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EP-4737450-A1 - HETEROAROMATIC FORMAMIDE COMPOUNDS AND USES THEREOF IN MEDICINE

EP4737450A1EP 4737450 A1EP4737450 A1EP 4737450A1EP-4737450-A1

Abstract

The present invention relates to heteroaromatic formamide compounds and the uses thereof in medicine. In particular, the present invention relates to heteroaromatic formamide compounds represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing said compounds, and the use of the same as a therapeutic agent, in particular, the use as a selective inhibitor for plasma kallikrein (PKa) and the use in treating and/or preventing diseases which may benefit from the inhibition of plasma kallikrein, especially the use in treating and/or preventing diabetic macular edema (DME), age-related macular degeneration (AMD), choroidal neovascularization, hereditary angioedema (HAE), cerebral edema after stroke, etc.

Inventors

  • WANG, YONGGANG
  • YU, FEI
  • GAO, YANSHAN
  • FU, Dengrong
  • SUN, XICHENG
  • WU, Gongxiong

Assignees

  • Longwood Pharmaceuticals (Hangzhou) Co., Ltd

Dates

Publication Date
20260506
Application Date
20240620

Claims (17)

  1. A compound represented by the general formula (I) or a pharmaceutically acceptable prodrug or salt thereof: wherein, ring A is 5-6 membered heteroaryl or phenyl; ring B is 5-10 membered monocyclic or bicyclic aryl or heteroaryl; m 4 is 0 or 1; when m 4 is 1, ring C is selected from the group consisting of 5-6 membered heteroaryl, phenyl, and 9-10 membered bicyclic heteroaryl; when m 4 is 0, ring C is selected from the group consisting of 5-6 membered heteroaryl fused to 5-6 membered heterocyclyl, phenyl fused to 5-6 membered heterocyclyl, 5-6 membered heteroaryl fused to C 3-6 cycloalkyl, and phenyl fused to C 3-6 cycloalkyl; R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of 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; each Ra is independently selected from the group consisting of -(C 1-6 alkylene) n -C 1-6 alkoxy, -(C 1-6 alkylene) n -O-C 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 -O-C 3-6 cycloalkyl, halogen, -OH, -SH, -NH 2 , -C(O)NH 2 , -NO 2 , -CN, C 2-6 alkenyl, C 2-6 alkynyl, - C 1-6 alkylene-O-C 1-6 alkylene-C(O)-NH 2 , -C 1-6 alkylene-O-C 1-6 alkylene-C(O)-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-O-C 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 heterocyclyl, -(C 1-6 alkylene) n -O-(C 1-6 alkylene) n -4-7 membered monocyclic or bicyclic heterocyclyl, -NH-4-7 membered monocyclic or bicyclic heterocyclyl, -N(C 1-6 alkyl)-4-7 membered monocyclic or bicyclic heterocyclyl, -C 1-6 alkylene-O-C 1-6 alkylene-NH 2 , -C 1-6 alkylene-O-C 1-6 alkylene-N(C 1-6 alkyl) 2 and -C 1-6 alkylene-O-C 1-6 alkylene-NH-C 1-6 alkyl, and the C 1-6 alkylene, 5-6 membered heteroaryl, 4-7 membered monocyclic or bicyclic heterocyclyl, and C 3-6 cycloalkyl are each independently optionally substituented with one or more substituents selected from the group consisting of 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; each Rb is independently selected from the group consisting of 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 heterocyclyl, -(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, -NH 2 , -C(O)NH 2 , -NO 2 , C 2-6 alkenyl, C 2-6 alkynyl, -(C 1-6 alkylene) n -4-7 membered monocyclic or bicyclic heterocyclyl fused to phenyl and -O-phenyl, and the C 3-6 cycloalkyl, 4-7 membered monocyclic or bicyclic heterocyclyl, 9-10 membered bicyclic heteroaryl, phenyl, and 5-6 membered heteroaryl are each independently optionally substituented with one or more substituents selected from the group consisting of 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 hydroxyalkyl, -CN, -OH, -SH, -NH 2 , -C(O)NH 2 , and -NO 2 ; each Rc is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halogen, -NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -(C 1-6 alkylene) n -C 1-6 alkoxy, formamidinyl, N-hydroxyformamidinyl, -C(=NH)-NH-C 1-6 alkyl, -C(=NH)-N(C 1-6 alkyl) 2 , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, -CN, -OH, -SH, -S-C 1-6 alkyl, -C(O)NH 2 , - NO 2 , -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NH-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6-membered heterocyclyl, -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, and the 3-6 membered heterocyclyl and 5-6 membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of 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; or, two adjacent Rc together with the atoms to which they are attached form a C 3-6 cycloalkyl or 5-6 membered heterocyclyl, and the C 3-6 cycloalkyl or 5-6 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of 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; the heterocyclyl and heteroaryl each containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S; m 1 is 0, 1 or 2; m 2 is 0, 1, 2, or 3; m 3 is 0, 1, 2, or 3; and each n is independently 0 or 1.
