Somatostatin receptor subtype 4 (SSTR4) agonists and their applications

Abstract

The present invention discloses nitrogen-containing heterocyclic derivatives of somatostatin receptor subtype 4 (SSTR4) small molecule agonists, as well as pharmaceutical compositions, preparation methods, and uses thereof. The nitrogen-containing heterocyclic derivatives of SSTR4 small molecule agonists are represented by formula (I), where specific substituents and definitions are as described herein. The nitrogen-containing heterocyclic derivatives of SSTR4 small molecule agonists exhibit good binding and agonist activity with SSTR4. Such compounds or pharmaceutical compositions thereof have great potential in the treatment and / or prevention of pain disorders associated with the SSTR4 receptor.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 423,351, filed with the U.S. Patent and Trademark Office on November 7, 2022, the entire contents of which are incorporated herein by reference for all purposes.

[0002] The present invention is in the field of medicinal chemistry, and specifically relates to nitrogen-containing heterocyclic derivatives of somatostatin receptor subtype 4 (SSTR4) small molecule agonists, their pharmaceutical compositions, methods of preparation and uses. [Background technology]

[0003] Painkillers are essential medications for patients suffering from many illnesses because they relieve pain and improve quality of life. As the global population ages and the incidence of chronic diseases such as diabetes, arthritis, joint or bone pain, epilepsy, depression, nerve damage, and various cancers increases, the demand for pain medications is also increasing significantly. Currently, the global pain treatment market is dominated by opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). However, opioids can cause side effects such as respiratory depression, addiction, and constipation, and opioid abuse can also cause a social crisis. Therefore, there is a need to develop non-addictive painkillers to meet the urgent needs of patients.

[0004] Somatostatin, also known as somatotropin release inhibitory factor, is a cyclic peptide produced by various human organs and tissues. It can act systemically and locally to inhibit the secretion of various hormones, growth factors, and neurotransmitters (including insulin and glucagon). Somatostatin plays an important role in regulating cell proliferation, glucose homeostasis, inflammation, and pain. The biological properties of somatostatin are mediated through the somatostatin G protein-coupled receptor family, also known as SSTRs or SSIs. This family has five subtype receptors: SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5.

[0005] SSTR4 receptors are distributed in the axons and cell bodies of dorsal root ganglion neurons in rats, monkeys, and humans. It is generally believed that modulating the SSTR4 pathway can alleviate or inhibit pain and inflammatory processes. Recent studies have shown that somatostatin can relieve pain even when opioid drugs are ineffective, and it plays an important role in neuromodulation, including SSTR4-mediated pain control (Chrubasik J, Chrubasik S, Martin E, Acta Neurobiol Exp (Wars), 1993, 53(1):289-96; Penn RD; Paice JA, Kroin JS, Pain, 1992 Apr;49(1):13-19).

[0006] Other studies have shown that the lack of SSTR4 makes mice more susceptible to persistent pain and unable to obtain any analgesic effects (Van Op den Bosch J, et al., J Cell Mol Med, 2009, 13:3283-3295; Helyes Z. et al., Proc Natl Acad Sci US A. 2009, 106:13088-13093). Therefore, selective SSTR4 agonists may provide useful treatments for pain and / or inflammation (Ahmed F. Abdel-Magid, ACS Med Chem Lett. 2015, 6, 110). While most SSTR subtypes are involved in regulating homeostatic hormones, SSTR4 appears to play a functional role in regulating sensory neurotransmitters (Pruyank A. Shenoy, Frontiers in Pharm. 2018, vol. 9, article 495).

[0007] SSTR4 regulates dorsal root ganglion neurons through various mechanisms, including opening G protein-coupled inwardly rectifying potassium channels to enhance potassium currents and inhibiting voltage-dependent calcium channels such as transient receptor potential vanilloid-1 and ankyrin-1 channels to reduce calcium currents, thereby controlling pain transmission.

[0008] SSTR4 small molecule agonists have been reported in the literature (Michael Ankersen, Michael Crider, Shengquan Liu, Bin Ho, Henrik S. Andersen, and Carsten Stidsen J. Am. Chem. Soc. 1998, 120, 1368-1373; Mia Engstrom, Jussi Tomperi, Kamel El-Darwish, Mikaela Åhman, Juha-Matti Savola, and Siegfried Wurster, JPET, 2005, 312:332-338; A. Michael Crider and Ken A. Witt, Mini-Reviews in Medicinal Chemistry, 2007, 7, 213-220). Some of these agonists have demonstrated promising anti-inflammatory and analgesic effects (Boglarka Kantas et al.; Int. J. Mol. Sci. 2019, 20, 6245; Eva Szokea, Neuropharmacology 178 (2020) 108198). Pharmaceutical companies have filed several patent applications to protect their SSTR4 agonists and explore their potential as novel analgesics (U.S. Patent No. 971282, U.S. Patent No. 9957267, U.S. Patent No. 10166214, U.S. Patent No. 10577336, U.S. Patent Application Publication No. 20120190691A1, U.S. Patent Application Publication No. 20180092880A1, WO 2021233427A1, WO 2021233428A1). Among them, a compound developed by Eli Lilly and Company is currently in Phase 2 clinical trials. Recently, the binding structure of the SSTR4 receptor and its ligand was reported, which may be useful for better ligand design (Wenli Zhao et al. Cell Research, 2022, 0:1-12).

[0009] Provided herein is a class of SSTR4 agonists that can provide effective pain treatments to meet the needs of patients. The drawings are provided to enhance understanding of the technical aspects of the present application and constitute a part of the specification, and are used in combination with the embodiments described in the present application to explain technical features, and should not be considered to limit the scope of the technical aspects of the present application. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Van Op den Bosch J,et al,J Cell Mol Med,2009,13:3283-3295 [Non-patent document 2] Helyes Z.et al,Proc Natl Acad Sci US A.2009,106:13088-13093 [Non-patent document 3] Ahmed F.Abdel-Magid,ACS med Chem Lett.2015,6,110 [Non-patent document 4] Pruyank A.Shenoy,Frontiers in Pharm.2018,vol 9,article 495 [Brief explanation of the drawings]

[0011] [Figure 1A] 10 is a graphical representation showing the change over time in swelling of one side of the paw before and after modeling for a group of models in an exemplary embodiment of the present disclosure. [Figure 1B] 10 is a graphical representation showing the percent change in unilateral paw swelling over time for a group of models before and after modeling in an exemplary embodiment of the present disclosure. [Figure 1C] 1 is a plot showing anti-edema efficacy in an exemplary embodiment of the present disclosure. [Figure 1D] FIG. 1 shows chemical structures of reference compounds in exemplary embodiments of the present disclosure. [Figure 2A]FIG. 1 shows the time-effect curve of compound 8 in the CCI model in an exemplary embodiment of the present disclosure. [Figure 2B] 1 is a graphical representation of data distribution for compound 8 in a CCI model in an exemplary embodiment of the present disclosure. [Figure 3] 1 shows the concentration vs. response curve of Compound 8 on hERG in an exemplary embodiment of the present disclosure. Summary of the Invention [Means for solving the problem]

[0012] In one aspect, disclosed herein is a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof: [ka] During the ceremony, R 1 and R 2 are independently selected from H, deuterium, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, C4-C9 alkylcycloalkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl; The substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, and substituted aryl are substituted with 1 to 3 substituents independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, or halogenated C1-C3 alkyl groups; or R 1 and R 2 are linked to form 3-, 4-, 5-, and 6-membered rings; A is selected from: [ka] During the ceremony, n=1, 2, 3, 4, m=1, 2, 3, 4, R 3is selected from the group consisting of H, deuterium, C1-C6 alkyl, oxygen-containing alkyl, and nitrogen-containing alkyl; B is selected from the group consisting of an aromatic ring, a substituted aromatic ring, a heterocyclic ring, a substituted heterocyclic ring, an alkylheterocyclic ring, and a substituted alkylheterocyclic ring; The substituted heterocycle or alkylheterocycle is substituted with 1 to 3 independently selected from the group consisting of deuterium, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, alkylsilyl, aryl, substituted aryl, or oxygen-, sulfur-, or selenium-containing alkyl.

[0013] In yet another aspect, disclosed herein is a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated compound, metabolite, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0014] In yet another aspect, disclosed herein is a method for treating and / or preventing an SSTR4 receptor-associated disease or disorder, the method comprising administering a pharmaceutically effective amount of a pharmaceutical composition comprising a compound of formula (I).

[0015] In yet another aspect, disclosed herein is a method for preparing a compound of Formula (I), the method comprising reacting a first compound having a protecting group and a carboxylic acid group with a second compound having an amine group to form a first intermediate compound, deprotecting the protecting group on the first intermediate compound under acidic conditions to form a second intermediate; and reacting the second intermediate with an amine compound to form a compound of formula (I).

[0016] Other features and iterations of the present invention are described in more detail below. DETAILED DESCRIPTION OF THE INVENTION

[0017] Disclosed herein is a class of SSTR4 agonists, as well as their preparation methods and applications. The compounds of the present invention exhibit excellent SSTR4 agonist activity, provide effective pain treatment, and meet the needs of patients.

[0018] The following is a summary of the subject matter detailed in the present invention, which is not intended to limit the scope of the claims.

[0019] (I) A compound comprising formula (I) or a salt thereof In one aspect, the present invention provides compounds of formula (I), or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated form, metabolite, or prodrug thereof, as disclosed in the embodiments of the present invention. [ka] In the formula, R 1 and R 2 is independently selected from H, deuterium, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, C4-C9 alkylcycloalkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, aryl, substituted aryl, alkylaryl, and substituted alkylaryl. The substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, and substituted aryl are substituted with 1 to 3 substituents independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, and halogenated C1-C3 alkyl groups; R 1 and R 2 may also be linked to form 3-, 4-, 5-, and 6-membered rings; A is selected from: [ka] During the ceremony, n=1, 2, 3, 4, m=1, 2, 3, 4, R 3 is selected from the group consisting of H, deuterium, C1-C6 alkyl, oxygen-containing alkyl, and nitrogen-containing alkyl; B is selected from the group consisting of an aromatic ring, a substituted aromatic ring, a heterocycle, a substituted heterocycle, an alkylheterocycle, and a substituted alkylheterocycle, and the substituted heterocycle or alkylheterocycle is substituted with 1 to 3 independently selected from the group consisting of halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, alkylsilyl, aryl, substituted aryl, and oxygen-, sulfur-, and selenium-containing alkyl.

[0020] In some embodiments, the compound comprises Formula (Ia): [ka] During the ceremony, R 3 is hydrogen or amidine, R 4 ~R 8 are independently hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, aryl, substituted aryl, sulfinyl, substituted sulfinyl, or a C1-C3 alkylsilyl group; R 3 ~R 8 are independently hydrogen or C1-C6 alkyl.

[0021] In some embodiments, the compound comprises Formula (Ib): [ka] During the ceremony, R 3 is hydrogen or amidine, R 4 ~R 8 are independently hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, aryl, substituted aryl, sulfinyl, substituted sulfinyl, or a C1-C3 alkylsilyl group; R 3 ~R 8 are independently hydrogen or C1-C6 alkyl.

[0022] Specifically, in some embodiments, the present invention provides compounds of formula (I), and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof: [ka] In the formula, R 1 and R 2 are independently selected from H, deuterium, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, C4-C9 alkylcycloalkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, aryl, substituted aryl, alkylaryl, and substituted alkylaryl; The substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, and substituted aryl are substituted with 1 to 3 substituents independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, and halogenated C1-C3 alkyl groups; R 1 and R 2 may also be linked to form 3-, 4-, 5-, and 6-membered rings; A is selected from: [ka] During the ceremony, n=1, 2, 3, 4, m=1, 2, 3, 4, R 3 is selected from the group consisting of H, deuterium, C1-C6 alkyl, oxygen-containing alkyl, and nitrogen-containing alkyl; B is selected from the group consisting of an aromatic ring, a substituted aromatic ring, a heterocycle, a substituted heterocycle, an alkylheterocycle, and a substituted alkylheterocycle, and the substituted heterocycle or alkylheterocycle is substituted with 1 to 3 independently selected from the group consisting of halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, alkylsilyl, aryl, substituted aryl, and oxygen-, sulfur-, and selenium-containing alkyl.

[0023] In some embodiments, R in formula (I)1 and R 2 are independently selected from H, deuterium, methyl, ethyl, propyl, butyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, C4-C9 alkylcycloalkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, aryl, substituted aryl, alkylaryl, and substituted alkylaryl.

[0024] In some embodiments, R in formula (I) 1 and R 2 are independently selected from H, deuterium, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclopropylethyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, aryl, substituted aryl, alkylaryl, and substituted alkylaryl.

[0025] In some embodiments, R in formula (I) 1 and R 2 are independently selected from H, deuterium, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclopropylethyl, ethenyl, propenyl, isopropenyl, phenyl, naphthyl, phenylmethyl, and phenylethyl.

[0026] In some embodiments, A in formula (I) is selected from: [ka] In the formula, n=1 and m=1.

[0027] In some embodiments, A in formula (I) is selected from: [ka] In the formula, n=1 and m=1.

[0028] In some embodiments, A in formula (I) is selected from: [ka] In the formula, n=1 and m=1.

