Heteroaromatic formamide compound and application thereof in medicine

Abstract

The invention relates to a heteroaromatic formamide compound and application thereof in medicine. Specifically, the invention relates to a heteroaromatic formamide compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, in particular to application of the compound as a therapeutic agent for plasma kallikins, kallikins, kallikins, kallikins, kallikins, kallikins, kallikins, kallikins, kallikins, kallikins and kallikins. The present invention relates to the use of a PKa selective inhibitor and to the use in the treatment and / or prevention of diseases that may benefit from plasma kallikrein inhibition, in particular for the prevention and / or treatment of diabetic macular edema (DME), age-related macular degeneration (AMD), choroidal neovascularization, hereditary angioedema (HAE), cerebral edema after stroke, and the like, and more particularly to the use in the prevention and / or treatment of diabetic macular edema (DME), age-related macular degeneration (AMD), choroidal neovascularization, hereditary angioedema (HAE), cerebral edema after stroke, etc. # imgabs0 #

Description

Heteroaromatic carboxamide compounds and their applications in medicine Technical Field

[0001] The present invention belongs to the field of biopharmaceuticals and relates to heteroaromatic carboxamide derivatives and their applications in medicine. Specifically, the present invention relates to a heteroaromatic carboxamide compound represented by general formula (I), a pharmaceutical composition containing the compound, and its use as a therapeutic agent, in particular, a method for synthesizing the compound and its pharmaceutically acceptable salts, and a method for preparing the compound as a selective inhibitor of human plasma kallikrein. Background Art

[0002] The kallikrein-kinin system (KKS) consists of two independently regulated proteolytic pathways, mediated by tissue kinin (TK) and tissue kinin (PK), which generate bradykinin and stimulate the bradykinin receptor, respectively. The effects of KKS on retinal vascular permeability are primarily mediated by bradykinin. Both TK and PK are widely distributed in various tissues and may be regulated by different mechanisms. Components of plasma KKS are primarily synthesized in the liver and secreted into the blood. Plasma prekallikrein (PPK), a component of the KKS signaling pathway, is an abundant serine protease zymogen that is converted to catalytically active plasma kallikrein (PKa) by factor XIIa (FXIIa) and participates in inflammatory responses. PKa cleaves kininogen to produce bradykinin. Bradykinin (BK) is a non-peptide that stimulates the BK receptor, which is abundantly expressed in vascular cells, glial cells, and neurons. BK is a strong inflammatory factor. Activation of BK receptors can bind to B1R and B2R, which can promote the increase of bradykinin levels by stimulating the release of mediators such as eicosanoids, endothelial-derived hyperpolarizing factor, NO, propylene glycol, tissue plasminogen activator (tPA) and glucose transporter-1 / 2 (glu1 / 2), further mediating multiple signal cascade reactions. These mediators, together with inflammation, angiogenesis, vasodilation and increased vascular permeability, can induce the formation of DME.

[0003] Plasma kallikrein plays a role in a variety of inflammatory disorders and can have many effects in disorders such as hereditary angioedema (HAE), retinopathy or diabetic retinopathy, proliferative and non-proliferative retinopathy, diabetic macular edema (DME), clinically important macular edema, cystoid macular edema, CME after cataract extraction, CME induced by cryotherapy, CME induced by uveitis, endophthalmitis, vascular embolism, retinal edema, complications associated with cataract surgery for diabetic retinopathy, hypertensive retinopathy, retinal damage, dry and wet age-related macular degeneration (AMD), polypoidal choroidal vasculopathy, vitreous detachment after choroidal neovascularization, for example in conjunction with tissue and / or organ transplantation. Ischemia-reperfusion injury in all kinds of situations associated with it, surgically induced brain injury, focal cerebral ischemia, global cerebral ischemia, glioma-associated edema, spinal cord injury, pain, ischemia, cerebral ischemia, neurological and cognitive deficits, 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 transformation of ischemic stroke, blood coagulation disorders such as thrombosis, itching, inflammatory disorders (such as multiple sclerosis), encephalitis, Alzheimer's disease, increased blood pressure associated with diabetes or hyperlipidemia, renal insufficiency, chronic kidney disease, heart failure, Microalbuminuria, albuminuria, proteinuria, cerebral hemorrhage, deep vein thrombosis, coagulation after fibrinolytic therapy, angina, angioedema, sepsis, lupus, gout, psoriasis, inflammatory bowel disease, diabetes, diabetic complications, Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, stroke, epilepsy, allergic edema, such as airflow obstruction from long-standing allergic sinusitis or perennial rhinitis; airflow obstruction from acute asthma, and other diseases.

[0004] Plasma kallikrein inhibitors are considered useful in treating a wide range of conditions, particularly in treating edema in diseases such as ischemia-reperfusion injury associated with stroke, retinopathy or edema-associated diseases such as hereditary angioedema, macular edema, and cerebral edema.

[0005] Currently, treatments for acute ischemic stroke primarily consist of general management and specific therapies. Specific therapies are key to treating ischemic stroke and primarily include improving cerebral blood circulation and neuroprotection. The earlier neuroprotection is initiated and the progression of brain neuronal death is mitigated, the more effectively it can prevent harmful substances from damaging the brain, buying more time for the brain. Currently, edaravone and butylphthalide are the mainstream neuroprotective drugs in clinical practice in China. Others include citicoline, monosialotetrahexosylganglioside sodium, and cinepazide. However, overall therapeutic efficacy is suboptimal, and their use as adjunctive medications remains elusive. The development of new, effective, and safe anti-stroke drugs or drug combinations is urgently needed to address these pressing clinical needs. Because cerebral ischemic injury is associated with multiple mechanisms, including excessive free radical formation, excitatory amino acid toxicity, intracellular calcium overload, and inflammatory responses, regardless of the underlying mechanism, the ultimate outcome is neuronal cell death, functional impairment, and the formation of cerebral infarction. The kallikrein-kinin system (KKS) mediates thrombosis, vascular permeability, and blood pressure changes during cerebral ischemia. The contact kinin pathway is initiated by activation of coagulation factor XIIa (FXIIa), which cleaves plasma prekallikrein to plasma kallikrein (PK). PK then acts on high-molecular-weight kininogen, inducing the release of the proinflammatory peptide hormone bradykinin (BK). BK binds to its endothelial bradykinin receptors 1 and 2 (B1R / B2R), initiating several inflammatory signaling cascades that lead to thrombin generation and the influx of circulating immune cells, ultimately leading to thrombosis and neuroinflammation. Inhibition of PK after stroke can significantly reduce cerebral thrombosis, stabilize the blood-brain barrier, and thus reduce the number of brain-infiltrating immune cells (Seminars in Immunopathology 2023, 45:389–410). At the same time, inhibition of PK can also reduce NMDA receptor-mediated excitotoxicity and ischemic neuronal death (Stroke 2014, Vol 45, Issue suppl_1, Abstract W P210).

[0006] Current conventional neuroprotective mechanisms have limited clinical benefits. The KKS system is closely associated with stroke-related bleeding, edema, inflammation, and neuroprotection. PK inhibition can significantly mitigate stroke-induced cerebral thrombosis, stabilize the blood-brain barrier, and thereby reduce the number of brain-infiltrating immune cells. It can also inhibit NMDA receptor-mediated excitotoxicity and ischemic neuronal death, significantly reducing the extent of cerebral infarction.

[0007] Plasma kallikrein inhibitors are considered particularly useful in the treatment of retinal diseases such as diabetic macular edema (DME) associated with diabetes and / or hypertension.

[0008] Proteomic analysis of vitreous samples from patients with diabetic macular hole (DME) revealed an 11.0-fold increase in plasma prekallikrein (PPK) and plasma kallikrein (PK) compared to control vitreous samples from patients with macular holes (p<0.0001) (Diabetes 2015, 64, 3588–3599). Studies have shown that systemic administration of a PKal inhibitor reduces retinal vascular permeability and retinal blood flow abnormalities in diabetic mice (Diabetes 2011, 60, 590–1598). Additional preclinical evidence suggests that plasma kallikrein (PK) may contribute to VEGF-mediated retinal edema (Investig. Ophthalmol. Vis. Sci. 2016, 57, 2390–2399). Current treatment strategies for DR and DME are primarily limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatments are not universally effective in all patients, and potential side effects persist in a significant proportion of patients. Currently, the treatment of DME mainly relies on anti-VEGF therapy, but some patients (about 50%) do not respond to VEGF therapy. This means that nearly 50% of patients cannot receive effective treatment. Preclinical studies have shown that activation of KKS in the eye can induce retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis of the vitreous of DME eyes showed that the KKS and VEGF pathways are potential independent biological pathways. In addition, the correlation between DME-related proteins in the vitreous and the KKS pathway is significantly higher than that with the VEGF pathway. Preclinical experiments in 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).

[0009] The present invention provides a method for preparing a novel highly selective and effective PKa small molecule inhibitor.

[0010] Summary of the Invention

[0011] The present invention provides a novel selective plasma kallikrein small molecule inhibitor, which provides an effective treatment solution for diseases such as stroke, HAE, diabetic macular edema (DME) and age-related macular degeneration (AMD) caused by retinal microvascular disorders.

[0012] Specifically, the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable prodrug or salt thereof:

[0013] in,

[0014] Ring A is a 5-6 membered heteroaryl group or a phenyl group;

[0015] Ring B is a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group;

[0016] m4 is 0 or 1;

[0017] When m4 is 1, ring C is selected from 5-6 membered heteroaryl, phenyl and 9-10 membered bicyclic heteroaryl;

[0018] When m4 is 0, ring C is selected from a 5-6 membered heteroaryl fused to a 5-6 membered heterocyclic group, a phenyl fused to a 5-6 membered heterocyclic group, a 3-6 Cycloalkyl fused 5-6 membered heteroaryl and C 3-6 cycloalkyl-fused phenyl;

[0019] R 1 、R 2 、R 3 and R 4 Each independently selected H atom, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 alkylene) n -C 1-6 Alkoxy and C 1-6 hydroxyalkyl;

[0020] Each Ra is independently selected from -(C 1-6 alkylene) n -C 1-6 Alkoxy, -(C 1-6 alkylene) n -OC 1-6 Alkylene-C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkoxy, -(C 1-6 alkylene) n -C 3-6 Cycloalkyl, -(C 1-6 alkylene) n -OC 3-6 Cycloalkyl, halogen, -OH, -SH, -NH2, -C(O)NH2, -NO2, -CN, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 1-6Alkylene-C(O)-NH-C 1-6 Alkyl, -(C 1-6 alkylene) n -5-6 membered heteroaryl, -O-(C 1-6 alkylene) n -5-6 membered heteroaryl, -(C 1-6 alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -(C 1-6 alkylene) n -O-(C 1-6 alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -NH-4-7 membered monocyclic or bicyclic heterocyclic group, -N(C 1-6 alkyl)-4-7 membered monocyclic or bicyclic heterocyclic group, -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 Alkyl, the C 1-6 Alkylene, 5-6 membered heteroaryl, 4-7 membered monocyclic or bicyclic heterocyclic group and C 3-6 The cycloalkyl groups are each independently optionally selected from C 1-6 Alkyl, oxo, -(C 1-6 alkylene) n -C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 substituted by one or more substituents selected from alkoxy, halogen and -OH;

[0021] Each 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 -4-7 membered monocyclic or bicyclic heterocyclic group, -(C 1-6 alkylene) n -5-6 membered heteroaryl, -(C 1-6 alkylene) n-9-10 membered bicyclic heteroaryl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, phenyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy, -(C 1-6 alkylene) n -C 1-6 Alkoxy, -OH, -SH, -NH2, -C(O)NH2, -NO2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 1-6 alkylene) n - a 4-7 membered monocyclic or bicyclic heterocyclic group fused to a phenyl group and -O-phenyl, said C 3-6 Cycloalkyl, 4-7 membered monocyclic or bicyclic heterocyclic group, 9-10 membered bicyclic heteroaryl, phenyl and 5-6 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, -(C 1-6 alkylene) n -C 1-6 Alkoxy, C 1-6 Substituted with one or more substituents selected from hydroxyalkyl, -CN, -OH, -SH, -NH2, -C(O)NH2 and -NO2;

[0022] Each Rc is independently selected from 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 Alkoxy, carbamimidoyl, N-hydroxycarbamimidoyl, -C(=NH)-NH-C 1-6 Alkyl, -C(=NH)-N(C 1-6 Alkyl)2, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -CN, -OH, -SH, -SC 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, 3-6 membered heterocyclic group, -NH-(C 1-6 alkylene) n -C 3-6Cycloalkyl, -NH-(C 1-6 alkylene) n - 3-6 membered heterocyclic group and 5-6 membered heteroaryl, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl are each independently optionally selected from C 1-6 Alkyl, oxo, -(C 1-6 alkylene) n -C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 substituted by one or more substituents selected from alkoxy, halogen and -OH;

[0023] Alternatively, two adjacent Rc atoms together with their attached atoms form a C 3-6 Cycloalkyl or 5-6 membered heterocyclic group, the C 3-6 Cycloalkyl or 5-6 membered heterocyclic group are each independently optionally selected from C 1-6 Alkyl, oxo, -(C 1-6 alkylene) n -C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 substituted by one or more substituents selected from alkoxy, halogen and -OH;

[0024] The heterocyclic group and heteroaryl group each contain 1, 2, 3 or 4 heteroatoms selected from N, O and S atoms;

[0025] m1 is 0, 1, or 2;

[0026] m2 is 0, 1, 2, or 3;

[0027] m3 is 0, 1, 2, or 3; and

[0028] Each n is independently 0 or 1.

[0029] In some embodiments of the present invention, the compound represented by general formula (I) or a pharmaceutically acceptable prodrug or salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable prodrug or salt thereof,

[0030] in,

[0031] Ring A, Ring B, Ring C, R 1 、R 2 、R 3 、R 4 , Ra, Rb, Rc, m1, m2 and m3 are as defined in the general formula (I).

[0032] 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 a compound represented by general formula (III) or a pharmaceutically acceptable prodrug or salt thereof,

[0033] in,

[0034] Ring A, Ring B, Ring C, Ra, Rb, Rc, m1, m2 and m3 are as defined in the general formula (I).

[0035] 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 a compound represented by general formula (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0036] in,

[0037] Ring A, Ring B, Ra, Rb, Rc, m1, m2 and m3 are as defined in the general formula (I);

[0038] Ring C is selected from a 5-6 membered heteroaryl fused to a 5-6 membered heterocyclic group, a phenyl fused to a 5-6 membered heterocyclic group, a C 3-6 Cycloalkyl fused 5-6 membered heteroaryl and C 3-6 cycloalkyl-fused phenyl;

[0039] In particular, ring C is selected from cyclopentapyridinyl, cyclopentamidazolyl and dihydrofuropyridinyl.

[0040] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0041] Ring A is selected from the group consisting of triazolyl, pyrazolyl, thiazolyl, oxadiazolyl, oxazolyl, thienyl, thiadiazolyl, pyridinyl, isoxazolyl, imidazolyl, pyrrolyl, furanyl, isothiazolyl, phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl and tetrazolyl;

[0042] In particular,

[0043] Selected from

[0044] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0045] Ring B is selected from phenyl, quinolinyl, imidazopyridinyl, pyridinyl, imidazolyl, naphthyl, triazolyl, pyrazolyl, thiazolyl, oxadiazolyl, oxazolyl, thienyl, thiadiazolyl, isoxazolyl, pyrrolyl, furanyl, isothiazolyl, phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, isoquinolinyl, indolyl, indazolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl and benzothiazolyl;

[0046] In particular,

[0047] Selected from

[0048] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0049] Ring C is selected from the group consisting of pyridyl, phenyl, pyrimidinyl, thiadiazolyl, thiazolyl, triazolyl, pyrazolyl, oxadiazolyl, oxazolyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, furanyl, isothiazolyl, pyrazinyl, pyridazinyl, triazinyl, isoquinolinyl, pyrrolopyridinyl, imidazopyridinyl, triazolopyridinyl, benzisoxazolyl, benzothiazolyl, and pyrazolopyridinyl;

[0050] In particular,

[0051] Selected from

[0052] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0053] Each Ra is independently selected from -(C 1-6 alkylene) n -C 1-6 Alkoxy, -(C 1-6 alkylene) n -OC 1-6 Alkylene-C 1-6 Alkoxy, -(C 1-6 alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -(C 1-6 alkylene) n -O-(C 1-6 alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -NH-4-7 membered monocyclic or bicyclic heterocyclic group, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6Alkyl, C 1-6 Halogenated alkoxy, -(C 1-6 alkylene) n -C 3-6 Cycloalkyl, -(C 1-6 alkylene) 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 alkylene) n -5-6 membered heteroaryl, -O-(C 1-6 alkylene) n -5-6 membered heteroaryl and -C 1-6 Alkylene-OC 1-6 Alkylene-N(C 1-6 Alkyl) 2, the C 1-6 Alkylene, 5-6 membered heteroaryl, 4-7 membered monocyclic or bicyclic heterocyclic group and C 3-6 The cycloalkyl groups are each independently optionally selected from C 1-6 Alkyl, oxo, -(C 1-6 alkylene) n -C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 substituted by one, two, three or four substituents of alkoxy, halogen and -OH, each n is independently 0 or 1, and the 4-7 membered monocyclic or bicyclic heterocyclic group and the 5-6 membered heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O and S atoms, preferably selected from pyrimidine, pyrazolyl, pyridinyl, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, oxetanyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azabicyclo[2.2.1]heptyl, isoxazolyl, tetrahydropyranyl, pyrazinyl and 1-oxa-6-azaspiro[3.3]heptyl;

[0054] In particular, each Ra is independently selected from Tetrahydrofuranyl, oxetanyl, difluoromethyl, trifluoromethyl, methyl, Cl atom, -CN, Morpholinyl, Pyrazinyl, pyrimidinyl,

[0055] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0056] Each Rb is independently selected from halogen, -CN, -(C 1-6 alkylene) 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 Halogenated alkyl, C 1-6 Alkoxy, -(C 1-6 alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -C 1-6 Alkylene-5-6 membered heteroaryl, -C 1-6 Alkylene-9-10 membered bicyclic heteroaryl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 1-6 Alkylene-phenyl fused 4-7 membered monocyclic or bicyclic heterocyclic group and -O-phenyl, each n is independently 0 or 1, the 4-7 membered monocyclic or bicyclic heterocyclic group, 9-10 membered bicyclic heteroaryl, phenyl and 5-6 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl and C 1-6 The alkyl group is substituted by one, two or three substituents of the alkyl group, wherein the 4-7 membered monocyclic or bicyclic heterocyclic group, the 9-10 membered bicyclic heteroaryl group and the 5-6 membered heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O and S atoms, preferably selected from dihydropyridyl, 3-azabicyclo[3.1.0]hexanyl, pyrazolyl, morpholinyl, piperidinyl, pyrrolopyridinyl, 7-azabicyclo[2.2.1]heptanyl, aza yl, azetidinyl, 2-azabicyclo[2.2.1]heptanyl, pyrrolidinyl, 5-azaspiro[2.4]heptanyl, thiazolidinyl, indazolyl, dihydropyrimidinyl, and triazolyl;

[0057] In particular, each Rb is independently selected from Cl atom, -CN, Cyclopropyl, F atom, Methyl, ethyl, Cl atoms, trifluoromethyl, cyclohexyl, Methoxy, ethoxy,

[0058] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0059] Each Rc is independently selected from 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 alkylene) n -C 1-6 Alkoxy, carbamimidoyl, N-hydroxycarbamimidoyl, -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 heterocyclic group, -NH-(C 1-6 alkylene) n -C 3-6 Cycloalkyl, -NH-(C 1-6 alkylene) n -3-6 membered heterocyclic group and 5-6 membered heteroaryl group, each n is independently 0 or 1, and the 3-6 membered heterocyclic group and 5-6 membered heteroaryl group are each independently optionally selected from C 1-6 Alkyl, oxo, C 1-6 substituted by one, two or three substituents selected from alkoxy, halogen and -OH, the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O and S atoms, preferably selected from pyrrolidinyl, azetidinyl, oxetanyl and triazolyl;

[0060] Alternatively, two adjacent Rc together with the atom to which they are attached form a piperazinyl, piperidinyl, pyrrolidinyl or dihydrofuran, wherein the piperazinyl, piperidinyl, pyrrolidinyl or dihydrofuran is each independently optionally selected from C 1-6 Alkyl, oxo, C 1-6 substituted by one, two or three substituents of alkoxy, halogen and -OH;

[0061] In particular, each Rc is independently selected from methyl, -NH2, -CH2NH2, -CH2NHCH3, F atom, methoxy, difluoromethyl, carbamimidoyl, N-hydroxycarbamimidoyl, Cl atom, ethyl, methylthio, -N(CH3)2, -NH-CH3, -CN, Pyrrolidinyl, cyclopropyl, -C(=NH)-NH-CH3, -NH-cyclobutyl, -NH-CH2-cyclopropyl, -NH-CH2-oxetanyl, azetidinyl, and hydroxyethyl.

[0062] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof, Selected from

[0063] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0064] Selected from

[0065] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0066] Selected from

[0067] In some embodiments of the present invention, in the compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable prodrug or salt thereof,

[0068] When each Rc is selected as carbamimidoyl, N-hydroxycarbamimidoyl or -NH2, the pharmaceutically acceptable prodrug of the compound is selected from:

[0069] C of carbamimidoyl and -NH2 1-6 Carbonate;

[0070] N-hydroxycarbamimidoyl C 1-6 Carbonate, C 1-6 Carboxylate, phenylcarboxylate or pyridinecarboxylate, phenylcarboxylate and pyridinecarboxylate may be substituted by one or more halogens, C 1-6 Alkyl or C 1-6 substituted with alkoxy;

[0071] and / or

[0072] The pharmaceutically acceptable salt is selected from toluenesulfonate, methanesulfonate, hydrochloride, acetate and citrate.

[0073] Typical compounds of the present invention include, but are not limited to:

[0074] The present invention also provides a method for preparing the compound represented by general formula (I), which comprises:

[0075] The compound represented by general formula (IA) and the compound represented by general formula (IB) can undergo 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);

[0076] in,

[0077] Ring A, Ring B, Ring C, R 1 -R 4 , Ra, Rb, Rc, m1, m2, m3 and m4 are as defined in the general formula (I).

[0078] The present invention also provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

[0079] The compound represented by general formula (IA) and the compound represented by general formula (IIB) can undergo 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);

[0080] in,

[0081] Ring A, Ring B, Ring C, R 1 -R 4 , Ra, Rb, Rc, m1, m2 and m3 are as defined in the general formula (I).

[0082] The present invention also provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, comprising:

[0083] The compound represented by general formula (IIIA) and the compound represented by general formula (IIIB) can undergo 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);

[0084] in,

[0085] Ring A, Ring B, Ring C, Ra, Rb, Rc, m1, m2 and m3 are as defined in the general formula (I).

[0086] The present invention also provides a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

[0087] The compound represented by general formula (IIIA) and the compound represented by general formula (IVB) can undergo 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);

[0088] in,

[0089] Ring A, Ring B, Ring C, Ra, Rb, Rc, m1, m2 and m3 are as defined in the general formula (I).

[0090] The above reaction is preferably carried out in a solvent. The solvent used includes but is not limited to: N,N-dimethylformamide, dichloromethane; the alkaline reagent used includes but is not limited to: pyridine, triethylamine and N,N-diisopropylethylamine.

[0091] 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 comprises a therapeutically effective amount of a compound represented by general formula (I), (II), (III) or (IV) or a tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, a prodrug or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0092] The present invention also relates to the use of a compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating ocular microangiopathy-related diseases.

[0093] The present invention also relates to a compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used as a medicine.

[0094] The present invention also relates to a compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used to treat diseases related to ocular microangiopathy.

[0095] The present invention also relates to a method for treating ocular microangiopathy-related diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0096] In some embodiments of the present invention, the ocular microangiopathy-related disorder is selected from 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 angiomatous proliferation, macular telangiectasia, ischemic retinopathy, iris neovascularization, intraocular neovascularization, corneal neovascularization, retinal neovascularization, polypoidal choroidal vasculopathy (PCV), choroidal neovascularization, retinal degeneration, diabetic complications of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema; in particular, selected from diabetic retinopathy (DR), diabetic macular edema (DME), retinal vein occlusion (RVO), central retinal vein occlusion (CRVO) and wet age-related macular degeneration (wet AMD).

