Heteroarylcarboxamide compounds and their use in pharmaceuticals

Abstract

The present invention relates to heteroarylcarboxamide compounds and their pharmaceutical uses. Specifically, the present invention relates to heteroarylcarboxamide compounds represented by general formula (I), methods for producing the same, pharmaceutical compositions containing the compound, and their use as therapeutic agents, particularly as plasma kallikrein (PKa) selective inhibitors, and in the treatment and / or prevention of diseases that may benefit from plasma kallikrein inhibition, particularly for the prevention and / or treatment of diabetic macular edema (DME), age-related macular degeneration (AMD), choroidal angiogenesis, hereditary angioedema (HAE), and post-stroke cerebral edema. JPEG2026525258000208.jpg2785

Description

[Technical Field]

[0001] The present invention belongs to the field of biopharmaceuticals and relates to heteroarylcarboxamide compounds and their use in pharmaceuticals. Specifically, the present invention relates to heteroarylcarboxamide compounds represented by general formula (I) and pharmaceutical compositions containing said compounds, as well as their use as therapeutic agents, and in particular to methods for synthesizing pharmaceutically acceptable salts thereof, and to methods for producing and using them as human plasma kallikrein selective inhibitors. [Background technology]

[0002] The kallikrein-kinin system (KKS) consists of two independently regulated proteolytic pathways mediated by tissue kinins (TK) and tissue kinins (PK), each producing bradykinin and stimulating bradykinin receptors. The KKS's effect on retinal vascular permeability is primarily mediated by bradykinin. Both TK and PK are widely distributed in various tissues and may be regulated by different mechanisms. The components of plasma KKS are mainly synthesized in the liver and secreted into the bloodstream. Plasma prekallikrein (PPK) in the KKS signaling pathway is an abundant serine protease enzyme that is converted by factor XIIa (FXIIa) to plasma kallikrein (PKa), which is catalytically active and involved in inflammatory responses. PKa cleaves kininogen to produce bradykinin. Bradykinin (BK) is a non-peptide that stimulates BK receptors, which are highly expressed in blood vessels, glial cells, and nerve cells. BK is a potent inflammatory factor that, upon activation of BK receptors, binds to B1R and B2R, promoting an increase in bradykinin concentration. This further mediates various signaling cascades by stimulating the release of mediators such as eicosanoids, endothelial hyperpolarizing factor, NO, allyl alcohol, tissue plasminogen activator (tPA), and glucose transporter-1 / 2 (glu1 / 2). These mediators induce inflammation, angiogenesis, vasodilation, increased vascular permeability, and the formation of DME.

[0003] Plasma kallikrein plays a role in several inflammatory disorders, including hereditary angioedema (HAE), retinopathy or diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular edema (DME), clinically significant macular edema, cystic macular edema, CME after cataract extraction, CME induced by cryotherapy, CME induced by uveitis, endophthalmitis, vascular occlusion, retinal edema, complications related to cataract surgery in diabetic retinopathy, hypertensive retinopathy, retinal trauma, atrophic and exudative age-related macular degeneration (AMD), polypoid choroidal vasculopathy, choroidal neovascularization, posterior vitreous detachment, ischemia-reperfusion injury, surgically induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma-associated edema, spinal cord injury, pain, ischemia, focal brain ischemia, etc., in all kinds of contexts related to tissue and / or organ transplantation. Ischemic stroke, neurological and cognitive impairment, deep vein thrombosis, stroke, myocardial infarction, acquired angioedema, high-altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, obstructive hydrocephalus, radiation-induced edema, lymphedema, traumatic brain injury, hemorrhagic stroke, intracerebral hemorrhage, hemorrhagic changes in ischemic stroke, blood coagulation disorders such as thrombosis, itching, disorders caused by inflammatory components (multiple sclerosis, etc.), encephalitis, Alzheimer's disease, elevated blood pressure associated with diabetes or hyperlipidemia, renal failure, chronic kidney disease, heart failure, microalbumin It can have numerous implications in conditions such as sinusitis, albuminuria, proteinuria, cerebral hemorrhage, deep vein thrombosis, coagulation after fibrinolytic therapy, angina pectoris, angioedema, sepsis, lupus, gout, psoriasis, inflammatory bowel disease, diabetes mellitus, diabetic complications, Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, stroke, epilepsy, allergic edema, airflow obstruction in chronic allergic sinusitis or perennial rhinitis, airflow obstruction in acute asthma, and other diseases.

[0004] Plasma kallikrein is considered suitable for the treatment of a wide range of diseases, particularly disease-related edema formation, such as edema associated with ischemia-reperfusion injury in stroke, retinopathy, or other edema-related diseases, hereditary angioedema, macular edema, and cerebral edema.

[0005] Currently, acute ischemic stroke is treated primarily with general and specific therapies. Specific therapy is key to treating acute ischemic stroke and mainly involves improving cerebral blood circulation and neuroprotection. The earlier neuroprotection is performed after a stroke, the more effectively the progression of cerebral nerve death is reduced, preventing more damage to the brain from harmful substances and buying more time for the brain. Currently, edaravone and butylphthalide are the main neuroprotective agents used in domestic clinical practice, along with citicoline, monosialotetrahexosyl ganglioside sodium, and cinepazide. However, the overall therapeutic effect is not ideal, and it is difficult to shed the label of "adjunct agent." Therefore, there is an urgent need to develop new, effective, and safe anti-stroke drugs or pharmaceutical compositions to meet the urgent clinical needs. Cerebral ischemic injury involves many mechanisms, including excessive free radical generation, toxic effects of excitatory amino acids, intracellular calcium overload, and inflammatory responses. Regardless of the mechanism, it ultimately leads to nerve cell death, functional impairment, and the formation of cerebral infarct lesions. The kallikrein-kinin system (KKS) mediates thrombus formation, vascular permeability, and changes in blood pressure during cerebral ischemia. The contact kinin pathway is initiated by activation of coagulation factor XII (FXIIa), which cleaves plasma prekallikrein into plasma kallikrein (PK). Subsequently, PK acts on high molecular weight kininogen, inducing the release of the inflammatory peptide hormone bradykinin (BK). When BK binds to endothelial bradykinin receptors 1 and 2 (B1R / B2R), several inflammatory signaling cascades are initiated, leading to thrombin generation and influx of circulating immune cells, ultimately resulting in thrombus formation and neuroinflammation. Inhibiting PK after stroke can significantly reduce cerebral thrombus formation, stabilize the blood-brain barrier, and decrease the number of infiltrating immune cells in the brain (Seminars in Immunopathology 2023, 45:389 - 410). Simultaneously, PK inhibition also reduces excitotoxicity and ischemia-induced neuronal cell death mediated by NMDA receptors (Stroke 2014, Vol 45, Issue suppl_1, Abstract W P210).

[0006] Currently, the clinical benefits of conventional neuroprotective mechanisms are limited. The KKS system is closely involved in stroke-related bleeding, edema, inflammation, and neuroprotection. PK inhibitors can significantly reduce cerebral thrombus formation during stroke, stabilize the blood-brain barrier, decrease the number of infiltrating immune cells in the brain, and further suppress excitotoxicity and ischemic neuronal death mediated by NMDA receptors, significantly reducing the extent of cerebral infarction.

[0007] Plasma kallikrein is considered particularly useful in the treatment of retinopathy, such as retinopathy-related macular edema (DME) associated with diabetes and / or hypertension.

[0008] Proteomic analysis of vitreous samples from DME patients revealed that plasma prekallikrein (PPK) and plasma kallikrein were 11.0-fold (p<0.0001) elevated compared to the vitreous humor of control patients with macular holes (Diabetes 2015, 64, 3588-3599). Systemic continuous administration of PKal inhibitors has been shown to reduce retinal vascular permeability and retinal blood flow abnormalities in diabetic mice (Diabetes 2011, 60, 590-1598). Furthermore, preclinical studies have suggested that plasma kallikrein (PK) may cause VEGF-mediated retinal edema (Investig. Ophthalmol. Vis. Sci. 2016, 57, 2390-2399). Current treatment strategies for DR and DME are mainly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatments are not effective in all patients, and a significant percentage of patients experience residual potential side effects. Currently, treatment for DME relies primarily on anti-VEGF therapy, but some patients (approximately 50%) do not respond to VEGF therapy. This means that nearly 50% of patients are not receiving effective treatment. Preclinical studies have shown that activation of KKS in the eye induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis of the vitreous humor of DME suggests that the KKS pathway and the VEGF pathway are potentially independent biological pathways. Furthermore, the association between DME-related proteins in the vitreous humor and the KKS pathway is significantly higher than the association with the VEGF pathway. Preclinical experiments using diabetic animals have shown that inhibiting the KKS system is an effective way to reduce retinal vascular permeability (Invest Ophthalmol Vis Sci. 2016; 57(6): 2390-2399). This invention provides a method for preparing novel, highly selective, effective small molecule PKa inhibitors. [Overview of the project]

[0009] The present invention provides a novel selective low molecular weight inhibitor of plasma kallikrein, and provides an effective treatment strategy for diseases such as stroke, HAE, diabetic macular edema (DME) and age-related macular degeneration (AMD) caused by retinal microvascular disorders. Specifically, the present invention relates to a compound of formula (I): The compound shown in JPEG2026525258000002.jpg2785 or a pharmaceutically acceptable prodrug or salt thereof is provided. In the formula, Ring A is a 5- to 6-membered heteroaryl or phenyl; Ring B is a 5- to 10-membered monocyclic or bicyclic aryl or heteroaryl; m4 is 0 or 1; When m4 is 1, ring C is selected from 5- to 6-membered heteroaryl, phenyl and 9- to 10-membered bicyclic heteroaryl; <00004​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1-6 Alkilen) n -C 3-6 Cycloalkyl, -(C 1-6 Alkilen) n -OC 3-6 Cycloalkyl, halogen, -OH, -SH, -NH2, -C(O)NH2, -NO2, -CN, C 2-6 Alkenil, C 2-6 Alkinyl, -C 1-6 Alkylene-OC 1-6 Alkylene-C(O)-NH2, -C 1-6 Alkylene-OC 1-6 Alkylene-C(O)-N(C) 1-6 Alkyl)2,-C 1-6 Alkylene-OC 1-6 Alkylene-C(O)-NH-C 1-6 Alkyl, -(C 1-6 Alkilen) n -5-6 member heteroaryl, -O-(C 1-6 Alkilen) n -5-6 member heteroaryl, -(C 1-6 Alkilen) n -4-7 member monocyclic or bicyclic heterocyclyl, -(C 1-6 Alkilen) n -O-(C 1-6 Alkilen) n -4- to 7-membered monocyclic or bicyclic heterocyclil, -NH-4- to 7-membered monocyclic or bicyclic heterocyclil, -N(C 1-6 Alkyl)-4~7 member monocyclic or bicyclic heterocyclyl, -C 1-6 Alkylene-OC 1-6 Alkylene-NH2,-C 1-6 Alkylene-OC 1-6 Alkylene-N(C) 1-6 Alkyl)2 and -C 1-6 Alkylene-OC 1-6 Alkylene-NH-C 1-6 Selected from alkyl, the C 1-6 Alkylenes, 5-6 membered heteroaryls, 4-7 membered monocyclic or bicyclic heterocyclines, and C 3-6 Each cycloalkyl group is independently C 1-6Alkyl, oxo, -(C 1-6 alkylene) n -C 1-6 alkoxyl, -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkoxyl, and may be substituted with one or more substituents selected from halogen and -OH; Each Rb is independently halogen, -CN, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -O-(C 1-6 alkylene) n -C 3-6 cycloalkyl, -C(O)-C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene) n -4- to 7-membered monocyclic or bicyclic heterocyclyl, -(C 1-6 alkylene) n -5- to 6-membered heteroaryl, -(C 1-6 alkylene) n -9- to 10-membered bicyclic heteroaryl, -C 2-6 alkenyl-C 3-6 cycloalkyl, phenyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxyl, -(C 1-6 alkylene) n -C 1-6 alkoxyl, -OH, -SH, -NH2, -C(O)NH2, -NO2, C 2-6 alkenyl, C 2-6 alkynyl, -(C 1-6 alkylene) n -4- to 7-membered monocyclic or bicyclic heterocyclyl fused to phenyl and -O-phenyl, and the C 3-6 cycloalkyl, 4- to 7-membered monocyclic or bicyclic heterocyclyl, 9- to 10-membered bicyclic heteroaryl, phenyl and 5- to 6-membered heteroaryl are each independently halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, -(C1-6 (alkylene) n -C 1-6 may be substituted with one or more substituents selected from alkoxyl, C 1-6 hydroxyalkyl, -CN, -OH, -SH, -NH2, -C(O)NH2, and -NO2; Each Rc is independently C 1-6 alkyl, C 1-6 haloalkyl, halogen, -NH2, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, -(C 1-6 alkylene) n -C 1-6 may be substituted with one or more substituents selected from alkoxyl, formamidinyl, N-hydroxyformamidinyl, -C(=NH)-NH-C 1-6 alkyl, -C(=NH)-N(C 1-6 alkyl)2, C 1-6 haloalkoxyl, C 1-6 hydroxyalkyl, -CN, -OH, -SH, -S-C 1-6 alkyl, -C(O)NH2, -NO2, -C 1-6 alkylene-NH2, -C 1-6 alkylene-NH-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, -NH-(C 1-6 alkylene) n -C 3-6 cycloalkyl, -NH-(C 1-6 alkylene) n selected from 3- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl, and the 3- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are each independently C 1-6 alkyl, oxo, -(C 1-6 alkylene) n -C 1-6 may be substituted with one or more substituents selected from alkoxyl, -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkoxyl, halogen, and -OH; Alternatively, two adjacent Rc atoms, together with the atom they are bonded to, become C 3-6 Forming a cycloalkyl or a 5-6 membered heterocycline, the C 3-6 Cycloalkyl or 5-6 membered heterocyclyl molecules are each independently C 1-6 Alkyl, oxo, -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 They may be substituted with one or more substituents selected from alkoxyls, halogens, and -OH groups; The heterocyclyl and heteroaryl each contain a heteroatom selected from 1, 2, 3, or 4 N, O, and S atoms; m1 is 0, 1, or 2; m2 is 0, 1, 2, or 3; m3 is 0, 1, 2, or 3; and Each n is independently either 0 or 1.

[0010] In some embodiments of the present invention, the compound represented by general formula (I) or a pharmaceutically acceptable prodrug or salt thereof is the compound represented by general formula (II) or a pharmaceutically acceptable prodrug or salt thereof. JPEG2026525258000003.jpg2485 During the ceremony, Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , R 4 Ra, Rb, Rc, m1, m2, and m3 are defined as shown in general formula (I).

[0011] In some embodiments of the present invention, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable prodrug or salt thereof is the compound represented by general formula (III) or a pharmaceutically acceptable prodrug or salt thereof. JPEG2026525258000004.jpg2273In formula, Rings A, B, C, Ra, Rb, Rc, m1, m2, and m3 are defined by general formula (I).

[0012] In some embodiments of the present invention, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable prodrug or salt thereof is the compound represented by general formula (IV) or a pharmaceutically acceptable prodrug or salt thereof, JPEG2026525258000005.jpg2475In formula, Rings A, B, Ra, Rb, Rc, m1, m2, and m3 are defined by general formula (I); Ring C is selected from a 5-6 member heteroaryl condensed with a 5-6 member heterocyclil, a phenyl condensed with a 5-6 member heterocyclil, a 5-6 member heteroaryl condensed with a C3-6 cycloalkyl, and a phenyl condensed with a C3-6 cycloalkyl; In particular, ring C is selected from cyclopentapyridinyl, cyclopentaimidazolyl, and dihydrophlopyridinyl.

[0013] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, Ring A is selected from triazolyl, pyrazolyl, thiazolyl, oxadiazolyl, oxazolyl, thienyl, thiadiazolyl, pyridyl, isoxazolyl, imidazolyl, pyrrolyl, furyl, isothiazolyl, phenyl, pyrimidyl, piperidinyl, pyridadinyl, triazinyl, and tetrazolyl; especially, JPEG2026525258000006.jpg49170

[0014] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, Ring B is selected from phenyl, quinolyl, imidazopyridyl, pyridyl, imidazolyl, naphthyl, triazolyl, pyrazolyl, thiazolyl, oxadiazolyl, oxazolyl, thienyl, thiadiazolyl, isoxazolyl, pyrrolyl, furyl, isothiazolyl, phenyl, pyrimidyl, piperidinyl, pyridadinyl, triazinyl, isoquinolyl, indolyl, indazolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, and benzthiazolyl; especially, JPEG2026525258000007.jpg14136

[0015] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, Ring C is selected from pyridyl, phenyl, pyrimidyl, thiadiazolyl, thiazolyl, triazolyl, pyrazolyl, oxadiazolyl, oxazolyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, furyl, isothiazolyl, piperidinyl, pyridadinyl, triazinyl, isoquinolyl, pyrrolopyridyl, imidazopyridyl, triazopyridyl, benzisoxazolyl, benzthiazolyl, and pyrazolopyridyl; especially, JPEG2026525258000008.jpg70170

[0016] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, Ra is independently -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, -(C 1-6 Alkilen) n -OC 1-6 Alkylene-C 1-6 Alkoxyl, -(C 1-6 Alkilen) n -4-7 member monocyclic or bicyclic heterocyclyl, -(C1-6 Alkilen) n -O-(C 1-6 Alkilen) n -4- to 7-membered monocyclic or bicyclic heterocyclils, -NH-4- to 7-membered monocyclic or bicyclic heterocyclils, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Haloalkoxyl, -(C 1-6 Alkilen) n -C 3-6 Cycloalkyl, -(C 1-6 Alkilen) n -OC 3-6 Cycloalkyl, halogen, -CN, -C 1-6 Alkylene-OC 1-6 Alkylene-C(O)-N(C) 1-6 Alkyl)2,-(C 1-6 Alkilen) n -5-6 member heteroaryl, -O-(C 1-6 Alkilen) n -5-6 member heteroaryl and -C 1-6 Alkylene-OC 1-6 Alkylene-N(C) 1-6 Selected from alkyl)2, the C 1-6 Alkylenes, 5-6 membered heteroaryls, 4-7 membered monocyclic or bicyclic heterocyclines, and C 3-6 Each cycloalkyl group is independently C 1-6 Alkyl, oxo, -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6The substituents may be substituted with 1, 2, 3, or 4 substituents selected from alkoxyls, halogens, and -OH, where n is independently 0 or 1, and the 4-7 membered monocyclic or bicyclic heterocyclils and 5-6 membered heteroaryls each independently contain 1, 2, or 3 heteroatoms selected from N, O, and S atoms, preferably selected from pyrimidyl, pyrazolyl, pyridyl, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, oxetanyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azabicyclo[2.2.1]heptyl, isoxazolyl, tetrahydropyranyl, piperidinyl, and 1-oxa-6-azaspiro[3.3]heptanyl; JPEG2026525258000009.jpg236170

[0017] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, Rb is independently halogen, -CN, and -(C) 1-6 Alkilen) n -C 3-6 Cycloalkyl, -OC 1-6 Alkylene-C 3-6 Cycloalkyl, -C(O)-C 3-6 Cycloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, -(C 1-6 Alkilen) n -4-7 member monocyclic or bicyclic heterocyclil, -C 1-6 Alkylene-5 to 6-membered heteroaryl, -C 1-6 Alkylene-9~10 membered bicyclic heteroaryl, -C 2-6 Alkenil-C 3-6 Cycloalkyl, -(C 1-6 Alkilen) n-Selected from 4-7 member monocyclic or bicyclic heterocyclils condensed with phenyl and -O-phenyl, where n is independently 0 or 1, and the 4-7 member monocyclic or bicyclic heterocyclil, 9-10 member bicyclic heteroaryl, phenyl and 5-6 member heteroaryl are independently halogen, oxo, and C 1-6 Alkyl and C 1-6 They may be substituted with one, two, or three substituents selected from haloalkyls, and the 4-7 member monocyclic or bicyclic heterocyclil, 9-10 member bicyclic heteroaryl, and 5-6 member heteroaryl each independently contain one, two, or three heteroatoms selected from N, O, and S atoms, preferably selected from dihydropyridyl, 3-azabicyclo[3.1.0]hexyl, pyrazolyl, morpholinyl, piperidinyl, pyrrolopyridyl, 7-oxabicyclo[2.2.1]heptanyl, azepinyl, azetidinyl, 2-azabicyclo[2.2.1]heptanyl, pyrrolidinyl, 5-azaspiro[2.4]heptanyl, thiazolidinyl, indazolyl, dihydropyrimidyl, and triazolyl; JPEG2026525258000010.jpg115170

[0018] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, Each Rc is independently C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, -NH2, -C 1-6 Alkylene-NH2,-C 1-6 Alkylene-NH-C 1-6 Alkyl, -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, formamidinyl, N-hydroxyformamidinyl, -C(=NH)-NH-C 1-6 Alkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Hydroxyalkyl, -CN, C3-6 Cycloalkyl, 3-6 membered heterocyclyl, -NH-(C 1-6 Alkilen) n -C 3-6 Cycloalkyl, -NH-(C 1-6 Alkilen) n - Selected from 3- to 6-membered heterocyclyls and 5- to 6-membered heteroaryls, where n is independently 0 or 1, and the 3- to 6-membered heterocyclyls and 5- to 6-membered heteroaryls are independently C 1-6 Alkyl, oxo, C 1-6 The 3-6 membered heterocyclyl and 5-6 membered heteroaryl each independently contain one, two, or three heteroatoms selected from alkoxyls, halogens, and -OH groups, preferably selected from pyrrolidinyl, azetidinyl, oxetanyl, and triazolyl groups; Alternatively, two adjacent Rc atoms, together with the atom they are bonded to, form piperazinyl, piperidinyl, pyrrolidinyl, or dihydrofuran, and each of these piperazinyl, piperidinyl, pyrrolidinyl, or dihydrofuran is independently C 1-6 Alkyl, oxo, C 1-6 It may be substituted with one, two, or three substituents selected from alkoxyls, halogens, and -OH groups; JPEG2026525258000011.jpg48170

[0019] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, JPEG2026525258000012.jpg140160JPEG2026525258000013.jpg134166

[0020] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, JPEG2026525258000014.jpg78167JPEG2026525258000015.jpg245170JPEG2026525258000016.jpg164168

[0021] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, JPEG2026525258000017.jpg45168JPEG2026525258000018.jpg246170JPEG2026525258000019.jpg102164

[0022] In some embodiments of the present invention, a compound represented by general formula (I), (II), (III), or (IV) or a pharmaceutically acceptable prodrug or salt thereof, When each Rc is selected to formamidinil, N-hydroxyformamidinil, or -NH2, the pharmaceutically acceptable prodrug of the compound is: Formamidinyl and -NH2 C 1-6 Carbonate ester; N-hydroxyformamidinyl C 1-6 Carbonate ester, C 1-6 Carboxylic acid esters, phenyl carboxylic acid esters, or pyridyl carboxylic acid esters, phenyl carboxylic acid esters and pyridyl carboxylic acid esters contain one or more halogens, C 1-6 Alkyl or C 1-6 It is also fine if substituted with an alkoxyl. Selected from, and / or The pharmaceutically acceptable salts are selected from toluenesulfonates, methylsulfonates, hydrochlorides, acetates, and citrates.

[0023] Representative compounds of the present invention include, but are not limited to, the following. JPEG2026525258000020.jpg40140JPEG2026525258000021.jpg211150JPEG2026525258000022.jpg214166JPEG2026525258000023.jpg240164JPEG2026525258000024.jpg236166JPEG2026525258000025.jp g231161JPEG2026525258000026.jpg246159JPEG2026525258000027.jpg250166JPEG202652525800002 8.jpg230159JPEG2026525258000029.jpg220166JPEG2026525258000030.jpg235164JPEG20265252580 00031.jpg231166JPEG2026525258000032.jpg230156JPEG2026525258000033.jpg246167JPEG2026525 258000034.jpg225164JPEG2026525258000035.jpg246166JPEG2026525258000036.jpg231167JPEG202 6525258000037.jpg226166JPEG2026525258000038.jpg241164JPEG2026525258000039.jpg225168JPE G2026525258000040.jpg225167JPEG2026525258000041.jpg250170JPEG2026525258000042.jpg169169

[0024] The present invention further provides a method for producing a compound represented by general formula (I), the method being: Includes JPEG2026525258000043.jpg19150. Compounds represented by general formula (IA) and compounds represented by general formula (IB) can undergo an amidation reaction in the presence of a condensing agent such as HATU, TCFH, DCC, CDI, BEP, PyBOP, or DMTMM to obtain the compound represented by general formula (I). During the ceremony, Ring A, Ring B, Ring C, R 1 -R4 Ra, Rb, Rc, m1, m2, m3, and m4 are defined as shown in general formula (I).

[0025] The present invention further provides a method for producing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method being: Includes JPEG2026525258000044.jpg19149. Compounds represented by general formula (IA) and compounds represented by general formula (IIB) can undergo an amidation reaction in the presence of a condensing agent such as HATU, TCFH, DCC, CDI, BEP, PyBOP, or DMTMM to obtain the compound represented by general formula (II). During the ceremony, Ring A, Ring B, Ring C, R 1 -R 4 Ra, Rb, Rc, m1, m2, and m3 are defined as shown in general formula (I).

[0026] The present invention further provides a method for producing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method being: Includes JPEG2026525258000045.jpg20149. Compounds represented by general formula (IIIA) and compounds represented by general formula (IIIB) can undergo an amidation reaction in the presence of a condensing agent such as HATU, TCFH, DCC, CDI, BEP, PyBOP, or DMTMM to obtain the compound represented by general formula (III). During the ceremony, Rings A, B, C, Ra, Rb, Rc, m1, m2, and m3 are defined by general formula (I).

[0027] The present invention further provides a method for producing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method being: Includes JPEG2026525258000046.jpg20150. Compounds represented by general formula (IIIA) and compounds represented by general formula (IVB) can undergo an amidation reaction in the presence of a condensing agent such as HATU, TCFH, DCC, CDI, BEP, PyBOP, or DMTMM to obtain the compound represented by general formula (IV). During the ceremony, Rings A, B, C, Ra, Rb, Rc, m1, m2, and m3 are defined by general formula (I).

[0028] The above reaction is preferably carried out in a solvent, and the solvent used includes, but is not limited to, N,N-dimethylformamide and dichloromethane. The alkaline reagent used includes, but is not limited to, pyridine, triethylamine and N,N-diisopropylethylamine.

[0029] The present invention also provides a pharmaceutical composition comprising a compound represented by general formula (I), (II), (III), or (IV) and a pharmaceutically acceptable carrier. The pharmaceutical composition contains a therapeutically effective amount of the compound represented by general formula (I), (II), (III), or (IV) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, a prodrug, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0030] The present invention also relates to the use of compounds represented by general formula (I), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, for preparing drugs for the treatment of ocular microvascular lesion-related disorders.

[0031] The present invention also relates to compounds represented by general formula (I), (II), (III), or (IV) used as pharmaceuticals, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.

[0032] The present invention also relates to compounds represented by general formula (I), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, used for the treatment of ocular microvascular lesion-related disorders.

[0033] The present invention also relates to a method for treating ocular microvascular lesion-related disorders, comprising administering to a patient in need a compound represented by general formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0034] In some embodiments of the present invention, the microvascular lesion-related disorders of the ocular region include diabetic retinopathy (DR), diabetic macular edema (DME), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), macular degeneration, retinopathy of prematurity (ROP), neovascular glaucoma, retinitis pigmentosa (RP), proliferative and non-proliferative retinopathy, retinal angiomatoid proliferation, macular telangiectasia, ischemic retinopathy, iris neovascularization, intraocular neovascularization, corneal neovascularization, retinal neovascularization, polypoidal choroidal vasculopathy (PCV), and choroid. Selected from diabetic complications of retinal vascular permeability associated with neovascularization, retinal degeneration, and diabetic retinopathy and diabetic macular edema, particularly diabetic retinopathy (DR), diabetic macular edema (DME), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), and exudative age-related macular degeneration (exudative AMD); in particular, selected from diabetic retinopathy (DR), diabetic macular edema (DME), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO), and exudative age-related macular degeneration (exudative AMD).

[0035] Compounds represented by general formulas (I) to (IV) are converted to corresponding salts by known methods. The salts are preferably water-soluble. Examples of pharmaceutically acceptable and non-toxic acid addition salts include salts formed by an amino group with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods known in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, toluenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanes. This includes sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, pentanoates, etc. In particular, it is selected from toluenesulfons, methylsulfons, hydrochlorides, acetates, and citrates.

[0036] The compounds of the present invention, or pharmaceutically acceptable salts thereof, in pure form, or suitable pharmaceutical compositions thereof, can be administered by any acceptable method of administration for administering drugs having similar effects. The drug compositions of the present invention may be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, diluents, or excipients, and may be prepared as formulations in solid, semi-solid, liquid, or gaseous form, such as tablets, capsules, powders, granules, nanoparticles, suspensions, emulsions, gels, liposomes, solutions, and injections. Typical routes of administration of the pharmaceutical compositions include, but are not limited to, oral or parenteral administration. As used herein, the term parenteral administration includes subcutaneous, intravenous, intramuscular, intraocular, or injectable methods. The pharmaceutical compositions of the present invention are formulated such that, upon administration to a patient, the encapsulated active ingredient becomes bioavailable. The compositions administered to a subject or patient may be in the form of one or more dosing units; for example, tablets may be single-dose units, and containers of the compounds of the present invention in aerosol form may contain multiple dosing units. Practical methods for preparing the aforementioned dosage forms are already known to those skilled in the art, or will become known to those skilled in the art. In any case, the administered composition contains a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for treating the disease or condition in question in accordance with the teachings of the present invention.

[0037] The pharmaceutical compositions of the present invention may be in solid or liquid form. In one embodiment, the carrier is fine particles, and therefore the composition is in the form of, for example, tablets or powders. The carrier may also be liquid, and the composition is, for example, an oral syrup or an injectable solution. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, in which case semi-solid, semi-liquid, suspension, and gel forms are included in the forms considered as either solid or liquid as herein. As a solid composition for oral administration, the pharmaceutical composition may be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewing gum, or wafers. Such solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders (such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth gum, or gelatin); excipients (such as starch, lactose, or dextrin); disintegrants (e.g., alginic acid, sodium alginate, Primogel, corn starch, etc.); lubricants (such as magnesium stearate or Sterotex); flow enhancers (such as colloidal silicon dioxide); sweeteners (such as sucrose or saccharin); flavoring agents (such as peppermint, methyl salicylate, or orange flavor); and colorants.

[0038] If the pharmaceutical composition is in the form of a capsule (e.g., a gelatin capsule), in addition to the above-mentioned substances, it may include a liquid carrier such as polyethylene glycol or vegetable oil. The pharmaceutical composition may also be in the form of a liquid, such as an elixir, syrup, solution, emulsion, or suspension. The liquid may be intended for oral administration or injection, as two examples. If intended for oral administration, a preferred composition may include, in addition to the compounds of the present invention, one or more selected from sweeteners, preservatives, colorants, and flavor enhancers. A composition intended for injection may include one or more selected from surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers, and isotonic agents.