[0029] In some embodiments, R in formula (I) 3 are independently selected from H, deuterium, methyl, ethyl, propyl, butyl, oxygen-containing alkyl, and nitrogen-containing alkyl.

[0030] In some embodiments, R in formula (I) 3 are independently selected from H, deuterium, methyl, ethyl, propyl, butyl, aldehyde, ester, carboxyl, and nitrogen-containing alkyl.

[0031] In some embodiments, R in formula (I) 3 are independently selected from H, deuterium, methyl, ethyl, propyl, butyl, aldehyde, ester, carboxyl, methylamino, formylamide, and amidine.

[0032] In some embodiments, B in formula (I) is selected from phenyl, pyridine, imidazole, and pyrimidine fused with pyridine.

[0033] In some embodiments, B in Formula (I) is selected from a substituted aromatic ring, a substituted heterocyclic ring, and a substituted alkylheterocyclic ring, wherein the substituted aromatic ring, heterocyclic ring, and alkylheterocyclic ring are independently substituted with 1 to 3 substituents selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, (3,3-dimethylbutyl)oxy, trimethylsilyl, phenyl, 3-methoxyphenyl, and sulfonyl groups.

[0034] Additionally, the compound of formula (I) is selected from the following compounds 1-23, and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof: [ka]

[0035] (II) A process for preparing a compound having formula (I) In some aspects, the present application provides methods for preparing the above compounds or stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof.

[0036] The preparation method includes the following steps: (1) Compound (I-1) and compound (I-2) are subjected to a condensation reaction to obtain compound (I-3). [ka] (2) The Boc group of compound (I-3) is deprotected under acidic conditions to give compound (I-4) or a compound of formula (I). [ka] (3) Compound (I-4) is reacted with compound (I-5) under alkaline conditions to obtain compound (I-6), i.e., the compound of formula (I). [ka] (4) Compound (I-7) and compound (I-2) are subjected to a condensation reaction to obtain compound (I-8), i.e., the compound of formula (I). [ka]

[0037] (III) A composition comprising a compound of formula (I) In certain embodiments, the present invention provides pharmaceutical compositions comprising compounds of formula (I) and their stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs, together with at least one pharmaceutically acceptable excipient. (a) A compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof: (b) Excipients.

[0038] The disclosed pharmaceutical compositions comprise at least one pharmaceutically acceptable excipient. Non-limiting examples of suitable excipients include diluents, binders, fillers, buffers, pH adjusters, disintegrants, dispersants, stabilizers, preservatives, and colorants. The amount and type of excipient can be selected based on established pharmaceutical principles.

[0039] The pharmaceutical composition can be mixed with one or more excipients to form a solid, liquid, or cream formulation. Methods for preparing solid, liquid, or cream formulations are well established in the art.

[0040] (IV) How to use In another aspect, the present invention provides a method for treating an SSTR4 receptor-associated disease or disorder, comprising administering to an individual in need thereof a pharmaceutical composition comprising a compound of formula (I).

[0041] Without being bound by any particular theory, it is believed that the compounds of formula (I) function primarily as agonists to mediate activity at the SSTR4 receptor. Binding at this site is believed to have the potential to treat conditions such as pain, addiction, depression, stress, anxiety, autoimmune disease, or neurological disorders.

[0042] These compounds can be administered via a variety of routes. For example, the compounds of formula (I) can be administered orally via solid or liquid formulations (tablets, gel capsules, sustained-release capsule powders, solutions, or suspensions in aqueous or non-aqueous liquids), parenterally (including subcutaneous, intradermal, or intravenous injection, either as a solution, suspension, or emulsion in a carrier), or topically (such as transdermal or transmucosal administration, including, but not limited to, oral, rectal, vaginal, and sublingual administration).

[0043] In one embodiment, the compound can be administered in saline or in combination with the aforementioned pharmaceutically acceptable excipients. The compound can be administered as a primary or adjuvant therapy, or after local intervention (surgery, radiation therapy, local chemotherapy), or can be co-administered with at least one other chemotherapeutic agent.

[0044] Suitable subjects for research may include, but are not limited to, humans and companion animals (such as cats, dogs, rodents, and horses), research animals (such as rabbits, sheep, pigs, dogs, primates, mice, rats, and other rodents), livestock (such as cows, cattle, pigs, goats, sheep, horses, deer, chickens, and other poultry), zoo animals, and primates (such as chimpanzees, monkeys, and gorillas). There is no age limit for the subject. In a preferred embodiment, the experimental subject may be a human.

[0045] Generally, the compound of formula (I) is administered in a therapeutically effective amount, including a prophylactic dose or a lower dose, for example, when co-administered with another preparation.As used herein, the term "effective amount" refers to the amount of compound that is sufficient to provide a circulating concentration high enough to exert a beneficial effect on the receptor.Those skilled in the art can determine the exact dosage based on the desired amount, side effects, and patient's medical history.

[0046] Generally, the compounds of formula (I) have a binding affinity to the SSTR4 receptor of less than about 100 nM. 50 In various embodiments, compounds comprising one of Formulas (I), (II), (III), (IV), or (V) have an EC50 of less than about 100 nM, or less than 10 nM, or less than about 5 nM, or less than about 1 nM. 50 It has.

[0047] Generally, compounds of formula (I) have an EC of less than 100 nM in the whole cell cAMP assay. 50 In various embodiments, compounds of formula (I) have an EC50 of less than about 100 nM, or less than 10 nM, or less than about 5 nM, or less than about 1 nM.50 It has.

[0048] Beneficial effects The compounds of the present invention exhibit excellent binding ability to the SSTR4 receptor and exhibit potent agonist activity against the SSTR4 receptor. These compounds are well suited for pharmaceutical use and have high clinical utility. Furthermore, the synthetic process of the compounds disclosed in the present application is simple, contributing to their considerable economic value.

[0049] Definitions and explanations of terms Unless otherwise stated, groups and terms defined in the specification and claims, including the examples set forth in the Tables, exemplary definitions, preferred definitions, and those specifically defined for the compounds in the Examples, can be freely combined and interchanged. Subsequent definitions of groups and compound structures must fall within the scope disclosed herein.

[0050] The compounds described herein may have asymmetric centers.Compounds of the present invention that contain asymmetrically substituted atoms can be separated into optical isomers or racemates.Unless a specific stereochemical form or isomeric form is specifically indicated, all chiral, non-enantiomeric, racemic, and all geometric isomeric forms of the structure are intended.

[0051] As used herein, the term "alkyl" refers to a lower alkyl having from 1 to 6 carbon atoms in its main chain and up to a total of 20 carbon atoms, which may be straight, branched, or cyclic, including methyl, ethyl, propyl, isopropyl, butyl, hexyl, and the like.

[0052] The term "aromatic," as used herein alone or as part of another moiety, refers to any optionally substituted monocyclic or heterocyclic conjugated planar ring system containing delocalized electrons. Preferred aromatic moieties include single rings (such as furan or benzene), fused rings, or tricyclic moieties having ring portions containing 5 to 14 atoms. The term "aromatic" encompasses the definition of "aryl," as defined below.

[0053] The term "aryl" or "Ar" as used herein alone or as part of another moiety refers to any optionally substituted monocyclic or bicyclic aromatic group, preferably a single ring or fused ring system having 6 to 10 carbon atoms in the ring portion. Examples include phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.

[0054] The terms "carbocycle" or "carbocyclic," as used herein alone or as part of another moiety, refer to any optionally substituted aromatic or non-aromatic monocyclic or polycyclic ring system in which all atoms in the ring are carbon, preferably having 5 or 6 carbon atoms in each ring. Exemplary substituents can include one or more of alkyl, substituted alkyl, alkane, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, formyl, aminoformyl, carbocycle, cyano, ester, ether, halogen, heterocycle, hydroxy, ketone, enone, phosphate, nitro, and thiol groups.

[0055] The term "heteroaromatic ring," as used herein alone or as part of another moiety, refers to an optionally substituted aromatic moiety having at least one heteroatom in at least one ring, preferably five or six atoms in each ring. Preferred heteroaromatic ring moieties have one or two oxygen atoms and / or one to four nitrogen atoms in each ring and are bonded to the remainder of the molecule through a carbon. Exemplary moieties include furan, benzofuran, oxazole, isoxazole, oxadiazole, benzoxazole, benzodiazole, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, quinoline, pyrimidine, diazine, indole, isoindole, indazole, benzimidazole, indolizine, benzotriazole, carbazole, pyrrolopyridine, quinoxaline, quinazoline, and quinoline. Exemplary substituents may include one or more of alkyl, substituted alkyl, alkane, alkoxy, acyl, acyloxy, alkene, alkenoxy, aryl, aryloxy, amino, acylamino, formyl, aminoformyl, carbocycle, cyano, ester, ether, halogen, heterocycle, hydroxy, keto, ketoenol, phosphate, nitro, and thio groups.

[0056] The terms "heterocycle" or "heterocyclic," as used herein alone or as part of another moiety, refer to a bicyclic, aromatic, or non-aromatic moiety having at least one heteroatom, preferably five or six atoms in each ring. Preferred heterocyclic moieties have one or two oxygen atoms and / or one to four nitrogen atoms in each ring and are bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclic moieties include the heteroaromatic ring compounds described above. Exemplary substituents can include one or more of alkyl, substituted alkyl, alkane, alkoxy, acyl, acyloxy, alkene, alkenoxy, aryl, aryloxy, amino, acylamino, formyl, aminoformyl, carbocycle, cyano, ester, ether, halogen, heterocycle, hydroxy, keto, ketoenol, phosphate, nitro, and thio groups.

[0057] As used herein, the term "protecting group" refers to a group that can protect a particular moiety, and can be removed after the protection reaction without interfering with the remainder of the molecule. When the protected moiety is an oxygen atom (forming a protected hydroxy group), exemplary protecting groups include ethers (e.g., allyl, triphenylmethyl (trityl or Tr), benzyl, para-methoxybenzyl (PMB), para-methylphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), beta-methoxyethoxymethyl (MEM), tetrahydropyran (THP), ethoxyethyl (EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-trimethylsilylethoxymethyl (SEM)), esters (e.g., benzoyl (Bz), vinyl carbonate, trichloroethyl carbonate (Troc), 2-trimethylsilyl carbonate), and methylsilane ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS)), and the like. When the protected moiety is a nitrogen atom (thus forming a protected amine), exemplary protecting groups include benzyl (e.g., para-methoxybenzyl (PMP), 3,4-dimethoxybenzyloxy (PMB)), ester (e.g., benzoyl (Bz)), carbonyl (e.g., para-methoxybenzylcarbonyl (Moz), tert-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (FMOC)), acetyl, formylamino, N-methylsilyl, etc. For various protecting groups and their synthetic methods, reference may be made to "Greene's Protective Groups in Organic Synthesis" (4th Edition), co-authored by P.G.M.Wuts and T.W. Greene, John Wiley & Sons, Inc.

[0058] As used herein, a "substituted hydrocarbon group" refers to a hydrocarbon moiety substituted with at least one non-carbon atom, including moieties in which a carbon chain atom is replaced with a heteroatom such as nitrogen, oxygen, silicon, phosphorus, boron, or a halogen atom, and moieties in which the carbon chain contains additional substituents, such as alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenyloxy, aryl, aryloxy, amino, acylamino, aldehyde, formylamino, carbocyclyl, cyano, ester, ether, halogen, heterocyclyl, hydroxy, keto, ketal, phosphino, nitro, and thio groups.

[0059] The terms "comprise," "include," and "have" are inclusive and mean that there may be additional elements other than the listed elements. Having described the invention in detail, it will be apparent that modifications and variations can be made without departing from the scope of the invention as defined in the appended claims.

[0060] Other features and advantages of the invention will be set forth in the description which follows, and in part will become apparent or may be learned by the practice of the invention. The objectives and other advantages of the invention may be realized and obtained through the structure particularly pointed out in the written description, claims and drawings. [Example]

[0061] The following examples illustrate various embodiments of the present invention. Hereinafter, the general formula compounds of the present invention, their preparation methods and applications will be described in more detail with specific examples. The examples shown below are for illustrative purposes and are intended to explain the present invention, and are not to be construed as limiting the scope of protection provided by the present invention. All techniques achieved based on the contents described herein are included in the scope intended to be protected by the present invention.

[0062] Unless otherwise stated, raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. The following abbreviations are used in this application: DCM: dichloromethane; DMF: N,N-dimethylformamide; EA: ethyl acetate; EtOH: ethanol; HATU: azabenzotriazole tetramethyluronium hexafluorophosphate; Na2SO4: sodium sulfate; NaHSO4: sodium bisulfate; TEA: triethylamine. Compounds are named according to conventional naming conventions in the art, and commercially available reagents are referenced by supplier catalog names.