[0097] The compounds represented by general formula (I) to general formula (IV) can be converted into corresponding salts by known methods. Examples of the salts, which are preferably water-soluble, pharmaceutically acceptable non-toxic acid addition salts, are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (such as 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 (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, toluenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. In particular, it is selected from the group consisting of tosylate, methanesulfonate, hydrochloride, acetate and citrate.

[0098] The pure form of the compound of the present invention or its pharmaceutically acceptable salt or an appropriate pharmaceutical composition can be administered by any acceptable mode of administration of a similarly effective medicament. The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into solid, semisolid, liquid or gaseous preparations, such as tablets, capsules, powders, granules, nanoparticles, suspensions, emulsions, gels, liposomes, solutions, injections. Typical routes of administration of the pharmaceutical composition include, but are not limited to, oral or parenteral administration. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intraocular injection or infusion techniques. The pharmaceutical composition of the present invention is formulated to allow the active ingredient contained therein to be bioavailable after administration of the composition to the patient. The composition to be administered to an individual or patient is in the form of one or more dosage units, wherein, for example, a tablet can be a single dose unit, while a container containing the compound of the present invention in aerosol form can accommodate multiple dosage units. Actual methods of preparing such dosage forms are known, or will become known, to those skilled in the art. The composition to be administered will in any case contain a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, so as to treat the disease or condition of interest in accordance with the teachings of the invention.

[0099] The pharmaceutical compositions of the present invention may be in solid or liquid form. In one aspect, the carrier is a microparticle, such that the composition is, for example, in tablet or powder form. The carrier may be a liquid, and the composition may be, for example, an oral syrup or an injectable liquid. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, with semi-solid, semi-liquid, suspension, and gel forms being included within the forms considered herein as solid or liquid. For oral solid compositions, the pharmaceutical composition may be formulated into forms such as powders, granules, compressed tablets, pills, capsules, chewable tablets, powder tablets, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more of the following substances may be present: binders, such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, xanthan gum or gelatin; excipients, such as starch, lactose or dextrin; disintegrants, such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants, such as magnesium stearate or hydrogenated vegetable oil (Sterotex); glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; flavorings, such as mint, methyl salicylate or orange flavoring; and coloring agents.

[0100] The pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, which may contain, in addition to the above-mentioned types of substances, a liquid carrier, such as polyethylene glycol or a vegetable oil. The pharmaceutical composition may be in liquid form, such as a tincture, syrup, solution, emulsion or suspension. This liquid may be taken orally or delivered by injection, as two examples. When taken orally, the preferred composition contains, in addition to the compounds of the present invention, one or more of a sweetener, a preservative, a dye / colorant and a flavor enhancer. In compositions intended to be administered by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersant, a suspending agent, a buffer, a stabilizer and an isotonic agent may be included.

[0101] The compounds and pharmaceutical compositions of the present invention may be further combined with one or more, preferably one, additional therapeutic agent. The compounds of the present invention may be combined with one or more additional therapeutic agents selected from the group consisting of: anti-VEGF monoclonal or dual antibodies, antidiabetic agents, agents for treating overweight and / or obesity; agents for treating hypertension, pulmonary hypertension, heart failure and / or atherosclerosis; and agents for treating ocular diseases.

[0102] It can be combined with other drugs for the treatment of type II diabetes, selected from GK agonists, GLP-1 receptor agonists, exenatide, liraglutide, semaglutide, dulaglutide, loxenatide, albiglutide; α-glucosidase inhibitors, voglibose, acarbose; SGLT-2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, rupagliflozin Luseogliflozin and Tofogliflozin; one or more of the DPP-4 inhibitors sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, gemigliptin, and teneligliptin; and metformin. The pharmaceutical composition can be used to prevent, slow the progression of, or treat one or more metabolic disorders selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, hyperglycemia, postprandial hyperglycemia, impaired fasting blood glucose, overweight, obesity, hypertension, insulin resistance, and / or metabolic syndrome; or to improve glycemic control and / or lower fasting plasma glucose; or to prevent, slow, delay, or reverse diabetic complications.

[0103] It can be combined with other drugs for treating hypertension, such as angiotensin II receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), beta-blockers, diuretics, alpha-blockers, etc. It is selected from felodipine sustained-release tablets, nifedipine, nitrendipine, nisoldipine, nicardipine, lacidipine, lercanidipine, amlodipine, levamlodipine, verapamil, diltiazem, captopril, enalapril, benazepril, lislopril, ramipril, fosinopril, cilazapril, perindopril, quinapril, imidapril, zofenopril, losartan, valsartan, irbesartan, irbesartan, candesartan cilexetil, telmisartan, olmesartan medoxomil, etc.

[0104] Drugs that can be combined with other agents for treating heart failure and / or atherosclerosis are selected from mevastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cholestyramine, colestipol, aspirin, clopidogrel, cilostazol, ω-3 polyunsaturated fatty acids, ω-6 monounsaturated fatty acids, heparin, heparan sulfate, chondroitin sulfate, dextran sulfate, finerenone, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors evolocumab (Repatha), alirocumab (Policida), inclisiran (Leqvio), etc.

[0105] It can be combined with other drugs to treat pulmonary hypertension, selected from bosentan, riociguat, macitentan, selexipag, etc.

[0106] Other therapeutic agents that can be combined with it for the treatment of ocular diseases include intravitreally administered corticosteroids, intravitreally administered anti-VEGF therapeutics, anti-Ang2 inhibitors, dual anti-VEGF / anti-Ang2 inhibitors, complement inhibitors (complement factor 3, 5, B and D inhibitors, etc.), anti-PDGF, dual anti-VEGF / anti-PDGF, VAP-1 inhibitors, bradykinin receptor 1 (BK1) antagonists, Tie-2 agonists, CCR-2 antagonists, etc.

[0107] Other anti-VEGF monoclonal or dual-antibody drugs that can be combined with it are selected from aflibercept (Eylea), bevacizumab (Avastin), ranibizumab (Lucentis), pegaptanib (Macugen), and faricimab (Vabysmo).

[0108] In some embodiments of the present invention, the stroke includes hemorrhagic and acute ischemic stroke, and the drug that can be combined with other drugs for treating stroke is selected from alteplase, ceteplasm, edaravone, butylphthalide, citicoline or dextroborneol, etc.

[0109] Terminology

[0110] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0111] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6 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 ,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-chain isomers thereof.

[0112] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0113] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, and the like.

[0114] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0115] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.

[0116] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 3-20 The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., C 3-12 cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (ie, C 3-8 cycloalkyl), cycloalkyl having 4 to 7 ring atoms (i.e., C 4-7 cycloalkyl) or a cycloalkyl having 3 to 6 ring atoms (i.e., C 3-6 cycloalkyl).

[0117] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0118] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0119] The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon 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 spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), and more preferably has 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocycloalkyl group. Non-limiting examples include:

[0120] The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the 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 fused cycloalkyl). The fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cycloalkyl groups. Non-limiting examples include:

[0121] The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the 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) carbon atoms (i.e., a 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0122] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group) or a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group) or a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

[0123] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0124] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0125] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which 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 spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0126] wait.

[0127] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, 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 fused heterocyclyl). The fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

[0128] wait.

[0129] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), 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 bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). According to the number of constituent rings, heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0130] wait.

[0131] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., 6- to 10-membered aromatic group), more preferably an aromatic group having 8 to 10 ring atoms (i.e., 8- to 10-membered polycyclic aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc.

[0132] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The 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 polycyclic heteroaryl).

[0133] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0134] Non-limiting examples of the polycyclic heteroaryl group include indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, benzofuranyl, quinazolinyl, carbazolyl, pyrrolotriazinyl, and the like.

[0135] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0136] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0137] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0138] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0139] The term "hydroxy" refers to -OH.

[0140] The term "mercapto" refers to -SH.

[0141] The term "amino" refers to -NH2.

[0142] The term "cyano" refers to -CN.

[0143] The term "nitro" refers to -NO2.

[0144] The term "oxo" or "oxo" refers to "=0".

[0145] The term "carbonyl" refers to C=O.

[0146] The term "carboxy" refers to -C(O)OH.

[0147] The compounds of the present invention may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. These include cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in the compounds of the present invention may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included 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. An isomer of a compound of the present invention can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereoisomers is typically accomplished by chromatography.

[0148] In the chemical structure of the compound of the present invention, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0149] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium. "Optional" or "optionally" means that the event or circumstances described below can but do not necessarily occur, and includes both situations where the event or circumstances occur and where they do not occur. For example, "alkyl optionally substituted with halogen or cyano" includes both situations where the alkyl is substituted with halogen or cyano and situations where the alkyl is not substituted with halogen and cyano.

[0150] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1-6, more preferably 1-3, and even more preferably 1-2 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0151] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0152] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0153] As used herein, the term "treat" includes treatment of a disease or condition in a mammal, particularly a human, and includes: (a) inhibiting the infection, disease or condition, i.e., arresting or delaying the development of the infection, disease or condition; (b) relieving the infection, disease or condition, i.e., causing regression of the disease or condition, and / or (c) curing the infection, disease or condition.

[0154] As used herein, the term "prophylaxis" includes prophylactic therapy in mammals, particularly humans, to reduce the likelihood of developing an infection, disease, or condition. Patients may be selected for prophylactic therapy based on their increased risk of infection, disease, or condition compared to the general population. "Prophylaxis" may include treatment of subjects who have not yet developed an infection or clinical condition, and prevention of a second occurrence of the same or similar infection or clinical condition.

[0155] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate therapeutically effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0156] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0157] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0158] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting. DETAILED DESCRIPTION

[0159] The following examples are only used to illustrate the present invention, but are not used to limit the present invention. Any modifications, changes, variations, etc. made within the scope of protection of the present invention are all within the scope of protection of the present invention.

[0160] The compounds provided herein can be prepared using the specific synthetic schemes described below from readily available starting materials, which can be synthesized using methods known in the art or commercially available. Experimental methods in the following examples, where specific conditions are not specified, can be determined by conventional methods and conditions by those skilled in the art through routine optimization procedures.

[0161] Unless otherwise stated, the present invention uses conventional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and each step and condition can refer to conventional operating steps and conditions in the art.

[0162] In the following embodiments, commonly used abbreviations are:

[0163] AcOH: acetic acid, CAS number: 64-19-7

[0164] tBuOK: Potassium tert-butoxide, CAS number: 865-47-4

[0165] Cs2CO3: Cesium carbonate, CAS number: 534-17-8

[0166] BAST: Bis(2-methoxyethyl)aminosulfur trifluoride, CAS No.: 202289-38-1

[0167] BEP: 2-Bromo-1-ethylpyridinium tetrafluoroborate, CAS No.: 878-23-9

[0168] PyBOP: Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate CAS No.: 128625-52-5

[0169] DMTMM: 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride CAS No.: 3945-69-5

[0170] CDI: Carbonyldiimidazole, CAS No.: 208-488-9

[0171] CuI: Cuprous iodide, CAS No.: 7681-65-4

[0172] CuCl: Cuprous chloride, CAS number: 7758-89-6

[0173] CuSO4: Copper sulfate, CAS number: 7758-98-7

[0174] NaH: Sodium hydride, CAS number: 7646-69-7

[0175] NaOMe: sodium methoxide, CAS number: 124-41-4

[0176] NaN3: Sodium azide, CAS number: 26628-22-8

[0177] NH4HCO3: Ammonium bicarbonate, CAS number: 1066-33-7

[0178] Na2CO3: sodium carbonate, CAS number: 497-19-8

[0179] K2CO3: Potassium carbonate, CAS number: 584-08-7

[0180] NaBH4: sodium borohydride, CAS number: 16940-66-2

[0181] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, CAS No.: 148893-10-1

[0182] cataCXium APd-G3: [n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, CAS: 1651823-59-4

[0183] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, CAS No.: 148893-10-1

[0184] dppf Pd G3: (methanesulfonic acid (1,1'-bis(diphenylphosphino)ferrocene)(2'-amino-1,1'-biphenyl-2-yl)palladium, CAS number: 1445086-28-1

[0185] Pd(PPh3)2Cl2: Palladium dichlorobis(phenylphosphine), CAS No.: 1445086-28-1

[0186] Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, CAS number: 72287-26-4

[0187] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium, CAS number: 51364-51-3

[0188] Pd / C: Palladium carbon catalyst, CAS number: 13566-03-5

[0189] Pd(PPh3)4:Tetrakis(triphenylphosphine)palladium, CAS No.:14221-01-3

[0190] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium, CAS number: 51364-51-3

[0191] Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium, CAS No.: 53199-31-8

[0192] Ruphos:1'-biphenyl; 2-dicyclohexylphosphino-2',6'-diisopropylbiphenyl; 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, CAS No.: 787618-22-8

[0193] RuPhos Palladacycle G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate, CAS No. 1445085-77-7

[0194] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, CAS No.: 161265-03-8

[0195] PE: petroleum ether;

[0196] EtOAc: ethyl acetate, CAS number: 141-78-6

[0197] Boc: tert-butyloxycarbonyl

[0198] DIEA: N,N-diisopropylethylamine, CAS number: 7087-68-5

[0199] DMF: N,N-dimethylformamide, CAS number: 68-12-2

[0200] DMS.BH3: Dimethyl sulfide borane, CAS number: 13292-87-0

[0201] DCM: dichloromethane, CAS number: 75-09-2

[0202] Selectfluor: N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate), CAS No.: 140681-55-6

[0203] TCFH, Tetramethylchlorouronium hexafluorophosphate, CAS No.: 94790-35-9

[0204] TFA: trifluoroacetic acid, CAS number: 76-05-1

[0205] THF: Tetrahydrofuran, CAS number: 109-99-9

[0206] THP: 2-tetrahydropyran

[0207] LiBH4: lithium borohydride, CAS number: 16949-15-8

[0208] L-Selectride: lithium tri-sec-butylborohydride, CAS number: 38721-52-7

[0209] Zn(CN)2: Zinc cyanide, CAS number: 557-21-1

[0210] NMP: N-methylpyrrolidone, CAS number: 872-50-4

[0211] MeOH: methanol, CAS number: 67-56-1

[0212] MeCN: acetonitrile, CAS number: 75-05-8

[0213] NaBH3CN: sodium cyanoborohydride, CAS number: 25895-60-7

[0214] NBS: N-bromosuccinimide, CAS No.: 128-08-5

[0215] NCS: N-chlorosuccinimide, CAS No.: 128-09-6

[0216] nBuLi: n-butyllithium, CAS number: 109-72-8

[0217] SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride, CAS number: 76513-69-4

[0218] TEA: triethylamine, CAS number: 121-44-8

[0219] Ti(OEt)4: Tetraethyl titanate CAS No.: 3087-36-3

[0220] pTsOH: p-toluenesulfonic acid, CAS number: 104-15-4

[0221] (t-Bu)3P*HBF4: tri-n-butylphosphonium tetrafluoroborate, CAS No.: 113978-91-9

[0222] d7-DMF: 7-deuterium-N,N-dimethylformamide, CAS number: 4472-41-7

[0223] CDCl3: deuterated chloroform, CAS number: 865-49-6

[0224] d6-DMSO: deuterated dimethyl sulfoxide, CAS number: 2206-27-1

[0225] MS: Mass spectrometry

[0226] ESI: electrospray ionization

[0227] 1 HNMR: hydrogen nuclear magnetic resonance

[0228] TLC: Thin layer chromatography

[0229] Chiral HPLC: Chiral High Performance Liquid Chromatography

[0230] Prep-HPLC: High-Preparative Liquid Chromatography

[0231] Prep-TLC: Preparative Thin Layer Chromatography

[0232] LCMS: Liquid chromatography-mass spectrometry

[0233] Rf: ratio shift value;

[0234] min: minutes

[0235] g: grams

[0236] mg: milligrams

[0237] rt: room temperature

[0238] mol: mole

[0239] mmol:mmol

[0240] mL: milliliters

[0241] M: mole / liter

[0242] Intermediate synthesis

[0243] 5-(Aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride (Intermediate 1) was prepared according to the following synthetic route:

[0244] To a solution of 5-cyano-4,6-dimethylpyridin-2-amine (50.0 g, 340 mmol, 1.00 eq) in MeOH (100 mL) was added 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). The mixture was stirred at 80°C under H2 (50 psi) for 20 hours. LC-MS indicated that the starting material was consumed and the product was formed. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*80 mm*10 um; mobile phase: [water (HCl)-ACN]; gradient: 0% to 10% B over 5 minutes) to afford the title compound (Intermediate 1) (10.0 g, 53.3 mmol, 15.7% yield, HCl) as a white solid. LCMS (ESI): m / z 152 [M+1] +; 1 H NMR (400MHz, DMSO-d6) δ 8.54 (br s, 3H), 7.93 (br s, 2H), 6.70 (s, 1H), 3.93 (d, J = 4.2Hz, 2H), 2.58 (s, 3H), 2.45 (s, 3H).

[0245] 1-(4-(Bromomethyl)benzyl)pyridin-2(1H)-one (Intermediate 2) was prepared according to the following synthetic route:

[0246] To a solution of pyridin-2(1H)-one (25.0 g, 262 mmol, 1.00 eq) in MeCN (500 mL) was added 1,4-bis(bromomethyl)benzene (104.08 g, 394.33 mmol, 1.50 eq) and KCO (72.7 g, 525 mmol, 2.00 eq). The reaction was stirred at 80°C for 12 hours. TLC (plate 1: PE:EtOAc = 1:1, Rf = 0.45) indicated complete consumption of the starting material, with a major new spot of greater polarity detected. The reaction mixture was filtered and the filter cake washed with DCM (200 mL). The mixture was then diluted with H2O (500 mL) and extracted with 1500 mL (500 mL * 3) of DCM. The combined organic layers were washed with brine (500 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product. The residue was purified by column chromatography (SiO 2 , PE / EtOAc=1 / 0 to 1 / 1, plate 2, PE:EtOAc=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. LCMS (ESI): m / z 278 [M+1] +;1 H NMR (400MHz, CDCl3) δ7.70-7.69 (d, J=1.6Hz, 1H), 7.68-7.53 (m, 1H), 7.40 -7.38(d,J=8Hz,2H),7.28-7.26(d,J=8Hz,2H),6.59-6.56(d,J=8.8Hz,1H),6.41-6.38(m,1H),5.19(s,2H),4.53(s,2H).

[0247] (3-Fluoro-4-methoxypyridin-2-yl)methanamine hydrochloride (Intermediate 3) was prepared according to the following synthetic route:

[0248] Step 1: Preparation of tert-butyl (4-chloro-3-fluoropyridin-2-yl)methylcarbamate: To a solution of 3-fluoro-4-chloropyridine (100 g, 760 mmol, 104 mL, 1.00 eq) and (tert-butyloxycarbonyl)glycine (226 g, 1.29 mol, 1.70 eq) in MeCN (1.00 liter) and H O (250 mL) was added AgOTf (19.5 g, 76.0 mmol, 0.100 eq) and TFA (17.3 g, 152 mmol, 11.3 mL, 0.200 eq). A solution of (NH ) S O (312 g, 1.37 mol, 297 mL, 1.80 eq) in H O (500 mL) was then added dropwise at 66° C. over a period of 0.5 h. The mixture was stirred at 66° C. for 0.25 h. TLC (PE / EtOAc=3 / 1, Rf=0.420) showed that the starting material was completely consumed and a new spot with greater polarity was formed. The pH of the reaction mixture was adjusted to 8 by adding an aqueous NaOH solution at 0°C, then diluted with 500mL H2O and extracted with EtOAc (1.00L x 3). The combined organic layers were washed with brine (500mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE:EtOAc=1:0-3:1, PE:EtOAc=3:1, Rf=0.420). The title compound (46.0g, 176mmol, 23.2% yield) was obtained as a yellow solid. LCMS (ESI): m / z 261[M+1]+; 1 H NMR (400MHz, CDCl3) δ8.25 (d, J = 5.2Hz, 1H), 7.29 (t, J = 5.2Hz, 1H), 5.68 (br s, 1H), 4.54 (br d, J = 2.8Hz, 2H), 1.46 (s, 9H).

[0249] Step 2: Preparation of tert-butyl (4-methoxy-3-fluoropyridin-2-yl)methylcarbamate: To a solution of tert-butyl (4-chloro-3-fluoropyridin-2-yl)methylcarbamate (35.0 g, 134 mmol, 1.00 eq) in MeOH (350 mL) was added NaOMe (5.40 M, 24.7 mL, 1.00 eq) 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 about 33% of the starting material remained. Several new peaks appeared on LC-MS, and about 40% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with 100 mL of H2O and extracted with EtOAc (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 give a residue. The residue was purified by column chromatography (PE / EtOAc=1 / 0 to 3 / 1, PE / EtOAc=3 / 1, Rf=0.210). The residue was purified by preparative HPLC (column: Welch Ultimate XB-NH2 250*50*10um; mobile phase: [hexane-ethanol]; gradient: 1%-30% B, 15 minutes). The title compound was obtained as a yellow oily liquid (13.5 g, 52.7 mmol, 39.2% yield, 100% purity). LCMS (ESI): m / z 257 [M+1]+.

[0250] Step 3: Preparation of (3-fluoro-4-methoxypyridin-2-yl)methanamine hydrochloride (Intermediate 3): To a solution of tert-butyl (4-methoxy-3-fluoropyridin-2-yl)methylcarbamate (13.5 g, 52.7 mmol, 1.00 eq) in MeOH (60.0 mL) was added HCl / MeOH (4 M, 5.00 mL, 3.80 eq) at 0°C. The mixture was stirred at 70°C for 1.8 hours. LC-MS showed that the starting material was completely consumed and a major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The title compound (Intermediate 3) (10.0 g, crude, HCl) was obtained as a light yellow solid. LCMS (ESI): m / z 157 [M+1] +; 1 H NMR (400MHz, 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).

[0251] 3-Chloro-6-(chloromethyl)quinoline (Intermediate 4) was prepared according to the following synthetic route:

[0252] Step 1: Stock solution A: 6-(methylformate)quinoline (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, Temp = 100°, C 1 / 4" PFA coil, (100 mL) Residence time: 4 min Flow reaction: 100 g 57 min LCMS showed that the starting material was mostly consumed and the desired MS was detected. The reaction mixture was poured into 2 L of H2O, forming some yellow solid, which was then filtered and the filter cake concentrated to give a residue. The residue was slurried with EtOAc (500 mL), filtered, and the filter cake was washed with EtOAc (80.0 mL) to give the title compound as a yellow solid (58.0 g, 261 mmol, 48.99% yield) LCMS (ESI): m / z 222 [M+1]+; 1 H NMR (400MHz, CDCl3) δ9.00 (d, J = 2.4Hz, 1H), 8.88 (d, J = 2.4Hz, 1H), 8.67 (d, J = 1.2Hz, 1H), 8.30-8.20 (m, 1H), 8.15-8.05 (m, 1H), 3.94 (s, 3H).

[0253] Step 2: 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, Temp = 100°C, 1 / 4" PFA coil (100 mL), residence time: 4 min, flow reaction: 100 g. 57 min, LCMS showed that the starting material was mostly consumed and the desired MS was detected. The reaction mixture was poured into 2 L of H2O, some yellow solid formed, which was then filtered and the filter cake concentrated to give a residue. The residue was slurried with EtOAc (500 mL), filtered, and the filter cake was washed with EtOAc (80.0 mL) to give the title compound (58.0 g, 261 mmol, 48.99% yield) as a yellow solid. LCMS (ESI): m / z 194 [M+1]+; 1 H NMR (400MHz, CDCl3) δ8.83(d,J=2.4Hz,1H),8.55(d,J=2.4Hz,1H),8.00(d,J=8.8Hz ,1H),7.89(s,1H),7.73(dd,J1=8.8Hz,J2=1.6Hz,1H),5.48(brs,1H),4.71(s,2H).