[0039] The compounds and pharmaceutical compositions of the present invention may be further combined with one or more, preferably one, additional therapeutic agents. The compounds of the present invention may be combined with one or more additional therapeutic agents selected from the group consisting of anti-VEGF monospecific or bispecific antibodies, antidiabetic agents, agents useful for treating overweight and / or obesity, agents for treating hypertension, pulmonary hypertension, heart failure and / or atherosclerosis, and agents for treating eye diseases.

[0040] Additional agents for the treatment of type II diabetes that can be used in combination with the compounds of the present invention include GK agonists, GLP-1 receptor agonists, exenatide, liraglutide, somaglutide, dulaglutide, loxenatide, abiritide; α-glucosidase inhibitors, voglibose, acarbose; One or more SGLT-2 inhibitors selected from canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin; DPP-4 inhibitors selected from sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, gemigliptin, teneligliptin, and metformin. Pharmaceutical compositions using these substances are useful for preventing, delaying the progression of, or treating one or more metabolic diseases selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, hyperglycemia, postprandial hyperglycemia, abnormal fasting blood glucose, overweight, obesity, hypertension, insulin resistance, and / or metabolic syndrome. Alternatively, they may improve blood glucose control and / or lower fasting plasma glucose. Or they may prevent, delay, stunt, or reverse diabetic complications.

[0041] Additional agents for the treatment of hypertension that can be used in combination with the compounds of the present invention include angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), β-receptor blockers, diuretics, and α-receptor blockers, and are particularly selected from felodipine extended-release tablets, nifedipine, nitrendipine, nisoldipine, nicardipine, lasidipine, relcanidipine, amlodipine, levamlodipine, verapamil, diltiazem, captopril, enalapril, benazepril, risiropril, ramipril, fosinopril, cilazapril, perindopril, quinapril, imidapril, zofenopril, losartan, valsartan, irbesartan, candesartan medoxomil, telmisartan, and olmesartan medoxomil.

[0042] Additional agents for the treatment of heart failure and / or atherosclerosis that can be used in combination with the compounds of the present invention are selected from mevastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cholestyramine, colestipol, aspirin, clopidogrel, cilostazol, omega-3 polyunsaturated fatty acids, omega-6 monounsaturated fatty acids, heparin, heparan sulfate, chondroitin sulfate, dextran sulfate, phenerizone, and proprotein converter subtilisin 9 (PCSK9) inhibitors such as ilotuzumab (Levion, Evolocumab), alirocumab, and inclisiran (Leqvio).

[0043] Additional agents for the treatment of pulmonary hypertension that can be used in combination with the compounds of the present invention are selected from the group consisting of bosentan, riocicept, maxitentan, celepag, and the like.

[0044] Additional agents for the treatment of ocular diseases that can be used in combination with the compounds of the present invention include intravitreal corticosteroids, intravitreal anti-VEGF therapeutics, anti-Ang2 inhibitors, dual anti-VEGF / anti-Ang2 inhibitors, complement inhibitors (such as complement 3, 5, B, and D inhibitors), anti-PDGF, dual anti-VEGF / anti-PDGF, VAP-1 inhibitors, bradykinin receptor 1 (BK1) antagonists, Tie-2 agonists, and CCR-2 antagonists.

[0045] Additional anti-VEGF monospecific or bispecific antibodies that can be used in combination with the compounds of the present invention are selected from the group consisting of aflibercept (ziv-aflibercept, Eylea), bevacizumab (Avastin), ranibizumab (Lucentis), pegaptanib (Macugen), and falisimab (Vabysmo).

[0046] In some embodiments of the present invention, stroke includes hemorrhagic stroke and acute ischemic stroke, and additional agents for the treatment of stroke that can be used in combination with the compounds of the present invention are selected from the group consisting of alteplase, cetiprase, edaravone, butylphthalide, citicoline, or dextroborneol.

[0047] Explanation of terms Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0048] The term "alkyl" refers to a saturated, linear or branched aliphatic hydrocarbon group that has 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., C 1-20 Alkyl). The above alkyl is an alkyl having 1 to 12 carbon atoms (i.e., C 1-12 Alkyl) is preferred, and alkyl having 1 to 6 carbon atoms (i.e., C 1-6Alkyl is more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 This includes 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.

[0049] The term "alkylene group" refers to a divalent alkyl group, where the alkyl is as defined above, and it has 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., C 1-20 Alkylene group). The above alkylene group is an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12An alkylene group is preferred, and an alkylene group having 1 to 6 carbon atoms (i.e., a C1-6 alkylene group) is more preferred. Non-limiting examples include -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0050] The term "alkenyl" refers to an alkyl group whose molecule contains at least one carbon-carbon double bond, the definition of which is as described above, and which has 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) (i.e., C 2-12 Alkenyl). The above alkenyl is an alkenyl having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyls are preferred. Non-limiting examples include vinyl, propenyl, isopropenyl, and butenyl.

[0051] The term "alkynyl" refers to an alkyl group whose molecule contains at least one carbon-carbon triple bond, the definition of which is as described above, and which has 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) (i.e., C 2-12 Alkynnyl). The above alkynyl is an alkynyl having 2 to 6 carbon atoms (i.e., C 2-6 Alkynnyl is preferred. Non-limiting examples include ethinyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0052] The term "alkoxy" refers to -O-(alkyl), and the definition of alkyl is as described above. Non-restrictive examples include methoxy, ethoxy, propoxy, and butoxy.

[0053] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic whole-carbocyclic (i.e., monocyclic cycloalkyl) or polycyclic (i.e., polycyclic cycloalkyl) system having 3 to 20 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., C 3-20 Cycloalkyl). The above cycloalkyl is a cycloalkyl having 3 to 12 ring atoms (i.e., C 3-12 Cycloalkyl is preferred, and a cycloalkyl having 3 to 8 ring atoms (i.e., C 3-8 Cycloalkyl), cycloalkyl having 4 to 7 ring atoms (i.e., C 4-7 Cycloalkyl) or cycloalkyl having 3 to 6 ring atoms (i.e., C 3-6 Cycloalkyl is more preferred.

[0054] The above monocyclic cycloalkyl compounds include, as non-limiting examples, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl.

[0055] The above polycyclic cycloalkyls include spirocycloalkyls, condensed cycloalkyls, and crosslinked cycloalkyls.

[0056] The term "spirocycloalkyl" refers to a polycyclic system in which rings share one carbon atom (called a spiro atom), and which may contain one or more double bonds within the ring, or may contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with an oxo group to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), provided that at least one whole carbon ring is included and the linking point is located on that whole carbon ring, which has 5 to 20 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., a 5-20 membered spirocycloalkyl). The above spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e., a 6 to 14-membered spirocycloalkyl), and more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e., a 7 to 10-membered spirocycloalkyl). The above spirocycloalkyl includes monospirocycloalkyl or polyspirocycloalkyl (e.g., bisspirocycloalkyl), preferably monospirocycloalkyl or bisspirocycloalkyl, and more preferably 3-member / 4-member, 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 3-member, 5-member / 4-member, 5-member / 5-member, 5-member / 6-member, 5-member / 7-member, 6-member / 3-member, 6-member / 4-member, 6-member / 5-member, 6-member / 6-member, 6-member / 7-member, 7-member / 5-member or 7-member / 6-member monospirocycloalkyl. Non-limiting examples are: Includes files such as JPEG2026525258000047.jpg1761.

[0057] The term "condensed cycloalkyl" refers to a polycyclic system in which rings share two adjacent carbon atoms, and is obtained by condensing one or more monocyclic cycloalkyls, or by condensing a monocyclic cycloalkyl with one or more heterocyclyl, aryl, or heteroaryl groups, where the linkage point is in the monocyclic cycloalkyl, which may contain one or more double bonds within its ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5 to 20-membered condensed cycloalkyl). The above condensed cycloalkyl is preferably a condensed cycloalkyl having 6 to 14 ring atoms (i.e., a 6 to 14-membered condensed cycloalkyl), and more preferably a condensed cycloalkyl having 7 to 10 ring atoms (i.e., a 7 to 10-membered condensed cycloalkyl). The above-mentioned condensed cycloalkyls include bicyclic condensed cycloalkyls and polycyclic condensed cycloalkyls (e.g., tricyclic condensed cycloalkyls, tetracyclic condensed cycloalkyls, etc.), preferably bicyclic condensed cycloalkyls or tricyclic condensed cycloalkyls, and more preferably 3-member / 4-member, 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 3-member, 5-member / 4-member, 5-member / 5-member, 5-member / 6-member, 5-member / 7-member, 6-member / 3-member, 6-member / 4-member, 6-member / 5-member, 6-member / 6-member, 6-member / 7-member, 7-member / 5-member, or 7-member / 6-member bicyclic condensed cycloalkyls. Non-limiting examples are: Includes JPEG2026525258000048.jpg15128.

[0058] The term "crosslinked cycloalkyl" refers to a polycyclic system of all carbon atoms sharing two carbon atoms that are not directly linked to each other, which may contain one or more double bonds within the ring, and which has 5 to 20 carbon atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., 5 to 20-membered crosslinked cycloalkyl). The above crosslinked cycloalkyl is preferably a crosslinked cycloalkyl having 6 to 14 carbon atoms (i.e., a 6 to 14-membered crosslinked cycloalkyl), and more preferably a crosslinked cycloalkyl having 7 to 10 carbon atoms (i.e., a 7 to 10-membered crosslinked cycloalkyl). The above crosslinked cycloalkyl includes bicyclic crosslinked cycloalkyl and polycyclic crosslinked cycloalkyl (e.g., tricyclic crosslinked cycloalkyl, tetracyclic crosslinked cycloalkyl, etc.), and is preferably a bicyclic or tricyclic crosslinked cycloalkyl. Non-limiting examples are: Includes JPEG2026525258000049.jpg15128.

[0059] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or polycyclic heterocycle system (i.e., polycyclic heterocyclyl) that contains at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur within its ring (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with an oxo group to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), and has 3 to 20 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., a 3-20 membered heterocyclyl). The above heterocyclil is preferably a heterocyclil having 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclil), more preferably a heterocyclil having 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclil) or a heterocyclil having 4 to 7 ring atoms (i.e., a 4 to 7-membered heterocyclil), even more preferably a heterocyclil having 3 to 6 ring atoms (i.e., a 3 to 6-membered heterocyclil), or preferably a heterocyclil having 5 or 6 ring atoms (i.e., a 5 or 6-membered heterocyclil).

[0060] The above monocyclic heterocyclils include, as non-exclusive examples, pyrrolidinil, tetrahydropyranil, dihydropyridyl, tetrahydropyridyl, piperidinil, piperazinil, morpholinil, thiomorpholinil, and homopiperazinil.

[0061] The above-mentioned polycyclic heterocyclils include spiroheterocyclils, condensed heterocyclils, and cross-linked heterocyclils.

[0062] The term "spiroheterothericrill" refers to a polycyclic heterocyclic system in which rings share one atom (called a spiro atom), which may contain one or more double bonds within the rings, and which contain at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with an oxo group to form a sulfoxide or sulfone, but not containing -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclil is included and the linking point is located on the monocyclic heterocyclil, which has 5 to 20 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., a 5 to 20-membered spiroheterothericrill). The above spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclyl), and more preferably a spiroheterocyclyl having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclyl). The above spiroheterocyclils include monospiroheterocyclils and polyspiroheterocyclils (e.g., bisspiroheterocyclils), preferably monospiroheterocyclils or bisspiroheterocyclils, and more preferably 3-member / 4-member, 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 3-member, 5-member / 4-member, 5-member / 5-member, 5-member / 6-member, 5-member / 7-member, 6-member / 3-member, 6-member / 4-member, 6-member / 5-member, 6-member / 6-member, 6-member / 7-member, 7-member / 5-member, or 7-member / 6-member monospiroheterocyclils. Non-limiting examples are: JPEG2026525258000050.jpg25147

[0063] The term "condensed heterocyclyl" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings, and which may contain one or more double bonds within the rings, and which may contain at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with an oxo group to form a sulfoxide or sulfone, i.e., -OO-, -OS-, or - (excluding SS-), it is a monocyclic heterocyclil condensed with one or more monocyclic heterocyclils, or a monocyclic heterocyclil condensed with one or more cycloalkyl, aryl, or heteroaryl groups, where the linkage point is on the monocyclic heterocyclil and it has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5 to 20-membered condensed heterocyclil). The above condensed heterocyclil is preferably a condensed heterocyclil having 6 to 14 ring atoms (i.e., a 6 to 14-membered condensed heterocyclil), and more preferably a condensed heterocyclil having 7 to 10 ring atoms (i.e., a 7 to 10-membered condensed heterocyclil). The above-mentioned condensed heterocyclils include bicyclic and polycyclic condensed heterocyclils (e.g., tricyclic condensed heterocyclils, tetracyclic condensed heterocyclils, etc.), preferably bicyclic or tricyclic condensed heterocyclils, and more preferably 3-member / 4-member, 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 3-member, 5-member / 4-member, 5-member / 5-member, 5-member / 6-member, 5-member / 7-member, 6-member / 3-member, 6-member / 4-member, 6-member / 5-member, 6-member / 6-member, 6-member / 7-member, 7-member / 5-member, or 7-member / 6-member bicyclic condensed heterocyclils. Non-limiting examples are: JPEG2026525258000051.jpg67145

[0064] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic system in which two atoms are not directly linked, and which may contain one or more double bonds within its rings, and which may contain at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with an oxo group to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), and which has 5 to 20 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., a 5 to 20-membered bridged heterocyclyl). The above-mentioned cross-linked heterocyclils are preferably cross-linked heterocyclils having 6 to 14 ring atoms (i.e., 6 to 14 membered cross-linked heterocyclils), and more preferably cross-linked heterocyclils having 7 to 10 ring atoms (i.e., 7 to 10 membered cross-linked heterocyclils). Depending on the number of rings, they can be divided into bicyclic cross-linked heterocyclils and polycyclic cross-linked heterocyclils (e.g., tricyclic cross-linked heterocyclils, tetracyclic cross-linked heterocyclils, etc.), and are preferably bicyclic cross-linked heterocyclils or tricyclic cross-linked heterocyclils. Non-limiting examples are: Includes files such as JPEG2026525258000052.jpg17128.

[0065] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, and having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6 to 14-membered aryl). The above aryl is preferably an aryl having 6 to 10 ring atoms (i.e., a 6 to 10-membered aryl), and preferably an aryl having 8 to 10 ring atoms (i.e., an 8 to 10-membered aryl). The above monocyclic aryl is, for example, phenyl. The above polycyclic aryl includes, as non-limiting examples, naphthyl, anthryl, phenanthryl, and the like.

[0066] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, which contains at least one heteroatom (e.g., 1, 2, 3, or 4) selected from nitrogen, oxygen, and sulfur within its ring (the nitrogen may be optionally oxidized to form a nitrogen oxide, and the sulfur may be optionally substituted with an oxo group to form a sulfoxide or sulfone, but without -OO-, -OS-, or -SS-), and which has 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) (i.e., a 5-14 membered heteroaryl). The above heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5 or 6-membered monocyclic heteroaryl), or preferably a heteroaryl having 8 to 10 ring atoms (i.e., an 8 to 10-membered heteroaryl).

[0067] The above monocyclic heteroaryls include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, flazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidyl, pyridonyl, and N-alkylpyridone. JPEG2026525258000053.jpg14128

[0068] The above polycyclic heteroaryls include, as non-exclusive examples, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, benzofuryl, quinazolinyl, carbazolyl, pyrrolotriadinyl, and others.

[0069] The term "haloalkyl" refers to a compound in which an alkyl group is substituted with one or more halogens, where the alkyl group is as defined above.

[0070] The term "haloalkoxyl" refers to a compound in which an alkoxyl is substituted with one or more halogens, where the alkoxyl is as defined above.

[0071] The term "hydroxyalkyl" refers to a compound in which one or more alkyl groups are substituted with hydroxyls, where the alkyl group is as defined above.

[0072] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0073] The term "hydroxy" refers to the -OH group.

[0074] The term "mercapto group" refers to the -SH group.

[0075] The term "amino group" refers to -NH2.

[0076] The term "cyano group" refers to -CN.

[0077] The term "nitro group" refers to -NO2.

[0078] The term "oxo" or "oxo group" refers to "=O".

[0079] The term "carbonyl" refers to C=O.

[0080] The term "carboxy" refers to -C(O)OH.

[0081] Compounds according to the present invention may exist in the form of specific stereoisomers. The term "stereoisomer" refers to an isomer that has the same structure but differs in the spatial arrangement of atoms. This includes cis-trans (or Z-E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in compounds according to the present invention may include other chiral atoms. All such stereoisomers and mixtures thereof are within the scope of the present invention. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a compound of the present invention can be prepared by asymmetric synthesis or by chiral additives, or, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer can be formed with a suitable optically active acid or base, and the diastereomer can be resolved by conventional methods known in the art to obtain a pure product of the isomer. Furthermore, the separation of enantiomers and diastereomers is generally achieved by chromatography.

[0082] In the chemical structure of the compound described in the present invention, JPEG2026525258000054.jpg27169

[0083] The compounds relating to this disclosure include all suitable isotopic derivatives of the compound. The term “isotope derivative” refers to a compound in which at least one atom is substituted with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds relating to this disclosure include stable and radioactive isotopes such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2H (deuterium, D), 3H (tritium, T), 11C, 13C, 14C, 15N, 17O, 18O, 32p, 33p, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 125I, 129I, and 131I, with deuterium being preferred. “Optionally” or “optionally” means that the event or situation described below may or may not occur, and includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "alkyl groups optionally substituted with halogens or cyano groups" includes cases where the alkyl group is substituted with a halogen or cyano group, and cases where the alkyl group is not substituted with a halogen or cyano group.

[0084] "Substitution" or "being substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3, and even more preferably 1 to 2, are substituted by a number of substituents that correspond to each other independently. Those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) with little effort. For example, an amino group or hydroxyl group with free hydrogen can become unstable when bonded to a carbon atom with an unsaturated bond (e.g., an olefin).

[0085] "Pharmaceutical composition" indicates a mixture of one or more compounds described herein or pharmaceutically acceptable salts thereof with other chemical components, and other components such as pharmaceutically acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living organism and contribute to the absorption of the active ingredient, thereby further exerting biological activity.

[0086] "Pharmacologically acceptable salt" refers to a salt of the compound relating to this disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in the body of a mammal and possess the desired biological activity. They may be prepared individually in the final separation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. Generally, bases for forming pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. Generally, acids for forming pharmaceutically acceptable salts include inorganic acids and organic acids.

[0087] As used herein, the term “treat” includes treating a disease or condition in mammals, in particular humans, and includes (a) inhibiting an infection, disease or condition, i.e., inhibiting or delaying the progression of an infection, disease or condition; (b) alleviating an infection, disease or condition, i.e., causing the disease or condition to subside; and / or (c) curing an infection, disease or condition.

[0088] As used herein, the term “prevent” includes prophylactic therapy in mammals, particularly humans, aimed at reducing the likelihood of developing an infection, disease, or symptom. Patients receiving prophylactic therapy may be selected on the basis of having an increased risk of developing an infection, disease, or symptom compared to the general population. “Prevent” may also include treatment of subjects who have not yet developed an infection or clinical symptom, and prevention of secondary occurrences of the same or similar infection or clinical symptom.

[0089] With respect to drugs or pharmacological activators, the term "therapeutic dose" refers to a dose of the drug or agent sufficient to produce, or at least partially produce, the desired effect. The therapeutic dose is determined on a person-by-person basis, depending on the age and general condition of the recipient, as well as the specific active substance. However, a suitable therapeutic dose for an individual can be determined by a person skilled in the art through ordinary testing.

[0090] As used herein, the term “pharmaceutically acceptable” means that these compounds, materials, compositions and / or dosage forms are, within reasonable medical judgment, free from excessive toxicity, irritation, allergic reactions or other problems or complications, applicable to patient tissues, have a reasonable profit-benefit ratio, and are effective for the desired use.

[0091] As used herein, the singular forms "one," "one type," and "the said" include multiple quotations, and vice versa, unless otherwise specified in the context.

[0092] The term "approximately," when used with parameters such as pH, concentration, and temperature, indicates that the parameter may vary within ±10%, and in some cases, more preferably within ±5%. As those skilled in the art will understand, when the parameter is not critical, the number is generally given simply for illustrative purposes, not as a limitation. [Modes for carrying out the invention]

[0093] The following examples are for illustrative purposes only and do not limit the present invention. Any modifications, changes, or alterations made within the scope of protection of the present invention are all included within the scope of protection of the present invention.

[0094] The compounds provided by the present invention can be prepared from readily available starting materials using a specific synthesis scheme described later. These starting materials can be synthesized or commercially available according to methods known in the art. Experimental methods not specifically specified in the following examples can be determined by those skilled in the art using conventional methods and conditions and conventional optimization procedures.

[0095] Unless otherwise specified, the present invention identifies compounds using conventional methods such as mass spectrometry and nuclear magnetic resonance, and each step and condition may refer to the usual operating procedures and conditions in the art.

[0096] In the following examples, the commonly used abbreviations are as follows: AcOH: Acetic acid, CAS number: 64-19-7 tBuOK: Potassium tert-butoxide, CAS number: 865-47-4 Cs2CO3: Cesium carbonate, CAS number: 534-17-8 BAST: Bis(2-methoxyethyl)aminosulfur trifluoride, CAS number: 202289-38-1 BEP: 2-bromo-1-ethylpyridinium tetrafluoroborate, CAS number: 878-23-9 PyBOP: Hexafluorophosphate (benzotriazole-1-yloxy)tripyrrolidinophosphonium, CAS number: 128625-52-5 DMTMM: 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride, CAS number: 3945-69-5 CDI: Carbonyldiimidazole, CAS number: 208-488-9 CuI: Cuprous iodide, CAS number: 7681-65-4 CuCl: Cuprous chloride, CAS number: 7758-89-6 CuSO4: Copper sulfate, CAS number: 7758-98-7 NaH: Sodium hydride, CAS number: 7646-69-7 NaOMe: Sodium methoxide, CAS number: 124-41-4 NaN3: Sodium azide, CAS number: 26628-22-8 NH4HCO3: Ammonium bicarbonate, CAS number: 1066-33-7 Na2CO3: Sodium carbonate, CAS number: 497-19-8 K2CO3: Potassium carbonate, CAS number: 584-08-7 NaBH4: Sodium borohydride, CAS number: 16940-66-2 HATU:2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, CAS number: 148893-10-1 cataCXium A Pd-G3: Methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II), CAS: 1651823-59-4 Xantphos:4,5-bis(diphenylphosphin)-9,9-dimethylxanthene, CAS number: 148893-10-1 dppf Pd G3: (methanesulfonic acid) (1,1'-bis(diphenylphosphino)ferrocene) (2'-amino-1,1'-biphenyl-2-yl)palladium, CAS number: 1445086-28-1 Pd(PPh3)2Cl2: Bis(phenylphosphine)dichloropalladium, CAS number: 1445086-28-1 Pd(dppf)Cl2:[1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium, CAS number: 72287-26-4 Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium, CAS number: 51364-51-3 Pd / C: Palladium-carbon catalyst, CAS number: 13566-03-5 Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium, CAS number: 14221-01-3 Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium, CAS number: 51364-51-3 Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium, CAS number: 53199-31-8 Ruphos:1'-biphenyl;2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl;2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, CAS No.: 787618-22-8 RuPhos Palladacycle G3: Methanesulfonic acid (2-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), CAS number: 1445085-77-7 Xantphos:4,5-bis(diphenylphosphin)-9,9-dimethylxanthene, CAS number: 161265-03-8 PE: Petroleum ether; siRNA: Acetyl acetate, CAS number: 141-78-6 Boc:tert-butoxycarbonyl DIEA: N,N-diisopropylethylamine, CAS number: 7087-68-5 DMF: N,N-dimethylformamide, CAS number: 68-12-2 DMS.BH3: Dimethyl sulfide borane, CAS number: 13292-87-0 DCM: Dichloromethane, CAS number: 75-09-2 Selectfluor: N-fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate), CAS number: 140681-55-6 TCFH: Tetramethylchlorourea hexafluorophosphate, CAS number: 94790-35-9 TFA: Trifluoroacetic acid, CAS number: 76-05-1 THF: Tetrahydrofuran, CAS number: 109-99-9 THP: 2-tetrahydropyran LiBH4: Lithium borohydride, CAS number: 16949-15-8 L-Selectride: Lithium tri-sec-butylbohydride, CAS number: 38721-52-7 Zn(CN)2: Zinc cyanide, CAS number: 557-21-1 NMP: N-methylpyrrolidone, CAS number: 872-50-4 MeOH: Methanol, CAS number: 67-56-1 MeCN: Acetonitrile, CAS number: 75-05-8 NaBH3CN: Sodium borohydride, CAS number: 25895-60-7 NBS: N-bromosuccinimide, CAS number: 128-08-5 NCS: N-chlorosuccinimide, CAS number: 128-09-6 nBuLi: n-butyllithium, CAS number: 109-72-8 SEMCl:2-(trimethylsilyl)ethoxymethyl chloride, CAS number: 76513-69-4 TEA: Triethylamine, CAS number: 121-44-8 Ti(OEt)4: Tetraethyl titanate, CAS number: 3087-36-3 pTsOH: p-toluenesulfonic acid, CAS number: 104-15-4 (t-Bu)3P * HBF4: Tri-n-butylphosphine tetrafluoroborate, CAS number: 113978-91-9 d7-DMF:7 Deuterated N,N-dimethylformamide, CAS number: 4472-41-7 CDCl3: Deuterated chloroform, CAS number: 865-49-6 d6-DMSO: Deuterated dimethyl sulfoxide, CAS number: 2206-27-1 MS: Mass spectrometry ESI: Electrospray Ionization 1 HNMR: Proton Nuclear Magnetic Resonance Spectrum TLC: Thin-layer chromatography Chiral HPLC: Chiral High-Performance Liquid Chromatography Prep-HPLC: High-pressure preparative liquid chromatography Prep-TLC: Preparative Thin-Layer Chromatography LCMS: Liquid Chromatography Mass Spectrometry Rf: ratio shift value; min: minutes g: grams mg: milligrams rt: room temperature mol: mole mmol: mmol mL: milliliter M: moles / liter

[0097] Synthesis of intermediates 5-(aminomethyl)-4,6-dimethylpyridine-2-amine hydrochloride (intermediate 1) was prepared according to the following synthetic route: JPEG2026525258000055.jpg20855-5-cyano-4,6-dimethylpyridine-2-amine (50.0 g, 340 mmol, 1.00 eq) was dissolved in MeOH (100 mL) and Raney nickel (5.00 g, 58.4 mmol, 1.72 eq) and NH3.H2O (114 g, 973.73 mmol, 125.00 mL, 30% purity, 2.87 eq) were added. The mixture was stirred at 80°C under H2 (50 psi) for 20 hours. LC-MS showed that the starting materials were consumed and the product was formed. The mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 * 80 mm * 10 μm; mobile phase: [water (HCl)-ACN]; gradient: 0%~10% B over 5 min) to obtain the title compound (intermediate 1) as a white solid (10.0 g, 53.3 mmol, 15.7% yield, HCl). LC-MS (ESI): m / z 152 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (br s, 3H), 7.93 (br s, 2H), 6.70 (s, 1H), 3.93 (d, J = 4.2 Hz, 2H), 2.58 (s, 3H), 2.45 (s, 3H).

[0098] 1-(4-(bromomethyl)benzyl)pyridine-2(1H)-one (intermediate 2) was prepared according to the following synthetic route: JPEG2026525258000056.jpg24128

[0099] To a solution of pyridine-2(1H)-one (25.0 g, 262 mmol, 1.00 eq) in MeCN (500 mL), 1,4-bis(bromomethyl)benzene (104.08 g, 394.33 mmol, 1.50 eq) and K2CO3 (72.7 g, 525 mmol, 2.00 eq) were added. The reaction mixture was stirred at 80°C for 12 hours. TLC (plate 1:PE:siRNA=1:1, Rf=0.45) showed that the starting materials were completely consumed and one major new spot with greater polarity was detected. The reaction mixture was filtered, and the filtered cake was washed with DCM (200 mL). It was then diluted with H2O (500 mL) and extracted with 1500 mL (500 mL x 3) of DCM. The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, PE / SiO7 = 1 / 0 to 1 / 1, plate 2, PE:SiO7 = 1:1, Rf = 0.45). The title compound (intermediate 2) (8.00 g, 28.8 mmol, 10.9% yield) was obtained as a white solid. LC-MS (ESI): m / z 278 [M+1]+; 1 H NMR (400 MHz, CDCl3) δ 7.70-7.69 (d, J = 1.6 Hz, 1H), 7.68-7.53 (m, 1H), 7.40 -7.38 (d, J = 8 Hz, 2H), 7.28-7.26 (d, J = 8 Hz, 2H), 6.59-6.56(d, J = 8.8 Hz, 1H), 6.41-6.38 (m, 1H), 5.19 (s,2H), 4.53 (s, 2H).

[0100] (3-Fluoro-4-methoxypyridine-2-yl)methylamine hydrochloride (intermediate 3) was prepared according to the following synthetic route: JPEG2026525258000057.jpg40128

[0101] Step 1: Preparation of tert-butyl (4-chloro-3-fluoropyridine-2-yl)methylcarbamate: AgOTf (19.5 g, 76.0 mmol, 0.100 eq) and TFA (17.3 g, 152 mmol, 11.3 mL, 0.200 eq) were added to a solution of 3-fluoro-4-chloropyridine (100 g, 760 mmol, 104 mL, 1.00 eq) and (tert-butoxycarbonyl)glycine (226 g, 1.29 mol, 1.70 eq) in MeCN (1.00 L) and H2O (250 mL). Then, a solution of (NH4)2S2O8 (312 g, 1.37 mol, 297 mL, 1.80 eq) in H2O (500 mL) was added dropwise over 0.5 hours at 66°C. The mixture was stirred at 66°C for 0.25 hours. TLC (PE / siRNA=3 / 1, Rf=0.420) showed that the starting material was completely consumed and new, more polar spots had formed. The pH of the reaction mixture was adjusted to 8 by adding aqueous NaOH at 0°C, then diluted with 500 mL H2O and extracted with siRNA (1.00 L x 3). The combined organic layer was washed with brine (500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE:siRNA=1:0~3:1, PE:siRNA=3:1, Rf=0.420). The title compound (46.0 g, 176 mmol, 23.2% yield) was obtained as a yellow solid. LCMS(ESI): m / z 261 [M+1]+; 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 5.2 Hz, 1H), 7.29 (t, J = 5.2 Hz, 1H), 5.68 (br s, 1H), 4.54 (br d, J = 2.8 Hz, 2H), 1.46 (s, 9H).

