolved in dichloromethane (20 mL), and Burgess reagent (1.38 g, 5.8 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give crude (2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate tert-butyl ester 9D. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to give tert-butyl (2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 9D (230 mg, yield: 40%, pale yellow oil). MS (ESI): m / z = 398.1 [M+H] +

[0210] Step 5: 2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (9E) [ka] Tert-butyl (2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 9D (230 mg, 0.58 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature overnight. The reaction solution was rotary evaporated in vacuo to give 2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 9E (200 mg, crude product). This was used in the next step as is. MS (ESI): m / z = 298.1 [M+H] +

[0211] Step 6: (1R,5S,6r)-6-((2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (9F) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (182 mg, 0.8 mmol) and HATU (304 mg, 0.8 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 0.5 h. Next, 2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 9E (200 mg, 0.67 mmol) and DIEA (0.5 mL) were added and stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give crude product 9F. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give (1R,5S,6r)-6-((2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 9F (170 mg, yield: 50.1%, yellow oil). MS (ESI): m / z = 507.1 [M+H] +

[0212] Step 7: (1R,5S,6r)-N-(2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 9) [ka] (1R,5S,6r)-6-((2-(8-(benzylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 9F (170 mg, 0.336 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature for 3 hours. The reaction solution was rotary evaporated in vacuo to remove the solvent and obtain the crude product. The crude product was purified by preparative HPLC to obtain the product (compound 9) (43 mg, yield: 31.5%) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 8.38(s,1H),8.12(d,1H),7.40(d,2H),7.32(t,2H),7.27(d,1H),7.23(s,1H),6.67(d,1H), 6.56(t,1H),4.35(s,2H),2.88(d,2H),2.70(d,2H),1.64(s,6H),1.56(t,1H),1.49(M,2H). MS (ESI): m / z = 407.0 [M+H] +

[0213] Example 10 (1R,5S,6r)-N-(2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 10) [ka]

[0214] Step 1: 3-(isobutylthio)pyridine-2-carbonitrile (10A) [ka] After preparing 6B as described above, 1-bromo-2-methylpropane (1.48 mg, 10.87 mmol) and potassium carbonate (3 g, 21.74 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and rotary evaporated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-(isobutylthio)pyridine-2-carbonitrile 10A (800 mg, yield: 57.5%) as a yellow oil. MS (ESI): m / z = 193.1 [M+H] +

[0215] Step 2: (3-(isobutylthio)pyridin-2-yl)methanamine hydrochloride (10B) [ka] 3-(Isobutylthio)pyridine-2-carbonitrile 10A (800 mg, 4.17 mmol) was dissolved in methanol (30 mL), 1 mL of concentrated hydrochloric acid was added, and then 10% palladium-carbon (catalytic amount) was added. The reaction mixture was then filtered under suction to give crude (3-(isobutylthio)pyridin-2-yl)methanamine hydrochloride 10B (1.0 g). MS (ESI): m / z = 197.1 [M+H] +

[0216] Step 3: (1-(((3-(isobutylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester (10C) [ka] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (1.01 g, 5.0 mmol) and HATU (1.9 g, 5.0 mmol) were dissolved in DMF (30 mL) and reacted at room temperature for 15 min. After that, (3-(isobutylthio)pyridin-2-yl)methanamine 10B (1 g, 4.17 mmol) and DIEA (1.27 g, 9.87 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=2 / 1) to give a pale yellow solid (1-(((3-(isobutylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 10C (680 mg, yield: 61.1%). MS (ESI): m / z = 382.1 [M+H] +

[0217] Step 4: tert-Butyl (2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (10D) [ka] (1-(((3-(isobutylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 10C (680 mg, 1.78 mmol) was dissolved in dichloromethane (20 mL), and Burgess reagent (1.68 g, 7.14 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl (2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 10D (280 mg, yield: 56.9%, pale yellow oil). MS (ESI): m / z = 364.1 [M+H] +

[0218] Step 5: 2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (10E) [ka] Tert-butyl (2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 10D (280 mg, 0.77 mmol) was dissolved in a hydrochloric acid-dioxane solution (8 mL) and reacted at room temperature overnight. The reaction solution was rotary evaporated in vacuo to give 2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 10E (250 mg, crude product). This was used in the next step as is. MS (ESI): m / z = 264.1 [M+H] +

[0219] Step 6: (1R,5S,6r)-6-((2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (10F) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (258 mg, 1.14 mmol) and HATU (433 mg, 1.14 mmol) were dissolved in DMF (10 mL) and reacted at room temperature for 0.5 h. Next, 2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 10E (250 mg, 0.95 mmol) and DIEA (368 mg, 2.85 mmol) were added and stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give (1R,5S,6r)-6-((2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 10F (300 mg, yield: 77.7%, yellow oil). MS (ESI): m / z = 473.1 [M+H] +

[0220] Step 7: (1R,5S,6r)-N-(2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 10) [ka] (1R,5S,6r)-6-((2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 10F (300 mg, 0.63 mmol) was dissolved in 5 mL of hydrochloric acid-dioxane solution and reacted at room temperature for 1 hour. The reaction mixture was dried by rotary evaporation under vacuum to remove the solvent, and the product was lyophilized to give the target compound, (1R,5S,6r)-N-(2-(8-(isobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 10) (60 mg, yield: 76.9%, white solid). 1 H NMR(400MHz,DMSO-d6) δ 8.40(s,1H),8.12(d,1H),7.22(s,1H),6.64(d,1H),6.58(t,1H),2.95(d,2H),2.89( d,2H),2.72(d,2H),1.88(M,1H),1.64(s,6H),1.57(M,1H),1.50(M,2H),1.03(d,6H). MS (ESI): m / z = 373.1 [M+H] +

[0221] Example 11 (1R,5S,6r)-N-(2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 11) [ka]

[0222] Step 1: 3-((cyclobutylmethyl)thio)pyridine-2-carbonitrile (11A) [ka] After preparing 6B as described above, cyclobutyl bromomethane (1.31 g, 8.80 mmol) and potassium carbonate (3.05 g, 22.0 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and rotary evaporated in vacuo to give 3-((cyclobutylmethyl)thio)pyridine-2-carbonitrile 11A (crude product). The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-((cyclobutylmethyl)thio)pyridine-2-carbonitrile 11A (840 mg, yield: 56%, yellow oil). MS (ESI): m / z = 205.1 [M+H] +

[0223] Step 2: (3-((cyclobutylmethyl)thio)pyridin-2-yl)methanamine hydrochloride (11B) [ka] 3-((cyclobutylmethyl)thio)pyridine-2-carbonitrile 11A (840 mg, 4.12 mmol) was dissolved in methanol (20 mL), hydrochloric acid (1 mL) was added, and 10% palladium-carbon (catalytic amount) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 3 days (during which time, new palladium-carbon replacement was required). The reaction solution was filtered under suction to give (3-((cyclobutylmethyl)thio)pyridin-2-yl)methanamine hydrochloride 11B (1.07 g, crude product). MS (ESI): m / z = 209.1 [M+H] +

[0224] Step 3: (1-(((3-((cyclobutylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester (11C) [ka] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (1.05 g, 5.14 mmol) and HATU (2.15 g, 5.65 mmol) were dissolved in N,N-dimethylformamide (30 mL) and reacted at room temperature for 0.5 h. Then, (3-((cyclobutylmethyl)thio)pyridin-2-yl)methanamine 11B (1.07 g, 5.14 mmol) and DIEA (2.1 mL) were added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product. The crude product, (1-(((3-((cyclobutylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 11C, was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give (1-(((3-((cyclobutylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 11C (800 mg, yield: 39.6%, pale yellow oil). MS (ESI): m / z = 394.2 [M+H] +

[0225] Step 4: tert-Butyl (2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (11D) [ka] (1-(((3-((cyclobutylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 11C (800 mg, 2.04 mmol) was dissolved in dichloromethane (20 mL), Burgess reagent (971 mg, 4.07 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with dichloromethane, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated in vacuo to give the crude product. The crude product, tert-butyl (2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 11D, was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to give tert-butyl (2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 11D (290 mg, yield: 38%, pale yellow oil). MS (ESI): m / z = 376.2 [M+H] +

[0226] Step 5: 2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (11E) [ka] Tert-butyl (2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 11D (290 mg, 0.773 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature overnight. The reaction solution was rotary evaporated in vacuo to give 2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 11E (215 mg, crude product). This was used in the next step as is. MS (ESI): m / z = 276.1 [M+H] +

[0227] Step 6: (1R,5S,6r)-6-((2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (11F) [ka] (1R,5S,6R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (213 mg, 0.938 mmol) and HATU (357 mg, 0.938 mmol) were dissolved in N,N-dimethylformamide (10 mL) and the mixture was stirred at room temperature for 0.5 h. Next, 2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 11E (215 mg, 0.782 mmol) and DIEA (0.5 mL) were added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated in vacuo to give the crude product (1R,5S,6r)-6-((2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 11F. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give (1R,5S,6r)-6-((2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 11F (180 mg, yield: 47.6%, yellow oil). MS (ESI): m / z = 485.1 [M+H] +