  2. The compound or a pharmaceutically acceptable prodrug or salt thereof according to claim 1, which is a compound represented by the general formula (II) or a pharmaceutically acceptable prodrug or salt thereof, wherein, ring A, ring B, ring C, R 1 , R 2 , R 3 , R 4 , Ra, Rb, Rc, m 1 , m 2 and m 3 are as defined in claim 1.
  3. The compound or a pharmaceutically acceptable prodrug or salt thereof according to claim 1 or 2, which is a compound represented by the general formula (III) or a pharmaceutically acceptable prodrug or salt thereof, wherein, ring A, ring B, ring C, Ra, Rb, Rc, m 1 , m 2 and m 3 are as defined in claim 1.
  4. The compound or a pharmaceutically acceptable prodrug or salt thereof according to claim 1 or 2, which is a compound represented by the general formula (IV) or a pharmaceutically acceptable prodrug or salt thereof, wherein, ring A, ring B, Ra, Rb, Rc, m 1 , m 2 and m 3 are as defined in claim 1; ring C is selected from the group consisting of 5-6 membered heteroaryl fused to 5-6 membered heterocyclyl, phenyl fused to 5-6 membered heterocyclyl, 5-6 membered heteroaryl fused to C 3-6 cycloalkyl, and phenyl fused to C 3-6 cycloalkyl; and in particular, ring C is selected from the group consisting of cyclopentopyridinyl, cyclopentoimidazolyl and dihydrofuropyridinyl.
  5. The compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 4, wherein ring A is selected from triazolyl, pyrazolyl, thiazolyl, oxadiazolyl, oxazolyl, thienyl, thiadiazolyl, pyridyl, isoxazolyl, imidazolyl, pyrrolyl, furyl, isothiazolyl, phenyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, and tetrazolyl; in particular, is selected from the group consisting of
  6. The compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 5, wherein ring B is selected from the group consisting of 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, benzothiophenyl, quinazolinyl, and benzothiazolyl; in particular, is selected from the group consisting of
  7. The compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 6, wherein ring C is selected from the group consisting of pyridinyl, 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, is selected from the group consisting of
  8. The compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 7, wherein each Ra is independently selected from the group consisting of -(C 1-6 alkylene) n -C 1-6 alkoxy, -(C 1-6 alkylene) n -O-C 1-6 alkylene-C 1-6 alkoxy, -(C 1-6 alkylene) n -4-7 membered monocyclic or bicyclic heterocyclyl, -(C 1-6 alkylene) n -O-(C 1-6 alkylene) n -4-7 membered monocyclic or bicyclic heterocyclyl, -NH-4-7 membered monocyclic or bicyclic heterocyclyl, 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 -O-C 3-6 cycloalkyl, halogen, -CN, -C 1-6 alkylene-O-C 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-O-C 1-6 alkylene-N(C 1-6 alkyl) 2 , and the C 1-6 alkylene, 5-6 membered heteroaryl, 4-7 membered monocyclic or bicyclic heterocyclyl, and C 3-6 cycloalkyl are each independently optionally substituted with one, two, three or four substituents selected from the group consisting of 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, each n is independently 0 or 1, the 4-7 membered monocyclic or bicyclic heterocyclyl and the 5-6 membered heteroaryl each independently contain 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S, preferably selected from the group consisting of pyrimidinyl, 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 the group consisting of tetrahydrofuryl, oxetanyl, difluoromethyl, trifluoromethyl, methyl, Cl atom, -CN, morpholinyl, pyrazinyl, pyrimidinyl, and/or each Rb is independently selected from the group consisting of halogen, -CN, -(C 1-6 alkylene) n -C 3-6 cycloalkyl, -O-C 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 heterocyclyl, -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-4-7 membered monocyclic or bicyclic heterocyclyl fused to phenyl and -O-phenyl, each n being independently 0 or 1, the 4-7 membered monocyclic or bicyclic heterocyclyl, 9-10 membered bicyclic heteroaryl, phenyl, and 5-6 membered heteroaryl are each independently optionally substituted