[0102] Step 2: Preparation of tert-butyl (4-methoxy-3-fluoropyridine-2-yl)methylcarbamate: NaOMe (5.40 M, 24.7 mL, 1.00 eq) was added to a solution of tert-butyl (4-chloro-3-fluoropyridine-2-yl)methylcarbamate (35.0 g, 134 mmol, 1.00 eq) in MeOH (350 mL) at 0°C. The mixture was stirred at 0°C for 2 hours. The mixture was stirred at 66°C for 34 hours. LC-MS showed that approximately 33% of the starting material remained. Several new peaks were shown by LC-MS, and approximately 40% of the target compound was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with 100 mL H2O and extracted with ELISA (200 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (PE / Â=1 / 0~3 / 1, PE / Â=3 / 1, Rf=0.210). The residue was purified by preparative HPLC (column: Welch Ultimate XB-NH2250*50*10um; mobile phase: [hexane-ethanol]; gradient: 1%~30% B, 15 min). The title compound (13.5 g, 52.7 mmol, 39.2% yield, 100% purity) was obtained as a yellow oily liquid. LCMS(ESI): m / z 257 [M+1]+.

[0103] Step 3: Preparation of (3-fluoro-4-methoxypyridine-2-yl)methylamine hydrochloride (Intermediate 3): At 0°C, HCl / MeOH (4 M, 5.00 mL, 3.80 eq) was added to a solution of (4-methoxy-3-fluoropyridine-2-yl)methylcarbamate tert-butyl (13.5 g, 52.7 mmol, 1.00 eq) in MeOH (60.0 mL). The mixture was stirred at 70°C for 1.8 hours. LC-MS showed that the starting material was completely consumed and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. As a yellow solid, the title compound (Intermediate 3) (10.0 g, crude product, HCl) was obtained as a pale yellow solid. LC-MS (ESI): m / z 157 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 6.4 Hz, 1H), 7.56 (t, J = 6.8 Hz, 1H), 4.45 (d, J = 2.40 Hz, 2H), 4.14 (s, 3H).

[0104] 3-Chloro-6-(chloromethyl)quinoline (intermediate 4) was prepared according to the following synthetic route: JPEG2026525258000058.jpg43138

[0105] Step 1: Stock solution A: 6-Quinolinecarboxylate methyl (100 g, 534 mmol, 1.00 eq) in DMF (500 mL). Stock solution B: NCS (214 g, 1.60 mol, 3.00 eq) in DMF (1498 mL). Pump A: 10.30 mL / min, Pump B: 14.54 mL / min, Temperature = 100°C, C1 / 4 PFA coil, (100 mL) Residence time: 4 min. Lowe reaction: 100 g. After 57 minutes, LC-MS showed that most of the raw materials had been consumed and the target MS was detected. The reaction mixture was poured into 2 L H2O to form a yellow solid, then filtered, and the filter cake was concentrated to obtain the residue. The residue was slurryed with Depositphotos (500 mL), filtered, and the filter cake was washed with Depositphotos (80.0 mL) to obtain the title compound as a yellow solid (58.0 g, 261 mmol, 48.99% yield). LC-MS (ESI): m / z 222 [M+1]+; 1 H NMR (400 MHz, CDCl3) δ 9.00 (d, J = 2.4 Hz, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.67 (d, J = 1.2 Hz, 1H), 8.30 - 8.20 (m, 1H), 8.15 - 8.05 (m, 1H), 3.94 (s, 3H).

[0106] Step 2: Stock solution B: DMF (1498 mL) solution of NCS (214 g, 1.60 mol, 3.00 eq). Pump A: 10.30 mL / min, Pump B: 14.54 mL / min, Temperature = 100°C, 1 / 4" PFA coil (100 mL), Residence time: 4 min, Flow reaction: 100 g. After 57 minutes, LC-MS showed that most of the starting material had been consumed and the target MS was detected. The reaction mixture was poured into 2 L H2O to form a yellow solid, then filtered, and the filter cake was concentrated to obtain the residue. The residue was slurryed with SiO2 (500 mL), filtered, and the filter cake was washed with SiO2 (80.0 mL) to obtain the title compound (58.0 g, 261 mmol, 48.99% yield) as a yellow solid. LC-MS (ESI): m / z 194 [M+1]+; 1 H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 2.4 Hz, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.73 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 1H), 5.48 (brs, 1H), 4.71 (s, 2H).

[0107] Step 3: Compound 3 (18.0 g, 92.9 mmol, 1.00 eq) was mixed with SOCl2 (196 g, 1.65 mol, 120 mL, 17.8 eq), and the mixture was stirred at 20°C for 3 hours. LC-MS showed that the starting material was consumed and the desired MS was detected. The reaction mixture was concentrated to obtain a residue, which was then slurred with SiO2 (100 mL), filtered, and the filtered cake was diluted with SiO2 (400 mL). The combined organic layer was washed with NaHCO3 (saturated, 150 mL x 2) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (14.0 g, 65.6 mmol, 70.6% yield, 99.4% purity) as a yellow solid. LC-MS (ESI): m / z 212[M+1]+; 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.14 - 7.97 (m, 2H), 7.84 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 1H), 4.98 (s, 2H).

[0108] 2-(bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (intermediate 5) was prepared according to the following synthetic route: JPEG2026525258000059.jpg21135

[0109] Step 1: To a solution of 3-bromo-2-aminopyridine (11 g, 63.58 mmol) and cyclopropyl borate (10.92 g, 127.16 mmol) in toluene (200 mL) and H2O (20 mL), Pd(OAc)2 (1.43 g, 6.36 mmol), SPhos (5.22 g, 12.72 mmol), and then K3PO4 (40.49 g, 190.74 mmol) were added. The mixture was stirred overnight at 100°C and diluted with water (1.0 L). The reaction mixture was extracted with DCM (300 mL x 3), and the organic layer was filtered through a Celite pad. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (elution with siRNA) to obtain the title compound (8.0 g, 93.77% yield) as a yellow solid. LCMS (ESI): m / z 135.2 [M+H] + .

[0110] Step 2: A solution of 3-cyclopropyl-2-aminopyridine (2.0 g, 14.91 mmol) and 1,3-dibromo-2-propanone (4.83 g, 22.37 mmol) in DME (30 mL) was stirred overnight at 90°C. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (elution at DCM:MeOH = 30:1) to obtain the title compound (intermediate 5) as a yellow solid (2.75 g, 73.47% yield). LCMS (ESI): m / z 252.9[m+H]+.

[0111] 1-(2-Cyano-4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)benzyl)-1H-pyrazole-4-carboxylic acid (Intermediate 6) was prepared according to the following synthetic route: JPEG2026525258000060.jpg51128

[0112] Step 1: To a solution of compound Int6-1 (0.5 g, 2.46 mmol) in NMP (10 mL) were added compound 6,6-difluoro-3-azabicyclo[3.1.0]hexane (0.38 g, 2.46 mmol) and K2CO3 (0.85 g, 6.15 mmol), and the mixture was stirred at 120 °C for 16 h. After monitoring the completion of the reaction by LCMS, the mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL × 3). The combined layers were dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluting with polyethylene: ethyl acetate = 100:0 to 85:15), and the target compound Int6-2 (0.48 g, 64.51% yield) was obtained as a white solid. LCMS (ESI): m / z 304.0 [M+H]+.

[0113] Step 2: To a solution of compound Int6-2 (0.28 g, 2.93 mmol) in MeOH (10 mL) was added NaBH4 (0.042 g, 1.12 mmol), and the mixture was stirred at room temperature for 0.5 h. After monitoring the completion of the reaction by LCMS, the reaction mixture was diluted with water (100 mL) and extracted with DCM (100 mL × 3). The organic layer was washed with brine and water, and dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain the target white solid compound Int6-3 (0.275 g, 97.56% yield). LCMS (ESI): m / z 306 [M + H]+.

[0114] Step 3: Int6-3 (0.24 g, 0.79 mmol), 5 (0.15 g, 1.19 mmol), and pTsOH (0.45 g, 0.24 mmol) were added to MeCN (10 mL), and the mixture was stirred at 65 °C for 16 h. The completion of the reaction was monitored by LCMS. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, the organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was eluted by column chromatography (PE: EA = 2:1) to obtain the target compound Int6-4 (0.125 g, yield 38.43%) as a white solid. LCMS (ESI): m / z 414.2 [M + H]+.

[0115] Step 4: Compound Int6-4 (0.115 g, 0.28 mmol), Zn(CN)2 (0.066 g, 0.56 mmol), zinc powder (0.010 g, 0.15 mmol), (t-Bu)3P·HBF4 (0.016 g, 0.056 mmol), and Pd2(dba)3 (0.026 g, 0.028 mmol) were added to NMP (10 mL). The reaction mixture was purged with nitrogen for 5 min. The mixture was stirred at 80 °C for 2 h. After monitoring the completion of the reaction by LCMS, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluted with dichloromethane: methanol = 20:1) to obtain the target compound Int6-5 (0.095 g, 95.03% yield) as a white solid. LCMS (ESI): m / z 359.3 [M+H]+.

[0116] Step 5: Compound F (95 mg, 0.27 mmol) was mixed with 2 M sodium hydroxide solution in methanol (12 mL) and stirred at 30°C for 16 hours. After monitoring for reaction completion by LC-MS, the reaction mixture was acidified to pH = 6 with 1 M HCl and extracted with DCM (100 mL * 3). The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain the desired intermediate 6 (82 mg, yield 89.83%) as a white solid. LC-MS (ESI): m / z 345.2 [M + H]+.

[0117] 2-(aminomethyl)-3-fluoro-N-methylpyridine-4-amine hydrochloride (intermediate 7) was prepared according to the following synthetic route: JPEG2026525258000061.jpg46128

[0118] Step 1: Preparation of tert-butyl (2-chloro-3-fluoropyridine-4-yl)carbamate: Under nitrogen protection, 2-chloro-3-fluoro-4-iodopyridine (500 mg, 1.90 mmol), tert-butyl carbamate (250 mg, 2.1 mmol), tris(dibenzylideneacetone)dipalladium (87 mg, 0.10 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (58 mg, 0.1 mmol), and cesium carbonate (1230 mg, 3.80 mmol) were sequentially added to dioxane (10 mL), and the mixture was heated to 100°C and reacted for 3 hours. The mixture was filtered, the filtrate was collected, and the residue was concentrated under reduced pressure to obtain the residue. The residue was separated and purified by column chromatography (EA:PE = 1:10) to obtain the title compound (450 mg, yield: 96%) as a yellow oily liquid. MS (ESI) M / Z: 247.1 [M+H] + .

[0119] Step 2: Preparation of tert-butyl (2-chloro-3-fluoropyridine-4-yl)(methyl)carbamate: Under nitrogen protection, compound Int7-1 (350 mg, 1.40 mmol) was added to N,N-dimethylformamide (3 mL), cooled to 0°C, sodium hydride (68 mg, 1.70 mmol) was added, and the mixture was reacted at 0°C for 30 minutes. A solution of methane iodide (397 mg, 2.8 mmol) dissolved in N,N-dimethylformamide (2 mL) was slowly added dropwise, and the mixture was allowed to return to room temperature naturally for 1 hour. Water (25 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined and washed with water (50 mL) and saturated sodium chloride (50 mL), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was separated and purified by column chromatography (EA:PE = 1:5) to obtain the title compound (285 mg, yield: 78%) as a yellow solid. MS (ESI) M / Z: 261.1 [M+H] + .

[0120] Step 3: Preparation of (2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridine-4-yl)(methyl)carbamate tert-butyl: Under nitrogen protection, compound Int7-2 (280 mg, 1.10 mmol), potassium [((tert-butoxycarbonyl)amino)methyl]trifluoroborate (521 mg, 2.20 mmol), methylsulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (44 mg, 0.06 mmol), and potassium phosphate (466 mg, 2.20 mmol) were sequentially added to a mixed solution of dioxane (4 mL) and water (1 mL), and the mixture was heated to 100°C and reacted for 16 hours. The mixture was filtered, the filtrate was collected, and the residue was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (EA:PE = 1:5) to obtain compound Int7-3 (230 mg, yield: 59%) as a yellow solid. MS (ESI) M / Z: 356.2 [M+H] + .

[0121] Step 4: Preparation of 2-(aminomethyl)-3-fluoro-N-methylpyridine-4-amine hydrochloride: Compound Int7-3 (230 mg, 0.60 mmol) was added to a solution of dioxane hydrogen chloride (4.0 M, 5 mL) and reacted at room temperature for 1 hour. Concentrated under reduced pressure, (intermediate 7) (120 mg, yield: 100%) was obtained as a white solid. MS (ESI) M / Z: 156.2 [M+H] + .

[0122] 3-(3,3-difluorocyclobutyl)-1-(4-((5-fluoro-2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (intermediate 8) was prepared according to the following synthetic route: JPEG2026525258000062.jpg50128

[0123] Step 1: Preparation of methyl 3-(3,3-difluorocyclobutyl)-3-oxopropanoate: To a solution of compound Int8-1 (600 mg, 4.41 mmol) in THF (20 mL), CDI (720 mg, 4.41 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Then, compound Int8-2 (830 mg, 5.29 mmol) and MgCl2 (500 mg, 5.29 mmol) were added, and the mixture was stirred overnight at room temperature. After monitoring for completion of the reaction by LC-MS, the mixture was diluted with water (100 mL) and extracted with EA (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by preparative TLC (PE:EA = 3:1) to obtain the title compound (610 mg, 72.01% yield) as a pale yellow oil. MS (ESI) m / z: 193.0 [M+H]+. 1 H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 3.52 (s, 2H), 3.26 (pd, J = 8.8, 2.6 Hz, 1H), 2.89 - 2.72 (m, 4H).

[0124] Step 2: Preparation of (E)-2-(3,3-difluorocyclobutane-1-carbonyl)-3-(dimethylamino)acrylate methyl: To a solution of compound Int8-3 (610 mg, 3.17 mmol) in DMF (10 mL), DMF-DMA (566 mg, 4.75 mmol) was added, and the mixture was stirred at 70°C for 1 hour. After monitoring for completion of the reaction by LC-MS, the mixture was concentrated under reduced pressure to obtain the title compound (784 mg, 100% yield) as a yellow oil. MS (ESI) m / z: 248.2 [M+H]+.

[0125] Step 3: Preparation of methyl 3-(3,3-difluorocyclobutyl)-1H-pyrazole-4-carboxylate: To a solution of compound Int8-4 (784 mg, 3.17 mmol) in t-BuOH (10 mL), hydrated hydrazine (238 mg, 4.75 mmol) and acetic acid (285 mg, 4.75% mmol) were added, and the mixture was stirred at 60°C for 1 hour. After monitoring for completion of the reaction by LC-MS, the mixture was diluted with NaHCO3 solution (50 mL) and extracted with EA (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel chromatography (elution at PE:EA = 100:0 to 50:50) to obtain the title compound (423 mg, 61.71% yield) as a white solid. MS (ESI) m / z: 217.1 [M+H]+.

[0126] 1 H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 8.28 (s, 1H), 3.72 (d, J = 10.8 Hz, 4H), 3.03 - 2.70 (m, 4H).

[0127] Step 4: Preparation of 3-(3,3-difluorocyclobutyl)-1-(4-((5-fluoro-2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate methyl: Compound Int8-5 (204 mg, 0.69 mmol) and K2CO3 (238 mg, 1.72 mmol) were added to a solution of compound Int8-4 (150 mg, 0.69 mmol) in DMF (8 mL), and the mixture was stirred overnight at room temperature. After monitoring for reaction completion by LC-MS, the mixture was diluted with water (50 mL) and extracted with EA (50 mL * 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA = 0:1) to obtain the title compound (245 mg, 81.85% yield) as a white solid. MS (ESI) m / z: 432.2 [M+H]+.

[0128] 1 H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.11 - 7.99 (m, 1H), 7.57 (ddd, J = 10.3, 7.2, 3.4 Hz, 1H), 7.27 (q, J = 8.3 Hz, 4H), 6.44 (dd, J = 10.0, 5.4 Hz, 1H), 5.30 (s, 2H), 5.01 (s, 2H), 3.72 (s, 3H), 3.67 - 3.60 (m, 1H), 2.97 - 2.85 (m, 2H), 2.84 - 2.71 (m, 2H).

[0129] Step 5: Preparation of 3-(3,3-difluorocyclobutyl)-1-(4-((5-fluoro-2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate methyl: Add NaOH (2M, 1mL, 2 mmol) to a solution of compound Int8-6 (40 mg, 0.093 mmol) in MeOH (2 mL), and stir the mixture overnight at room temperature. Add HCl solution (2M, 1mL, 2 mmol) to quench the reaction mixture and concentrate under reduced pressure to obtain the title compound (38 mg, 100% yield). MS (ESI) M / Z: 503.21 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 6.0 Hz, 1H), 8.28 (s, 1H), 7.90 (d, J = 5.6 Hz, 1H), 7.77 (dd, J = 6.8, 2.0 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.30 - 7.21 (m, 4H), 6.58 - 6.49 (m, 2H), 6.42 - 6.37 (m, 1H), 6.26 - 6.19 (m, 1H), 5.30 (s, 2H), 5.07 (s, 2H), 4.79 (dd, J = 8.4, 5.6Hz, 2H), 4.68 (dd, J = 6.8, 5.6 Hz, 2H), 4.55 - 4.46 (m, 1H), 4.37 (dd, J = 5.6, 2.0 Hz, 2H), 2.73 (d, J = 4.8 Hz, 3H).

[0130] 1-Ethyl-1,4,5,6-tetrahydrocyclopenta[d]imidazole-4-amine (intermediate 9) was prepared according to the following synthetic route: JPEG2026525258000063.jpg74149

[0131] Step 1: To a solution of Int9-1 (15.0 g, 118.94 mmol) in DMF (180 mL), Cs2CO3 (58.13 g, 178.41 mmol) and ethane iodide (27.83 g, 178.4 mmol) were added, and the mixture was stirred at 70°C for 16 hours. After monitoring for reaction completion by LC-MS, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (elution at PE:SiO=100:0~0:100) to obtain the Int9-2 compound (6.2 g, 33.81% yield). MS(ESI)M / Z: 155.2[M+H]+.

[0132] Step 2: Add NBS (7.87 g, 44.24 mmol) to a solution of compound Int9-2 (6.2 g, 40.22 mmol) in acetic acid (25 mL), and stir the mixture at 70°C for 6 hours. After monitoring for reaction completion by LC-MS, the reaction mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 7-8 with a saturated Na2CO3 solution. The mixture was diluted with H2O (50 mL) and extracted with DCM (300 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution at PE:siRNA = 100:0 to 0:100) to obtain the target compound Int9-3 (3.5 g, 37.34% yield). MS(ESI)M / Z: 235.0[M+H]+.

[0133] Step 3: To a solution of compound Int9-3 (3.5 g, 15.02 mmol) in N,N-dimethylacetamide (25 mL) and water (5 mL), 3,3-dimethoxy-1-propene (2.15 g, 21.03 mmol) and N,N-dicyclohexylmethylamine (4.11 g, 21.03 mmol) were added. The mixture was purged with nitrogen for 5 minutes. Then, PdCl2[P(O-TOl)3]2 (0.71 g, 0.90 mmol) was added, and the mixture was stirred at 120°C for 4 hours. After monitoring for completion of the reaction by LC-MS, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The reaction mixture was poured into 200 mL of water and extracted with EA (200 mL x 3). The combined organic layer was dried over anhydrous Na2SO4. The residue was purified by reverse-phase HPLC to obtain compound Int9-4 (1.4 g, 38.8% yield). MS(ESI)M / Z:241.2[M+H]+.

[0134] Step 4: Under a nitrogen atmosphere, compound Int9-4 (1.1 g, 4.99 mmol) was dissolved in THF (20 mL) and treated with KHMDS (10 mL of 1 M THF solution, 10 mmol) at 0 °C. The mixture was stirred for 1 hour, and after monitoring the completion of the reaction by LCMS, it was poured into a cooled mixture of EtOAc (100 mL) and acetic acid (15 mL). After stirring for 30 minutes, the mixture was filtered. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (300 mL * 3). The combined organic layers were dried over anhydrous Na2SO4. The organic phase was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with DCM:MeOH = 100:0 to 92:8) to obtain compound Int9-5 (586 mg, yield 55.81%). MS (ESI) M / Z: 209.1 [M+H] + .

[0135] Step 5: A solution of compound Int9-5 (586 mg, 2.81 mmol) in water (1 mL), AcOH (5 mL) and HCl (1.5 mL) was then heated at 70 °C for 3 hours. The completion of the reaction was monitored by LCMS. The pH of the reaction mixture was adjusted to pH 7-8 with Na2CO3. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (100 mL * 3). The combined layers were dried over anhydrous Na2SO4. The organic phase was concentrated to obtain the desired compound Int9-6 (410 mg, 97% yield). MS(ESI)M / Z:151.0[M+H]+.

[0136] Step 6: A mixture of compound Int9-6 (310 mg, 2.06 mmol) was dissolved in toluene (20 mL), and Ti(OEt)4 (1.41 g, 6.18 mmol) was added and stirred for 15 minutes, followed by treatment with tert-butylsulfinamide (620 mg, 5.15 mmol). The mixture was heated at 100°C for 8 hours. The completion of the reaction was monitored by LC-MS. After cooling to room temperature and treatment with saturated NaCl aqueous solution (10 mL), the mixture was stirred for 1 hour and filtered through Celite. The filtered cake was stirred twice in THF (20 mL) for 10 minutes each time and filtered through Celite. The combined organic phase was concentrated, and the residue was purified by silica gel chromatography (DCM:MeOH=95:5) to obtain compound Int9-7 (330 mg, 63.10% yield). MS(ESI)M / Z:254.2[M+H]+.

[0137] Step 7: Under a nitrogen atmosphere, compound Int9-7 (330 mg, 1.3 mmol) was dissolved in THF (15 mL) and treated with L-Selectride (1.9 mL 1 M THF solution, 1.9 mmol) at 0°C. The mixture was stirred for 1.5 hours, and the completion of the reaction was monitored by LC-MS. Then, MeOH (2 mL) was added dropwise to the reaction. The solvent was evaporated under vacuum, and the residue was diluted with H2O (50 mL) and extracted with DCM (80 mL x 3). The combined layers were dried over anhydrous Na2SO4. The organic phase was concentrated to obtain the target compound Int9-8 (340 mg, 100% yield), which was used without further purification. MS(ESI)M / Z: 256.1[M+H]+.

[0138] Step 8: The mixture of compound Int9-8 (340 mg, 1.33 mmol) in isopropanol (10 mL) was treated with 2 M HCl / 1,4-dioxane in isopropanol solution (1 mL) and stirred for 2 hours. After monitoring for reaction completion by LC-MS, the mixture was concentrated, and the residue was purified by reverse phase to obtain oily intermediate 9 (122 mg, 60.6% yield). MS(ESI)M / Z: 152.2[M+H]+.

[0139] (6,8-dimethylimidazo[1,5-a]pyridine-7-yl)methylamine (intermediate 10) was prepared according to the following synthetic route: JPEG2026525258000064.jpg67128

[0140] Step 1: At 0°C, m-CPBA (3.07 g, 15.1 mmol, 85% purity, 2.00 eq) was added to a solution of compound Int10-1 (1.00 g, 7.57 mmol, 1.00 eq) in DCM (10.0 mL), and the mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with H2O (20.0 mL), extracted with siRNA (30.0 mL x 3), washed with sat. aq. NaHCO3 (30.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was ground using PE / DCM = 5 / 1 (50.0 / 10.0 mL) at 20°C for 30 minutes. Compound Int10-2 (1.00 g, 6.75 mmol, 89.2% yield) was obtained as a white solid. MS(ESI)M / Z: 149 [M+H]+.

[0141] Step 2: A solution of compound Int10-2 (1.00 g, 6.75 mmol, 1.00 eq) in POCl3 (16.4 g, 107 mmol, 10.0 mL) was stirred in the mixture at 100°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / siRNA = 100 / 1 to 5 / 1). A colorless oily compound Int10-3 (0.700 g, 4.20 mmol, 62.2% yield) was obtained. MS(ESI)M / Z: 167 [M+H]+.

[0142] Step 3: Preparation: Compound Int10-3 (400 mg, 2.40 mmol, 1.00 eq), potassium [((tert-butoxycarbonyl)amino)methyl]trifluoroborate (854 mg, 3.60 mmol, 1.50 eq)) was dissolved in dioxane (10.0 mL) and H2O (2.00 mL). K3PO4 (1.53 g, 7.20 mmol, 3 eq) and CataCXium A Pd G3 (175 mg, 240 μmol, 0.100 eq) were added, and the mixture was stirred at 110°C for 3 hours. LC-MS (EW47914-123-P1A) showed that the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC to obtain the white solid compound Int10-4 (100 mg, 383 μmol, 15.9% yield). MS(ESI)M / Z: 206 [M+H]+.

[0143] Step 4: At 0°C, compound Int10-4 (140 mg, 536 μmol, 1.00 eq) was dissolved in DCM (2.00 mL) and HCl / dioxane (2 M, 2.00 mL, 7.47 eq) was added. The combined mixture was stirred at 20°C for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. Compound Int10-5 (100 mg, 506 μmol, 94.4% yield, HCl) was obtained as a white solid. MS(ESI)M / Z: 162 [M+H]+.

[0144] Step 5: The compound Int10-5 (100 mg, 506 μmol, 1.00 equivalent, HCl) was mixed with HCOOH (24.8 mg, 506 μmol, 2.00 mL, 98% purity, 1.00 equivalent) and Ac2O (1.00 mL), and the mixture was stirred at 50°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue, which was then diluted with sat. aq. NaHCO3 (10 mL), extracted with RINKAN (20.0 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The compound Int10-6 (85.0 mg, 496 μmol, 98.1% yield) was obtained as a yellow solid. MS(ESI)M / Z: 172 [M+H]+. MS(ESI)M / Z: 172 [M+H]+.

[0145] Step 6: Raney nickel (10.0 mg, 117 μmol, 1.00 eq) was added to the flask under an argon atmosphere, and methanol (2.00 mL) was added to the flask under an argon atmosphere. Under an argon atmosphere, a solution of compound Int10-6 (20.0 mg, 117 μmol, 1 eq) and NH3·H2O (2.12 g, 18.2 mmol, 2.33 mL, 30% purity, 156 eq) in MeOH (2 mL) was added to the flask, the suspension was then degassed, purged three times with H2, and the reaction mixture was stirred at 25°C under H2 (50 Psi) for 5 hours. LC-MS showed that Int10-6 was completely consumed and the target mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. Intermediate 10 (20.0 mg, 114 μmol, 97.7% yield) was obtained as a yellow solid. MS(ESI)M / Z: 176 [M+H]+.

[0146] (6,8-dimethylimidazo[1,5-a]pyridine-7-yl)methylamine (intermediate 11) was prepared according to the following synthetic route: JPEG2026525258000065.jpg22128

[0147] Step 1: At 25°C, compound 2-chloroacetaldehyde (733.98 mg, 3.74 mmol) was added to a solution of compound Int11-1 (500 mg, 3.40 mmol) in EtOH (10 mL). The mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated to obtain the crude product. The crude product was ground using EA (5 mL) at 25°C for 30 minutes. Compound Int11-2 (560 mg, 96% yield) was obtained as a yellow solid. MS(ESI)m / z: 172.2[m+H]+.

[0148] Step 2: Raney nickel (41.90 mg, 0.71 mmol) was added to the flask under an Ar atmosphere. Then, MeOH (15 mL) was added to the flask under an Ar atmosphere. Compound Int11-2 (300 mg, 1.75 mmol) and a solution of ammonium hydroxide (3 mL) in MeOH (10 mL) were added to the flask under an Ar atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred overnight under H2 at 25°C. The reaction mixture was filtered. The filtrate was concentrated to obtain the yellow solid intermediate 11 (275 mg, yield 89.56%). MS(ESI) m / z: 176.2[m+H]+.

[0149] (3-Fluoro-4-(methylthio)pyridine-2-yl)methylamine (intermediate 12) was prepared according to the following synthetic route: JPEG2026525258000066.jpg59128

[0150] Step 1: Compound Int12-1 (400 mg, 2.12 mmol) and sodium methanethiolate (163 mg, 2.33 mmol) were added to DMF (5 mL) and reacted at 50°C for 2 hours. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with water (50 mL × 1) and saturated sodium chloride aqueous solution (50 mL × 1), respectively. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified by normal-phase column chromatography (petroleum ether / ethyl acetate = 0-100%) to obtain compound Int12-2 (250 mg, yield: 59%) as a white solid. MS (ESI) M / Z: 202.0 [M+H] + .

[0151] Step 2: Compound Int12-2 (250 mg, 1.2 mmol) was added to methanol (20 mL), sodium borohydride (900 mg, 2.4 mmol) was added at 0°C, and the mixture was reacted overnight at room temperature. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with water (50 mL x 1) and saturated sodium chloride aqueous solution (50 mL x 1), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product Int12-3 (200 mg), which was used directly in the next step. MS (ESI) M / Z: 174.0 [M+H] + .

[0152] Step 3: Crude product Int12-3 was added to dichloromethane (10 mL), thionyl chloride (280 mg, 2.4 mmol) was added dropwise, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain crude product Int12-4 (190 mg), which was used directly in the next step. MS (ESI) M / Z: 192.0 [M+H] + .

[0153] Step 4: Crude product Int12-4 was added to aqueous ammonia (20 mL) and reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain crude product 399-4 (150 mg), which was used directly in the next step. MS (ESI) M / Z: 173.0 [M+H] + .

[0154] (7-Fluoro-1-methyl-1H-pyrrolo[3,2-c]pyridine-6-yl)methylamine hydrochloride (intermediate 13) was prepared according to the following synthetic route: JPEG2026525258000067.jpg41128

[0155] Step 1: To a solution of compound Int13-1 (1.0 g, 6.82 mmol) in acetonitrile (8 mL), TsOH (65 mg, 0.34 mmol) and NIS (1.69 g, 7.5 mmol) were added, and the mixture was stirred overnight at 70°C. After monitoring for reaction completion by LC-MS, the reaction mixture was diluted with water (150 mL) and extracted with EA (150 mL x 3). The combined organic phase was concentrated, and the residue was purified by flash chromatography (PE:EA = 100:0 to 70:30) to obtain the target compound Int13-2 (1.68 g, yield 90.37%) as a pale yellow solid. MS (ESI) m / z: 273.0 [M+H] + .

[0156] Compound Int13-2 (1.38 g, 5.07 mmol) was dissolved in DCE (24 mL) and H2O (8 mL). Compound Int13-3 (2.01 g, 10.14 mmol) and Na2CO3 (1.61 g, 15.21 mmol) were added, and the mixture was purged with nitrogen for 5 minutes. Pd(PPh3)4 (590 mg, 0.51 mmol) was added, and the mixture was stirred overnight at 100°C. After monitoring for reaction completion by LC-MS, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The reaction mixture was poured into H2O (200 mL) and extracted with DCM (200 mL x 3). The residue was purified by flash chromatography (PE:EA = 100:0~83:17) to obtain the target compound Int13-4 (800 mg, yield 72.91%). MS (ESI) m / z: 217.0 [m+H]+.

[0157] Step 3: Hydrogen chloride (2.5 mL) was added to a solution of compound Int13-4 (800 mg, 3.69 mmol) in EtOH (15 mL), and the mixture was stirred at 80°C for 2 hours. After monitoring for reaction completion by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (80 mL), alkalized to pH=8-9 with saturated NaHCO3 solution, and extracted with DCM (200 mL * 3 mL). The combined organic phase was concentrated under reduced pressure to obtain the target compound Int13-5 (524 mg, 83.19% yield) as a white solid, which was used without further purification. MS(ESI)m / z: 171.0[m+H]+.

