Substituted pyrazole compounds as serine protease inhibitors

Abstract

To provide compounds useful for the inhibition of thrombin and / or kallikrein, pharmaceutical compositions, and methods for treating and / or preventing a disease or disorder in a subject.SOLUTION: For example, the following Compound 1 and Compound 2 are illustrated.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority under 35 U.S.C.§ 119(e) to U.S. Provisional Application No. 62 / 126,424, filed on Feb. 27, 2015, which is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] The present disclosure relates to compounds, e.g., certain substituted pyrazole compounds, which exhibit biological activity, e.g., inhibitory activity, against serine proteases such as thrombin and plasma kallikrein.

[0003] Serine proteases are a large family of enzymes with diverse biological functions, sharing the presence of an active - site serine residue and an important function. Their central function is the catalytic cleavage of peptide - bond substrates by a Ser - His - Asp triad in the active site (Kraut, J. Annual Review of Biochemistry 1977, 46, 331 - 358). The present disclosure relates to compounds, e.g., heterocycloalkyl - substituted pyrazolyl compounds, which exhibit biological activity, e.g., inhibitory activity, against serine proteases such as thrombin and various kallikreins. In mammalian systems, vascular injury results in bleeding events that are addressed by the blood - coagulation cascade. This cascade involves at least 13 interconnected factors and various cofactors

[0004] ​​​​​​​​​​​​​ including exogenous and endogenous pathways involving activation of platelets and other regulatory proteins. Upon vascular injury , plasma factor VII interacts with exposed tissue factor (TF), and the resulting TF- factor VIIa complex initiates a series of complex events. Factor Xa is produced directly "downstream" of the TF-factor VIIa complex and amplified variably by the endogenous pathway. Subsequently , factor Xa acts as a catalyst for thrombin formation (factor IIa), which in turn is the direct precursor to fibrinolysis. This results in a fibrinolytic blood clot, which stops bleeding . Lysis is brought about by fibrinolysis of the polymer clot into fibrin monomers, returning the system to the pre-coagulation state. This cascade is a complex balance of factors and cofactors and is tightly regulated .

[0005] In disease states, unwanted up- or down-regulation of any factor can lead to conditions such as bleeding or thrombosis. Historically, anticoagulants have been used in patients at risk of thromboembolic complications such as angina, stroke, and heart attack. Warfarin has been dominant as the most promising anticoagulant therapy. Warfarin is a vitamin K antagonist developed in the 1940s that inhibits, among others, factors II, VII, IX, and X . It is administered orally, but its ease of use is tempered by other effects such as its very long half-life (greater than 2 days ) and significant drug-drug interactions. Importantly, because vitamin K is a ubiquitous cofactor within the coagulation cascade, antagonism can inhibit many coagulation factors simultaneously, and thus serious bleeding complications can be caused . . .

[0006] Naturally occurring polysaccharide heparin, which activates antithrombin III (AT III), an endogenous inhibitor of many factors in the coagulation cascade, has received considerable attention. The need for non-oral administration of heparin-derived therapeutic agents and the inconvenient requirements for the careful management of orally available warfarin have been the driving force for the discovery and development of orally available drugs with a wide therapeutic concentration range for safety and efficacy. Indeed, the position of thrombin in the coagulation cascade has made it a common target for drug discovery. Thrombin is a central protein in the coagulation process and is activated and amplified upon vascular injury. Thrombin generation triggers the cascade with various factors in the coagulation cascade, ultimately depositing fibrin, the backbone of the blood clot. The blood clot causes the cessation of bleeding events associated with vascular injury. Finally, thrombin and related proteins cause the dissolution of the blood clot by "fibrinolysis", returning the system to its pre-injury state. In the "normal" state of injury, this thrombin generation and blood clot deposition are desirable. In certain disease states, blood clot deposition is undesirable. Common thrombotic events are the clinical consequences of blood clot deposition and accumulation in arteries, veins, or the heart. When the accumulated blood clot structure finally breaks down and enters the vascular system, the blood clot is moved to the brain and / or lungs, resulting in stroke, myocardial infarction (heart attack), pulmonary embolism, paralysis, and ultimately death. Compounds that inhibit thrombin have been shown in the literature to be useful as anticoagulants in vitro and in vivo, and in the clinic, they have been shown to meet the very unmet medical needs of patients. A detailed discussion of thrombin and its role in the coagulation process can be found in Wieland, H.A., e tc., "The Molecular Basis of Blood Coagulation", Marcel Dekker, Inc., New York, 1997. tc., "The Molecular Basis of Blood Coagulation", Marcel Dekker, Inc., New York, 1997.

[0007] Indeed, the position of thrombin in the coagulation cascade has made it a common target for drug discovery. Thrombin is a central protein in the coagulation process and is activated and amplified upon vascular injury. Thrombin generation triggers the cascade with various factors in the coagulation cascade, ultimately depositing fibrin, the backbone of the blood clot. The blood clot causes the cessation of bleeding events associated with vascular injury. Finally, thrombin and related proteins cause the dissolution of the blood clot by "fibrinolysis", returning the system to its pre-injury state. In the "normal" state of injury, this thrombin generation and blood clot deposition are desirable. In certain disease states, blood clot deposition is undesirable. Common thrombotic events are the clinical consequences of blood clot deposition and accumulation in arteries, veins, or the heart. When the accumulated blood clot structure finally breaks down and enters the vascular system, the blood clot is moved to the brain and / or lungs, resulting in stroke, myocardial infarction (heart attack ), pulmonary embolism, paralysis, and ultimately death. ) Compounds that inhibit thrombin have been shown in the literature to be useful as anticoagulants in vitro and in vivo, and in the clinic, they have been shown to meet the very unmet medical needs of patients. A detailed discussion of thrombin and its role in the coagulation process can be found in Wieland, H.A., e tc., "The Molecular Basis of Blood Coagulation", Marcel Dekker, Inc., New York, 1997. tc., "The Molecular Basis of Blood Coagulation", Marcel Dekker, Inc., New York, 1997. et al., 2003, Curr Opin Investig Drugs, 4:26 4 - 71, Gross, P. L. & Weitz, J. I., 2008, Arterio scler Thromb Vasc Biol, 28:380 - 6, Hirsh, J. , et al., 2005, Blood, 105:453 - 63, Prezelj, A. , et al., 2007, Curr Pharm Des, 13:287 - 312, including can be found in various references, all of which are hereby incorporated by reference in their entirety for all purposes. Further, although not wishing to be bound by any theory, the use of direct thrombin inhibitors (DTIs), such as hirudin - based anticoagulants, has been considered to be very good precedent, and thus, there is great interest in the discovery and development of new DTIs, specifically, DTIs having selectivity for inhibiting thrombin over other related serine proteases. Kallikrein is a subgroup of serine proteases classified into plasma kallikrein and tissue kallikrein. Plasma kallikrein (KLKB1 ) liberates kinins (bradykinin and kallidin), which are peptides involved in blood pressure regulation and activation of inflammation, from kininogen. In the contact activation pathway of the coagulation cascade, plasma kallikrein assists in the conversion of factor XII to factor XIIa (Keel, M.; Tr entz, O. Injury 2005, 36, 691 - 709). Factor XIIa converts factor XI to factor XIa, which then activates factor IX, and together with its cofactor factor VIIIa forms the tenase complex, which ultimately activates factor X ). Factor XIIa converts factor XI to factor XIa, which then activates factor IX, and together with its cofactor factor VIIIa forms the tenase complex, which ultimately activates factor X ). Plasma kallikrein assists in the conversion of factor XII to factor XIIa (Keel, M.; Tr entz, O. Injury 2005, 36, 691 - 709). Factor XIIa converts factor XI to factor XIa, which then activates factor IX, and together with its cofactor factor VIIIa forms the tenase complex, which ultimately activates factor X Activate the zymogen to factor Xa. In the fibrinolytic part of the coagulation cascade, plasma kallikrein in has the function of converting plasminogen to plasmin. Therefore, it has been proposed that plasma kallikrein inhibitors may be useful for the treatment of thrombotic and fibrinolytic diseases and disease states (U.S. Patent No. 7,625,944, Bird et al. Throm bosis and Hemostasis 2012, 107, Dhaval Kol te, MD et al., Cardiology in Review, 2015).

[0008] Tissue kallikrein (KLK, e.g., KLK1) is subdivided into various types and has been widely studied in cancer and inflammation biology. It has been found that various kallikrein KLKs are upregulated or downregulated in various types of cancer such as cervical cancer, testicular cancer, and non-small cell lung adenocarcinoma (Caliendo et al. J. Med. Chem., 2012, 5 5, 6669). Furthermore, the overexpression of various KLKs in the skin has led to the recognition that certain kallikrein inhibitors may be useful for certain dermatological conditions including rare skin diseases such as atopic dermatitis, psoriasis, and Netherton syndrome (Freit as et al. Bioorganic & Medicinal Chemistr y Letters 2012, 22, 6072 - 6075). A detailed discussion of tissue kallikrein, plasma kallikrein, their functions and potential roles in various diseases can be found in Renne, T.; Gruber, A. Thromb Haemost 2012, 107, 1012 - 3, Sotiropoulou, G.; Pampalakis, G ​​​​.Trends in Pharmacological Sciences 2012 ,33,623 - 634, Pampalakis, G.; Sotiropoulou, G .Chapter 9 Pharmacological Targeting of Human Tissue Kallikrein - Related Peptidas es. In Proteinases as Drug Targets, Dunn, B , Ed. The Royal Society of Chemistry: 2012 ; pp 199 - 228, Caliendo, G.; Santagada, V.; Per issutti, E.; Severino, B.; Fiorino, F.; Frecen tese, F.; Juliano, L. J Med Chem 2012, 55, 666 9 - 86 can be found in various references, which are hereby incorporated by reference in their entirety for all purposes .

Summary of the Invention

[0009] Embodiments of the present invention include compounds having the following structure

Chemical formula

[0010] In some embodiments, the compound may be a pharmaceutically acceptable salt, ester, solvate, or prodrug of a compound of formula (IV). In some embodiments, the compound is neither an ester, a solvate, nor a prodrug.

[0011] In some embodiments, X may be a bond or substituted or unsubstituted alkylene . In some embodiments, Z may be a bond or substituted or unsubstituted alkylene . In some embodiments, X may be a bond or substituted or unsubstituted alkylene, and Z may be a bond or substituted or unsubstituted alkylene.

[0012] In some embodiments, X is a bonded or substituted or unsubstituted alkylene, Z is a bonded or substituted or unsubstituted alkylene, Y can be -N-, and W is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, -C(O)R 6 -C(O)OR 6 -C(O)NR 6 R 7 -SO2R 6 or also SO2NR 6 R 7 wherein R 6 and R 7 are independently a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl, or when both R and R 6 and R 7 are present, they can combine to form a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene, and include compounds.