[0254] Step 3: SOCl2 (196 g, 1.65 mol, 120 mL, 17.8 eq) was added to compound 3 (18.0 g, 92.9 mmol, 1.00 eq), and the mixture was stirred at 20 ° C for 3 hours. LCMS showed that the starting material was consumed and the required MS was detected. The reaction mixture was concentrated to give a residue, which was then slurried with EtOAc (100 mL), filtered and the filter cake was diluted with EtOAc (400 mL), and the combined organic layers were washed with NaHCO3 (saturated, 150 mL×2) and brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (14.0 g, 65.6 mmol, 70.6% yield, 99.4% purity) as a yellow solid. LCMS (ESI): m / z 212 [M+1]+; 1 H NMR (400MHz, CDCl3) δ8.90 (d, J = 2.4Hz, 1H), 8.59 (d, J = 2.4Hz, 1H), 8.14-7.97 (m, 2H), 7.84 (dd, J1 = 8.8Hz, J2 = 1.6Hz, 1H), 4.98 (s, 2H).

[0255] 2-(Bromomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (Intermediate 5) was prepared according to the following synthetic route:

[0256] 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) were added 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). The mixture was stirred at 100°C overnight and diluted with water (1.0 L). The reaction mixture was extracted with DCM (300 mL*3) and the organic layer was filtered through a celite pad. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (eluted with EtOAc) to give the title compound as a yellow solid (8.0 g, 93.77% yield). LCMS (ESI): m / z 135.2 [M+H] + .

[0257] Step 2: A solution of 3-cyclopropyl-2-aminopyridine (2.0 g, 14.91 mmol) and 2-carbonyl-1,3-dibromopropane (4.83 g, 22.37 mmol) in DME (30 mL) was stirred at 90° C. overnight. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluting with DCM:MeOH=30:1) to give the title compound (Intermediate 5) as a yellow solid (2.75 g, 73.47% yield). LCMS (ESI): m / z 252.9 [m+H]+.

[0258] 1-(2-Cyano-4-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)benzyl)-1H-pyrazole-4-carboxylic acid (Intermediate 6) was prepared according to the following synthetic route:

[0259] 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 hours. After the reaction was completed as monitored 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 (eluted with polyethylene:ethyl acetate = 100:0 to 85:15) to give the desired compound Int6-2 (0.48 g, 64.51% yield) as a white solid. LCMS (ESI): m / z 304.0 [M+H]+.

[0260] Step 2: NaBH4 (0.042 g, 1.12 mmol) was added to a solution of compound Int6-2 (0.28 g, 2.93 mmol) in MeOH (10 mL), and the mixture was stirred at room temperature for 0.5 hours. After LCMS monitoring of the reaction was completed, the reaction mixture was diluted with water (100 mL) and extracted with DCM (100 mL*3). The organic layer was washed with brine, water, and dried over anhydrous sodium sulfate. The organic phase was filtered and the filtrate was concentrated under reduced pressure to give the desired white solid compound Int6-3 (0.275 g, yield 97.56%). LCMS (ESI): m / z 306[M+H]+.

[0261] 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 hours. After the reaction was completed, it was monitored by LCMS. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL * 3). The combined organic layer was 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 give the desired compound Int6-4 (0.125 g, yield 38.43%) as a white solid. LCMS (ESI): m / z 414.2 [M+H] +.

[0262] 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 dissolved in NMP (10 mL). The reaction mixture was flushed with nitrogen for 5 minutes. The mixture was stirred at 80 ° C for 2 hours. After the reaction was completed by LCMS monitoring, 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 dimethylmethane chloride:methanol=20:1) to give the desired compound Int6-5 (0.095 g, 95.03% yield) as a white solid. LCMS (ESI): m / z 359.3 [M+H] + .

[0263] 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 h. After the reaction was completed by LCMS monitoring, 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 give the desired intermediate 6 (82 mg, yield 89.83%) as a white solid. LCMS (ESI): m / z 345.2 [M + H] +.

[0264] 2-(Aminomethyl)-3-fluoro-N-methylpyridin-4-amine hydrochloride (Intermediate 7) was prepared according to the following synthetic route:

[0265] Step 1: Preparation of tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate: Under nitrogen, 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(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol), and cesium carbonate (1230 mg, 3.80 mmol) were added sequentially to dioxane (10 mL). The mixture was heated to 100°C and reacted for 3 hours. The filtrate was filtered, collected, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (EA:PE = 1:10) to obtain the title compound (450 mg, yield: 96%) as a yellow oil. MS (ESI) M / Z: 247.1 [M+H] + .

[0266] Step 2: Preparation of tert-butyl (2-chloro-3-fluoropyridin-4-yl)(methyl)carbamate: Under nitrogen, compound Int7-1 (350 mg, 1.40 mmol) was added to N,N-dimethylformamide (3 mL), cooled to 0°C, and sodium hydride (68 mg, 1.70 mmol) was added. The mixture was reacted at 0°C for 30 minutes. A solution of iodomethane (397 mg, 2.8 mmol) dissolved in N,N-dimethylformamide (2 mL) was slowly added dropwise. The mixture was naturally returned to room temperature and reacted for 1 hour. Water (25 mL) was added and extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain a 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] + .

[0267] Step 3: Preparation of tert-butyl (2-(((tert-Butyloxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)(methyl)carbamate: Under nitrogen protection, compound Int7-2 (280 mg, 1.10 mmol), potassium [(tert-Butyloxycarbonylamino)methyl]trifluoroborate (521 mg, 2.20 mmol), methanesulfonic 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 added sequentially to a mixed solution of dioxane (4 mL) and water (1 mL), and the temperature was raised to 100°C for 16 hours. The mixture was filtered, the filtrate was collected, and 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] + .

[0268] Step 4: Preparation of 2-(Aminomethyl)-3-fluoro-N-methylpyridin-4-amine hydrochloride: Compound Int7-3 (230 mg, 0.60 mmol) was added to a solution of hydrogen chloride in dioxane (4.0 M, 5 mL) and allowed to react at room temperature for 1 hour. The mixture was concentrated under reduced pressure to afford (Intermediate 7) (120 mg, 100% yield) as a white solid. MS (ESI) M / Z: 156.2 [M+H] + .

[0269] 3-(3,3-Difluorocyclobutyl)-1-(4-((5-fluoro-2-oxopyridin-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (Intermediate 8) was prepared according to the following synthetic route:

[0270] 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) was added CDI (720 mg, 4.41 mmmol), and the mixture was stirred at room temperature for 2 hours. Compound Int8-2 (830 mg, 5.29 mmol) and MgCl2 (500 mg, 5.29 mmmol) were then added and stirred at room temperature overnight. After the reaction was completed as monitored by LCMS, 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 give the crude product. The residue was purified by preparative TLC (PE:EA=3:1) to give the title compound (610 mg, 72.01% yield) as a light yellow oil. MS (ESI) m / z:193.0[M+H]+. 1H NMR (400MHz, CDCl3) δ3.77 (s, 3H), 3.52 (s, 2H), 3.26 (pd, J = 8.8, 2.6Hz, 1H), 2.89–2.72 (m, 4H).

[0271] Step 2: Preparation of (E)-2-(3,3-difluorocyclobutane-1-carbonyl)-3-(dimethylamino)acrylate: To a solution of compound Int8-3 (610 mg, 3.17 mmol) in DMF (10 mL) was added DMF-DMA (566 mg, 4.75 mmol) and the mixture was stirred at 70°C for 1 hour. After completion of the reaction, monitored by LCMS, the reaction was concentrated under reduced pressure to afford the title compound (784 mg, 100% yield) as a yellow oil. MS (ESI) m / z: 248.2 [M+H]+.

[0272] 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) were added hydrazine hydroxide (238 mg, 4.75 mmol), acetic acid (285 mg, 4.75% mmol), and the mixture was stirred at 60° C. for 1 hour. After completion of the reaction monitored by LCMS, the mixture was diluted with NaHCO 3 solution (50 mL) and extracted with EA (50 mL). The organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel chromatography (eluted with PE:EA=100:0 to 50:50) to give the title compound (423 mg, 61.71% yield) as a white solid. MS (ESI) m / z: 217.1 [M+H] +.

[0273] 1 H NMR (400MHz, DMSO) δ13.24 (s, 1H), 8.28 (s, 1H), 3.72 (d, J = 10.8Hz, 4H), 3.03–2.70 (m, 4H).

[0274] Step 4: Preparation of methyl 3-(3,3-difluorocyclobutyl)-1-(4-((5-fluoro-2-oxopyridin-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylate: To a solution of compound Int8-4 ((150 mg, 0.69 mmol)) in DMF (8 mL) were added compound Int8-5 (204 mg, 0.69 mmmol), K2CO3 (238 mg, 1.72 mmol), and the mixture was stirred at room temperature overnight. After completion of the reaction monitored by LCMS, the mixture was diluted with water (50 mL) and extracted with EA (50 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA=0:1) to give the title compound (245 mg, 81.85% yield) as a white solid. MS (ESI) m / z: 432.2 [M+H]+.

[0275] 1 H NMR (400MHz, DMSO) δ8.40(s,1H),8.11–7.99(m,1H),7.57(ddd,J=10.3,7.2,3.4Hz,1H),7.27(q,J=8.3Hz,4H),6.44(d d,J=10.0,5.4Hz,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).

[0276] Step 5: Preparation of methyl 3-(3,3-difluorocyclobutyl)-1-(4-((5-fluoro-2-oxopyridin-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylate: To a solution of compound Int8-640 mg, 0.093 mmol) in MeOH (2 mL) was added NaOH (2 M, 1 mL, 2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of HCl solution (2 M, 1 mL, 2 mmol) and concentrated under reduced pressure to give the title compound (38 mg, 100% yield). MS (ESI) M / Z: 503.21 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ8.30(d,J=6.0Hz,1H),8.28(s,1H),7.90(d,J=5.6Hz,1H),7.77(dd,J=6.8,2.0Hz,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=6.8,5.6Hz,2H),4.55–4.46(m,1H),4.37(dd,J=5.6,2.0Hz,2H),2.73(d,J=4.8Hz,3H).

[0277] 1-Ethyl-1,4,5,6-tetrahydrocyclopentadienyl[d]imidazol-4-amine (Intermediate 9) was prepared according to the following synthetic route:

[0278] Step 1: To a solution of Int9-1 (15.0 g, 118.94 mmol) in DMF (180 mL) was added Cs2CO3 (58.13 g, 178.41 mmol), iodoethane (27.83 g, 178.4 mmol), and the mixture was stirred at 70 ° C for 16 hours. After the reaction was completed by LCMS monitoring, 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 (eluted with PE: EtOAc = 100: 0 to 0: 100) to give Int9-2 compound (6.2 g, 33.81% yield). MS (ESI) M / Z: 155.2 [M + H] +.

[0279] Step 2: To a solution of compound Int9-2 (6.2 g, 40.22 mmol) in acetic acid (25 mL) was added NBS (7.87 g, 44.24 mmol), and the mixture was stirred at 70 ° C for 6 hours. After the reaction was completed by LCMS monitoring, the reaction mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 7-8 with a saturated solution of Na2CO3. The mixture was diluted with H2O (50 mL) and extracted with DCM (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 PE:EtOAc=100:0~0:100) to give the desired compound Int9-3 (3.5 g, 37.34% yield). MS (ESI) M / Z: 235.0[M+H]+.

[0280] 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) were added 3,3-dimethoxy-1-propylene (2.15 g, 21.03 mmol) and N, N-dicyclohexylmethylamine (4.11 g, 21.03 mmol). The mixture was purged with nitrogen for 5 minutes. PdCl2[P(O-TOl)3]2 (0.71 g, 0.90 mmol) was then added, and the mixture was stirred at 120 ° C for 4 hours. After the reaction was completed, 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*3). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by reverse phase HPLC to give compound Int9-4 (1.4 g, 38.8% yield).

[0281] MS (ESI) M / Z: 241.2 [M+H] +.

[0282] 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 1 M THF solution, 10 mmol) at 0 ° C. The mixture was stirred for 1 hour, monitored by LCMS after completion of the reaction, and then 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 give compound Int9-5 (586 mg, yield 55.81%). MS (ESI) M / Z: 209.1 [M+H] + .

[0283] Step 5: To a solution of compound Int9-5 (586 mg, 2.81 mmol) in water (1 mL), AcOH (5 mL) and HCl (1.5 mL), the mixture was heated at 70 ° C for 3 hours. After the reaction was completed, it was monitored by LCMS. The pH of the reaction mixture was adjusted to 7-8 with Na2CO3. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (100 mL*3). The combined layer was dried over anhydrous Na2SO4. The organic phase was concentrated to give the desired compound Int9-6 (410 mg, 97% yield). MS (ESI) M / Z: 151.0 [M+H] +.

[0284] 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 stirred for 15 minutes and then treated with tert-butylsulfenamide (620 mg, 5.15 mmol). The mixture was heated at 100 ° C for 8 hours. The reaction was monitored by LCMS. After cooling to room temperature and treating with saturated NaCl aqueous solution (10 mL). The mixture was stirred for 1 hour and then filtered on diatomaceous earth. The filter cake was stirred in THF (20 mL) for 10 minutes twice and filtered on diatomaceous earth. The combined organic phases were concentrated and the residue was purified by silica gel chromatography (DCM: MeOH = 95: 5) to give compound Int9-7 (330 mg, 63.10% yield). MS (ESI) M / Z: 254.2 [M+H] +.

[0285] 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 1M THF solution, 1.9 mmol) at 0 ° C. The mixture was stirred for 1.5 hours and monitored by LCMS after completion of the reaction. The reactant was then treated dropwise with MeOH (2 mL). The solvent was evaporated in vacuo, and the residue was diluted with H2O (50 mL) and extracted with DCM (80 mL*3). The combined layers were dried over anhydrous Na2SO4. The organic phase was concentrated to give the desired compound Int9-8 (340 mg, 100% yield) and used without further purification. MS (ESI) M / Z: 256.1 [M+H]+.

[0286] Step 8: A mixture of compound Int9-8 (340 mg, 1.33 mmol) in isopropanol (10 mL) was treated with a solution of 2M HCl / 1,4-dioxane in isopropanol (1 mL) and stirred for 2 hours. After the reaction was completed by LCMS monitoring, 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] +.

[0287] (6,8-Dimethylimidazo[1,5-a]pyridin-7-yl)methanamine (Intermediate 10) was prepared according to the following synthetic route:

[0288] Step 1: To a solution of compound Int10-1 (1.00 g, 7.57 mmol, 1.00 eq) in DCM (10.0 mL) was added m-CPBA (3.07 g, 15.1 mmol, 85% purity, 2.00 eq) at 0 ° C, and then stirred at 20 ° C for 2 hours. The reaction mixture was diluted with H2O (20.0 mL) and extracted with EtOAc (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 a residue. The crude product was triturated with 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] +.

[0289] Step 2: To a solution of compound Int10-2 (1.00 g, 6.75 mmol, 1.00 eq) in POCl (16.4 g, 107 mmol, 10.0 mL), the mixture was stirred at 100 ° C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO , PE / EtOAc = 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] +.

[0290] Step 3: Preparation of: To a solution of compound Int10-3 (400 mg, 2.40 mmol, 1.00 eq), potassium ((tert-butyloxycarbonyl)amino)methyl)trifluoroborate (854 mg, 3.60 mmol, 1.50 eq) in dioxane (10.0 mL) and H2O (2.00 mL) were added K3PO4 (1.53 g, 7.20 mmol, 3 eq) and CataCXammonium APdG3 (175 mg, 240 μmol, 0.100 eq), 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 give a residue. The residue was purified by preparative HPLC to obtain compound Int10-4 (100 mg, 383 μmol, 15.9% yield) as a white solid. MS (ESI) M / Z: 206 [M+H] +.

[0291] Step 4: To a solution of compound Int10-4 (140 mg, 536 μmol, 1.00 eq) in DCM (2.00 mL) was added HCl / dioxane (2 M, 2.00 mL, 7.47 eq) at 0 ° C. The combined mixture was stirred at 20 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. White solid compound Int10-5 (100 mg, 506 μmol, 94.4% yield, HCl) was obtained. MS (ESI) M / Z: 162 [M+H] +.

[0292] Step 5: Compound Int10-5 (100 mg, 506 μmol, 1.00 equiv, HCl) was added to a solution of HCOOH (24.8 mg, 506 μmol, 2.00 mL, 98% purity, 1.00 equiv) 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 a residue, which was then diluted with sat. aq. NaHCO3 (10 mL), extracted with EtOAc (20.0 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. Compound Int10-6 (85.0 mg, 496 μmol, 98.1% yield) was obtained as a yellow solid. MS (ESI) M / Z: 172 [M+H]+.

[0293] Step 6: under argon atmosphere, Raney nickel (10.0 mg, 117 μmol, 1.00 eq) is added to a flask, and methanol (2.00 mL) is added to a flask under argon atmosphere. Under argon atmosphere, compound Int10-6 (20.0 mg, 117 μmol, 1 eq) and NH in MeOH (2 mL) H2O (2.12 g, 18.2 mmol, 2.33 mL, 30% purity, 156 eq) are added to a flask, and the suspension is then degassed and purged three times with H2. The reaction mixture is stirred for 5 hours at 25 ° C under H2 (50 Psi). LC-MS shows that Int10-6 is completely consumed and the required mass is detected. The reaction mixture is filtered and concentrated under reduced pressure to obtain a residue. Yellow solid intermediate 10 (20.0 mg, 114 μmol, 97.7% yield) is obtained. MS (ESI) M / Z: 176 [M+H] +.

[0294] (6,8-Dimethylimidazo[1,5-a]pyridin-7-yl)methanamine (Intermediate 11) was prepared according to the following synthetic route:

[0295] Step 1: To a solution of compound Int11-1 (500 mg, 3.40 mmol) in EtOH (10 mL) was added compound 2-chloroacetaldehyde (733.98 mg, 3.74 mmol) at 25 ° C. The mixture was stirred at 80 ° C for 16 hours. The reaction mixture was concentrated to give a crude product. The crude product was triturated with EA (5 mL) at 25 ° C for 30 minutes. A yellow solid compound Int11-2 (560 mg, 96% yield) was obtained. MS (ESI) m / z: 172.2 [m + H] +.

[0296] Step 2: Raney nickel (41.90 mg, 0.71 mmol) was added to a flask under an Ar atmosphere. MeOH (15 mL) was then added to the flask under an Ar atmosphere. Compound Int11-2 (300 mg, 1.75 mmol) and ammonium hydroxide (3 mL) were added to a flask in MeOH (10 mL) under an Ar atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred at 25 ° C under H2 overnight. The reaction mixture was filtered. The filtrate was concentrated to give intermediate 11 (275 mg, 89.56% yield) as a yellow solid. MS (ESI) m / z: 176.2 [m+H] +.

[0297] (3-Fluoro-4-(methylthio)pyridin-2-yl)methanamine (Intermediate 12) was prepared according to the following synthetic route:

[0298] Step 1: Compound Int12-1 (400 mg, 2.12 mmol) and sodium thiomethoxide (163 mg, 2.33 mmol) were added to DMF (5 mL) and reacted at 50°C for 2 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a 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] + .

[0299] 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 allowed to react overnight at room temperature. Water (80 mL) was added and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product Int12-3 (200 mg), which was used directly in the next step. MS (ESI) M / Z: 174.0 [M+H] + .

[0300] Step 3: Add crude Int12-3 to dichloromethane (10 mL) and dropwise add thionyl chloride (280 mg, 2.4 mmol). React at room temperature for 1 hour. Concentrate under reduced pressure to obtain crude Int12-4 (190 mg), which can be used directly in the next step. MS (ESI) M / Z: 192.0 [M+H] + .

[0301] Step 4: Add crude Int12-4 to aqueous ammonia (20 mL) and react at room temperature for 2 hours. Concentrate under reduced pressure to obtain crude 399-4 (150 mg), which can be used directly in the next step. MS (ESI) M / Z: 173.0 [M+H] + .

[0302] (7-Fluoro-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)methanamine hydrochloride (Intermediate 13) was prepared according to the following synthetic route:

[0303] Step 1: To a solution of compound Int13-1 (1.0 g, 6.82 mmol) in acetonitrile (8 mL) were added TsOH (65 mg, 0.34 mmol), NIS (1.69 g, 7.5 mmol), and the mixture was stirred at 70 ° C overnight. After the reaction was completed by LCMS monitoring, the reaction mixture was diluted with water (150 mL) and extracted with EA (150 mL * 3). The combined organic phase was concentrated and the residue was purified by flash chromatography (PE: EA = 100: 0 to 70: 30) to give the desired compound Int13-2 (1.68 g, yield 90.37%) as a light yellow solid. MS (ESI) m / z: 273.0 [M + H] + .

[0304] Step 2: To a solution of compound Int13-2 (1.38 g, 5.07 mmol) in DCE (24 mL) and H2O (8 mL) was added compound Int13-3 (2.01 g, 10.14 mmol), Na2CO3 (1.61 g, 15.21 mmol), 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 at 100 ° C overnight. After the reaction was completed by LCMS monitoring, 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*3). The residue was purified by flash chromatography (PE:EA=100:0 to 83:17) to obtain the desired compound Int13-4 (800 mg, 72.91% yield). MS (ESI) m / z: 217.0 [m+H]+.

[0305] Step 3: To a solution of compound Int13-4 (800 mg, 3.69 mmol) in EtOH (15 mL) was added hydrogen chloride (2.5 mL) and the mixture was stirred at 80 ° C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure by LCMS monitoring. The residue was diluted with H2O (80 mL), basified with saturated NaHCO3 solution to pH = 8 to 9, and extracted with DCM (200 mL * 3 mL). The combined organic phases were concentrated under reduced pressure to give the desired compound Int13-5 (524 mg, 83.19% yield) as a white solid, which was used without further purification.

[0306] MS (ESI) m / z: 171.0 [m+H] +.

[0307] Step 4: A solution of compound Int13-5 (270 mg, 1.58 mmol) in DMF (9 mL) was cooled to 0 ° C at 0 ° C, NaH (189 mg, 4.74 mmol) was added, and the solution was stirred at 0 ° C for 0.5 hours. After adding iodomethane (269 mg, 1.90 mmol), the mixture was allowed to reach room temperature and the solution was stirred for 1 hour. After the reaction was completed by LCMS monitoring, the reaction mixture was quenched by adding saturated ammonium chloride (15 mL), diluted with water (150 mL) and extracted with EA (150 mL * 3). The combined organic matter was concentrated. The residue was purified by flash chromatography (PE: EA = 100: 0 to 80: 20) to obtain the desired compound Int13-6 (275 mg, yield 94.11%).

[0308] MS (ESI) m / z: 185.0 [m+H] +.

[0309] Step 5: To a solution of compound Int13-6 (180 mg, 0.98 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was added compound Int13-7 (348 mg, 1.47 mmol), K3PO4 (624 mg, 2.94 mmol), and the mixture was purged with nitrogen for 5 minutes. CataCXiumAPdG3 (71 mg, 0.098 mmol) was added, and the mixture was stirred at 100 ° C overnight. After completion of the reaction monitored by LCMS, the mixture was diluted with water (120 mL) and extracted with EA (120 mL * 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA = 100:0 to 50:50) to give the desired compound Int13-8 (200 mg, 73.43% yield) as a white solid. MS (ESI) m / z: 280.2 [m+H] +.

[0310] Step 6: A solution of compound Int13-8 (200 mg, 0.72 mmol) in 4M HCl in dioxane (10 mL) was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was monitored by LCMS and concentrated under reduced pressure to give the desired compound Intermediate 13 (154 mg HCl salt, 100% yield).

[0311] MS (ESI) m / z: 180.2 [m+H] +.

[0312] (7-Fluoro-1H-pyrrolo[3,2-c]pyridin-6-yl)methanamine hydrochloride (Intermediate 14) was prepared according to the following synthetic route:

[0313] Step 1: To a solution of compound Int13-5 (180 mg, 1.06 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was added compound Int13-7 (377 mg, 1.59 mmol), K3PO4 (675 mg, 3.18 mmol), and the mixture was purged with nitrogen for 5 minutes. CataCXiumAPdG3 (62 mg, 0.085 mmol) was added, and the mixture was stirred at 105 ° C overnight. After the reaction was completed by LCMS monitoring, the mixture was diluted with water (100 mL) and extracted with EA (100 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA=100:0:0:100) to give the desired compound Int14-1 (172 mg, 61.44% yield) as a light yellow solid. MS (ESI) m / z: 266.2 [m+H] +.