[0063] at 500 MHz using a Bruker Avance Neo 500 MHz liquid-state superconducting nuclear magnetic resonance spectrometer 1 H NMR data were collected and recorded. CDCl3 was used as the solvent, and TMS (δ = 0) was used as the internal standard. Chemical shifts (δ values) are reported in ppm. Mass spectrometry was performed using a Waters ACQUITY UPLC system equipped with an ACQUITY UPLC BEH C8, 50 mm x 2.1 mm, 1.7 μm (20180306-C8-08) chromatography column. Mobile phase A consisted of 0.01% TFA / HO, and mobile phase B was CH3CN. The flow rate was 0.2 mL / min, the column temperature was 30 °C, and the detection wavelength was UV-210 nm. High-performance liquid chromatography (HPLC) was performed using a Thermo UltiMate 3000 liquid chromatography system equipped with a Venusil ASB C18 (4.6 x 250 mm, 5 μm) chromatography column. Mobile phase A was a phosphoric acid solution at pH 1.5, and mobile phase B was CH3CN. The flow rate was 1.0 mL / min, the column temperature was 35°C, and the detection wavelength was UV-215 nm. The injection volume was 2 μL. The gradient elution conditions were as follows: elution was performed at a flow rate of 1.0 mL / min, starting with 95% A and 5% B for 10 minutes, followed by a 5-minute wash with 20% A and 80% B, and finally a 5-minute wash with 95% A and 5% B. The percentages indicate the volume percentage of the mobile phase in the elution solution.

[0064] Example 1: Synthesis of Compound 1 The synthetic route to (1R,5S,6s)-N-(2-(imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 1 is shown in Reaction Scheme 1. Reaction Scheme 1 [ka]

[0065] Step 1: Synthesis of tert-butyl (2-methyl-1-oxo-1-((pyridin-2-ylmethyl)amino)propan-2-yl)carbamate 3 [ka] 2 g of pyridin-2-ylmethylamine 1 (18.5 mmol) and 20 mL of DCM (solvent) were added to a 100 mL round-bottom flask. 2-(tert-Butoxycarbonylamino)-2-methylpropanoic acid 2 (3.95 g, 19.4 mmol) and HATU (8.44 g, 22.2 mmol) were added to the mixture, and finally TEA (10 mL) was added. The reaction mixture was stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated to give tert-butyl (2-methyl-1-oxo-1-((pyridin-2-ylmethyl)amino)propan-2-yl)carbamate 3 (5.4 g, 98%). MS m / z: [M+H] + 294.18.

[0066] Step 2: Synthesis of tert-butyl (2-(imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 4 [ka] tert-Butyl (2-methyl-1-oxo-1-((pyridin-2-ylmethyl)amino)propan-2-yl)carbamate 3 (5.4 g, 18.4 mmol) was weighed into a 250 mL round-bottom flask and dissolved in 60 mL of DCM. An appropriate amount of molecular sieves was added and stirred for 30 minutes. Burgess reagent (6.58 g, 27.6 mmol) was added to the mixture and stirring was continued for 2 hours. LC-MS showed complete reaction of the starting material. The mixture was filtered and the filtrate was directly used for column chromatography purification. The product tert-butyl (2-(imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 4 (2 g, 98.5%) was obtained. MS m / z: [M+H] + 276.71.

[0067] Step 3: Synthesis of 2-(imidazo[1,5-a]pyridin-3-yl)propan-2-amine 5 [ka] In a 50 mL round-bottom flask, tert-butyl (2-(imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 4 (2 g, 1.3 mmol) was mixed with EtOH / HCl (10 mL). The mixture was stirred at room temperature for 30 minutes and then vacuum distilled. This process afforded 2-(imidazo[1,5-a]pyridin-3-yl)propan-2-amine 5 (1.8 g, 99%). The product was analyzed by MS (m / z): [M+H] + Characterized by 176.12.

[0068] Step 4: Synthesis of tert-butyl (1R,5S,6s)-6-((2-(imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 7. [ka] 2-(Imidazo[1,5-a]pyridin-3-yl)propan-2-amine 5 (1.8 g, 10.2 mmol) and 20 mL of DCM (solvent) were added to a 100 mL round-bottom flask. (1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 6 (2.59 g, 10.71 mmol) and HATU (4.65 g, 12.24 mmol) were added to the mixture. Finally, TEA (10 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. LC-MS confirmed the complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to give tert-butyl (1R,5S,6s)-6-((2-(imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (4.0 g, 97%). MS m / z: [M+H] + 399.24 7.

[0069] Step 5: Synthesis of (1R,5S,6s)-N-(2-(imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide (compound 1) [ka] tert-Butyl (1R,5S,6s)-6-((2-(imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 7 (4.0 g, 10 mmol) and EtOH / HCl (20 mL) were added to a 50 mL round-bottom flask. Stirring was continued at room temperature for 30 minutes, followed by vacuum distillation to give (1R,5S,6s)-N-(2-(imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide (2.98 g, 99%), compound 1. 1H NMR(500MHz,chloroform-d) δ 8.75(dd,J=7.4,1.5Hz,1H),8.17(s,1H),7.75-7.68(m,1H),7.34-7.26(m,1H),7.01(s,1H),6.99-6.92(m,1H),3.12-3.00 (m,5H),2.71(t,J=5.8Hz,1H),2.49-2.40(m,2H),1.95-1.87(m,1H),1.77-1.68(m,1H),1.69(s,5H),1.65-1.55(m,1H).MS m / z:[M+H] + 299.19, HPLC>95%.

[0070] Example 2: Synthesis of Compound 2 The synthetic route to (1R,5S,6s)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 2 is shown in Reaction Scheme 2. Reaction Scheme 2 [ka]

[0071] Step 1: Synthesis of tert-butyl (1-(((3-chloropyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 9 [ka] (3-Chloropyridin-2-yl)methanamine 8 (2 g, 14 mmol) and 20 mL of DCM as a solvent were added to a 100 mL round-bottom flask. 2-(tert-Butoxycarbonylamino)-2-methylpropanoic acid 2 (3.42 g, 16.8 mmol) and HATU (6.38 g, 16.8 mmol) were added to the mixture, and finally TEA (10 mL) was added. The mixture was stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO solution. The organic layer was dried over anhydrous NaSO and concentrated to give tert-butyl (1-(((3-chloropyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 9 (4.59 g, 100%). MS m / z: [M+H] 328.14.

[0072] Step 2: Synthesis of tert-butyl (2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 10 [ka] tert-Butyl (1-(((3-chloropyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 9 (4.59 g, 14 mmol) was added to a 250 mL round-bottom flask. 60 mL of DCM was added to the flask to dissolve tert-butyl (1-(((3-chloropyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate. An appropriate amount of molecular sieves was added and stirred for 30 minutes, and then Burgess reagent (5.0 g, 21 mmol) was added to the mixture. The mixture was stirred for 2 hours. LC-MS indicated complete reaction of the starting material. The mixture was filtered, and the filtrate was directly subjected to flash column chromatography to give the product tert-butyl (2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 10 (1.3 g, 30%). MS m / z: [M+H]+ 310.13.

[0073] Step 3: Synthesis of 2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-amine 11 [ka] tert-Butyl (2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 10 (1.3 g, 4.2 mmol) and EtOH / HCl (10 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 30 min, followed by vacuum distillation to give 2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-amine 11 (790 mg, 90%). MS m / z: [M+H] + 210.08.

[0074] Step 4: Synthesis of tert-butyl (1R,5S,6s)-6-((2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 12 [ka] 2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-amine 11 (790 mg, 3.8 mmol) was placed in a 100 mL round-bottom flask and DCM was added as the solvent. Subsequently, (1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 6 (1.0 g, 4.2 mmol) and HATU (1.75 g, 4.6 mmol) were added to the mixture. Finally, TEA (10 mL) was added. The mixture was stirred at room temperature for 1 h. LC-MS analysis confirmed the completion of the reaction of the starting material. The mixture was extracted with DCM and NaHSO solution, and the organic layer was dried over anhydrous NaSO, concentrated, and purified by column chromatography to give tert-butyl (1R,5S,6s)-6-((2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (1.64 g, 100%) 12. MS m / z: [M+H]+ 433.20.

[0075] Step 5: Synthesis of (1R,5S,6s)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide 12. [ka] tert-Butyl (1R,5S,6s)-6-((2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 12 (1.64 g, 3.8 mmol) and EtOH / HCl (20 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 30 min, followed by vacuum distillation to give (1R,5S,6s)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 2 (1.1 g, 90%). 1 H NMR(500MHz,chloroform-d) δ 9.18(dd,J=7.3,1.3Hz,1H),8.26(s,1H),7.59(dd,J=7.4,1.5Hz,1H),7.11(t,J=7.3Hz,1H),6.98(s,1H),3.11- 3.04(m,5H),2.71(t,J=5.8Hz,1H),2.48-2.40(m,3H),1.94-1.87(m,1H),1.76-1.68(m,1H),1.64-1.56m,1H).MS m / z:[M+H] + 333.15, HPLC>95%.

[0076] Example 3: Synthesis of Compound 3 The synthetic route to (1R,5S,6s)-N-(2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 3 is shown in Reaction Scheme 3. Reaction Scheme 3 [ka]

[0077] Step 1: Synthesis of tert-butyl (1-(((3-bromopyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 14. [ka] 3-Bromo-2-pyridinylmethanamine 13 (2 g, 10.7 mmol) and 20 mL of DCM as a solvent were added to a 100 mL round-bottom flask. 2-(tert-Butoxycarbonylamino)-2-methylpropanoic acid 2 (2.6 g, 12.8 mmol) and HATU (4.86 g, 12.8 mmol) were added to the mixture. Finally, TEA (10 mL) was added and stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the solution was concentrated to give tert-butyl (1-(((3-bromopyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 14 (3.9 g, 100%). MS m / z: [M+H] + 372.09.

[0078] Step 2: Synthesis of tert-butyl (2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 15. [ka] tert-Butyl (1-(((3-bromopyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 14 (3.9 g, 10.7 mmol) was weighed and added to a 250 mL round-bottom flask. tert-Butyl (1-(((3-bromopyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 14 was dissolved in 60 mL of DCM. An appropriate amount of molecular sieves was added and stirred for 30 minutes. Next, Burgess reagent (3.8 g, 16 mmol) was added to the mixture and stirred for 2 hours. LC-MS indicated complete reaction of the starting material. The mixture was filtered and the filtrate was used for column chromatography to give the product tert-butyl (2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 15 (1.1 g, 30%). MS m / z: [M+H] + 354.08.

[0079] Step 3: Synthesis of 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-amine 16. [ka] tert-Butyl (2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 15 (1.1 g, 3.2 mmol) was added to a 50 mL round-bottom flask. EtOH / HCl (5 mL) was added to the mixture, which was stirred at room temperature for 30 min, and then vacuum distilled to give 2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-amine 16 (740 mg, 90%). ss MS m / z: [M+H] + 254.03.

[0080] Step 4: Synthesis of tert-butyl (1R,5S,6s)-6-((2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 17. [ka] 2-(8-Bromoimidazo[1,5-a]pyridin-3-yl)propan-2-amine 16 (740 mg, 2.9 mmol) was added to a 100 mL round-bottom flask. 10 mL of DCM was added to the mixture as a solvent. (1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 6 (770 mg, 3.2 mmol) and HATU (1.3 g, 3.5 mmol) were added to the mixture. Finally, TEA (5 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the solution was concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6s)-6-((2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 17 (1.1 g, 80%). MS m / z: [M+H] + 477.15.

[0081] Step 5: Synthesis of (1R,5S,6s)-N-(2-(8ss-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide (compound 3). [ka] tert-Butyl (1R,5S,6s)-6-((2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 17 (1.1 g, 2.3 mmol) was added to a 50 mL round-bottom flask. EtOH / HCl (10 mL) was added and stirred at room temperature for 30 minutes. Vacuum distillation was performed to give (1R,5S,6s)-N-(2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 3 (790 mg, 90%). 1H NMR(500MHz,chloroform-d) δ 9.25(dd,J=7.3,1.3Hz,3H),8.11(s,3H),7.69(dd,J=7.4,1.5Hz,3H),7.14(t,J=7.3Hz,3H),6.98(s,3H),3.11-3.04(m,11H),3. 03(dd,J=4.2,2.9Hz,1H),2.71(t,J=5.8Hz,3H),2.48-2.40(m,6H),1.94-1.87(m,3H),1.76-1.68(m,21H),1.64-1.56(m,3H).MS m / z:[M+H] + 377.10, HPLC>95%.

[0082] Example 4: Synthesis of Compound 4 The synthetic route to (1R,5S,6s)-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 4 is shown in Reaction Scheme 4. Reaction Scheme 4 [ka]

[0083] Step 1: Synthesis of tert-butyl (1-((cyclopropyl(pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 19. [ka] Cyclopropyl(pyridin-2-yl)methanamine 18 (2 g, 13.5 mmol) was placed in a 100 mL round-bottom flask, and 20 mL of DCM was added as a solvent. Subsequently, 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid 2 (3.3 g, 16.2 mmol) and HATU (6.16 g, 16.2 mmol) were introduced into the mixture. Finally, TEA (10 mL) was added. The mixture was stirred at room temperature for 1 h. LC-MS analysis showed the completion of the reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution, and the organic layer was dried over anhydrous Na2SO4 and concentrated to give tert-butyl (1-((cyclopropyl(pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 19 (4.5 g, 100%). MS m / z: [M+H] + 334.21.

[0084] Step 2: Synthesis of tert-butyl (2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 20. [ka] Compound tert-butyl (1-((cyclopropyl(pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 19 (4.5 g, 13.5 mmol) was added to a 250 mL round-bottom flask and dissolved in 60 mL of DCM, followed by the addition of an appropriate amount of molecular sieves. The mixture was stirred for 30 min, followed by the addition of Burgess reagent (4.8 g, 20 mmol), and stirring was continued for another 2 h. LC-MS indicated complete reaction of the starting material. The mixture was filtered, and the filtrate was directly subjected to column chromatography for purification to give tert-butyl (2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 20 (1.28 g, 30%). MS m / z: [M+H] + 316.20.