[0013] Some embodiments include compounds where X can be a substituted or unsubstituted methylene, a substituted or unsubstituted ethylene, a substituted or unsubstituted propylene, a substituted or unsubstituted butylene, or a substituted or unsubstituted pentylene, and Z can be a bond. In some embodiments, X can be a bond and Z can be a substituted or unsubstituted methylene, a substituted or unsubstituted ethylene, a substituted or unsubstituted propylene, a substituted or unsubstituted butylene, or a substituted or unsubstituted pentylene. In some embodiments, X is a substituted or unsubstituted methylene, a substituted or unsubstituted ethylene, a substituted or unsubstituted It can be unsubstituted butylene, or substituted or unsubstituted pentylene, and Z can be substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, or substituted or unsubstituted pentylene. In some embodiments both X and Z can be branched alkylene and X and Z can be covalently bonded. In some embodiments, Z can be one or more substituents including -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, substituted or unsubstituted alkyl, substituted or unsubstituted hetero alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and can be substituted methylene, substituted ethylene, substituted propylene, substituted butylene, or substituted pentylene.

[0014] Some embodiments include compounds where X can be substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, or substituted or unsubstituted pentylene, and Z can be -C(O)-. In some embodiments, W can be hydrogen. In some embodiments, W can be substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, -C(O)R 6 -C(O)OR 6 -C(O)NR 6 R 7 -SR 6 -SOR 6 -SO2R6 , or -SO2NR 6 It could be. Some In this embodiment, W is -OH, -NH2, -SH, -CN, -CF3, -NO2, oxy. -SO, halogen, -COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaromatic alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl , substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Substituted alkyl, substituted heteroalkyl, substituted alkenyl, substituted aryl, substituted heteroalkyl ... It may be a tereoalkenyl, a substituted cycloalkyl, or a substituted heterocycloalkyl. In some embodiments, W is -COR 6 , -C(O)OR 6 , -C(O)NR 6 R 7 , -SO2R 6 , or -SO2NR 6 R 7 where R 6 and R 7 is replaced or is unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 6 Reach BiR 7 can be combined to form a substituted or unsubstituted alkylene.

[0015] In some embodiments, W may be absent and X is -NR 8 -, and Y is a bond or may be substituted or unsubstituted alkylene, Z being -NR 9 -, including compounds. may be absent, and X is -NR 8 -, and Y is a bond or a substituted or unsubstituted alkyl group. It can be -NR 9 In some embodiments where it can be -, Y is substituted or un substituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or un substituted butylene, or substituted or unsubstituted pentylene. In some embodiments R 8 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, -COR 6 -, - C(O)OR 6 -, -C(O)NR 6 R 7 -, -SR 6 -, -SOR 6 -, -SO2R 6 or -SO2NR 6 R 7 can be, and R 9 is substituted or unsubstituted alkyl, substituted or unsub stituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl -, -COR 6 -, -C(O)OR 6 -, -C(O)NR 6 R 7 -, -SR 6 -, -SOR 6 -, - SO2R 6 or -SO2NR 6 R 7 can be.

[0016] Some embodiments include compounds where Y can be -O- and W can be absent. In some embodiments where Y can be -O- and W can be absent, X can be substituted or un substituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or un substituted butylene, or substituted or unsubstituted pentylene, and Z can be a bond can be obtained. In some embodiments, X can be a bond, and Z can be a substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, or substituted or unsubstituted pentylene. In some embodiments, X can be a substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, or substituted or unsubstituted pentylene, and Z can be a substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, or substituted or unsubstituted pentylene. In some embodiments, V can be hydrogen or a substituted or unsubstituted methyl.

[0017] In some embodiments, L

[0018] In some embodiments, L 1 can be -S-, -O-, -NR 5 -, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene, R 1 can be a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted condensed-ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl, and R 5 can be hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted hetero cycloalkyl. In some embodiments, L 1 can be -NR 5 - or substituted or unsubstituted heteroalkylene, and R 1 can be a substituted or unsubstituted alkyl or substituted or unsubstituted heteroaryl. In some embodiments, L 1 is -NR5 - may be, and R 1 may be a substituted or unsubstituted heteroaryl or a substituted or unsubstituted hete rocycloalkyl, and may be a substituted alkyl having one or more substituents. Some embodiments, R 1 may be a substituted alkyl substituted by a chloro-substituted thiophenyl Some embodiments, L 1 may be a substituted or unsubstituted heteroalkyl and R 1 may be a substituted or unsubstituted heteroaryl.

[0019] Some embodiments, L 2 may be a bond, a substituted or unsubstituted alkylene, -C(O) -, or -SO2-, and R 2 may be hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted a ryl, a substituted or unsubstituted fused-ring aryl, a substituted or unsubstituted heteroaryl, or may be a substituted or unsubstituted heterocycloalkyl. Some embodiments, L 2 may be a bond, and R 2 may be hydrogen. Some embodiments, L 2 may be -C(O) -, and R 2 may be a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted fused-ring aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted hete rocycloalkyl.

[0020] Some embodiments, L 4 may be a bond, and R 4is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl , or may be substituted or unsubstituted heteroaryl.

[0021] In some embodiments, the compound(s) may be included in those listed in Table A, Table B, Table C, or Table D.

[0022] Embodiments of the present invention include one or more of the compounds described above, or one or more compounds(s) included in those listed in Table A, Table B, Table C, or Table D, and a pharmaceutically acceptable excipient. The present invention also relates to a pharmaceutical composition comprising an agent.

[0023] Embodiments of the present invention are methods for treating and / or preventing one or more diseases or disorders in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound as described above or a pharmaceutical composition comprising such a compound to treat or prevent said disease(s) or disorder(s).

[0024] In some embodiments of the methods described herein, the disease or disorder to be treated may include one or more thrombotic diseases or disorders and / or may be associated with the formation of a blood clot or the potential for a blood clot. In some embodiments, the thrombotic disease or disorder may be acute coronary syndrome, pulmonary embolism, and / or thrombosis. In some embodiments, the pulmonary embolism may be venous thromboembolism, arterial thromboembolism, and / or cardiogenic thromboembolism. In some embodiments, the venous thromboembolism may include deep vein thrombosis and / or pulmonary embolism. In some embodiments, the deep vein thrombosis and / or pulmonary embolism may occur after a medical procedure. ​​​​​​​​​​​In some embodiments, the thrombotic disease or disorder may be associated with coagulation insufficiency or disseminated intravascular coagulation. In some embodiments, a subject with coagulation insufficiency may have undergone percutaneous coronary intervention (PCI). In some embodiments, the thrombotic disease or disorder may be associated with a clot thrombus or the potential for clot thrombus formation, and may further be accompanied by a stroke and / or one or more transient ischemic attacks (TIAs). In some embodiments, the thrombotic disease or disorder associated with a clot thrombus or the potential for clot thrombus formation may further be accompanied by a stroke, and the subject may have non-valvular atrial fibrillation. In some embodiments, the thrombotic disease or disorder may be associated with a clot thrombus or the potential for clot thrombus formation, and may further be accompanied by pulmonary hypertension. In some embodiments, pulmonary hypertension may be caused by one or more left heart disorders and / or chronic thromboembolic diseases. In some embodiments, pulmonary hypertension may be associated with one or more lung diseases including idiopathic or other pulmonary fibrosis and / or hypoxia.

[0025] In some embodiments, venous thromboembolism may be associated with the formation of thrombi in veins related to one or more acquired or genetic risk factors and / or peripheral venous embolism caused by thrombus detachment. In some embodiments, one or more risk factors may include a history of venous thromboembolism. In some embodiments, cardiogenic thromboembolism may be due to the formation of thrombi in the heart related to arrhythmias, cardiac valve defects, artificial heart valves or heart diseases, and / or peripheral arterial embolism caused by thrombus detachment. In some embodiments, thrombus detachment may be in the brain (ischemic stroke). In some embodiments, thrombus detachment may be transient It can cause transient ischemic attack (TIA). In some embodiments, cardiogenic thromboembolism may be caused by non-valvular atrial fibrillation. In some embodiments, thrombosis may be arterial thrombosis . In some embodiments, arterial thrombosis may be caused by one or more underlying atherosclerotic processes within the artery. In some embodiments, one or more underlying atherosclerotic processes within the artery may occlude or close the artery, cause myocardial ischemia (angina pectoris, acute coronary syndrome), cause myocardial infarction, occlude or close peripheral arteries (ischemic peripheral arterial disease), and / or occlude or close the artery after a vascular procedure (reocclusion or restenosis after percutaneous coronary angioplasty, reocclusion or restenosis after percutaneous transluminal angioplasty of peripheral arteries).

[0026] In some embodiments, the disease or disorder may include fibrosis, Alzheimer's disease, multiple sclerosis , pain, cancer, inflammation, and / or type I diabetes. In some embodiments, the disease or disorder may be associated with recurrent cardiac events after myocardial infarction.

[0027] In some embodiments, the treatment or prevention may include adjuvant therapy. In some embodiments , the subject may have myocardial infarction, and the adjuvant therapy may be concurrent with thrombolytic therapy. In some embodiments, the subject may have unstable angina, thrombosis, and / or heparin-induced thrombocytopenia, and the adjuvant therapy may be combined with antiplatelet therapy. In some embodiments , the subject may have non-valvular atrial fibrillation, and the adjuvant therapy may be concurrent with one or more other therapies.

[0028] In some embodiments of the methods described herein, the disease or disorder is related to kallikrein It can be a kallikrein-related disease. In some embodiments, the kallikrein-related disease can be a thrombotic disease, a fibrinolytic disease, a fibrotic disease, certain cancers, an inflammatory condition, or a dermatological condition. .

[0029] In some embodiments, the kallikrein-related disease can be an ophthalmic disease. In some embodiments, the present compound or the present pharmaceutical composition can be administered in the form of an ophthalmic composition for topical application to the eye. In some embodiments, the ophthalmic composition can be in the form of eye drops. In some embodiments, the present compound or the present pharmaceutical composition can be administered in the form of an ophthalmic composition by intravitreal injection. In some embodiments, the ophthalmic disease can be diabetic macular edema, hereditary angioedema, age-related macular degeneration, or diabetic retinopathy.

[0030] In some embodiments where the disease or disorder can be certain cancers, the certain cancers can be cervical cancer, testicular cancer, or non-small cell lung adenocarcinoma. In some embodiments, the cancer can be limited small cell lung cancer. In some embodiments, the cancer can be glioma. In some embodiments, the cancer can be breast cancer. In some embodiments, the cancer can be micrometastasis. In some embodiments, the micrometastasis can be blood or liver micrometastasis. In some embodiments, the cancer can be lung metastasis. In some embodiments, the cancer can be prostate cancer.

[0031] In some embodiments where the disease or disorder can be an inflammatory condition, the inflammatory condition can be sepsis, inflammatory bowel disease, systemic inflammatory response syndrome, inflammatory arthritis, or rheumatoid arthritis. .

[0032] In some embodiments where the disease or disorder can be a dermatological condition, said dermatological condition can be atopic dermatitis, psoriasis, or Netherton syndrome.