with one, two or three substituents selected from the group consisting of halogen, oxo, C 1-6 alkyl, and C 1-6 haloalkyl, and the 4-7 membered monocyclic or bicyclic heterocyclyl, the 9-10 membered bicyclic heteroaryl group, and the 5-6 membered heteroaryl each independently contain 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S, preferably selected from the group consisting of dihydropyridinyl, 3-azabicyclo[3.1.0]hexyl, pyrazolyl, morpholinyl, piperidinyl, pyrrolopyridinyl, 7-azabicyclo[2.2.1]heptyl, azepinyl, azetidinyl, 2-azabicyclo[2.2.1]heptyl, pyrrolidinyl, 5-azaspiro[2.4]heptyl, thiazolidinyl, indazolyl, dihydropyrimidinyl and triazolyl; in particular, each Rb is independently selected from the group consisting of Cl atom, -CN, cyclopropyl, F atom, methyl, ethyl, Cl atom, trifluoromethyl, cyclohexyl, methoxy, ethoxy, and/or each Rc is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halogen, -NH 2 , -C 1-6 alkylene-NH 2 , -C 1-6 alkylene-NH-C 1-6 alkyl, -(C 1-6 alkylene) n -C 1-6 alkoxy, formamidinyl, N-hydroxyformamidinyl, -C(=NH)-NH-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 hydroxyalkyl, -CN, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -NH-(C 1-6 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 substituted with one, two or three substituents selected from the group consisting of C 1-6 alkyl, oxo, C 1-6 alkoxy, halogen, and -OH, the 3-6 membered heterocyclyl and 5-6 membered heteroaryl each independently containing 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, preferably selected from pyrrolidinyl, azetidinyl, oxetanyl and triazolyl; or two adjacent Rc together with the atoms to which they are attached form piperazinyl, piperidinyl, pyrrolidinyl, or dihydrofuran, each independently optionally substituted with one, two, or three substituents selected from the group consisting of C 1-6 alkyl, oxo, C 1-6 alkoxy, halogen, and -OH; in particular, each Rc is independently selected from the group consisting of methyl, -NH 2 , -CH 2 NH 2 , -CH 2 NHCH 3 , F atom, methoxy, difluoromethyl, formamidinyl, N-hydroxyformamidinyl, Cl atom, ethyl, methylthio, -N(CH 3 ) 2 , -NH-CH 3 , -CN, , pyrrolidinyl, cyclopropyl, -C(=NH)-NH-CH 3 , -NH-cyclobutyl, -NH-CH 2 -cyclopropyl, -NH-CH 2 -oxetanyl, azetidinyl, and hydroxyethyl.
  9. The compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 8, wherein is selected from the group consisting of and
  10. The compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 9, wherein is selected from the group consisting of
  11. The compound or a pharmaceutically acceptable prodrug or salt thereof according to claim 1 to 10, wherein is selected from the group consisitng of
  12. The compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 11, wherein when each Rc is selected from the group consisting of formamidinyl, N-hydroxyformamidinyl, or -NH 2 , the pharmaceutically acceptable prodrug of the compound is selected from the group consisting of: C 1-6 carbonate of formamidinyl and -NH 2 ; C 1-6 carbonate, C 1-6 carboxylate, phenylcarboxylate or pyridylcarboxylate of N-hydroxyformamidinyl, and phenylcarboxylate and pyridylcarboxylate may be substituted with one or more halogens, C 1-6 alkyl or C 1-6 alkoxy; and/or the pharmaceutically acceptable salt is selected from the group consisting of tosylate, mesylate, hydrochloride, acetate, and citrate.
  13. The compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 12, selected from the group consisting of: and
  14. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 13, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  15. Use of a compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the treatment of hereditary angioedema (HAE) and cerebral edema after stroke and neuroprotection.
  16. Use of a compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the treatment of cerebral edema caused by stroke and nerve damage.
  17. Use of a compound or a pharmaceutically acceptable prodrug or salt thereof according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the treatment of an ocular microangiopathy-associated disorder; in particular, the ocular microangiopathy-associated disorder is selected from the group consisting of 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 hyperplasia, 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; particularly selected from the group consisting of diabetic retinopathy, diabetic macular edema, retinal vein occlusion, central retinal vein occlusion and wet age-related macular degeneration.