[0085] Step 3: Synthesis of 2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-amine 21. [ka] tert-Butyl (2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 20 (1.28 g, 4.05 mmol) and EtOH / HCl (10 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 30 min, followed by vacuum distillation to give 2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-amine 21 (775 mg, 89%). MS m / z: [M+H] + 216.15.

[0086] Step 4: Synthesis of tert-butyl (1R,5S,6s)-6-((2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 22. [ka] 2-(1-Cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-amine 21 (790 mg, 3.6 mmol) was transferred to a 100 mL round-bottom flask and 20 mL of DCM was added as a solvent. (1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 6 (965 mg, 4.0 mmol) and HATU (1.6 g, 4.3 mmol) were added to the mixture. Finally, TEA (10 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS indicated complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to give tert-butyl (1R,5S,6s)-6-((2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 22 (1.49 g, 94%). MS m / z: [M+H] + 439.27.

[0087] Step 5: Synthesis of (1R,5S,6s)-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 4. [ka] tert-Butyl (1R,5S,6s)-6-((2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 22 (1.49 g, 3.4 mmol) and EtOH / HCl (20 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 30 min, followed by vacuum distillation to give (1R,5S,6s)-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 4 (1.05 g, 88%). 1 H NMR(500MHz,chloroform-d) δ 8.82(dd,J=7.2,1.3Hz,1H),7.63(dd,J=9.6,1.5Hz,1H),7.23-7.15(m,1H),7.06-6.96(m,2H),3.12-3.00(m,4H),2.84-2.75(m,1H), 2.71(t,J=5.8Hz,1H),2.49-2.40(m,2H),1.95-1.87(m,1H),1.72(s,6H),1.77-1.68(m,1H),1.65-1.55(m,1H),1.08-0.94(m,4H).MS m / z:[M+H] + 339.22, HPLC>95%.

[0088] Example 5: Synthesis of Compound 5 A synthetic route to (1R,5S,6s)-N-(2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 5 is shown in Reaction Scheme 5. Reaction Scheme 5 [ka]

[0089] Step 1: Synthesis of tert-butyl (1-((bromo(pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 24. [ka] To bromo(pyridin-2-yl)methanamine 23 (2 g, 10.7 mmol) in a 100 mL round-bottom flask was added 20 mL of DCM as a solvent. 2-(tert-Butoxycarbonylamino)-2-methylpropanoic acid 2 (2.6 g, 12.8 mmol) and HATU (4.86 g, 12.8 mmol) were added to the mixture. Finally, TEA (10 mL) was added and stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the solution was concentrated to give tert-butyl (1-((bromo(pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 24 (3.9 g, 100%). MS m / z: [M+H] + 372.09.

[0090] Step 2: Synthesis of tert-butyl (2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 25. [ka] tert-Butyl (1-((bromo(pyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 24 (3.9 g, 10.7 mmol) was weighed and added to a 250 mL round-bottom flask and dissolved in 60 mL of DCM. An appropriate amount of molecular sieves was added and stirred for 30 minutes. Burgess reagent (3.8 g, 16 mmol) was then added to the mixture and stirred for another 2 hours. LC-MS showed complete reaction of the starting material. The mixture was filtered, and the filtrate was directly subjected to column chromatography for purification to give the product tert-butyl (2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 25 (1.1 g, 30%). MS m / z: [M+H] + 352.08.

[0091] Step 3: Synthesis of 2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-amine [ka] tert-Butyl (2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 25 (1.1 g, 3.2 mmol) and EtOH / HCl (5 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 30 min, followed by vacuum distillation to give 2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-amine 26 (740 mg, 90%). MS m / z: [M+H] + 254.03.

[0092] Step 4: Synthesis of tert-butyl (1R,5S,6s)-6-((2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 27. [ka] 2-(1-Bromoimidazo[1,5-a]pyridin-3-yl)propan-2-amine 26 (740 mg, 2.9 mmol) was added to a 100 mL round-bottom flask. Next, 10 mL of DCM was added to the flask as a solvent. (1R,5S,6s)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 6 (770 mg, 3.2 mmol) and HATU (1.3 g, 3.5 mmol) were added to the mixture. Finally, TEA (5 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the solution was concentrated to give tert-butyl (1R,5S,6s)-6-((2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 27 (1.1 g, 80%). MS m / z: [M+H] + 477.15.

[0093] Step 5: Synthesis of (1R,5S,6s)-N-(2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 5. [ka] tert-Butyl (1R,5S,6s)-6-((2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 27 (1.1 g, 2.3 mmol) and EtOH / HCl (10 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature for 30 minutes, followed by vacuum distillation to give (1R,5S,6s)-N-(2-(1-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 5 (790 mg, 90%). 1H NMR(500MHz,chloroform-d) δ 8.83(dd,J=7.4,1.5Hz,3H),7.77(dd,J=8.9,1.4Hz,3H),7.35-7.28(m,3H),7.06-6.96(m,6H),3.11-3.04(m,11H),3.03(d MS m / z:[M+H] + 377.10, HPLC>95%.

[0094] Example 6: Synthesis of Compound 6 The synthetic route to (1R,5S,6r)-3-carbamimidoyl-N-(2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 6 is shown in Reaction Scheme 6. Reaction Scheme 6 [ka]

[0095] Step 1: Synthesis of (1R,5S,6r)-3-carbamimidoyl-N-(2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 6 [ka] (1R,5S,6r)-N-(2-(8-(4-Methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide Compound 12 (500 mg, 1.2 mmol) was added to a 100 mL round-bottom flask. 1H-Pyrazole-1-methanol hydrochloride (210 mg, 1.4 mmol) and DIPEA (4 mL) were added to the flask. The mixture was stirred at room temperature for 1 hour. Completion of the reaction was confirmed by LC-MS. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous NaSO, concentrated, and purified by column chromatography to give (1R,5S,6r)-3-carbamimidoyl-N-(2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 6 (322 mg, 60%). 1 H NMR (500 MHz, chloroform-d) δ 9.18 (dd, J = 7.2, 1.4 Hz, 1H), 8.21 (s, 1H), 7.86 (dd, J = 6.9, 1.5 Hz, 1H), 7.46-7.40 (m, 2H), 7.28 (s, 1H), 7.10 (t, J = 7.1 Hz, 1H), 6.97 (d, J = 12.6 Hz, 1H), 6.97-6.92 (m, 2H), 5.51(s,2H),3.82(s,2H),3.72(dd,J=12.2,1.6Hz,2H),3.57(dd,J=12.4,1.6Hz,2H ),2.64(t,J=6.7Hz,1H),2.40-2.31(m,2H),1.88-1.79(m,1H),1.62-1.53(m,1H).MS m / z:[M+H] + 477.25, HPLC>95%.

[0096] Example 7: Synthesis of Compound 7 The synthetic route to (1R,5S,6r)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 7 is shown in Reaction Scheme 7. Reaction Scheme 7 [ka]

[0097] Step 1: Synthesis of tert-butyl (1-(((3-chloropyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 29. [ka] 3-Chloropyridin-2-ylmethanamine 28 (2 g, 14.0 mmol) was added to a 100 mL round-bottom flask. 20 mL of DCM was added as a solvent. 2-(tert-Butoxycarbonylamino)-2-methylpropanoic acid 2 (3.41 g, 16.8 mmol) and HATU (6.39 g, 16.8 mmol) were added to the mixture. Finally, TEA (10 mL) was added and stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the solution was concentrated to give tert-butyl (1-(((3-chloropyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 29 (4.6 g, 100%). MS m / z: [M+H] + 328.14.

[0098] Step 2: Synthesis of tert-butyl (2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 30. [ka] tert-Butyl (1-(((3-chloropyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 29 (4.6 g, 14.0 mmol) was weighed and added to a 250 mL round-bottom flask and dissolved in 60 mL of DCM. An appropriate amount of molecular sieves was added and stirred for 30 minutes. Burgess reagent (5.0 g, 21.0 mmol) was then added to the mixture and stirred for 2 hours. LC-MS showed complete reaction of the starting material. The mixture was filtered, and the filtrate was directly purified by column chromatography to give the product tert-butyl (2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (1.3 g, 30%) 30. MS m / z: [M+H] + 310.13.

[0099] Step 3: Synthesis of 2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-amine 31. [ka] tert-Butyl (2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 30 (1.3 g, 4.2 mmol) was added to a 50 mL round-bottom flask. EtOH / HCl (5 mL) was added and stirred at room temperature for 30 minutes. The mixture was distilled under reduced pressure to give 2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-amine 31 (793 mg, 90%). MS m / z: [M+H] + 210.08.

[0100] Step 4: Synthesis of tert-butyl (1R,5S,6r)-6-((2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 32. [ka] 2-(8-Chloroimidazo[1,5-a]pyridin-3-yl)propan-2-amine 31 (793 mg, 3.8 mmol) was added to a 100 mL round-bottom flask. 20 mL of DCM was added as a solvent. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 60 (1.0 g, 4.2 mmol) and HATU (1.7 g, 4.5 mmol) were added to the mixture. Finally, TEA (5 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the solution was concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-((2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (1.3 g, 80%) 32. MS m / z: [M+H] + 433.20.

[0101] Step 5: Synthesis of (1R,5S,6r)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 7. [ka] tert-Butyl (1R,5S,6r)-6-((2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 32 (1.3 g, 3.0 mmol) was added to a 50 mL round-bottom flask. 10 mL of EtOH / HCl was added to the flask, stirred at room temperature for 30 minutes, and then distilled under reduced pressure to give (1R,5S,6r)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 7 (899 mg, 90%). 1H NMR(500MHz,chloroform-d) δ 9.18(dd,J=7.3,1.3Hz,1H),8.26(s,1H),7.59(dd,J=7.4,1.5Hz,1H),7.11(t,J=7.3Hz,1H),6.98(s,1H),3.07- 2.96(m,4H),2.68(t,J=7.4Hz,1H),2.30-2.17(m,2H),1.94-1.87(m,1H),1.77-1.68(m,7H),1.59-1.50(m,1H). MS m / z:[M+H] + 333.15, HPLC>95%.

[0102] Example 8: Synthesis of Compound 8 The synthetic route to (1R,5S,6r)-N-(2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 8 is shown in Reaction Scheme 8. Reaction Scheme 8 [ka]

[0103] Step 1: Synthesis of tert-butyl (1R,5S,6r)-6-((2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 33 [ka] 2-(8-Bromoimidazo[1,5-a]pyridin-3-yl)propan-2-amine 16 (500 mg, 2 mmol) was added to a 100 mL round-bottom flask, and 10 mL of DCM was added as a solvent. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 60 (531 mg, 2.2 mmol) and HATU (912 mg, 2.4 mmol) were added to the mixture. Finally, TEA (5 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS indicated complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-((2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 33 (764 mg, 80%). MS m / z: [M+H] + 477.15.(1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid

[0104] Step 2: Synthesis of (1R,5S,6r)-N-(2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 8. [ka] tert-Butyl (1R,5S,6r)-6-((2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 33 (764 mg, 1.6 mmol) was added to a 50 mL round-bottom flask, followed by 5 mL of EtOH / HCl. The mixture was stirred at room temperature for 30 min and then distilled under reduced pressure to give (1R,5S,6r)-N-(2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 8 (543 mg, 90%). 1 H NMR(500MHz,chloroform-d) δ 9.25(dd,J=7.3,1.3Hz,1H),8.11(s,1H),7.69(dd,J=7.4,1.5Hz,1H),7.14(t,J=7.3Hz,1H),6.98(s,1H),3.07-2 .96(m,4H),2.68(t,J=7.4Hz,1H),2.30-2.17(m,2H),1.94-1.87(m,1H),1.77-1.68(m,7H),1.59-1.50(m,1H).MS m / z:[M+H] + 377.10, HPLC>95%.

[0105] Example 9: Synthesis of Compound 9 The synthetic route to (1R,5S,6r)-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 9 is shown in Reaction Scheme 9. Reaction Scheme 9 [ka]

[0106] Step 1: Synthesis of tert-butyl (1R,5S,6r)-6-((2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 34 [ka] 2-(1-Cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-amine 21 (500 mg, 2.3 mmol) was added to a 100 mL round-bottom flask, followed by 10 mL of DCM as solvent. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 60 (609 mg, 2.5 mmol) and HATU (1.0 g, 2.8 mmol) were added to the mixture. Finally, TEA (5 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS indicated complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-((2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 34 (806 mg, 80%). MS m / z: [M+H] + 439.27.

[0107] Step 2: Synthesis of (1R,5S,6r)-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 9. [ka] tert-Butyl (1R,5S,6r)-6-((2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 34 (806 mg, 1.8 mmol) was added to a 50 mL round-bottom flask, followed by EtOH / HCl (5 mL). The mixture was stirred at room temperature for 30 min, and then vacuum distilled to give (1R,5S,6r)-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 9 (548 mg, 90%). 1 H NMR(500MHz,chloroform-d) δ 8.82(dd,J=7.2,1.3Hz,1H),7.63(dd,J=9.6,1.5Hz,1H),7.22-7.15(m,1H),7.05-6.96(m,2H),3.07-2.96(m,4H),2.83-2.76( m,1H),2.68(t,J=7.4Hz,1H),2.30-2.17(m,2H),1.94-1.87(m,1H),1.77-1.68(m,7H),1.59-1.50(m,1H),1.08-0.94(m,4H).MS m / z:[M+H] + 339.22, HPLC>95%.