[0033] In some embodiments, the compound can act by inhibiting thrombin and / or kallikrein. In some embodiments, the compound can act by inhibiting tissue kallikrein and / or plasma kallikrein. In some embodiments, the compound can have inhibitory activity against thrombin and / or plasma kallikrein in the range of 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 1 0-100 μM, 100-200 μM, 200-500 μM, or 500-1000 μM, or more.

[0034] In some embodiments, the amount of the compound administered can be a therapeutically effective dose sufficient to achieve a plasma concentration of the compound or its active metabolite(s) in the range of 1-10 nM, 10-100 nM , 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-5 00 μM, or 500-1000 μM, or more.

[0035] Embodiments of the invention also relate to the compounds or pharmaceutical compositions described herein for use in a method for treating and / or preventing one or more diseases or disorders in a subject as described herein.

[0036] Brief description of the drawings is not applicable.

DETAILED DESCRIPTION OF THE INVENTION

[0037] I. Definitions ​​​​​​The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valency known in the art of chemistry.

[0038] When substituents are specified by their conventional chemical formulas written from left to right, they equally encompass chemically identical substituents obtained by writing the structure from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0039] As used herein, the term "bonded" means a stable covalent bond, and certain preferred points of attachment will be apparent to those skilled in the art.

[0040] The term "halogen" or "halo" includes fluorine, chlorine, bromine, and iodine. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0041] Unless otherwise specified, the term "alkyl" means straight-chain (i.e., unbranched), branched-chain, or a combination thereof, alone or as part of another substituent, and may be fully saturated, monounsaturated, or polyunsaturated, and may include divalent and polyvalent radicals having the specified number of carbon atoms (i.e., C1-C means 1 to 10 carbons). Examples of saturated hydrocarbon radicals include methyl, ethyl, n-propyl, iso- 10 ​Propyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl) Groups such as methyl, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Homologs and isomers are included, but not limited thereto. The unsaturated alkyl group is a group having one or more double bonds or triple bonds. Examples of the unsaturated alkyl group include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers, but not limited thereto. Therefore, the term "alkyl" refers to a C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group substituted with a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. Examples of the cyclic alkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, etc., but not limited thereto. Vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers, but not limited thereto. 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers, but not limited thereto. 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers, but not limited thereto. 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers, but not limited thereto. Therefore, the term "alkyl" refers to a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group substituted with a C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group substituted with a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. l C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group substituted with a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. 16 C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group substituted with a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. l C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group substituted with a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. 16 C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group substituted with a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. l C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group substituted with a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. 16 C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group substituted with a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. C1~C8 linear saturated, C3~C8 branched saturated, C3~C8 cyclic saturated, C3~C8 cyclic unsaturated, and C1~C8 linear or branched saturated or unsaturated aliphatic hydrocarbon group substituted with a C3~C8 cyclic saturated or unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms. Examples of the cyclic alkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, etc., but not limited thereto. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, etc., but not limited thereto.

[0042] The term "alkylene" means a divalent radical derived from saturated or unsaturated alkyl, which is defined and exemplified above as a single entity or as part of another substituent, but not limited to -CH2CH2CH2CH2-, etc. The term "alkylene" means a divalent radical derived from saturated or unsaturated alkyl, which is defined and exemplified above as a single entity or as part of another substituent, but not limited to -CH2CH2CH2CH2-, etc. The term "alkylene" means a divalent radical derived from saturated or unsaturated alkyl, which is defined and exemplified above as a single entity or as part of another substituent, but not limited to -CH2CH2CH2CH2-, etc. Typically, the alkyl (or alkylene) group has 1~24 carbon atoms and preferably has 10 or fewer carbon atoms. The base is preferred in the compounds disclosed in this specification. "Lower alkyl" or "lower alkylene" generally refers to a shorter-chain alkyl or alkylene group having 8 or fewer carbon atoms. "Heteroalkyl", unless otherwise specified, alone or in combination with another term, means a stable straight-chain or branched-chain consisting of at least 1 carbon atom and at least 1 heteroatom selected from the group consisting of O, N, P, Si, and S, or a combination thereof, and the nitrogen atom and sulfur atom can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heteroatom(s) O, N, P, S, and Si can be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. The heteroalkyl group can be fully saturated, monounsaturated, or polyunsaturated, and can include divalent and polyvalent radicals having the specified number of atoms. Thus, the term "heteroalkyl" can refer to a saturated or unsaturated straight-chain or branched-chain containing 2 to 16 atoms along the chain, a cyclic saturated or unsaturated group containing 3 to 8 atoms in the ring, etc. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH-2-CH3, -CN, etc. For example, up to 2 heteroatoms such as -CH2-NH-OCH3 are consecutive. is a group.

[0043] The term "heteroalkyl", unless otherwise specified, alone or in combination with another term, means a stable straight-chain or branched-chain consisting of at least 1 carbon atom and at least 1 heteroatom selected from the group consisting of O, N, P, Si, and S, or a combination thereof, and the nitrogen atom and sulfur atom can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heteroatom(s) O, N, P, S, and Si can be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. The heteroalkyl group can be fully saturated, monounsaturated, or polyunsaturated, and can include divalent and polyvalent radicals having the specified number of atoms. Thus, the term "heteroalkyl" can refer to a saturated or unsaturated straight-chain or branched-chain containing 2 to 16 atoms along the chain, a cyclic saturated or unsaturated group containing 3 to 8 atoms in the ring, etc. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2- CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, - S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3 CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)- CH3, -O-CH3, -O-CH-2-CH3, -CN, etc. For example, up to 2 heteroatoms such as -CH2-NH-OCH3 are consecutive. CH3, -O-CH3, -O-CH-2-CH3, -CN, etc., but are not limited thereto. For example, up to 2 heteroatoms such as -CH2-NH-OCH3 are consecutive. are consecutive.It may also be.

[0044] Similarly, the term "heteroalkylene", unless otherwise specified, alone or as part of another substituent, is defined and exemplified above, but is not limited to -CH2-CH2-S-CH2 -CH2- and -CH2-S-CH2-CH2-NH-CH2-, etc., and means a divalent radical derived from hetero alkyl. In the case of a heteroalkylene group, the heteroatom may occupy one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylene diamino, etc.). Furthermore, in the case of an alkylene and heteroalkylene linking group, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written . For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2- . As described above, a heteroalkyl group, when used herein, is -C(O )R', -C(O)NR', -NR'R'', -OR', -SR', and / or -SO 2R', etc., and includes a group bonded to the rest of the molecule via a heteroatom. When "heteroalkyl" is listed and then followed by a listing of specific heteroalkyl groups such as -NR'R'', it is understood that the terms heteroalkyl and -NR'R'' are neither redundant nor mutually exclusive . Rather, this specific heteroalkyl group is listed to supplement clarity. Therefore, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups such as -NR'R''.

[0045] The terms "cycloalkyl" and "heterocycloalkyl", unless otherwise specified, alone or in combination with other terms, each refer to "alkyl" and "heteroalkyl", respectively as defined above, and are exemplified by, but not limited to, cycloalkyl groups such as cyclopentyl, cyclohexyl, etc., and hetero means the cyclic version of "kill". "Cycloalkyl" and "heterocycloalkyl" groups include, for example, monocyclic rings having 3 to 8 ring members, as well as bicyclic rings having 4 to 16 ring members, tricyclic rings having 5 to 24 ring members, etc. In addition, in the case of heterocycloalkyl, the hetero atoms can occupy the positions where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohe xenyl, 3-cyclohexenyl, cycloheptyl, etc., but are not limited to these. Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridi l), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3 -morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tet rahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-pi perazinyl, etc., but are not limited to these. "Cycloalkylene" and "hetero cycloalkylene" each mean a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively, alone or as part of another substituent.

[0046] The term "alkenyl" refers to C2-C linear unsaturated, C2-C 16 branched unsaturated 11 substituted with a C3-C8 cyclic saturated and unsaturated aliphatic hydrocarbon group having a specific number of carbon atoms, C5-C8 unsaturated cyclic, and C2-C 16 including linear or branched unsaturated aliphatic hydrocarbon groups. The double bond can occur at any stable point along the chain, and the carbon-carbon double bond can have either a cis configuration or a trans configuration. For example, this definition includes ethenyl, propenyl ​​​ ryl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl , undecenyl, 1,5 - octadienyl, 1,4,7 - nonatrieneyl, cyclopenta nyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexen yl, butenylcyclopentyl, l - pentenyl - 3 - cyclohexenyl, etc., but not limited to these. Similarly, "heteroalkenyl" refers to a heteroalkyl having one or more double bonds, and the heteroalkyl is as defined above. The term "alkynyl" has its usual meaning as defined above, but in addition refers to an alkyl having one or more triple bonds. The term "cycloalkenyl" is as defined above, but in addition refers to a cycloalkyl having one or more double bonds. The term "heterocycloalkenyl" is as defined above, but in addition refers to a heterocycloalkyl having one or more double bonds. The term "acyl" means -C(O)R, where R is

[0047] substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, unless otherwise specified. The term "aryl" means a polyunsaturated, aromatic, hydrocarbon substituent, which may be fused together (i.e., fused - ring aryl) or a single ring or multiple rings (preferably 1 - 3 rings) covalently bonded to each other, and each ring has 4 - 20 carbon atoms, unless otherwise specified.

[0048] The term "acyl" means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, unless otherwise specified. The term "aryl" means a polyunsaturated, aromatic, hydrocarbon substituent, which may be fused together (i.e., fused - ring aryl) or a single ring or multiple rings (preferably 1 - 3 rings) covalently bonded