[0158] Step 4: The solution of compound Int13-5 (270 mg, 1.58 mmol) in DMF (9 mL) was cooled to 0°C, NaH (189 mg, 4.74 mmol) was added, and the solution was stirred at 0°C for 0.5 hours. After adding methane iodide (269 mg, 1.90 mmol), the mixture was allowed to return to room temperature and the solution was stirred for 1 hour. After monitoring for reaction completion by LC-MS, saturated ammonium chloride (15 mL) was added to quench the reaction mixture, which was then diluted with water (150 mL) and extracted with EA (150 mL x 3). The combined organic matter was concentrated. The residue was purified by flash chromatography (PE:EA = 100:0 to 80:20) to obtain the target compound Int13-6 (275 mg, yield 94.11%). MS (ESI) m / z: 185.0 [m+H]+.

[0159] Step 5: Compound Int13-7 (348 mg, 1.47 mmol) and K3PO4 (624 mg, 2.94 mmol) were added to a solution of compound Int13-6 (180 mg, 0.98 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL), and the mixture was purged with nitrogen for 5 minutes. CataCXium A Pd G3 (71 mg, 0.098 mmol) was added, and the mixture was stirred overnight at 100°C. After monitoring for reaction completion by LC-MS, the mixture was diluted with water (120 mL) and extracted with EA (120 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA = 100:0 to 50:50) to obtain the target compound Int13-8 (200 mg, yield 73.43%) as a white solid. MS(ESI)m / z:280.2[m+H]+.

[0160] Step 6: A solution of compound Int13-8 (200 mg, 0.72 mmol) in 4 M HCl / dioxane (10 mL) was stirred at room temperature for 2 hours. The reaction was monitored for completion by LC-MS, and the mixture was concentrated under reduced pressure to obtain the target compound intermediate 13 (154 mg HCl salt, 100% yield). MS(ESI)m / z:180.2[m+H]+.

[0161] (7-Fluoro-1H-pyrrolo[3,2-c]pyridine-6-yl)methylamine hydrochloride (intermediate 14) was prepared according to the following synthetic route: JPEG2026525258000068.jpg24128

[0162] Step 1: Compound Int13-5 (180 mg, 1.06 mmol) was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). Compound Int13-7 (377 mg, 1.59 mmol) and K3PO4 (675 mg, 3.18 mmol) were added, and the mixture was purged with nitrogen for 5 minutes. CataCXium A Pd G3 (62 mg, 0.085 mmol) was added, and the mixture was stirred overnight at 105°C. After monitoring for reaction completion by LC-MS, the mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA = 100:0:0:100) to obtain the target compound Int14-1 (172 mg, yield 61.44%) as a pale yellow solid. MS(ESI)m / z:266.2[m+H]+.

[0163] Step 2: A solution of compound Int14-1 (172 mg, 0.65 mmol) in 4 M HCl / dioxane (10 mL) was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS, and the mixture was concentrated under reduced pressure to obtain the target compound intermediate 14 (130 mg HCl salt, 100% yield). MS(ESI) m / z: 166.0[m+H]+.

[0164] (7-Fluoro-1-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-yl)methylamine hydrochloride (intermediate 15) was prepared according to the following synthetic route: JPEG2026525258000069.jpg21152

[0165] Step 1: Add DMS-BH3 (1.08 mL, 10.8 mmol, 10 M / L) to a solution of compound Int13-6 (200 mg, 1.08 mmol) in THF (5 mL), purge the mixture with nitrogen for 3 minutes, and stir overnight at 65°C. Cool the reaction mixture to room temperature, add MeOH (8 mL), stir at 60°C for 0.5 hours, and concentrate under reduced pressure. Then, dilute the residue with water (120 mL) and extract with EA (120 mL x 3). The combined organic matter was concentrated. The residue was purified by flash chromatography (PE:EA = 100:0:0:100) to obtain compound Int15-1 (71 mg, yield 35.12%). MS (ESI) m / z: 187.0 [m+H]+.

[0166] Step 2: Compound Int13-7 (180 mg, 0.76 mmol) and K3PO4 (242 mg, 1.14 mmol) were added to a solution of compound Int15-1 (71 mg, 0.38 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL), and the mixture was purged with nitrogen for 5 minutes. CataCXium A Pd G3 (27 mg, 0.038 mmol) was added, and the mixture was stirred overnight at 100°C. After monitoring for reaction completion by LC-MS, the mixture was diluted with water (120 mL) and extracted with EA (120 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA = 100:0:0:100) to obtain the target compound Int15-2 (60 mg, 56.05% yield) as a white solid. MS(ESI)m / z:282.2[m+H]+.

[0167] Step 3: A solution of compound Int15-2 (60 mg, 0.21 mmol) in 4.0 M HCl / dioxane (5 mL) was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS, and the mixture was concentrated under reduced pressure to obtain intermediate 15 (47 mg HCl salt, 100% yield). MS(ESI) m / z: 182.0[m+H]+.

[0168] (7-Fluoro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-yl)methylamine hydrochloride (intermediate 16) was prepared according to the following synthetic route: JPEG2026525258000070.jpg21150

[0169] Step 1: Add DMS-BH3 (3.52 mL, 35.2 mmol, 10 M / L) to a solution of compound Int13-5 (600 mg, 3.52 mmol) in THF (8 mL). Purge the mixture with nitrogen for 3 minutes and stir overnight at 65°C. Cool the reaction mixture to room temperature, add MeOH (10 mL), stir at 60°C for 0.5 hours, and concentrate under reduced pressure. The residue was then diluted with water (200 mL) and extracted with EA (300 mL x 3). The combined organic matter was concentrated. The residue was purified by flash chromatography (PE:EA = 100:0:0:100) to obtain the target compound Int16-1 (405 mg, yield 66.71%). MS (ESI) m / z: 173.0 [m+H]+.

[0170] Step 2: Compound Int13-7 (550 mg, 2.32 mmol) and K3PO4 (738 mg, 3.48 mmol) were added to a solution of compound Int16-1 (200 mg, 1.16 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL), and the mixture was purged with nitrogen for 5 minutes. CataCXium A Pd G3 (84 mg, 0.12 mmol) was added, and the mixture was stirred overnight at 100°C. After monitoring for reaction completion by LC-MS, the mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA = 100:0:0:100) to obtain the target compound Int16-2 (178 mg, yield 57.47%) as a white solid. MS(ESI)m / z:268.0[m+H]+.

[0171] Step 3: A solution of compound Int16-2 (178 mg, 0.67 mmol) in 4 M HCl / dioxane (8 mL) was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS, and the mixture was concentrated under reduced pressure to obtain the target compound intermediate 16 (136 mg, HCl salt, 100% yield). MS(ESI) m / z: 168.0[m+H]+.

[0172] 1-(4-(cyclopropylmethoxy)benzyl)-1H-pyrazole-4-carboxylic acid (intermediate 17) was prepared according to the following synthetic route: JPEG2026525258000071.jpg44145

[0173] Step 1: At room temperature, (bromomethyl)cyclopropane (500 mg, 3.75 mmol), K2CO3 (1.037 g, 7.51 mol), and Int17-1 (550 mg, 4.5 mmol) were added to acetone (5 mL), and the mixture was heated to 60°C and stirred for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and separated and purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound Int17-2 (440 mg, yield: 72.7%) as a white solid. MS (ESI) M / Z: 177.1[M+1]+.

[0174] Step 2: Under nitrogen protection, compound Int17-2 (480 mg, 2.47 mmol) was added to MeOH (3 mL), cooled to 0°C, replaced three times with N2, NaBH4 (309 mg, 7.41 mmol) was added, and the mixture was stirred at 0°C for 2 hours. 1 M / L NH4Cl aqueous solution (3 mL) was added, the mixture was filtered through Celite, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound Int17-3 (440 mg, crude product) as a yellow oily liquid. MS (ESI) M / Z: 179.1 [M+H] + .

[0175] Step 3: At room temperature, compound Int17-3 (440 mg, 2.47 mmol) was added to dichloromethane (3 mL), cooled to 0°C, and a solution of Int17-3 dissolved in PBr3 (1.34 g, 4.96 mmol) was added. The mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to alkaline with saturated sodium bicarbonate aqueous solution, extracted with DCM (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound Int17-4 (661 mg, crude) as a white solid. MS (ESI) M / Z: 241.1[M+1] + .

[0176] Step 4: At room temperature, Int17-4 (661 mg, 2.75 mmol) was added to DMF (5 mL), and K2CO3 (1.51 g, 11 mmol) and pyrrole-3-carboxylate methyl (381.15 mg, 3.025 mol) were added in small increments, and the mixture was stirred at room temperature for 12 hours. Water (30 mL) was added, and the mixture was extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated and purified by flash chromatography (PE:EA=3:1, Rf=0.4) to obtain compound Int17-5 (334 mg, yield: 42.4%) as a white solid. MS (ESI) M / Z: 287.1[M+1] + .

[0177] Step 5: At room temperature, compound Int17-5 (60 mg, 0.21 mmol) was added to MeOH (3 mL), dissolved in NaOH aqueous solution (1 M) (1 ml), and the mixture was stirred at room temperature for 12 hours. The pH of the reaction mixture was adjusted to acidity with 1 N hydrogen chloride aqueous solution, extracted with DCM (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 17 (60 mg) as a white solid. MS (ESI) M / Z: 273.3 [M+1] + .

[0178] (7-Fluoro-2,3-dihydrofluoro[3,2-c]pyridine-6-yl)methylamine hydrochloride (intermediate 18) was prepared according to the following synthetic route: JPEG2026525258000072.jpg53128

[0179] Step 1: NaH (1.96 g, 40.2 mol, 60% purity) was added in small increments to a solution of methyl glycolate (2.4 g, 40.2 mmol) in dimethoxyethane (50 mL) under ice bath. The reaction mixture was heated to room temperature and stirred for 30 minutes. Then, Int18-1 (9 g, 40.2 mmol) was dissolved in ethylene glycol dimethyl (10 mL) and added dropwise to the reaction mixture, and the mixture was reacted at 35°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and quenched with saturated sodium bicarbonate solution. The organic phase was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by flash chromatography (PE:EA = 5:1~1:2) to obtain the target compound Int18-2 (6.4 g, yield 65%) as a white solid. MS(ESI) m / z: 246.0[M+H]+.

[0180] Step 2: Ethyl Int18-2 (6.4 g, 26 mmol) was dissolved in a mixed solvent of tetrahydrofuran (60 mL) and water (16 mL), and lithium monohydrate (4.45 g, 106.8 mmol) was added. The mixture was heated to 40°C and reacted for 2 days. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with tetrahydrofuran. The filter cake was then dissolved in a mixed solvent of ethyl acetate and water, and the system was acidified to pH 6-7 with 1M hydrochloric acid in an ice bath. The mixture was separated, the aqueous phase was extracted with ethyl acetate, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated using a rotary evaporator to obtain compound Int18-3 (2.9 g, 15.6 mmol, 60%). MS m / z (ESI): 188.0 [M+H]+.

[0181] Step 3: Compound Int13-7 (2.45 g, 10.4 mmol) and K3PO4 (3.30 g, 15.6 mmol) were added to a solution of compound Int18-3 (0.96 g, 5.2 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL), and the mixture was purged with nitrogen for 5 minutes. CataCXium A Pd G3 (376 mg, 0.53 mmol) was added, and the mixture was stirred overnight at 100°C. After monitoring for reaction completion by LC-MS, the mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA = 5:1 to 1:2) to obtain the target compound Int18-4 (733 mg, 50% yield) as a white solid. MS (ESI) m / z: 283.1 [M + H]+.

[0182] Step 4: A solution of compound Int18-4 (733 mg, 2.6 mmol) in anhydrous ethanol (40 mL) was hydrogenated overnight under 3 atmospheres using 20% ​​palladium hydroxide (150 mg). The catalyst was filtered off using a Celite pad, and the filtrate was concentrated to obtain compound Int18-5 (629 mg, 90%), MS(ESI) m / z: 269.1[M+H]+.

[0183] Step 5: A solution of compound Int18-5 (629 mg, 2.34 mmol) in 4M HCl dioxane (8 mL) was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS, and the mixture was concentrated under reduced pressure to obtain the target compound intermediate 18 (440 mg, HCl salt, 92% yield). MS(ESI) m / z: 169.0[M+H]+.

[0184] Example 1. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (compound 1) was prepared according to the following synthetic route: JPEG2026525258000073.jpg50146

[0185] Step 1: NaN3 (175 mg, 2.70 mmol, 1.50 eq) was added to a solution of intermediate 2 (500 mg, 1.80 mmol, 1.00 eq) in DMF (5.00 mL). The mixture was stirred at 25°C for 1 hour. TLC (plate 1, petroleum ether:ethyl acetate = 1:1) showed that reactant 1 was completely consumed and a new spot had formed. The reaction mixture was partitioned between H2O (30.0 mL) and HCl (50.0 mL). The organic phase was separated, washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. A colorless oily compound 1-1 (350 mg, 1.46 mmol, 81.0% yield) was obtained. LCMS (ESI): m / z 241.

[0186] Step 2: The solutions of compound 1-1 (350 mg, 1.46 mmol, 1.00 eq), compound 1-2 (122 mg, 1.46 mmol, 121 μL, 1.00 eq), CuSO4 (72.7 mg, 291 μmol, 0.200 eq), and sodium ascorbate (288 mg, 1.46 mmol, 1.00 eq) in t-BuOH (20.0 mL) and H2O (5.00 mL) were degassed, purged three times with N2, and then the mixture was stirred at 25°C under an N2 atmosphere for 2 hours. TLC (Plate 1, dichloromethane:methanol = 10:1) showed consumption of the starting material and the expected new spots. The residue was diluted with H2O (30.0 mL) and extracted with SiO2 (50.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO₂, dichloromethane:MeOH = 10:1, dichloromethane:methanol = 10:1). Compounds 1-3 (100 mg, 308 μmol, 21.1% yield) were obtained as white solids. LC-MS (ESI): m / z 325; 1H NMR (400 MHz, DMSO-d6)δ 7.90 (s, 1H), 7.29-7.27 (m, 2H), 7.24 - 7.18 (m, 2H), 6.56 - 6.53 (d, J = 9.2 Hz, 1H), 6.13 - 6.09 (t, J = 6.8 Hz, 2H), 5.48 (s, 2H), 5.07 (s, 2H), 3.85 (s, 3H).

[0187] Step 3: At 0°C, NaOH (24.6 mg, 616 μmol, 2.00 eq) was added to a solution of compound 1-3 (100 mg, 308 μmol, 1.00 eq) in MeOH (1.00 mL) and H2O (0.500 mL). The mixture was stirred at 25°C for 1 hour. LC-MS confirmed the detection of the target mass. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was dissolved in water (5.00 mL) and acidified to pH=3 with 2 M HCl. The solid was collected by filtration to obtain the residue. Compound 1-4 (90.0 mg, 290 μmol, 94.0% yield) was obtained as a white solid. LC-MS (ESI): m / z 311.

[0188] Step 4: A mixture of compounds 1-4 (50.0 mg, 161 μmol, 1.00 eq), intermediate 1 (30.2 mg, 161 μmol, 1.00 eq, HCl), HATU (91.9 mg, 241 μmol, 1.50 eq), and TEA (48.9 mg, 483 μmol, 67.2 μL, 3.00 eq) in DMF (1.00 mL) was degassed, purged three times with N2, and then the mixture was stirred at 25°C under an N2 atmosphere for 2 hours. TLC (plate 1, dichloromethane:methanol = 10:1) showed that compounds 1-4 had been consumed and one new spot was detected. The residue was diluted with H2O (30.0 mL) and extracted with HCl (50 mL). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, dichloromethane:methane = 10:1, plate 1, dichloromethane:methanol = 10:1) to obtain title compound 1 (21.92 mg, 49.3 μmol, yield 30.6%, purity 98.6%) as a white solid. LC-MS (ESI): m / z 444; 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.31 - 7.27 (m, 2H), 7.20 (s, 2H), 6.91 (s, 1H), 6.58 - 6.56 (d, J = 9.2 Hz, 2H), 6.18 - 6.10 (m, 2H), 5.47 (s, 1H), 5.09(s, 1H), 4.49 - 4.48 (d, J = 4.8 Hz, 2H), 4.39 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H).

[0189] Example 2. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-3-(methoxymethyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (compound 2) was prepared according to the following synthetic route: JPEG2026525258000074.jpg62156

[0190] Step 1: Compound 2-1 (305 mg, 1.80 mmol, 1.00 eq) and K2CO3 (496 mg, 3.60 mmol, 2.00 eq) were added to a solution of intermediate 2 (500 mg, 1.80 mmol, 1.00 eq) in DMF (20.00 mL). The mixture was stirred at 60°C for 12 hours. TLC (Plate 1: DCM:MeOH = 10:1, Rf = 0.34) showed that compound 2-1 was completely consumed. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0-10 / 1, Plate 2: DCM:MeOH = 10:1, Rf = 0.34). A white solid compound 2-2 (300 mg, 816 μmol, 45.4% yield) was obtained, LC-MS (ESI): m / z 368 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.76-7.74 (d, J = 8 Hz, 1H), 7.73-7.72 (m, 1H), 7.42-7.40 (m, 4H), 6.40-6.38 (m, 1H), 6.23-6.20 (t, J = 12 Hz, 1H), 5.29 (s, 2H), 5.06 (s,2H), 4.48 (s, 2H), 3.71 (s, 3H), 3.22 (s, 3H).

[0191] Step 2: To a solution of compound 2-2 (300 mg, 816 μmol, 1.00 eq) in MeOH (2.00 mL) and H2O (2.00 mL), NaOH (163 mg, 4.08 mmol, 5.00 eq) was added. The mixture was stirred at 25°C for 1 hour. TLC (Plate 1:DCM:MeOH = 10:1, Rf = 0.15) showed that compound 2-2 was completely consumed. The mixture was concentrated under reduced pressure to remove MeOH, and then the pH was adjusted to 6-7 with 1 M HCl. The mixture was then concentrated under reduced pressure to obtain the crude product. Compound 2-3 (280 mg, crude product) was obtained as a white solid. LCMS (ESI): m / z 352[M-1]-;

[0192] Step 3: Intermediate 1 (26.6 mg, 141 μmol, 1.00 eq, HCl), HATU (80.7 mg, 212 μmol, 1.50 eq), and TEA (71.6 mg, 707 μmol, 98.5 μL, 5.00 eq) were added to a solution of compounds 2-3 (50.0 mg, 141 μmol, 1.00 eq) in DMF (2.00 mL). The mixture was stirred at 25°C under N2 for 2 hours. LC-MS confirmed the detection of the target mass. NaHCO3 (5.00 mL) was added to the mixture and stirred for 0.5 hours. The mixture was then diluted with 10.0 mL H2O and extracted with 30.0 mL DCM (10.0 mL x 3). The combined organic layer was washed with 20.0 mL (10.0 mL x 2) brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1, Rf = 0.38). Title compound 2 (60.0 mg, 121 μmol, 85.6% yield, 98.2% purity) was obtained as a white solid. LC-MS (ESI): m / z 487 [M+1]+; 1 H NMR δ (400 MHz, CD3OD -d4) δ 8.11 (s, 1H), 7.99-7.97 (m, 1H), 7.80-7.79 (m, 1H), 7.34-7.26 (m, 4H), 6.84-6.71 (m, 3H), 5.34-5.31 (m, 4H), 4.59 (s, 2H), 4.45 (s, 2H), 3.31-3.30 (m, 3H), 2.59 (s, 3H), 2.46 (s, 3H).

[0193] Example 3. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-5-((3-chloroquinoline-6-yl)methyl)thiophene-2-carboxamide (compound 3) was prepared according to the following synthetic route: JPEG2026525258000075.jpg48147

[0194] Step 1: Compound 3-1 (526 mg, 2.83 mmol, 1.20 eq), Na2CO3 (499.78 mg, 4.72 mmol, 2.00 eq), and Pd(dppf)Cl2 (172 mg, 236 μmol, 0.100 eq) were added to a solution of intermediate 4 (500 mg, 2.36 mmol, 1.00 eq) in DMF (25.0 mL). The mixture was then degassed, purged three times with N2, and heated to 60°C, stirred for 12 hours. LC-MS showed that intermediate 4 was consumed and the target MS was detected. The reaction mixture was diluted with H2O (25.0 mL), then extracted with RINKAN (20.0 mL x 2), washed with water (30.0 mL x 1) and brine (30.0 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 40 mm x 15 μm; mobile phase: [water (FA)-ACN]; gradient: 49%-79% B over 15 minutes) to obtain the target compound 3-2 (360 mg, 1.13 mmol, 48.0% yield) as a yellow solid. LC-MS (ESI): m / z 318 [M+1]+; 1 H NMR(400MHz, DMSO-d6)δ 8.85 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.86 (s, 1H), 7.77 - 7.62 (m, 2H), 7.07 (d, J = 3.6 Hz, 1H), 4.43 (s, 2H), 3.76 (s, 3H).

[0195] Step 2: At 0°C, a solution of compound 3-2 (460 mg, 1.45 mmol, 1.00 eq) in MeOH (2.00 mL) was added to a solution of NaOH (4 M, 724 μL, 2.00 eq) in H2O (2.00 mL), and the mixture was stirred at 50°C for 2 hours. LC-MS showed that compound 3-2 was consumed and the desired MS was detected. The reaction mixture was concentrated to obtain a residue, diluted with H2O (3.00 mL), and the pH was adjusted to 6 with 1 M HCl. The mixture was then lyophilized to obtain a white solid compound 3-3 (600 mg, crude product). LC-MS (ESI): m / z 304 [M+1]+; 1 H NMR(400MHz, DMSO-d6) δ 8.85 (d, J = 2.4 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.86 (s, 1H), 7.72 (dd, J 1 = 8.8 Hz, J2= 1.6 Hz, 1H), 7.49 (d, J = 3.6 Hz, 1H), 6.98 (d, J = 3.6 Hz, 1H), 4.39 (s, 2H).

[0196] Step 3: To a solution of compound 3-3 (90.0 mg, 296 μmol, 1.00 eq) in DMF (5.00 mL), HATU (338 mg, 889 μmol, 3.00 eq), DIEA (191 mg, 1.48 mmol, 258 μL, 5.00 eq), and intermediate 1 (66.7 mg, 356 μmol, 1.20 eq, HCl) were added, and the mixture was stirred at 25°C for 1 hour. Compound 3-3 was consumed by LC-MS, the reaction mixture was diluted with H2O (10.0 mL), then extracted with RINKAN (20.0 mL*3), the combined organic layers were washed with water (30.0 mL*1) and brine (30.0 mL*1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 28%-58% B over 10 minutes) to obtain the title compound 3 (30.0 mg, 67.4 μmol, 22.8% yield, 98.2% purity) as a yellow solid. LC-MS (ESI): m / z 437 [M+1]+; 1 H NMR(400MHz, DMSO-d6) δ8.80 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 4.8 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.38 (d, J = 2.8 Hz, 1H), 6.83 (d, J = 3.6 Hz, 1H), 6.31 (s, 1H), 4.51 (d, J = 4.8 Hz, 2H), 4.33 (s, 2H), 2.51 (s, 3H), 2.31 (s, 3H).

[0197] Example 4. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-4-(tetrahydrofuran-2-yl)-1H-pyrazole-3-carboxamide (compound 4) was prepared according to the following synthetic route: JPEG2026525258000076.jpg65154

[0198] Step 1: At 0°C, NaH (1.03 g, 25.8 mmol, 60.0% purity, 1.30 eq) was added to a solution of compound 4-1 (5.00 g, 19.8 mmol, 1.00 eq) in THF (40.0 mL). The mixture was stirred at 0°C for 0.5 hours. Then, SEMCl (3.97 g, 23.8 mmol, 4.21 mL, 1.20 eq) was added to the mixture at 0°C. The reaction mixture was stirred at 25°C for 1 hour. LC-MS showed that compound 4-1 was completely consumed and one major peak with the desired m / z was detected. The reaction mixture was quenched at 0°C with saturated aqueous NH4Cl (20.0 mL), then diluted with H2O (20.0 mL), and extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1~3:1, petroleum ether:ethyl acetate = 3:1). A yellow, oily compound 4-2 (6.00 g, 15.7 mmol, 79.1% yield) was obtained. LC-MS (ESI): m / z 383 [M+1]+; 1 H NMR(400MHz, DMSO-d6) δ 7.41 (s, 1H), 5.48 (s, 2H), 3.95 (s, 3H), 3.56 (t, J = 8.4 Hz, 1H), 0.90 (t, J = 8.4 Hz, 1H), -0.01 (s, 9H).

[0199] Step 2: A mixture of compound 4-2 (250 mg, 654 μmol, 1.00 eq), compound 4-3 (256 mg, 1.31 mmol, 2.00 eq), Ad2nBuP-Pd G3 (47.6 mg, 65.4 μmol, 0.100 eq), and K3PO4 (278 mg, 1.31 mmol, 2.00 eq) was placed in a microwave tube in 1,4-dioxane (2.00 mL) and H2O (0.400 mL). The sealed tube was heated under microwave at 110°C for 2 hours. LC-MS showed that compound 4-2 was completely consumed and one peak with the desired mass was detected. H2O (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80.0 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Moon C18 150*40mm*15um; mobile phase: [water (TFA)-ACN]; gradient: 35%-65% B over 15 minutes). The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, petroleum ether:ethyl acetate = 1:1). Compound 4-4 was obtained as a yellow oily liquid (75.0 mg, 8.55% yield). LC-MS (ESI): m / z 325 [M+1]+.

[0200] Step 3: Under an N2 atmosphere, compound 4-4 (75.0 mg, 231 μmol, 1.00 eq) was added to a solution of Pd / C (50.0 mg, 10.0% purity) in MeOH (2.00 mL). The suspension was degassed and purged three times with H2. The mixture was stirred under H2 (15 Psi) at 25°C for 12 hours. LC-MS showed that compound 4-4 was completely consumed and one main peak with the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. A colorless oily compound 4-5 (73.0 mg, 207 μmol, yield 89.5%, purity 92.5%) was obtained. LC-MS (ESI): m / z 327 [M+1]+.

[0201] Step 4: Compound 4-5 (73.0 mg, 224 μmol, 1.00 eq) was dissolved in 1,4-dioxane (0.500 mL) and HCl / 1,4-dioxane (4.00 M, 280 μL, 5.00 eq) was added. The mixture was stirred at 70°C for 12 hours. LC-MS showed that compound 4-5 was completely consumed and one main peak with the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (HCl conditions; column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water(HCl)-ACN]; gradient: 8%-38%B over 9 min). A yellowish oily compound 4-6 (11.0 mg, 56.1 μmol, yield 25.1%) was obtained. LCMS(ESI):m / z 394 [M+1]+;1HNMR (400MHz, CDCl3) δ 7.37 - 7.20 (m, 7H), 6.62 (d, J = 8.8 Hz, 1H), 6.17 (t, J = 6.4 Hz, 1H), 5.38 - 5.22 (m, 3H), 5.13 (s, 2H), 4.03 - 3.95 (m, 1H), 3.92 (s, 3H), 3.87 -3.77 (m, 1H), 2.58 - 2.36 (m, 1H), 2.07 - 1.85 (m, 2H), 1.68 - 1.62 (m, 1H).

[0202] Step 5: To a solution of compound 4-6 (10.0 mg, 25.4 μmol, 1.00 eq) in MeOH (0.500 mL), NaOH (2.03 mg, 50.8 μmol, 2.00 eq) and H2O (0.100 mL) were added. The mixture was stirred at 25°C for 3 hours. LC-MS showed that compound 4-6 was completely consumed and one main peak with the desired mass was detected. The pH of the reaction mixture was adjusted to 3 with 1.00 M HCl. The reaction mixture was then concentrated under reduced pressure to obtain the residue. Compound 4-7 (9.00 mg, 23.7 μmol, yield 93.3%) was obtained as a yellow solid. LC-MS (ESI): m / z 380 [M+1]+.

[0203] Step 6: HATU (13.5 mg, 35.6 μmol, 1.50 eq) and TEA (7.20 mg, 71.2 μmol, 9.91 μL, 3.00 eq) were added to a solution of compound 4-7 (9.00 mg, 23.7 μmol, 1.00 eq) and intermediate 1 (4.30 mg, 28.5 μmol, 1.20 eq) in DMF (1.00 mL). The mixture was stirred at 25°C for 1 hour. LC-MS showed that compound 4-7 was completely consumed and one main peak with the desired mass was detected. The reaction mixture was partitioned between ethyl acetate (80.0 mL) and H2O (80.0 mL). The organic phase was separated, washed with 60.0 mL (20.0 mL x 3) of NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters xbridge 150*25mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 18%-38% B over 8 minutes). Title compound 4 (2.13 mg, 4.13 μmol, 17.4% yield) was obtained as a yellow solid. LCMS(ESI):m / z 513 [M+1]+;1HNMR (400MHz, CDCl3) δ 7.39 - 7.29 (m, 3H), 7.26 - 7.23 (m, 2H), 7.19 - 7.12 (m, 2H), 6.88 (t, J = 4.8 Hz, 1H), 6.61 (d, J = 9.2 Hz, 1H), 6.30 (s, 1H), 6.17 (t, J = 6.4 Hz, 1H), 5.30 (t, J = 6.8 Hz, 1H), 5.21 - 5.10 (m, 6H), 4.50 (d, J = 4.8 Hz, 2H), 3.99 - 3.92 (m, 1H), 3.85 - 3.77 (m, 1H), 2.51 (s, 3H), 2.49 - 2.42 (m, 1H), 2.32 (s, 3H), 1.97 - 1.91 (m, 2H), 1.73 - 1.67 (m, 1H).

[0204] Example 5. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-1-((3-chloroquinoline-6-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (compound 5) was prepared according to the following synthetic route: JPEG2026525258000077.jpg48146

[0205] Step 1: Cs2CO3 (384 mg, 1.18 mmol, 1.00 eq) was added to a solution of intermediate 4 (250 mg, 1.18 mmol, 1.00 eq) and compound 2-1 (261 mg, 1.53 mmol, 1.30 eq) in DMF (5.00 mL), and the reaction mixture was stirred at 80°C for 2 hours. LC-MS showed that compound 4 was consumed and one peak with the desired mass was detected. The reaction mixture was filtered with MeOH (10.0 mL), and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, Rf = 0.30). Compound 5-1 (230 mg, 665 μmol, 56.4% yield) was obtained as a white solid. LCMS(ESI):m / z 346 [M+1]+;1HNMR (400MHz, CDCl3) δ 8.84 (d, J = 2.4 Hz, 1H), 8.12 - 8.07 (m, 2H), 7.89 (s, 1H), 7.62 - 7.55 (m, 2H), 5.49 (s, 2H), 4.76 (s, 2H), 3.81 (s, 3H), 3.49 (s, 3H).