[0108] Example 10: Synthesis of Compound 10 A synthetic route to (1R,5S,6r)-N-(2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 10 is shown in Reaction Scheme 10. Reaction Scheme 10 [ka]

[0109] Step 1: Synthesis of tert-butyl (1-(((3-methoxypyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 36. [ka] (3-Methoxypyridin-2-yl)methanamine 35 (2 g, 14.5 mmol) was added to a 100 mL round-bottom flask, followed by 20 mL of DCM as the solvent. 2-(tert-Butoxycarbonyl)amino-2-methylpropanoic acid 2 (3.54 g, 17.4 mmol) and HATU (6.62 g, 17.4 mmol) were added to the mixture. Finally, TEA (10 mL) was added and stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the solution was concentrated to give tert-butyl (1-(((3-methoxypyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 36 (4.7 g, 100%). MS m / z: [M+H] + 324.19.

[0110] Step 2: Synthesis of tert-butyl (2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 37. [ka] tert-Butyl (1-(((3-methoxypyridin-2-yl)methyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate 36 (4.7 g, 14.5 mmol) was weighed into a 250 mL round-bottom flask and dissolved in 60 mL of DCM. An appropriate amount of molecular sieves was added and stirred for 30 minutes. Burgess reagent (5.2 g, 21.8 mmol) was then added to the mixture and stirred for 2 hours. LC-MS analysis showed complete reaction of the starting material. The mixture was filtered, and the filtrate was directly concentrated. The product was purified by column chromatography to give tert-butyl (2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 37 (1.3 g, 30%). MS m / z: [M+H] + 306.18.

[0111] Step 3: Synthesis of 2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-amine 38 [ka] tert-Butyl (2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 37 (1.3 g, 4.4 mmol) was added to a 50 mL round-bottom flask, followed by EtOH / HCl (5 mL). The mixture was stirred at room temperature for 30 min and then vacuum distilled to give 2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-amine 38 (813 mg, 90%). MS m / z: [M+H] + 206.13.

[0112] Step 4: Synthesis of tert-butyl (1R,5S,6r)-6-((2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 39 [ka] 2-(8-Methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-amine 38 (813 mg, 4.0 mmol) was added to a 100 mL round-bottom flask, followed by 20 mL of DCM as solvent. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 6 (1.1 g, 4.4 mmol) and HATU (1.8 g, 4.8 mmol) were added to the mixture. Finally, TEA (5 mL) was added and stirred at room temperature for 1 h. LC-MS indicated complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-((2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 39 (1.4 g, 80%). MS m / z: [M+H] + 429.25.

[0113] Step 5: Synthesis of (1R,5S,6r)-N-(2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 10 [ka] tert-Butyl (1R,5S,6r)-6-((2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 39 (1.4 g, 3.2 mmol) was added to a 50 mL round-bottom flask, followed by EtOH / HCl (10 mL). The mixture was stirred at room temperature for 30 minutes. Vacuum distillation afforded (1R,5S,6r)-N-(2-(8-methoxyimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 10 (946 mg, 90%). 1H NMR(500MHz,chloroform-d) δ 8.72(dd,J=7.2,1.4Hz,1H),8.42(s,1H),7.10(t,J=7.3Hz,1H),7.04-6.97(m,2H),3.91(s,3H),3.07-2.96(m,4H) ),2.68(t,J=7.4Hz,1H),2.30-2.17(m,2H),1.94-1.87(m,1H),1.73(dd,J=12.4,6.7Hz,7H),1.59-1.50(m,1H).MS m / z:[M+H] + 329.20, HPLC>95%.

[0114] Example 11: Synthesis of Compound 11 The synthetic route to (1R,5S,6r)-N-(2-(8-(trimethylsilyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 11 is shown in Reaction Scheme 11. Reaction Scheme 11 [ka]

[0115] Step 1: Synthesis of tert-butyl (1R,5S,6r)-6-((2-(8-(trimethylsilyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 41 [ka] 2-(8-(Trimethylsilyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 40 (500 mg, 2.0 mmol) was added to a 100 mL round-bottom flask, followed by 10 mL of DCM as solvent. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 60 (530 mg, 2.2 mmol) and HATU (912.55 mg, 2.4 mmol) were added to the mixture. Finally, TEA (5 mL) was added and stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the organic layer was concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-((2-(8-(trimethylsilyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 41 (753 mg, 80%). MS m / z: [M+H] + 471.27.

[0116] Step 2: Synthesis of (1R,5S,6r)-N-(2-(8-(trimethylsilyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 11 [ka] tert-Butyl (1R,5S,6r)-6-((2-(8-(trimethylsilyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 41 (753 mg, 1.6 mmol) was added to a 50 mL round-bottom flask, followed by EtOH / HCl (5 mL). The mixture was stirred at room temperature for 30 min. Vacuum distillation afforded (1R,5S,6r)-N-(2-(8-(trimethylsilyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 11 (533 mg, 90%).1 H NMR(500MHz,chloroform-d) δ 9.07(dd,J=7.1,1.3Hz,1H),7.95(s,1H),7.51(dd,J=8.3,1.5Hz,1H),7.01(s,1H),6.91(dd,J=8.2,7.1Hz,1H),3.06-2.9 6(m,4H),2.64(t,J=7.0Hz,1H),2.32-2.20(m,2H),1.94-1.87(m,1H),1.78-1.69(m,1H),1.58-1.49(m,1H),0.12(s,7H). MS m / z:[M+H] + 371.23, HPLC>95%.

[0117] Example 12: Synthesis of Compound 12 The synthetic route to (1R,5S,6r)-N-(2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 12 is shown in Reaction Scheme 12. Reaction Scheme 12 [ka]

[0118] Step 1: Synthesis of tert-butyl (2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 42. [ka] tert-Butyl (2-(8-bromoimidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 15 (1.0 g, 2.8 mmol) was added to a 100 mL round-bottom flask, followed by 10 mL of DMF as a solvent. Bis(triphenylphosphine)palladium(II) dichloride (211 mg, 0.3 mmol) and 4-methoxyphenylboronic acid (511 mg, 3.4 mmol) were added to the mixture. The mixture was heated to 80 °C and stirred for 2 h. LC-MS indicated complete reaction of the starting material. The mixture was extracted with water and ethyl acetate (EA). The organic layer was dried over anhydrous NaSO, concentrated, and purified by column chromatography to give tert-butyl (2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 42 (748 mg, 70%). MS m / z: [M+H] + 382.21.

[0119] Step 2: Synthesis of 2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 43 [ka] tert-Butyl (2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 42 (748 mg, 2.0 mmol) was added to a 50 mL round-bottom flask, followed by EtOH / HCl (5 mL). The mixture was stirred at room temperature for 30 min, then vacuum distilled to give 2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine (673 mg, 90%) 43. MS m / z: [M+H] + 282.16.

[0120] Step 3: Synthesis of tert-butyl (1R,5S,6r)-6-((2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 44 [ka] 2-(8-(4-Methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 43 (673 mg, 1.8 mmol) was added to a 100 mL round-bottom flask, followed by 10 mL of DCM as solvent. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 60 (472 mg, 2.0 mmol) and HATU (821 mg, 2.2 mmol) were added to the mixture. Finally, TEA (5 mL) was added and stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the organic layer was concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-((2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 44 (727 mg, 80%). MS m / z: [M+H] + 505.28.

[0121] Step 4: Synthesis of (1R,5S,6r)-N-(2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 12 [ka] tert-Butyl (1R,5S,6r)-6-((2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 44 (727 mg, 1.4 mmol) was added to a 50 mL round-bottom flask. 5 mL of EtOH / HCl was added and stirred at room temperature for 30 minutes. Vacuum distillation was performed to give (1R,5S,6r)-N-(2-(8-(4-methoxyphenyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 12 (524 mg, 90%). 1 H NMR(500MHz,chloroform-d) δ 9.18(dd,J=7.2,1.4Hz,1H),8.21(s,1H),7.86(dd,J=6.9,1.5Hz,1H),7.46-7.40(m,2H),7.10(t,J=7.1Hz,1H),7.00-6.94(m,2H),6.94(s MS m / z:[M+H] + 405.23, HPLC>95%.

[0122] Example 13: Synthesis of Compound 13 The synthetic route to (1R,5S,6r)-N-(2-(8-(methylsulfinyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 13 is shown in Reaction Scheme 13. Reaction Scheme 13 [ka]

[0123] Step 1: Synthesis of tert-butyl (1R,5S,6r)-6-((2-(8-(methylsulfinyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 46 [ka] 2-(8-(Methylsulfinyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 45 (500 mg, 2.1 mmol) was added to a 100 mL round-bottom flask, followed by 20 mL of DCM as solvent. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 60 (554 mg, 2.3 mmol) and HATU (958 mg, 2.5 mmol) were added to the mixture. Finally, TEA (5 mL) was added and stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4, and the organic layer was concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-((2-(8-(methylsulfinyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 46 (774 mg, 80%). MS m / z: [M+H] + 461.22.

[0124] Step 2: Synthesis of (1R,5S,6r)-N-(2-(8-(methylsulfinyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 13 [ka] tert-Butyl (1R,5S,6r)-6-((2-(8-(methylsulfinyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 46 (774 mg, 1.7 mmol) was added to a 50 mL round-bottom flask, followed by EtOH / HCl (10 mL). The mixture was stirred at room temperature for 30 min, and then vacuum distilled to give (1R,5S,6r)-N-(2-(8-(methylsulfinyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 13 (552 mg, 90%). 1 H NMR(500MHz,chloroform-d) δ 9.24(dd,J=6.6,1.3Hz,1H),8.02-7.95(m,2H),7.20(t,J=6.8Hz,1H),6.98(s,1H),3.06-2.96(m,4H),2.86( MS m / z:[M+H] + 361,17, HPLC>95%.

[0125] Example 14: Synthesis of Compound 16 The synthetic route to (1R,5S,6r)-N-((8-bromoimidazo[1,5-a]pyridin-3-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 16 is shown in Reaction Scheme 14. Reaction Scheme 14 [ka]

[0126] Step 1: Synthesis of tert-butyl (1R,5S,6r)-6-(((8-bromoimidazo[1,5-a]pyridin-3-yl)methyl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 48. [ka] 8-Bromoimidazo[1,5-a]pyridin-3-ylmethanamine 47 (500 mg, 2.2 mmol) was added to a 100 mL round-bottom flask, followed by 10 mL of DCM as solvent. (1R,5S,6r)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-6-carboxylic acid (578 mg, 2.4 mmol) 60 and HATU (989 mg, 2.6 mmol) were added to the mixture. Finally, TEA (5 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS indicated complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-(((8-bromoimidazo[1,5-a]pyridin-3-yl)methyl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 48 (791 mg, 80%). MS m / z: [M+H] + 449.12.

[0127] Step 2: Synthesis of (1R,5S,6r)-N-((8-bromoimidazo[1,5-a]pyridin-3-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 16 [ka] tert-Butyl (1R,5S,6r)-6-(((8-bromoimidazo[1,5-a]pyridin-3-yl)methyl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 48 (791 mg, 1.8 mmol) was added to a 50 mL round-bottom flask, followed by EtOH / HCl (5 mL), and the mixture was stirred at room temperature for 30 min. Vacuum distillation afforded (1R,5S,6r)-N-((8-bromoimidazo[1,5-a]pyridin-3-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 16 (566 mg, 90%). 1H NMR(500MHz,chloroform-d) δ 9.25(dd,J=8.1,1.3Hz,1H),7.70(dd,J=7.6,1.5Hz,1H),7.63(s,1H),7.50(t,J=4.1Hz,1H),7.08(dd,J=8.1,7.3Hz,1H),4.60(d,J=4.1H MS m / z:[M+H] + 349.07, HPLC>95%.

[0128] Example 15: Synthesis of Compound 17 The synthetic route to (1R,5S,6r)-N-((S)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 17 is shown in Reaction Scheme 15. Reaction Scheme 15 [ka]

[0129] Step 1: Synthesis of tert-butyl (1R,5S,6r)-6-(((S)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate compound 17 [ka] (S)-1-(8-Bromoimidazo[1,5-a]pyridin-3-yl)ethan-1-amine 50 (500 mg, 2.1 mmol) was added to a 100 mL round-bottom flask, followed by 10 mL of DCM as solvent. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 60 (554 mg, 2.3 mmol) and HATU (951 mg, 2.5 mmol) were added to the mixture. Finally, TEA (5 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS indicated complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-(((S)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 50 (778 mg, 80%). MS m / z: [M+H] + 463.13.

[0130] Step 2: Synthesis of (1R,5S,6r)-N-((S)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 17 [ka] tert-Butyl (1R,5S,6r)-6-(((S)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 50 (778 mg, 1.7 mmol) was added to a 50 mL round-bottom flask, followed by EtOH / HCl (5 mL), and the mixture was stirred at room temperature for 30 min. Vacuum distillation afforded (1R,5S,6r)-N-((S)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 17 (556 mg, 90%). 1H NMR(500MHz,chloroform-d) δ 9.26(dd,J=8.4,1.3Hz,1H),7.70(dd,J=7.6,1.5Hz,1H),7.54(s,1H),7.21(d,J=8.2Hz,1H),7.11(dd,J=8.3,7.4Hz,1H),5.05-4.97(m,1 H),3.06-2.96(m,4H),2.56(t,J=7.4Hz,1H),2.31-2.21(m,2H),1.94-1.87(m,1H),1.78-1.69(m,1H),1.63(s,1H),1.58-1.49(m,1H).MS m / z:[M+H] + 363.08, HPLC>95%.