[0049] to each other, and each ring has 4 - 20 carbon atoms, unless otherwise specified. carbon atoms, unless otherwise specified. contains from 1 to 10 atoms, preferably from 5 to 10 atoms. The fused ring aryls are fused together refer to a plurality of rings, and at least one of the fused rings is an aryl ring. The term "heteroaryl" is defined as including 1 to 4 heteroatoms selected from N, O, and S, and the nitrogen atoms and sulfur atoms are optionally oxidized, and the nitrogen atom(s) is / are optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., includes a plurality of rings fused together, and at least one of the fused rings is a heteroaromatic ring). 5,6-fused ring heteroarylene refers to two rings fused together, where one ring has 5 members and the other ring has 6 members, and at least one ring is a heteroaryl ring. Similarly, 6,6-fused ring heteroarylene refers to two rings fused together, where one ring has 6 members and the other ring has 6 members, and at least one ring is a heteroaryl ring. 6,5-fused ring heteroarylene refers to two rings fused together, where one ring has 6 members and the other ring has 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group may be bonded to the rest of the molecule via a carbon atom or a heteroatom. Non-limiting examples of the aryl group and the heteroaryl group include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2 -imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl ​​​​​​​​​​Soxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thia ril, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyr idyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purini l, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl, etc. can be mentioned. Each substituent for the above aryl ring system and heteroaryl ring system is selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene" each mean a divalent radical derived from aryl and heteroaryl, either alone or as part of another substituent. Therefore, the term "aryl" can represent an unsubstituted, mono-substituted, di-substituted, or tri-substituted monocyclic, polycyclic, biaryl, and heterocyclic aromatic group that is covalently bonded at any ring position capable of forming a stable covalent bond, and certain preferred bonding points are obvious to those skilled in the art (for example, 3-indolyl, 4-imidazolyl ). Aryl substituents are independently halo, nitro, cyano, trihalomethyl, C alkyl, aryl C alkyl, C0~ alkyloxy C0~ 1~16 alkyl, aryl C0~ 1~16 alkyloxy C0~ 16 alkyl, 16 aryl C0~ alkyloxy C0~ 16 alkyl, C0~ 16 alkylthio C0~ 16 alkyl, 16 alkyl, aryl C0~ 16 alkylthio C0~ 16 alkyl, C0~ 16 alkyl amino C0~ 16 alkyl, aryl C0~16 Alkylamino C0~ 16 Alkyl, Di(arylC1~ 16 Alkyl)amino C0~ 16 Alkyl, C1~ 16 Alkylcar bonyl C0~ 16 Alkyl, arylC 1~16 Alkylcarbonyl C0~ 16 Alkyl , C1~ 16 Alkylcarboxy C0~ 16 Alkyl, arylC1~ 16 Alkylcar boxy C0~ 16 Alkyl, C 1~16 Alkylcarbonylamino C0~ 16 Alkyl, ArylC1~ 16 Alkylcarbonylamino C0~ 16 Alkyl, -C0~ 16 Alk ylCOOR4, -C0~ 16 Selected from the group consisting of alkylCONR5R6, wherein R 4, R5, and R6 are independently hydrogen, C1~C 11 Alkyl, arylC0~C 11 Al kyl selected, or R5 and R6 together with the nitrogen to which they are attached form a cyclic system containing 3 to 8 carbon atoms with or without a C 1~16 Alkyl, arylC0~C 16 Alkyl, or C0~Cl1 6 alkylaryl substituent. Examples of aryl include, but are not limited to, pyrazolyl and triazolyl. For the sake of brevity, the term "aryl", when used in combination with other terms (e.g., aryloxy, ar ylthioxy, arylalkyl), is defined as above.

[0050] For the sake of brevity, the term "aryl", when used in combination with other terms (e.g., aryloxy, ar ylthioxy, arylalkyl), is defined as above. It includes both a reel ring and a heteroaryl ring. Therefore, terms such as "arylalkyl", "a rylalkyl", etc. are intended to include radicals in which an aryl group is bonded to an alkyl group (e.g., benzyl, phenethyl, pyr idylmethyl, etc.), and as this aryl group, a carbon atom (e.g., a methylene group) is, for example, an oxygen atom (e.g., phenoxymeth yl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.), or an alkyl group replaced by a sulfur atom. Therefore, terms such as "arylalkyl" etc. (e.g., (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyr idylcyclopentyl) represent an aryl group defined as being bonded via an alkyl group having the indicated number of carbon atoms.

[0051] The above terms (e.g., "alkyl", "heteroalkyl", "aryl", and "hete roaryl") each include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided herein.

[0052] Substituents for alkyl radicals and heteroalkyl radicals (often including groups referred to as alkylene, alkenyl , heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl , cycloalkenyl, and heterocycloalkenyl) are numbers in the range of 0 to (2m'+1) (where m' is the total number of carbon atoms in such a radical ), and are -OR', =O, =NR', =N-OR', -NR'R'', -SR' ), -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO 2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', - NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R '')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN, and -NO2, among others, but not limited to these various groups, can be one or more. R', R'', and R''' are each preferably independent and are hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When the compounds disclosed herein contain more than one R group, for example, when more than one of these groups are present, each R group is independently selected as an R', R'', and R''' group. When R' and R'' are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the consideration of the above substituents, one of ordinary skill in the art would understand that the term "alkyl" is intended to include groups containing carbon atoms bonded to groups other than hydrogen, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0053] Similar to the substituents described for alkyl radicals, substituents for aryl and heteroaryl groups are diverse. For example, a number in the range of 0 to the total number of open valences on the aromatic ring system such that, -OR’, -NR’R’’, -SR’, -halogen, -SiR’R’’R’’’, - OC(O)R’, -C(O)R’, -CO2R’, -CONR’R’’, -OC(O)N R’R’’, -NR’’C(O)R’, -NR’-C(O)NR’’R’’’, -NR’ ’C(O)2R’, -NR-C(NR’R’’)=NR’’’, -S(O)R’, -S( O)2R’, -S(O)2NR’R’’, -NRSO2R’, -CN, -NO2, -R’ 、-N3、-CH(Ph)2、fluoro(C1-C4)alkoxy, and fluoro(C1 -C4)alkyl, where R’, R’’, and R’’’ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds disclosed herein contain more than one R group, for example, when more than one of those groups are present, each R group is independently selected as an R’, R’’, and R’’’ group, respectively.

[0054] Two or more substituents can optionally combine to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are, although not necessarily, typically found to be attached to the cyclic base structure. In one embodiment, the ring-forming substituent is attached to adjacent members of the base structure. For example,Two ring-forming substituents attached to adjacent members of the cyclic base structure create a fused ring structure In another embodiment, the ring-forming substituent is attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of the cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituent is attached to non-adjacent members of the base structure

[0055] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula -T -C(O)-(CRR’) q -U-, where T and U are independently -NR-, -O-, -CRR’-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be replaced by a substituent of the formula -A-(CH2) -B-, where A and B are independently r -CRR’-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S( O)2NR’-, or a single bond, and r is an integer from 1 to 4. One of the single bonds of the newly formed ring may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be replaced by a substituent of the formula -(C RR’) -X’-(C’’R’’’) s -, where s d and d are independently integers from 0 to 3, and X’ is -O-, -NR’-, -S-, -S( O)-, -S(O)2-, or -S(O)2NR’-. The substituents R, R’, R’’ and R’’’ are preferably independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted ​is selected from unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0056] As used herein, the terms "heteroatom" or "ring heteroatom" are intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0057] The term "alkyloxy" (e.g., methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms bonded through an oxygen bridge (-O-).

[0058] The term "alkylthio" (e.g., methylthio, ethylthio, propylthio, cyclohexylthio, etc.) represents an alkyl group as defined above having the indicated number of carbon atoms bonded through a sulfur bridge (-S-).

[0059] The term "alkylamino" represents one or two alkyl groups as defined above having the indicated number of carbon atoms bonded through an amine bridge. These two alkyl groups, together with the nitrogen to which they are attached, can form a cyclic system containing 3 to 8 carbon atoms with or without a C1-C alkyl, aryl C0-C alkyl, or C0-C alkylaryl substituent. alkyl, aryl C0-C 16 alkyl, or C0-C alkylaryl substituent having or having 16 no 3 to 8 carbon atoms which can form a cyclic system. 16

[0060] The term "alkylaminoalkyl" is defined as having the indicated number of carbon atoms. ​​​​​​​​​​Represents an alkylamino group bonded via a given alkyl group.

[0061] The term "alkyloxy(alkyl)amino" (e.g., methoxy(methyl)amine, ethoxy (propyl)amine) represents an alkyloxy group bonded via an amino group, and the amino group itself has an alkyl substituent.

[0062] The term "alkylcarbonyl" (e.g., cyclooctylcarbonyl, pentylcarbonyl, 3-hexylcarbonyl) represents an alkyl group having the indicated number of carbon atoms bonded via a carbonyl group.

[0063] The term "alkylcarboxy" (e.g., heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl group as defined above, and then this carbonyl is bonded via oxygen.

[0064] The term "alkylcarboxyalkyl" represents an alkylcarboxy group bonded via an alkyl group having the indicated number of carbon atoms as defined above.

[0065] The term "alkylcarbonylamino" (e.g., hexylcarbonylamino, cyclopentyl carbonylaminomethyl, methylcarbonylaminophenyl) represents an alkylcarbonyl group as defined above, and then this carbonyl is bonded via the nitrogen atom of an amino group.

[0066] The nitrogen group itself may be substituted with an alkyl group or an aryl group.

[0067] ​​​​​​The term "oxo", as used herein, refers to oxygen double-bonded to a carbon atom atom.

[0068] The term "alkylsulfonyl", as used herein, refers to a moiety having the formula -S(O2)- R', where R' is an alkyl group as defined above. R' may have a specific number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0069] The term "carbonyloxy" represents a carbonyl group bonded through an oxygen bridge .

[0070] In the above definitions, the terms "alkyl" and "alkenyl" may be used interchangeably, as is apparent to one of ordinary skill in the art , as long as stable chemical entities are formed

[0071] The term "linker" refers to a bonding group placed between substituents, e.g., as described herein, e.g., in formula (Ia), and generally denoted as R and the groups to be substituted, e.g., n referred to as R 1 , R 2 , R 3 , or R 4 and the group to be substituted, e.g., for example, the "ring A" group in formula (Ia). In some embodiments , the linker may be an amide (-CONH-R n or -NHCO-R n ), a thioamide (-CSNH-R n or -NHCS-R n ), a carboxyl (-CO2- R n or -OCOR n ), a carbonyl (-CO-R n ), a urea (-NHCONH-R n ), a thiourea (-NHCSNH-R n ​)、sulfonamide (-NHSO2-R n or -SO2NH-R n )、ether (-O-R n )、sulfonyl (-SO2-R n )、s ulfoxyl (-SO-R n )、carbamoyl (-NHCO2-R n 、or -OCON H-R n )、or amino (-NHR n ) and the linking moiety may be mentioned.

[0072] "Substituent", as used herein, means a group selected from the following moieties : (A) -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted he terocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl , and heteroaryl, which are substituted with at least one substituent selected from the following : (i) oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen , -COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, ari yl, and heteroaryl, which are substituted with at least one substituent selected from the following : (a) oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, haloge -COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsub stituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, which is substituted with at least one substituent selected from oxo, -OH, -NH2, -SH, -CN, - CF3, -NO2, halogen, -COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsub stituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted hetero aryl.

[0073] The "size-limited substituent" or "size-limited substituent group" means, when used herein, a group selected from all of the substituents described above for "substituent", and each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2-20 membered heteroalkyl, each substituted or unsubstituted cyclo 20 alkyl is substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 4-8 membered heterocycloalkyl. The "lower substituent" or "lower substituent group" means, when used herein, a group selected from all of the substituents described above for "substituent", and each substituted or unsubstituted alkyl is substituted or unsub stituted C1-C8 alkyl, and each substituted or unsubstituted heteroalkyl is substituted or

[0074] The "lower substituent" or "lower substituent group" means, when used herein, a group selected from all of the substituents described above for "substituent", and each substituted or unsubstituted alkyl is substituted or unsub stituted C1-C8 alkyl, and each substituted or unsubstituted heteroalkyl is substituted or unsubstituted C1-C8 alkyl, and each substituted or unsubstituted heteroalkyl is substituted or unsubstituted C1-C8 alkyl, and each substituted or unsubstituted heteroalkyl is substituted or or unsubstituted 2- to 8-membered heteroalkyl, and each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C5-C7 cycloalkyl, and each substituted or unsubstituted heterocyclo alkyl is substituted or unsubstituted 5- to 7-membered heterocycloalkyl.