[0314] Step 2: A solution of compound Int14-1 (172 mg, 0.65 mmol) in 4M HCl in dioxane (10 mL) was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was monitored by LCMS and concentrated under reduced pressure to afford the desired compound Intermediate 14 (130 mg HCl salt, 100% yield). MS (ESI) m / z: 166.0 [m+H]+.

[0315] (7-Fluoro-1-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)methanamine hydrochloride (Intermediate 15) was prepared according to the following synthetic route:

[0316] Step 1: To a solution of compound Int13-6 (200 mg, 1.08 mmol) in THF (5 mL) was added DMS-BH3 (1.08 mL, 10.8 mmol, 10 M / L), the mixture was purged with nitrogen for 3 minutes, and stirred at 65 ° C overnight. The reaction mixture was cooled to room temperature, MeOH (8 mL) was added, stirred at 60 ° C for 0.5 hours, and concentrated under reduced pressure. The residue was then diluted with water (120 mL) and extracted with EA (120 mL * 3). The combined organics were concentrated. The residue was purified by flash chromatography (PE: EA = 100: 0: 0: 100) to give compound Int15-1 (71 mg, yield 35.12%). MS (ESI) m / z: 187.0 [m + H] +.

[0317] Step 2: To a solution of compound Int15-1 (71 mg, 0.38 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added compound Int13-7 (180 mg, 0.76 mmol), K3PO4 (242 mg, 1.14 mmol), and the mixture was purged with nitrogen for 5 minutes. CataCXiumAPdG3 (27 mg, 0.038 mmol) was added, and the mixture was stirred at 100 ° C overnight. After completion of the reaction monitored by LCMS, the mixture was diluted with water (120 mL) and extracted with EA (120 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA=100:0:0:100) to give the desired compound Int15-2 (60 mg, 56.05% yield) as a white solid. MS (ESI) m / z: 282.2 [m+H] +.

[0318] Step 3: A solution of compound Int15-2 (60 mg, 0.21 mmol) in 4.0 M HCl in dioxane (5 mL) was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was monitored by LCMS and concentrated under reduced pressure to afford Intermediate 15 (47 mg HCl salt, 100% yield). MS (ESI) m / z: 182.0 [m+H]+.

[0319] ((7-Fluoro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)methanamine hydrochloride (Intermediate 16) was prepared according to the following synthetic route:

[0320] Step 1: To a solution of compound Int13-5 (600 mg, 3.52 mmol) in THF (8 mL) was added DMS-BH3 (3.52 mL, 35.2 mmol, 10 M / L), the mixture was purged with nitrogen for 3 minutes, and stirred at 65 ° C overnight. The reaction mixture was cooled to room temperature, MeOH (10 mL) was added, stirred at 60 ° C for 0.5 hours, and concentrated under reduced pressure. The residue was then diluted with water (200 mL) and extracted with EA (300 mL * 3). The combined organics were concentrated. The residue was purified by flash chromatography (PE: EA = 100: 0: 0: 100) to give the desired compound Int16-1 (405 mg, yield 66.71%). MS (ESI) m / z: 173.0 [m + H] +.

[0321] Step 2: To a solution of compound Int16-1 (200 mg, 1.16 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added compound Int13-7 (550 mg, 2.32 mmol), K3PO4 (738 mg, 3.48 mmol), and the mixture was purged with nitrogen for 5 minutes. CataCXiumAPdG3 (84 mg, 0.12 mmol) was added, and the mixture was stirred at 100 ° C overnight. After completion of the reaction monitored by LCMS, the mixture was diluted with water (200 mL) and extracted with EA (200 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA=100:0:0:100) to give the desired compound Int16-2 (178 mg, 57.47% yield) as a white solid. MS (ESI) m / z: 268.0 [m+H] +.

[0322] Step 3: A solution of compound Int16-2 (178 mg, 0.67 mmol) in 4M HCl in dioxane (8 mL) was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was monitored by LCMS and concentrated under reduced pressure to afford the desired compound Intermediate 16 (136 mg, HCl salt, 100% yield). MS (ESI) m / z: 168.0 [m+H]+.

[0323] 1-(4-(Cyclopropylmethoxy)benzyl)-1H-pyrazole-4-carboxylic acid (Intermediate 17) was prepared according to the following synthetic route:

[0324] Step 1: (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) at room temperature and heated to 60°C with stirring for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The product was isolated and purified by column chromatography (ethyl acetate:petroleum ether = 0-100%) to afford compound Int17-2 (440 mg, yield: 72.7%) as a white solid. MS (ESI) M / Z: 177.1 [M+1]+.

[0325] Step 2: Under nitrogen, compound Int17-2 (480 mg, 2.47 mmol) was added to MeOH (3 mL), cooled to 0°C, and the N2 atmosphere was replaced three times. NaBH4 (309 mg, 7.41 mmol) was added, and the mixture was stirred at 0°C for 2 h. 1 M / L NH4Cl aqueous solution (3 mL) was added, and 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] + .

[0326] 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 dissolved in PBr3 (1.34 g, 4.96 mmol) was added, and stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to alkaline with saturated aqueous sodium bicarbonate solution, and extracted with DCM (10 mL × 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.

[0327] MS (ESI) M / Z: 241.1 [M+1] + .

[0328] Step 4: At room temperature, Int17-4 (661 mg, 2.75 mmol) was weighed and added to DMF (5 mL). K2CO3 (1.51 g, 11 mmol) and methyl pyrrole-3-carboxylate (381.15 mg, 3.025 mol) were added portionwise and stirred at room temperature for 12 h. Water (30 mL) was added and the mixture was extracted with DCM (30 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was isolated 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] + .

[0329] Step 5: Compound Int17-5 (60 mg, 0.21 mmol) was added to MeOH (3 mL) at room temperature, and a solution of 1 M NaOH (1 ml) was added. The mixture was stirred at room temperature for 12 hours. The pH of the reaction mixture was adjusted to acidic with 1 N aqueous hydrogen chloride solution, and the mixture was extracted with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Intermediate 17 (60 mg) as a white solid. MS (ESI) M / Z: 273.3 [M+1] + .

[0330] (7-Fluoro-2,3-dihydrofluoro[3,2-c]pyridin-6-yl)methanamine hydrochloride (Intermediate 18) was prepared according to the following synthetic route:

[0331] Step 1: NaH (1.96 g, 40.2 mol, 60% purity) was added portionwise to a solution of methyl glycolate (2.4 g, 40.2 mmol) in ethylene glycol dimethyl ether (50 mL) under an ice bath. The reaction mixture was warmed to room temperature and stirred for 30 minutes. Int18-1 (9 g, 40.2 mmol) was then dissolved in ethylene glycol dimethyl ether (10 mL) and added dropwise to the reaction mixture. The mixture was allowed to react at 35°C for 2 hours. After completion of the reaction, 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 concentrated. The residue was purified by flash chromatography (PE:EA = 5:1 to 1:2) to afford the desired compound Int18-2 (6.4 g, 65% yield) as a white solid. MS (ESI) m / z: 246.0 [M+H]+.

[0332] Step 2: Dissolve ethyl Int18-2 (6.4 g, 26 mmol) in a mixture of tetrahydrofuran (60 mL) and water (16 mL), then add hydrazine hydroxide monohydrate (4.45 g, 106.8 mmol). Heat to 40°C and react for 2 days. Upon completion, cool the reaction mixture to room temperature, filter, and wash the filter cake with tetrahydrofuran. The filter cake is then dissolved in a mixture of ethyl acetate and water and acidified to a pH of 6-7 with 1M hydrochloric acid in an ice-water bath. Separate the mixture, extract the aqueous phase with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate into a rotary evaporator to yield compound Int18-3 (2.9 g, 15.6 mmol, 60%). MS m / z (ESI): 188.0 [M+H]+.

[0333] Step 3: To a solution of compound Int18-3 (0.96 g, 5.2 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) were added compound Int13-7 (2.45 g, 10.4 mmol) and K3PO4 (3.30 g, 15.6 mmol), and the mixture was purged with nitrogen for 5 minutes. CataCXiumAPdG3 (376 mg, 0.53 mmol) was added, and the mixture was stirred at 100 ° C overnight. After completion of the reaction, the mixture was diluted with water (200 mL) and extracted with EA (200 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA=5:1 to 1:2) to give the desired compound Int18-4 (733 mg, 50% yield) as a white solid. MS (ESI) m / z: 283.1 [M+H] +.

[0334] Step 4: A solution of compound Int18-4 (733 mg, 2.6 mmol) in anhydrous ethanol (40 mL) was hydrogenated with 20% palladium hydroxide (150 mg) at 3 atmospheres overnight. The catalyst was removed by filtration through a celite pad, and the filtrate was concentrated to give compound Int18-5 (629 mg, 90%), MS (ESI) m / z: 269.1 [M+H]+.

[0335] Step 5: A solution of compound Int18-5 (629 mg, 2.34 mmol) in 4M HCl in dioxane (8 mL) was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was monitored by LCMS and concentrated under reduced pressure to afford the desired compound Intermediate 18 (440 mg, HCl salt, 92% yield). MS (ESI) m / z: 169.0 [M+H]+.

[0336] Example 1. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-1,2,3-triazole-4-carboxamide (Compound 1) was prepared according to the following synthetic route:

[0337] Step 1: To a solution of intermediate 2 (500 mg, 1.80 mmol, 1.00 eq) in DMF (5.00 mL) was added NaN 3 (175 mg, 2.70 mmol, 1.50 eq). 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 was formed. The reaction mixture was distributed between H 2 O (30.0 mL) and EtOAc (50.0 mL). The organic phase was separated, washed with brine (30.0 mL), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give a residue. Compound 1-1 (350 mg, 1.46 mmol, 81.0% yield) was obtained as a colorless oil. LCMS (ESI): m / z 241.

[0338] Step 2: A solution 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), CuSO 4 (72.7 mg, 291 μmol, 0.200 eq) and ascorbic acid sodium salt (288 mg, 1.46 mmol, 1.00 eq) in t-BuOH (20.0 mL) and H 2 O (5.00 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 25° C. under a N 2 atmosphere for 2 hours. TLC (plate 1, dichloromethane: methanol = 10:1) showed that the starting material was consumed and a new spot was predicted. The residue was diluted with H 2 O (30.0 mL) and extracted with EtOAc (50.0 mL). The combined organic layers were washed with brine (30.0 mL), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to obtain a residue. The residue (dichloromethane:methanol=10:1) was purified by preparative TLC (SiO2, dichloromethane:MeOH=10:1). Compound 1-3 (100 mg, 308 μmol, 21.1% yield) was obtained as a white solid. LCMS (ESI): m / z 325; 1H NMR(400MHz, DMSO-d6)δ7.90(s,1H),7.29-7.27(m,2H),7.24-7.18(m,2H),6.56-6.53(d,J= 9.2Hz, 1H), 6.13-6.09 (t, J = 6.8Hz, 2H), 5.48 (s, 2H), 5.07 (s, 2H), 3.85 (s, 3H).

[0339] Step 3: At 0 ° C, to a solution of compound 1-3 (100 mg, 308 μmol, 1.00 eq) in MeOH (1.00 mL) and H2O (0.500 mL) was added NaOH (24.6 mg, 616 μmol, 2.00 eq). The mixture was stirred at 25 ° C for 1 hour. LC-MS showed that the required mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was dissolved in water (5.00 mL) and acidified to pH = 3 with 2M HCl. Filter and collect the solid to obtain a residue. Obtain white solid compound 1-4 (90.0 mg, 290 μmol, 94.0% yield). LCMS (ESI): m / z 311.

[0340] Step 4: A mixture of compound 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 and purged with N 2 three times, and then the mixture was stirred at 25° C. under a N 2 atmosphere for 2 hours. TLC (plate 1, dichloromethane: methanol = 10:1) showed that compound 1-4 was consumed and a new spot was detected. The residue was diluted with H 2 O (30.0 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (30.0 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue (plate 1, dichloromethane:methanol = 10:1) was purified by preparative TLC (SiO2, dichloromethane:methane = 10:1) to give the title compound 1 (21.92 mg, 49.3 μmol, 30.6% yield, 98.6% purity) as a white solid. LCMS (ESI): m / z 444; 1H NMR(400MHz,DMSO-d6)δ7.90(s,1H),7.31-7.27(m,2H),7.20(s,2H),6.91(s,1H),6.58-6.56(d,J=9.2Hz,2H),6 .18-6.10(m,2H),5.47(s,1H),5.09(s,1H),4.49-4.48(d,J=4.8Hz,2H),4.39(s,2H),2.40(s,3H),2.22(s,3H).

[0341] Example 2. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 2) was prepared according to the following synthetic route:

[0342] Step 1: To a solution of intermediate 2 (500 mg, 1.80 mmol, 1.00 eq) in DMF (20.0 mL) was added compound 2-1 (305 mg, 1.80 mmol, 1.00 eq) and K2CO3 (496 mg, 3.60 mmol, 2.00 eq). 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 * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0-10 / 1, plate 2: DCM: MeOH = 10: 1, Rf = 0.34). White solid compound 2-2 (300 mg, 816 μmol, yield 45.4%) was obtained, LCMS (ESI): m / z 368 [M+1] +; 1 H NMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 7.76-7.74 (d, J = 8Hz, 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=12Hz,1H),5.29(s,2H),5.06(s,2H),4.48(s,2H),3.71(s,3H),3.22(s,3H).

[0343] 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) was added NaOH (163 mg, 4.08 mmol, 5.00 eq). 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 1M HCl. It was then concentrated under reduced pressure to give a crude product. Compound 2-3 (280 mg, crude product) was obtained as a white solid. LCMS (ESI): m / z 352 [M-1] -;

[0344] Step 3: To a solution of compound 2-3 (50.0 mg, 141 μmol, 1.00 eq) in DMF (2.00 mL) were added 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). The mixture was stirred at 25° C. under N 2 for 2 hours. LC-MS showed that the desired mass was detected. NaHCO 3 (5.00 mL) was added to the mixture and stirred for 0.5 hours. It was then diluted with 10.0 mL of H 2 O and extracted with 30.0 mL of DCM (10.0 mL*3). The combined organic layers were washed with 20.0 mL (10.0 mL*2) of brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO 2 , DCM:MeOH=10:1, Rf=0.38) to obtain the title compound 2 as a white solid (60.0 mg, 121 μmol, 85.6% yield, 98.2% purity), LCMS (ESI): m / z 487 [M+1] +; 1 H NMRδ(400MHz,CD3OD-d4)δ8.11(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).

[0345] Example 3. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-5-((3-chloroquinolin-6-yl)methyl)thiophene-2-carboxamide (Compound 3) was prepared according to the following synthetic route:

[0346] Step 1: To a solution of intermediate 4 (500 mg, 2.36 mmol, 1.00 eq) in DMF (25.0 mL) were added 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), and the mixture was degassed and purged with N2 three times. The mixture was heated to 60°C and stirred for 12 hours. LCMS showed that intermediate 4 was consumed and the desired MS was detected. The reaction mixture was diluted with H2O (25.0 mL), then extracted with EtOAc (20.0 mL*2), and 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 give a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150*40 mm*15 um; mobile phase: [water (FA)-ACN]; gradient: 49%-79% B in 15 minutes) to give the desired compound 3-2 (360 mg, 1.13 mmol, 48.0% yield) as a yellow solid. LCMS (ESI): m / z 318 [M+1]+; 1 H NMR (400MHz, DMSO-d6) δ8.85(d,J=2.4Hz,1H),8.53(d,J=2.4Hz,1H),8.01(d,J=8.8Hz ,1H),7.86(s,1H),7.77-7.62(m,2H),7.07(d,J=3.6Hz,1H),4.43(s,2H),3.76(s,3H).

[0347] 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 NaOH (4 M, 724 μL, 2.00 eq) in H2O (2.00 mL), and the mixture was stirred at 50 ° C for 2 hours. LCMS showed that compound 3-2 was consumed and the required MS was detected. The reaction mixture was concentrated to give a residue and diluted with H2O (3.00 mL), and the pH was adjusted to 6 with 1M HCl, and the mixture was then freeze-dried to give compound 3-3 (600 mg, crude product) as a white solid. LCMS (ESI): m / z 304 [M + 1] +; 1H NMR (400MHz, DMSO-d6) δ8.85(d,J=2.4Hz,1H),8.55(d,J=2.0Hz,1H),8.01(d,J=8.8Hz,1H),7.86(s,1H),7.72(dd,J 1＝ 8.8Hz, J2=1.6Hz, 1H), 7.49 (d, J=3.6Hz, 1H), 6.98 (d, J=3.6Hz, 1H), 4.39 (s, 2H).

[0348] Step 3: To a solution of compound 3-3 (90.0 mg, 296 μmol, 1.00 eq) in DMF (5.00 mL) were added 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), and the mixture was stirred at 25 ° C for 1 hour. LCMS showed that compound 3-3 was consumed, and the reaction mixture was diluted with H2O (10.0 mL), then extracted with EtOAc (20.0 mL*3), and 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 give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water(NH4HCO3)-ACN]; gradient: 28%-58% B in 10 minutes) to give the title compound 3 (30.0 mg, 67.4 μmol, 22.8% yield, 98.2% purity) as a yellow solid. LCMS (ESI): m / z 437 [M+1]+; 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=2.0Hz,1H),8.09(d,J=1.6Hz,1H),8.04(d,J=4.8Hz,1H),7.64-7.54(m,2H),7.38 (d,J=2.8Hz,1H),6.83(d,J=3.6Hz,1H),6.31(s,1H),4.51(d,J=4.8Hz,2H),4.33(s,2H),2.51(s,3H),2.31(s,3H).

[0349] Example 4. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-4-(tetrahydrofuran-2-yl)-1H-pyrazole-3-carboxamide (Compound 4) was prepared according to the following synthetic route:

[0350] Step 1: To a solution of compound 4-1 (5.00 g, 19.8 mmol, 1.00 eq) in THF (40.0 mL) was added NaH (1.03 g, 25.8 mmol, 60.0% purity, 1.30 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hours. SEMCl (3.97 g, 23.8 mmol, 4.21 mL, 1.20 eq) was then added to the mixture at 0°C. The reaction mixture was stirred at 25°C for 1 hour. LC-MS showed complete consumption of compound 4-1, and a major peak with the desired m / z was detected. The reaction mixture was quenched by adding saturated water. NH4Cl (20.0 mL) was added at 0°C, 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 a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate = 100:1 to 3:1, petroleum ether:ethyl acetate = 3:1). Compound 4-2 (6.00 g, 15.7 mmol, 79.1% yield) was obtained as a yellow oil. LCMS (ESI): m / z 383 [M+1] +; 1 H NMR (400MHz, DMSO-d6) δ7.41 (s, 1H), 5.48 (s, 2H), 3.95 (s, 3H), 3.56 (t, J = 8.4Hz, 1H), 0.90 (t, J = 8.4Hz, 1H), -0.01 (s, 9H).

[0351] 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 at 110 ° C in a microwave for 2 hours. LC-MS showed that compound 4-2 was completely consumed and a 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 layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a 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 (petroleum ether:ethyl acetate = 1:1) was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1). Compound 4-4 was obtained as a yellow oil (75.0 mg, 8.55% yield). LCMS (ESI): m / z 325 [M+1]+.

[0352] Step 3: Under 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 with H2 three times. The mixture was stirred at 25 ° C for 12 hours under H2 (15 Psi). LC-MS showed that compound 4-4 was completely consumed and a main peak of the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. Compound 4-5 (73.0 mg, 207 μmol, yield 89.5%, purity 92.5%) was obtained as a colorless oil. LCMS (ESI): m / z 327 [M+1] +.

[0353] Step 4: To a solution of compound 4-5 (73.0 mg, 224 μmol, 1.00 eq) in 1,4-dioxane (0.500 mL) was added HCl / 1,4-dioxane (4.00 M, 280 μL, 5.00 eq). The mixture was stirred at 70°C for 12 hours. LC-MS analysis showed complete consumption of compound 4-5, and a major peak with the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (HCl conditions; column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (HCl)-ACN]; gradient: 8% to 38% B over 9 minutes). Compound 4-6 (11.0 mg, 56.1 μmol, 25.1% yield) was obtained as a yellow oil. LCMS(ESI):m / z 394[M+1]+; 1HNMR (400MHz, CDCl3) δ7.37-7.20 (m, 7H), 6.62 (d, J = 8.8Hz, 1H), 6.17 (t ,J=6.4Hz,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).

[0354] Step 5: To a solution of compound 4-6 (10.0 mg, 25.4 μmol, 1.00 eq) in MeOH (0.500 mL) was added NaOH (2.03 mg, 50.8 μmol, 2.00 eq) and H2O (0.100 mL). The mixture was stirred at 25°C for 3 hours. LC-MS showed that compound 4-6 was completely consumed, and a major 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 a residue. Compound 4-7 (9.00 mg, 23.7 μmol, 93.3% yield) was obtained as a yellow solid. LCMS (ESI): m / z 380 [M+1] +.

[0355] Step 6: 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) were added HATU (13.5 mg, 35.6 μmol, 1.50 eq) and TEA (7.20 mg, 71.2 μmol, 9.91 μL, 3.00 eq). The mixture was stirred at 25° C. for 1 hour. LC-MS showed that compound 4-7 was completely consumed, and a major 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*3) of NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters xbridge 150*25 mm 10 μm; mobile phase: [water (NH4HCO3) -ACN]; gradient: 18% - 38% B in 8 minutes). The title compound 4 was obtained as a yellow solid (2.13 mg, 4.13 μmol, 17.4% yield). LCMS (ESI): m / z 513 [M+1] +; 1H NMR (400 MHz, 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=6.8Hz,1H),5.21-5.10(m,6H),4.50(d,J=4.8Hz,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).

[0356] Example 5. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-((3-chloroquinolin-6-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (Compound 5) was prepared according to the following synthetic route:

[0357] Step 1: 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) was added Cs2CO3 (384 mg, 1.18 mmol, 1.00 eq) and the reaction mixture was stirred at 80 ° C for 2 hours. LC-MS showed that compound 4 was consumed and a 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 a 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) δ8.84 (d, J = 2.4Hz, 1H), 8.12-8.07 (m, 2H), 7.8 9(s,1H),7.62-7.55(m,2H),5.49(s,2H),4.76(s,2H),3.81(s,3H),3.49(s,3H).

[0358] Step 2: To a solution of compound 5-1 (230 mg, 665 μmol, 1.00 eq) in THF (2.00 mL) and MeOH (2.00 mL) was added a solution of 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 a main peak with the desired mass was detected. The reaction mixture was concentrated to remove MeOH. Then, the pH of the mixture was adjusted to 7 with 1.00 M HCl, and the mixture was then concentrated under vacuum to obtain a 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) δ8.86 (d, J = 2.4Hz, 1H), 8.57 (d, J = 2.4Hz, 1H), 8.06-7.98 (m, 2H) ,7.81(d,J=1.2Hz,1H),7.64(dd,J1=8.8Hz,J2=2.0Hz,1H),5.48(s,2H),4.61(s,2H),3.21(s,3H).

[0359] Step 3: 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) were added HATU (189 mg, 497 μmol) and TEA (101 mg, 995 μmol. 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 saturated NaHCO 3 aqueous solution. 50.0 mL, extracted with ethyl acetate (50.0 mL x 3), and the combined organic phases were dried over Na 2 SO 4 and concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters xbridge 150*25 mm 10 μm; mobile phase: [water (NH4HCO3) - ACN]; gradient: 25% to 45% B over 8 minutes) to afford the 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]+; 1H NMR (400 MHz, 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, J = 8.8 Hz,J2=1.8Hz,1H),6.11(s,1H),5.64(s,2H),5.51(s,2H),4.49(s,2H),4.26(d,J=4.4Hz,2H),3.13(s,3H),2.29(s,3H),2.16(s,3H).

[0360] Example 6. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl-1H-1,2,3-triazole-4-carboxamide (Compound 6) was prepared according to the following synthetic route:

[0361] 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*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 (eluted with EtOAc) to give the desired compound 6-1 (0.556 g, 38.97% yield) as a yellow solid. LCMS (ESI): m / z 214.0 [m+H]+.

[0362] Step 2: To a solution of 6-1 (0.556 g, 2.61 mmol) and 6-2 (0.24 g, 2.87 mmol) in tert-butanol (4 mL) and water (4 mL) was added sodium ascorbyl palmitate (52 mg, 0.26 mmol) and CuSO4 (42 mg, 0.26 mmol). After stirring the mixture at room temperature for 3 hours, the mixture was diluted with water (200 mL) and extracted with DCM (50 mL*3). The combined organic layers were concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1 elution) 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]+.