[0131] Example 16: Synthesis of Compound 18 The synthetic route to (1R,5S,6r)-N-((R)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 18 is shown in Reaction Scheme 16. Reaction Scheme 16 [ka]

[0132] Step 1: Synthesis of tert-butyl (1R,5S,6r)-6-(((R)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 52 [ka] (R)-1-(8-Bromoimidazo[1,5-a]pyridin-3-yl)ethan-1-amine 51 (500 mg, 2.1 mmol) was added to a 100 mL round-bottom flask, followed by 10 mL of DCM as solvent. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid (554 mg, 2.3 mmol) 60 and HATU (951 mg, 2.5 mmol) were added to the mixture. Finally, TEA (5 mL) was added, and the mixture was stirred at room temperature for 1 h. LC-MS indicated complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to give tert-butyl (1R,5S,6r)-6-(((R)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 52 (778 mg, 80%). MS m / z: [M+H] + 463.13.

[0133] Step 2: Synthesis of (1R,5S,6r)-N-((R)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 18 [ka] tert-Butyl (1R,5S,6r)-6-(((R)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 52 (778 mg, 1.7 mmol) was added to a 50 mL round-bottom flask, followed by EtOH / HCl (5 mL). The mixture was stirred at room temperature for 30 minutes, and then vacuum distilled to give the product (1R,5S,6r)-N-((R)-1-(8-bromoimidazo[1,5-a]pyridin-3-yl)ethyl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 18 (556 mg, 90%). 1H NMR(500MHz,chloroform-d) δ 9.26(dd,J=8.4,1.3Hz,1H),7.70(dd,J=7.6,1.5Hz,1H),7.54(s,1H),7.21(d,J=8.2Hz,1H),7.11(dd,J=8.3,7.4Hz,1H),5.05-4.97(m,1 H),3.06-2.96(m,4H),2.56(t,J=7.4Hz,1H),2.31-2.21(m,2H),1.94-1.87(m,1H),1.78-1.69(m,1H),1.63(s,1H),1.58-1.49(m,1H).MS m / z:[M+H] + 363.08, HPLC>95%.

[0134] Example 17: Synthesis of Compound 19 The synthetic route to (1R,5S,6r)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-formyl-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 19 is shown in Reaction Scheme 17. Reaction Scheme 17 [ka]

[0135] Step 1: Synthesis of (1R,5S,6r)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-formyl-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 19 [ka] 2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-amine 11 (500 mg, 2.4 mmol) was added to a 100 mL round-bottom flask, followed by 10 mL of DCM as solvent. (1R,5S,6r)-3-formyl-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 41 (447 mg, 2.6 mmol) and HATU (1.1 g, 2.9 mmol) were added to the mixture. Finally, TEA (5 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to give (1R,5S,6r)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-formyl-3-azabicyclo[3.1.1]heptane-6-carboxamide Compound 19 (693 mg, 80%). 1 H NMR(500MHz,chloroform-d) δ 9.18(dd,J=7.3,1.3Hz,1H),8.26(s,1H),7.78(s,1H),7.59(dd,J=7.4,1.5Hz,1H),7.15-7.08(m,1H),6.98(s,1H),3.72(dd,J =12.4,2.0Hz,2H),3.57(dd,J=12.3,2.0Hz,2H),2.66-2.60(m,1H),2.58-2.48(m,2H),1.85-1.76(m,1H),1.65-1.56(m,1H).MS m / z:[M+H] + 361.14, HPLC>95%.

[0136] Example 18: Synthesis of Compound 21 A synthetic route to (1R,5S,6r)-3-carbamimidoyl-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 21 is shown in Reaction Scheme 18. Reaction Scheme 18 [ka]

[0137] Step 1: Synthesis of (1R,5S,6r)-3-carbamimidoyl-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 21 [ka] (1R,5S,6r)-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)prop-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 7 (500 mg, 1.5 mmol) was added to a 100 mL round-bottom flask, followed by 1H-pyrazole-1-methanol hydrochloride (263 mg, 1.8 mmol) and DIPEA (4 mL). The mixture was stirred at room temperature for 1 hour. Completion of the reaction was confirmed by LC-MS. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous NaSO, concentrated, and purified by column chromatography to give (1R,5S,6r)-3-carbamimidoyl-N-(2-(8-chloroimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide Compound 21 (337 mg, 60%). 1 H NMR(500MHz,chloroform-d) δ 9.18(dd,J=7.3,1.3Hz,1H),8.26(s,1H),7.59(dd,J=7.4,1.5Hz,1H),7.15-7.06(m,2H),6.98(s,1H),5.51(s,2H),3.72(dd,J=1 MS m / z:[M+H] + 375.17, HPLC>95%.

[0138] Example 19: Synthesis of Compound 22 A synthetic route to (1R,5S,6r)-3-carbamimidoyl-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 22 is shown in Reaction Scheme 19. Reaction Scheme 19 [ka]

[0139] Step 1: Synthesis of (1R,5S,6r)-3-carbamimidoyl-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 22 [ka] (1R,5S,6r)-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide Compound 9 (500 mg, 1.5 mmol) was added to a 100 mL round-bottom flask, followed by 1H-pyrazole-1-methanol hydrochloride (264 mg, 1.8 mmol) and DIPEA (4 mL). The mixture was stirred at room temperature for 1 hour. Completion of the reaction was confirmed by LC-MS. The mixture was extracted with DCM and NaHSO4 solution. The organic layer was dried over anhydrous NaSO, concentrated, and purified by column chromatography to give (1R,5S,6r)-3-carbamimidoyl-N-(2-(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide Compound 22 (342 mg, 60%). 1H NMR (500MHz, chloroform-d) δ 8.82(dd,J=7.2,1.3Hz,1H),7.63(dd,J=9.6,1.5Hz,1H),7.28(s,1H),7.22 -7.15(m,1H),7.06-6.96(m,2H),5.51(s,2H),3.72(dd,J=12.2,1.6Hz,2H) ,3.57(dd,J=12.4,1.6Hz,2H),2.83-2.76(m,1H),2.64(t,J=6.7Hz,1H),2. 40-2.31(m,2H),1.88-1.79(m,1H),1.62-1.53(m,1H),1.08-0.94(m,5H).MS m / z:[M+H] + 381.24, HPLC>95%.

[0140] Example 20: Synthesis of Compound 23 A synthetic route to (1R,5S,6r)-N-(2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 23 is shown in Reaction Scheme 20. [ka]

[0141] Step 1: Synthesis of tert-butyl (2-methyl-1-(((3-(methylselanyl)pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate 54 [ka] (3-(methylselanyl)pyridin-2-yl)methanamine (2 g, 9.9 mmol) was added to a 100 mL round-bottom flask, followed by 20 mL of DCM as a solvent. 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (2.42 g, 11.9 mmol) and HATU (4.52 g, 11.9 mmol) were added to the mixture. Finally, TEA (10 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO4 solution, and the organic layer was dried over anhydrous Na2SO4 and concentrated to give tert-butyl (2-methyl-1-(((3-(methylselanyl)pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (3.8 g, 100%). MS m / z: [M+H]+ 388.11 54.

[0142] Step 2: Synthesis of tert-butyl (2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 55 [ka] tert-Butyl (2-methyl-1-(((3-(methylselanyl)pyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamate 54 (3.8 g, 9.9 mmol) was weighed and added to a 250 mL round-bottom flask and dissolved in 60 mL of DCM. An appropriate amount of molecular sieves was added, and the reaction mixture was stirred for 30 minutes. Burgess reagent (3.4 g, 14.8 mmol) was added to the mixture. The reaction mixture was stirred for 2 hours. LC-MS indicated complete reaction of the starting material. The mixture was filtered, and the filtrate was directly subjected to column chromatography for purification to give tert-butyl (2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate (1.1 g, 30%) 55. MS m / z: [M+H]+ 370.10.

[0143] Step 3: Synthesis of 2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 56 [ka] tert-Butyl (2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamate 55 (1.1 g, 3.0 mmol) and EtOH / HCl (5 mL) were added to a 50 mL round-bottom flask. The reaction mixture was stirred at room temperature for 30 minutes, then vacuum distilled to give 2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine 56 (724 mg, 90%). MS m / z: [M+H]+ 270.05.

[0144] Step 4: Synthesis of tert-butyl (1R,5S,6r)-6-((2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 57 [ka] 2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-amine (724 mg, 2.7 mmol) and 20 mL of DCM as solvent were added to a 100 mL round-bottom flask. (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic acid 60 (723 mg, 3.0 mmol) and HATU (1.2 g, 3.2 mmol) were added to the reaction mixture. Finally, TEA (5 mL) was added and the mixture was stirred at room temperature for 1 h. LC-MS showed complete reaction of the starting material. The mixture was extracted with DCM and NaHSO solution, and the organic layer was dried over anhydrous NaSO, concentrated, and purified by column chromatography to give tert-butyl (1R,5S,6r)-6-((2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate 57 (1.1 g, 80%). MS m / z: [M+H] 493.17.

[0145] Step 5: Synthesis of (1R,5S,6r)-N-(2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 23 [ka] tert-Butyl (1R,5S,6r)-6-((2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (1.1 g, 2.2 mmol) and EtOH / HCl (10 mL) were added to a 50 mL round-bottom flask. The reaction mixture was stirred at room temperature for 30 minutes and then vacuum distilled to give (1R,5S,6r)-N-(2-(8-(methylselanyl)imidazo[1,5-a]pyridin-3-yl)propan-2-yl)-3-azabicyclo[3.1.1]heptane-6-carboxamide compound 23 (775 mg, 90%). 1 H NMR(500MHz,chloroform-d) δ 9.05(dd,J=7.0,1.5Hz,1H),7.98(s,1H),7.55(s,1H),7.49(dd,J=7.9,1.5Hz,1H),7.21(dd,J=7.9,7.1Hz,1H),3.01(t,J=5.6Hz,1H),2.95(m,J= 12.2,5.0,4.1Hz,2H),2.86(m,J=12.2,5.0,4.2Hz,2H),2.66(q,J=5.0Hz ,1H),2.66-2.55(m,2H),2.53(s,2H),2.09-1.98(m,2H),1.92(s,4H).MS m / z:[M+H] + 393.12.

[0146] Biological Research and Testing Example 21: Evaluation of affinity in radioligand binding Radioligand binding affinity assessment was performed at Eurofins according to the method described in reference (ROHRER, L., RAULF, F., BRUNS, C., BUETTNER, R., HOFSTAEDTER, F. and SCHULE, R. (1993), Cloning and characterization of the fourth human somatostatin receptor, Proc. Natl. Acad. Sci. USA, 90:4196). The detailed procedure is outlined below.

[0147] SSTR-1 binding assay Cell membrane homogenates (5 μg protein) were incubated with 0.1 nM [125I]Tyr11-somatostatin-14 in a buffer containing 25 mM Hepes / Tris (pH 7.4), 5 mM MgCl2, 1 mM CaCl2, and 0.5% BSA for 180 min at 37°C, in the presence or absence of test compound. Nonspecific binding was determined in the presence of 1 μM somatostatin-28. After incubation, samples were quickly vacuum filtered through glass fiber filters presoaked in 0.3% PEI (GF / B, Packard) and washed multiple times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). Filters were dried and then counted for radioactivity using a liquid scintillation counter (Topcount, Packard) with scintillation fluid (Microscint 0, Packard). Results are expressed as percent inhibition of specific binding of the control radioligand. The standard reference compound was natural somatostatin-28, and multiple concentrations were tested in each experiment.

[0148] SSTR-4 binding assay Cell membrane homogenates (8 μg of protein) were incubated with 0.1 nM [125I]Tyr11-somatostatin-14 in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, and 0.2% BSA for 120 min at 22°C, in the presence or absence of test compound. Nonspecific binding was determined in the presence of 1 μM somatostatin-14. After incubation, samples were rapidly filtered under vacuum through glass fiber filters presoaked in 0.3% PEI (GF / B, Packard) and washed multiple times with ice-cold buffer containing 50 mM Tris-HCl and 0.5% BSA using a 96-sample cell harvester (Unifilter, Packard). Filters were dried and then counted for radioactivity using a liquid scintillation counter (Topcount, Packard) with scintillation mixture (Microscint 0, Packard). Results are expressed as percent inhibition of specific binding of the control radioligand. The standard reference compound was somatostatin-14, with multiple concentrations tested in each experiment. [Table 1]

[0149] Example 22: FLIPR assay for evaluating agonists of SSTR1-5 The test was carried out at HD Biosciences (Shanghai, China) according to the following steps.

[0150] Step 1: Test compounds were diluted to a 400x stock solution in DMSO in a 384-well plate.

[0151] Step 2: 1 μL of compound solution from step 1 was transferred to 79 μL of assay buffer and a 5x standard solution was made in a 384-well plate using the Bravo method.