[0206] Step 2: Compound 5-1 (230 mg, 665 μmol, 1.00 eq) was added to a solution of THF (2.00 mL) and meOH (2.00 mL) with NaOH (186 mg, 4.66 mmol, 7.00 eq) in H2O (1.00 mL). The mixture was stirred at 50°C for 3 hours. LC-MS showed that compound 5-1 was completely consumed and one main peak with the desired mass was detected. The reaction mixture was concentrated to remove the MeOH. The pH of the mixture was then adjusted to 7 with 1.00 M HCl, and the mixture was then concentrated under vacuum to obtain the residue. Compound 5-2 (220 mg, 663 μmol, 99.7% yield) was obtained as a white solid. LCMS(ESI):m / z 332 [M+1]+;1HNMR (400MHz, CDCl3) δ 8.86 (d, J = 2.4 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.81 (d, J = 1.2 Hz, 1H), 7.64 (dd, J1= 8.8 Hz, J2= 2.0 Hz, 1H), 5.48 (s, 2H), 4.61 (s, 2H), 3.21 (s, 3H).

[0207] Step 3: HATU (189 mg, 497 μmol) and TEA (101 mg, 995 μmol) were added to a solution of compound 5-2 (110 mg, 332 μmol, 1.00 eq) and intermediate 1 (60.2 mg, 398 μmol, 1.20 eq) in DMF (2.00 mL). The mixture was stirred at 25°C for 1 hour. LC-MS showed that compound 5-2 was consumed and one peak with the desired mass was detected. The reaction mixture was diluted with 50.0 mL of saturated NaHCO3 aqueous solution, extracted with ethyl acetate (50.0 mL x 3), and the combined organic phase was dried over Na2SO4 and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 25%-45% B over 8 minutes) to obtain title compound 5 (41.79 mg, 87.6 μmol, 26.4% yield, 97.5% purity) as a white solid. LCMS(ESI):m / z 465[M+1]+;1HNMR (400MHz, CDCl3) δ 8.88 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 7.65 (dd, J1= 8.8 Hz, J2= 1.8 Hz, 1H), 6.11 (s, 1H), 5.64 (s, 2H), 5.51 (s, 2H), 4.49 (s, 2H), 4.26 (d, J = 4.4 Hz, 2H), 3.13 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H).

[0208] Example 6. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (compound 6) was prepared according to the following synthetic route: JPEG2026525258000078.jpg50143

[0209] Step 1: Under nitrogen protection, a solution of intermediate 5 (1.68 g, 6.69 mmol) and NaN3 (0.76 g, 11.71 mmol) in DMF (20 mL) was stirred overnight at room temperature. The mixture was diluted with water (400 mL) and extracted with DCM (100 mL x 3). The organic layer was then filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution with siRNA) to obtain the target compound 6-1 (0.556 g, 38.97% yield) as a yellow solid. LC-MS (ESI): m / z 214.0[m+H]+.

[0210] Step 2: Sodium ascorbate (52 mg, 0.26 mmol) and CuSO4 (42 mg, 0.26 mmol) were added to tert-butanol (4 mL) and water (4 mL) solutions of 6-1 (0.556 g, 2.61 mmol) and 6-2 (0.24 g, 2.87 mmol). The mixture was stirred at room temperature for 3 hours, then diluted with water (200 mL) and extracted with DCM (50 mL * 3). The combined organic layers were concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (elution at DCM:MeOH = 10:1) to obtain the target compound 6-3 (0.65 g, yield 87.38%) as a yellow solid. LCMS (ESI): m / z: 298.0 [m+H]+.

[0211] Step 3: To a solution of compound 6-3 (0.1 g, 0.34 mmol) in MeOH (1.5 mL) and water (1.5 mL), NaOH (0.068 g, 1.7 mmol) was added. After stirring the mixture at room temperature for 1 hour, the reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The pH was adjusted to 4-5 with hydrochloric acid solution (1.0 M), and the mixture was concentrated under reduced pressure to obtain the desired yellow solid compound 6-4 (0.095 g, 99.70% yield). LCMS (ESI): 284.0 [M + H]+.

[0212] Step 4: Compounds 6-4 (0.095 g, 0.34 mmol), compound 2 (0.051 g, 0.34 mmol), DIEA (0.066 g, 0.51 mmol), and HATU (0.13 g, 0.34 mmol) were added to DMF (3 mL). The mixture was stirred overnight at room temperature and diluted with water (100 mL). The mixture was extracted with DCM (50 mL * 3). The combined organic layer was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (DCM: MeOH = 10:1) to obtain title compound 6 (5.69 mg, 4.07% yield) as a white solid. LCMS (ESI): 417.2 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 7.83 (s, 1H), 7.40 (d, J = 9.4 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.21 (s, 1H), 5.72 (s, 2H), 4.33 (d, J = 4.9 Hz, 2H), 3.30 - 3.27 (m, 2H), 2.34 (s, 3H), 2.21 (s, 3H), 1.97 - 1.88 (m, 1H), 0.92 (q, J = 6.0 Hz, 2H), 0.67 (d, J = 5.1 Hz, 2H).

[0213] Example 7. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-1-(2-cyano-4-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)benzyl)-1H-pyrazole-4-carboxamide (compound 7) was prepared according to the following synthetic route: JPEG2026525258000079.jpg26128 Intermediate 6 (0.040 g, 0.12 mmol) and Intermediate 1 (0.022 g, 0.14 mmol) were mixed in DMF (3 mL) to which DIEA (0.047 g, 0.36 mmol) and HATU (0.046 g, 0.12 mmol) were added. The mixture was stirred at room temperature for 2 hours, and the completion of the reaction was monitored by LC-MS. The reaction mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine and water and dried over anhydrous Na2SO4. The organic layers were then concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain the title compound 7 (37.41 mg, 67.44% yield) as a white solid. LC-MS (ESI) M / Z: 478.4[m+H]+; 1 H NMR (400 MHz, DMSO) δ 8.17 (s, 1H), 8.00 (s, 1H), 7.86 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.7, 2.7 Hz, 1H), 6.23 (d, J = 26.4 Hz, 3H), 5.33 (s, 2H), 4.25 (d, J = 4.8 Hz, 2H), 3.63 (d, J = 10.4 Hz, 2H), 3.56 (d, J = 8.4 Hz, 2H), 2.71 (d, J = 10.5 Hz, 2H), 2.34 (s, 3H), 2.21 (s, 3H).

[0214] Example 8. N-(4-carbamoylbenzyl)-1-(2-cyano-4-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)benzyl)-1H-pyrazole-4-carboxamide (compound 8) was prepared according to the following synthetic route: JPEG2026525258000080.jpg31131 Intermediate 6 (82 mg, 0.24 mmol) and intermediate 8-1 (80 mg, 0.36 mmol) were mixed in DMF (3 mL) to which DIEA (93 mg, 0.72 mmol) and HATU (91 mg, 0.24 mol) were added, and the mixture was stirred at room temperature for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic layer was washed with brine and water and dried over Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient elution, water / acetonitrile 100 / 0~50 / 50, HCl) to obtain the title compound 8 (27.61 mg HCl salt, 24.38% yield). LCMS(ESI)M / Z:476.2[M+H]+; 1 H NMR (400 MHz, DMSO) δ 9.33 (s, 2H), 9.12 (s, 2H), 8.84 (t, J = 5.9 Hz, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.7, 2.4 Hz, 1H), 5.37 (s, 2H), 4.47 (d, J = 5.6 Hz, 2H), 3.64 (d, J = 10.4 Hz, 2H), 3.57 (d, J = 9.2 Hz, 2H), 2.72 (d, J = 10.8 Hz, 2H).

[0215] Example 9. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-1-(3-chloroquinoline-6-yl)methyl-1H-1,2,3-triazole-4-carboxamide (compound 9) was prepared according to the following synthetic route: JPEG2026525258000081.jpg50151

[0216] Step 1: NaN3 (100 mg, 1.54 mmol, 1.09 eq) was added to a solution of intermediate 4 (300 mg, 1.41 mmol, 1.00 eq) in DMF (5.00 mL), and the mixture was stirred at 20°C for 12 hours. LC-MS showed that intermediate 4 was consumed and the desired mass was detected. The reaction mixture was diluted with NaHCO3 (saturated, 10.0 mL), then extracted with SiO3 (15.0 mL x 2), washed with water (20.0 mL x 1) and brine (30.0 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 9-1 (260 mg, 1.19 mmol, 84.1% yield) as a yellow solid. LC-MS (ESI): m / z 219 [M+1]+; 1 H NMR (400 MHz, CDCl3)δ 8.85 (d, J = 2.4 Hz, 1H), 8.26 - 8.02 (m, 2H), 7.83 - 7.59 (m, 2H), 4.57 (s, 2H).

[0217] Step 2: Compound 9-1 (270 mg, 1.23 mmol, 1.00 eq) and Compound 9-2 (103.82 mg, 1.23 mmol, 103 μL, 1.00 eq) were mixed in H2O (5.00 mL) and t-BuOH (5.00 mL). Sodium ascorbate (1 M, 1.23 mL, 1.00 eq) and CuSO4 (2 M, 123 μL, 0.20 eq) were added, and the reaction mixture was stirred at 20°C for 12 hours. LC-MS showed that Compound 9-1 was consumed and the desired mass was detected. The reaction mixture was filtered, and the mortar was concentrated to obtain the desired compound 9-3 (330 mg, 1.09 mmol, 88.3% yield) as a yellow solid. LC-MS (ESI): m / z 303 [M+1]+; 1H NMR (400 MHz, DMSO-d6)δ 8.97 (s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.76 (dd, J1= 8.8 Hz, J2= 1.6 Hz, 1H), 5.90 (s, 2H), 3.83 (s, 3H).

[0218] Step 3: To a solution of compound 9-3 (300 mg, 991 μmol, 1.00 eq) in MeOH (5.00 mL), a solution of NaOH (79.3 mg, 1.98 mmol, 2.00 eq) in H2O (5 mL) was added at 0°C, and the mixture was stirred at 50°C for 1 hour. LC-MS showed that compound 9-3 had been consumed and the desired MS was detected. The reaction mixture was concentrated to remove the MeOH, then the pH was adjusted to 6 with 1 M HCl, and the mixture was concentrated to obtain the target compound 9-4 (400 mg, crude product) as a yellow solid. LC-MS (ESI): m / z 289 [M+1]+; 1 H NMR (400 MHz, DMSO-d6)δ 9.10 - 8.76 (m, 2H), 8.64 - 8.53 (m, 1H), 8.12 - 7.73 (m, 3H), 6.25 - 5.66 (m, 2H).

[0219] Step 4: A mixture of compound 9-4 (100 mg, 346 μmol, 1.00 eq) and compound intermediate 1 (78.0 mg, 416 μmol, 1.20 eq, HCl) in DMF (8 mL) was mixed with HATU (395 mg, 1.04 mmol, 3.00 eq) and DIEA (224 mg, 1.73 mmol, 302 μL, 5.00 eq), and the mixture was then stirred at 20°C for 1 hour. LC-MS showed that compound 9-4 was consumed and the desired mass was detected. The reaction mixture was diluted with H2O (5.0 mL), then extracted with SiO (10.0 mL x 2), the combined organic layer was washed with water (20.0 mL x 2) and brine (30.0 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; gradient: 15%-45% B over 10 minutes) to obtain the title compound 9 (0.0250 g, 58.9 μmol, 17.0% yield, 99.4% purity) as a yellow solid. LC-MS (ESI): m / z 422 [M+1]+; 1 H NMR(400 MHz, CDCl3)δ 8.87 (d, J = 2.0 Hz, 1H), 8.22 - 8.10 (m, 2H), 8.06 (s, 1H), 7.69 - 7.62 (m, 1H), 7.59 (dd, J = 2.0, 8.8 Hz, 1H), 7.09 - 6.98 (m, 1H), 6.30 (s, 1H), 5.76 (s, 2H), 4.55 (d, J = 5.2 Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H).

[0220] Example 10. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-1-((3-chloroquinoline-6-yl)methyl)-1H-pyrazole-4-carboxamide (compound 10) was prepared according to the following synthetic route: JPEG2026525258000082.jpg56153

[0221] Step 1: Add intermediate 4 (200 mg, 0.94 mmol) and a solution of methyl 1H-pyrazole-4-carboxylate (143 mg, 1.12 mmol) and K2CO3 (300 mg, 2.16 mmol) to DMF (3 mL) and stir the mixture at room temperature for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with H2O (30 mL), extracted with siRNA (50 mL * 3), and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (siRNA) to obtain compound 10-1 (180 mg, 63% yield) as a white solid. LC-MS (ESI): m / z 302 [M + H] + .

[0222] Step 2: To a solution of compound 10-1 (180 mg, 0.60 mmol) in MeOH (4 mL) and H2O (1 mL), NaOH (96 mg, 2.39 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. After monitoring for completion of the reaction by LC-MS, the pH of the reaction mixture was adjusted to 4-5 with 1.0 M hydrochloric acid solution. The reaction mixture was diluted with H2O (20 mL), extracted with DCM: MeOH = 10.1 (20 mL * 3), and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 10-2 (146 mg, 85% yield) as a white solid. LC-MS (ESI): m / z 288 [M + H]+.

[0223] Step 3: To a mixture of compound 10-2 (120 mg, 416 μmol, 1.00 eq) and compound intermediate 1 (93 mg, 500 μmol, 1.20 eq, HCl) in DMF (10 mL), HATU (474 ​​mg, 1.2 mmol, 3.00 eq) and DIEA (269 mg, 2.07 mmol, 363 μL, 5.00 eq) were added, and the mixture was stirred at 20°C for 1 hour. LC-MS showed that compound 10-2 was consumed and the desired mass was detected. The reaction mixture was diluted with H2O (5.0 mL), then extracted with siRNA (10.0 mL x 2), washed with water (20.0 mL x 2) and brine (30.0 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by Prep-HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water (NH4HCO3)-MeCN]; gradient: 15%-45% B over 10 minutes) to obtain title compound 10 (30 mg, 20% yield) as a yellow solid. LC-MS (ESI): m / z 421 [M+1]+; 1 H NMR(400 MHz, CDCl3)δ 8.88 (d, J = 2.0 Hz, 1H), 8.24 - 8.12 (m, 2H), 8.08 (s, 1H), 7.94 (s, 1H), 7.68 - 7.63 (m, 1H), 7.59 (dd, J = 2.0, 8.8 Hz, 1H), 7.09 - 6.98 (m, 1H), 6.32 (s, 1H), 5.76 (s, 2H), 4.56 (d, J = 5.2 Hz, 2H), 2.55 (s, 3H), 2.31 (s, 3H).

[0224] Example 11. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-1,2,4-triazole-3-carboxamide (compound 11) was prepared according to the following synthetic route: JPEG2026525258000083.jpg46145

[0225] Step 1: K2CO3 (521 mg, 3.77 mmol, 2.00 eq) and compound 11-1 (240 mg, 1.89% mmol, 1.00 eq) were added to a solution of intermediate 2 (400 mg, 1.89 mmol, 1.00 eq) in DMF (10.0 mL). The mixture was stirred at 50°C for 12 hours. LC-MS showed that compound 11-1 was consumed and the desired MS was detected. The reaction mixture was diluted with H2O (10.0 mL), then extracted with SiO2 (20.0 mL*2), washed with water (30.0 mL*1) and brine (30.0 mL*1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 0:1, Rf1 = 0.14, Rf2 = 0.48) to obtain compound 11-2 (120 mg, 21.0% yield) as a white solid. LC-MS (ESI): m / z 325[M+1]+.

[0226] Step 2: NaOH (4 M, 165 μL, 2.00 eq) was added to a solution of compound 11-2 (100 mg, 330 μmol, 1.00 eq) in MeOH (3.00 mL). The mixture was stirred at 20°C for 2 hours. LC-MS showed that compound 11-2 was consumed and the desired MS was detected. The reaction mixture was diluted with THF (10.0 mL) and then concentrated under reduced pressure to obtain compound 11-3 (120 mg, crude product) as a white solid. LC-MS (ESI): m / z 309[M-1]-.

[0227] Step 3: Intermediate 1 (26.2 mg, 173 μmol, 1.20 eq), HATU (82.3 mg, 217 μmol, 1.50 eq), and TEA (43.8 mg, 433 μmol, 60.3 μL, 3.00 eq) were added to a solution of compound 11-3 (48.0 mg, 144 μmol, 1.00 eq) in DMF (3.00 mL). The mixture was stirred at 25°C for 2 hours. TLC (DCM:MeOH = 10:1) showed that compound 11-3 was completely consumed. The reaction mixture was partitioned between DCM (40.0 mL) and H2O (40.0 mg). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue (plate 2, DCM:MeOH=10:1) was purified by preparative TLC (SiO2, DCM:MeOH=10:1) to obtain the title compound 11 (21.7 mg, 48.7 μmol, 33.8% yield, 99.6% purity) as a white solid. LCMS(ESI): m / z 444 [M+1]+; 1 H NMR δ 7.98 (s, 1H), 7.36 - 7.32 (m, 2H), 7.30 - 7.28 (m, 3H), 7.26 - 7.25 (m, 1H), 6.93 (s, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.25 (s, 1H), 6.19 - 6.16 (m, 1H), 5.36 (s, 2H), 5.14 (s, 2H), 4.58 - 4.57 (m, 4H), 2.47 (s, 3H), 2.29 (s, 3H).

[0228] Example 12. N-(4-carbamoylbenzyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (compound 12) was prepared according to the following synthetic route: JPEG2026525258000084.jpg52145

[0229] Step 1: Add intermediate 2 (200 mg, 0.72 mmol) and a solution of 1H-pyrazole-4-carboxylate methyl (110 mg, 0.86 mmol) to DMF (3 mL), add K2CO3 (300 mg, 2.16 mmol), and stir the mixture at room temperature for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with H2O (30 mL), extracted with siRNA (50 mL * 3), and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (siRNA) to obtain compound 12-1 (120 mg, 51.7% yield) as a white solid. LC-MS (ESI): m / z 324.2 [M + H]+.

[0230] Step 2: To a solution of compound 12-1 (120 mg, 0.37 mmol) in MeOH (4 mL) and H2O (1 mL), NaOH (89 mg, 2.22 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. After monitoring for completion of the reaction by LC-MS, the pH of the reaction mixture was adjusted to 4-5 with 1.0 M hydrochloric acid solution. The reaction mixture was diluted with H2O (20 mL), extracted with DCM: MeOH = 10.1 (20 mL * 3), and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 12-2 (100 mg, 87.7% yield) as a white solid. LC-MS (ESI): m / z 310.1 [M + H]+.

[0231] Step 3: Add a mixture of compound 12-2 (100 mg, 0.32 mmol) and compound 8-1 (48 mg, 0.32 mmol), HATU (120 mg, 0.32 mmol), and TEA (160 mg, 1.60 mmol) to DMF (3 mL) and stir at room temperature for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with H2O (20 mL), extracted with DCM:MeOH = 10:1 (20 mL * 3), and dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. Purification by Prep-TLC (DCM:MeOH = 7:1) yielded title compound 12 as a white solid (20.06 mg, 14.1% yield). LC-MS (ESI): m / z 441.2 [M + H] + ; 1 H NMR (400 MHz, DMSO) δ 9.32 (s, 2H), 9.11- 9.01 (m, 2H), 8.83 (m, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.78 - 7.77 (m, 3H), 7.51-7.49 (m, 2H), 7.44 - 7.40 (m, 1H), 7.26 - 7.23 (m, 4H), 6.42-6.39 (m, 1H), 6.23 - 6.22 (m, 1H), 5.32 (s, 2H), 5.08 (s, 2H), 4.54 - 4.47 (m, 2H).

[0232] Example 13. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-4-(4-((2-oxopyridine-1(2H)-yl)methylbenzyl)picolinamide (compound 13) was prepared according to the following synthetic route: JPEG2026525258000085.jpg53150

[0233] Step 1: Intermediate 2 (200 mg, 719 μmol, 1.00 eq), compound 13-1 (227 mg, 862 μmol, 1.20 eq), Pd(t-Bu3P)2 (36.8 mg, 71.9 μmol, 0.10 eq), and DIEA (371 mg, 2.88 mmol, 500 μL, 4.00 eq) were placed in 1,4-dioxane (2 mL) and H2O (0.4 mL) and placed in a microwave tube. The sealed tube was heated under microwave at 110°C for 1 hour. LC-MS showed that the desired mass of product was detected. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane and H2O. Crude product 13-2 (70 mg) was purified by preparative TLC. LC-MS (ESI): m / z 335 [M+1]+.

[0234] Step 2: Compound 13-2 (70.0 mg, 209 μmol, 1.00 eq) was dissolved in MeOH (1.00 mL) and H2O (1.00 mL) and NaOH (41.9 mg, 1.05 mmol, 5.00 eq) was added. The mixture was stirred at 25°C for 2 hours. LC-MS showed that the desired mass was detected. The mixture was concentrated under reduced pressure to remove the MeOH, and then the pH was adjusted to 6-7 with 1 M HCl. The mixture was then concentrated under reduced pressure to obtain the crude product. Compound 13-3 (60.0 mg, 187 μmol, 89.5% yield) was obtained as a white solid. LC-MS (ESI): m / z 321 [M+1]+.

[0235] Step 3: Intermediate 2 (35.2 mg, 187 μmol, 1.00 eq, HCl), HATU (106 mg, 280 μmol, 1.50 eq), and TEA (94.7 mg, 936 μmol, 130 μL, 5.00 eq) were added to a solution of compound 13-3 (60.0 mg, 187 μmol, 1.00 eq) in DMF (2.00 mL). The mixture was stirred at 25°C under an N2 atmosphere for 12 hours. LC-MS showed that the desired mass was detected. NaHCO3 (5.00 mL) was added to the mixture and stirred for 0.5 hours. It was then diluted with 10.0 mL H2O and extracted with 30.0 mL DCM (10.0 mL x 3). The combined organic layer was washed with 20.0 mL (10.0 mL x 2) brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The title compound 13 (21.0 mg, 44.5 μmol, 23.7% yield, 96.0% purity) was obtained as a white solid by preparative HPLC (column: Waters xbridge 150*25 mm*10 μm; mobile phase: [water (NH4HCO3)-MeCN]; gradient: 20%-50% B over 10 minutes). LC-MS (ESI): m / z 454 [M+1]+; 1 H NMR δ (400 MHz, CDCl3) δ 8.36-8.35 (d, J = 4.8 Hz, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.32-7.27 (m, 1H), 7.26-7.25 (m, 2H), 7.23-7.14 (m, 3H), 6.62-6.60 (d, J = 8 Hz, 1H), 6.22 (s, 1H), 6.17-6.14 (m, 1H), 5.11 (s, 2H), 4.56-4.55 (d, J = 5.2 Hz, 2H), 4.37 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H).

[0236] Example 14. 1-(4-((1H-pyrazole-1-yl)methyl)benzyl)-N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (Compound 14) Compound 14 was prepared according to the following synthetic route: JPEG2026525258000086.jpg55153

[0237] Step 1: At 0°C, a solution of pyrrole (0.25 g, 3.67 mmol, 1.00 eq) in THF (10.0 mL) was mixed with NaH (293 mg, 7.34 mmol, 60.0% purity, 2.00 eq) and 1,4-bis(bromomethyl)benzene (1.00 g, 3.79 mmol, 1.03 eq). The reaction mixture was stirred at 25°C for 2 hours. TLC (petroleum ether:ethyl acetate = 3:1) indicated that the pyrrole had been consumed. The residue was diluted with H2O (30.0 mL) and extracted with SiO2 (50.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue (Plate 1, petroleum ether:ethyl acetate = 3:1) was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 20:1-3:1). Compound 14-1 (300 mg, 1.19 mmol, 32.5% yield) was obtained as a white solid. LC-MS (ESI): m / z 251[M+1]+.

[0238] Step 2: To a solution of compound 14-1 (200 mg, 796 μmol, 1.00 eq) in DMF (4.00 mL), K2CO3 (220 mg, 1.59 mmol, 2.00 eq) and compound 2-1 (136 mg, 796 μmol, 1.00 eq) were added. The mixture was stirred at 25°C for 2 hours. TLC (plate 1, dichloromethane:methanol = 10:1) showed that reactant 1 was completely consumed and two new spots were formed. The residue was diluted with H2O (30.0 mL) and extracted with siRNA (50.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue (dichloromethane:methanol = 10:1) was purified by preparative TLC (SiO2, dichloromethane:methane = 10:1). A white solid compound 14-2 (90.0 mg, 264 μmol, 33.2% yield) was obtained. LC-MS (ESI): m / z 341 [M+1]+; 1H NMR (400 MHz, DMSO-d6)δ 8.41 (s, 1H), 7.80 (s,1H), 7.44 (s,1H), 7.25 - 7.22 (m, 2H), 7.19 - 7.17 (m, 2H), 6.25 (s,1H), 5.33 - 5.30 (m, 4H), 4.49 (s, 2H), 3.72 (s, 3H), 3.34 (s, 1H).

[0239] Step 3: At 0°C, NaOH (23.5 mg, 588 μmol, 4.00 eq) was added to a solution of compound 14-2 (50.0 mg, 147 μmol, 1.00 eq) in MeOH (1.00 mL) and H2O (0.20 mL). The mixture was stirred at 25°C for 4 hours. LC-MS showed that the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was diluted with water (10.0 mL), pH adjusted to 3 with HCl (1.00 M), and then concentrated under reduced pressure to obtain the residue. Compound 14-3 (45.0 mg, 138 μmol, 93.9% yield) was obtained as a white solid. LC-MS (ESI): m / z 327 [M+1]+.

[0240] Step 4: Intermediate 1 (25.0 mg, 165 μmol, 1.20 eq), TEA (41.9 mg, 414 μmol, 57.6 μL, 3.00 eq), and HATU (78.6 mg, 207 μmol, 1.50 eq) were added to a solution of compound 14-3 (45.0 mg, 138 μmol, 1.00 eq) in DMF (2.00 mL). The mixture was stirred at 25°C for 2 hours. LC-MS showed that the desired mass was detected. The reaction mixture was partitioned between HCl (20.0 mL) and H2O (20.0 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH4HCO3)-ACN]; gradient: minimum 16%-46% B). The title compound 14 (23.29 mg, 50.03 μmol, yield 36.28%, purity 98.71%) was obtained as a white solid. LC-MS (ESI): m / z 460 [M+1]+;1 H NMR (400 MHz, CDCl3)δ 7.90 (s, 1H), 7.88 (s, 1H), 7.55 - 5.54 (m, 1H), 7.39 - 7.38 (m, 1H), 7.21 - 7.17 (m, 4H), 6.29 - 6.25 (m, 2H), 5.32 (s, 2H), 5.21 (s, 2H), 4.53 - 4.45 (m, 6H), 3.13 (s, 3H), 2.48 (s, 3H), 2.30 (s, 3H). Using appropriate raw materials, the compounds shown in the table below were prepared using the same procedures as described above in Examples 2, 3, 5, and 6.

[0241] [Table 1] JPEG2026525258000088.jpg234147 JPEG2026525258000089.jpg229147 JPEG2026525258000090.jpg239147JPEG2026525258000091.jpg234147 JPEG2026525258000092.jpg132147

[0242] Example 15. N-(4-carbamoylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridine-2-yl)methyl)-1H-pyrazole-4-carboxamide (compound 15) was prepared according to the following synthetic route: JPEG2026525258000093.jpg61148

[0243] Step 1: To a solution of intermediate 5 (0.2 g, 0.8 mmol) in DMF (3 mL), methyl 1H-pyrazole-4-carboxylate (0.12 g, 0.96 mmol) and K2CO3 (0.33 g, 2.4 mmol) were added, and the mixture was stirred overnight at room temperature. After monitoring for completion of the reaction by LC-MS, the mixture was diluted with water (100 mL) and extracted with DCM (100 mL * 3). The combined organic layer was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel (siRNA) chromatography to obtain the target compound 15-1 (0.123 g, 52.12% yield) as a yellow solid. LC-MS (ESI): m / z 297.6 [M + H]+.

[0244] Step 2: Compound 15-1 (0.123 g, 0.42 mmol) was added to MeOH (3 mL) and water (1.5 mL) with NaOH (0.17 g, 4.2 mmol) and stirred at room temperature for 1 hour. After monitoring for completion of the reaction by LC-MS, the pH of the reaction mixture was adjusted to 4-5 with 1.0 M hydrochloric acid solution. The mixture was extracted with DCM (100 mL * 3). The combined organic layer was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the desired yellow solid compound 15-2 (0.1 g, 85.34% yield). LC-MS (ESI): m / z 283.5 [M + H]+.

[0245] Step 3: Compound 8-1 (0.052 g, 0.35 mmol), DIEA (0.068 g, 0.52 mmol), and HATU (0.13 g, 0.35 mmol) were added to compound 15-2 (0.1 g, 0.35 mmol) in DMF (3 mL) and stirred at room temperature for 2 hours. After monitoring for completion of the reaction by LC-MS, the reaction mixture was diluted with water (100 mL) and extracted with DCM (50 mL * 3). The combined organic layer was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluted at DCM:MeOH = 10:1) to obtain title compound 15 (28.69 mg, 19.59% yield) as a white solid. LC-MS (ESI): m / z 414.1 [M + H] +; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 129.3 Hz, 3H), 8.77 (s, 1H), 8.35 (s, 1H), 8.23 ​​(s, 1H), 7.89 (s, 1H), 7.80 - 7.69 (m, 3H), 7.49 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 9.1 Hz, 1H), 7.02 (d, J = 9.1 Hz, 1H), 5.42 (s, 2H), 4.47 (d, J = 5.6 Hz, 2H), 1.93 (s, 1H), 0.92 (d, J = 6.9 Hz, 2H), 0.67 (d, J (= 4.6 Hz, 2H).

[0246] Example 16. N-(4-carbamoylbenzyl)-1-(4-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)-2-ethylbenzyl)-1H-pyrazole-4-carboxamide (compound 16) was prepared according to the following synthetic route: JPEG2026525258000094.jpg64146

[0247] Step 1: To a solution of compound 16-1 (160 mg, 0.39 mmol) in dioxane (10 mL), potassium trifluorovinylborate (79 mg, 0.58 mmol), Na2CO3 (124 mg, 1.17 mmol), H2O (2 mL), and Pd(dppf)Cl2 (29 mg, 0.039 mmol) were added. The reaction mixture was purged with nitrogen for 5 minutes. The mixture was stirred at 100°C for 2 hours. After monitoring for completion of the reaction by LC-MS, the mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (elution at PE:EA = 3:1) to obtain the target compound 16-2 (106 mg, yield 75.99%) as a colorless oily liquid. MS (ESI) M / Z: 360.2 [M+H] + .

[0248] Step 2: Pd / C (31 mg, 0.29 mmol) was added to a solution of compound 16-2 (106 mg, 0.29 mmol) in MeOH (10 mL). The reaction mixture was purged with H2 for 5 minutes and carried out under H2 protection. The mixture was stirred at room temperature for 2 hours. After monitoring for completion of the reaction by LC-MS, the mixture was filtered and the filtrate was concentrated under reduced pressure. From the residue, the target compound 16-3 (100 mg, 93.81% yield) was obtained as a colorless oily liquid. MS (ESI) M / Z: 384.2 [M+Na] + .

[0249] Step 3: The mixture of compound 16-3 (100 mg, 0.28 mmol) in MeOH (2 mL) was treated with 2 M aqueous sodium hydroxide solution (1 mL), and the reaction mixture was stirred at room temperature for 16 hours. After monitoring for completion of the reaction by LC-MS, the reaction mixture was acidified to pH = 5–6 with 1 M HCl. The reaction product was concentrated under reduced pressure to obtain the target compound 16-4 (96 mg, 100% yield) as a white solid. MS (ESI) M / Z: 348.0 [M+H] + .