[0363] 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) was added NaOH (0.068 g, 1.7 mmol). The mixture was stirred at room temperature for 1 h, and 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, yield 99.70%). LCMS (ESI): 284.0 [M+H] +.

[0364] Step 4: Compound 6-4 (0.095 g, 0.34 mmol), compound 2 (0.051 g, 0.34 mmol), DIEA (0.066 g, 0.51 mmol), HATU (0.13 g, 0.34 mmol) were added to DMF (3 mL). The mixture was stirred at room temperature overnight 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 give the title compound 6 (5.69 mg, 4.07% yield) as a white solid. LCMS (ESI): 417.2 [M+H] +;1H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.41(s,1H),8.35(s,1H),7.83(s,1H),7.40(d,J=9.4Hz,1H),7.01(d,J=8.2Hz,1H),6.21(s,1H),5.72(s ,2H),4.33(d,J=4.9Hz,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=6.0Hz,2H),0.67(d,J=5.1Hz,2H).

[0365] Example 7. Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-(2-cyano-4-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)benzyl)-1H-pyrazole-4-carboxamide (Compound 7) according to the following synthetic route:

[0366] To a mixture of intermediate 6 (0.040 g, 0.12 mmol) and intermediate 1 (0.022 g, 0.14 mmol) in DMF (3 mL) was added DIEA (0.047 g, 0.36 mmol) and HATU (0.046 g, 0.12 mmol). After the mixture was stirred at room temperature for 2 hours, the reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (100 mL) and extracted with DCM (100 mL*3). The combined organic layers were washed with brine, water and dried over anhydrous Na2SO4. The organic layer was then concentrated under reduced pressure, and the residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound 7 as a white solid (37.41 mg, 67.44% yield). LCMS (ESI) M / Z:478.4[m+H]+; 1H NMR (400MHz, DMSO) δ8.17(s,1H),8.00(s,1H),7.86(s,1H),7.29(d,J=8.8Hz,1H),6.94(d,J=2.4Hz,1H),6.83(dd,J=8.7,2.7Hz,1H),6.23(d,J=26 .4Hz,3H),5.33(s,2H),4.25(d,J=4.8Hz,2H),3.63(d,J=10.4Hz,2H),3.56(d,J=8.4Hz,2H),2.71(d,J=10.5Hz,2H),2.34(s,3H),2.21(s,3H).

[0367] Example 8. N-(4-Carbamoylbenzyl)-1-(2-cyano-4-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)benzyl)-1H-pyrazole-4-carboxamide (Compound 8) was prepared according to the following synthetic route:

[0368] To a mixture of intermediate 6 (82 mg, 0.24 mmol) and intermediate 8-1 (80 mg, 0.36 mmol) in DMF (3 mL) was added DIEA (93 mg, 0.72 mmol), HATU (91 mg, 0.24 mol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction monitored 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, 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 to 50 / 50, HCl) to give the title compound 8 (27.61 mg HCl salt, 24.38% yield). LCMS (ESI) M / Z: 476.2 [M+H]+; 1H NMR (400MHz, DMSO) δ9.33(s,2H),9.12(s,2H),8.84(t,J=5.9Hz,1H),8.21(s,1H), 7.92(s,1H),7.78(d,J=8.0Hz,2H),7.49(d,J=8.0Hz,2H),7.33(d,J=8.4Hz,1H) ,6.95(d,J=2.4Hz,1H),6.84(dd,J=8.7,2.4Hz,1H),5.37(s,2H),4.47(d,J=5. 6Hz, 2H), 3.64 (d, J = 10.4Hz, 2H), 3.57 (d, J = 9.2Hz, 2H), 2.72 (d, J = 10.8Hz, 2H).

[0369] Example 9. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-(3-chloroquinolin-6-yl)methyl-1H-1,2,3-triazole-4-carboxamide (Compound 9) was prepared according to the following synthetic route:

[0370] Step 1: To a solution of intermediate 4 (300 mg, 1.41 mmol, 1.00 eq) in DMF (5.00 mL) was added NaN 3 (100 mg, 1.54 mmol, 1.09 eq), and the mixture was stirred at 20 ° C for 12 hours. LCMS showed that intermediate 4 was consumed and the expected mass was detected. The reactant was diluted with NaHCO 3 (saturated, 10.0 mL), then extracted with EtOAc (15.0 mL x 2), washed with water (20.0 mL x 1) and brine (30.0 mL x 1) and washed with water. The combined organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give compound 9-1 (260 mg, 1.19 mmol, 84.1% yield) as a yellow solid. LCMS (ESI): m / z 219 [M + 1] +; 1 H NMR (400MHz, CDCl3) δ8.85 (d, J = 2.4Hz, 1H), 8.26-8.02 (m, 2H), 7.83-7.59 (m, 2H), 4.57 (s, 2H).

[0371] Step 2: To a mixture of 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) in H2O (5.00 mL) and t-BuOH (5.00 mL) were added vitamin C sodium salt (1 M, 1.23 mL, 1.00 eq) and CuSO4 (2 M, 123 μL, 0.20 eq), and the reaction mixture was stirred at 20 ° C for 12 hours. LCMS showed that compound 9-1 was consumed and the desired mass was detected. The reaction mixture was filtered and the filter cake was concentrated to give the desired compound 9-3 (330 mg, 1.09 mmol, 88.3% yield) as a yellow solid. LCMS (ESI): m / z 303 [M + 1] +; 1 H NMR (400MHz, DMSO-d6) δ8.97(s,1H),8.90(d,J=2.4Hz,1H),8.61(d,J=2.0Hz,1H),8.07(d ,J=8.8Hz,1H),7.87(s,1H),7.76(dd,J1=8.8Hz,J2=1.6Hz,1H),5.90(s,2H),3.83(s,3H).

[0372] 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. LCMS showed that compound 9-3 was consumed, and the desired MS was detected. The reaction mixture was concentrated to remove MeOH, and the pH was then adjusted to 6 with 1M HCl, and the mixture was then concentrated to give the desired compound 9-4 (400 mg, crude) as a yellow solid. LCMS (ESI): m / z 289[M+1]+; 1 H NMR (400MHz, DMSO-d6) δ9.10-8.76(m,2H),8.64-8.53(m,1H),8.12-7.73(m,3H),6.25-5.66(m,2H).

[0373] Step 4: To 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 added 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 stirred at 20 ° C for 1 hour. LCMS showed that compound 9-4 was consumed and the required mass was detected. The reactant was diluted with H2O (5.0 mL), then extracted with EtOAc (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 give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water(NH4HCO3)-MeCN]; gradient: 15%-45% B in 10 minutes) to give the title compound 9 (0.0250 g, 58.9 μmol, 17.0% yield, 99.4% purity) as a yellow solid. LCMS (ESI): m / z 422 [M+1]+; 1H NMR (400MHz, CDCl3) δ8.87(d,J=2.0Hz,1H),8.22-8.10(m,2H),8.06(s,1H),7.69-7.62(m,1H),7.59(dd,J=2 .0,8.8Hz,1H),7.09-6.98(m,1H),6.30(s,1H),5.76(s,2H),4.55(d,J=5.2Hz,2H),2.53(s,3H),2.33(s,3H).

[0374] Example 10. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide (Compound 10) was prepared according to the following synthetic route:

[0375] Step 1: In DMF (3 mL), a solution of intermediate 4 (200 mg, 0.94 mmol) and 1H-pyrazole-4-carboxylic acid methyl ester (143 mg, 1.12 mmol) was added KCO (300 mg, 2.16 mmol), and the mixture was stirred at room temperature for 2 h. After LCMS monitoring of the reaction was complete, the reaction mixture was diluted with H O (30 mL) and extracted with EtOAc (50 mL*3), and dried over anhydrous NaSO. The organic phase was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc) to obtain compound 10-1 (180 mg, 63% yield) as a white solid. LCMS (ESI): m / z 302 [M+H]+.

[0376] Step 2: A solution of compound 10-1 (180 mg, 0.60 mmol) in MeOH (4 mL) and H2O (1 mL) was added NaOH (96 mg, 2.39 mmol) at 0 ° C, and the mixture was stirred at room temperature for 2 h. After the reaction was completed by LCMS monitoring, 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) and 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 desired compound 10-2 (146 mg, 85% yield) as a white solid. LCMS (ESI): m / z 288[M+H]+.

[0377] 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) was added HATU (474 ​​mg, 1.2 mmol, 3.00 eq) and DIEA (269 mg, 2.07 mmol, 363 μL, 5.00 eq), and the mixture was stirred at 20 ° C for 1 hour. LCMS showed that compound 10-2 was consumed and the required mass was detected. The reactant was diluted with H2O (5.0 mL), then extracted with EtOAc (10.0 mL x 2), washed with water (20.0 mL x2) and brine (30.0 mL x 1) and the combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge C18 150*50mm*10um; mobile phase: [water(NH4HCO3)-MeCN]; gradient: 15%-45% B in 10 minutes) to give the title compound 10 (30 mg, 20% yield, as a yellow solid. LCMS (ESI): m / z 421[M+1]+; 1 H NMR (400MHz, CDCl3) δ8.88(d,J=2.0Hz,1H),8.24-8.12(m,2H),8.08(s,1H),7.94(s,1H),7.68-7.63(m,1H),7.59(d d,J=2.0,8.8Hz,1H),7.09-6.98(m,1H),6.32(s,1H),5.76(s,2H),4.56(d,J=5.2Hz,2H),2.55(s,3H),2.31(s,3H).

[0378] Example 11. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-1,2,4-triazole-3-carboxamide (Compound 11) was prepared according to the following synthetic route:

[0379] Step 1: To a solution of intermediate 2 (400 mg, 1.89 mmol, 1.00 eq) in DMF (10.0 mL) were added K2CO3 (521 mg, 3.77 mmol, 2.00 eq) and compound 11-1 (240 mg, 1.89% mmol, 1.00 eq). The mixture was stirred at 50°C for 12 hours. LCMS showed that compound 11-1 was consumed and the desired MS was detected. The reaction mixture was diluted with H2O (10.0 mL) and then extracted with EtOAc (20.0 mL*2). 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 a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 0:1, Rf1 = 0.14, Rf2 = 0.48) to give compound 11-2 (120 mg, 21.0% yield) as a white solid. LCMS (ESI): m / z 325 [M+1] +.

[0380] Step 2: To a solution of compound 11-2 (100 mg, 330 μmol, 1.00 eq) in MeOH (3.00 mL) was added NaOH (4 M, 165 μL, 2.00 eq). The mixture was stirred at 20 ° C for 2 hours. LCMS showed that compound 11-2 was consumed and the required MS was detected. The reaction mixture was diluted with THF (10.0 mL) and then concentrated under reduced pressure to give compound 11-3 (120 mg, crude product) as a white solid. LCMS (ESI): m / z 309 [M-1] -.

[0381] Step 3: To a solution of compound 11-3 (48.0 mg, 144 μmol, 1.00 eq) in DMF (3.00 mL) was added 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). 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 distributed 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 a residue. The residue (plate 2, DCM:MeOH = 10:1) was purified by preparative TLC (SiO2, DCM:MeOH = 10:1) to give 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] +; 1H NMRδ7.98 (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=8.0Hz,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).

[0382] Example 12. N-(4-Carbamoylbenzyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 12) was prepared according to the following synthetic route:

[0383] Step 1: A solution of intermediate 2 (200 mg, 0.72 mmol) and 1H-pyrazole-4-carboxylic acid methyl ester (110 mg, 0.86 mmol) in KCO (300 mg, 2.16 mmol) was added to DMF (3 mL) and the mixture was stirred at room temperature for 2 h. After the reaction was completed by LCMS monitoring, the reaction mixture was diluted with H O (30 mL) and extracted with EtOAc (50 mL*3), and dried over anhydrous Na SO. The organic phase was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc) to give compound 12-1 (120 mg, 51.7% yield) as a white solid. LCMS (ESI): m / z 324.2 [M+H]+.

[0384] Step 2: A solution of compound 12-1 (120 mg, 0.37 mmol) in MeOH (4 mL) and H2O (1 mL) was added NaOH (89 mg, 2.22 mmol) at 0 ° C, and the mixture was stirred at room temperature for 2 h. After the reaction was completed by LCMS monitoring, 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) and 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 give the desired compound 12-2 (100 mg, 87.7% yield) as a white solid. LCMS (ESI): m / z 310.1[M+H]+.

[0385] Step 3: 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), TEA (160 mg, 1.60 mmol) was added to DMF (3 mL) and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with H2O (20 mL) and 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. The title compound 12 was purified by Prep-TLC (DCM:MeOH=7:1) to give a white solid (20.06 mg, 14.1% yield). LCMS (ESI): m / z 441.2 [M+H]+; 1 H NMR(400MHz,DMSO)δ9.32(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).

[0386] Example 13. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-4-(4-((2-oxopyridin-1(2H)-yl)methylbenzyl)picolinamide (Compound 13) was prepared according to the following synthetic route:

[0387] Step 1: Intermediate 2 (200 mg, 719 μmol, 1.00 eq), compound 13-1 (227 mg, 862 μmol, 1.20 eq) and Pd(t-Bu 3 P) 2 (36.8 mg, 71.9 μmol, 0.10 eq), DIEA (371 mg, 2.88 mmol, 500 μL, 4.00 eq) were placed in a microwave tube in 1,4-dioxane (2 mL) and HO (0.4 mL). The sealed tube was heated at 110 ° C. in a microwave for 1 hour. LC-MS showed that the desired mass of the product was detected. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane and HO. The crude product 13-2 (70 mg) was purified by preparative TLC. LCMS (ESI): m / z 335 [M+1] +.

[0388] Step 2: To a solution of compound 13-2 (70.0 mg, 209 μmol, 1.00 eq) in MeOH (1.00 mL) and H2O (1.00 mL) was added NaOH (41.9 mg, 1.05 mmol, 5.00 eq). 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 MeOH, and then the pH was adjusted to 6-7 with 1 M HCl. It was then concentrated under reduced pressure to give the crude product. Compound 13-3 (60.0 mg, 187 μmol, 89.5% yield) was obtained as a white solid. LCMS (ESI): m / z 321[M+1]+.

[0389] Step 3: To a solution of compound 13-3 (60.0 mg, 187 μmol, 1.00 eq) in DMF (2.00 mL) were added 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). The mixture was stirred at 25° C. under a N atmosphere for 12 hours. LC-MS showed that the desired mass was detected. NaHCO (5.00 mL) was added to the mixture and stirred for 0.5 hours. It was then diluted with 10.0 mL of H O and extracted with 30.0 mL of DCM (10.0 mL*3). The combined organic layers were washed with 20.0 mL (10.0 mL*2) of brine, dried over Na SO, filtered and concentrated under reduced pressure to obtain a residue. Preparative HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [water(NH4HCO3)-MeCN]; gradient: 20%-50% B over 10 minutes) afforded the title compound 13 (21.0 mg, 44.5 μmol, 23.7% yield, 96.0% purity) as a white solid. LCMS (ESI): m / z 454 [M+1]+; 1 H NMRδ(400MHz, CDCl3)δ8.36-8.35(d,J=4.8Hz,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=8Hz,1H),6.22(s,1H),6.17-6.14(m,1H),5.11(s,2H),4.56-4.55(d,J=5.2Hz,2H),4.37(s,2H),2.46(s,3H),2.28(s,3H).

[0390] Example 14. 1-(4-((1H-pyrazol-1-yl)methyl)benzyl)-N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (Compound 14)

[0391] Compound 14 was prepared according to the following synthetic route:

[0392] Step 1: To a solution of pyrrole (0.25 g, 3.67 mmol, 1.00 eq) in THF (10.0 mL) at 0°C was added 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 was consumed. The residue was diluted with H2O (30.0 mL) and extracted with EtOAc (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 a residue. The residue (plate 1, petroleum ether:ethyl acetate = 3:1) was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 20:1 to 3:1). Compound 14-1 (300 mg, 1.19 mmol, 32.5% yield) was obtained as a white solid. LCMS (ESI): m / z 251 [M+1] + .

[0393] Step 2: To a solution of compound 14-1 (200 mg, 796 μmol, 1.00 eq) in DMF (4.00 mL) was added K2CO3 (220 mg, 1.59 mmol, 2.00 eq) and compound 2-1 (136 mg, 796 μmol, 1.00 eq). 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 EtOAc (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 a residue. The residue (dichloromethane:methanol=10:1) was purified by preparative TLC (SiO2, dichloromethane:methane=10:1). White solid compound 14-2 (90.0 mg, 264 μmol, yield 33.2%) was obtained. LCMS (ESI): m / z 341 [M+1] +; 1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),7.80(s,1H),7.44(s,1H),7.25–7.22(m,2H),7.1 9–7.17(m,2H),6.25(s,1H),5.33–5.30(m,4H),4.49(s,2H),3.72(s,3H),3.34(s,1H).

[0394] Step 3: At 0 ° C, 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) was added NaOH (23.5 mg, 588 μmol, 4.00 eq). The mixture was stirred at 25 ° C for 4 hours. LC-MS showed that the required mass was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (10.0 mL) and adjusted to pH = 3 with HCl (1.00 M), and then concentrated under reduced pressure to obtain a residue. White solid compound 14-3 (45.0 mg, 138 μmol, 93.9% yield) was obtained. LCMS (ESI): m / z 327 [M + 1] +.

[0395] Step 4: To a solution of compound 14-3 (45.0 mg, 138 μmol, 1.00 eq) in DMF (2.00 mL) were added 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). 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 EtOAc (20.0 mL) and H 2 O (20.0 mL). The organic phase was separated, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: minimum 16%-46% B). The title compound 14 (23.29 mg, 50.03 μmol, 36.28% yield, 98.71% purity) was obtained as a white solid. LCMS (ESI): m / z 460 [M+1] +; 1H NMR(400MHz, CDCl3)δ7.90(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).

[0396] The compounds shown in the following table were prepared using procedures similar to those described in Examples 2, 3, 5 and 6 using appropriate starting materials.

[0397] Table 1.

[0398] Example 15. N-(4-Carbamoylbenzyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (Compound 15) was prepared according to the following synthetic route:

[0399] Step 1: To a solution of intermediate 5 (0.2 g, 0.8 mmol) in DMF (3 mL) were added 1H-pyrazole-4-carboxylic acid methyl ester (0.12 g, 0.96 mmol), K2CO3 (0.33 g, 2.4 mmol), and the mixture was stirred at room temperature overnight. After the reaction was completed as monitored by LCMS, 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 (EtOAc elution) chromatography to give the desired compound 15-1 (0.123 g, 52.12% yield) as a yellow solid. LCMS (ESI): m / z 297.6 [M+H]+.

[0400] Step 2: Compound 15-1 (0.123 g, 0.42 mmol) was added NaOH (0.17 g, 4.2 mmol) to MeOH (3 mL) and water (1.5 mL) and stirred at room temperature for 1 h. After the reaction was completed, 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 layers were filtered through celite, and the filtrate was concentrated under reduced pressure to give the desired yellow solid compound 15-2 (0.1 g, 85.34% yield). LCMS (ESI): m / z 283.5 [M+H] +.

[0401] Step 3: Compound 15-2 (0.1 g, 0.35 mmol) was added to compound 8-1 (0.052 g, 0.35 mmol), DIEA (0.068 g, 0.52 mmol), HATU (0.13 g, 0.35 mmol) in DMF (3 mL) and stirred at room temperature for 2 h. After the reaction was completed as monitored by LCMS, 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 with DCM:MeOH=10:1) to give the title compound 15 (28.69 mg, 19.59% yield) as a white solid. LCMS (ESI): m / z 414.1 [M+H]+; 1 HNMR(400MHz,DMSO-d6)δ9.11(d,J=129.3Hz,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=8.0Hz,2H ), 7.41 (d, J = 9.1Hz, 1H), 7.02 (d, J = 9.1Hz, 1H), 5.42 (s, 2H), 4.47 (d, J = 5.6Hz, 2H), 1.93 (s, 1H), 0.92 (d, J = 6.9Hz, 2H), 0.67 (d, J = 4.6Hz, 2H).

[0402] Example 16. N-(4-Carbamoylbenzyl)-1-(4-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)-2-ethylbenzyl)-1H-pyrazole-4-carboxamide (Compound 16) was prepared according to the following synthetic route:

[0403] Step 1: To a solution of compound 16-1 (160 mg, 0.39 mmol) in dioxane (10 mL) were added 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). The reaction mixture was flushed with nitrogen for 5 minutes. The mixture was stirred at 100°C for 2 hours. After the reaction was completed as monitored by LCMS, the mixture was diluted with water (50 mL) and extracted with EA (50 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 column chromatography (eluted with PE:EA=3:1) to give the desired compound 16-2 (106 mg, 75.99% yield) as a colorless oily liquid. MS (ESI) M / Z: 360.2 [M+H] + .

[0404] 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 flushed with H2 for 5 minutes and protected with H2. The mixture was stirred at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue gave the desired compound 16-3 (100 mg, 93.81% yield) as a colorless oily liquid. MS (ESI) M / Z: 384.2 [M+Na] + .

[0405] Step 3: A 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 h. After the reaction was completed by LCMS monitoring, the reaction mixture was acidified to pH = 5-6 with 1 M HCl. The reaction was concentrated under reduced pressure to give the desired compound 16-4 (96 mg, 100% yield) as a white solid. MS (ESI) M / Z: 348.0 [M+H] + .

[0406] Step 4: To a solution of compound 16-4 (70 mg, 0.2 mmol) in DMF (2 mL) were added DIEA (78 mg, 0.6 mmol) and HATU (92 mg, 0.24 mmol), and the mixture was stirred at room temperature for 10 minutes. 8-1 (45 mg, 0.3 mmol) was then added to the reactant. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure by LCMS monitoring. The residue was purified by preparative TLC (DCM: MeOH = 15: 1) to give compound 16 (5.54 mg, 5.74% yield) as a white solid. MS (ESI) M / Z: 479.1 [M+H] + ; HPLC: 254nm: 98.558%, 214nm: 98.700%; 1H NMR (400MHz, DMSO-d6) δ9.28(s,2H),8.98(s,2H),8.74(t,J=6.0Hz,1H),8.37(s,1H) ,8.00(s,1H),7.86(s,1H),7.75(d,J=8.3Hz,2H),7.47(d,J=8.3Hz,2H),7.10(d,J =8.9Hz,1H),6.38(d,J=6.9Hz,2H),5.22(s,2H),4.45(d,J=5.9Hz,2H),3.58(s,2 H), 3.50 (s, 2H), 2.67 (d, J = 10.7Hz, 2H), 2.60–2.52 (m, 2H), 1.03 (t, J = 7.5Hz, 3H).

[0407] Example 17. (R)-N-(1-Ethyl-1,4,5,6-tetrahydrocyclopenta[d]imidazol-4-yl)-3-(methoxymethyl)-1-(4-(2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 130) and (S)-N-(1-Ethyl-1,4,5,6-tetrahydrocyclopenta[d]imidazol-4-yl)-3-(methoxymethyl)-1-(4-(2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 131) were prepared according to the following synthetic route:

[0408] To a solution of SM 5 (45 mg, 0.13 mmol) in DMF (3 mL) were added HATU (54 mg, 0.14 mmol) and DIEA (51 mg, 0.39 mmol), and the mixture was stirred at room temperature for 10 minutes. Compound 8 (39 mg, 0.26 mmol) was then added to the reactant. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL*3). The combined organics were concentrated. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the desired compound (32 mg, 51.64% yield) as a white solid. The 32 mg compound was then subjected to SFC separation (AD chiral column) to give 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: 254nm: 998.453%, 214nm: 98.272%; 1H NMR (400MHz, DMSO) δ8.23(s,1H),8.02(d,J=7.8Hz,1H),7.75(dd,J=6.7,1.6Hz,1H),7.50(s,1H),7.40(ddd,J=8.9, 6.6,2.0Hz,1H),7.23(q,J=8.1Hz,4H),6.39(d,J=9.0Hz,1H),6.22(t,J=6.7Hz,1H),5.25(s,2H),5.07(d,J=7.4H z, 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 the title compound 131 (retention time 5.04 min, 9.46 mg), MS (ESI) m / z: 487.3 [M+H] + ; HPLC: 254nm: 97.604%, 214nm: 97.761%; 1H NMR(400MHz, DMSO) δ8.23(s,1H),8.03(d,J=7.8Hz,1H),7.75(dd,J=6.8,1.8Hz,1H),7.50(s,1H),7.41(ddd,J=8.9,6.6,2.0Hz,1H),7.24(q,J=8 .2Hz,4H),6.39(d,J=9.2Hz,1H),6.22(td,J=6.7,1.3Hz,1H),5.25(s,2H),5.07(d,J=6.5Hz,3H),4.48(s,2H),3.90(q,J=7.1Hz,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=12.8,8.4,4.0Hz,1H),1.30(t,J=7.3Hz,3H).