[0228] Step 7: (1R,5S,6r)-N-(2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 11) [ka] (1R,5S,6r)-6-((2-(8-((cyclobutylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 11F (180 mg, 0.372 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature for 3 hours. The reaction solution was rotary evaporated in vacuo to remove the solvent, and the crude product was obtained. The crude product was purified by preparative HPLC to obtain a white solid (Compound 11) (12 mg, yield: 83.9%). 1 H NMR(400MHz,DMSO-d6) δ 8.60(s,1H),8.38(s,1H),8.18(d,1H),7.26(s,1H),6.69(d,1H),6.64(t,1H),3.19(d,2H),3.08( d,2H),2.98(d,2H),2.59-2.56(M,3H),2.13(M,2H),1.94-1.78(M,4H),1.70(s,6H),1.67(M,1H). MS (ESI): m / z = 385.1 [M+H] +

[0229] Example 12 (1R,5S,6r)-N-(2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 12) [ka]

[0230] Step 1: 3-(cyclobutylthio)pyridine-2-carbonitrile (12A) [ka] After preparing 6B as described above, bromocyclobutane (964 mg, 7.2 mmol) and potassium carbonate (2.98 g, 21.6 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and rotary evaporated in vacuo to give 3-(cyclobutylthio)pyridine-2-carbonitrile 12A (crude product) (1.1 g, yield: 80.3%, yellow oil). MS (ESI): m / z = 191.0 [M+H] +

[0231] Step 2: (3-(cyclobutylthio)pyridin-2-yl)methanamine (12B) [ka] 3-(Cyclobutylthio)pyridine-2-carbonitrile 12A (1.1 g, 5.7 mmol) was dissolved in methanol (30 mL), and then Raney nickel (catalytic amount) and aqueous ammonia (3 mL) were added. The reaction mixture was reacted at room temperature for 18 hours. The reaction mixture was filtered under suction to give (3-(cyclobutylthio)pyridin-2-yl)methanamine 12B (crude product) (1.0 g, yield: 89.3%) as a yellow oil. MS (ESI): m / z = 195.1 [M+H] +

[0232] Step 3: (1-(((3-(cyclobutylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester (12C) [ka] (3-(Cyclobutylthio)pyridin-2-yl)methanamine 12B (400 mg, 2.06 mmol) was dissolved in dry DMF (20 mL), and then HATU (1.175 g, 3.09 mmol) was added and stirred at room temperature for 0.5 h. Next, 2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (0.502 g, 2.47 mmol) and triethylamine (1.67 g, 16.5 mmol) were added and stirred at room temperature for 2 h. The reaction was quenched with water, and the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and rotary evaporated to give the crude product as an oil. The crude product was purified by silica gel column (petroleum ether / ethyl acetate=1 / 1) to give (1-(((3-(cyclobutylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 12C (300 mg, yield: 38.4%). MS (ESI): m / z = 380.1 [M+H] +

[0233] Step 4: tert-Butyl (2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (12D) [ka] (1-(((3-(cyclobutylthio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 12C (300 mg, 0.792 mmol) was dissolved in dry dichloromethane (10 mL), and Burgess reagent (283.1 mg, 1.188 mmol) was added and stirred at room temperature overnight. The reaction mixture was rotary evaporated in vacuo to give the crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl (2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 12D (100 mg, yield: 35.1%). MS (ESI): m / z = 362.1 [M+H] +

[0234] Step 5: 2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (12E) [ka] Tert-butyl (2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 12D (100 mg, 0.277 mmol) was dissolved in a methanol solution of HCl (10 mL) and stirred at room temperature for 2 hours. The solvent was then evaporated to dryness to give crude 2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 12E (90 mg). This was used directly in the next step. MS (ESI): m / z = 262.1 [M+H] +

[0235] Step 6: (1R,5S,6r)-6-((2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (12F) [ka] 2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 12E (90 mg, 0.344 mmol) was dissolved in dry DMF (5 mL), and then HATU (197 mg, 0.518 mmol) was added and stirred at room temperature for 0.5 h. Next, (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (95 mg, 0.416 mmol) and triethylamine (278 mg, 2.75 mmol) were added and stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to give the crude product as an oil. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to give (1R,5S,6r)-6-((2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 12F (65 mg, yield: 40.1%). MS (ESI): m / z = 471.1 [M+H] +

[0236] Step 7: (1R,5S,6r)-N-(2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 12) [ka] (1R,5S,6r)-6-((2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 12F (65 mg, 0.138 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was dried, and the solvent was removed to obtain the crude product. The crude product was purified by preparative HPLC to obtain (1R,5S,6r)-N-(2-(8-(cyclobutylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 12) (11.7 mg, yield: 22.9%). 1 H NMR(400MHz,CD3OD) δ 8.13(d,1H),7.29(s,1H),6.60(t,1H),6.56(d,1H),4.12-4.05(M,1H),3.02(d,2H),2. 85(d,2H),2.59-2.51(M,2H),2.13-2.01(M,4H),1.77(s,6H),1.70(M,2H),1.48(t,1H). MS (ESI): m / z = 371.0 [M+H] +

[0237] Example 13 (1R,5S,6r)-N-(2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 13) [ka]

[0238] Step 1: 3-((cyclopentylmethyl)thio)pyridine-2-carbonitrile (13A) [ka] After preparing 6B as described above, cyclopentyl bromomethane (1 g, 6.13 mmol) and potassium carbonate (2.5 g, 18.1 mmol) were added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate and rotary evaporated in vacuo to give 3-((cyclopentylmethyl)thio)pyridine-2-carbonitrile 13A (crude product). The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 3-((cyclopentylmethyl)thio)pyridine-2-carbonitrile 13A (850 mg, yield: 56%, yellow oil). MS (ESI): m / z = 219.1 [M+H] +

[0239] Step 2: (3-((cyclopentylmethyl)thio)pyridin-2-yl)methanamine (13B) [ka] 3-((cyclopentylmethyl)thio)pyridine-2-carbonitrile 13A (850 mg, 5.5 mmol) was dissolved in methanol (30 mL), hydrochloric acid (2 mL) was added, and 10% palladium-carbon (catalytic amount) was added. The mixture was reacted at room temperature under a hydrogen atmosphere for 3 days (during which time, new palladium-carbon replacement was required). The reaction solution was filtered under suction to give (3-((cyclopentylmethyl)thio)pyridin-2-yl)methanamine 13B (800 mg, crude product). MS (ESI): m / z = 223.1 [M+H] +

[0240] Step 3: (1-(((3-((cyclopentylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester (13C) [ka] 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (900 mg, 3.96 mmol) and HATU (1.5 g, 3.96 mmol) were dissolved in N,N-dimethylformamide (15 mL) and reacted at room temperature for 0.5 h. Next, (3-((cyclopentylmethyl)thio)pyridin-2-yl)methanamine 13B (800 mg, 3.6 mmol) and DIEA (1.4 g, 10.9 mmol) were added and stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give crude product 13C. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to give (1-(((3-((cyclopentylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 13C (500 mg, yield: 34.2%, pale yellow oil). MS (ESI): m / z = 408.1 [M+H] +

[0241] Step 4: tert-Butyl (2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (13D) [ka] (1-(((3-((cyclopentylmethyl)thio)pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamic acid tert-butyl ester 13C (500 mg, 1.22 mmol) was dissolved in dichloromethane (10 mL), and Burgess reagent (732 mg, 3.07 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give crude product 13D. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give tert-butyl (2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 13D (260 mg, yield: 54%, pale yellow oil). MS (ESI): m / z = 390.1 [M+H] +

[0242] Step 5: 2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (13E) [ka] Tert-butyl (2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 13D (260 mg, 0.668 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature overnight. The reaction solution was rotary evaporated in vacuo to give 2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 13E (200 mg, crude product). This was used in the next step as is. MS (ESI): m / z = 290.1 ​​[M+H] +

[0243] Step 6: (1R,5S,6r)-6-((2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (13F) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (173 mg, 0.761 mmol) and HATU (289 mg, 0.761 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at room temperature for 0.5 h. Next, 2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 13E (200 mg, 0.692 mmol) and DIEA (0.5 mL) were added and stirred at room temperature overnight. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give crude product 13F. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to give (1R,5S,6r)-6-((2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 13F (200 mg, yield: 58%, yellow oil). MS (ESI): m / z = 499.1 [M+H] +