[0250] Step 4: To a solution of compound 16-4 (70 mg, 0.2 mmol) in DMF (2 mL), DIEA (78 mg, 0.6 mmol) and HATU (92 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Then, 8-1 (45 mg, 0.3 mmol) was added to the reaction. The mixture was stirred at room temperature for 1 hour. After monitoring for completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain compound 16 (5.54 mg, 5.74% yield) as a white solid. MS (ESI) M / Z: 479.1 [M+H] + ;HPLC: 254 nm: 98.558%,214 nm:98.700%; 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 2H), 8.98 (s, 2H), 8.74 (t, J = 6.0 Hz, 1H), 8.37 (s, 1H), 8.00 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.9 Hz, 1H), 6.38 (d, J = 6.9 Hz, 2H), 5.22 (s, 2H), 4.45 (d, J = 5.9 Hz, 2H), 3.58 (s, 2H), 3.50 (s, 2H), 2.67 (d, J = 10.7 Hz, 2H), 2.60 - 2.52 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H).

[0251] Example 17. (R) -N-(1-ethyl-1,4,5,6-tetrahydrocyclopenta[d]imidazole-4-yl)-3-(methoxymethyl)-1-(4-(2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (compound 130) and (S) -N-(1-ethyl-1,4,5,6-tetrahydrocyclopenta[d]imidazole-4-yl)-3-(methoxymethyl)-1-(4-(2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (compound 131) were prepared according to the following synthetic route: JPEG2026525258000095.jpg34145

[0252] To a solution of SM 5 (45 mg, 0.13 mmol) in DMF (3 mL), HATU (54 mg, 0.14 mmol) and DIEA (51 mg, 0.39 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Compound 8 (39 mg, 0.26 mmol) was then added to the reaction product. The mixture was stirred at room temperature for 1 hour. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic matter was concentrated. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to obtain the target compound as a white solid (32 mg, yield 51.64%). The 32 mg of compound was then separated by SFC (AD chiral column) to obtain the title compound 130 as a white solid (retention time 3.92 min, 9.21 mg), MS (ESI) m / z: 487.3 [M+H]. + ;HPLC: 254 nm: 998.453%, 214 nm: 98.272%; 1 H NMR (400 MHz, DMSO) δ 8.23 ​​(s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.75 (dd, J = 6.7, 1.6 Hz, 1H), 7.50 (s, 1H), 7.40 (ddd, J = 8.9, 6.6, 2.0 Hz, 1H), 7.23 (q, J = 8.1 Hz, 4H), 6.39 (d, J = 9.0 Hz, 1H), 6.22 (t, J = 6.7 Hz, 1H), 5.25 (s, 2H), 5.07 (d, J = 7.4 Hz, 3H), 4.48 (s, 2H), 3.90 (q, J = 7.2 Hz, 2H), 3.15 (s, 3H), 2.85 (dt, J = 16.8, 6.4 Hz, 1H), 2.80 - 2.70 (m, 1H), 2.63 - 2.56 (m, 1H), 2.17 - 2.05 (m, 1H), 1.30 (t, J = 7.3 Hz, 3H) and title compound 131 (retention time 5.04 min, 9.46 mg), MS (ESI) m / z: 487.3 [M+H] + HPLC: 254 nm: 97.604%, 214 nm: 97.761% were obtained. 1H NMR (400 MHz, DMSO) δ 8.23 ​​(s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.75 (dd, J = 6.8, 1.8 Hz, 1H), 7.50 (s, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.0 Hz, 1H), 7.24 (q, J = 8.2 Hz, 4H), 6.39 (d, J = 9.2 Hz, 1H), 6.22 (td, J = 6.7, 1.3 Hz, 1H), 5.25 (s, 2H), 5.07 (d, J = 6.5 Hz, 3H), 4.48 (s, 2H), 3.90 (q, J = 7.1 Hz, 2H), 3.15 (s, 3H), 2.91 - 2.81 (m, 1H), 2.78 - 2.70 (m, 1H), 2.63 - 2.56 (m, 1H), 2.12 (ddd, J = 12.8, 8.4, 4.0 Hz, 1H), 1.30 (t, J = 7.3 Hz, 3H).

[0253] Using appropriate raw materials, the compounds shown in the table below were prepared using the same procedure as described above in Examples 2, 15, 16, and 17.

[0254] [Table 2] JPEG2026525258000097.jpg50147

[0255] Example 18. N-((6,8-dimethylimidazo[1,5-a]pyridine-7-yl)methyl)-3-(methoxymethyl)-1-(4-(2-oxopyridine-1(2H)-yl)benzyl)-1H-pyrazole-4-carboxamide (compound 147) was prepared according to the following synthetic route: JPEG2026525258000098.jpg30128

[0256] A mixture of compound 9 (30 mg, 84.90 μmol, 1 eq), compound 8 (20.0 mg, 114 μmol, 1.34 eq), and EDCI (48.8 mg, 255 μmol, 3.00 eq) in Py (1.00 mL) was stirred at 20°C for 2 hours. LC-MS (EW47914-151-P1A1) showed that the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1). Compound 147 (7.39 mg, 13.6 μmol, 16.0% yield, 94.4% purity) was obtained as a pale yellow solid and confirmed by proton nuclear magnetic resonance spectroscopy (EW47914-151-P1A), liquid chromatography-mass spectrometry (EW47914-51-P1B), and high-performance liquid chromatography (EW4791451-P1J). MS (ESI) m / z: 511 [M+H] + ; 1 H NMR: EW47914-151-P1A (400 MHz, CDC13) δ 8.07 (s, 1H), 7.96 - 7.87 (m, 2H), 7.69 (s, 1H), 7.41 (s, 1H), 7.35 - 7.29 (m, 2H), 7.28 - 7.28 (m, 1H), 7.25 (dd, J1= 1.8, J2= 6.8 Hz, 1H), 7.22 - 7.18 (m, 2H), 6.61 (d, J = 9.2 Hz, 1H), 6.18 - 6.14 (m, 1H), 5.21 (s, 2H), 5.13 (s, 2H), 4.52 (d, J = 4.8 Hz, 2H), 4.47 (s, 2H), 3.11 (s, 3H), 2.50 (s, 3H), 2.30 (s, 3H).

[0257] Example 19. N-((1H-pyrrolo[3,2-c]pyridine-2-yl)methyl)-1-(2-cyano-4-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-3-yl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (compound 157) was prepared according to the following synthetic route: JPEG2026525258000099.jpg25128

[0258] To a solution of 157-1 (prepared according to the synthesis method of intermediate 6) (23 mg, 0.059 mmol) in DMF (2 mL), DIEA (23 mg, 0.18 mmol) and HATU (27 mg, 0.071 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Then, 157-2 (10 mg, 0.065 mmol) was added to the reaction. The mixture was stirred at room temperature for 1 hour. After monitoring for completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 12:1) to obtain the title compound as a white solid (15.77 mg, 51.45% yield). MS (ESI) m / z: 518.3 [m+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.65 (s, 1H), 8.47 (t, J = 5.5 Hz, 1H), 8.20 (s, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.42 (d, J = 5.3 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.89 - 6.81 (m, 1H), 6.34 (s, 1H), 5.34 (s, 2H), 4.58 (d, J = 7.6 Hz, 4H), 3.64 (d, J = 10.4 Hz, 2H), 3.57 (d, J = 8.5 Hz, 2H), 3.22 (s, 3H), 2.72 (d, J = 10.7 Hz, 2H).

[0259] Example 20. N-((5,7-dimethylimidazo[1,2-a]pyridine-6-yl)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl]benzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (compound 142) was prepared according to the following synthetic route: JPEG2026525258000100.jpg28128

[0260] Compound 142-1 (45.28 mg, 0.12 mmol) of 1-(4-((2-oxopyridine-1(2H)yl)methyl)benzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (prepared according to the synthesis method of intermediate 2-3) was dissolved in DMF (3 mL) and HATU (45.63 mg, 0.12 mol) and DIEA (46.53 mg, 0.36 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. Compound intermediate 11 (31.54 mg, 0.18 mmol) was then added to the reaction. The mixture was stirred at room temperature for 2 hours. After monitoring for completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain the title compound (20.74 mg, 32.33% yield) as a white solid. MS(ESI)m / z:535.2[m+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.32 (t, J = 4.8 Hz, 1H), 7.79 (s, 1H), 7.74 (dd, J = 6.6, 1.8 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.40 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.32 (s, 1H), 7.25 (s, 4H), 6.38 (d, J = 9.2 Hz, 1H), 6.21 (td, J = 6.7, 1.3 Hz, 1H), 5.36 (s, 2H), 5.05 (s, 2H), 4.48 (d, J = 4.7 Hz, 2H), 2.62 (s, 3H), 2.38 (s, 3H); 19 F NMR (400 MHz, DMSO-d6) δ -59.52 (s).

[0261] Using appropriate raw materials, the compounds shown in the table below were prepared using the same procedures as described above in Examples 17, 18, 19, and 20.

[0262] [Table 3] JPEG2026525258000102.jpg225147JPEG2026525258000103.jpg225147JPEG2026525258000104.jpg236147 JPEG2026525258000105.jpg227147JPEG2026525258000106.jpg235154JPEG2026525258000107.jpg240154

[0263] Example 21. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-3-(difluoromethyl)-1-(4-(2-oxopyridine-1(2H)-yl)methylbenzyl)-1H-pyrazole-4-carboxamide (compound 69) was prepared according to the following synthetic route: JPEG2026525258000108.jpg60138

[0264] Example 21. N-((6-amino-2,4-dimethylpyridine-3-yl)methyl)-3-(difluoromethyl)-1-(4-(2-oxopyridine-1(2H)-yl)methylbenzyl)-1H-pyrazole-4-carboxamide (compound 69) was prepared according to the following synthetic route: Step 1: Preparation of (Z)-2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate ethyl: To a solution of compound 69-1 (2.0 g, 12.04 mmol) in acetic anhydride (20 mL), triethyl orthoformate 2 (3.57 g, 24.08 mmol) was added, and the mixture was stirred at 100 °C for 4 hours. After monitoring the completion of the reaction by LC-MS, the reaction solution was concentrated to obtain the desired title compound (2.67 g, 100% yield) as a yellow oil, which was used directly in the next step. MS(ESI)M / Z:223.1[M+H]+.

[0265] Step 2: Preparation of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate: Hydrazine hydrate (0.7 mL, 14.42 mmol) was added to a solution of compound 69-2 (2.67 g, 12.02 mmol) in EtOH (30 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, it was monitored by LC-MS, the solvent was evaporated under vacuum, and the residue was purified by chromatography on a silica gel column (DCM:MeOH=100:0-96:4) to obtain the title compound as a white solid (1.74 g, yield 76.15%). MS(ESI)M / Z:191.0[M+H]+.

[0266] Step 3: Preparation of 3-(difluoromethyl)-1-(4-((2-oxopyridine-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylate ethyl: Intermediate 2 (500 mg, 1.80 mmol) was added to a solution of compound 69-3 (380 mg, 1.19 mmol) in DMF (10 mL). The combined organic phase was concentrated, and the residue was purified by preparative TLC (PE:EA=1:1) to obtain the title compound (400 mg, 57.38% yield). MS(ESI)M / Z:388.1[M+H]+; 1 H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 7.77 (dd, J = 6.7, 2.0 Hz, 1H), 7.41 (ddt, J = 8.7, 6.5, 2.1 Hz, 1H), 7.37 - 7.27 (m, 4H), 7.11 (dd, J = 53.6, 2.2 Hz, 1H), 6.41 (d, J = 9.1 Hz, 1H), 6.23 (td, J = 6.6, 1.3 Hz, 1H), 5.40 (s, 2H), 5.08 (d, J = 2.0 Hz, 2H), 4.23 (qd, J = 7.1, 2.2Hz, 2H), 1.26 (td, J = 7.1, 2.2 Hz, 3H).

[0267] Step 4: Preparation of 3-(difluoromethyl)-1-(4-((2-oxopyridine-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid: Add NaOH (2M, 1mL, 2 mmol) to a solution of compound 69-4 (50 mg, 0.13 mmol) in MeOH (2 mL), and stir the mixture overnight at room temperature. Quench the reaction mixture by adding HCl solution (2M, 1mL, 2 mmol), concentrate under reduced pressure, and obtain the title compound (162 mg, 100% yield) as a white solid. MS(ESI)M / Z: 360.2[M+H]+.

[0268] Step 5: Preparation of 1-(4-(cyclopropylmethyl)benzyl)-N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide: HATU (59 mg, 0.16 mmol) and DIEA (50 mg, 0.39 mmol) were added to a solution of compound 69-5 (45 mg, 0.13 mmol) in DMF (2 mL), and the mixture was stirred at room temperature for 10 minutes. Intermediate 3 (20 mg, 0.13 mmol) was then added to the reaction product. The mixture was stirred at room temperature for 1 hour. After monitoring for completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to obtain the title compound (43.54 mg, yield 70.59%) as a white solid. MS(ESI)M / Z:493.4[M+H]+;HPLC: 254 nm: 95.822%, 214 nm: 97.754%; 1 H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.14 (s, 1H), 7.76 (dd, J = 6.8, 1.8 Hz, 1H), 7.50 - 7.14 (m, 6H), 6.39 (d, J = 9.1 Hz, 1H), 6.20 (dd, J = 27.4, 20.7 Hz, 4H), 5.35 (s, 2H), 5.07 (s, 2H), 4.25 (d, J = 4.6 Hz, 2H), 2.33 (s, 3H), 2.19 (s, 3H).

[0269] Example 22. 1-(4-(cyclopropylmethyl)benzyl)-N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (compound 91) was prepared according to the following synthetic route: JPEG2026525258000109.jpg79128

[0270] Step 1: Preparation of methyl 4-(cyclopropylmethyl)benzoate: To a solution of 4-methylformate benzyl chloride (2 g, 10.83 mmol) in toluene (20 mL) and water (1 mL) under N2 conditions, cyclopropyl trifluoroborate potassium (1.92 g, 13.00 mmol), Ru phos (0.51 g, 1.08 mmol), Pd2(dba)3 (0.99 g, 1.08 mmol), and K2CO3 (2.99 g, 21.66 mmol) were added and the mixture was stirred at 120°C for 4 hours. The mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layer was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA = 20:1) to obtain the title compound (1.15 g, 55.80% yield) as a colorless oily liquid. MS(ESI)M / Z:232.1[M+ACN+H]+.

[0271] Step 2: Preparation of (4-(cyclopropylmethyl)phenyl)methanol: Compound 91-3 (100 mg, 0.53 mmol) was dissolved in THF (3 mL) and stirred at 0°C for 15 minutes, then added to the solution. LiAlH4 (30 mg, 0.80 mmol) was added to the reaction solution and stirred at 0°C for 30 minutes. After monitoring the completion of the reaction by LC-MS, water (2.0 mL) was added to the reaction solution, and a large amount of white solid precipitated. The reaction solution was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain the title compound (56 mg, yield 65.67%) as a colorless oily liquid. MS(ESI)M / Z:145.1[M-18+H]+.

[0272] Step 3: Preparation of 1-(bromomethyl)-4-(cyclopropylmethyl)benzene: PBr3 (125.87 mg, 0.46 mmol) was slowly added to a solution of compound 91-4 (50 mg, 0.31 mmol) in DCM (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. TLC indicated that the reaction was complete. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The organic layer was washed three times with brine, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (PE:EA = 30:1) to obtain the title compound (45 mg, yield 64.86%) as a colorless oily liquid. 1 H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J = 8.0 Hz, 2H), 7.03 (dd, J = 15.1, 6.3 Hz, 2H), 4.50 (s, 2H), 2.29 (s, 2H), 0.80 - 0.69 (m, 1H), 0.32 - 0.22 (m, 2H), 0.03 - -0.04 (m, 2H).

[0273] Step 4: Preparation of 1-(4-(cyclopropylmethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate ethyl: Compound 3 (35 mg, 0.16 mmol) was dissolved in DMF (2 mL), to which 91-5 (32 mg, 0.18 mmol) and K2CO3 (44 mg, 0.32 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After monitoring the completion of the reaction by LC-MS, the mixture was diluted with water (50 mL), extracted with EA (50 mL x 3), and dried over Na2SO4. The combined organic layer was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA = 5:1) to obtain the title compound (39 mg, 76.38% yield) as a colorless oily liquid. MS (ESI) M / Z: 329.2[M+H]+.

[0274] Step 5: Preparation of 1-(4-(cyclopropylmethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylic acid: Add NaOH (2M, 1mL, 2 mmol) to a solution of compound 91-6 (40 mg, 0.12 mmol) in MeOH (2 mL), and stir the mixture at room temperature for 1 hour. After monitoring the completion of the reaction by LC-MS, the reaction mixture was quenched by adding HCl solution (2M, 1.05 mL, 2.1 mmol), concentrated under reduced pressure, and obtained the title compound (70 mg, 100% yield) as a white solid. MS(ESI)m / z: 301.2[m+H]+.

[0275] Step 6: Preparation of 1-(4-(cyclopropylmethyl)benzyl)-N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide: N-(4-carbamoylbenzyl)-1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxamide (compound 105) was prepared according to the following synthetic route: DIEA (47 mg, 0.36 mmol) and HATU (55 mg, 0.14 mmol) were added to a solution of compound 91-7 (35 mg, 0.12 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 10 minutes. Intermediate 3 (21 mg, 0.13 mmol) was then added to the reaction product. The mixture was stirred at room temperature for 1 hour. After monitoring for completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain the title compound (15.76 mg, 30.84% ​​yield) as a brown solid. MS(ESI)m / z:439.4[m+H]+;HPLC: 254 nm: 98.800%, 214 nm: 98.780%; 1H NMR (400 MHz, DMSO-d6) δ 8.43 (t, J = 5.3 Hz, 1H), 8.29 - 8.20 (m, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.18 (dd, J = 6.8, 4.4 Hz, 3H), 5.27 (s, 2H), 4.57 - 4.46 (m, 4H), 3.92 (s, 3H), 3.27 (s, 3H), 2.47 (d, J = 7.0 Hz, 2H), 0.97 - 0.88 (m, 1H), 0.49 - 0.40 (m, 2H), 0.17 (q, J = 4.9 Hz, 2H).

[0276] Example 23. N-((3-fluoro-4-(methylthio)pyridine-2-yl)methyl)-3-(methoxymethyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl ester)benzyl)-1H-pyrazole-4-carboxamide (compound 132) was prepared according to the following synthetic route: JPEG2026525258000110.jpg33128

[0277] Crude products 2-3 (35 mg, 0.098 mmol), crude intermediate 12 (17 mg, 0.098 mmol), HATU (37 mg, 0.098 mmol), and TEA (0.046 mL, 0.33 mmol) were sequentially added to DMF (2 mL) and reacted at room temperature for 1 hour. Water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with water (50 mL × 1) and saturated sodium chloride aqueous solution (50 mL × 1), respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was separated using a preparative plate (DCM:MeOH = 10:1) to obtain compound 132 (5 mg, yield: 12.0%) as a white solid. MS (ESI) M / Z: 508.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 8.60 - 8.52 (m, 1H), 8.22 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.33 - 7.25 (m, 4H), 7.24 - 7.17 (m, 4H), 7.01 (t, J = 5.5 Hz, 1H), 6.63 - 6.57 (m, 1H), 6.17 - 6.10 (m, 1H), 5.21 (s, 2H), 5.12 (s, 2H), 4.74 (dd, J = 4.9, 2.1 Hz, 2H), 4.61 (s, 2H), 3.42 (s, 3H), 2.48 (s, 3H).

[0278] Example 24. N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-3-(methoxymethyl)-1-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide (compound 113) was prepared according to the following synthetic route: JPEG2026525258000111.jpg58144

[0279] Step 1: Preparation of 1-(4-(bromomethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate methyl: At room temperature, compound 3-(methoxymethyl)-1H-pyrazole-4-carboxylate methyl (200 mg, 1.18 mmol) and potassium carbonate (324 mg, 2.35 mmol) were sequentially added to acetonitrile (5 mL), and the mixture was stirred at room temperature for 5 minutes. Then, 1,4-bis(bromomethyl)benzene (261 mg, 1.44 mmol) was added, and the mixture was stirred at 80°C for 16 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with water (20 mL) and saturated sodium chloride aqueous solution (20 mL), respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated and purified by column chromatography (EA:PE = 0-100%) to obtain the title compound (110 mg, yield: 25%) as a white solid. MS (ESI) M / Z: 353.0 [M+H] + .

[0280] Step 2: Preparation of 3-(methoxymethyl)-1-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate methyl: At room temperature, 113-2 (60 mg, 0.17 mmol) was added to acetonitrile (3 mL), and K2CO3 (30 mg, 0.217 mol) and 1,3-dihydro-2H-pyrrolo[3,2-b]pyridine-2-one (25 mg, 0.19 mol) were added in portions. The mixture was heated from room temperature to 80°C and stirred for 12 hours. Water (10 mL) was added, and the mixture was extracted with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Separation and purification by TLC (DCM:MeOH=10:1, Rf=0.5) yielded the title compound (22 mg, yield: 31.8%) as a white solid. MS (ESI) M / Z: 407.17 [M+1]+.

[0281] Step 3: Preparation of 3-(methoxymethyl)-1-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid: At room temperature, compound 113-3 (22 mg, 0.054 mmol) was added to methanol (3 mL), and a solution of sodium hydroxide (10 mg, 0.25 mmol) dissolved in water (1 mL) was added. The mixture was stirred at room temperature for 24 hours. The pH of the reaction mixture was adjusted to acidity using 1N aqueous hydrogen chloride solution, extracted with DCM (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (25 mg, crude) as a white solid. MS (ESI) M / Z: 393 [M+1] + .

[0282] Step 4: Preparation of N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-3-(methoxymethyl)-1-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide: At room temperature, add compounds 113-4 (25 mg, 0.063 mmol), 5 (11.8 mg, 0.075 mmol), HATU (28.72 mg, 0.075 mmol), and triethylamine (25.45 mg, 0.252 mmol) sequentially to DMF (2 mL), stir at room temperature for 1 hour, add water (10 mL), and mix with DCM (10 mL). Extraction was performed using 3 mL of solution, the organic phase was combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated and purified by column chromatography (methanol:dichloromethane = 0-100%) to obtain the title compound (4 mg, yield: 11.86%) as a white solid. MS (ESI) M / Z: 531.21 [M+1] + ; 1H NMR (400 MHz, DMSO-D6) δ 8.39 (t, J = 5.4 Hz, 1H), 8.22 (s, 1H), 8.20 (d, J = 5.5 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.15 (dd, J = 6.7, 5.5 Hz, 1H), 6.76 (d, J = 7.1 Hz, 1H), 6.45 (t, J = 7.0 Hz, 1H), 5.25 (s, 2H), 5.21 (s, 2H), 4.49 (dd, J = 5.4, 2.3 Hz, 2H), 4.46 (s, 2H), 3.88 (s, 3H), 3.47 (s, 2H), 3.21 (s, 3H).

[0283] Using appropriate raw materials and following the same procedures as described in Examples 21, 22, 23, and 24, the compounds shown in the table below were prepared.

[0284] [Table 4] JPEG2026525258000113.jpg246154JPEG2026525258000114.jpg158154

[0285] Example 25. N-(4-carbamoylbenzyl)-1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxamide (compound 105) was prepared according to the following synthetic route: JPEG2026525258000115.jpg58149

[0286] Step 1: Preparation of 1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxylate methyl: 1H-pyrazole-4-carboxylate methyl (134.69 mg, 1.07 mmol) and K2CO3 (246.01 mg, 1.78 mmol) were added to a solution of 4-(cyclopropylmethyl)benzyl bromide (200 mg, 0.89 mmol) in DMF (8 mL), and the mixture was stirred at room temperature for 1 hour. After monitoring the completion of the reaction by LC-MS, the mixture was diluted with water (20 mL) and EA (10 mL) was added. 3 Extraction was performed using ) and dried over Na2SO4. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA=10:1) to obtain target compound 1 (202 mg, yield 84.11%) as a white solid. MS(ESI)m / z:271.2[m+H]+.

[0287] Step 2: Preparation of 1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxylic acid: To a solution of compound 105-1 (50 mg, 0.18 mmol) in MeOH (2 mL), NaOH (2 M, 0.3 mL, 0.6 mmol) was added, and the mixture was stirred overnight at room temperature. After monitoring the completion of the reaction by LC-MS, the reaction mixture was quenched by adding HCl solution (2 M, 0.35 mL, 0.7 mmol), concentrated under reduced pressure, and the title compound (82.51 mg, 100% yield) was obtained as a white solid. MS(ESI) m / z: 257.2[m+H]+.

[0288] Step 3: Preparation of N-(4-carbamoylbenzyl)-1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxamide: Add HATU (68.44 mg, 0.18 mol) and DIEA (69.79 mg, 0.54 mmol) to a solution of compound 105-2 (47.41 mg, 0.18 mmol) in DMF (3 mL), and stir the mixture at room temperature for 0.5 hours. Then, add 4-carbamoylbenzylamine (29.54 mg, 0.20 mmol) to the reaction. Stir the mixture at room temperature for 2 hours. After monitoring the completion of the reaction by LC-MS, dilute the reaction mixture with H2O (20 mL) and prepare a DCM:MeOH = 8:1 (10 mL) solution. 3Extraction was performed using ) and dried over Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=8:1) to obtain the target compound 105 (54.03 mg, yield 75.38%) as a white solid. MS(ESI) m / z: 38.82[m+H]+; HPLC: 254 nm: 97.718%, 214 nm: 98.699%; 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.22 (dd, J = 17.4, 8.1 Hz, 7H), 5.30 (s, 2H), 4.42 (d, J = 5.9 Hz, 2H), 2.47 (d, J = 7.0 Hz, 2H), 0.98 - 0.87 (m, 1H), 0.48 - 0.40 (m, 2H), 0.17 (q, J = 5.0 Hz, 2H).

[0289] Example 26. (Z)-1-(4-(cyclopropylmethyl)benzyl)-N-(4-(N'-hydroxycarbamoyl)benzyl)-1H-pyrazole-4-carboxamide (compound 348) was prepared according to the following synthetic route: JPEG2026525258000116.jpg22145

[0290] Step 1: Preparation of N-(4-cyanobenzyl)-1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxamide: 1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxylic acid (50 mg, 0.20 mol) was dissolved in DMF (2 mL), to which DIEA (77 mg, 0.60 mmol) and HATU (91 mg, 0.24 mmol) were added. The mixture was stirred at room temperature for 10 minutes. Then, compound 4-(aminomethyl)benzonitrile (34 mg, 0.26 mmol) was added to the reaction. The mixture was stirred at room temperature for 30 minutes. After monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 60:1) to obtain the title compound (30.0 mg, 41.51% yield) as a white solid. MS (ESI) m / z: 371.2 [M+H] + .

[0291] Step 2: Preparation of (Z)-1-(4-(cyclopropylmethyl)benzyl)-N-(4-(N'-hydroxycarbamoyl)benzyl)-1H-pyrazole-4-carboxamide: To a solution of compound 348-1 (20 mg, 0.054 mmol) in EtOH (6 mL) and H2O (2 mL), hydroxylamine hydrochloride (18.76 mg, 0.27 mmol) and Na2CO3 (28.62 mg, 0.27 mol) were added. The mixture was refluxed at 85°C under nitrogen for 2 hours. After monitoring for completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=8:1) and reverse-phase column to obtain the title compound 348 (7.50 mg, 34.4% yield) as a white solid. MS (ESI) m / z: 404.3 [M+H] + ;HPLC: 254 nm: 98.695%, 214 nm: 99.018%; 1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 11.22 (s, 1H), 9.01 (s, 2H), 8.83 (t, J = 5.9 Hz, 1H), 8.27 (s, 1H), 7.92 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.22 (q, J = 8.0 Hz, 4H), 5.30 (s, 2H), 4.47 (d, J = 5.9 Hz, 2H), 2.47 (d, J = 7.0 Hz, 2H), 1.24 (s, 1H), 0.93 (d, J = 6.5 Hz, 1H), 0.53 - 0.38 (m, 2H), 0.17 (d, J = 4.7 Hz, 2H).

[0292] Example 27. N-(4-carbamoylbenzyl)-1-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (compound 153) was prepared according to the following synthetic route: JPEG2026525258000117.jpg84140

[0293] Step 1: Preparation of methyl 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylate: Compound SM2 (686 mg, 3.3 mmol) and K2CO3 (829 mg, 6.0 mmol) were added to a solution of compound 153-1 (850 mg, 3.0 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL). This mixture was purged with nitrogen for 5 minutes. Then, Pd(dppf)Cl2 (219 mg, 0.3 mmol) was added, and the mixture was stirred at 100°C for 4 hours. After monitoring the completion of the reaction by LCMS, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The reaction mixture was poured into 100 mL of water, and EA (100 mL) 3Extraction was performed using ). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by silica gel chromatography (eluting at PE:EA = 100:0 to 90:10) to obtain the title compound (805 mg, 94.30% yield). 1 H NMR (400 MHz, DMSO) δ8.16(d, J=9.8 Hz, 2H), 7.51(d, J=7.9 Hz, 1H), 5.58(s, 1H.

[0294] Step 2: Preparation of methyl 4-cyclohexyl-3-(trifluoromethyl)benzoate: Pd / C (200 mg) was added to a solution of compound 153-2 (805 mg, 2.83 mmol) in MeOH (15 mL), and the mixture was stirred at room temperature for 16 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted at PE:EA = 100:0 to 90:10) to obtain the title compound (800 mg, yield 98.68%). 1 H NMR (400 MHz, DMSO) δ 8.24 - 8.01 (m, 2H), 7.81 (d, J = 8.2 Hz, 1H), 3.90 (d, J = 10.4 Hz, 3H), 2.87 (t, J = 11.1 Hz, 1H), 1.77 (dd, J = 44.5, 10.7 Hz, 5H), 1.56 (dd, J = 22.3, 10.6 Hz, 2H), 1.32 (dt, J = 23.8, 11.9 Hz, 3H).

[0295] Step 3: Preparation of (4-cyclohexyl-3-(trifluoromethyl)phenyl)methanol: A solution of compound 153-3 (200 mg, 0.7 mmol) in dry THF (10 mL) was cooled to -5°C. LiAlH4 (1 M THF solution) (1.05 mL, 1.05 mmol) was added dropwise to the solution. The mixture was allowed to return to room temperature and the solution was stirred at room temperature for 2 hours. After monitoring for completion of the reaction by LC-MS, the reaction was quenched with saturated NH4Cl solution. The reaction mixture was diluted with water (50 mL) and EA (50 mL) 3Extraction was performed using ). The combined organic matter was concentrated. The residue was purified by preparative TLC (PE:EA=8:1) to obtain the title compound (152 mg, 84.24% yield). 1 H NMR (400 MHz, DMSO) δ 7.63 - 7.43 (m, 3H), 5.30 (q, J = 5.8 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H), 2.80 (t, J = 11.2 Hz, 1H), 1.82 - 1.67 (m, 5H), 1.51 (dd, J = 22.6, 10.6 Hz, 2H), 1.34 (dd, J = 23.8, 10.3 Hz, 3H).