[0409] The compounds shown in the following table were prepared using procedures similar to those described in Examples 2, 15, 16 and 17 using appropriate starting materials.

[0410] Table 2.

[0411] Example 18. N-((6,8-dimethylimidazo[1,5-a]pyridin-7-yl)methyl)-3-(methoxymethyl)-1-(4-(2-oxopyridin-1(2H)-yl)benzyl)-1H-pyrazole-4-carboxamide (Compound 147) was prepared according to the following synthetic route:

[0412] 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 required mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a 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, as confirmed by H NMR (EW47914-151-P1A), liquid chromatography-mass spectrometry (EW47914-51-P1B), and HPLC (EW4791451-P1J). MS (ESI) m / z: 511 [M+H] + ; 1H NMR:EW47914-151-P1A(400MHz,CDC13)δ8.07(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=6.8Hz,1H ),7.22-7.18(m,2H),6.61(d,J=9.2Hz,1H),6.18-6.14(m,1H),5.21(s,2H),5.13( s,2H),4.52(d,J=4.8Hz,2H),4.47(s,2H),3.11(s,3H),2.50(s,3H),2.30(s,3H).

[0413] Example 19. N-((1H-pyrrolo[3,2-c]pyridin-2-yl)methyl)-1-(2-cyano-4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (Compound 157) was prepared according to the following synthetic route:

[0414] To a solution of 157-1 (prepared according to the synthetic method of intermediate 6) (23 mg, 0.059 mmol) in DMF (2 mL) were added DIEA (23 mg, 0.18 mmol) and HATU (27 mg, 0.071 mmol), and the mixture was stirred at room temperature for 10 minutes. 157-2 (10 mg, 0.065 mmol) was then added to the reactants. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, as monitored by LCMS. The residue was purified by preparative TLC (DCM:MeOH=12:1) to give the title compound (15.77 mg, 51.45% yield) as a white solid. MS (ESI) m / z: 518.3 [m+H]+. 1H NMR(400MHz, DMSO-d6) δ11.46(s,1H),8.65(s,1H),8.47(t,J=5.5Hz,1H),8.20(s,1H ),8.03(d,J=5.2Hz,1H),7.42(d,J=5.3Hz,1H),7.31(d,J=8.7Hz,1H),6.96(d,J= 2.5Hz,1H),6.89–6.81(m,1H),6.34(s,1H),5.34(s,2H),4.58(d,J=7.6Hz,4H),3 .64(d,J=10.4Hz,2H), 3.57(d,J=8.5Hz,2H), 3.22(s,3H), 2.72(d,J=10.7Hz,2H).

[0415] Example 20. N-((5,7-Dimethylimidazo[1,2-a]pyridin-6-yl)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl]benzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide (Compound 142) was prepared according to the following synthetic route:

[0416] To a solution of 1-(4-((2-oxopyridin-1(2H)yl)methyl)benzyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (prepared according to the synthetic method of Intermediate 2-3) compound 142-1 (45.28 mg, 0.12 mmol) in DMF (3 mL) were added HATU (45.63 mg, 0.12 mol) and DIEA (46.53 mg, 0.36 mmol), 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 completion of the reaction, the reaction mixture was concentrated under reduced pressure, as monitored by LCMS. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (20.74 mg, 32.33% yield) as a white solid. MS (ESI) m / z: 535.2 [m+H]+. 1H NMR(400MHz, DMSO-d6) δ8.35(s,1H),8.32(t,J=4.8Hz,1H),7.79(s,1H),7.74(d d,J=6.6,1.8Hz,1H),7.54(d,J=1.2Hz,1H),7.40(ddd,J=8.9,6.6,2.1Hz,1H) ,7.32(s,1H),7.25(s,4H),6.38(d,J=9.2Hz,1H),6.21(td,J=6.7,1.3Hz,1H ),5.36(s,2H),5.05(s,2H),4.48(d,J=4.7Hz,2H),2.62(s,3H),2.38(s,3H); 19 F NMR(400MHz,DMSO-d6)δ-59.52(s).

[0417] The compounds shown in the following table were prepared using procedures similar to those described in Examples 17, 18, 19 and 20 using appropriate starting materials.

[0418] Table 3.

[0419] Example 21. N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-3-(difluoromethyl)-1-(4-(2-oxopyridin-1(2H)-yl)methylbenzyl)-1H-pyrazole-4-carboxamide (Compound 69) was prepared according to the following synthetic route:

[0420] Step 1: Preparation of ethyl (Z)-2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate: To a solution of compound 69-1 (2.0 g, 12.04 mmol) in acetic anhydride (20 mL) was added triethyl orthoformate 2 (3.57 g, 24.08 mmol), and the mixture was stirred at 100°C for 4 hours. After completion of the reaction, as monitored by LCMS, the reaction solution was concentrated to afford the desired title compound (2.67 g, 100% yield) as a yellow oil, which was used directly in the next reaction. MS (ESI) M / Z: 223.1 [M+H]+.

[0421] Step 2: Preparation of ethyl 3-(difluoromethyl)-1H-pyrazole-4-carboxylate: To a solution of compound 69-2 (2.67 g, 12.02 mmol) in EtOH (30 mL) was added hydrazine hydrate (0.7 mL, 14.42 mmol), and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated in vacuo and the residue was purified by chromatography on a silica gel column (DCM:MeOH=100:0-96:4) to give the title compound (1.74 g, 76.15% yield) as a white solid. MS (ESI) M / Z: 191.0 [M+H]+.

[0422] Step 3: Preparation of ethyl 3-(difluoromethyl)-1-(4-((2-oxopyridin-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylate: To a solution of compound 69-3 (380 mg, 1.19 mmol) in DMF (10 mL) was added intermediate 2 (500 mg, 1.80 mmol. The combined organic phases were concentrated, and the residue was purified by preparative TLC (PE:EA=1:1) to give the title compound (400 mg, 57.38% yield). MS (ESI) M / Z: 388.1 [M+H] +; 1H NMR (400MHz, DMSO) δ8.60(s,1H),7.77(dd,J=6.7,2.0Hz,1H),7.41(ddt,J=8.7,6.5,2.1Hz,1H),7.37–7.27(m,4H),7.11(dd,J=53.6,2.2Hz,1H),6 .41(d,J=9.1Hz,1H),6.23(td,J=6.6,1.3Hz,1H),5.40(s,2H),5.08(d,J=2.0Hz,2H),4.23(qd,J=7.1,2.2Hz,2H),1.26(td,J=7.1,2.2Hz,3H).

[0423] Step 4: Preparation of 3-(difluoromethyl)-1-(4-((2-oxopyridin-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid: To a solution of compound 69-4 (50 mg, 0.13 mmol) in MeOH (2 mL) was added NaOH (2 M, 1 mL, 2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of HCl solution (2 M, 1 mL, 2 mmol) and concentrated under reduced pressure to give the title compound (162 mg, 100% yield) as a white solid. MS (ESI) M / Z: 360.2 [M+H]+.

[0424] Step 5: Preparation of 1-(4-(cyclopropylmethyl)benzyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide: To a solution of compound 69-5 (45 mg, 0.13 mmol) in DMF (2 mL) were added HATU (59 mg, 0.16 mmol), DIEA (50 mg, 0.39 mmol), and the mixture was stirred at room temperature for 10 minutes. Intermediate 3 (20 mg, 0.13 mmol) was then added to the reactant. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, monitored by LCMS. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (43.54 mg, 70.59% yield) as a white solid. MS (ESI) M / Z: 493.4[M+H]+; HPLC: 254nm: 95.822%, 214nm: 97.754%; 1H NMR (400MHz, DMSO) δ8.35(s,1H),8.14(s,1H),7.76(dd,J=6.8,1.8Hz,1H),7.50–7.14(m,6H),6.39(d,J=9.1Hz,1 H), 6.20 (dd, J = 27.4, 20.7Hz, 4H), 5.35 (s, 2H), 5.07 (s, 2H), 4.25 (d, J = 4.6Hz, 2H), 2.33 (s, 3H), 2.19 (s, 3H).

[0425] Example 22. 1-(4-(Cyclopropylmethyl)benzyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide (Compound 91) was prepared according to the following synthetic route:

[0426] Step 1: Preparation of methyl 4-(cyclopropylmethyl)benzoate: To a solution of methyl 4-formylbenzene chloride (2 g, 10.83 mmol) in toluene (20 mL) and water (1 mL) under N2 were added potassium cyclopropyl trifluoroborate (1.92 g, 13.00 mmol), Ruphos (0.51 g, 1.08 mmol), Pd2(dba)3 (0.99 g, 1.08 mmol), K2CO3 (2.99 g, 21.66 mmol) and stirred at 120°C for 4 hours. The mixture was diluted with water (50 mL) and extracted with EA (50 mL*3). The combined organic layers were filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=20:1) to give the title compound (1.15 g, 55.80% yield) as a colorless oily liquid. MS (ESI) M / Z: 232.1 [M+ACN+H]+.

[0427] 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 before being added to the solution. LiAlH 4 (30 mg, 0.80 mmol) was added to the reaction solution and stirred at 0° C. for 30 minutes. After the reaction was monitored by LCMS, water (2.0 mL) was added to the reaction solution, and a large amount of white solid was precipitated. The reaction solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE: EA=10: 1) to give the title compound (56 mg, 65.67% yield) as a colorless oily liquid.

[0428] MS (ESI) M / Z: 145.1 [M-18+H]+.

[0429] 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 showed that the reaction was complete. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL*3). The organic layer was washed 3 times with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (PE:EA=30:1) to give the title compound (45 mg, 64.86% yield) as a colorless oily liquid. 1H NMR(400MHz, DMSO-d6) δ7.17(d,J=8.0Hz,2H),7.03(dd,J=15.1,6.3Hz,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).

[0430] Step 4: Preparation of ethyl 1-(4-(cyclopropylmethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate: To a solution of compound 3 (35 mg, 0.16 mmol) in DMF (2 mL) were added 91-5 (32 mg, 0.18 mmol) and K2CO3 (44 mg, 0.32 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, which was monitored by LCMS, the mixture was diluted with water (50 mL), extracted with EA (50 mL*3), and dried over Na2SO4. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EA=5:1) to give the title compound (39 mg, 76.38% yield) as a colorless oily liquid. MS (ESI) M / Z: 329.2 [M+H]+.

[0431] Step 5: Preparation of 1-(4-(cyclopropylmethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylic acid: To a solution of compound 91-6 (40 mg, 0.12 mmol) in MeOH (2 mL) was added NaOH (2 M, 1 mL, 2 mmol) and the mixture was stirred at room temperature for 1 hour. After the reaction was completed as monitored by LCMS, the reaction mixture was quenched by adding HCl solution (2 M, 1.05 mL, 2.1 mmol) and concentrated under reduced pressure to give the title compound (70 mg, 100% yield) as a white solid. MS (ESI) m / z: 301.2 [m+H]+.

[0432] Step 6: Preparation of 1-(4-(cyclopropylmethyl)benzyl)-N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide:

[0433] 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 reactants. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure by LCMS monitoring. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (15.76 mg, 30.84% ​​yield) as a brown solid. MS (ESI) m / z: 439.4[m+H]+; HPLC: 254nm: 98.800%, 214nm: 98.780%; 1H NMR (400MHz, DMSO-d6) δ8.43(t,J=5.3Hz,1H),8.29–8.20(m,2H),7.24(d,J=8.1Hz,2H),7.18(dd,J=6.8,4.4Hz,3H),5.27(s,2H),4 .57–4.46(m,4H),3.92(s,3H),3.27(s,3H),2.47(d,J=7.0Hz,2H),0.97–0.88(m,1H),0.49–0.40(m,2H),0.17(q,J=4.9Hz,2H).

[0434] Example 23. N-((3-Fluoro-4-(methylthio)pyridin-2-yl)methyl)-3-(methoxymethyl)-1-(4-(2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 132) was prepared according to the following synthetic route:

[0435] Crude product 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 added sequentially 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, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was separated on a preparative plate (DCM:MeOH = 10:1) to obtain compound 132 (5 mg, yield: 12.0%) as a white solid.

[0436] MS (ESI) M / Z: 508.2 [M+H] + .

[0437] 1H NMR (400MHz, Chloroform-d) δ8.60–8.52(m,1H),8.22(d,J=5.2Hz,1H),7.90(s,1H),7.33–7.25(m,4H),7.24–7.17(m,4H),7.01(t,J=5.5Hz, 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=4.9,2.1Hz,2H),4.61(s,2H),3.42(s,3H),2.48(s,3H).

[0438] Example 24. N-((3-Fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide (Compound 113) was prepared according to the following synthetic route:

[0439] Step 1: Preparation of methyl 1-(4-(bromomethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate: Methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (200 mg, 1.18 mmol) and potassium carbonate (324 mg, 2.35 mmol) were added sequentially to acetonitrile (5 mL) at room temperature. The mixture was stirred at room temperature for 5 minutes. 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 aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (EA:PE = 0-100%) to afford the title compound (110 mg, yield: 25%) as a white solid. MS (ESI) M / Z: 353.0 [M+H] + .

[0440] Step 2: Preparation of methyl 3-(methoxymethyl)-1-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate: 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]pyridin-2-one (25 mg, 0.19 mol) were added portionwise, and the mixture was heated from room temperature to 80°C and stirred for 12 h. 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 a residue. The residue was separated and purified by TLC (DCM:MeOH = 10:1, Rf = 0.5) to give the title compound (22 mg, yield: 31.8%) as a white solid. MS (ESI) M / Z: 407.17 [M+1]+.

[0441] Step 3: Preparation of 3-(methoxymethyl)-1-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid: Compound 113-3 (22 mg, 0.054 mmol) was added to methanol (3 mL) at room temperature. A solution of sodium hydroxide (10 mg, 0.25 mmol) dissolved in water (1 mL) was added and stirred at room temperature for 24 hours. The pH of the reaction solution was adjusted to acidic with 1N aqueous hydrogen chloride solution and extracted with DCM (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (25 mg, crude) as a white solid. MS (ESI) M / Z: 393 [M+1] + .

[0442] Step 4: Preparation of N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-3-(methoxymethyl)-1-(4-((2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide: Compound 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) was added sequentially to DMF (2 mL), stirred at room temperature for 1 h, and water (10 mL) was added. 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 a residue. The residue was separated and purified by column chromatography (methanol:dichloromethane = 0-100%) to give the title compound (4 mg, yield: 11.86%) as a white solid. MS (ESI) M / Z: 531.21 [M+1]+ ; 1H NMR (400MHz, DMSO-D6) δ8.39(t,J=5.4Hz,1H),8.22(s,1H),8.20(d,J=5.5Hz,1H),7. 55(d,J=6.8Hz,1H),7.25(d,J=8.1Hz,2H),7.20(d,J=8.2Hz,2H),7.15(dd,J=6.7, 5.5Hz,1H),6.76(d,J=7.1Hz,1H),6.45(t,J=7.0Hz,1H),5.25(s,2H),5.21(s,2H) ,4.49(dd,J=5.4,2.3Hz,2H),4.46(s,2H),3.88(s,3H),3.47(s,2H),3.21(s,3H).

[0443] The compounds listed in the table below were prepared using procedures similar to those described in Examples 21, 22, 23 and 24 using appropriate starting materials.

[0444] Table 4.

[0445] Example 25. N-(4-Carbamoylbenzyl)-1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 105) was prepared according to the following synthetic route:

[0446] Step 1: Preparation of methyl 1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxylate: To a solution of 4-(cyclopropylmethyl)benzyl bromide (200 mg, 0.89 mmol) in DMF (8 mL) were added methyl 1H-pyrazole-4-carboxylate (134.69 mg, 1.07 mmol) and K2CO3 (246.01 mg, 1.78 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, which was monitored by LCMS, the mixture was diluted with water (20 mL), extracted with EA (10 mL*3), 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 give the desired compound 1 (202 mg, 84.11% yield) as a white solid. MS (ESI) m / z: 271.2 [m+H]+.

[0447] 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) was added NaOH (2 M, 0.3 mL, 0.6 mmol), and the mixture was stirred at room temperature overnight. After the reaction was completed as monitored by LCMS, the reaction mixture was quenched by adding HCl solution (2 M, 0.35 mL, 0.7 mmol) and concentrated under reduced pressure to give the title compound (82.51 mg, 100% yield) as a white solid. MS (ESI) m / z: 257.2 [m+H]+.

[0448] Step 3: Preparation of N-(4-carbamoylbenzyl)-1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxamide: To a solution of compound 105-2 (47.41 mg, 0.18 mmol) in DMF (3 mL) were added HATU (68.44 mg, 0.18 mol) and DIEA (69.79 mg, 0.54 mmol), and the mixture was stirred at room temperature for 0.5 hours. 4-carbamoylbenzylamine (29.54 mg, 0.20 mmol) was then added to the reaction. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, which was monitored by LCMS, the reaction mixture was diluted with H2O (20 mL) and extracted with DCM:MeOH=8:1 (10 mL*3), 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 give the desired compound 105 (54.03 mg, 75.38% yield) as a white solid. MS (ESI) m / z: 38.82 [m+H]+; HPLC: 254 nm: 97.718%, 214 nm: 98.699%; 1H NMR (400MHz, DMSO-d6) δ8.65(t,J=5.7Hz,1H),8.25(s,1H),7.90(s,1H),7.70(d,J=8.1Hz,2H),7.31(d,J=8.0Hz,2H),7.22(dd,J=17.4 ,8.1Hz,7H),5.30(s,2H),4.42(d,J=5.9Hz,2H),2.47(d,J=7.0Hz,2H),0.98–0.87(m,1H),0.48–0.40(m,2H),0.17(q,J=5.0Hz,2H).

[0449] 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:

[0450] Step 1: Preparation of N-(4-cyanobenzyl)-1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxamide: To a solution of 1-(4-(cyclopropylmethyl)benzyl)-1H-pyrazole-4-carboxylic acid (50 mg, 0.20 mol) in DMF (2 mL) were added DIEA (77 mg, 0.60 mmol), HATU (91 mg, 0.24 mmol), and the mixture was stirred at room temperature for 10 minutes. Compound 4-(aminomethyl)benzonitrile (34 mg, 0.26 mmol) was then added to the reaction. The mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, as monitored by LCMS. The residue was purified by preparative TLC (DCM:MeOH=60:1) to give the title compound (30.0 mg, 41.51% yield) as a white solid. MS (ESI) m / z: 371.2 [M+H] + .

[0451] 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) were added hydroxylamine hydrochloride (18.76 mg, 0.27 mmol) and Na2CO3 (28.62 mg, 0.27 mol). The mixture was refluxed at 85°C under nitrogen for 2 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:MeOH=8:1) and reverse phase column to give the title compound 348 (7.50 mg, 34.4% yield) as a white solid. MS (ESI) m / z: 404.3 [M+H] + ; HPLC: 254nm: 98.695%, 214nm: 99.018%; 1H NMR (400MHz, DMSO-d6) δ12.85(s,1H),11.22(s,1H),9.01(s,2H),8.83(t,J=5.9Hz ,1H),8.27(s,1H),7.92(s,1H),7.67(d,J=8.0Hz,2H),7.48(d,J=8.0Hz,2H),7 .22(q,J=8.0Hz,4H),5.30(s,2H),4.47(d,J=5.9Hz,2H),2.47(d,J=7.0Hz,2H) ,1.24(s,1H),0.93(d,J=6.5Hz,1H),0.53–0.38(m,2H),0.17(d,J=4.7Hz,2H).

[0452] 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:

[0453] Step 1: Preparation of methyl 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylate: To a solution of compound 153-1 (850 mg, 3.0 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) were added compound SM2 (686 mg, 3.3 mmol) and K2CO3 (829 mg, 6.0 mmol). The mixture was purged with nitrogen for 5 minutes. Pd(dppf)Cl2 (219 mg, 0.3 mmol) was then added and the mixture was stirred at 100°C for 4 hours. After completion of the reaction, which was monitored 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 extracted with EA (100 ml * 3). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by silica gel chromatography (eluted with PE:EA = 100:0 to 90:10) to give the title compound (805 mg, 94.30% yield). 1 HNMR (400MHz, DMSO) δ 8.16 (d, J=9.8Hz, 2H), 7.51 (d, J=7.9Hz, 1H), 5.58 (s, 1H).

[0454] 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 h. After the reaction was completed by LCMS monitoring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with PE: EA = 100: 0 to 90: 10) to give the title compound (800 mg, 98.68% yield). 1H NMR (400MHz, DMSO) δ8.24–8.01(m,2H),7.81(d,J=8.2Hz,1H),3.90(d,J=10.4Hz,3H),2.87(t,J=11.1H z, 1H), 1.77 (dd, J = 44.5, 10.7Hz, 5H), 1.56 (dd, J = 22.3, 10.6Hz, 2H), 1.32 (dt, J = 23.8, 11.9Hz, 3H).

[0455] Step 3: Preparation of (4-cyclohexyl-3-(trifluoromethyl)phenyl)methanol: Cool to a solution of compound 153-3 (200 mg, 0.7 mmol) in dry THF (10 mL) at -5 ° C. LiAlH4 (1 M in THF) (1.05 ml, 1.05 mmol) was added dropwise to the solution. The mixture was allowed to reach room temperature, and the solution was stirred at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the reaction was quenched with saturated NH4Cl solution. The reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL*3). The combined organics were concentrated. The residue was purified by preparative TLC (PE:EA=8:1) to give the title compound (152 mg, 84.24% yield). 1H NMR (400MHz, DMSO) δ7.63–7.43(m,3H),5.30(q,J=5.8Hz,1H),4.52(d,J=5.7Hz,2H),2.80(t,J=1 1.2Hz, 1H), 1.82–1.67 (m, 5H), 1.51 (dd, J=22.6, 10.6Hz, 2H), 1.34 (dd, J=23.8, 10.3Hz, 3H).

[0456] Step 4: Preparation of 4-(bromomethyl)-1-cyclohexyl-2-(trifluoromethyl)benzene: Cool to a DCM (10 mL) solution of compound 153-4 (152 mg, 0.59 mmol) at -0 ° C. Phosphorus tribromide (160 mg, 0.59 mmol) was added to the solution. The mixture was allowed to reach room temperature, and the solution was stirred at room temperature for 10 minutes. After the reaction was completed by LCMS monitoring, the reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL*3). The combined organics were concentrated. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (115 mg, 60.8% yield). 1H NMR (400MHz, DMSO) δ7.77–7.56(m,3H),4.77(s,2H),2.80(t,J=11.7Hz,1H),1.83–1.65(m,5H),1.52(dd,J=21.7,9.9Hz,2H),1.38–1.29(m,3H).

[0457] Step 5: Preparation of ethyl 1-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate: To a solution of compound 153-5 (115 mg, 0.36 mmol) in DMF (8 mL) was added compound 205-1 (72 mg, 0.40 mmol), K2CO3 (124 mg, 0.90 mmol), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL*3). The combined organic phases were concentrated, and the residue was purified by preparative TLC (PE:EA=2:1) ​​to give the desired title compound (60 mg, 39.48% yield). 1H NMR (400MHz, DMSO) δ8.50(s,1H),7.68–7.57(m,2H),7.52(d,J=8.1Hz,1H),5.40(s,2H),4.52(s,2H),4.21(p,J=6.9H z,2H),3.25(s,3H),2.80(t,J=11.4Hz,1H),1.85–1.62(m,5H),1.49(dd,J=23.5,11.7Hz,2H),1.37–1.22(m,6H).