[0244] Step 7: (1R,5S,6r)-N-(2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 13) [ka] (1R,5S,6r)-6-((2-(8-((cyclopentylmethyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 13F (200 mg, 0.401 mmol) was dissolved in a hydrochloric acid-methanol solution (10 mL) and reacted at room temperature for 3 hours. The reaction mixture was dried by rotary evaporation in vacuo, and the solvent was removed to obtain the crude product (Compound 13). The crude product was purified by preparative HPLC to obtain a white solid (50 mg, yield: 31.3%). 1 H NMR(400MHz,DMSO-d6) δ 8.37(s,1H),8.12(d,1H),7.21(s,1H),6.64(d,1H),6.58(t,1H),3.05(d,2H),2.87(d,2H),2.69(d,2H),2.17-2. 09(M,1H),2.03-1.97(M,1H),1.84-1.78(M,2H),1.64(s,6H),1.56(t,1H),1.53-1.48(M,4H),1.35-1.28(M,3H). MS (ESI): m / z = 399.2 [M+H] +

[0245] Example 14 (1R,5S,6r)-N-(2-(1-methyl-7-(methylthio)-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 14) [ka]

[0246] Step 1: 7-(((trimethylsilyl)methyl)thio)-1H-indazole-3-carbonitrile (14B) [ka] Under nitrogen protection, 7-bromo-1H-indazole-3-carbonitrile 14A (500 mg, 2.26 mmol) and palladium catalyst (CAS No.: 2230788-58-4) (40 mg) were dissolved in THF (15 mL) in a sealed tube. A 1M / L LiHMDS / THF solution (9 mL, 9.05 mmol) was added, followed by (trimethylsilyl)methanethiol (353 mg, 2.94 mmol). The reaction was allowed to proceed overnight at 100 °C. After completion of the reaction, the mixture was quenched with water (500 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed once with 50 mL of saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The mixture was filtered under suction and the organic phase was dried. The resulting residue was purified by silica gel column (petroleum ether / ethyl acetate=1 / 1) to give 7-(((trimethylsilyl)methyl)thio)-1H-indazole-3-carbonitrile 14B (396 mg, yield: 67.17%) as a pale yellow solid. MS (ESI): m / z = 262.1 [M+H] +

[0247] Step 2: 1-methyl-7-(((trimethylsilyl)methyl)thio)-1H-indazole-3-carbonitrile (14C) [ka] 7-(((trimethylsilyl)methyl)thio)-1H-indazole-3-carbonitrile 14B (1 g, 3.83 mmol) and K2CO3 (1.58 g, 11.49 mmol) were dissolved in DMF (20 mL), followed by the addition of iodomethane (0.95 g, 6.88 mmol) and the reaction mixture was allowed to react for 1 h. After completion of the reaction, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed once with 50 mL of saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The organic phase was dried, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give 1-methyl-7-(((trimethylsilyl)methyl)thio)-1H-indazole-3-carbonitrile 14C (0.65 g, yield: 61.7%) as an off-white solid. MS (ESI): m / z = 276.1 [M+H] +

[0248] Step 3: 1-Methyl-7-(methylthio)-1H-indazole-3-carbonitrile (14D) [ka] 1-Methyl-7-(((trimethylsilyl)methyl)thio)-1H-indazole-3-carbonitrile 14C (0.65 g, 2.36 mmol) was added to 1 M / L TBAF / THF solution (50 mL) and reacted for 2 h. After completion of the reaction, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phase was washed once with 150 mL of saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The organic phase was suction filtered and dried, and the resulting residue was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to give 1-methyl-7-(methylthio)-1H-indazole-3-carbonitrile 14D (0.38 g, 79.20% yield) as a pale yellow solid. MS (ESI): m / z = 204.1 [M+H] +

[0249] Step 4: 2-(1-methyl-7-(methylthio)-1H-indazol-3-yl)propan-2-amine (14E) [ka] Cerium trichloride (869 mg, 3.55 mmol) was added to DMF (30 mL) and stirred for 0.5 h. The mixture was then cooled to -60 °C. A 1.3 M MeLi / THF solution (2.73 mL, 3.55 mmol) was added at a temperature not exceeding -40 °C and stirred for 0.5 h. Next, 1-methyl-7-(methylthio)-1H-indazole-3-carbonitrile 14D (180 mg, 0.89 mmol) was added, and the mixture was slowly warmed to room temperature and allowed to react for 4 h. Upon completion of the reaction, the reaction mixture was quenched with saturated aqueous NaOH (10 mL), water (50 mL) was added, filtered, and extracted with ethyl acetate (30 mL × 3). The organic phase was washed once with 100 mL of saturated aqueous NaCl and dried over anhydrous sodium sulfate. After filtration, the organic phase was dried, and the resulting residue was purified by silica gel column (petroleum ether / ethyl acetate=2 / 1) to give 2-(1-methyl-7-(methylthio)-1H-indazol-3-yl)propan-2-amine 14E (65 mg, yield: 31.2%) as a white solid. MS (ESI): m / z = 236.1 [M+H] +

[0250] Step 5: (1R,5S,6r)-6-((2-(1-methyl-7-(methylthio)-1H-indazol-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (14F) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (75 mg, 0.33 mmol) and HATU (126 mg, 0.33 mmol) were dissolved in DMF (4 mL). 2-(1-methyl-7-(methylthio)-1H-indazol-3-yl)propan-2-amine 14E (65 mg, 0.28 mmol) and DIEA (107 mg, 0.99 mmol) were added and reacted for 1 h. After completion of the reaction, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed once with 20 mL of saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the organic phase was dried, and the resulting residue was purified by preparative plate (petroleum ether:ethyl acetate=2:1) ​​to give (1R,5S,6r)-6-((2-(1-methyl-7-(methylthio)-1H-indazol-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 14F (110 mg, yield: 88.5%) as a viscous off-white crude solid. MS (ESI): m / z = 445.1 [M+H] +

[0251] Step 6: (1R,5S,6r)-N-(2-(1-methyl-7-(methylthio)-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 14) [ka] The crude product (1R,5S,6r)-6-((2-(1-methyl-7-(methylthio)-1H-indazol-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester n-hexane 14F (110 mg) was added to 4M / L HCl / dioxane (3 mL) and stirred for 30 min. After completion of the reaction, the mixture was dried in a vacuum oven and purified by prep-HPLC to give (1R,5S,6r)-N-(2-(1-methyl-7-(methylthio)-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 14) (24.7 mg, yield: 78.6%). 1 H NMR(400MHz,DMSO-d6) δ 8.33(s,1H),7.71(d,1H),7.23(d,1H),7.03(t,1H),4.29(s,3H),2.86( d,2H),2.68(d,2H),2.54(s,3H),1.63(s,6H),1.58(t,1H),1.45(M,2H). MS (ESI): m / z = 345.1 [M+H] +

[0252] Example 15 (1R,5S,6r)-N-(2-(7-(methylthio)-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 15) [ka]

[0253] Step 1: 7-(methylthio)-1H-indazole-3-carbonitrile (15A) [ka] 7-(((trimethylsilyl)methyl)thio)-1H-indazole-3-carbonitrile 14B (0.85 g, 2.36 mmol) was added to 1 M / L TBAF / THF solution (10 mL) and reacted for 24 h. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed once with 50 mL of saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, suction filtered, and the resulting residue was purified on a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to give white 7-(methylthio)-1H-indazole-3-carbonitrile 15A (0.51 g, yield: 82.8%). MS (ESI): m / z = 190.1 [M+H] +

[0254] Step 2: 7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbonitrile (15B) [ka] 7-(Methylthio)-1H-indazole-3-carbonitrile 15A (490 mg, 2.59 mmol) and CsCO (2.54 g, 7.78 mmol) were added to DMF (10 mL) and stirred for 0.5 h. Next, 2-(trisilyl)ethoxymethyl chloride (649 mg, 3.89 mmol) was added and the reaction was allowed to proceed for 1 h. After completion of the reaction, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed once with 50 mL of saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The organic phase was suction filtered and dried, and the resulting residue was purified by silica gel column (petroleum ether / ethyl acetate=5 / 1) to give 7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbonitrile 15B (750 mg, yield: 90.7%) as an off-white solid. MS (ESI): m / z = 320.1 [M+H] +

[0255] Step 3: 2-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propan-2-amine (15C) [ka] Cerium trichloride ( (2.30 g, 9.40 mmol) was dissolved in DMF (40 mL) and stirred for 0.5 h. The mixture was then cooled to -60 °C. A 1.3 M MeLi / THF solution (7.23 mL, 9.40 mmol) was added at a temperature not exceeding -40 °C and stirred for 0.5 h. Next, 7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbonitrile 15B (750 mg, 2.35 mmol) was added, and the mixture was slowly warmed to room temperature and reacted at room temperature for 4 h. After completion of the reaction, the mixture was quenched with saturated aqueous NaOH (20 mL), water (50 mL) was added, filtered, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed once with 50 mL of saturated aqueous NaCl and dried over anhydrous sodium sulfate. The organic phase was suction filtered and dried, and the resulting residue was purified by silica gel column (petroleum ether / ethyl acetate=2 / 1) to give 2-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propan-2-amine 15C (260 mg, yield: 31.5%) as a white solid. MS (ESI): m / z = 352.1 [M+H] +