[0075] The term "about" when used in the context of a numerical value refers to a range of ±10% of that numerical value, unless otherwise explicitly indicated.

[0076] II. Compounds In one aspect, a compound having the structure of formula (Ia),

Chemical formula

[0077] In some embodiments, the compound is a pharmaceutically acceptable salt, ester, solvate, or prodrug of the compound of formula (Ia). In some embodiments, the compound is neither an ester, nor a solvate, nor a prodrug.

[0078] In some embodiments, when it is a compound having the structure of formula (Ib) below, L 4 and R 4 are absent.

Chemical formula

[0079] In some embodiments, a compound according to formula (Ib) having the structure of formula (II) below is provided.

Chemical formula

[0080] In some embodiments, the compound has the structure of formula (II), and L 3 is a bond or substituted or unsubstituted alkylene, and R 3 is substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkyl. In some embodiments, R 3 is substituted or unsubstituted heteroalkyl. In some embodiments, R 3 is substituted or unsubstituted cycloalkyl. In some embodiments, R 3 is substituted or unsubstituted cyclo hexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cycloheptyl, In some embodiments, R 3 is substituted or unsubstituted cycloalkenyl. In some embodiments, R 3 is substituted or unsubstituted cyclohexenyl. In some embodiments, R 3 is substituted or unsubstituted heterocycloalkyl. In some embodiments, R 3 is substituted or unsubstituted piperidinyl. In some embodiments R 3 is substituted or unsubstituted pyrrolidinyl. In some embodiments, R 3 is substituted or unsubstituted pyrrolidinyl. In some embodiments, R 3 is substituted or unsubstituted azetidinyl. In some embodiments, R 3 is substituted or unsubstituted oxetanyl. In some embodiments, R 3 is substituted or unsubstituted oxolanyl is. In some embodiments, R 3 is a substituted or unsubstituted oxanyl.

[0081] In addition to any of the above embodiments in which the present compound has the structure of formula (II), in some embodiments L 1 is -S-, -O-, -NR 5 -, a substituted or unsubstituted alkylene, or a substituted or unsubstituted heteroalkylene, wherein R 5 is as described in formula Ia, R 1 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted condensed ring aryl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 1 is a substituted or unsubstituted phenyl. In some embodiments, R 1 is an unsubstituted phenyl. In some embodiments, R 1 is a substituted or unsubstituted pyridyl. In some embodiments R 1 is a substituted or unsubstituted pyridazinyl. In some embodiments, R 1 is a substituted or unsubstituted pyrimidinyl. In some embodiments, R 1 is a substituted or unsubstituted thienyl. In some embodiments, R 1 is a substituted or unsub stituted furyl. In some embodiments, R 1 is an unsubstituted pyridyl. In some embodiments, R 1 is an unsubstituted pyridazinyl. In some embodiments, R 1 is an unsubstituted pyrimidinyl. In some embodiments, R 1 is an unsubstituted thienyl. In some embodiments, R 1 is chlorosubstituted thienyl. In some embodiments , R 1 is unsubstituted furyl. In some embodiments, R 1 is substituted or unsubstituted morpholinyl. In some embodiments, R 1 is substituted or unsubstituted oxanyl . In some embodiments, R 1 is substituted or unsubstituted oxetanyl. I n some embodiments, R 1 is unsubstituted morpholinyl. In some embodiments, R 1 is unsubstituted oxanyl. In some embodiments, R 1 is unsubstituted oxetan yl. In some embodiments, R 1 is substituted or unsubstituted benzodioxinyl . In some embodiments, R 1 is substituted or unsubstituted naphthyl. In some embodiments, R 1 is unsubstituted benzodioxinyl. In some embodiments, R 1 is unsubstituted naphthyl. In some embodiments, L 2 and R 2 are absent . In some embodiments, L 2 is a bond. In some embodiments, L 2 is a bon d and R 2 is hydrogen.

[0082] In addition to any of the above embodiments in which the compound has the structure of formula (II), R 2 is hydrogen , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsub a substituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, or a substituted or unsubstituted hetero cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted fused-ring aryl , or a substituted or unsubstituted heteroaryl. In some embodiments, R 2 is a substituted or unsubstituted phenyl. In some embodiments, R 2 is an unsubstituted phenyl . In some embodiments, R 2 is a substituted or unsubstituted pyridyl. In some embodiments, R 2 is a substituted or unsubstituted pyridazinyl. In some embodiments , R 2 is a substituted or unsubstituted pyrimidinyl. In some embodiments, R 2 is a substituted or unsubstituted thienyl. In some embodiments, R 2 is a substituted or unsubstituted furyl. In some embodiments, R 2 is an unsubstituted pyridyl. In some embodiments, R 2 is an unsubstituted pyridazinyl. In some embodiments, R 2 is an unsubstituted pyrimidinyl. In some embodiments, R 2 is an unsubstituted thienyl . In some embodiments, R 2 is a chloro-substituted thienyl. In some embodiments, R 2 is an unsubstituted furyl. In some embodiments, R 2 is a substituted or unsubstituted morpholinyl. In some embodiments, R 2 is a substituted or unsubstituted o xanyl. In some embodiments, R 2 is a substituted or unsubstituted oxetanyl There is. In some embodiments, R 2 is unsubstituted morpholinyl. In some embodiments R 2 is unsubstituted oxanyl. In some embodiments, R 2 is unsubstituted oxetanyl. In some embodiments, R 2 is substituted or unsubstituted benzodiox inyl. In some embodiments, R 2 is substituted or unsubstituted naphthyl. In some embodiments, R 2 is unsubstituted benzodioxinyl. In some embodiments R 2 is unsubstituted naphthyl.

[0083] In some embodiments, compounds according to formula (Ia) having the structure of the following formula (III) are provided.

Chemical formula

[0084] In some embodiments, L 4 is a bond, and R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and compounds according to formula (III) are provided In some embodiments, R 4 is halogen. In some embodiments, R 4 is unsubstituted alkyl. In addition to any embodiment in which the compound has the structure of formula (III), in some embodiments, L is a bond or substituted or unsubstituted alkylene 3 and R and R 3is a substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocycloalkyl. In some embodiments, R is a substituted or unsubstituted heteroalkyl. In some embodiments, R 3 is a substituted or unsubstituted cycloalkyl. In some embodiments, R is a substituted or unsubstituted cycloalkyl. In some embodiments, R 3 is a substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cycloheptyl. In some embodiments, R 3 is a substituted or unsubstituted cycloalkenyl. In some embodiments, R is a substituted or unsubstituted cyclohexenyl. In some embodiments, R is a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 3 is a substituted or unsubstituted piperidinyl. In some embodiments, R 3 is a substituted or unsubstituted pyrrolidinyl. In some embodiments, R 3 is a substituted or unsubstituted pyrrolidinyl. In some embodiments, R is a substituted or unsubstituted azetidinyl. In some embodiments, R 3 is a substituted or unsubstituted oxetanyl. In some embodiments, R is a substituted or unsubstituted oxolanyl. In some embodiments, R 3 is a substituted or unsubstituted oxanyl. In addition to any of the above embodiments where the compound has the structure of formula (III), some embodiments, R 3 is a substituted or unsubstituted pyrrolyl. In some embodiments, R is a substituted or unsubstituted pyrrolyl. In some embodiments, R 3 is a substituted or unsubstituted azetidinyl. In some embodiments, R is a substituted or unsubstituted oxetanyl. In some embodiments, R 3 is a substituted or unsubstituted oxolanyl. In some embodiments, R is a substituted or unsubstituted oxanyl. In some embodiments, R 3 is a substituted or unsubstituted oxolanyl. In some embodiments, R is a substituted or unsubstituted oxanyl. In some embodiments, R 3 is a substituted or unsubstituted oxanyl.

[0085] embodiments, some In an embodiment, L 1 is -S-, -O-, -NR 5 -, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene, wherein R 5 is as described in Formula Ia, and R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted condensed ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. In some embodiments, R 1 is substituted or unsubstituted phenyl. In some embodiments, R 1 is unsubstituted phenyl . In some embodiments, R 1 is substituted or unsubstituted pyridyl. In some embodiments R 1 is substituted or unsubstituted pyridazinyl. In some embodiments R 1 is substituted or unsubstituted pyrimidinyl. In some embodiments, R 1 is substituted or unsubstituted thienyl. In some embodiments, R 1 is substituted or un substituted furyl. In some embodiments, R 1 is unsubstituted pyridyl. In some embodiments, R 1 is unsubstituted pyridazinyl. In some embodiments, R 1 is unsubstituted pyrimidinyl. In some embodiments, R 1 is unsubstituted thienyl . In some embodiments, R 1 is chloro-substituted thienyl. In some embodiments R 1 is unsubstituted furyl. In some embodiments, R 1is a substituted or unsubstituted morpholinyl. In some embodiments, R is a substituted or unsubstituted oxanyl 1 . In some embodiments, R is a substituted or unsubstituted oxetanyl. 1 In some embodiments, R is an unsubstituted morpholinyl. In some embodiments 1 , R is an unsubstituted oxanyl. In some embodiments, R 1 is an unsubstituted oxetanyl. In some embodiments, R 1 is a substituted or unsubstituted benzodioxinyl . In some embodiments, R 1 is a substituted or unsubstituted naphthyl. In some embodiments, R 1 is an unsubstituted benzodioxinyl. In some embodiments , R 1 is an unsubstituted naphthyl. In some embodiments , R 1 is absent. In some embodiments, L 2 and R 2 are absent . In some embodiments, L 2 is a bond. In some embodiments, L 2 is a bond and R 2 is hydrogen.

[0086] In addition to any of the above embodiments in which the compound has the structure of formula (III), R 2 is hydrogen , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted hetero cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused-ring aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R 2 is substituted or unsubstituted phenyl. In some embodiments, R 2 is unsubstituted phenyl In some embodiments, R 2 is substituted or unsubstituted pyridyl. In some embodiments, R 2 is substituted or unsubstituted pyridazinyl. In some embodiments R 2 is substituted or unsubstituted pyrimidinyl. In some embodiments, R 2 is substituted or unsubstituted thienyl. In some embodiments, R 2 is substituted or unsubstituted furyl. In some embodiments, R 2 is unsubstituted pyridyl. In some embodiments, R 2 is unsubstituted pyridazinyl. In some embodiments, R 2 is unsubstituted pyrimidinyl. In some embodiments, R 2 is unsubstituted thienyl In some embodiments, R 2 is chloro-substituted thienyl. In some embodiments R 2 is unsubstituted furyl. In some embodiments, R 2 is substituted or un substituted morpholinyl. In some embodiments, R 2 is substituted or unsubstituted oxa nyl. In some embodiments, R 2 is substituted or unsubstituted oxetanyl In some embodiments, R 2 is unsubstituted morpholinyl. In some embodiments R 2 is unsubstituted oxanyl. In some embodiments, R 2 is unsubstituted oxa tetanyl. In some embodiments, R 2is a substituted or unsubstituted benzodioxini le. In some embodiments, R 2 is a substituted or unsubstituted naphthyl. In some embodiments, R 2 is an unsubstituted benzodioxinyl. In some embodiments is, R 2 is an unsubstituted naphthyl.