[0458] 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) was added NaOH (2 M, 0.5 mL, 1 mmol), 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) and concentrated under reduced pressure to give the title compound (90 mg, 100% yield) as a white solid. MS (ESI) M / Z: 397.0 [M+H] + .

[0459] Step 7: Preparation of N-(4-carbamoylbenzyl)-1-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide: To a solution of compound 153-7 (30 mg, 0.076 mmol) in DMF (3 mL) were added HATU (30 mg, 0.08 mmol) and DIEA (30 mg, 0.24 mmol), and the mixture was stirred at room temperature for 10 minutes. Compound 4-carbamoylbenzylamine (12 mg, 0.84 mmol) was then added to the reactant. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, as monitored by LCMS. The residue was purified by reverse phase HPLC to give 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] +; 1H NMR (400MHz, DMSO) δ9.31(s,2H),9.03(s,2H),8.59(t,J=5.8Hz,1H),8.35(s,1H),7.78(d,J=8.2Hz,2H),7.69–7.57(m,2H),7.51(d,J=8.1Hz,3H), 5.39(s,2H),4.64–4.33(m,4H),3.22(s,3H),2.78(d,J=10.6Hz,1H),1. 79(s,2H),1.74–1.59(m,3H),1.56–1.41(m,2H),1.32(t,J=10.8Hz,3H).

[0460] Example 28. N-(4-Carbamoylbenzyl)-1-(4-cyclopropyloxy-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 379) was prepared according to the following synthetic route:

[0461] Step 1: Preparation of methyl 4-cyclopropyloxy-3-(trifluoromethyl)benzoate: To a solution of compound 379-1 (400 mg, 1.82 mmol) in toluene (16 mL) and H2O (4 mL) were added potassium cyclopropyl trifluoroborate (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). The mixture was purged with oxygen for 2 minutes. The mixture was then stirred at 70°C under oxygen overnight. After completion of the reaction, which was monitored by LCMS, 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 mL*3). The combined organics were concentrated. The residue was purified by reverse phase column to give the desired title compound (94 mg, 19.88% yield) as an oil. MS (ESI) m / z: 261.1 [m+H] +.

[0462] Step 2: Preparation of (4-cyclopropyloxy-3-(trifluoromethyl)phenyl)methanol: Cool to a solution of compound 379-2 (50 mg, 0.34 mmol) in dry THF (15 mL) at 0 ° C. LiBH4 (39 mg, 1.80 mmol) was added dropwise to the solution. The mixture was allowed to reach room temperature, and the solution was stirred at room temperature overnight. After completion of the reaction, it was monitored by LCMS. The reaction was quenched with saturated NH4Cl solution. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL*3). The combined organics were concentrated. The residue was purified by chromatography on a silica gel column (PE:EA=100:0 to PE:EA=0:100) to give the desired title compound (36 mg, 42.92% yield). MS (ESI) m / z:215.0[m-OH]+.

[0463] Step 3: Preparation of 4-(chloromethyl)-1-cyclopropyloxy-2-(trifluoromethyl)benzene: To a solution of compound 379-3 (36 mg, 0.16 mmol) in DCM (5 mL) was slowly added SOCl2 (38 mg, 0.32 mmol) at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours. After completion of the reaction monitored by LCMS, the reaction mixture was diluted with a saturated solution of NaHCO3 (10 mL) and extracted with DCM (30 mL*3). The combined organic phases were concentrated under reduced pressure to obtain the title compound (26 mg, yield 66.91%). MS (ESI) m / z: 251.0 [m+H]+.

[0464] Step 4: Preparation of 1-(4-cyclopropyloxy-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylic acid methyl ester: To a solution of compound 379-4 (26 mg, 0.10 mmol) in DMF (5 mL) was added compound pyrrole-3-carboxylic acid methyl ester (15 mg, 0.12 mmol) and K2CO3 (27 mg, 0.20 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA=100:0 to 50:50) to give the title compound (18 mg, 50.99% yield). MS (ESI) m / z:341.1[m+H]+.

[0465] Step 5: Preparation of 1-(4-cyclopropyloxy-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxylic acid: To a solution of compound 379-5 (18 mg, 0.053 mmol) in MeOH (2 mL) was added NaOH (2 M, 1 mL, 2 mmol), and the mixture was stirred at room temperature overnight. After completion of the reaction, it was monitored by LCMS. The reaction mixture was quenched by the addition of HCl solution (2 M, 1 mL, 2 mmol) and concentrated under reduced pressure to give the title compound (17 mg). MS (ESI) m / z: 327.0 [m+H] +.

[0466] Step 6: Preparation of N-(4-carbamoylbenzyl)-1-(4-cyclopropyloxy-3-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide: To a solution of compound 379-6 (17 mg, 0.052 mmol) in DMF (2 mL) were added DIEA (20 mg, 0.16 mmol) and HATU (22 mg, 0.057 mmol), 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. After completion of the reaction, the reaction mixture was monitored by LCMS. After completion of the reaction, the reaction mixture was purified by reverse phase column to obtain the title compound 379 (5.45 mg, 21.18% yield) as a white solid.

[0467] MS (ESI) m / z: 458.4 [m+H]+; 1H NMR (400MHz, DMSO) δ9.31(s,2H),9.04(s,2H),8.83(t,J=5.7Hz,1H),8.32(s,1H),7.94(s,1H),7.77(d,J=8.2Hz,2H),7.61(d,J=7. 6Hz, 2H), 7.55–7.41 (m, 3H), 5.36 (s, 2H), 4.48 (d, J = 5.6Hz, 2H), 4.02 (dt, J = 8.3, 4.3Hz, 1H), 0.88–0.74 (m, 2H), 0.69–0.56 (m, 2H).

[0468] The compounds listed in the table below were prepared using procedures similar to those described in Examples 25, 26, 27 and 28 using appropriate starting materials.

[0469] Table 5.

[0470] Example 29. N-(4-Carbamoylbenzyl)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxamide (Compound 128) was prepared according to the following synthetic route:

[0471] Step 1: Preparation of 4-phenoxybenzyl alcohol: Under nitrogen, compound 128-1 (1.0 g, 5.05 mmol) was added to methanol (10 mL). The temperature was cooled to 0°C, and sodium borohydride (575 mg, 15.14 mmol) was added. The mixture was allowed to return to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride (50 mL) was added and extracted with EA (50 mL x 3). The organic phases were combined, washed with water (100 mL) and saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was isolated and purified by column chromatography (EA:PE = 0-100%) to afford the title compound (850 mg, yield: 85%) as a white solid. MS (ESI) M / Z: 202.1 [M+H] + .

[0472] Step 2: Preparation of 4-phenoxybenzyl bromide: Under nitrogen, compound 128-2 (800 mg, 4.00 mmol) was added to DCM (10 mL). The temperature was 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 and stirred for 1 hour. The temperature was cooled to 0°C, and the pH of the reaction mixture was adjusted to approximately 8 with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with DCM (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (850 mg, yield: 80%) as a white solid. MS (ESI) M / Z: 263.0 [M+H] + .

[0473] Step 3: Preparation of methyl 1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate: Compound 128-4 (780 mg, 2.52 mmol) was added to ethanol (10 mL) at room temperature. A solution of sodium hydroxide (504 mg, 12.60 mmol) dissolved in water (2 mL) was added and stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to acidic with 1N aqueous hydrogen chloride solution. The solution was extracted with DCM (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (700 mg, yield: 94%) as a white solid. MS (ESI) M / Z: 295.1 [M+H] + .

[0474] Step 4: Preparation of 1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid: Methyl pyrazole-4-carboxylate (354 mg, 2.70 mmol) and potassium carbonate (2.1 g, 15.26 mmol) were added sequentially to DMF (10 mL) at room temperature. The mixture was stirred at room temperature for 5 minutes. Compound 128-3 (800 mg, 3.05 mmol) was added and stirred at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with water (50 mL) and saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was isolated and purified by column chromatography (EA:PE = 0-100%) to afford the title compound (780 mg, yield: 94%) as a white solid. MS (ESI) M / Z: 309.1 [M+H] + .

[0475] Step 5: Preparation of N-(4-carbamoylbenzyl)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxamide: Compound 128-5 (50 mg, 0.17 mmol), HATU (77 mg, 0.20 mmol), and triethylamine (52 mg, 0.51 mmol) were added sequentially to DMF (2 mL) at room temperature. The mixture was stirred at room temperature for 0.5 h. 4-Aminomethylbenzylamine (45 mg, 0.20 mmol) was then added and stirred at room temperature for 0.5 h. 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 a residue. The residue was isolated and purified by column chromatography (methanol:dichloromethane = 0-100%) to afford the title compound (25 mg, yield: 35%) as a yellow solid. MS (ESI) M / Z: 426.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6)δ9.09(s,3H),8.78(t,J=8.4Hz,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=6.0Hz,2H).

[0476] Using appropriate starting materials, a procedure similar to that described in Examples 22 and 29 was used to prepare

[0477] The following table lists the compounds.

[0478] Table 6.

[0479] Example 30. 3-((3-fluoro-3-(methoxymethyl)azetidin-1-yl)methyl)-N-(3-fluoro-4-methoxypyridin-2-yl)methyl (Compound 205) was prepared according to the following synthetic route:

[0480] Step 1: Preparation of ethyl 3-(hydroxymethyl)-1-(4-((2-oxopyridin-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylate: To a mixture of intermediate 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) was added K2CO3 (994 mg, 7.20 mmol, 2.0 eq), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (30 mL), extracted with EtOAc (20 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 silica gel column (PE / EA=1 / 2) to give the title compound (700 mg, 53.0% yield) as a white solid. MS (ESI) m / z: 368.2 [M+H] + .

[0481] Step 2: Preparation of ethyl 3-(bromomethyl)-1-(4-((2-oxopyridin-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxylate: To a solution of compound 205-2 (30 mg, 0.08 mmol, 1.0 eq) in anhydrous MeCN (5 mL) was added PBr3 (43 mg, 0.16 mmol, 2.0 eq) at room temperature, and the mixture was stirred at 80°C for 1 h. After completion of the reaction monitored by TLC, the reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (10 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 preparative TLC (PE / EA=1 / 1) to give the title compound (24 mg, 68.6% yield) as a white solid. MS (ESI) m / z: 431.2 [M+H] + .

[0482] Step 3: Preparation of ethyl 3-((3-fluoro-3-(methoxymethyl)azetidin-1-yl)methyl)-1-(4-((2-oxopyridine-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate: A mixture of compound 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) was added DIEA (16 mg, 0.12 mmol, 2.0 eq), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (10 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 preparative TLC (DCM / MeOH=10 / 1) to give the title compound (12 mg, 46.2% yield) as a white solid. MS (ESI) m / z: 469.3 [M+H] + .

[0483] Step 4: Preparation of 3-((3-fluoro-3-(methoxymethyl)azetidin-1-yl)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl ester)benzyl)-1H-pyrazole-4-carboxylic acid: 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) was added NaOH (5 mg, 0.12 mmol, 4.0 eq) at room temperature, and the mixture was stirred at 60°C for 2 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 4-5 with HCl solution (4.0 M), as monitored by LCMS. The crude title compound was concentrated under vacuum and used directly in the next step. MS (ESI) m / z: 441.3 [M+H] + .

[0484] Step 5: Preparation of 3-((3-fluoro-3-(methoxymethyl)azetidin-1-yl)methyl)-N-(3-fluoro-4-methoxypyridin-2-yl)methyl: A mixture of compound 205-6 (from the concentrate of the previous step) and intermediate 3 (8 mg, 0.04 mmol, 1.2 eq) in DMF (2 mL) was added HATU (19 mg, 0.05 mmol, 1.5 eq), TEA (10 mg, 0.10 mmol, 3.0 eq), and the mixture was stirred at room temperature overnight. After the reaction was completed as monitored by LCMS, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 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 preparative TLC (DCM / MeOH=10 / 1) to give the title compound (3.5 mg, 23.6% yield over two steps) as a white solid. MS (ESI) m / z: 579.3 [M+H] + ; 1H NMR (400MHz, Methanol-d4)δ8.23(d,J=5.6Hz,1H),8.06(s,1H),7.65(dd,J=6.7,2.0Hz,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=6.7,1.4Hz,1H),5.26(s,2H),5.16(s,2H),4.64(d,J=2.4Hz,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).

[0485] Example 31. N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-3-((3-fluorooxetan-3-yl)methoxy)methyl (Compound 235) was prepared according to the following synthetic route:

[0486] Step 1: Preparation of ethyl 3-((3-fluorooxetan-3-yl)methoxy)methyl)-1-(4-(2-oxopyridin-1(2H)-yl)methylbenzyl)-1H-pyrazole-4-carboxylate: To a solution of compound (3-fluoroheterocyclobutane-3-yl)methanol (25 mg, 0.24 mmol, 2.0 eq) in THF (2 mL) was added NaH (11 mg, 0.26 mmol, 2.2 eq) at 0°C, and the mixture was stirred at 0°C for 1 h. To the above mixture was added dropwise compound 205-3 (50 mg, 0.12 mmol, 1.0 eq) at 0°C. The resulting mixture was stirred at room temperature for another 1 hour. After completion of the reaction monitored by LCMS, the reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (10 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 preparative TLC (DCM / MeOH=10 / 1) to give the title compound (25 mg, 47.3% yield) as a white solid. MS (ESI) m / z: 456.3 [m+H] + .

[0487] Step 2: Preparation of 3-((3-fluorobutane-3-yl)methoxy)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid: To a solution of compound 235-1 (25 mg, 0.06 mmol, 1.0 eq) in MeOH (0.8 mL) and H2O (0.2 mL) was added LiOH·H2O (10 mg, 0.24 mmol, 4.0 eq) at room temperature, and the mixture was stirred at 60°C for 2 hours. After completion of the reaction as monitored by LCMS, the pH of the reaction mixture was adjusted to 4-5 with HCl solution (4.0 M). The crude title compound was obtained after concentration under vacuum and used directly in the next step. MS (ESI) m / z: 428.3 [m+H]+.

[0488] Step 3: Preparation of N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-3-((3-fluorooxetane-3-yl)methoxy)methyl: A mixture of compound 235-1 (from the previous step) and intermediate 3 (14 mg, 0.07 mmol, 1.2 eq) in DMF (3 mL) was added HATU (34 mg, 0.09 mmol, 1.5 eq), TEA (18 mg, 0.18 mmol, 3.0 eq), and the mixture was stirred at room temperature overnight. After the reaction was completed as monitored by LCMS, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 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 preparative TLC (DCM / MeOH=10 / 1) to give the title compound (3.5 mg, 10.3% yield over two steps) as a white solid. MS (ESI) m / z: 566.3 [m+H] +. 1H NMR (400MHz,Chloroform-d)δ8.21(d,J=5.5Hz,1H),8.12-8.09(d,J=11.0Hz,1H) ,7.90(s,1H),7.36-7.26(m,3H),7.23-7.19(m,2H),6.82(t,J=6.0Hz,1H),6. 60(d,J=9.1,1H),6.15(td,J=6.7,1.4Hz,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).

[0489] Example 32. N-((3-Fluoro-4-methoxypyridin-2-yl)methyl)-3-(3-hydroxy-3-methylazetidin-1-yl)-1-(4-(2-oxopyridin-1(2H)-yl)benzyl)-1H-pyrazole-4-carboxamide (Compound 296) was prepared according to the following synthetic route:

[0490] Step 1: Preparation of ethyl 3-(3-hydroxy-3-methylζ-1-yl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate: Compound 134-1 (40 mg, 0.096 mmol), 3-methylazetidin-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 at 120°C overnight. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified on 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] + .

[0491] Step 2: Preparation of 3-(3-hydroxy-3-methylζ-1-yl)-1-(4-((2-oxopyridin-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 at room temperature overnight. The reaction mixture was neutralized with dioxane hydrochloride solution to pH 5-6 and concentrated under reduced pressure to obtain the crude title compound, which was used directly in the next step. MS (ESI) M / Z: 395.1 [M+H] + .

[0492] Step 3: Preparation of N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-3-(3-hydroxy-3-methylazetidin-1-yl)-1-(4-(2-oxopyridin-1(2H)-yl)benzyl)-1H-pyrazole-4-carboxamide: The 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 added to DMF (2 mL) in sequence 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, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was separated on 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]+ ; 1H NMR (400MHz, Methanol-d4)δ8.15(d,J=7.8,5.6Hz,1H),7.87(s,1H),7.69–7.62(m,1H),7 .49(ddd,J=8.9,6.7,2.1Hz,1H),7.31–7.25(m,2H),7.25–7.18(m,2H),7.09(dd,J=6.7 ,5.6Hz,1H),6.58–6.50(m,1H),6.36(td,J=6.7,1.4Hz,1H),5.16(s,2H),5.08(s,2H), 4.56(d,J=2.2Hz,2H),3.94(s,3H),3.54–3.43(m,2H),3.38–3.29(m,2H),1.23(s,3H).

[0493] The compounds listed in the table below were prepared using procedures similar to those described in Examples 8, 30, 31 and 32 using appropriate starting materials.

[0494] Table 7.

[0495] Example 33. N-((3-Fluoro-4-methoxypyridin-2-yl)methyl)-2',4'-dimethyl-1-(4-(2-oxopyridin-1(2H)yl)methyl]benzyl)-1H-,2'-H-[3,3'-bipyrazole]-4-carboxamide (Compound 221) was prepared according to the following synthetic route:

[0496] Step 1: Preparation of 2',4'-dimethyl-1-(4-(2-oxopyridin-1(2H)yl)methyl)benzyl)-1H,2'-H-[3,3'-bipyrazole]-4-carboxylic acid: Under nitrogen protection, compound 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 added sequentially to 1,4-dioxane (3 mL) and water (0.6 mL), and the reaction was carried out at 110°C overnight. The mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was separated on 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] + .

[0497] Step 2: Preparation of ethyl 2',4'-dimethyl-1-(4-(2-oxopyridin-1(2H)yl)methyl)benzyl)-1H,2'-H-[3,3'-bipyrazole]-4-carboxylate: 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 at room temperature overnight. The reaction mixture was neutralized with dioxane hydrochloride solution to a pH of 5-6 and concentrated under reduced pressure to afford the crude title compound, which was used directly in the next step. MS (ESI) M / Z: 404.2 [M+H] + .

[0498] Step 3: Preparation of N-((3-fluoro-4-methoxypyridin-2-yl)methyl)-2',4'-dimethyl-1-(4-(2-oxopyridin-1(2H)yl)methyl]benzyl)-1H-,2'-H-[3,3'-bipyrazole]-4-carboxamide: The 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 added to DMF (2 mL) in sequence 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, washed with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was separated on 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 (400MHz, Methanol-d4)δ8.26(s,1H),8.14–8.08(m,1H),7.67(ddd,J=6.8,2.1,0.7Hz,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=6.7,1.4Hz,1H),5.39(s,2H),5.1 7(s,2H),4.52(d,J=2.2Hz,2H),3.93(s,3H),3.62(s,3H),1.86(s,3H).

[0499] The compounds listed in the table below were prepared using procedures similar to those described in Example 33 using appropriate starting materials.

[0500] Table 8.

[0501] Example 34. N-(2,6-difluoro-3-methoxybenzyl)-3-(3,3-difluorocyclobutyl)-1-(4-((5-fluoro-2-oxopyridin-1(2H)yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 209) was prepared according to the following synthetic route:

[0502] To a solution of intermediate 8 (38 mg, 0.091 mmol) in DMF (2 mL) were added DIEA (35 mg, 0.27 mmol) and HATU (38 mg, 0.10 mmol), 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. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure by LCMS monitoring. The residue was purified by preparative TLC (DCM: MeOH = 11: 1) to give the title compound (11.41 mg, 21.89% yield) as a white solid. MS (ESI) m / z: 573.4 [M+H] + ; HPLC: 254nm: 99.478%, 214nm: 99.303%; 1H NMR(400MHz, DMSO) δ8.27(t,J=5.1Hz,1H),8.18(s,1H),8.10–7.94(m,1H),7.57(ddd,J=1 0.3,7.2,3.4Hz,1H),7.29(d,J=8.1Hz,2H),7.21(d,J=8.1Hz,2H),7.11(td,J=9.2,5. 1Hz,1H),7.00(t,J=9.1Hz,1H),6.43(dd,J=10.0,5.4Hz,1H),5.26(s,2H),5.01(s,2H ),4.39(d,J=4.9Hz,2H),3.81(s,3H),3.75(dd,J=8.7,6.1Hz,1H),2.93–2.69(m,4H).

[0503] Example 35. N-((3-Fluoro-4-(methylamino)pyridin-2-yl)methyl)-3-(oxetan-3-yl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 260) was prepared according to the following synthetic route:

[0504] 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 added sequentially to N,N-dimethylformamide (3 mL) at room temperature. The mixture was stirred at room temperature for 10 minutes. Intermediate 7 (126 mg, 0.73 mmol) was then added and stirred at room temperature for 16 hours. Water (25 mL) was added and the mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with water (50 mL) and saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain a 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] + ; 1H NMR(400MHz, DMSO-d6) δ8.30(d,J=6.0Hz,1H),8.28(s,1H),7.90(d,J=5.6Hz,1H),7.77(dd, J=6.8,2.0Hz,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=6.8,5.6Hz,2H),4.55–4.46(m,1H),4.37(dd,J=5.6,2.0Hz,2H),2.73(d,J=4.8Hz,3H).

[0505] The compounds listed in the table below were prepared using procedures similar to those described in Examples 34 and 35 using appropriate starting materials.

[0506] Table 9.

[0507] Example 36. N-((6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)methyl)-3-(methoxymethyl)-1-(4-(2-oxopyridin-1(2H)-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide (Compound 144) was prepared according to the following synthetic route:

[0508] Step 1: Preparation of tert-butyl 2-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate: To a solution of tert-butyl 2,4-dichloro-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.0 g, 3.45 mmol) in MeOH (30 mL) were added AcOH (2.07 g, 34.5 mmol) and Zn (900 mg, 13.8 mmol), and the mixture was stirred at 70 ° C for 3 hours. After completion of the reaction, 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 (eluted with PE:EA=100:0 to 60:40) to give the desired title compound (600 mg, 68.03% yield). MS (ESI) M / Z: 256.0 [M+H] +.

[0509] Step 2: Preparation of tert-butyl 2-vinyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate: To a solution of compound 144-2 (730 mg, 2.85 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added compound SM 2 (572 mg, 4.28 mmol) and Na2CO3 (906 mg, 8.55 mmol. Pd(dppf)Cl2 (208 mg, 0.29 mmol) was added, and the mixture was stirred at 100°C for 3 hours. After the reaction was completed by monitoring by LCMS, 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*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 PE:EA=100:0 to 50:50) to give the desired title compound (600 mg, 84.99% yield) as a white solid. 1H NMR (400MHz, DMSO) δ8.74(d,J=7.9Hz,1H),6.82(dd,J=17.3,10.5Hz,1H),6.52(d,J=17.4Hz, 1H), 5.74 (d, J = 10.7Hz, 1H), 4.63 (d, J = 12.8Hz, 2H), 4.54 (t, J = 16.2Hz, 2H), 1.46 (s, 9H).

[0510] Step 3: Preparation of tert-butyl 2-formyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate: To a solution of compound 144-3 (500 mg, 2.02 mmol) in 1,4-dioxane (20 mL) and water (20 ml) were added NaIO4 (1.3 g, 6.06 mmol) and K2OsO4*2H2O (74 mg, 0.2 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed as monitored by LCMS, the reaction mixture was poured into 100 mL of water and extracted with EA (100 mL*3). The combined organics were concentrated. The residue was purified by preparative TLC (EA:PE=1:1) to give the desired title compound (218 mg, 43.25% yield) as a white solid. MS (ESI) M / Z: 268.2 [M+H]+.

[0511] Step 4: Preparation of tert-butyl 2-(aminomethyl)-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate: To a solution of compound 144-4 (218 mg, 0.87 mmol) in MeOH (2 mL) were added NH3-MeOH (7.0 M, 5 mL) and AcOH (0.1 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was then added with NaBH4 (20 mg, 0.52 mmol) and stirred at room temperature for 30 minutes. After completion of the reaction, which was monitored by LCMS, the reaction mixture was diluted with H2O (80 mL) and extracted with DCM (80 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 reverse phase HPLC to give the title compound (105 mg, 47.97% yield). MS (ESI) M / Z: 251.2 [M+H]+.