[0256] Step 4: (1R,5S,6r)-6-((2-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15D) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (201 mg, 0.89 mmol) and HATU (338 mg, 0.89 mmol) were dissolved in DMF (10 mL), followed by the addition of 2-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propan-2-amine 15C (260 mg, 0.74 mmol) and DIEA (287 mg, 2.22 mmol). The reaction was allowed to proceed for 1 h. After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (15 mL × 3). The organic phase was washed once with 40 mL of saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The organic phase was filtered under suction and dried, and the resulting residue was purified by preparative plate (petroleum ether:ethyl acetate=2:1) ​​to give (1R,5S,6r)-6-((2-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 15D (200 mg, yield: 48.2%) as a viscous, off-white, semi-solid crude product. MS (ESI): m / z = 561.1 [M+H] +

[0257] Step 5: (1R,5S,6r)-N-(2-(7-(methylthio)-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 15) [ka] The crude product (1R,5S,6r)-6-((2-(7-(methylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 15D (200 mg) was added to a TFA:DCM=1:3 solution (10 mL) and stirred for 30 min. After completion of the reaction, the mixture was dried in a vacuum oven and purified by pre-HPLC to give (1R,5S,6r)-N-(2-(7-(methylthio)-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 15) (20 mg, yield: 17%). 1 H NMR(400MHz,DMSO-d6) δ 12.74(s,1H),8.30(s,1H),7.70(d,1H),7.22(d,1H),7.02(d,1H),2.86( d,2H),2.68(d,2H),2.54(s,3H),1.66(s,6H),1.59(t,1H),1.46(M,2H). MS (ESI): m / z = 331.1 [M+H] +

[0258] Example 16 (1R,5S,6r)-N-(2-(2-(methylthio)phenyl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 16) [ka]

[0259] Step 1: 2-(2-(methylthio)phenyl)propan-2-amine (16B) [ka] Under nitrogen protection, cerium trichloride (1.45 g, 5.90 mmol) was added to THF (10 mL) and cooled to -60 °C with stirring. Methyllithium (4.54 mL, 1.3 mmol / mL) was slowly added at a temperature not exceeding -40 °C, followed by stirring for 0.5 h. Next, 2-(methylthio)benzonitrile 16A (220 mg, 1.48 mmol) was dissolved in THF (2 mL) and slowly added to the reaction mixture. The mixture was stirred for an additional 4 h. After completion of the reaction, the mixture was quenched with saturated aqueous sodium hydroxide (10 mL) and suction filtered. The filter cake was washed with ethyl acetate (5 mL). Water (20 mL) was added to the filtrate, which was then extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed once with 50 mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The organic phase was dried to give 2-(2-(methylthio)phenyl)propan-2-amine 16B (300 mg) as an off-white solid. MS (ESI): m / z = 182.1 [M+H] +

[0260] Step 2: (1R,5S,6r)6-((2-(2-(2-(methylthio)phenyl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (16C) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (180 mg, 0.80 mmol) and HATU (302 mg, 0.80 mmol) were dissolved in DMF (5 mL), and then 2-(2-(methylthio)phenyl)propan-2-amine 16B (120 mg, 0.66 mmol) and DIEA (256 mg, 1.99 mmol) were added and the mixture was allowed to react for 1 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed once with 20 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the organic phase was dried. The resulting residue was purified by preparative plate (petroleum ether: ethyl acetate = 2:1) to give (1R,5S,6r)6-((2-(2-(2-(methylthio)phenyl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 16C (60 mg, yield: 23.3%) as a pale yellow solid. MS (ESI): m / z = 391.1 [M+H] +

[0261] Step 3: (1R,5S,6r)-N-(2-(2-(methylthio)phenyl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 16) [ka] (1R,5S,6r)-N-(2-(2-(2-(methylthio)phenyl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 16C (60 mg, 0.153 mmol) was added to 4 M / L HCl / dioxane (5 mL) and stirred for 30 min. After completion of the reaction, the mixture was evaporated under vacuum and purified by prep-HPLC to give (1R,5S,6r)-N-(2-(2-(methylthio)phenyl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 16) (30 mg, yield: 67.2%). 1H NMR(400MHz,DMSO-d6) δ 7.97(s,1H),7.25(d,1H),7.20(d,1H),7.16(t,1H),7.06(t,1H),2.86(d,2H),2.70(d,2H),2.40(s,3H),1.62(s,6H),1.56-1.53(M,3H). MS (ESI): m / z = 290.9 [M+H] +

[0262] Example 17 (1R,5S,6r)-N-(2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (compound 17) [ka]

[0263] Step 1: tert-Butyl (2-(1-iodo-8-methylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (17B) [ka] tert-Butyl (2-(8-methylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 17A (2.0 g, 6.9 mmol) and NIS (2.4 g, 10.7 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 2 h. LCMS monitoring showed the reaction was complete. The reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. After rotary evaporation under vacuum, the sample was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to finally give (2-(1-iodo-8-methylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 17B (1.6 g, yield: 55.8%, green solid). MS (ESI): m / z = 416.0 [M+H] +

[0264] Step 2: (2-(8-methyl-1-(((trimethylsilyl)methyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamic acid tert-butyl ester (17C) [ka] tert-Butyl (2-(1-iodo-8-methylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 17B (1.23 g, 3.0 mmol), trismethylsilylmethanethiol (428 mg, 3.6 mmol), and metal palladium catalyst (CAS: 2230788-58-4) (61 mg, 0.07 mmol) were dissolved in THF, and LiHMDS (1.0 M, THF, 7.2 mL) was added dropwise to a microwave reactor. The air was evacuated and the reactor was sealed. The reaction temperature was 100 °C, and the reaction time was 16 h. The reaction was then quenched with methanol, and the organic phase was dried under vacuum. The sample was purified by column chromatography (petroleum ether / ethyl acetate=2 / 1) to finally obtain (2-(8-methyl-1-(((trimethylsilyl)methyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamic acid tert-butyl ester 17C (380 mg, yield: 31.5%, white solid). MS (ESI): m / z = 408.0 [M+H] +

[0265] Step 3: tert-Butyl (2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (17D) [ka] (2-(8-methyl-1-(((trimethylsilyl)methyl)thio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamic acid tert-butyl ester 17C (380 mg, 0.93 mmol) was dissolved in a tetrahydrofuran solution of TBAF (20 mL), heated to 50 °C, and reacted overnight. The reaction solution was evaporated under vacuum and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give (2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate tert-butyl ester 17D (153 mg, yield: 48.8%, white solid). MS (ESI): m / z = 336.0 [M+H] +

[0266] Step 4: 2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride (17E) [ka] tert-Butyl (2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 17D (153 mg, 0.65 mmol) was dissolved in HCl / dioxane (5 mL) and reacted at room temperature for 1 h. The reaction mixture was then rotary evaporated under vacuum to give crude 2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine hydrochloride 17E (110 mg, crude, white solid). MS (ESI): m / z = 236.1 [M+H] +

[0267] Step 5: (1R,5S,6r)-6-((2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (17F) [ka] (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid 1F (127 mg, 0.56 mmol) and HATU (213 mg, 0.56 mmol) were dissolved in DMF (6 mL) and stirred for 30 min. The crude product, 2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 17E (110 mg, 0.46 mmol) and DIEA (181 mg, 1.4 mmol) were added to the reaction mixture and stirred for 2 h. The mixture was then extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Purification by column chromatography (petroleum ether / ethyl acetate = 2 / 1) gave (1R,5S,6r)-6-((2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 17F (120 mg, yield: 57.8%, white solid). MS (ESI): m / z = 445.1 [M+H] +

[0268] Step 6: (1R,5S,6r)-N-(2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3,1,0]hexane-6-carboxamide (compound 17) [ka] (1R,5S,6r)-6-((2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester 17F (120 mg, 0.27 mmol) was dissolved in HCl / dioxane (6 mL) and reacted at room temperature for 1 h. The reaction mixture was then evaporated under vacuum, and the crude product was purified by preparative HPLC to give (1R,5S,6r)-N-(2-(8-methyl-1-(methylthio)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (Compound 17) (58 mg, yield: 62.4%, white solid). 1 H NMR(400MHz,DMSO-d6) δ 8.39(s,1H),8.11(d,1H),6.55-6.48(M,2H),2.91(M,2H),2.75-2.67(M,2H),2.61(s,3H),2.39(s,3H),1.63(s,6H),1.56-1.51(M,3H). MS (ESI): m / z = 345.0 [M+H] +

[0269] Test example: Test Example 1. Measurement of human somatostatin type IV receptor SSTR4 agonist activity Test Objective: Measure the agonist effect of test compounds on the SSTR4 receptor using a cell-based human SSTR4 cAMP assay.

[0270] Cell culture and reagent preparation: Cell line: Flp-In-CHO-SSTR4 stable expressing cell line (stable pool); Complete medium: Ham's F-12K + 10% FBS + 1x penicillin-streptomycin (PS) + 600 μg / ml hygromycin B; Cell seeding medium: Ham's F-12K + 10% FBS; Experimental buffer: 1x HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX.