[0087] In some embodiments, L 3 is a bond, and R 3 is a substituted or unsubstituted heterocyclic alkyl, or a substituted or unsubstituted heterocycloalkenyl, and a compound having the following structure of formula (IV) according to formula (III) is provided, wherein,

Chemical formula

[0088] or substituted or unsubstituted alkylene. In some embodiments, Z is a bond or substituted or unsubstituted alkylene. In some embodiments, X is a bond or substituted or unsubstituted alkylene and Z is a bond or substituted or unsubstituted alkylene. In some embodiments where X is a bond or substituted or unsubstituted alkylene and Z is a bond or substituted or unsubstituted alkylene, Y is -N- and W is hydrogen, substituted

[0089] or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, -C(O)R or unsubstituted alkylene, Y is -N-, and W is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, -C(O)R or non-substituted alkyl, substituted or non-substituted heteroalkyl, substituted or non-substituted aryl, -C(O)R -C(O)R 6 -C(O)OR 6 -C(O)NR 6 R 7 -SO2R 6 or is SO2NR 6 R 7 and in the formula, R 6 and R 7 are independently substituted or unsubstituted alkyl a cycloalkyl, substituted or unsubstituted, or a heterocycloalkyl, substituted or unsubstituted, or when both R and R 6 are present, they may combine to form a substituted or unsubstituted alkylene, or a substituted or unsubstituted heteroalkylene. 7 In some embodiments, X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is a bond. In some embodiments, X is a bond and Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. In some embodiments, X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. In some embodiments, both X and Z are branched alkylene and X and Z are covalently bonded. In some embodiments, Z is -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, substituted or unsubstituted

[0090] alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is a bond. In some embodiments, X is a bond and Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. In some embodiments, X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. In some embodiments, both X and Z are branched alkylene and X and Z are covalently bonded. In some embodiments, Z is -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is a bond. In some embodiments, X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. In some embodiments, both X and Z are branched alkylene and X and Z are covalently bonded. In some embodiments, Z is -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. In some embodiments, both X and Z are branched alkylene and X and Z are covalently bonded. In some embodiments, Z is -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. In some embodiments, both X and Z are branched alkylene and X and Z are covalently bonded. In some embodiments, Z is -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. In some embodiments, both X and Z are branched alkylene and X and Z are covalently bonded. In some embodiments, Z is -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, substituted or unsubstituted A substituted methylene, substituted ethylene, substituted propylene, substituted butylene, or substituted pentylene having one or more substituents selected from the group consisting of substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is -C(O)-. In some embodiments, W is hydrogen. In some embodiments, W is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, -C(O)R , -C(O)OR

[0091] , -C(O)NR 6 6 6 7 6 6 6 6 6 6 6 6 substituted alkenyl, substituted heteroalkenyl, substituted cycloalkyl, or substituted heterocycloalkyl; In some embodiments, W is -COR. 6 , -C(O)OR 6 , -C( O)NR 6 R 7 , -SO2R 6 , or -SO2NR 6 R 7 where R 6 and R 7 is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted substituted aryl, and substituted or unsubstituted heteroaryl; or Or R 6 and R 7 combine to form a substituted or unsubstituted alkylene.

[0092] In some embodiments, W is absent and X is -NR 8 - and Y is a bond or or substituted or unsubstituted alkylene; Z is -NR 9 - W is absent, X is -NR 8 -, Y is a bond or a substituted or unsubstituted alkylene, and Z is -N R 9 In some embodiments where -, Y is substituted or unsubstituted methylene, substituted or is unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and In some embodiments, R is selected from the group consisting of substituted or unsubstituted pentylene. 8 is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted Unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, -COR 6 , -C(O)OR 6 , -C(O)NR 6R 7 , -SR 6 , -SOR 6 , -SO2R 6 , and -SO2NR 6 R 7 R 9 is a substituted or unsubstituted alkyl, substituted or unsubstituted substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl LE, -COR 6 , -C(O)OR 6 , -C(O)NR 6 R 7 , -SR 6 , -SOR 6 , - SO2R 6 , and -SO2NR 6 R 7 is selected from the group consisting of:

[0093] In some embodiments, Y is -O- and W is absent. In some embodiments where W is absent, X is a substituted or unsubstituted methylene, substituted or unsubstituted aryl, or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is a bond. In some embodiments, X is a bond and Z is a substituted or unsubstituted methylene, substituted or is unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and In some embodiments, X is selected from the group consisting of substituted or unsubstituted pentylene. is a substituted or unsubstituted methylene, a substituted or unsubstituted ethylene, a substituted or unsubstituted propene, The group consisting of propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene. Z is selected from substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pen selected from the group consisting of tylenes.

[0094] In some embodiments, V is hydrogen or substituted or unsubstituted methyl.

[0095] In addition to any of the above embodiments in which the compound has the structure of formula (IV), in some embodiments, L embodiments, L 1 is -S-, -O-, -NR 5 -, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene, and R 1 is substituted or unsubstituted alkyl substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl, and R is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heterocycloalkyl. In some embodiments, L 5 is hydrogen substituted or unsubstituted alkyl, or substituted or unsubstituted heterocycloalkyl. In some embodiments, L is -NR 1 - or substituted or unsubstituted heteroalkyl, and R 5 is substituted or unsubstituted alkyl or substituted or unsubstituted heteroaryl. In some embodiments, L is -NR 1 - and R is substituted alkyl having one or more substituents selected from the group consisting of substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. In some embodiments, R 1 is -NR 5 - and R 1 is substituted alkyl having one or more substituents selected from the group consisting of substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. In some embodiments, R is substituted alkyl having one or more substituents selected from the group consisting of substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. In some embodiments, R is substituted alkyl having one or more substituents selected from the group consisting of substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. In some embodiments, R 1 is substituted alkyl substituted by chlorosubstituted thiophenyl. In some embodiments, L is substituted or unsubstituted heteroalkyl, and R 1 is substituted or unsubstituted heteroalkyl, and R1 is a substituted or unsubstituted heteroaryl. In some embodiments, L 1 and R 1 are any of the specific groups described above for any of formulae (Ia), (I b), (II), or (III). can be.

[0096] In addition to any of the above embodiments in which the compound has the structure of formula (IV), in some embodiments, L is a bond, substituted or unsubstituted alkylene, -C(O)-, or -S 2 O2-, and R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted hetero 2 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. In some embodiments, L is a bond and R 2 is hydrogen. In some embodiments, L 2 is -C(O)- and R 2 is substituted 2 or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cyclo alkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. In some embodiments, L and R 2 and R 2 are any of the specific groups described above for any of formulae (Ia), (Ib), (II), or ( III).

[0097] In addition to any of the above embodiments in which the compound has the structure of formula (IV), in some embodiments, In this embodiment, L 4 is a bond, and R 4 is hydrogen, halogen, substituted or unsubstituted alkyl aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted In some embodiments, L is unsubstituted heteroaryl. 4 and R 4 is represented by the formula (Ia Any of the above described for any of (Ib), (II), or (III). It may be a specific group.

[0098] In some embodiments, when L is a compound having a structure of formula (V): 2 Conclusion R 2 Compounds according to formula (IV) and enumerated embodiments thereof are provided, wherein will be done. [ka] In some embodiments, the compound is a pharma- ceutically acceptable salt, ester, or both of the compounds of formula (V). In some embodiments, the compound is an ester, solvate, or prodrug. It is not a ester, solvate or prodrug.

[0099] Exemplary compounds according to the present disclosure, such as polysubstituted aromatic compounds, are provided herein. In Tables A and B below, the registration number, chemical name (i.e., International Union of Pure and Applied Chemistry [IUPAC [name], calculated molecular weight (MW), and biological activity (i.e., thrombin and KL In Table C below, chemical names are disclosed. .

[0100] With reference to Table A below, the disclosed compounds are classified as thrombin proteases as described herein. The inhibition of ゼ activity was assayed. In Table A, the inhibition levels in the thrombin assay are shown as follows. a: IC 50 ≦0.1 μM, b: 0.1 μM < IC 50 < 1 μM, c: 1 μM < IC 50 < 10 μM, d: 10 μM < IC 50 < 100 μM, e: IC 50 ≧100 μM. Thus, in some embodiments, the compounds specifically described in Table A below are provided.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

[0101] With reference to Table B below, the disclosed compounds are selected from the group consisting of the KLKB1 proteases described herein. The inhibitors of KLKB1 enzyme activity were assayed for inhibition of KLKB1 enzyme activity. The levels are as follows: a: IC 50 ≦1μM, b:1μM <IC 50 <10 μM, c:IC 50 ≧10 μM. Thus, in some embodiments, The compounds described herein are provided. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

Table 2-6

Table 2-7

Table 2-8

[0102] In some embodiments, compounds are provided as specifically set forth in Table C below.

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

Table 3-47

[0103] For the following Table D, the disclosed compounds are compared with chymotrypsin and X as described herein. The inhibitors of Factor Ia protease activity were assayed. Table D shows the inhibitors of Factor Ia protease activity in the assay. The inhibition levels are shown as follows: a: IC 50 ≦0.1μM, b:0.1μM <IC 50 <1μM, c:1μM <IC 50 <10μM, d:10μM <IC 50 <100 μM, e :I C 50 ≧100 μM. Thus, in some embodiments, The compounds described herein are provided. [Table 4] The compounds disclosed herein include racemic mixtures, stereoisomers, and mixtures of the compounds, For example, isotopically and radiolabeled compounds are also included. See, e.g., Goding, 1986, MO NOCLONAL ANTIBODIES PRINCIPLES AND PRACT See ICE; Academic Press, p. 104. Such isomers include For example, the compounds may be isolated by standard resolution techniques, including fractional crystallization, chiral chromatography, etc. For example, Eliel, EL & Wilen SH, 1993, STERE ORGANIC CHEMISTRY IN ORGANIC COMPOUNDS; John Wil See Wiley & Sons, New York.

[0104] In some embodiments, the compounds disclosed herein have chiral centers and can occur as racemates, racemic mixtures, and individual enantiomers or diastereoisomers, and all such isomeric forms, as well as mixtures thereof, are contemplated for use in the compounds and methods described herein. The compounds contemplated for use in the compounds and methods described herein do not include compounds known in the art that are too unstable to synthesize and / or isolate.