Description

Technical field The invention belongs to the field of biomedicine, and relates to heteroaromatic formamide compounds and uses thereof in medicine. Specifically, the invention relates to a heteroaromatic formamide compound represented by general formula (I), a pharmaceutical composition containing the compound, and the use as a therapeutic agent, in particular to synthesis methods of the compound and pharmaceutically acceptable salts of the compound, and the use thereof as a selective inhibitor for human plasma kallikrein. Background The kallikrein-kinin system (KKS) consists of two independently regulated proteolytic pathways, mediated by tissue kinin (TK) and tissue kinin (PK), that produce bradykinin and stimulate the bradykinin receptor, respectively. The effect of KKS on retinal vascular permeability is mainly mediated by bradykinin. Both TK and PK are widely distributed in various tissues and may be regulated by different mechanisms. The components of plasma KKS are mainly synthesized in the liver and secreted into the blood. The plasma prekallikrein (PPK) in KKS signaling pathway is an abundant serine protease proenzyme, which can be converted to the catalytically active plasma kallikrein (PKa) by factor XIIa (FXIIa), and participates in inflammatory reactions. PKa cleaves kininogen to produce bradykinin. Bradykinin (BK) is a non-peptide that stimulates the BK receptor, which is abundantly expressed in vascular, glial, and neuronal cells. BK is a potent inflammatory factor, and activation of the BK receptor allows it to bind to B1R and B2R, can promote increase of bradykinin level to further mediate various signal cascades by stimulating release of mediators such as eicosanoids, endothelium-derived hyperpolarizing factor, NO, allyl alcohol, tissue-type plasminogen activator (tPA) and glucose transporter-1/2 (glu1/2). These mediators, together with inflammation, angiogenesis, vasodilation, and increased vascular permeability, can induce DME formation. Plasma kallikrein plays a role in a variety of inflammatory conditions and may have many effects in the conditions, 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 following choroidal neovascularization, ischemia-reperfusion injury such as in all kinds of scenarios associated with tissue and/or organ transplantation, operation-induced cerebral injury, cerebral ischemia, global ischemia, edema associated with glioma, spinal cord injury, pain, ischemia, cerebral ischemia, neurological and cognitive deficits, deep vein embolism, 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 thrombus, itching, disorders of inflammatory components 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, diabetes, diabetic complications, Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, stroke, epilepsy, allergic edema, airflow blockage such as chronic allergic sinusitis or perennial rhinitis, airflow blockage in acute asthma, and other diseases. Plasma kallikrein inhibitors are considered as suitable for the treatment of a wide range of conditions, in particular for the treatment of edema formation in diseases, such as edema formation associated with ischemic reperfusion injury of stroke, retinopathy or edema associated diseases such as hereditary angioedema, macular edema and cerebral edema. At present, the treatment of acute ischemic stroke is mainly general treatment and specific treatment. Specific treatment is the key to the treatment of ischemic stroke, mainly including the improvement of cerebral blood circulation and neuroprotection. When stroke occurs, the earlier neuroprotection is carried out to reduce the progress of brain nerve death, the more effective it is to prevent the damage of harmful substances to the brain and win more time for the brain. At present, edaravone and butylphthalide are the mains