[0271] Test procedure: (1) The Flp-In-CHO-SSTR4 stable expressing cell line was cultured in complete medium at 37°C and 5% CO2 until it became 70% to 90% confluent. (2) After TrypLE digestion, the cells were resuspended in seeding medium and seeded at 7,000 cells per well into a 384-well cell culture plate (384PE culture plate), followed by overnight culture at 37°C and 5% CO2. (3) Working solutions (8X) of the positive control compound and test compound were prepared. (4) The cell culture plate was removed, inverted and centrifuged at 200 g for 5 seconds at room temperature to remove the medium, and then 15 μl of experimental buffer was quickly added to each experimental well, followed by centrifugation at 200 g for 5 seconds at room temperature. (5) 2.5 μl of the 8× compound working solution diluted in step (3) was added to the corresponding test wells, centrifuged at 200 g for 5 s at room temperature, and incubated at 37° C. for 10 min. (6) A 4 μM Forskolin working solution (8X) was prepared. (7) After removing the cell plate and equilibrating it at room temperature, 2.5 μl of the 8X Forskolin working solution prepared in step (6) was added to the corresponding test wells and incubated at 200 g, RT, 5 s, and 37°C for 30 min. (8) Eu-cAMP tracer and Uliaght-anti-cAMP were frozen and thawed, and Eu-cAMP tracer was diluted 50-fold and Uliaght-anti-cAMP was diluted 150-fold with detection buffer. (9) After 10 μl of Eu-cAMP tracer was added to all experimental wells, 10 μl of detection buffer was added to the NC wells and 10 μl of Uliaght-anti-cAMP was added to the remaining experimental wells. (10) The reaction plate was centrifuged at 200 g for 30 s at room temperature and left to stand at 25°C for 1 h, after which data were collected using Envision.

[0272] Data analysis Z' coefficient = 1-3*(SDMax+SDMin) / (MeanMax-MeanMin) CVMax=(SDMax / Average Max)*100% CVMin=(SDMin / Average Min)*100% S / B = Signal / Background Solvent control (Min): Measurement buffer Positive control (Max): 1,000 nM Somatostatin 14 Compound EC50 was calculated by nonlinear fitting using GraphPad. Y=Bottom+(Top-Bottom) / (1+10^((LogEC50-X)*HillSlope)) X: logarithmic value of compound concentration; Y: HTRF ratio

[0273] Table 1. Measurement results of human somatostatin type IV receptor SSTR4 agonist activity [Table 2]

[0274] Conclusion: The compounds of the present invention have significant agonistic activity on the human somatostatin type IV receptor SSTR4.

[0275] Test Example 2. Metabolic stability of liver microsomes The metabolic degradation of the test compounds was analyzed at 37°C using collected human liver microsomes and male rat liver microsomes, respectively. The final incubation reaction system solution contained phosphate buffer (pH 7.4), a positive control compound (dextromethorphan) or test compound (200 μM, 1.5 μL), and liver microsomes (0.5 mg / mL, 238.5 μL). After preincubation at 37°C for 5 min, the reaction was initiated by adding NADPH (5 mM, 60 μL). A fixed amount of the reaction mixture (30 μL) was sampled at fixed time points (0, 5, 15, 30, and 60 min) to quench the reaction in solution. After centrifugation (4000 rpm, 15 min), the supernatant (100 μL) was mixed with distilled water (100 μL) and analyzed by LC-MS / MS to measure the amount of compound. First-order reaction kinetics (C t =C0×e -ket, T 1 / 2 The half-life was calculated using the formula: = Ln2 / ke.

[0276] Table 2. Measurement results of human liver microsomes and male rat liver microsomes [Table 3]

[0277] Conclusion: The compounds of the present invention have good metabolic stability in liver microsomes.

[0278] Test Example 3. Pharmacokinetic evaluation Rats were used as test animals, and the plasma drug concentrations of Compound 1a and Compound 14 were measured at different time points after oral and intravenous administration to rats by LC / MS / MS. The pharmacokinetic behavior of the compounds of the present invention in rats was investigated, and their pharmacokinetic properties were evaluated.

[0279] Test Agents: Compound 1a and Compound 14. Test animals: For each compound, six healthy adult Sprague-Dawley (SD) rats (male) were divided into oral and intravenous groups (three rats each). Rats were purchased from Shanghai SIPPR / BK Laboratory Animal Co., Ltd. Animal Production License Number: SCXK(Shanghai)2008-0016.

[0280] Drug preparation: A certain amount of the drug was weighed and dissolved in 5% dimethylacetamide (DMA) + 5% polyethylene glycol-15 hydroxystearate (solutol) + 90% saline to prepare a 0.2 mg / mL solution.

[0281] Dosage: SD rats were fasted overnight and then administered orally and intravenously at a dose of 10.0 mg / kg orally and 1.0 mg / kg intravenously.

[0282] Test procedure: Compounds 1a and 14 were administered orally and intravenously to rats. At 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose, 0.2 mL of blood was collected from the submandibular vein or other appropriate vessel, placed in K2-EDTA tubes, and stored on ice. Within 1 hour, plasma was centrifuged at 6800 xg for 6 minutes at 2-8°C, stored at -80°C, and subjected to LC / MS / MS analysis. Rats were fed 4 hours post-dose.

[0283] Table 3. Pharmacokinetic parameters in rats [Table 4]

[0284] Conclusion: The compounds of the present invention are well absorbed pharmacokinetically.

[0285] Test Example 4. Effectiveness Evaluation-1 Experimental design Male SD rats (7-8 weeks old) were injected with 50 μL of CFA into the center of the left hind paw. 24 hours after modeling, baseline PWT values ​​were measured and the rats were randomly assigned to groups before drug administration.

[0286] Test drug Compound 1a, Compound 14, indomethacin, and Reference Compound A having the following structure (see Patent WO2014184275 for the synthesis method of Reference Compound A) [ka]

[0287] Animal Grouping Eight animals were assigned to each group, and the animals were weighed and then dosed according to Table 4.

[0288] Table 4. Study group and dose table [Table 5]

[0289] NOTE: IP is intraperitoneal injection and PO is oral administration.

[0290] Compound efficacy testing: For all groups of animals, the paw withdrawal threshold (PWT) of the animals was measured using a Von Frey at 1 and 3 hours after the single administration.

[0291] Experimental results As shown in Figure 1, 24 hours after CFA injection, the PWT of rats decreased to approximately 3.6 g. This was significantly lower than that of normal rats, indicating the establishment of a mechanical hyperalgesia model. Three hours after administration of the positive control compound, indomethacin, significantly suppressed CFA-induced mechanical hyperalgesia in rats. Control Compound A, Compound 1a, and Compound 14 all suppressed CFA-induced mechanical hyperalgesia in rats. Furthermore, the efficacy of Compound 1a at 1 and 3 hours after administration was significantly superior to that of Control Compound A, and the efficacy of Compound 14 at 3 hours after administration was significantly superior to that of Control Compound A.

[0292] Table 5. Results of single-dose pharmacodynamic studies of compounds in the rat CFA pain model [Table 6]

[0293] Note: *p<0.05, ****p<0.0001 compared to the vehicle control group, using two-way ANOVA statistics. #p<0.05, ####p<0.0001 compared to the control Compound A group, using two-way ANOVA statistics.

[0294] Test Example 5. Effectiveness Evaluation-2 Pharmacodynamic study of multiple oral doses (PO) of Compound 1a and Compound 14 in the rat CFA model 1. Summary The efficacy of Compound 1a and Compound 14 was evaluated in the rat CFA pain model using a mechanical hyperalgesia method. 2. Test Scheme 2.1 Test Drugs Indomethacin, Compound 1a and Compound 14 2.2 Experimental animals Seventy-two male SD rats, equally divided into nine groups, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. 2.3 Test Method After 3-7 days of adaptation, eight of the experimental animals were selected as a normal control group. Other animals were injected with 50 μL of CFA into the center of the left hind paw for modeling. 24 hours after injection modeling, the animals were subjected to measurement of their basal paw withdrawal threshold (PWT). Based on this baseline value, the animals were divided into the vehicle control group, indomethacin group, Compound 1a, 10 mpk group, Compound 1a, 30 mpk group, Compound 1a, 100 mpk group, Compound 14, 3 mpk group, Compound 14, 10 mpk group, and Compound 14, 30 mpk group, each consisting of eight animals. The animals were then weighed and orally administered the compounds according to Table 6. The paw withdrawal threshold (PWT) of all animals was measured using a Von Frey spectrometry at 1, 2, and 4 hours after administration to further evaluate the efficacy of the compounds of the present invention.