[0512] Step 5: Preparation of tert-butyl 2-((3-(methoxymethyl)-1-(4-(2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamido)methyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate: To a solution of compound 2-3 (46 mg, 0.13 mmol) in DMF (3 mL) were added HATU (54 mg, 0.14 mmol), DIEA (50 mg, 0.39 mmol), and the mixture was stirred at room temperature for 10 minutes. Compound 144-5 (55 mg, 0.22 mmol) was then added to the reactant. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, which was monitored by LCMS, the reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL*3). The combined organics were concentrated. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give the desired title compound (36 mg, 47.22% yield) as a white solid. MS (ESI) M / Z: 586.7 [M+H] + .

[0513] Step 6: Preparation of N-((6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)methyl)-3-(methoxymethyl)-1-(4-(2-oxopyridin-1(2H)-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide: To a solution of compound 144-6 (30 mg, 0.051 mmol) in DCM (2 mL) and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 5 hours. After completion of the reaction, it was monitored by LCMS. 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 give the title compound (13.44 mg, 54.04% yield). MS (ESI) M / Z: 486.2 [M+H]+. 1H NMR (400MHz, DMSO) δ8.62(t,J=38.9Hz,2H),8.28(s,1H),7.80–7.68(m,1H),7.41(ddd,J=8.8,6.7,2.0Hz,1H),7.26(q,J=8.3Hz,4H) ,6.40(d,J=9.1Hz,1H),6.22(t,J=6.7Hz,1H),5.29(s,2H),5.07(s,2H),4.72–4.43(m,6H),4.06(d,J=39.7Hz,2H),3.28(s,3H).

[0514] The compounds listed in the table below were prepared using procedures similar to those described in Example 36 using appropriate starting materials.

[0515] Table 10.

[0516] Example 37. N-((7-Fluoro-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-3-(oxetan-3-yl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 337) was prepared according to the following synthetic route:

[0517] To a solution of compound 260-1 (40 mg, 0.11 mmol) in DMF (3 mL) were added DIEA (43 mg, 0.33 mmol) and HATU (46 mg, 0.12 mmol), and the mixture was stirred at room temperature for 5 minutes. Intermediate 14 (25 mg, 0.12 mmol) was then added to the reaction. The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure by LCMS monitoring. The residue was purified by preparative TLC (DCM: MeOH = 11: 1) and reverse phase chromatography to give the title compound (23.56 mg, 41.99% yield) as a white solid. MS (ESI) m / z: 513.5 [M+H] + ; HPLC: 254nm: 98.115%, 214nm: 98.620%; 1H NMR (400MHz, DMSO) δ12.07(s,1H),8.60(d,J=2.3Hz,1H),8.35(t,J=5.4Hz,1H),8.28(s,1H),7.76(dd ,J=6.8,1.7Hz,1H),7.51(d,J=3.1Hz,1H),7.41(ddd,J=8.9,6.6,2.1Hz,1H),7.26(q,J=8.4Hz,4H ),6.65(t,J=3.3Hz,1H),6.40(d,J=9.1Hz,1H),6.22(td,J=6.7,1.3Hz,1H),5.29(s,2H),5.07(s, 2H), 4.80 (dd, J=8.5, 5.6Hz, 2H), 4.69 (dd, J=6.9, 5.7Hz, 2H), 4.55 (ddd, J=23.4, 10.4, 4.9Hz, 3H).

[0518] Example 38. N-((7-Fluoro-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (Compound 362) and N-((7-Fluoro-1-(2-hydroxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide (Compound 369) were prepared according to the following synthetic route:

[0519] Step 1: To a solution of compound 12-2 (50 mg, 0.14 mmol) in DMF (3 mL) were added DIEA (54 mg, 0.42 mmol) and HATU (59 mg, 0.15 mmol), and 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 the reaction was completed, the reaction mixture was concentrated under reduced pressure by LCMS monitoring. The residue was purified by preparative TLC (DCM: MeOH = 15: 1) and reverse phase chromatography to give the title compound 362 (27.57 mg, 38.26% yield) as a white solid. MS (ESI) m / z: 457.2 [M+H] + .

[0520] Step 2: At room temperature, NaH (1.31 mg, 0.03 mmol, 60% in oil) was added to DMF (2 mL). The atmosphere was replaced with N2 three times, and compound 362 (10 mg, 0.02 mmol) was slowly added dropwise to the reaction at 0°C. The reaction was allowed to react for 0.5 h. 2 (7.5 mg, 0.04 mmol) was then slowly added dropwise to the reaction, and the temperature was raised to 70°C and stirred for 72 h. Pre-TLC analysis (DCM:MeOH = 9:1, Rf = 0.4) yielded compound 369 (4.2 mg, 38.3% yield) as a white solid.

[0521] MS (ESI) M / Z: 313.2 [M+1] + ; 1H NMR (400MHz, DMSO-D6) δ8.53(d,J=2.1Hz,1H),8.46(t,J=5.6Hz,1H),8.20(d,J=0.7Hz,1H),7.84(d,J=0.7Hz,1H),7. 71(ddd,J=6.8,2.1,0.7Hz,1H),7.43(d,J=3.2Hz,1H),7.37(ddd,J=8.9,6.6,2.1Hz,1H),7.22(d,J=8.2Hz,2H),7. 17(d,J=8.3Hz,2H),6.58(t,J=2.9Hz,1H),6.36(ddd,J=9.2,1.4,0.7Hz,1H),6.18(td,J=6.7,1.4Hz,1H),5.26(s, 2H), 5.02 (s, 2H), 4.91 (t, J = 5.3Hz, 1H), 4.57 (dd, J = 5.6, 2.5Hz, 2H), 4.29 (t, J = 5.6Hz, 2H), 3.69 (q, J = 5.4Hz, 2H).

[0522] Example 39. N-((7-Fluoro-1-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-1-(4-(2-oxopyridin-1(2H)-yl)methyl]benzyl)-1H-pyrazole-4-carboxamide (Compound 383) was prepared according to the following synthetic route:

[0523] To a solution of compound 12-2 (35 mg, 0.11 mmol) in DMF (2.5 mL) were added DIEA (42 mg, 0.33 mmol) and HATU (46 mg, 0.12 mmol), and the mixture was stirred at room temperature for 5 minutes. Compound intermediate 15 (47 mg, 0.22 mmol) was then added to the reaction. The mixture was stirred at room temperature for 15 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure by LCMS monitoring. The residue was purified by preparative TLC (DCM: MeOH = 15: 1) and reverse phase chromatography to give the title compound (35.72 mg, 66.81% yield) as a white solid. MS (ESI) m / z: 473.5 [m + H] +; 1H NMR (400MHz, DMSO) δ8.38(t,J=5.6Hz,1H),8.24(s,1H),7.88(s,1H),7.78–7.70(m,2H),7.41(ddd,J=8.9,6.6,2.1Hz,1H),7.24(q,J=8.3Hz,4H),6. 40(d,J=9.1Hz,1H),6.22(td,J=6.7,1.3Hz,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).

[0524] The compounds listed in the table below were prepared using procedures similar to those described in Examples 37, 38 and 39 using appropriate starting materials.

[0525] Table 11.

[0526] Test Example 1. In vitro inhibitory activity test of the compounds of the present invention on plasma kallikrein (PKa), KLK1, and FXIa.

[0527] The ability of compounds of the invention to inhibit plasma kallikrein (PKK), KLK1, and FXIa was determined 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, containing 0.1% (w / v) BSA and 0.05% (v / v) Tween 20): Compounds were tested for PKK enzymatic activity inhibition using the FI method. PKK (R&D, Cat#2497-SE) and Pro-Phe-Arg-AMC (Nanjing Peptide Industry, Cat#NJP23946) solutions were prepared in reaction buffer (50 mM Tris-HCl, pH 7.5, 250 mM NaCl). The final concentrations of enzyme protein and Pro-Phe-Arg-AMC in the reaction mixture were 10 nM and 60 μM, respectively. The positive reference substance Avoralstat had a starting concentration of 100nM, 3-fold dilution, and 10+0 dose. 0.05μL of the compound in 100% DMSO was delivered to a 384-well plate by acoustic liquid delivery technology (Echo665; nanoliter range). The compound was tested in duplicate wells. 5μL of 2× enzyme solution was transferred to a 384 reaction plate and centrifuged at 1000rpm for 1 minute, incubated at 25°C for 15 minutes; 5μL of 2× Pro-Phe-Arg-AMC solution was transferred to a 384 reaction plate, centrifuged at 1000rpm for 1 minute, and incubated at 25°C for 3 hours. Finally, fluorescence was measured using BMG and an Envision reader with an excitation wavelength set to 355nm and an emission wavelength set to 460nm, and the FI signal (ex380 / em460) was read. IC was obtained using GraphPad Prism software. 50 Values ​​and nonlinear regression curve fitting.

[0528] These data were fitted to produce the best-fit IC 50 The results of these assays are shown in Table 12 below, with the numbers corresponding to the compound numbers. The control compounds were the PKa inhibitors KVD900 and Berotralstat.

[0529] Table 12.

[0530] The above results show that the compounds of the present invention have a strong inhibitory effect on plasma kallikrein (PKa) and have high selectivity.

[0531] Test Example 2. Evaluation of the inhibition of PKa by the compounds of the present invention in kaolin-activated human PPP:

[0532] Platelet-poor plasma (PPP) obtained from human whole blood and anticoagulated with sodium citrate was incubated with various concentrations of the test compound and 25, 75, 250, or 750 μg / mL kaolin in assay buffer for 20 minutes at 37° C. A concentration response of the test compound was obtained for each kaolin dose used. Positive drugs were diluted to the reference concentration and diluted 3-fold using the dilution as the first point.

[0533] 50 nL of compound was then transferred to a 384-well assay plate, with each well containing two replicates. The 384-well assay plate was centrifuged at 1000 rpm. 2.5 μL of human plasma working solution was added to each assay well. The 384-well assay plate was centrifuged at 1000 RPM. 2.5 μL of kaolin working solution was added to each assay well. The 384-well 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-well assay plate was centrifuged at 1000 RPM and incubated at 25°C for 60 minutes. Fluorescence signals were read by BMG.

[0534] The inhibition percentage of the compound was calculated according to the following formula:

[0535] Compound (inhibition %) = 100 * (average of negative control well values ​​- compound well values) / (average of negative control well values ​​- average of positive control well values)

[0536] The IC50 values ​​of the compounds according to the invention for PKa inhibition in kaolin-activated human PPP are shown in the table below, with the numbers corresponding to the compound numbers. The control compounds were the PKa inhibitors KVD900 and berotinostat.

[0537] Table 13.

[0538] The above results show that the compounds of the present invention have a strong inhibitory effect on plasma kallikrein (PKa) in kaolin-activated human PPP and are superior to the control compounds.

[0539] It will be appreciated by those skilled in the art that the present disclosure is not limited to the foregoing illustrative embodiments but can be embodied in other specific forms without departing from its essential attributes. It is therefore intended that the present disclosure be considered in all respects as illustrative and not restrictive, that references to the appended claims are to the embodiments rather than to the foregoing embodiments, that references to the literature are to the appended claims rather than to the foregoing examples, and that all variations coming within the meaning and range of equivalents of the claims are intended to be embraced herein.

[0540] All patents, patent applications, and literature references cited in this specification are hereby incorporated by reference in their entirety. In case of inconsistency, the present disclosure, including definitions, will control.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable prodrug or salt thereof: in, Ring A is a 5-6 membered heteroaryl or phenyl; Ring B is a 5-10 membered monocyclic or bicyclic aromatic or heteroaromatic group; m4 is 0 or 1; When m4 is 1, ring C is selected from 5-6 membered heteroaryl, phenyl and 9-10 membered bicyclic heteroaryl; When m4 is 0, ring C is selected from a 5-6 membered heteroaryl fused to a 5-6 membered heterocyclic group, a phenyl fused to a 5-6 membered heterocyclic group, 3-6 Cycloalkyl-fused 5-6 membered heteroaryl and C 3-6 Cycloalkyl-fused phenyl; R 1 , R 2 , R 3 and R 4 Each independently selects H atoms, halogens, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(C 1-6 Alkylene) n -C 1-6 Alkoxy and C 1-6 Hydroxyalkyl; Each Ra is independently selected from -(C 1-6 Alkylene) n -C 1-6 Alkoxy, -(C 1-6 Alkylene) n -OC 1-6 Alkylene-C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Haloalkoxy, -(C 1-6 Alkylene) n -C 3-6 Cycloalkyl, -(C 1-6 Alkylene) n -OC 3-6 Cycloalkyl, halogen, -OH, -SH, -NH2, -C(O)NH2, -NO2, -CN, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 Alkylene) n -5-6 membered heteroaryl, -O-(C 1-6 Alkylene) n -5-6 membered heteroaryl, -(C 1-6 Alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -(C 1-6 Alkylene) n -O-(C 1-6 Alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -NH-4-7 membered monocyclic or bicyclic heterocyclic group, -N(C 1-6 alkyl)-4-7 membered monocyclic or bicyclic heterocyclic group, -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 Alkyl, the C 1-6 Alkylene, 5-6 membered heteroaryl, 4-7 membered monocyclic or bicyclic heterocyclic group and C 3-6 The cycloalkyl groups are each independently optionally selected from C 1-6 Alkyl, oxo, -(C 1-6 Alkylene) n -C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 substituted by one or more substituents selected from alkoxy, halogen and -OH; Each 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 -4-7 membered monocyclic or bicyclic heterocyclic group, -(C 1-6 Alkylene) n -5-6 membered heteroaryl, -(C 1-6 Alkylene) n -9-10 membered bicyclic heteroaryl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, phenyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, -(C 1-6 Alkylene) n -C 1-6 Alkoxy, -OH, -SH, -NH2, -C(O)NH2, -NO2, C 2-6 Alkenyl, C 2-6 Alkynyl, -(C 1-6 Alkylene) n - a 4-7 membered monocyclic or bicyclic heterocyclic group fused to a phenyl group and -O-phenyl, the C 3-6 Cycloalkyl, 4-7 membered monocyclic or bicyclic heterocyclic group, 9-10 membered bicyclic heteroaryl, phenyl and 5-6 membered heteroaryl are each independently optionally selected from halogen, Oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -(C 1-6 Alkylene) n -C 1-6 Alkoxy, C 1-6 Substituted with one or more substituents selected from hydroxyalkyl, -CN, -OH, -SH, -NH2, -C(O)NH2 and -NO2; Each Rc is independently selected from 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 Alkoxy, carbamimidoyl, N-hydroxycarbamimidoyl, -C(=NH)-NH-C 1-6 Alkyl, -C(=NH)-N(C 1-6 Alkyl)2, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -CN, -OH, -SH, -SC 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, 3-6 membered heterocyclic group, -NH-(C 1-6 Alkylene) n -C 3-6 Cycloalkyl, -NH-(C 1-6 Alkylene) n - 3-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the 3-6 membered heterocyclyl and 5-6 membered heteroaryl are each independently selected from C 1-6 Alkyl, oxo, -(C 1-6 Alkylene) n -C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 substituted by one or more substituents selected from alkoxy, halogen and -OH; Alternatively, two adjacent Rc atoms together with the atoms to which they are attached form a C 3-6 Cycloalkyl or 5-6 membered heterocyclic group, the C 3-6 The cycloalkyl or 5-6 membered heterocyclic group is each independently optionally selected from C 1-6 Alkyl, oxo, -(C 1-6 Alkylene) n -C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 substituted by one or more substituents selected from alkoxy, halogen and -OH; The heterocyclic group and the heteroaryl group each contain 1, 2, 3 or 4 heteroatoms selected from 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 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, in, Ring A, Ring B, Ring C, R 1 , R 2 , R 3 , R 4 , Ra, Rb, Rc, m1, m2 and m3 are 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, in, Ring A, Ring B, Ring C, Ra, Rb, Rc, m1, m2 and m3 are 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, in, Ring A, Ring B, Ra, Rb, Rc, m1, m2 and m3 are as defined in claim 1; Ring C is selected from a 5-6 membered heteroaryl fused to a 5-6 membered heterocyclic group, a phenyl fused to a 5-6 membered heterocyclic group, a 3-6 Cycloalkyl-fused 5-6 membered heteroaryl and C 3-6 Cycloalkyl-fused phenyl; In particular, ring C is selected from cyclopentapyridinyl, cyclopentaimidazolyl and dihydrofuropyridinyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable prodrug or salt thereof, wherein: Ring A is selected from the group consisting of triazolyl, pyrazolyl, thiazolyl, oxadiazolyl, oxazolyl, thienyl, thiadiazolyl, pyridinyl, isoxazolyl, imidazolyl, pyrrolyl, furanyl, isothiazolyl, phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl and tetrazolyl; In particular, Selected from 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable prodrug or salt thereof, wherein: Ring B is selected from phenyl, quinolyl, imidazopyridinyl, pyridinyl, imidazolyl, naphthyl, triazolyl, pyrazolyl, thiazolyl, oxadiazolyl, oxazolyl, thienyl, thiadiazolyl, isoxazolyl, pyrrolyl, furanyl, isothiazolyl, phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, isoquinolinyl, indolyl, indazolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl and benzothiazolyl; In particular, Selected from 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable prodrug or salt thereof, wherein: Ring C is selected from pyridyl, phenyl, pyrimidinyl, thiadiazolyl, thiazolyl, triazolyl, pyrazolyl, oxadiazolyl, oxazolyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, furanyl, isothiazolyl, pyrazinyl, pyridazinyl, triazinyl, isoquinolinyl, pyrrolopyridinyl, imidazopyridinyl, triazolopyridinyl, benzisoxazolyl, benzothiazolyl and pyrazolopyridinyl; In particular, Selected from 8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable prodrug or salt thereof, wherein: Each Ra is independently selected from -(C 1-6 Alkylene) n -C 1-6 Alkoxy, -(C 1-6 Alkylene) n -OC 1-6 Alkylene-C 1-6 Alkoxy, -(C 1-6 Alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -(C 1-6 Alkylene) n -O-(C 1-6 Alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -NH-4-7 membered monocyclic or bicyclic heterocyclic group, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkyl, C 1-6 Haloalkoxy, -(C 1-6 Alkylene) n -C 3-6 Cycloalkyl, -(C 1-6 Alkylene) 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 Alkylene) n -5-6 membered heteroaryl, -O-(C 1-6 Alkylene) n -5-6 membered heteroaryl and -C 1-6 Alkylene-OC 1-6 Alkylene-N(C 1-6 Alkyl)2, the C 1-6 Alkylene, 5-6 membered heteroaryl, 4-7 membered monocyclic or bicyclic heterocyclic group and C 3-6 The cycloalkyl groups are each independently optionally selected from C 1-6 Alkyl, oxo, -(C 1-6 Alkylene) n -C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, halogen and -OH are substituted by one, two, three or four substituents, each n is independently 0 or 1, the 4-7 membered monocyclic or bicyclic heterocyclic group and the 5-6 membered heteroaryl group each independently contains 1, 2 or 3 heteroatoms selected from N, O and S atoms, preferably selected from pyrimidine, pyrazolyl, pyridinyl, pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, oxetanyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azabicyclo[2.2.1]heptyl, isoxazolyl, tetrahydropyranyl, pyrazinyl and 1-oxa-6-azaspiro[3.3]heptyl; In particular, each Ra is independently selected from Tetrahydrofuranyl, oxetanyl, difluoromethyl, trifluoromethyl, methyl, Cl atom, -CN, Morpholinyl, Pyrazinyl, pyrimidinyl, and / or Each Rb is independently selected from halogen, -CN, -(C 1-6 Alkylene) 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 Alkoxy, -(C 1-6 Alkylene) n -4-7 membered monocyclic or bicyclic heterocyclic group, -C 1-6 Alkylene-5-6 membered heteroaryl, -C 1-6 Alkylene-9-10 membered bicyclic heteroaryl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 1-6 Alkylene-phenyl fused 4-7 membered monocyclic or bicyclic heterocyclic group and -O-phenyl, each n is independently 0 or 1, and the 4-7 membered monocyclic or bicyclic heterocyclic group, 9-10 membered bicyclic heteroaryl, phenyl and 5-6 membered heteroaryl are each independently optionally selected from halogen, oxo, C 1-6 Alkyl and C 1-6 The 4-7 membered monocyclic or bicyclic heterocyclic group, the 9-10 membered bicyclic heteroaryl group and the 5-6 membered heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O and S atoms, preferably selected from dihydropyridyl, 3-azabicyclo[3.1.0]hexyl, pyrazolyl, morpholinyl, piperidinyl, pyrrolopyridinyl, 7-azabicyclo[2.2.1]heptyl, aza 1-Azabicyclo[2.2.1]heptanyl, pyrrolidinyl, 5-azaspiro[2.4]heptanyl, thiazolidinyl, indazolyl, dihydropyrimidinyl, and triazolyl; In particular, each Rb is independently selected from Cl atom, -CN, Cyclopropyl, F atom, Methyl, ethyl, Cl atoms, trifluoromethyl, cyclohexyl, Methoxy, ethoxy, and / or Each Rc is independently selected from 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 Alkylene) n -C 1-6 Alkoxy, carbamimidoyl, N-hydroxycarbamimidoyl, -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 heterocyclic group, -NH-(C 1-6 Alkylene) n -C 3-6 Cycloalkyl, -NH-(C 1-6 Alkylene) n -3-6 membered heterocyclyl and 5-6 membered heteroaryl, each n is independently 0 or 1, the 3-6 membered heterocyclyl and 5-6 membered heteroaryl are each independently optionally selected from C 1-6 Alkyl, oxo, C 1-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group each independently contain 1, 2 or 3 heteroatoms selected from N, O and S atoms, preferably selected from pyrrolidinyl, azetidinyl, oxetanyl and triazolyl; Alternatively, two adjacent Rc together with the atom to which they are attached form a piperazinyl, piperidinyl, pyrrolidinyl or dihydrofuran, wherein the piperazinyl, piperidinyl, pyrrolidinyl or dihydrofuran is each independently selected from C 1-6 Alkyl, oxo, C 1-6 substituted by one, two or three substituents of alkoxy, halogen and -OH; In particular, each Rc is independently selected from methyl, -NH2, -CH2NH2, -CH2NHCH3, F atom, methoxy, difluoromethyl, carbamimidyl, N-hydroxycarbamimidyl, Cl atom, ethyl, methylthio, -N(CH3)2, -NH-CH3、-CN、 Pyrrolidinyl, cyclopropyl, -C(=NH)-NH-CH3, -NH-cyclobutyl, -NH-CH2-cyclopropyl, -NH-CH2-oxetanyl, azetidinyl, and hydroxyethyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable prodrug or salt thereof, wherein: Selected from 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable prodrug or salt thereof, wherein: Selected from 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable prodrug or salt thereof, wherein: Selected from 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable prodrug or salt thereof, wherein: When each Rc is selected as carbamimidoyl, N-hydroxycarbamimidoyl or -NH2, the pharmaceutically acceptable prodrug of the compound is selected from: The C of carbamimidyl and -NH2 1-6 Carbonate; N-Hydroxycarbamimidyl C 1-6 Carbonate, C 1-6 carboxylate, phenylcarboxylate or pyridinecarboxylate, phenylcarboxylate and pyridinecarboxylate may be substituted by one or more halogens, C 1-6 Alkyl or C 1-6 Alkoxy substituted; and / or The pharmaceutically acceptable salt is selected from toluenesulfonate, methanesulfonate, hydrochloride, acetate and citrate.

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

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 the 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 preparation of a medicament for treating hereditary angioedema (HAE) and cerebral edema after stroke and neuroprotection.

16. Use of the 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 preparation of a medicament for treating cerebral edema and nerve damage caused by stroke.

17. Use of the 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 preparation of a medicament for treating ocular microangiopathy-related diseases; In particular, the ocular microangiopathy-related disorder is 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 angiomatous proliferation, macular telangiectasia, ischemic retinopathy, iris neovascularization, intraocular neovascularization, corneal neovascularization, retinal neovascularization, polypoidal choroidal vasculopathy, choroidal neovascularization, retinal degeneration, diabetic complications of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema; in particular, selected from diabetic retinopathy, diabetic macular edema, retinal vein occlusion, central retinal vein occlusion and wet age-related macular degeneration.

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