[0296] Step 4: Preparation of 4-(bromomethyl)-1-cyclohexyl-2-(trifluoromethyl)benzene: A solution of compound 153-4 (152 mg, 0.59 mmol) in DCM (10 mL) was cooled to -0°C. Phosphorus tribromide (160 mg, 0.59 mmol) was added to this solution. The mixture was allowed to return to room temperature and the solution was stirred at room temperature for 10 minutes. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with water (50 mL) and DCM (50 mL) 3 Extraction was performed using ). The combined organic matter was concentrated. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain the title compound (115 mg, 60.8% yield). 1 H NMR (400 MHz, DMSO) δ 7.77 - 7.56 (m, 3H), 4.77 (s, 2H), 2.80 (t, J = 11.7 Hz, 1H), 1.83 - 1.65 (m, 5H), 1.52 (dd, J = 21.7, 9.9 Hz, 2H), 1.38 - 1.29 (m, 3H).

[0297] Step 5: Preparation of 1-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate ethyl: Compound 205-1 (72 mg, 0.40 mmol) and K2CO3 (124 mg, 0.90 mmol) were added to a solution of compound 153-5 (115 mg, 0.36 mmol) in DMF (8 mL), and the mixture was stirred at room temperature for 3 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with water (50 mL) and DCM (50 mL) 3 Extraction was performed using ). The combined organic phase was concentrated, and the residue was purified by preparative TLC (PE:EA=2:1) ​​to obtain the desired title compound (60 mg, 39.48% yield). 1 H NMR (400 MHz, DMSO) δ 8.50 (s, 1H), 7.68 - 7.57 (m, 2H), 7.52 (d, J = 8.1 Hz, 1H), 5.40 (s, 2H), 4.52 (s, 2H), 4.21 (p, J = 6.9 Hz, 2H), 3.25 (s, 3H), 2.80 (t, J = 11.4 Hz, 1H), 1.85 - 1.62 (m, 5H), 1.49 (dd, J = 23.5, 11.7 Hz, 2H), 1.37 - 1.22 (m, 6H).

[0298] Step 6: Preparation of 1-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylic acid: To a solution of compound 153-6 (34 mg, 0.08 mmol) in MeOH (2 mL), NaOH (2 M, 0.5 mL, 1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding HCl solution (2 M, 0.5 mL, 1 mmol), concentrated under reduced pressure, and the title compound (90 mg, 100% yield) was obtained as a white solid. MS (ESI) M / Z: 397.0 [M+H] + .

[0299] Step 7: Preparation of N-(4-carbamoylbenzyl)-1-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide: HATU (30 mg, 0.08 mmol) and DIEA (30 mg, 0.24 mmol) were added to a solution of compound 153-7 (30 mg, 0.076 mmol) in DMF (3 mL), and the mixture was stirred at room temperature for 10 minutes. Then, compound 4-carbamoylbenzylamine (12 mg, 0.84 mmol) was added to the reaction. The mixture was stirred at room temperature for 1 hour. After monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain the hydrochloride salt of the title compound (22.18 mg, 55.55% yield) as a white solid. MS(ESI) m / z: 528.3[m+H]+; 1 H NMR (400 MHz, DMSO) δ 9.31 (s, 2H), 9.03 (s, 2H), 8.59 (t, J = 5.8 Hz, 1H), 8.35 (s, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.69 - 7.57 (m, 2H), 7.51 (d, J = 8.1 Hz, 3H), 5.39 (s, 2H), 4.64 - 4.33 (m, 4H), 3.22 (s, 3H), 2.78 (d, J = 10.6 Hz, 1H), 1.79 (s, 2H), 1.74 - 1.59 (m, 3H), 1.56 - 1.41 (m, 2H), 1.32 (t, J = 10.8 Hz, 3H).

[0300] Example 28. N-(4-carbamoylbenzyl)-1-(4-cyclopropoxy-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (compound 379) was prepared according to the following synthetic route: JPEG2026525258000118.jpg70144

[0301] Step 1: Preparation of 4-cyclopropoxy-3-(trifluoromethyl)methyl benzoate: Compound 379-1 (400 mg, 1.82 mmol) was dissolved in toluene (16 mL) and H2O (4 mL) to which potassium cyclopropyltrifluoroborate (673 mg, 4.55 mmol), 1,10-phenanthroline (131 mg, 0.73 mmol), Cu(OAc)2 (132 mg, 0.73 mmol), and K2CO3 (754 mg, 5.46 mmol) were added. The mixture was purged with oxygen for 2 minutes. The mixture was then stirred overnight at 70°C under oxygen. After monitoring the completion of the reaction by LC-MS, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The reaction mixture was poured into H2O (150 mL) and extracted with EA (150 mL³). The combined organic matter was concentrated. The residue was purified by reverse-phase column chromatography to obtain the desired oily title compound (94 mg, 19.88% yield). MS(ESI) m / z: 261.1[m+H]+.

[0302] Step 2: Preparation of (4-cyclopropoxy-3-(trifluoromethyl)phenyl)methanol: A solution of compound 379-2 (50 mg, 0.34 mmol) in dry THF (15 mL) was cooled to 0°C. LiBH4 (39 mg, 1.80 mmol) was added dropwise to the solution. The mixture was allowed to return to room temperature and the solution was stirred overnight at room temperature. After the reaction was complete, it was monitored by LC-MS. The reaction was quenched with saturated NH4Cl solution. The reaction mixture was diluted with water (100 mL) and EA (100 mL) 3 Extraction was performed using ). The combined organic matter was concentrated. The residue was purified by silica gel column chromatography (PE:EA=100:0 to PE:EA=0:100) to obtain the desired title compound (36 mg, 42.92% yield). MS(ESI)m / z:215.0[m-OH]+.

[0303] Step 3: Preparation of 4-(chloromethyl)-1-cyclopropoxy-2-(trifluoromethyl)benzene: SOCl2 (38 mg, 0.32 mmol) was slowly added at 0°C to a solution of compound 379-3 (36 mg, 0.16 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 0.5 hours. After monitoring for completion of the reaction by LC-MS, the reaction mixture was diluted with saturated NaHCO3 solution (10 mL) and extracted with DCM (30 mL x 3). The combined organic phase was concentrated under reduced pressure to obtain the title compound (26 mg, yield 66.91%). MS(ESI) m / z: 251.0[m+H]+.

[0304] Step 4: Preparation of 1-(4-cyclopropoxy-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylate methyl: Compound pyrrole-3-carboxylate methyl (15 mg, 0.12 mmol) and K2CO3 (27 mg, 0.20 mmol) were added to a solution of compound 379-4 (26 mg, 0.10 mmol) in DMF (5 mL). The mixture was stirred overnight at room temperature. After monitoring for completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA = 100:0~50:50) to obtain the title compound (18 mg, yield 50.99%). MS (ESI) m / z: 341.1 [m+H]+.

[0305] Step 5: Preparation of 1-(4-cyclopropoxy-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylic acid: Add NaOH (2M, 1mL, 2 mmol) to a solution of compound 379-5 (18 mg, 0.053 mmol) in MeOH (2 mL), and stir the mixture overnight at room temperature. After the reaction was complete, it was monitored by LC-MS. The reaction mixture was quenched by adding HCl solution (2M, 1mL, 2 mmol), concentrated under reduced pressure, and the title compound (17 mg) was obtained. MS(ESI) m / z: 327.0[m+H]+.

[0306] Step 6: Preparation of N-(4-carbamoylbenzyl)-1-(4-cyclopropoxy-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide: DIEA (20 mg, 0.16 mmol) and HATU (22 mg, 0.057 mmol) were added to a solution of compound 379-6 (17 mg, 0.052 mmol) in DMF (2 mL), and the mixture was stirred at room temperature for 5 minutes. Compound 8-1 (14 mg, 0.062 mmol) was then added to the reaction. The mixture was stirred at room temperature for 15 minutes. The completion of the reaction was monitored by LC-MS, and after the completion of the reaction, the reaction mixture was monitored by LC-MS again. The reaction mixture was purified by reverse-phase column chromatography to obtain the title compound 379 (5.45 mg, 21.18% yield) as a white solid. MS(ESI)m / z:458.4[m+H]+ ; 1 H NMR (400 MHz, DMSO) δ 9.31 (s, 2H), 9.04 (s, 2H), 8.83 (t, J = 5.7 Hz, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 7.6 Hz, 2H), 7.55 - 7.41 (m, 3H), 5.36 (s, 2H), 4.48 (d, J = 5.6 Hz, 2H), 4.02 (dt, J = 8.3, 4.3 Hz, 1H), 0.88 - 0.74 (m, 2H), 0.69 - 0.56 (m, 2H).

[0307] Using appropriate raw materials and following the same procedures as described in Examples 25, 26, 27, and 28, the compounds shown in the table below were prepared.

[0308] [Table 5] JPEG2026525258000120.jpg246154JPEG2026525258000121.jpg226147JPEG2026525258000122.jpg223147JPEG2026525258000123.jpg230154

[0309] N-(4-carbamoylbenzyl)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxamide (compound 128) was prepared according to the following synthetic route: JPEG2026525258000124.jpg68130

[0310] Example 29. N-(4-carbamoylbenzyl)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxamide (compound 128) was prepared according to the following synthetic route:

[0311] Step 1: Preparation of 4-phenoxybenzyl alcohol: Under nitrogen protection, compound 128-1 (1.0 g, 5.05 mmol) was added to methanol (10 mL), cooled to 0°C, sodium borohydride (575 mg, 15.14 mmol) was added, and the mixture was allowed to return to room temperature naturally and stirred for 1 hour. Saturated ammonium chloride aqueous solution (50 mL) was added, and the mixture was extracted with EA (50 mL × 3). The organic phases were combined and washed with water (100 mL) and saturated sodium chloride aqueous solution (100 mL), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated and purified by column chromatography (EA:PE = 0-100%) to obtain the title compound (850 mg, yield: 85%) as a white solid. MS (ESI) M / Z: 202.1 [M+H] + .

[0312] Step 2: Preparation of 4-phenoxybenzyl bromide: Under nitrogen protection, compound 128-2 (800 mg, 4.00 mmol) was added to DCM (10 mL), cooled to 0°C, and phosphorus tribromide (1.7 g, 6.00 mmol) dissolved in DCM (5 mL) was added dropwise. The mixture was allowed to return to room temperature naturally and stirred for 1 hour. After cooling to 0°C, the pH of the reaction mixture was adjusted to approximately 8 using saturated sodium bicarbonate aqueous solution (20 mL), extracted with DCM (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (850 mg, yield: 80%) as a white solid. MS (ESI) M / Z: 263.0 [M+H] + .

[0313] Step 3: Preparation of 1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate methyl: At room temperature, compound 128-4 (780 mg, 2.52 mmol) was added to ethanol (10 mL), and a solution of sodium hydroxide (504 mg, 12.60 mmol) dissolved in water (2 mL) was added. The mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to acidity using 1N aqueous hydrogen chloride solution, extracted with DCM (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (700 mg, yield: 94%) as a white solid. MS (ESI) M / Z: 295.1 [M+H] + .

[0314] Step 4: Preparation of 1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid: At room temperature, compound pyrazole-4-carboxylate methyl (354 mg, 2.70 mmol) and potassium carbonate (2.1 g, 15.26 mmol) were sequentially added to DMF (10 mL), and the mixture was stirred at room temperature for 5 minutes. Compound 128-3 (800 mg, 3.05 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride aqueous solution (50 mL), respectively, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated and purified by column chromatography (EA:PE = 0-100%) to obtain the title compound (780 mg, yield: 94%) as a white solid. MS (ESI) M / Z: 309.1 [M+H] + .

[0315] Step 5: Preparation of N-(4-carbamoylbenzyl)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxamide: At room temperature, compound 128-5 (50 mg, 0.17 mmol), HATU (77 mg, 0.20 mmol), and triethylamine (52 mg, 0.51 mmol) were sequentially added to DMF (2 mL), and the mixture was stirred at room temperature for 0.5 hours. Compound 4-carbamoylbenzylamine (45 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Water (10 mL) was added, and the mixture was extracted with DCM (10 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was separated and purified by column chromatography (methanol:dichloromethane = 0-100%) to obtain the title compound (25 mg, yield: 35%) as a yellow solid. MS (ESI) M / Z: 426.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 3H), 8.78 (t, J = 8.4 Hz, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.78 - 7.73 (m, 2H), 7.53 - 7.46 (m, 2H), 7.42 - 7.35 (m, 2H), 7.33 - 7.29 (m, 2H), 7.19 - 7.12 (m, 1H), 7.02 - 6.96 (m, 4H), 5.33 (s, 2H), 4.48 (d, J = 6.0 Hz, 2H).

[0316] Using appropriate raw materials and following the same procedures as described in Examples 22 and 29, the compounds shown in the table below were prepared.

[0317] [Table 6]

[0318] Example 30. 3-((3-fluoro-3-(methoxymethyl)azetidine-1-yl)methyl)-N-(3-fluoro-4-methoxypyridine-2-yl)methyl (compound 205) was prepared according to the following synthetic route: JPEG2026525258000126.jpg60153

[0319] Step 1: Preparation of 3-(hydroxymethyl)-1-(4-((2-oxopyridine-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylate ethyl: K2CO3 (994 mg, 7.20 mmol, 2.0 eq) was added to a mixture of intermediates 2 (1.00 g, 3.60 mmol, 1.0 eq) and 205-1 (734 mg, 4.32 mmol, 1.2 eq) in DMF (10 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with H2O (30 mL) and sorbed with ELISA (20 mL) 3 Extraction was performed using ) and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE / EA=1 / 2) to obtain the title compound (700 mg, 53.0% yield) as a white solid. MS (ESI) m / z: 368.2 [M+H] + .

[0320] Step 2: Preparation of 3-(bromomethyl)-1-(4-((2-oxopyridine-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylate ethyl: At room temperature, PBr3 (43 mg, 0.16 mmol, 2.0 eq) was added to a solution of compound 205-2 (30 mg, 0.08 mmol, 1.0 eq) in anhydrous MeCN (5 mL), and the mixture was stirred at 80°C for 1 hour. After monitoring the completion of the reaction by TLC, the reaction mixture was diluted with H2O (10 mL) and ethyl phosphate (10 mL) was added. 3 Extraction was performed using ) and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1 / 1) to obtain the title compound (24 mg, 68.6% yield) as a white solid. MS (ESI) m / z: 431.2 [M+H] + .

[0321] Step 3: Preparation of 3-((3-fluoro-3-(methoxymethyl)azetidine-1-yl)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate ethyl: DIEA (16 mg, 0.12 mmol, 2.0 eq) was added to a mixture of compounds 205-3 (24 mg, 0.06 mmol, 1.0 eq) and 205-4 (11 mg, 0.09 mmol, 1.5 eq) in DMF (2 mL), and the mixture was stirred at room temperature for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with H2O (10 mL) and ELISA (10 mL) was added. 3 Extraction was performed using ) and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the title compound (12 mg, 46.2% yield) as a white solid. MS (ESI) m / z: 469.3 [M+H] + .

[0322] Step 4: Preparation of 3-((3-fluoro-3-(methoxymethyl)azetidine-1-yl)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid: At room temperature, NaOH (5 mg, 0.12 mmol, 4.0 eq) was added to a solution of compound 205-5 (12 mg, 0.03 mmol, 1.0 eq) in EtOH (0.8 mL) and H2O (0.2 mL), and the mixture was stirred at 60°C for 2 hours. After monitoring the completion of the reaction by LC-MS, the pH of the reaction mixture was adjusted to pH=4-5 with HCl solution (4.0 M). The crude product of the title compound after concentration under vacuum was used directly in the next step. MS (ESI) m / z: 441.3 [M+H] + .

[0323] Step 5: Preparation of 3-((3-fluoro-3-(methoxymethyl)azetidine-1-yl)methyl)-N-(3-fluoro-4-methoxypyridine-2-yl)methyl: To a mixture of compound 205-6 (concentrate from the previous step) and intermediate 3 (8 mg, 0.04 mmol, 1.2 eq) in DMF (2 mL), HATU (19 mg, 0.05 mmol, 1.5 eq) and TEA (10 mg, 0.10 mmol, 3.0 eq) were added, and the mixture was stirred overnight at room temperature. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with H2O (10 mL) and toluene (10 mL) was added. 3 Extraction was performed using ) and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the title compound (3.5 mg, 2-step yield 23.6%) as a white solid. MS (ESI) m / z: 579.3 [M+H] + ; 1 H NMR (400 MHz, Methanol-d4) δ 8.23 ​​(d, J = 5.6 Hz, 1H), 8.06 (s, 1H), 7.65 (dd, J = 6.7, 2.0 Hz, 1H), 7.51-7.47 (m, 1H), 7.30-7.25 (m, 2H), 7.22-7.19 (m, 2H), 7.16-7.13 (m, 1H), 6.57-6.50 (m, 1H), 6.35 (td, J = 6.7, 1.4 Hz, 1H), 5.26 (s, 2H), 5.16 (s, 2H), 4.64 (d, J = 2.4 Hz, 2H), 3.95 (s, 3H), 3.78 (s, 2H), 3.49-3.43 (m, 2H), 3.39-3.31 (m, 2H), 3.31 (s, 3H), 3.22-3.08 (m, 2H).

[0324] Example 31. N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-3-((3-fluorooxetan-3-yl)methoxy)methyl (compound 235) was prepared according to the following synthetic route: JPEG2026525258000127.jpg55152

[0325] Step 1: Preparation of 3-((3-fluorooxetan-3-yl)methoxy)methyl)-1-(4-(2-oxopyridine-1(2H)-yl)methylbenzyl)-1H-pyrazole-4-carboxylate ethyl: At 0°C, NaH (11 mg, 0.26 mmol, 2.2 eq) was added to a solution of compound (3-fluorooxetan-3-yl)methanol (25 mg, 0.24 mmol, 2.0 eq) in THF (2 mL), and the mixture was stirred at 0°C for 1 hour. At 0°C, compound 205-3 (50 mg, 0.12 mmol, 1.0 eq) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature for a further 1 hour. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with H2O (10 mL) and ELISA (10 mL) 3 Extraction was performed using ) and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the title compound (25 mg, 47.3% yield) as a white solid. MS(ESI) m / z: 456.3[m+H]+.

[0326] Step 2: Preparation of 3-((3-fluorooxetan-3-yl)methoxy)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid: At room temperature, compound 235-1 (25 mg, 0.06 mmol, 1.0 eq) was dissolved in MeOH (0.8 mL) and H2O (0.2 mL), to which LiOH·H2O (10 mg, 0.24 mmol, 4.0 eq) was added, and the mixture was stirred at 60°C for 2 hours. After monitoring the completion of the reaction by LC-MS, the pH of the reaction mixture was adjusted to pH=4-5 with HCl solution (4.0 M). After concentration under vacuum, the crude product of the title compound was obtained and used directly in the next step. MS(ESI)m / z:428.3[m+H]+.

[0327] Step 3: Preparation of N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-3-((3-fluorooxetan-3-yl)methoxy)methyl: Compound 235-1 (from the previous step) and intermediate 3 (14 mg, 0.07 mmol, 1.2 eq) were mixed in DMF (3 mL), to which HATU (34 mg, 0.09 mmol, 1.5 eq) and TEA (18 mg, 0.18 mmol, 3.0 eq) were added, and the mixture was stirred overnight at room temperature. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with H2O (10 mL) and toluene (10 mL) was added. 3 Extraction was performed using ) and dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the title compound (3.5 mg, 2-step yield 10.3%) as a white solid. MS(ESI) m / z: 566.3[m+H]+. 1 H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 5.5 Hz, 1H), 8.12-8.09 (d, J = 11.0 Hz, 1H), 7.90 (s, 1H), 7.36-7.26 (m, 3H), 7.23-7.19 (m, 2H), 6.82 (t, J = 6.0 Hz, 1H), 6.60 (d, J = 9.1, 1H), 6.15 (td, J = 6.7, 1.4 Hz, 1H), 5.22 (s, 2H), 5.12 (s, 2H), 4.78 (s, 2H), 4.75-4.64 (m, 4H), 4.58-4.46 (m, 2H), 3.93 (s, 3H), 3.92-3.88 (m, 2H).

[0328] Example 32. N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-3-(3-hydroxy-3-methylazetidine-1-yl)-1-(4-(2-oxopyridine-1(2H)-yl)benzyl)-1H-pyrazole-4-carboxamide (compound 296) was prepared according to the following synthetic route: JPEG2026525258000128.jpg59156

[0329] Step 1: Preparation of 3-(3-hydroxy-3-methylazetidine-1-yl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate ethyl: Compound 134-1 (40 mg, 0.096 mmol), 3-methylazetidine-3-ol hydrochloride (18 mg, 0.14 mmol), XantphosPdG3 (18 mg, 0.019 mmol), and cesium carbonate (94 mg, 0.29 mmol) were added to NMP (2 mL) and reacted overnight at 120°C. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with water (50 mL x 1) and saturated sodium chloride aqueous solution (50 mL x 1), respectively. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was purified using a preparative plate (dichloromethane / methanol = 10:1) to obtain the title compound (25 mg, yield: 61.7%) as a white solid. MS (ESI) M / Z: 423.2 [M+H] + .

[0330] Step 2: Preparation of 3-(3-hydroxy-3-methylazetidine-1-yl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid: Compound 296-1 (25 mg, 0.059 mmol) and lithium hydroxide monohydrate (5 mg, 0.12 mmol) were added to methanol (2 mL) and water (0.4 mL) and reacted overnight at room temperature. The reaction mixture was adjusted to pH = 5-6 with dioxane hydrochloride solution, and the reaction mixture was concentrated under reduced pressure to obtain the crude product of the title compound, which can be used directly in the next step. MS (ESI) M / Z: 395.1 [M+H] + .

[0331] Step 3: Preparation of N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-3-(3-hydroxy-3-methylazetidine-1-yl)-1-(4-(2-oxopyridine-1(2H)-yl)benzyl)-1H-pyrazole-4-carboxamide: Crude product 296-2, intermediate 3 (17 mg, 0.089 mmol), HOBt (24 mg, 0.18 mmol), EDCI (35 mg, 0.18 mmol), and DIEA (0.041 mL, 0.24 mmol) were sequentially added to DMF (2 mL) and reacted at room temperature for 1 hour. Water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined and washed with water (50 mL × 1) and saturated sodium chloride aqueous solution (50 mL × 1), respectively. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was separated using a preparative plate (DCM:MeOH = 10:1) to obtain the title compound (10 mg, yield: 31.8%) as a white solid. MS (ESI) M / Z: 533.2 [M+H] + ; 1 H NMR (400 MHz, Methanol-d4) δ 8.15 (d, J = 7.8, 5.6 Hz, 1H), 7.87 (s, 1H), 7.69 - 7.62 (m, 1H), 7.49 (ddd, J = 8.9, 6.7, 2.1 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.25 - 7.18 (m, 2H), 7.09 (dd, J = 6.7, 5.6 Hz, 1H), 6.58 - 6.50 (m, 1H), 6.36 (td, J = 6.7, 1.4 Hz, 1H), 5.16 (s, 2H), 5.08 (s, 2H), 4.56 (d, J = 2.2 Hz, 2H), 3.94 (s, 3H), 3.54 - 3.43 (m, 2H), 3.38 - 3.29 (m, 2H), 1.23 (s, 3H).

[0332] Using appropriate raw materials and following the same procedures as described in Examples 8, 30, 31, and 32, the compounds shown in the table below were prepared.

[0333] [Table 7] JPEG2026525258000130.jpg235154JPEG2026525258000131.jpg224154JPEG2026525258000132.jpg235154JPEG20265252580 00133.jpg246154JPEG2026525258000134.jpg235154JPEG2026525258000135.jpg235154JPEG2026525258000136.jpg124154

[0334] Example 33. N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-2',4'-dimethyl-1-(4-(2-oxopyridine-1(2H)yl)methyl]benzyl)-1H-,2'-H-[3,3'-bipirazole]-4-carboxamide (compound 221) was prepared according to the following synthetic route: JPEG2026525258000137.jpg63152

[0335] Step 1: Preparation of 2',4'-dimethyl-1-(4-(2-oxopyridine-1(2H)yl)methyl)benzyl)-1H,2'-H-[3,3'-bipirazole]-4-carboxylic acid: Under nitrogen protection, compounds 221-1 (30 mg, 0.072 mmol), 221-2 (24 mg, 0.11 mmol), Pd(dppf)2Cl2 (6 mg, 0.0072 mmol), and potassium phosphate (54 mg, 0.25 mmol) were sequentially added to 1,4-dioxane (3 mL) and water (0.6 mL), and the mixture was reacted overnight at 110°C. The mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with water (50 mL x 1) and saturated sodium chloride aqueous solution (50 mL x 1), respectively. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was separated using a preparative plate (DCM:MeOH = 10:1) to obtain the title compound (12 mg, yield: 38.7%) as a white solid. MS (ESI) M / Z: 432.2 [M+H] + .

[0336] Step 2: Preparation of 2',4'-dimethyl-1-(4-(2-oxopyridine-1(2H)yl)methyl)benzyl)-1H,2'-H-[3,3'-bipyrazole]-4-carboxylate ethyl: Compound 221-3 (12 mg, 0.028 mmol) and lithium hydroxide monohydrate (3 mg, 0.056 mmol) were added to methanol (2 mL) and water (0.5 mL) and reacted overnight at room temperature. The reaction mixture was adjusted to pH 5-6 with dioxane hydrochloride solution, and the reaction mixture was concentrated under reduced pressure to obtain the crude product of the title compound, which was then used directly in the next step. MS (ESI) M / Z: 404.2 [M+H] + .

[0337] Step 3: Preparation of N-((3-fluoro-4-methoxypyridine-2-yl)methyl)-2',4'-dimethyl-1-(4-(2-oxopyridine-1(2H)yl)methyl]benzyl)-1H-,2'-H-[3,3'-bipirazole]-4-carboxamide: Crude product 221-4, intermediate 3 (7 mg, 0.034 mmol), HATU (13 mg, 0.034 mmol), and TEA (0.016 mL, 0.11 mmol) were sequentially added to DMF (2 mL) and reacted at room temperature for 1 hour. Water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined and washed with water (50 mL x 1) and saturated sodium chloride aqueous solution (50 mL x 1), respectively. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the residue. The residue was separated using a preparative plate (DCM:MeOH = 10:1) to obtain the title compound (6 mg, yield: 39.6%) as a white solid. MS (ESI) M / Z: 542.2 [M+H] + ; 1H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 8.14 - 8.08 (m, 1H), 7.67 (ddd, J = 6.8, 2.1, 0.7 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.33 - 7.28 (m, 5H), 7.11 - 7.03 (m, 1H), 6.58 - 6.51 (m, 1H), 6.36 (td, J = 6.7, 1.4 Hz, 1H), 5.39 (s, 2H), 5.17 (s, 2H), 4.52 (d, J = 2.2 Hz, 2H), 3.93 (s, 3H), 3.62 (s, 3H), 1.86 (s, 3H).

[0338] Using appropriate raw materials and following the same procedure as described in Example 33, prepare the compounds shown in the table below.

[0339] [Table 8]

[0340] Example 34. N-(2,6-difluoro-3-methoxybenzyl)-3-(3,3-difluorocyclobutyl)-1-(4-((5-fluoro-2-oxopyridine-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (compound 209) was prepared according to the following synthetic route: JPEG2026525258000139.jpg32128

[0341] To a solution of intermediate 8 (38 mg, 0.091 mmol) in DMF (2 mL), DIEA (35 mg, 0.27 mmol) and HATU (38 mg, 0.10 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Compound 209-1 (16 mg, 0.091 mmol) was then added to the reaction. This mixture was stirred at room temperature for 30 minutes. After monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 11:1) to obtain the title compound (11.41 mg, 21.89% yield) as a white solid. MS (ESI) m / z: 573.4 [M+H] + ;HPLC: 254 nm: 99.478%, 214 nm: 99.303%; 1 H NMR (400 MHz, DMSO) δ 8.27 (t, J = 5.1 Hz, 1H), 8.18 (s, 1H), 8.10 - 7.94 (m, 1H), 7.57 (ddd, J = 10.3, 7.2, 3.4 Hz, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.11 (td, J = 9.2, 5.1 Hz, 1H), 7.00 (t, J = 9.1 Hz, 1H), 6.43 (dd, J = 10.0, 5.4 Hz, 1H), 5.26 (s, 2H), 5.01 (s, 2H), 4.39 (d, J = 4.9 Hz, 2H), 3.81 (s, 3H), 3.75 (dd, J = 8.7, 6.1 Hz, 1H), 2.93 - 2.69 (m, 4H).

[0342] Example 35. N-((3-fluoro-4-(methylamino)pyridine-2-yl)methyl)-3-(oxetan-3-yl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (compound 260) was prepared according to the following synthetic route: JPEG2026525258000140.jpg29128

[0343] At room temperature, compound 260-1 (220 mg, 0.60 mmol), 1-hydroxybenzotriazole (122 mg, 0.90 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (172 mg, 0.9 mmol), and triethylamine (181 mg, 1.80 mmol) were sequentially added to N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 10 minutes. Compound intermediate 7 (126 mg, 0.73 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water (25 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride (50 mL), respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was separated and purified by column chromatography (dichloromethane:methanol = 0-10%) to obtain the title compound 260 (130 mg, yield: 43%) as a white solid. MS (ESI) M / Z: 503.21 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 6.0 Hz, 1H), 8.28 (s, 1H), 7.90 (d, J = 5.6 Hz, 1H), 7.77 (dd, J = 6.8, 2.0 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.30 - 7.21 (m, 4H), 6.58 - 6.49 (m, 2H), 6.42 - 6.37 (m, 1H), 6.26 - 6.19 (m, 1H), 5.30 (s, 2H), 5.07 (s, 2H), 4.79 (dd, J = 8.4, 5.6Hz, 2H), 4.68 (dd, J = 6.8, 5.6 Hz, 2H), 4.55 - 4.46 (m, 1H), 4.37 (dd, J = 5.6, 2.0 Hz, 2H), 2.73 (d, J = 4.8 Hz, 3H).

[0344] Using appropriate raw materials and following the same procedures as described in Examples 34 and 35, the compounds shown in the table below were prepared.

[0345] [Table 9] JPEG2026525258000142.jpg227147JPEG2026525258000143.jpg235154JPEG2026525258000144.jpg235154

[0346] Example 36. N-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-yl)methyl)-3-(methoxymethyl)-1-(4-(2-oxopyridine-1(2H)-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide (compound 144) was prepared according to the following synthetic route: JPEG2026525258000145.jpg80138

[0347] Step 1: Preparation of 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate tert-butyl: To a solution of 2,4-dichloro-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate tert-butyl (1.0 g, 3.45 mmol) in MeOH (30 mL), AcOH (2.07 g, 34.5 mmol) and Zn (900 mg, 13.8 mmol) were added, and the mixture was stirred at 70°C for 3 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated under reduced pressure, and the crude compound was purified by silica gel chromatography (eluting at PE:EA = 100:0 to 60:40) to obtain the desired title compound (600 mg, yield 68.03%). MS(ESI)M / Z: 256.0[M+H]+.