[0295] Table 6. Study Groups and Dosage Table [Table 7]

[0296] 2.4 Results: As shown in Figure 2, 24 hours after CFA injection in rats, PWT significantly decreased compared with the normal control group, indicating the establishment of a mechanical hyperalgesia model. The positive control compound, indomethacin, significantly inhibited CFA-induced mechanical hyperalgesia in rats at 2 and 4 hours after administration. Compound 1a dose-dependently inhibited CFA-induced mechanical hyperalgesia in rats at 2 and 4 hours after administration, with an effective dose of 10 mg / kg. Furthermore, in the 30 and 100 mg / kg groups, its efficacy at 4 hours after administration was significantly superior to that of the positive control compound, indomethacin. Compound 14 dose-dependently inhibited CFA-induced mechanical hyperalgesia in rats at 4 hours after administration, with an effective dose of 10 mg / kg.

[0297] Table 7. Results of a multiple-dose pharmacodynamic study of compounds 1a and 14 in the rat CFA pain model. [Table 8]

[0298] Note: *p<0.05, **p<0.01, ****p<0.0001 compared to the vehicle control group, using two-way ANOVA statistics. #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001 compared to the indomethacin group, using two-way ANOVA statistics.

[0299] Test Example 6. Selectivity test 1. Summary The selective activity of the compounds against human SSTR4 was evaluated by radioligand binding studies. 2. Test Procedure At 25°C, serial dilutions of different concentrations of the compound were added to the radioligand [ 125[I]Somatostatin-14 was incubated with CHO-K1 cell membrane homogenates expressing human SSTR1, 2, 3, 4, and 5 for 2 hours. The cell membranes were then filtered and washed, and the protein-bound radioactivity was measured using an appropriate instrument. The Ki values ​​of the corresponding targets were calculated using the Cheng-Prusoff equation. 3. Test Results The binding selectivity of different compounds to SSTR1-5 is shown in Table 1. The results show that compound 1a has the highest SSTR4 selectivity, which is superior to control compound A.

[0300] Table 8. In vitro human SSTR selectivity of compounds [Table 9]

[0301] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of each technical feature of the above embodiments are described, but as long as there is no contradiction in the combination of these technical features, all are deemed to be within the scope of the present specification.

[0302] The above examples represent only some embodiments of the present invention. Although the descriptions are detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make some modifications and improvements without departing from the technical spirit of the present invention, and these modifications and improvements fall within the scope of the present invention. Therefore, the scope of protection of the present invention shall be defined by the appended claims.

Claims

1. A compound represented by the following formula (I), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 1】 however, R １ is -H and C １－６ alkyl; L １ is selected from —NH— and —O—; R ２ , R ３ are each independently —H, C １－６ Alkyl, and C ３－６ cycloalkyl, wherein R ２ and R ３ are not both -H; or R ２ and R ３ are both -O- and -NR ９ -, -SO- and -SO ２ -, forming a 3-6 membered saturated cyclic group containing 0 to 1 groups selected from; R ４ , R ５ , R ６ , R ７ , R ８ are each independently —H, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkoxy C １－６ Alkyl, -(CH ２ ) ｍ -C ３－１０ Carbocyclic group, -(CH ２ ) ｍ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｍ -O-C ３－１０ Carbocyclic group, -(CH ２ ) ｍ -O- (3- to 10-membered heterocyclic group), phenyl, and 5- to 6-membered heteroaryl, wherein said heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S, and R ４ , R ５ , R ６ , R ７ , R ８ The alkyl, alkoxy, carbocyclic group, phenyl, heteroaryl or heterocyclic group in each of the above is independently —H, —F, —Cl, —Br, —I, hydroxy, mercapto group, cyano, amino, C １－４ Alkyl, and C １－４ optionally further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; R ９ is -H, C １－６ Alkyl, C １－４ Alkoxy C １－６ Alkyl, halogen, hydroxy, cyano, and C ３－６ cycloalkyl; A is C ６－１４ A is selected from the group consisting of aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclic group, and 5- to 14-membered cycloalkyl, and the aryl, heteroaryl, heterocyclic group, and cycloalkyl in A are each selected from the group consisting of 1 to 4 R １０ wherein said heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from the group consisting of N, O and S; L ２ is a single bond, -(CR ａ R ｂ ) ｎ - and - (CR ａ R ｂ ) ｎ O—, and R １０ are each independently —H, —F, —Cl, —Br, —I, hydroxy, cyano, amino, C １－６ Alkyl, C １－４ Alkoxy C １－６ Alkyl, C ３－６ cycloalkyl, and —SR １１ and at least one R １０ Ha-SR １１ where R １１ are each independently —H, C １－６ Alkyl, C １－４ Alkoxy C １－６ Alkyl, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), C ６－１０ and 5- to 6-membered heteroaryl, wherein said heterocyclic and heteroaryl groups contain 1 to 4 heteroatoms selected from N, O, and S, and said alkyl, alkoxy, aryl, heteroaryl, carbocyclic, or heterocyclic groups are each independently selected from —H, halogen, hydroxy, cyano, C １－４ Alkyl, and C １－４ optionally further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; R ａ and R ｂ are each independently —H and C １－６ alkyl; m, if present, is independently selected from 0, 1, 2 and 3; If n occurs, it is independently selected from 0, 1, 2 and 3.

2. L 1 is —NH—, 2. The compound of claim 1, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R 1 is —H.

3. 2. The compound of claim 1, which is a compound of formula (VI): or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 2】 L １ is selected from —NH— and —O—; L ２ is a single bond, and -(CR ａ R ｂ ) ｎ - and - (CR ａ R ｂ ) ｎ O—; where R ａ , R ｂ are independently —H and C １－６ alkyl; If n occurs, it is independently selected from 0, 1, 2 and 3.

4. 2. The compound of claim 1, which is a compound of formula (II): or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Transformation 3】 L １ is selected from —NH— and —O—; L ２ is a single bond, -(CR ａ R ｂ ) ｎ - and - (CR ａ R ｂ ) ｎ O—; where R ａ and R ｂ are each independently —H and C １－６ alkyl; If n occurs, it is independently selected from 0, 1, 2 and 3.

5. R 1 is —H; L 1 is —NH—; 5. The compound of claim 4, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein L 2 is selected from a single bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 O— and —CH 2 CH 2 O—.

6. R 2 and R 3 are each independently selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl, or The compound of claim 4, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together form a 3-6 membered saturated cyclic group containing 0 to 1 group selected from the group consisting of -O-, -SO- and -SO 2 -.

7. R 11 is each independently selected from the group consisting of -H, C 1-6 alkyl, C 1-4 alkoxyC 1-6 alkyl, -(CH 2 ) n -alkenyl, -(CH 2 ) n -alkynyl, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3- to 10-membered heterocyclic group), C 6-10 aryl, and 5- to 6-membered heteroaryl, wherein said heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and said alkyl, alkoxy, aryl, heteroaryl, carbocyclic group, or heterocyclic group is each independently selected from -H, halogen, hydroxy, cyano, C 1-4 alkyl, and C 1-4 5. The compound of claim 4, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, optionally further substituted with 0 to 4 substituents selected from the group consisting of alkoxy.

8. The compound according to claim 7, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 11 is independently selected from the group consisting of methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, and pyridyl.

9. 2. The compound of claim 1, which is a compound of formula (IV): or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 4】 R ４ But C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkoxy C １－６ Alkyl, -(CH ２ ) ｍ -C ３－１０ Carbocyclic group, -(CH ２ ) ｍ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｍ -O-C ３－１０ Carbocyclic group, -(CH ２ ) ｍ -O- (3- to 10-membered heterocyclic group), phenyl, and 5- to 6-membered heteroaryl, wherein said heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S, and R ４ wherein the alkyl, alkoxy, carbocyclic group, phenyl, heteroaryl or heterocycle is each independently —H, —F, —Cl, —Br, —I, hydroxy, mercapto group, cyano, amino, C １－４ Alkyl, and C １－４ It may be further substituted with 0 to 4 substituents selected from the group consisting of alkoxy.

10. 2. The compound of claim 1, which is a compound of formula (V): or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Transformation 5】 R ２ and R ３ However, each independently C １－６ Alkyl, and C ３－６ cycloalkyl, wherein R ２ and R ３ But both are not -H; or R ２ and R ３ together form a 3- to 6-membered saturated cycloalkyl; R ４ , R ５ , R ６ , R ７ are each independently -H, C １－６ Alkyl, C １－６ Alkoxy, and C １－６ Alkoxy C １－６ alkyl, and R ４ , R ５ , R ６ , R ７ wherein the alkyl and alkoxy are each independently —H, —F, —Cl, —Br, —I, hydroxy, mercapto, cyano, amino, C １－４ Alkyl, and C １－４ optionally further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; A is C ６－１４ A is selected from the group consisting of aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclic group, and 5- to 14-membered cycloalkyl, and the aryl, heteroaryl, heterocyclic group, and cycloalkyl in A are each independently selected from the group consisting of 1 to 4 R １０ wherein said heteroaryl or heterocyclic group contains 1 to 4 N atoms; L ２ is a single bond, and R １０ are each independently —H, —F, —Cl, —Br, —I, hydroxy, cyano, amino, C １－６ Alkyl, C １－４ Alkoxy C １－６ Alkyl, C ３－６ cycloalkyl, and —SR １１ and at least one R １０ Ga-SR １１ where R １１ are each independently -H, C １－６ Alkyl, C １－４ Alkoxy C １－６ Alkyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group) and 5- to 6-membered heteroaryl, wherein said heterocyclic group or heteroaryl contains 1 to 4 heteroatoms selected from the group consisting of O, S, and N, and said alkyl, alkoxy, carbocyclic, or heterocyclic groups are each independently selected from -H, halogen, hydroxy, cyano, C １－４ Alkyl, and C １－４ optionally further substituted with 0 to 4 substituents selected from the group consisting of alkoxy; R ａ and R ｂ are each independently —H and C １－６ alkyl; If n occurs, it is independently selected from 0, 1, 2 and 3.