[0152] Step 3: HEK293 / Gα15 / SSTR1-5 cells were cultured in DMEM medium (10% FBS).

[0153] Step 4: Once the cells reached 80% confluence, 0.25% trypsin-EDTA was used to detach the cells.

[0154] Step 5: Measure the cell density and dilute the cells to 1x10^6 / mL using DMEM (10% FBS).

[0155] Step 6: Using a multichannel pipette, dispense 30 µL of cells into each well of a Matrigel-coated 384-well plate (Corning 3764#) (30,000 cells per well) and culture at 37 °C, 5% CO for 20–24 h.

[0156] Step 7: 10 μL of dye was added to each well of the cell plate prepared in step 6.

[0157] Step 8: The dye and cells were incubated for 1 hour at 37°C, 5% CO2 in the dark.

[0158] Step 9: After 1 hour, load the FLIPR program, place the cell plate and compound plate (from step 2) into the machine with pipette tips, and press the run button. The program added 10 µL to 40 µL to the cell plate. Use the FLIPR to read the plate at room temperature according to the specified settings, and save the data. [Table 2]

[0159] Example 23: Acetic acid-induced writhing test The test compound was administered subcutaneously to KM mice (provided by Hunan Silaikejingda Experimental Animal Co., Ltd.) at a predetermined dose of 5 mL / kg. 15 minutes after administration, 0.6% acetic acid solution (5 mL / kg) was injected intraperitoneally. The mice were then placed in an observation box, and the number of writhing attacks within 30 minutes was recorded. The pain intensity was assessed based on the observation of the mice's writhing behavior. [Table 3]

[0160] Example 24: SD rat SNL model In the spinal nerve ligation (SNL) model, the L5 and L6 spinal nerves are tightly ligated using sutures. After surgery, animals exhibit clear neuropathic pain characterized by hyperesthesia in the hind paw on the ligated side for 7 to 14 days. Rats were surgically induced to induce tactile allodynia. Seven days after surgical recovery, baseline mechanical threshold testing was performed using Von Frey filaments (Shanghai Yuyan Scientific Instrument Co., Ltd., North Coast). Rats that successfully modeled were then selected for efficacy testing. After initial screening, rats were sequentially numbered and randomly assigned to groups. Experimental groups were established based on the test conditions. SD rats (provided by Hunan Silaikejingda Experimental Animal Co., Ltd.) in each group were administered the respective drugs. Mechanical pain thresholds on the model side of the hind paw were measured 1, 2, and 4 hours after administration, and the results were recorded. [Table 4]

[0161] Example 25: SD rat carrageenan model SD rats (provided by Hunan Silaikejingda Experimental Animal Co., Ltd.) were marked at the same location on the footpad. The thickness of the rat's footpad was measured using an electronic caliper for accuracy. The rats were then restrained, and 100 μl of 1% carrageenan was subcutaneously injected into the right hind footpad to induce inflammation, thereby establishing an acute inflammation model using carrageenan. Each compound was administered in advance according to its respective administration time point. The swelling of the rat's paw was measured at various time points before modeling (0 hours) and after modeling (2, 4, and 7 hours). The paw swelling before and after modeling was compared. The results under the conditions of this experiment are shown in Tables 5 and 6. In particular, a single subcutaneous injection of 30 mg / kg of compound 8 showed an anti-inflammatory tendency. The results of the carrageenan-induced acute inflammation model experiment are shown in Figure 1. [Table 5] [Table 6]

[0162] Example 26: SD rat CCI model Chronic constriction injury (CCI) of the sciatic nerve in SD rats (provided by Hunan Silaikejingda Experimental Animal Co., Ltd.) is a conventional model used to study neuropathic pain. In this model, the sciatic nerve is loosely ligated using non-absorbable 5-0 sutures, slightly compressing its outer sheath. Mechanical compression by the suture induces axonal injury, resulting in abnormal electrical discharges. Furthermore, local stimulation from the ligature induces the release of inflammatory mediators.

[0163] Furthermore, CCI selectively damages the larger myelinated fibers of the sciatic nerve while sparing the majority of unmyelinated C-fibers involved in pain transmission. Rats are first operated to induce tactile allodynia, and then, 7 days after surgical recovery, a baseline mechanical threshold test is performed using Von Frey filaments (Shanghai Yuyan Scientific Instrument Co., Ltd., North Coast). Rats with successful modeling are selected for efficacy testing.

[0164] After initial screening, rats were numbered sequentially and randomly assigned to groups based on their numbering using a random grouping method. Experimental groups were established based on the test conditions. Each group of rats was administered a drug, and the mechanical pain threshold of the model side of the hind paw was measured 1, 2, and 4 hours after administration, and the results were recorded.

[0165] Under the conditions of this experiment, a single subcutaneous injection of compound 8 significantly affected the CCI model in SD rats, as shown in Figure 2. The control compound did not show any significant therapeutic effect on neuropathic pain, highlighting the significant efficacy of compound 8.

[0166] Example 27: In vivo PK test results [Table 7]

[0167] Example 28: In vivo ADME test results chemical stability A 1 mM test compound spiking solution (spiking solution A) was prepared by adding 10 μL of 10 mM test compound stock solution to 90 μL of DMSO. 396 μL of buffer was added to tubes designated for different time points. Samples were preheated at 37°C for 10 minutes. 4 μL of spiking solution A was added to wells containing 396 μL of buffer designated as 0, 15, 45, or 60 minutes. A timer was started after the addition of the spiking solution. At each time point, 1200 μL of acetonitrile (ACN) containing an internal standard was added to the tube. The samples were centrifuged at 10,000 rpm for 5 minutes, and 100 μL of the supernatant was removed and analyzed by LC-MS / MS analysis. The results are shown in Table 8.

[0168] metabolic stability Buffers A, B, and C were prepared for use in metabolic studies. The buffers were as follows: Buffer A: 1.0 L of 0.1 M monobasic potassium phosphate buffer containing 1.0 mM EDTA; Buffer B: 1.0 L of 0.1 M dibasic potassium phosphate buffer containing 1.0 mM EDTA; and Buffer C: 0.1 M potassium phosphate buffer, 1.0 mM EDTA, pH 7.4, prepared by titrating 700 mL of Buffer B with Buffer A while monitoring with a pH meter.

[0169] Ketanserin was used as a reference compound. Spiking solutions of the reference and test compounds (500 μM spiking solution) were prepared by adding 10 μL of a 10 mM DMSO stock solution to 190 μL of ACN. 1.5 μL of the 500 μM spiking solution (0.75 mg / mL) and 18.75 μL of 20 mg / mL liver microsomes were added to 479.75 μL of Buffer C on ice.

[0170] A 6 mM NADPH stock solution was prepared by dissolving an appropriate amount of NADPH in Buffer C. Thirty microliters of 1.5 μM spiking solution containing 0.75 mg / mL microsome solution was dispensed into designated assay plates on ice at different time points (0, 5, 15, 30, and 45 min). For the 0-min sample, 135 μL of ACN containing IS was added to the wells of the 0-min plate, followed by 15 μL of 6 mM NADPH stock solution. All other plates were preincubated at 37°C for 5 min. The reaction and time were initiated by adding 15 μL of 6 mM NADPH stock solution to the plate. At 5, 15, 30, and 45 min, 135 μL of ACN containing the internal standard was added to the corresponding wells of the plate to terminate the reaction. After quenching the reaction, the plate was agitated for 10 minutes (600 rpm) on a vibrator (IKA, MTS 2 / 4) and centrifuged at 5594 g for 15 minutes (Thermo Multifuge x3R). 50 μL of supernatant was removed from each well and placed in a 96-well sample plate containing 50 μL of ultrapure water (Millipore, ZMQS50F01) for LC / MS analysis. The results are shown in Table 8.

[0171] Protein binding Spiking solutions of test and reference compounds The following solutions were prepared: Solution A (0.5 mM): 10 μL of the 10 mM stock solution was added to 190 μL of DMSO. Solution B (0.02 mM): 8 μL of Solution A was added to 192 μL of 0.05 M sodium phosphate buffer. The final DMSO concentration in Solution B was 4%.

[0172] Preparation of test and reference compounds in plasma A 380 μL aliquot of plasma was preloaded into wells designated for plasma and buffer in a 96-well plate. 20 μL of Solution B (0.02 mM test compound and reference compound) was spiked into the plasma preloaded in the 96-well plate. The final test concentration was 1 μM with 0.2% DMSO.

[0173] Dialysis sample loading Preparation of plasma to buffer system (duplicate) A 100 μL aliquot of blank dialysis buffer was applied to the receiver side of the dialysis chamber. Next, a 100 μL aliquot of plasma spiked with the test compound and reference compound was applied to the donor side of the dialysis chamber. The blank buffer was added to the receiver first, and the buffer and plasma chambers were clearly marked to avoid cross-contamination.

[0174] Preparation of plasma to buffer system (duplicate) A 100 μL aliquot of blank dialysis buffer was applied to the receiver side of the dialysis chamber. Next, a 100 μL aliquot of plasma spiked with the test compound and reference compound was applied to the donor side of the dialysis chamber. The blank buffer was added to the receiver first, and the buffer and plasma chambers were clearly marked to avoid cross-contamination.

[0175] Preparation of t = 0 min plasma samples of initial concentration (duplicate) A 25 μL aliquot of plasma spiked with test compound and reference compound was placed in a 96-well sample preparation plate as a t = 0 min plasma sample. The aliquot was mixed with an equal volume of blank buffer (50:50, v / v). The sample was quenched with 200 μL of acetonitrile containing an internal standard (IS). The dialysis block was covered with a plastic lid, and the entire apparatus was placed on a shaker (60 rpm) at 37 °C for 5 h.

[0176] Preparation of dialyzed samples after 5 h incubation Aliquots of 25 μL from both the donor and receiver sides of the dialysis machine were placed in a new sample preparation plate and mixed with an equal volume of the opposite matrix (blank buffer for plasma, and vice versa). The samples were quenched with 200 μL of acetonitrile containing an internal standard. All samples from 0 to 5 hours were vortexed at 600 rpm for 10 minutes, followed by centrifugation at 5594 g for 15 minutes (Thermo Multifugex 3R). 50 μL of the supernatant was transferred to a new 96-well plate, and the samples were mixed with 50 μL of Milli-Q water. The sample plate was covered and stored in a -20°C freezer. The samples were then analyzed by LC / MS / MS. The results are shown in Table 8.

[0177] solubility 10 μL of test compound was added to 990 μL of buffer. The sample tube was shaken at room temperature for 1 hour (1000 rpm). The sample was centrifuged at 1200 rpm for 10 minutes to precipitate undissolved particles. The supernatant was collected and subjected to LC-MSMS or LC-UV analysis. The results are shown in Table 8.

[0178] thermodynamic solubility Assay buffer was added to the compound powder to make a 4 mg / mL solution. The sample tube was shaken at 1000 rpm for 1 hour and then equilibrated at room temperature overnight. The sample was centrifuged at 12000 rpm for 10 minutes to precipitate undissolved particles. The supernatant was transferred to a new tube. The concentration of the supernatant after centrifugation was measured by LCMSMS detection. The results are shown in Table 9.

[0179] CYP inhibitors 0.1 M potassium phosphate buffer (K ​​buffer) (pH 7.4) was preheated. K buffer was prepared by mixing 9.5 mL of stock A with 40.5 mL of stock B. The total volume was brought to 500 mL with Milli-Q water. The buffer was titrated to pH 7.4 with KOH or H3PO4. Stock A (1 M potassium phosphate monobasic) was prepared by adding 136.5 g of potassium phosphate monobasic to 1 L of Milli-Q water. Stock B (1 M potassium phosphate dibasic) was prepared by adding 174.2 g of potassium phosphate dibasic to 1 L of Milli-Q water.

[0180] Serial dilutions (400x) of test compounds and reference inhibitors were prepared in a 96-well plate. 8 μL of 10 mM test compound was transferred to 12 μL of ACN. Inhibitor spiking solutions for CYP1A2, CYP2C9, and CYP2D6 were prepared in a cocktail by adding 12 μL of 1 mM α-naphthoflavone, 10 μL of 40 mM sulfaphenazole, 10 μL of 10 mM quinidine, and 8 μL of DMSO. Individual inhibitor spiking solutions for CYP3A4 and CYP2C19 were prepared by adding 8 μL of DMSO stock to 12 μL of ACN. 1:3 serial dilutions were performed in a DMSO:ACN mixture (v / v: 40:60).

[0181] NADPH cofactor was prepared by dissolving 66.7 mg of NADPH in 10 mL of 0.1 MK buffer (pH 7.4). 4x substrate (2 mL for each isoform) was prepared. HLM was added on ice as needed. 0.2 mg / mL HLM solution was prepared on ice by adding 10 μL of 20 mg / mL to 990 μL of 0.1 MK buffer. 400 μL of 0.2 mg / mL HLM was added to assay wells, followed by 2 μL of a 400x test compound set in designated wells on ice. 200 μL of 0.2 mg / mL HLM was added to assay wells, followed by 1 μL of a serially diluted reference inhibitor solution in designated wells on ice. The following solutions were added in duplicate to a 96-well plate on ice: 30 μL of 2x test compounds and reference compounds in 0.2 mg / mL HLM solution and 15 μL of 4x substrate solution. The 96-well assay plate and NADPH solution were preincubated at 37°C for 5 minutes. To initiate the reaction, 15 μL of preheated 8 mM NADPH solution was added to the assay plate. The assay plate was incubated at 37°C for 5, 10, and 45 minutes. The reaction was stopped by adding 120 μL of ACN containing IS. After quenching the reaction, the plate was shaken for 10 minutes (600 rpm / min) on a vibrator (IKA, MTS 2 / 4) and then centrifuged at 3220 g for 15 minutes. 50 μL of the supernatant was removed from each well and transferred to a 96-well sample plate containing 50 μL of ultrapure water (Millipore, ZMQS50F01) for LC / MS analysis. The results are shown in Table 9.