[0348] Step 2: Preparation of tert-butyl 2-vinyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate: Compound SM 2 (572 mg, 4.28 mmol) and Na2CO3 (906 mg, 8.55 mmol) were added to a solution of compound 144-2 (730 mg, 2.85 mmol) in 1,4-dioxane (20 mL) and water (4 mL). Pd(dppf)Cl2 (208 mg, 0.29 mmol) was added, and the mixture was stirred at 100°C for 3 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The reaction mixture was poured into 200 mL of water, and EA (200 mL) 3 Extraction was performed using ). The combined organic layers were dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting at PE:EA = 100:0 to 50:50) to obtain the desired title compound (600 mg, 84.99% yield) as a white solid. 1 H NMR (400 MHz, DMSO) δ 8.74 (d, J = 7.9 Hz, 1H), 6.82 (dd, J = 17.3, 10.5 Hz, 1H), 6.52 (d, J = 17.4 Hz, 1H), 5.74 (d, J = 10.7 Hz, 1H), 4.63 (d, J = 12.8 Hz, 2H), 4.54 (t, J = 16.2 Hz, 2H), 1.46 (s, 9H).

[0349] Step 3: Preparation of 2-formyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate tert-butyl: To a solution of compound 144-3 (500 mg, 2.02 mmol) in 1,4-dioxane (20 mL) and water (20 mL), NaIO4 (1.3 g, 6.06 mmol) and K2OsO4*2H2O (74 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After monitoring the completion of the reaction by LC-MS, the reaction mixture was poured into 100 mL of water, and EA (100 mL) was added. 3Extraction was performed using ). The combined organic matter was concentrated. The residue was purified by preparative TLC (EA:PE=1:1) to obtain the desired title compound (218 mg, yield 43.25%) as a white solid. MS(ESI)M / Z:268.2[M+H]+.

[0350] Step 4: Preparation of 2-(aminomethyl)-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate tert-butyl: Compound 144-4 (218 mg, 0.87 mmol) was dissolved in MeOH (2 mL), and NH3-MeOH (7.0 M, 5 mL) and AcOH (0.1 mL) were added to the solution. The mixture was stirred at room temperature for 30 minutes. Then, NaBH4 (20 mg, 0.52 mmol) was added to the mixture and stirred at room temperature for 30 minutes. After monitoring the completion of the reaction by LC-MS, the reaction mixture was diluted with H2O (80 mL) and DCM (80 mL) was added. 3 Extraction was performed using ). The combined organic layers were dried over anhydrous Na2SO4. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to obtain the title compound (105 mg, 47.97% yield). MS(ESI)M / Z: 251.2[M+H]+.

[0351] Step 5: Preparation of 2-((3-(methoxymethyl)-1-(4-(2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide)methyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate tert-butyl: To a solution of compound 2-3 (46 mg, 0.13 mmol) in DMF (3 mL), HATU (54 mg, 0.14 mmol) and DIEA (50 mg, 0.39 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Then, compound 144-5 (55 mg, 0.22 mmol) was added to the reaction. The mixture was stirred at room temperature for 1 hour. After monitoring the completion of the reaction by LCMS, the reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic matter was concentrated. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to obtain the desired title compound (36 mg, 47.22% yield) as a white solid. MS(ESI)M / Z: 586.7[M+H]+.

[0352] Step 6: Preparation of N-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-yl)methyl)-3-(methoxymethyl)-1-(4-(2-oxopyridine-1(2H)-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide: Compound 144-6 (30 mg, 0.051 mmol) was added to a solution of DCM (2 mL) and TFA (0.5 mL). The mixture was stirred at room temperature for 5 hours. After the reaction was complete, it was monitored by LC-MS. TEA (0.5 mL) was added to the reaction mixture. The mixture was concentrated. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to obtain the title compound (13.44 mg, 54.04% yield). MS(ESI)M / Z: 486.2[M+H]+. 1 H NMR (400 MHz, DMSO) δ 8.62 (t, J = 38.9 Hz, 2H), 8.28 (s, 1H), 7.80 - 7.68 (m, 1H), 7.41 (ddd, J = 8.8, 6.7, 2.0 Hz, 1H), 7.26 (q, J = 8.3 Hz, 4H), 6.40 (d, J = 9.1 Hz, 1H), 6.22 (t, J = 6.7 Hz, 1H), 5.29 (s, 2H), 5.07 (s, 2H), 4.72 - 4.43 (m, 6H), 4.06 (d, J = 39.7 Hz, 2H), 3.28 (s, 3H).

[0353] Using appropriate raw materials and following the same procedure as described in Example 36, the compounds shown in the table below were prepared.

[0354] [Table 10]

[0355] Example 37. N-((7-fluoro-1H-pyrrolo[3,2-c]pyridine-6-yl)methyl)-3-(oxetan-3-yl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (compound 337) was prepared according to the following synthetic route: JPEG2026525258000147.jpg28128

[0356] Compound 260-1 (40 mg, 0.11 mmol) was dissolved in DMF (3 mL), to which DIEA (43 mg, 0.33 mmol) and HATU (46 mg, 0.12 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. Intermediate 14 (25 mg, 0.12 mmol) was then added to the reaction. This mixture was stirred at room temperature for 30 minutes. After monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 11:1) and reverse-phase column chromatography to obtain the title compound (23.56 mg, 41.99% yield) as a white solid. MS (ESI) m / z: 513.5 [M+H] + ;HPLC: 254 nm: 98.115%, 214 nm: 98.620%; 1H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.35 (t, J = 5.4 Hz, 1H), 8.28 (s, 1H), 7.76 (dd, J = 6.8, 1.7 Hz, 1H), 7.51 (d, J = 3.1 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.26 (q, J = 8.4 Hz, 4H), 6.65 (t, J = 3.3 Hz, 1H), 6.40 (d, J = 9.1 Hz, 1H), 6.22 (td, J = 6.7, 1.3 Hz, 1H), 5.29 (s, 2H), 5.07 (s, 2H), 4.80 (dd, J = 8.5, 5.6 Hz, 2H), 4.69 (dd, J = 6.9, 5.7 Hz, 2H), 4.55 (ddd, J = 23.4, 10.4, 4.9 Hz, 3H).

[0357] Example 38. N-((7-fluoro-1H-pyrrolo[3,2-c]pyridine-6-yl)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (compound 362) and N-((7-fluoro-1-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridine-6-yl)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide (compound 369) were prepared according to the following synthetic route: JPEG2026525258000148.jpg26149

[0358] Step 1: Compound 12-2 (50 mg, 0.14 mmol) was dissolved in DMF (3 mL), to which DIEA (54 mg, 0.42 mmol) and HATU (59 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 5 minutes. Intermediate 14 (33 mg, 0.15 mmol) was then added to the reaction. The mixture was stirred at room temperature for 30 minutes. After monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) and reverse-phase column chromatography to obtain the title compound 362 (27.57 mg, 38.26% yield) as a white solid. MS (ESI) m / z: 457.2 [M+H] + .

[0359] Step 2: At room temperature, compound NaH (1.31 mg, 0.03 mmol, 60% in oil) was added to DMF (2 mL), replaced three times with N2, and compound 362 (10 mg, 0.02 mmol) was slowly added dropwise to the reaction mixture at 0°C. The mixture was reacted for 0.5 hours, and compound 2 (7.5 mg, 0.04 mmol) was slowly added dropwise to the reaction mixture. The temperature was raised to 70°C and the mixture was stirred for 72 hours. The mixture was purified by pre-TLC (DCM:MeOH=9:1, Rf=0.4) to obtain compound 369 (4.2 mg, 38.3% yield) as a white solid. MS (ESI) M / Z: 313.2[M+1] + ; 1H NMR (400 MHz, DMSO-D6) δ 8.53 (d, J = 2.1 Hz, 1H), 8.46 (t, J = 5.6 Hz, 1H), 8.20 (d, J = 0.7 Hz, 1H), 7.84 (d, J = 0.7 Hz, 1H), 7.71 (ddd, J = 6.8, 2.1, 0.7 Hz, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.37 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 6.58 (t, J = 2.9 Hz, 1H), 6.36 (ddd, J = 9.2, 1.4, 0.7 Hz, 1H), 6.18 (td, J = 6.7, 1.4 Hz, 1H), 5.26 (s, 2H), 5.02 (s, 2H), 4.91 (t, J = 5.3 Hz, 1H), 4.57 (dd, J = 5.6, 2.5 Hz, 2H), 4.29 (t, J = 5.6 Hz, 2H), 3.69 (q, J = 5.4 Hz, 2H).

[0360] Example 39. N-((7-fluoro-1-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-yl)methyl)-1-(4-(2-oxopyridine-1(2H)-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide (compound 383) was prepared according to the following synthetic route: JPEG2026525258000149.jpg28128

[0361] To a solution of compound 12-2 (35 mg, 0.11 mmol) in DMF (2.5 mL), DIEA (42 mg, 0.33 mmol) and HATU (46 mg, 0.12 mmol) were added, and the mixture was stirred at room temperature for 5 minutes. Then, compound intermediate 15 (47 mg, 0.22 mmol) was added to the reaction. This mixture was stirred at room temperature for 15 minutes. After monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH = 15:1) and reverse-phase column chromatography to obtain the title compound (35.72 mg, 66.81% yield) as a white solid. MS(ESI) m / z: 473.5[m+H]+; 1 H NMR (400 MHz, DMSO) δ 8.38 (t, J = 5.6 Hz, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.78 - 7.70 (m, 2H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.24 (q, J = 8.3 Hz, 4H), 6.40 (d, J = 9.1 Hz, 1H), 6.22 (td, J = 6.7, 1.3 Hz, 1H), 5.30 (s, 2H), 5.07 (s, 2H), 4.40 (dd, J = 5.5, 2.0 Hz, 2H), 3.46 (t, J = 8.7 Hz, 2H), 3.01 - 2.92 (m, 5H).

[0362] Using appropriate raw materials and following the same procedures as described in Examples 37, 38, and 39, the compounds shown in the table below were prepared.

[0363] [Table 11] JPEG2026525258000151.jpg246144JPEG2026525258000152.jpg30144

[0364] Test Example 1. In vitro inhibitory activity test of the compound of the present invention against plasma kallikrein (PKa), KLK1, and FXIa.

[0365] The ability of the compound of the present invention to inhibit plasma kallikrein (PKK), KLK1, and FXIa was measured in the presence of 1% (v / v) DMSO using the following biochemical assay in assay buffer (100 mM Tris, 150 mM NaCl, adjusted to pH 7.8 with HCl and containing 0.1% (w / v) BSA and 0.05% (v / v) Tween20): The PKK enzyme activity inhibition experiment of the compound was tested using the FI method. Solutions of PKK (R&D, Cat #2497-SE) and Pro-Phe-Arg-AMC (Nanjing Peptide, Cat #NJP23946) were prepared in reaction buffer (50 mM Tris-HCl, pH 7.5, 250 mM NaCl). The final concentrations of the enzyme protein and Pro-Phe-Arg-AMC in the reaction mixture were 10 nM and 60 μM, respectively. The starting concentration of the positive control Avoralstat was 100 nM, 3-fold dilution, and 10+0 dose. Using acoustic liquid dispensing technology (Echo665; nanoliter range), 0.05 μL of the compound in 100% DMSO was dispensed into a 384-well plate. The compound was tested in 2 wells. 5 μL of 2× enzyme solution was transferred to the 384-reaction plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 15 minutes; 5 μL of 2× Pro-Phe-Arg-AMC solution was transferred to the 384-reaction plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 3 hours. Finally, fluorescence was measured using a BMG and an Envision reader set to wavelength excitation at 355 nm and wavelength emission at 460 nm, and the FI signal (ex380 / em460) was read. IC was performed using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fittings were obtained.

[0366] This data is used to fit the optimal IC. 50 The values ​​obtained from these measurements are shown in Table 12 below, where the numbers correspond to the compound numbers. The control compounds were the PKa inhibitor KVD900 and berotralstat.

[0367] [Table 12] JPEG2026525258000154.jpg246152 JPEG2026525258000155.jpg244147 JPEG2026525258000156.jpg244147JPEG2026525258000157.jpg244147 JPEG2026525258000158.jpg244147JPEG2026525258000159.jpg244147JPEG2026525258000160.jpg244147 JPEG2026525258000161.jpg244147JPEG2026525258000162.jpg244147JPEG2026525258000163.jpg244147 JPEG2026525258000164.jpg25147

[0368] The above results demonstrate that the compound of the present invention has a potent inhibitory effect on plasma kallikrein (PKa) and exhibits high selectivity.

[0369] Test Example 2. Evaluation of the inhibitory effect of the compound of the present invention on PKa in kaolin-activated human PPP: Platelet-deficient plasma (PPP), obtained from human whole blood and treated with sodium citrate (Na citrate) anticoagulation, was incubated in assay buffer for 20 minutes at 37°C with various concentrations of the test compound and 25, 75, 250, or 750 μg / mL kaolin. The concentration response of the test compound was obtained for each dose of kaolin used. The positive drug was diluted according to the reference concentration, and the diluted solution was used as the first point for a 3-fold dilution.

[0370] Next, 50 nL of the compound was transferred to a 384 assay plate, with each well containing two repeats. The 384 assay plate was centrifuged at 1000 rpm. 2.5 μL of human plasma working solution was added to each assay well. The 384 assay plate was centrifuged at 1000 RPM. 2.5 μL of kaolin working solution was added to each assay well. The 384 assay plate was centrifuged at 1000 RPM and incubated at 25°C for 20 minutes. 5 μL of Pro-Phe-Arg-AMC working solution was added to each assay well. The 384 assay plate was centrifuged at 1000 RPM and incubated at 25°C for 60 minutes. The fluorescence signal was read using BMG.

[0371] The inhibition percentage of the compound was calculated according to the following formula: Compound (inhibition%) = 100 * (average value of negative control wells - compound well value) / (average value of negative control wells - average value of positive control wells) IC of the compound according to the present invention inhibits PKa in kaolin-activated human PPP. 50 The values ​​are shown in the table below, with the numbers corresponding to the compound numbers. The control compounds are the PKa inhibitor KVD900 and velotralstat.

[0372] [Table 13]

[0373] The above results indicate that the compound of the present invention has a potent inhibitory effect on plasma kallikrein (PKa) in kaolin-activated human PPP and is superior to the control compound.

[0374] To those skilled in the art, this disclosure is not limited to the explanatory embodiments described above and may be implemented in other specific forms without departing from the necessary attributes. Therefore, it is expected that all aspects are explanatory and not limiting, that the embodiments described above are merely illustrative examples to the appended claims, and that the referenced documents apply only to the appended claims and not to the embodiments described above, and that all modifications included within the meaning and scope of equivalence of claims are thus intended to be incorporated herein as expected.

[0375] All patents, patent applications, and references to documents described herein are incorporated herein in their entirety by reference. In the event of any conflict, the present disclosure, including definitions, shall prevail.

Claims

1. The compound represented by general formula (I), or a pharmaceutically acceptable prodrug or salt thereof. During the ceremony, Ring A is a 5- to 6-membered heteroaryl or phenyl; Ring B is a 5- to 10-membered monocyclic or bicyclic aryl or heteroaryl; m 4 is either 0 or 1; m 4 If is 1, ring C is selected from 5-6 membered heteroaryls, phenyls, and 9-10 membered bicyclic heteroaryls; m 4 If is 0, ring C is selected from a 5-6 member heteroaryl condensed with a 5-6 member heterocyclil, a phenyl condensed with a 5-6 member heterocyclil, a 5-6 member heteroaryl condensed with a C3-6 cycloalkyl, and a phenyl condensed with a C3-6 cycloalkyl; R 1 、R 2 、R 3 and 4 are each independently selected from H atom, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -(C 1-6 alkylene) n -C 1-6 alkoxyl and C 1-6 hydroxyalkyl; Ra is independently -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, -(C 1-6 Alkilen) n -OC 1-6 Alkylene-C 1-6 Alkoxyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Haloalkoxyl, -(C 1-6 Alkilen) n -C 3-6 Cycloalkyl, -(C 1-6 Alkilen) n -OC 3-6 Cycloalkyl, halogen, -OH, -SH, -NH 2 -C(O)NH 2 , -NO 2 ,-CN,C 2-6 Alkenil, C 2-6 Alkinyl, -C 1-6 Alkylene-OC 1-6 Alkylene-C(O)-NH 2 , -C 1-6 Alkylene-OC 1-6 Alkylene-C(O)-N(C) 1-6 Alkyl) 2 , -C 1-6 Alkylene-OC 1-6 Alkylene-C(O)-NH-C 1-6 Alkyl, -(C 1-6 Alkilen) n -5 to 6-membered heteroaryl, -O-(C 1-6 Alkilen) n -5 to 6-membered heteroaryl, -(C 1-6 Alkilen) n -4 to 7-membered monocyclic or bicyclic heterocyclils, -(C 1-6 Alkilen) n -O-(C 1-6 Alkilen) n -4 to 7-membered monocyclic or bicyclic heterocyclils, -NH-4 to 7-membered monocyclic or bicyclic heterocyclils, -N(C 1-6 Alkyl)-4 to 7-membered monocyclic or bicyclic heterocyclyl, -C 1-6 Alkylene-OC 1-6 Alkylene-NH 2 , -C 1-6 Alkylene-OC 1-6 Alkylene-N(C) 1-6 Alkyl) 2 and -C 1-6 Alkylene-OC 1-6 Alkylene-NH-C 1-6 Selected from alkyl, the C 1-6 Alkylenes, 5-6 membered heteroaryls, 4-7 membered monocyclic or bicyclic heterocyclines, and C 3-6 Each cycloalkyl group is independently C 1-6 Alkyl, oxo, -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 They may be substituted with one or more substituents selected from alkoxyls, halogens, and -OH groups; Rb is independently selected from halogen, -CN, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -O-(C 1-6 alkylene) n -C 3-6 cycloalkyl, -C(O)-C 3-6 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene) n -4- to 7-membered monocyclic or bicyclic heterocyclyl, -(C 1-6 alkylene) n -5- to 6-membered heteroaryl, -(C 1-6 alkylene) n -9- to 10-membered bicyclic heteroaryl, -C 2-6 alkenyl-C 3-6 cycloalkyl, phenyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxyl, -(C 1-6 alkylene) n -C 1-6 alkoxyl, -OH, -SH, -NH 2 , -C(O)NH 2 , -NO 2 , C 2-6 alkenyl, C 2-6 alkynyl, -(C 1-6 alkylene) n -4- to 7-membered monocyclic or bicyclic heterocyclyl fused to phenyl and -O-phenyl, and the C 3-6 cycloalkyl, 4- to 7-membered monocyclic or bicyclic heterocyclyl, 9- to 10-membered bicyclic heteroaryl, phenyl and 5- to 6-membered heteroaryl are each independently halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, -(C 1-6 alkylene) n -C 1-6 alkoxyl, C 1-6 hydroxyalkyl, -CN, -OH, -SH, -NH 2 , -C(O)NH 2 and -NO 2 They may be substituted with one or more substituents selected from; Each Rc is independently C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, -NH 2 , -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl) 2 ,-(C 1-6 Alkilen) n -C 1-6 Alkoxyl, formamidinyl, N-hydroxyformamidinyl, -C(=NH)-NH-C 1-6 Alkyl, -C(=NH)-N(C 1-6 Alkyl) 2 , C 1-6 Haloalkoxyl, C 1-6 Hydroxyalkyl, -CN, -OH, -SH, -SC 1-6 Alkyl, -C(O)NH 2 , -NO 2 , -C 1-6 Alkylene-NH 2 , -C 1-6 Alkylene-NH-C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -NH-(C 1-6 Alkilen) n -C 3-6 Cycloalkyl, -NH-(C 1-6 Alkilen) n - Selected from 3- to 6-membered heterocyclyls and 5- to 6-membered heteroaryls, the 3- to 6-membered heterocyclyls and 5- to 6-membered heteroaryls are each independently C 1-6 Alkyl, oxo, -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 They may be substituted with one or more substituents selected from alkoxyls, halogens, and -OH groups; Alternatively, two adjacent Rc atoms, together with the atom they are bonded to, become C 3-6 Forming a cycloalkyl or a 5-6 membered heterocycline, the C 3-6 Cycloalkyl or 5-6 membered heterocyclyl molecules are each independently C 1-6 Alkyl, oxo, -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 They may be substituted with one or more substituents selected from alkoxyls, halogens, and -OH groups; The heterocyclyl and heteroaryl each contain a heteroatom selected from 1, 2, 3, or 4 N, O, and S atoms; m 1 is 0, 1, or 2; m 2 is 0, 1, 2, or 3; m 3 is 0, 1, 2 or 3; and Each n is independently either 0 or 1.

2. The compound according to claim 1, or a pharmaceutically acceptable prodrug or salt thereof, which is a compound represented by general formula (II), or a pharmaceutically acceptable prodrug or salt thereof. During the ceremony, Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , R 4 Ra, Rb, Rc, m 1 , m 2 and m 3 This is as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable prodrug or salt thereof, which is a compound represented by general formula (III), or a pharmaceutically acceptable prodrug or salt thereof. During the ceremony, Ring A, Ring B, Ring C, Ra, Rb, Rc, m 1 , m 2 and m 3 This is as defined in claim 1.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable prodrug or salt thereof, which is a compound represented by general formula (IV), or a pharmaceutically acceptable prodrug or salt thereof. During the ceremony, Ring A, Ring B, Ra, Rb, Rc, m 1 , m 2 and m 3 This is as defined in claim 1; Ring C is selected from a 5-6 member heteroaryl condensed with a 5-6 member heterocyclil, a phenyl condensed with a 5-6 member heterocyclil, a 5-6 member heteroaryl condensed with a C3-6 cycloalkyl, and a phenyl condensed with a C3-6 cycloalkyl; In particular, ring C is selected from cyclopentapyridyl, cyclopentaimidazolyl, and dihydrofuranopyridinyl.

5. Ring A is selected from triazolyl, pyrazolyl, thiazolyl, oxadiazolyl, oxazolyl, thienyl, thiadiazolyl, pyridyl, isoxazolyl, imidazolyl, pyrrolyl, furyl, isothiazolyl, phenyl, pyrimidyl, pyrazinyl, pyridadinyl, triazinyl, and tetrazolyl; especially,

6. Ring B is selected from phenyl, quinolyl, imidazopyridyl, pyridyl, imidazolyl, naphthyl, triazolyl, pyrazolyl, thiazolyl, oxadiazolyl, oxazolyl, thienyl, thiadiazolyl, isoxazolyl, pyrrolyl, furyl, isothiazolyl, phenyl, pyrimidyl, pyrazinyl, pyridadinyl, triazinyl, isoquinolyl, indolyl, indazolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, and benzthiazolyl; especially, Any compound listed in any one of the items, or a pharmaceutically acceptable prodrug or salt thereof.

7. Ring C is selected from pyridyl, phenyl, pyrimidyl, thiadiazolyl, thiazolyl, triazolyl, pyrazolyl, oxadiazolyl, oxazolyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, furyl, isothiazolyl, pyrazinyl, pyridadinyl, triazinyl, isoquinolyl, pyrrolopyridyl, imidazopyridyl, triazolopyridyl, benzisoxazolyl, benzthiazolyl, and pyrazolopyridyl; especially, A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable prodrug or salt thereof.

8. Ra is independent of each other, -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, -(C 1-6 Alkilen) n -OC 1-6 Alkylene-C 1-6 Alkoxyl, -(C 1-6 Alkilen) n -4 to 7-membered monocyclic or bicyclic heterocyclils, -(C 1-6 Alkilen) n -O-(C 1-6 Alkilen) n -4- to 7-membered monocyclic or bicyclic heterocyclils, -NH-4- to 7-membered monocyclic or bicyclic heterocyclils, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Haloalkoxyl, -(C 1-6 Alkilen) n -C 3-6 Cycloalkyl, -(C 1-6 Alkilen) n -OC 3-6 Cycloalkyl, halogen, -CN, -C 1-6 Alkylene-OC 1-6 Alkylene-C(O)-N(C) 1-6 Alkyl) 2 ,-(C 1-6 Alkilen) n -5 to 6-membered heteroaryl, -O-(C 1-6 Alkilen) n -5 to 6-membered heteroaryls and -C 1-6 Alkylene-OC 1-6 Alkylene-N(C) 1-6 Alkyl) 2 Selected from, the C 1-6 Alkylenes, 5-6 membered heteroaryls, 4-7 membered monocyclic or bicyclic heterocyclines, and C 3-6 Each cycloalkyl group is independently C 1-6 Alkyl, oxo, -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 The substituents may be substituted with one, two, three, or four substituents selected from alkoxyls, halogens, and -OH, where n is independently 0 or 1, and the 4- to 7-membered monocyclic or bicyclic heterocyclils and 5- to 6-membered heteroaryls each independently contain one, two, or three heteroatoms selected from N, O, and S atoms, preferably selected from pyrimidyl, pyrazolyl, pyridyl, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, oxetanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxabicyclo[2.2.1]heptanyl, isoxazolyl, tetrahydropyranyl, pyrazinyl, and 1-oxa-6-azaspiro[3.3]heptanyl; Selected from; and / or Rb is independent of halogen, -CN, and -(C) 1-6 Alkilen) n -C 3-6 Cycloalkyl, -OC 1-6 Alkylene-C 3-6 Cycloalkyl, -C(O)-C 3-6 Cycloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, -(C 1-6 Alkilen) n -4 to 7-membered monocyclic or bicyclic heterocyclils, -C 1-6 Alkylene-5 to 6-membered heteroaryl, -C 1-6 Alkylene-9 to 10-membered bicyclic heteroaryl, -C 2-6 Alkenil-C 3-6 Cycloalkyl, -(C 1-6 Alkilen) n -Selected from 4- to 7-membered monocyclic or bicyclic heterocyclils condensed with phenyl and -O-phenyl, where n is independently 0 or 1, and the 4- to 7-membered monocyclic or bicyclic heterocyclil, 9- to 10-membered bicyclic heteroaryl, phenyl and 5- to 6-membered heteroaryl are independently halogen, oxo, and C 1-6 Alkyl and C 1-6 They may be substituted with one, two, or three substituents selected from haloalkyls, and the 4- to 7-membered monocyclic or bicyclic heterocyclil, 9- to 10-membered bicyclic heteroaryl, and 5- to 6-membered heteroaryl each independently contain one, two, or three heteroatoms selected from N, O, and S atoms, preferably selected from dihydropyridyl, 3-azabicyclo[3.1.0]hexyl, pyrazolyl, morpholinyl, piperidinyl, pyrrolopyridyl, 7-azabicyclo[2.2.1]heptanyl, azepinyl, azetidinyl, 2-azabicyclo[2.2.1]heptanyl, pyrrolidinyl, 5-azaspiro[2.4]heptanyl, thiazolidinyl, indazolyl, dihydropyrimidyl, and triazolyl; and / or Each Rc is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, -NH 2 , -C 1-6 Alkylene-NH 2 , -C 1-6 Alkylene-NH-C 1-6 Alkyl, -(C 1-6 Alkilen) n -C 1-6 Alkoxyl, formamidinyl, N-hydroxyformamidinyl, -C(=NH)-NH-C 1-6 Alkyl, -SC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl) 2 , C 1-6 Hydroxyalkyl, -CN, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, -NH-(C 1-6 Alkilen) n -C 3-6 Cycloalkyl, -NH-(C 1-6 Alkilen) n - Selected from 3- to 6-membered heterocyclyls and 5- to 6-membered heteroaryls, where n is independently 0 or 1, and the 3- to 6-membered heterocyclyls and 5- to 6-membered heteroaryls are independently C 1-6 Alkyl, oxo, C 1-6 The 3-6 membered heterocyclyl and 5-6 membered heteroaryl each independently contain one, two, or three heteroatoms selected from alkoxyls, halogens, and -OH groups, preferably selected from pyrrolidinyl, azetidinyl, oxetanyl, and triazolyl groups; Alternatively, two adjacent Rc atoms, together with the atom they are bonded to, form piperazinyl, piperidinyl, pyrrolidinyl, or dihydrofuran, and each of these piperazinyl, piperidinyl, pyrrolidinyl, or dihydrofurans is independently C 1-6 Alkyl, oxo, C 1-6 It may be substituted with one, two, or three substituents selected from alkoxyls, halogens, and -OH groups; In particular, Rc is independently methyl, -NH 2 ,-CH 2 NH 2 ,-CH 2 NHCH 3 F atom, methoxy, difluoromethyl, formamidinyl, N-hydroxyformamidinyl, Cl atom, ethyl, Cetanyl, Azetidinyl, A compound according to any one of claims 1 to 7, selected from and hydroxyethyl, or a pharmaceutically acceptable prodrug or salt thereof.

9. , or a pharmaceutically acceptable prodrug or salt thereof.

10. A compound according to any one of claims 9, or a pharmaceutically acceptable prodrug or salt thereof. The compound according to Claim 11, or a pharmaceutically acceptable prodrug or salt thereof.

12. Each Rc is formamidinyl, N-hydroxyformamidinyl, or -NH 2 If selected, the pharmaceutically acceptable prodrug of the compound is: Formamidinyl and -NH 2 C 1-6 Carbonate ester; N-hydroxyformamidinyl C 1-6 Carbonate ester, C 1-6 Selected from carboxylic acid esters, phenylcarboxylic acid esters, or pyridylcarboxylic acid esters, the phenylcarboxylic acid esters and pyridylcarboxylic acid esters contain one or more halogens, C 1-6 Alkyl or C 1-6 It is also acceptable if substituted with an alkoxyl; and / or The pharmaceutically acceptable salt is selected from toluenesulfonate, methylsulfonate, hydrochloride, acetate, and citrate, and is a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable prodrug or salt thereof.

13. A compound selected from any one of claims 1 to 12, or a pharmaceutically acceptable prodrug or salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable prodrug or salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

15. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable prodrug or salt thereof, or the pharmaceutical composition according to claim 14, in the manufacture of a drug for treating hereditary angioedema (HAE) and post-stroke cerebral edema and for neuroprotection.

16. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable prodrug or salt thereof, or the pharmaceutical composition according to claim 14, in the manufacture of a drug for treating cerebral edema and nerve damage caused by stroke.

17. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable prodrug or salt thereof, or the pharmaceutical composition according to claim 14, in the manufacture of a drug for treating microvascular lesion-related disorders of the eye. In particular, the microvascular lesion-related disorders of the eye are selected from diabetic retinopathy, diabetic macular edema, retinal vein occlusion, central retinal vein occlusion, macular degeneration, retinopathy of prematurity, neovascular glaucoma, retinitis pigmentosa, proliferative and non-proliferative retinopathy, retinal angiomatoid proliferation, macular telangiectasia, ischemic retinopathy, iris neovascularization, intraocular neovascularization, corneal neovascularization, retinal neovascularization, polypoidal choroidal angiopathy, choroidal neovascularization, retinal degeneration, diabetic retinopathy, and diabetic macular edema-related diabetic complications of retinal vascular permeability; in particular, they are selected from diabetic retinopathy, diabetic macular edema, retinal vein occlusion, central retinal vein occlusion, and wet age-related macular degeneration.

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