11. 2. The compound of claim 1, wherein A is any of the groups of the following formulae: or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof. 【Transformation 6】

12. 2. The compound of claim 1, wherein A is any of the groups of the following formulae: or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof. 【Transformation 7】

13. 2. The compound of claim 1, wherein A is any of the groups of the following formulae: or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof. 【Transformation 8】

14. A compound represented by the following formula (a), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 9】 However, the following formula: 【Chemistry 10】 represents a single or double bond, where the two formulae below are: 【Chemistry 11】 represents a double bond; X １ is CR １３ or NR １２ and X ２ is CR １３ or NR １２ and Or, X １ and its substituents are adjacent carbon atoms and its substituents R １３ and together form a benzene ring or a 5- or 6-membered heteroaromatic ring, and the benzene ring or the 5- or 6-membered heteroaromatic ring is １３ is substituted with; R １３ are each independently —H, halogen, cyano, or —(CH ２ ) ｎ -NR'R'', C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, -(CH ２ ) ｎ -5- to 6-membered heteroaryl, and -SR １１ selected from the group consisting of: R １２ is H, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; R １１ is -H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are each hydrogen, C １－６ Alkyl and halogenated C １－６ alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; R ２ and R ３ are each independently H, C １－６ Alkyl, halogenated C １－６ Alkyl, and -(CH ２ ) ｎ -OR; R ４ and R ５ are each independently H, C １－６ Alkyl, halogenated C １－６ Alkyl, and -(CH ２ ) ｎ -OR; n is 0, 1, 2 or 3; where at least one R １３ Ga-SR １１ It is a substituent. Claim 15: X 2 is CR 13 ; X 1 and its substituents together with the adjacent carbon atom and its substituent R 13 form a benzene ring or a 5- to 6-membered heteroaromatic ring, and the benzene ring or the 5- to 6-membered heteroaromatic ring is substituted with 1 to 4 R 13 ; R 13 are each independently selected from the group consisting of -H, halogen, cyano, -(CH 2 ) n -NR'R'', C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -OR, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3- to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -(CH 2 ) n -5- to 6-membered heteroaryl, and -SR 11 ; R 11 is selected from the group consisting of —H, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 2-6 alkenyl, —(CH 2 ) n —C 2-6 alkynyl, —(CH 2 ) n —C 3-10 carbocyclic group, —(CH 2 ) n —(3- to 10-membered heterocyclic group), —(CH 2 ) n —C 6-10 aryl, and —(CH 2 ) n —5- to 6-membered heteroaryl; each of R' and R'' is selected from the group consisting of hydrogen, C 1-6 alkyl, and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is selected from the group consisting of hydrogen, C 1-6 alkyl, and halogenated C 1-6 alkyl; R 2 and R 3 are each independently selected from the group consisting of H, C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —OR; R 4 and R 5 are each independently selected from the group consisting of H, C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —OR; n is 0, 1, 2 or 3; 15. The compound of claim 14, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein at least one R 13 is a -SR 11 substituent. Claim 16: X 2 is NR 12 ; X 1 and its substituents together with the adjacent carbon atom and its substituent R 13 form a benzene ring or a 5- to 6-membered heteroaromatic ring, and the benzene ring or the 5- to 6-membered heteroaromatic ring is substituted with 1 to 4 R 13 ; R 13 are each independently selected from the group consisting of -H, halogen, cyano, -(CH 2 ) n -NR'R'', C 1-6 alkyl, halogenated C 1-6 alkyl, -(CH 2 ) n -OR, -(CH 2 ) n -C 2-6 alkenyl, -(CH 2 ) n -C 2-6 alkynyl, -(CH 2 ) n -C 3-10 carbocyclic group, -(CH 2 ) n -(3- to 10-membered heterocyclic group), -(CH 2 ) n -C 6-10 aryl, -(CH 2 ) n -5- to 6-membered heteroaryl, and -SR 11 ; R 11 is selected from the group consisting of —H, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 2-6 alkenyl, —(CH 2 ) n —C 2-6 alkynyl, —(CH 2 ) n —C 3-10 carbocyclic group, —(CH 2 ) n —(3- to 10-membered heterocyclic group), —(CH 2 ) n —C 6-10 aryl, and —(CH 2 ) n —5- to 6-membered heteroaryl; each of R' and R'' is selected from the group consisting of hydrogen, C 1-6 alkyl, and halogenated C 1-6 alkyl, or R' and R'' together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is selected from the group consisting of hydrogen, C 1-6 alkyl, and halogenated C 1-6 alkyl; R 2 and R 3 are each independently selected from the group consisting of H, C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —OR; R 4 and R 5 are each independently selected from the group consisting of H, C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —OR; n is 0, 1, 2 or 3; 15. The compound of claim 14, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein at least one R 13 is -SR 11 .

17. A compound represented by the following formula (b), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 12】 however, R １３ are each independently H, halogen, cyano, -(CH ２ ) ｎ -NR'R'', C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, -(CH ２ ) ｎ -5- to 6-membered heteroaryl, and -SR １１ and at least one R １３ Ha-SR １１ and R １２ is H, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; R １１ is H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R is hydrogen, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; R' and R'' are each hydrogen, C １－６ Alkyl and halogenated C １－６ alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; n is 0, 1, 2 or 3; p is 1, 2, 3 or 4.

18. The compound of claim 1, wherein p is 1, 2, or 3; each R 13 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 3-10 carbocyclic group, and —SR 11 , and at least one R 13 is —SR 11 ; R 11 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —C 3-6 carbocyclic group; R 12 is selected from the group consisting of H, C 1-6 alkyl, and halogenated C 1-6 alkyl; 18. The compound of claim 17, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

19. The compound of claim 1, wherein p is 1 or 2; each R 13 is independently selected from the group consisting of H, C 1-6 alkyl, halogenated C 1-6 alkyl, and —SR 11 , and at least one R 13 is —SR 11 ; R 11 is selected from the group consisting of C 1-4 alkyl, and —(CH 2 ) n —C 3-4 carbocyclic groups; R 12 is selected from the group consisting of H, C 1-4 alkyl, and halogenated C 1-4 alkyl; 18. The compound of claim 17, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

20. The compound according to claim 1, wherein p is 1; R 13 is —SMe; 18. The compound of claim 17, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 12 is H or C 1-4 alkyl.

21. A compound represented by the following formula (b-1), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 13】 however, R １１ is H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R １２ is H, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; n is 0, 1, 2 or 3.

22. The compound of claim 1, wherein R 11 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —C 3-6 carbocyclic group; R 12 is selected from the group consisting of H, C 1-6 alkyl, and halogenated C 1-6 alkyl; 22. The compound of claim 21, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

23. The compound of claim 21, wherein R 11 is selected from the group consisting of C 1-4 alkyl, and —(CH 2 ) n —C 3-4 carbocyclic group; R 12 is selected from the group consisting of H, C 1-4 alkyl, and halogenated C 1-4 alkyl; 22. The compound of claim 21, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

24. The compound according to claim 21, wherein R 11 is methyl; 22. The compound of claim 21, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 12 is H or C 1-4 alkyl.

25. A compound represented by the following formula (c), (c-1) or (c-2), or a stereoisomer thereof, an N-oxide, a hydrate, a solvate or a pharmaceutically acceptable salt thereof: 【Chemistry 14】 however, R １３ are each independently H, halogen, cyano, -(CH ２ ) ｎ -NR'R'', C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, -(CH ２ ) ｎ -5- to 6-membered heteroaryl, and -SR １１ and at least one R １３ Ha-SR １１ and R １１ is H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R ４ and R ５ are each independently H, C １－６ Alkyl, halogenated C １－６ Alkyl, and -(CH ２ ) ｎ -OR; R' and R'' are each hydrogen, C １－６ Alkyl and halogenated C １－６ alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; n is 0, 1, 2 or 3; r is 1, 2, 3, 4 or 5.

26. r is 1, 2 or 3; each R 13 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 3-10 carbocyclic group, and —SR 11 , and at least one R 13 is —SR 11 ; R 11 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —C 3-6 carbocyclic group; R 4 and R 5 are each independently selected from the group consisting of H, and C 1-6 alkyl; 26. The compound of claim 25, wherein n is 0 or 1, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof.