[0182] LogD 10 μL of the 10 mM stock solution was placed in a 96-well plate. 300 μL of octanol was added to the plate. The plate was sealed and agitated on a plate shaker for 5 minutes. The plate was centrifuged at 2000 rpm for 5 minutes. The seal was removed, and 600 μL of potassium phosphate buffer (pH 7.4) was added. The plate was sealed, and the two phases were vigorously mixed on a plate shaker for 1 hour at 25°C. After mixing, the plate was centrifuged at 2000 rpm for 5 minutes, and the seal was removed. 10 μL of aqueous phase sample was aspirated from the aqueous phase plate and mixed with 10 μL of water (1:2 dilution). 180 μL of 50% ethanol was added to the aqueous phase sample plate (1:10 dilution) to achieve a 1:20 dilution. 50 μL of aqueous phase sample was mixed with 100 μL of 50% ethanol (containing IS) and placed in the aqueous phase sample plate to achieve a 1:60 dilution. Ten μL of the octanol phase (upper phase) was transferred to a new 96-well plate and 190 μL of 50% ethanol (1:20 dilution) was added. Ten μL of the 1:20 diluted octanol sample was transferred to a new 96-deep well plate and 390 μL of 50% ethanol (1:40 dilution) was added to achieve a 1:800 dilution. Fifty μL of the 1:800 diluted octanol sample was transferred again to a new 96-well plate and 100 μL of 50% ethanol containing IS was added to achieve a 1:2400 dilution. The samples were then ready for LC / MS analysis. The results are shown in Table 9.

[0183] hepatocyte stability The vial containing hepatocytes was removed from the liquid nitrogen storage unit and immediately placed in a shaking water bath at 37±1°C for 2 minutes±15 seconds. The hepatocytes were poured into 50 mL of Hepatocyte Thawing Medium, mixed gently, and centrifuged at 500 rpm for 3 minutes. After centrifugation, the supernatant was carefully aspirated without disturbing the pellet. The cell pellet was resuspended using 10 volumes of prewarmed KHB buffer (Krebs-Henseleit buffer, Sigma catalog number K3753-10X1L) containing 5.6 g / L HEPES. The pellet mixture was centrifuged at 500 rpm for 3 minutes, aspirated, and the supernatant was discarded without disturbing the cell pellet. Cell viability and yield were measured. The hepatocytes were counted, and the cell suspension was diluted to the appropriate cell density. The viable cell density was 2x10 6 The hepatocyte solution was kept on ice until use.

[0184] Two dosing solutions were prepared: pre-warmed KHB (1% DMSO). A 200 μM spiking solution was prepared by adding 20 μL of substrate stock solution (10 mM) to 980 μL of DMSO. Two dosing solutions were prepared by adding 10 μL of the 200 μM spiking solution to 990 μL of KHB (2 μM after dilution). The dosing solutions were centrifuged at 5594 g for 15 minutes (Thermo Multifuge ×3R). 50 μL of pre-warmed 2× dosing solution was added to designated wells at different time points. 50 μL of pre-warmed hepatocyte solution (2 × 10 6 100 μL of ACN containing IS was added to the wells designated for 15, 30, 60, and 120 minutes, and the wells were gently mixed, followed by 50 μL of pre-warmed hepatocyte solution (2 × 10 cells / mL). After hepatocyte addition, a timer was started. The assay was placed in a 37°C incubator. 100 μL of ACN containing IS was added to the wells designated for 0 minutes, the wells were gently mixed, and then 50 μL of pre-warmed hepatocyte solution (2 × 10 cells / mL) was added to the wells designated for 15, 30, 60, and 120 minutes. After hepatocyte addition, a timer was started. The assay was placed in a 37°C incubator. 6The wells were then sealed. At 15, 30, 60, and 120 minutes, 100 μL of ACN containing IS was added to each well. The wells were then sealed. After quenching, the plate was shaken at 600 rpm for 10 minutes using a vibrator (IKA, MTS 2 / 4). The plate was sonicated for 2 minutes and centrifuged at 5594 g for 15 minutes using a Thermo Multifuge ×3R. Fifty μL of the supernatant from each well was transferred to a 96-well sample plate containing 50 μL of ultrapure water (Millipore, ZMQS50F01) for LC / MS analysis. The results are shown in Table 9.

[0185] RBC distribution study 0.05 M sodium phosphate buffer (pH 7.4) was prepared using the following steps. Stock A, Stock B, and Stock C solutions were prepared by adding 156 g of monobasic sodium phosphate to 1 L of 1.0 M Milli-Q water, 142 g of dibasic sodium phosphate to 1 L of 1.0 M Milli-Q water, and 58.5 g of sodium chloride to 1 L of 1.0 M Milli-Q water, respectively. 20.25 mL of Stock B and 4.75 mL of Stock A were added to 35 mL of Stock C, and the total volume was brought to approximately 500 mL with Milli-Q water. The resulting buffer was titrated to pH 7.4 with NaOH or H3PO4, and the total volume was brought to 500 mL. The 0.05 M sodium phosphate buffer was preheated to 37 °C.

[0186] Preparation of fresh blank plasma and measurement of hematocrit. Tubes containing whole blood were centrifuged at 4000 rpm for 10 minutes. Plasma was collected and stored. Hematocrit (the amount of red blood cells relative to the total volume of whole blood) was measured using the following formula: Hematocrit value = Vred cells / Vblood = (Vblood-Vplasma) / Vblood Vblood: volume of whole blood applied Vplasma: the volume of plasma measured after centrifugation

[0187] Preparation of reference and test compound spiking solutions in plasma. 1.25 mM spiking solution A was prepared by adding 10 μL of 10 mM reference to 70 μL of plasma (8-fold dilution). 125 μM spiking solution B was prepared by adding 10 μL of 1.25 mM spiking solution to 90 μL of plasma (10-fold dilution).

[0188] Preparation of reference and test compounds in whole blood and plasma. For whole blood samples, 12 μL of spiking solution B (prepared above) was added to 288 μL of whole blood (25-fold dilution). For plasma samples, 6 μL of spiking solution B was added to 144 μL of plasma (25-fold dilution). The assay procedure used was as follows: The assay plate was placed in a 37°C incubator for 60 minutes. 300 μL of the compound spiking solution in whole blood described above was removed and centrifuged at 4000 rpm for 10 minutes. The plasma was then collected. 50 μL of plasma sample was removed, and 150 μL of acetonitrile (containing IS) was added and vortexed for 5 minutes. The sample was centrifuged at 6000 rpm for 15 minutes. The supernatant was removed and analyzed by LC / MS. [Table 8] [Table 9]

[0189] Example 29: hERG Test Results Compound 8 was dissolved in DMSO, and the final concentration of DMSO in the extracellular solution did not exceed 0.3%. The final concentrations of compound 8 were 0.3, 1, 3, 10, and 30 μM. The inhibitory effect of compound 8 on hERG current is shown in Table 10, and the concentration-response curve is shown in Figure 3. Under the conditions of this experiment, compound 8 did not exhibit a significant inhibitory effect on hERG potassium channel current. At 30 μM, the average inhibition rate on hERG current was -0.15% (N=2). [Table 10]

Claims

1. A compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, wherein: 【Chem.99】 During the ceremony, R １ and R ２ are independently selected from H, deuterium, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, C4-C9 alkylcycloalkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl; the C1-C6 alkyl, the substituted C3-C6 cycloalkyl, and the substituted aryl are substituted with 1 to 3 substituents independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, or halogenated C1-C3 alkyl groups; or R １ and R ２ are linked to form 3-, 4-, 5-, and 6-membered rings; A is selected from the following: 【Chemistry 100】 During the ceremony, n=1, 2, 3, 4, m=1, 2, 3, 4, R ３ is selected from the group consisting of H, deuterium, C1-C6 alkyl, oxygen-containing alkyl, and nitrogen-containing alkyl; B is selected from the group consisting of an aromatic ring, a substituted aromatic ring, a heterocyclic ring, a substituted heterocyclic ring, an alkylheterocyclic ring, and a substituted alkylheterocyclic ring; The compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, wherein said substituted heterocycle or said alkylheterocycle is substituted with 1 to 3 independently selected from the group consisting of deuterium, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, alkylsilyl, aryl, substituted aryl, or oxygen-, sulfur-, or selenium-containing alkyl.

2. R １ and R ２ is independently selected from H, deuterium, methyl, ethyl, propyl, and butyl.

3. R １ and R ２ is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclopropylethyl; R １ and R ２ may also be linked to form 3-, 4-, 5-, and 6-membered rings.

4. R １ and R ２ are independently selected from vinyl, propenyl, allyl, phenyl, naphthyl, phenylmethyl, and phenylethyl; R １ and R ２ may also be linked to form 3-, 4-, 5-, and 6-membered rings.

5. R １ and R ２ are independently selected from substituted C1-C6 alkyl, substituted C3-C6 cycloalkyl, substituted C2-C6 alkenyl, substituted aryl, and substituted alkylaryl; the substituents are selected from methyl, ethyl, propyl, methoxy, ethoxy, fluorine, chlorine, trifluoromethyl groups, or R １ and R ２ are linked to form a 3-membered ring, a 4-membered ring, a 5-membered ring, and a 6-membered ring.

6. A is selected from the following: 【Chemistry 101】 During the ceremony, n=1, m=1, R ３ is selected from H, deuterium, C1-C6 alkyl, oxygen-containing alkyl, and nitrogen-containing alkyl; said C1-C6 alkyl is independently selected from methyl, ethyl, propyl, and butyl; the oxygen-containing alkyls are independently selected from aldehyde groups, ester groups, and carboxyl groups; The compound of claim 1 , wherein the nitrogen-containing alkyl is independently selected from an alkylamino group, an amide group, and an amidine group.

7. 2. The compound of claim 1, wherein B is selected from an aromatic ring, a substituted aromatic ring, a heterocyclic ring, a substituted heterocyclic ring, an alkylheterocyclic ring, and a substituted alkylheterocyclic ring, wherein the aromatic ring is independently selected from phenyl and naphthyl, and the heterocyclic ring and the alkylheterocyclic ring are independently selected from furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazopyridazinyl, carbazolyl, purinyl, quinolyl, isoquinolyl, imidazopyridyl, or other fused heterocyclic rings.

8. 2. The compound of claim 1, wherein B is selected from a substituted aromatic ring, a substituted heterocyclic ring, a substituted alkylheterocyclic ring, and the substituents are independently selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, a C1-C9 alkoxy group, an alkylsilyl group, a phenyl group, a naphthyl group, a substituted aryl group, or a thionyl group.

9. The compound comprises the formula (Ia): 【Chemical Engineering 102】 During the ceremony, R ３ is hydrogen or amidine, R ４ ~R ８ are independently hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, aryl, substituted aryl, sulfinyl, substituted sulfinyl, or a C1-C3 alkylsilyl group; The substituted alkyl is substituted with 1 to 3 independently selected from the group consisting of deuterium, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, alkylsilyl, aryl, substituted aryl, or oxygen-, sulfur-, or selenium-containing alkyl; R ３ ~R ８ is independently hydrogen or C1-C6 alkyl.

10. The compound comprises the formula (Ib): 【Chemistry 103】 During the ceremony, R ３ is hydrogen or amidine, R ４ ~R ８ are independently hydrogen, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, aryl, substituted aryl, sulfinyl, substituted sulfinyl, or a C1-C3 alkylsilyl group; The substituted alkyl is substituted with 1 to 3 independently selected from the group consisting of deuterium, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, alkylsilyl, aryl, substituted aryl, or oxygen-, sulfur-, or selenium-containing alkyl; R ３ ~R ８ is independently hydrogen or C1-C6 alkyl.

11. 2. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is selected from any of the following compounds or a pharmaceutically acceptable salt thereof: 【Chemical 104】

12. 10. A pharmaceutical composition comprising the compound of claim 1 or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier.

13. 13. A method for treating and / or preventing an SSTR4 receptor-associated disease or disorder, comprising administering a pharmaceutically effective amount of the pharmaceutical composition of claim 12.

14. 14. The method of claim 13, wherein the SSTR4 receptor-associated disease or disorder is pain and / or pain prevention.

15. 15. The method of claim 14, wherein the pain and / or prevention of pain is associated with the SSTR4 receptor.

16. 15. The method of claim 14, wherein the SSTR4 receptor-associated disease or disorder is neuropathic pain, visceral pain, or a combination thereof.

17. A process for preparing a compound of formula (I), comprising: reacting a first compound having a protecting group and a carboxylic acid group with a second compound having an amine group to form a first intermediate compound; and deprotecting the protecting group on the first intermediate compound under acidic conditions to form a second intermediate; reacting said second intermediate with an amine compound to form said compound of formula (I).

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