[0105] The compounds disclosed herein may also contain atoms in one or more of the atoms that make up such compounds in proportions that are not naturally present. For example, the compounds may be radiolabeled with radioactive isotopes such as, for example, tritium ( 3H), iodine-125 ( 3 125I), or carbon-14 ( 125 14C). 14 All isotopic variations of the compounds disclosed herein are included within the scope contemplated, whether or not radioactive. In some embodiments, metabolites of the compounds disclosed herein are useful in the methods disclosed herein. In some embodiments, the compounds contemplated herein are provided in the form of prodrugs. The term "prodrug" refers to a compound that can be converted in vivo to a compound described herein (e.g.,

[0106] a biologically active compound). Prodrugs are, for example, administered in a form that can be converted in vivo to a compound described herein.

[0107] In some embodiments, the compounds contemplated herein are provided in the form of prodrugs. The term "prodrug" refers to a compound that can be converted in vivo to a compound described herein (e.g., a biologically active compound). Prodrugs are, for example, administered including ease (e.g., due to improved bioavailability in oral administration), etc., of the which may be useful for various reasons known in the art. A prodrug may also have improved solubility in a pharmaceutical composition compared to the biologically active compound. An example of a prodrug is a compound that, when administered as an ester (i.e., a "prodrug"), facilitates transmembrane transport to a cell where water solubility is harmful to mobility but beneficial, and is metabolically hydrolyzed to the active entity, boric acid, inside the cell. Conventional techniques for the selection and preparation of suitable prodrug derivatives are described, for example, in DESIGN OF PRODRUGS, (ed. H. Bundgaard, Elsevier, 1985) which is hereby incorporated by reference herein for limited purposes of describing the techniques and preparation of suitable prodrug derivatives.

[0108] Accordingly, in some embodiments, the compounds contemplated herein are provided in the form of prodrug esters. The term "prodrug ester" refers to derivatives of the compounds disclosed herein formed by the addition of various ester-forming groups that are hydrolyzed under physiological conditions, for example, any of the groups known in the art. Examples of prodrug ester groups include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, and methoxymethyl, as well as other groups known in the art including (5-R-2-oxo-1,3-dioxolen-4-yl)methyl groups. Other examples of prodrug ester groups are described, for example, in T. Higuchi and V. Stella, in ​​​​​​“Pro-drugs as Novel Delivery Systems”,V ol.14,ACSSymposium Series,American Ch emical Society (1975), and BIOREVERSIBLE CAR RIERS IN DRUG DESIGN:THEORY AND APPLICATION ION,edited by EBRoche,Pergamon Press:N ew York, 14-21 (1987) (Prodrugs for compounds containing carboxyl groups) (which provides examples of esters useful as esters). Each discloses a limited number of ester-forming groups capable of forming a prodrug ester. No. 6,399,413, filed on Oct. 23, 2003, and is incorporated herein by reference for such purposes.

[0109] In some embodiments, the prodrug is delivered via a transdermal route with a suitable enzyme or chemical reagent. When placed in the reservoir, the compound described herein useful for the methods described herein is can be slowly converted to

[0110] Certain compounds disclosed herein are available in solvated forms, including unsolvated forms, as well as hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are contemplated. Certain compounds of the invention exist in multiple crystalline or amorphous forms. Generally, all physical forms may be present in the compounds and methods contemplated herein. and are intended to be within the scope disclosed herein.

[0111] III. Biological activity In some embodiments, the compounds described herein are administered at a concentration of 1 μM or more, for example, at a concentration of about 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 2 2, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60 , 65, 70, 75, 80, 85, 90, 95, 100 μM, or even higher activity and exhibits inhibitory activity against thrombin. In some embodiments, the compound is 0 .1 μM to 1 μM, for example, about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0. 7, 0.8, 0.9, or 1.0 μM in activity and exhibits inhibitory activity against thrombin . In some embodiments, the compounds described herein are less than 0.1 μM, for example, about 1 , 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 10 0 nM in activity and exhibits inhibitory activity against thrombin. Ranges of values using any combination of the values listed herein as upper and / or lower limits are also contemplated, e.g ., 1 - 10 nM, 10 - 100 nM, 0.1 - 1 μM, 1 - 10 μM, 10 - 100 μM, 100 - 200 μM, 200 - 500 μM, or even 500 - 1000 μM but are not limited thereto. In some embodiments, the inhibitory activity is about 1 - 10 n M, 10 - 100 nM, 0.1 - 1 μM, 1 - 10 μM, 10 - 100 μM, 100 - 2 00 μM, 200 - 500 μM, or even 500 - 1000 μM. For quantitative purposes, it is understood that terms such as "activity", "inhibitory activity", "biological activity", "thrombin activity, etc." can be quantified in various ways known in the art in the context of the inhibitory compounds disclosed herein. Unless otherwise indicated, when used herein, such terms are in their ordinary sense and the IC 501 is used. 50(i.e., the concentration to achieve half-maximal inhibition) is referred to as.

[0112] Next, the inhibitory activity against thrombin inhibits the blood coagulation process. Thus, the compounds disclosed in the present specification are indicated for the treatment or management of thrombotic disorders. In some embodiments, the dosage or therapeutically effective dosage of the compounds disclosed herein is within the ranges described herein, for example, about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM , 10-100 μM, 100-200 μM, 200-500 μM, or even 500 -1000 μM, preferably within the range of about 1-10 nM, 10-100 nM, or 0.1-1 μM to achieve a plasma concentration of the compound or its active metabolite(s) sufficient to achieve a plasma concentration within the ranges described herein. Without wishing to be bound by any theory, such compounds are believed to be indicated for the treatment or management of thrombotic disorders. In some embodiments, the compounds described herein are active at 1 μM-10 μM, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 μM and exhibit inhibitory activity against KLKB1. In some embodiments, the compounds described herein are active at 10 μM or greater, for example, about 10, 20, 50, 100, 150, 200, 300, 400, 500, 60

[0113] 0, 700, 800, 900, 1000 μM, or even greater, and exhibit inhibitory activity against KLKB 1. In some embodiments, the compounds described herein are active at 1 μM or less, for example, about 900, 800, 700, 600, 500, 400, 300, 20 0, 100, 50 nM, or even less, and exhibit inhibitory activity against KLKB1. presented. Combinations of any of the values listed herein as upper and / or lower limits are also contemplated, e.g., 1 - 10 nM, 10 - 100 nM, 0.1 - 1 μM, 1 - 10 μM, 10 - 100 μM, 100 - 200 μM, 200 - 500 μM or even 500 - 1000 μM, but are not limited thereto. In some embodiments, the inhibitory activity is about 1 - 10 nM, 10 - 100 nM, 0.1 - 1 μM, 1 - 1 0 μM, 10 - 100 μM, 100 - 200 μM, 200 - 500 μM, or even 500 - 1000 μM. For quantitative purposes, terms such as "activity", "inhibitory activity", " biological activity", "KLKB1 activity", etc. are understood to be quantifiable in the context of the inhibitory compounds disclosed herein by various methods known in the art. Unless otherwise indicated when used herein, such terms refer, in their ordinary sense, to IC (i.e., the concentration to achieve half - maximal inhibition). The inhibitory activity against KLKB1 affects the coagulation cascade and the inflammatory response. Thus, it has been proposed that KLKB1 inhibitors can be useful for the treatment of thrombotic and fibrinolytic diseases and disease states . 50 (That is the concentration to achieve half - maximal inhibition).

[0114] Therefore, the compounds disclosed herein are adapted for the treatment or management of various diseases or disorders. In some embodiments, the dosage or therapeutically effective dosage of the compounds disclosed herein is within the ranges described herein, e.g., about 1 - 10 nM, 10 - 100 nM, 0.1 - 1 μM, 1 - 10 μM, 10 - 100 μM, 100 - 200 μM, 200 - 50 0 μM, 100 - 200 μM, 200 - 500 μM, or even

[0115] 500 - 1000 μM. In some embodiments, the dosage or therapeutically effective dosage of the compounds disclosed herein is within the ranges described herein, e.g., about 1 - 10 nM, 10 - 100 nM, 0.1 - 1 μM, 1 - 10 μM, 10 - 100 μM, 100 - 200 μM, 200 - 50 0 μM, 100 - 200 μM, 200 - 500 μM, or even 0 μM, or even 500 - 1000 μM, preferably about 1 - 10 nM, 10 - 10 0 nM, or a dose sufficient to achieve a plasma concentration of the compound or its active metabolite(s) within the range of 0.1 - 1 μM. Without wishing to be bound by any theory, such a compound is considered to be applicable to the treatment or management of diseases related to thrombin or kallikrein. In some embodiments, the present compound selectively inhibits thrombin and / or plasma kallikrein over related serine proteases such as trypsin, chymotrypsin, factor XIIa, factor XIa, factor Xa, and factor VIIa. In some embodiments,

[0116] the present compound inhibits chymotrypsin with an IC greater than 1 μM. In some embodiments, the present compound inhibits chymotrypsin with an IC greater than 10 μM. In some embodiments, 50 the present compound inhibits chymotrypsin with an IC greater than 100 μM. In some embodiments, 50 the present compound inhibits chymotrypsin with an IC greater than 1 μM. In some embodiments, 50 the present compound inhibits factor XIa with an IC greater than 1 μM. In some embodiments, 50 the present compound inhibits factor XIa with an IC greater than 10 μM. In some embodiments, 50 the present compound inhibits factor XIa with an IC greater than 100 μM. In some embodiments, 50 the present compound inhibits factor XIa with an IC greater than 100 μM.

[0117] In some embodiments, the present compound persists in plasma after intravenous injection. In some embodiments, more than 50% of the initial compound concentration remains in the plasma of mice 1 hour after intravenous injection. Continuing. In some embodiments, more than 50% of the initial compound concentration persists in the plasma of mice for 3 hours or more after intravenous injection.

[0118] IV. Methods of Treating and Preventing Diseases Thrombin-related diseases and conditions (e.g., thrombosis). Thrombotic diseases are the primary indications for thrombin inhibition due to the position of thrombin within the coagulation cascade and then the importance of the coagulation cascade in the progression of the blood coagulation process. However, without wishing to be bound by any theory, it is generally believed that the coagulation cascade, specifically thrombin, is important in various other disease states. Although not wishing to be bound by any theory, it is generally believed that the coagulation cascade, specifically thrombin, is important in various other disease states.

[0119] The compounds described herein, e.g., polysubstituted aromatic compounds, have been found to exhibit an inhibitory effect against thrombin (activated blood coagulation factor II, EC 3.4.21.5). This then inhibits the blood coagulation process.

[0120] This inhibitory effect is useful for the treatment of various thrombotic disorders such as acute vascular diseases such as acute coronary syndrome, venous, arterial, and cardiogenic thromboembolism, etc., but not limited thereto, and for the prevention of other conditions such as disseminated intravascular coagulation, etc., or other conditions associated with the presence or potential formation of blood clots. Other indications for the methods described herein include the following.