27. r is 1 or 2; each R 13 is independently selected from the group consisting of H, C 1-6 alkyl, halogenated C 1-6 alkyl, and —SR 11 , and at least one R 13 is —SR 11 ; R 11 is selected from the group consisting of C 1-4 alkyl, and —(CH 2 ) n —C 3-4 carbocyclic groups; R 4 and R 5 are each independently selected from the group consisting of H, and C 1-6 alkyl; 26. The compound of claim 25, wherein n is 0 or 1, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof.

28. r is 2; one R 13 is —SMe and the other is selected from the group consisting of H and C 1-4 alkyl; 26. The compound of claim 25, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently selected from the group consisting of H and C 1-4 alkyl.

29. r is 1; R 13 is —SMe; 26. The compound of claim 25, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently selected from the group consisting of H and C 1-4 alkyl.

30. A compound represented by the following formula (d), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 15】 however, R １３ are each independently H, halogen, cyano, -(CH ２ ) ｎ -NR'R'', C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, -(CH ２ ) ｎ -5- to 6-membered heteroaryl, and -SR １１ and at least one R １３ Ha-SR １１ and R １１ is H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are each hydrogen, C １－６ Alkyl and halogenated C １－６ alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; n is 0, 1, 2 or 3; r is 1, 2, 3, 4 or 5.

31. r is 1, 2 or 3; each R 13 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 3-10 carbocyclic group, and —SR 11 , and at least one R 13 is —SR 11 ; R 11 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —C 3-6 carbocyclic group; 31. The compound of claim 30, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

32. r is 1 or 2; each R 13 is independently selected from the group consisting of H, C 1-6 alkyl, halogenated C 1-6 alkyl, and —SR 11 , and at least one R 13 is —SR 11 ; R 11 is selected from the group consisting of C 1-4 alkyl, and —(CH 2 ) n —C 3-4 carbocyclic groups; 31. The compound of claim 30, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

33. r is 2; 31. The compound of claim 30, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein one R 13 is -SMe and the other is selected from the group consisting of H and C 1-4 alkyl.

34. r is 1; 31. The compound of claim 30, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R 13 is -SMe.

35. A compound represented by the following formula (d-1), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 16】 however, R １１ is H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R １３ are each independently H, halogen, cyano, -(CH ２ ) ｎ -NR'R'', C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, -(CH ２ ) ｎ -5- to 6-membered heteroaryl, and -SR １１ selected from the group consisting of: R' and R'' are each hydrogen, C １－６ Alkyl and halogenated C １－６ alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; n is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4.

36. q is 0, 1 or 2; each R 13 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 3-10 carbocyclic group, and —SR 11 ; R 11 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —C 3-6 carbocyclic group; 36. The compound of claim 35, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

37. q is 0 or 1; R 11 is selected from the group consisting of C 1-4 alkyl, and —(CH 2 ) n —C 3-4 carbocyclic groups; R 13 is selected from the group consisting of H, C 1-4 alkyl, and halogenated C 1-4 alkyl; 36. The compound of claim 35, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

38. q is 0; 36. The compound of claim 35, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 11 is C 1-4 alkyl.

39. A compound represented by the following formula (d-2), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 17】 however, R １１ is H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R １３ are each independently H, halogen, cyano, -(CH ２ ) ｎ -NR'R'', C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, -(CH ２ ) ｎ -5- to 6-membered heteroaryl, and -SR １１ selected from the group consisting of: R' and R'' are each hydrogen, C １－６ Alkyl and halogenated C １－６ alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; n is 0, 1, 2 or 3; q is 0, 1, 2, 3 or 4.

40. q is 0, 1 or 2; R 11 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —C 3-6 carbocyclic group; each R 13 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 3-10 carbocyclic group, and —SR 11 ; 40. The compound of claim 39, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

41. q is 0 or 1; R 11 is selected from the group consisting of C 1-4 alkyl, halogenated C 1-4 alkyl, and —(CH 2 ) n —C 3-4 carbocyclic group; each R 13 is independently selected from the group consisting of H, C 1-6 alkyl, and halogenated C 1-6 alkyl; 40. The compound of claim 39, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

42. q is 1; R 11 is methyl; 40. The compound of claim 39, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein R 13 is H or C 1-4 alkyl.

43. A compound represented by the following formula (d-3), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: [Chemistry 18] however, R １１ is H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R １３ is H, halogen, cyano, -(CH ２ ) ｎ -NR'R'', C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, -(CH ２ ) ｎ -5- to 6-membered heteroaryl, and -SR １１ selected from the group consisting of: R' and R'' are each hydrogen, C １－６ Alkyl and halogenated C １－６ alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; n is 0, 1, 2 or 3.

44. R 11 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —C 3-6 carbocyclic group; each R 13 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 3-10 carbocyclic group, and —SR 11 ; 44. The compound of claim 43, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

45. R 11 is selected from the group consisting of C 1-4 alkyl, halogenated C 1-4 alkyl, and —(CH 2 ) n —C 3-4 carbocyclic group; R 13 is selected from the group consisting of H, C 1-4 alkyl, and halogenated C 1-4 alkyl; 44. The compound of claim 43, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

46. ​​R 11 is methyl; 45. The compound of claim 44, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 13 is H or C 1-4 alkyl.

47. A compound represented by the following formula (e), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 19】 however, R １３ is H, halogen, cyano, -(CH ２ ) ｎ -NR'R'', C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ３－６ cycloalkyl, and —SR １１ and at least one R １３ Ha-SR １１ and R １１ is H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are each hydrogen, C １－６ Alkyl and halogenated C １－６ alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; n is 0, 1, 2 or 3; t is 1, 2, 3, 4 or 5.

48. t is 1, 2, or 3; each R 13 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 3-10 carbocyclic group, and —SR 11 , and at least one R 13 is —SR 11 ; R 11 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —C 3-6 carbocyclic group; 48. The compound of claim 47, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

49. t is 1 or 2; each R 13 is independently selected from the group consisting of H, C 1-6 alkyl, halogenated C 1-6 alkyl, and —SR 11 , and at least one R 13 is —SR 11 ; R 11 is selected from the group consisting of C 1-4 alkyl, and —(CH 2 ) n —C 3-4 carbocyclic groups; 48. The compound of claim 47, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

50. t is 1; 48. The compound of claim 47, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 11 is C 1-4 alkyl.

51. A compound represented by the following formula (e-1), or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof: 【Chemistry 20】 however, R １３ H, halogen, cyano, -(CH ２ ) ｎ -NR'R'', C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ３－６ cycloalkyl, and —SR １１ is selected from the group consisting of R １１ is H, C １－６ Alkyl, halogenated C １－６ Alkyl, -(CH ２ ) ｎ -OR, -(CH ２ ) ｎ -C ２－６ Alkenyl, -(CH ２ ) ｎ -C ２－６ Alkynyl, -(CH ２ ) ｎ -C ３－１０ Carbocyclic group, -(CH ２ ) ｎ -(3- to 10-membered heterocyclic group), -(CH ２ ) ｎ -C ６－１０ Aryl, and -(CH ２ ) ｎ - selected from the group consisting of 5- to 6-membered heteroaryl; R' and R'' are each hydrogen, C １－６ Alkyl and halogenated C １－６ alkyl, or R′ and R″ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic group; R is hydrogen, C １－６ Alkyl and halogenated C １－６ selected from the group consisting of alkyl; n is 0, 1, 2 or 3; s is 0, 1, 2, 3 or 4; 52. s is 0, 1, or 2; each R 13 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, —(CH 2 ) n —C 3-10 carbocyclic group, and —SR 11 ; R 11 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, and —(CH 2 ) n —C 3-6 carbocyclic group; 52. The compound of claim 51, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

53. s is 0 or 1; each R 13 is independently selected from the group consisting of H, C 1-6 alkyl, halogenated C 1-6 alkyl, and —SR 11 ; R 11 is selected from the group consisting of C 1-4 alkyl, and —(CH 2 ) n —C 3-4 carbocyclic groups; 52. The compound of claim 51, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

54. s is 0; 52. The compound of claim 51, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein R 11 is C 1-4 alkyl.

55. A compound of any of the following formulae: or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof: 【Chemistry 21】 56. The compound of any one of claims 1 to 55, or a stereoisomer, N-oxide, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, and trifluoromethanesulfonate, and combinations thereof.

57. a therapeutically effective amount of a compound according to any one of claims 1 to 56, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof; a pharmaceutically acceptable carrier or excipient; 10. A pharmaceutical composition comprising:

58. Use of a compound according to any one of claims 1 to 56, or a stereoisomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57, in the preparation of a medicament for the treatment and / or prevention of pain.

59. The use of claim 58, wherein the pain is neuralgia.

60. 59. The use of claim 58, wherein the pain is back pain, chronic back pain, trigeminal neuralgia, complex regional pain syndrome type I, complex regional pain syndrome type II, irritable bowel syndrome, diabetic neuropathy, osteoarthritis pain, cancer pain, and fibromyalgia.

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