[0121] It is recognized that cancer progression is associated with venous thrombosis, but how each disease is related is not understood. A meta-analysis of several clinical trials studying the treatment of VTE has shown that low molecular weight heparin (LMWH) improves overall survival in a subgroup of cancer patients. ​For example, Zacharski, L.R. & Lee, A.Y., 2008, Expert Opin Investig Drugs, 17:1029 - 1037, Falang a, A. & Piccioli, A., 2005, Current Opinion i n Pulmonary Medicine, 11:403 - 407, Smorenbu rg, S.M., et al., 1999, Thromb Haemost, 82:16 00 - 1604, Hettiarachchi, R.J., et al., 1999, T hromb Haemost, 82:947 - 952. See also subsequent clinical trials measuring survival in cancer patients. For example, Lee, A.Y.e t al., 2005, J Clin Oncol, 23:2123 - 2129, Kle rk, C.P. et al., J Clin Oncol 2005, 23:2130 - 2135, Kakkar, A.K., et al., 2004, J Clin Onco l, 22:1944 - 1948, Altinbas, M., et al., 2004, J Thromb Haemost, 2:1266 - 1271.

[0122] More recently, researchers have focused on the specific anti - cancer effects of DTI. For example, it has been shown that heparin significantly prolonged the survival of patients with limited - stage small - cell lung cancer . See, for example, Akl, E.A., et al., 2008, J Exp Clin Can cer Res, 27:4. Other treating physicians have observed that systemic use of argatroban in a rat glioma model reduced tumor mass and prolonged survival The study found that argatroban has emerged as a novel treatment for glioma, a notoriously difficult type of cancer to treat. For example, Hua, Y., et al. l.,2005,Acta Neurochir,Suppl 2005,95:403 -406, Hua, Y., et al., 2005, J Thromb Haemost , 3:1917-1923. More recently, Dabigatran etexilate, an FDA-approved DTI (e.g., Hughes, See B., 2010, Nat Rev Drug Discov, 9:903-906. It has been demonstrated that IL-16 inhibits both the invasion and metastasis of malignant breast tumors. DeFeo, K. et al., 2010, Thrombosis Research, 125(Appendix 2):S188-S188,Defeo,K.,et al.,2010, See Cancer Biol Ther, 10:1001-1008. Therefore, dabigatran etexilate treatment reduced tumor size in treated mice at 4 weeks. Tumor volume was reduced by 50% without weight loss. Dabigatran etexilate increased blood and liver function. It also reduced tumor cells in micrometastases by 50 to 60 percent. Trametexilate has potential not only for preventing thrombotic events in cancer patients but also for treating malignant tumors. They concluded that this treatment may also be beneficial as an adjunct to treatment of bronchitis.

[0123] Furthermore, hirudin and the LMWH nadroparin were shown to reduce pulmonary metastases when administered prior to cancer cell inoculation. For example, Hu, L., et al., 2004, Blood , 104:2746-51.

[0124] A novel thrombin inhibitor, d-Arg-Oic-Pro-d-Ala-Phe(p-Me ) was found to inhibit thrombin-stimulated invasion of the prostate cancer cell line PC-3 in a concentration-dependent manner. For example, Nieman, MT, et al., 2008, J Thro See mb Haemost, 6:837-845. This was observed in mice administered the pentapeptide via water. They also showed a fold reduction in tumor size and a reduction in total tumor weight compared to untreated mice. Microscopic examination of treated tumors showed a reduction in the number of large blood vessels, therefore, They concluded that IL-15 inhibited tumor angiogenesis. romb Haemostasis, 104:1044-8.

[0125] In light of these and related studies, it has been found that anticoagulants inhibit tumor metastasis, i.e., angiogenesis, cancer cell proliferation, and cell death. It has been suggested that it may affect adhesion, migration, and invasion processes. den,CJ,et al.,2010,Thromb Res,125 Supp See l 2:S77-79.

[0126] Alzheimer's disease. Very recent experiments have shown that the brain endothelium of patients with Alzheimer's disease Higher thrombin levels were observed in the cells. "Normal" thrombin levels were regulated C While associated with NS function, thrombin accumulation in the brain is toxic. Despite the fact that the bell remains unchanged, the neurothrombin inhibitor proteasome inhibitor It was also found that PN-1 was significantly decreased in the brains of patients with Alzheimer's disease. has been. Based on these findings, some clinical trial physicians have suggested that a decrease in thrombin present in the CNS would serve as proof that it is useful for the treatment of Alzheimer's disease (AD). For example, see Vaughan, P.J., et al., 1994, Brain Res, 668:160 - 170, Yin, X., et al., 2010, Am J Path ol, 176:1600 - 1606, Akiyama, H., et al., 1992, Neurosci Lett, 146:152 - 154.

[0127] Multiple sclerosis. Clinical trial physicians have found that hirudin treatment in animal models of multiple sclerosis (MS) showed a dramatic improvement in disease severity. For example, see Han, M.H., e t al., 2008, Nature, 451:1076 - 1081. Similar results were obtained after treatment with heparin (DTI) and dermatan sulfate, another anticoagulant. For example, see Chelmicka - Szorc, E. & Arnason, B.G. , 1972, Arch Neurol, 27:153 - 158, Inaba, Y., et al., 1999, Cell Immunol, 198:96 - 102. Other evidence indicates that naturally occurring antithrombin III has anti - inflammatory effects in diseases such as endotoxemia and other sepsis - related conditions. For example, see Wiedermann, C. J. & Romisch, J., 2002, Acta Med Austriaca, 2 9:89 - 92. Naturally occurring thrombin inhibitors are probably synthesized intracellularly and play a protective role in CNS inflammation. Therefore, therapeutic thrombin ​Thrombin inhibition has been proposed as a potential treatment for MS. For example, Luo, W., et al. , 2009, Thrombin, Maragoudakis, M. E.; Tsopano glou, N. E., Eds. Springer New York: 2009; pp1 See pages 133 - 159.

[0128] Pain. In a rat pain model with a partial lesion of the sciatic nerve, intrathecal hirudin prevented the development of neuropathic pain and suppressed the pain response for 7 days. The principal investigator found that neuropathic pain was mediated by thrombin generation, which then activated the PAR - 1 receptor in the spinal cord. Hirudin inhibited thrombin generation and ultimately produced analgesia. For example, see Garcia, P. S., et al., 2010, Thromb Haemost, 103: 1145 - 1151, Narita, M., et al., 2005, J Neurosci, 25: 10000 - 10009. Researchers hypothesize that thrombin and PAR are involved not only as part of the coagulation cascade but also in inflammation, nociception, and neurodevelopment. The development of DTI by cross - breeding unexploited pharmacologies will produce a pain therapeutic agent different from opioids and NSAIDs, for which the drawbacks have been well - documented. For example, see Garcia 2010 (ibid). Known thrombin inhibitors have been reported to be useful for the prevention of stroke in individuals with atrial fibrillation. The selective thrombin inhibitor ximelagatran was tested in two Phase III clinical trials ((SPORTIF III and SPORTIF V) comparing ximelagatran with warfarin for the prevention of cardioembolic events in patients with non - valvular atrial fibrillation. ​​​​ Fixed-dose ximelagatran administered without coagulation monitoring was used to treat high-risk patients with atrial fibrillation. At least as effectively as warfarin in patients at risk for well-controlled thromboembolism SPORTIF III clinical trial investigator, who found that the treatment prevented vascular endothelial cell death and was associated with reduced bleeding. Combining the results of PORTIF III and V, ximelagatran was found to be effective in all brain The composite outcome of stroke (ischemic or hemorrhagic), systemic embolic events, major bleeding, and death This was associated with a relative risk reduction of 16%. (Olsson, SBLancet 200 3,362(9397),1691-1698, Hirsh, J. et al.Bloo d 2005,105(2),453-463, Clemens,A.et al.WI PO Patent Application No. WO / 2008 / 009638. Without wishing to be bound by any theory, Further, although not desired, thrombin inhibition generally reduces the risk of heart failure in individuals with atrial fibrillation. It is reasonable to think that it may be useful in preventing stroke.

[0129] Known thrombin inhibitors have been reported to be useful in the treatment and prevention of acute coronary syndromes. (Clemens, A. et al. WIPO Patent Application No. WO / 2008 / 009638 ACS is a group of conditions caused by myocardial ischemia. It may be used as a prophylactic agent for infarction or a certain period after the event (e.g., myocardial post-infarction, post-MI, i.e., chronic therapy, secondary prevention). Further, although not desired, thrombin inhibition is generally useful in the treatment and prevention of acute coronary syndromes. It is reasonable to think that it could be useful.

[0130] It has been reported that known thrombin inhibitors are useful for preventing recurrent cardiac events after myocardial infarction. The selective thrombin inhibitor ximelagatran was studied in a Phase II clinical trial called ESTEEM to measure the efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with subacute myocardial injury. The results of the ESTEEM trial supported the concept that long-term treatment with an oral direct thrombin inhibitor reduces arterial thromboembolic events. Oral ximelagatran in combination with acetylsalicylic acid was effective in reducing the frequency of major cardiovascular events during 6 months of treatment in patients with subacute myocardial infarction compared to acetylsalicylic acid alone (Hirsh, J. et al. Blood 2005, 105 (2), 453-463). Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for preventing recurrent cardiac events after myocardial infarction.

[0131] It has been reported that known thrombin inhibitors are useful for the postoperative prevention of deep vein thrombosis. The selective thrombin inhibitor ximelagatran was found to be effective for the prevention of venous thromboembolism after medical procedures such as total hip or knee replacement (Francis, C. W. et al. Ann Intern Med 2002; 137: 648-55, Hei t, J. A. et al. Arch Intern Med 2001; 161: 221 5-21, Eriksson BI et al. Thromb Haemost 20 03; 89: 288-96). Without wishing to be bound by any theory, it is considered that thrombin inhibition may generally be useful for the postoperative prevention of deep vein thrombosis. ​ This is reasonable.

[0132] Known thrombin inhibitors such as dabigatran have been reported to be useful for the long-term treatment of pulmonary embolism (Robertson L, Kesteven P, McCaslin JE. Cochrane Database Syst Rev. 2015 Dec 4;12 ). Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary embolism.

[0133] Known thrombin inhibitors have been reported to be useful for the prevention of thrombosis in patients undergoing percutaneous coronary intervention. Percutaneous coronary intervention (PCI) requires aggressive anticoagulation therapy and has historically been achieved using unfractionated heparin. However in many patients, particularly those with heparin-induced thrombocytopenia (HIT), heparin is contraindicated. In the case of intravascular application, the intravascular collapse and hypercoagulable state characteristic of HIT mean that the patient is at risk of thrombosis during PCI (Lewis, B .E. et al. Catheterization and cardiovascu lar interventions 2002, 57(2), 177-184, Kok olis, S et al. Progress in cardiovascular diseases 2004, 46(6), 506-523). Dabigatran, which has already been claimed as a thrombin inhibitor and useful anticoagulant in a clinical setting, has also been published as a secondary agent in percutaneous interventional cardiac catheterization (Reil ). ). Ly et al. (WIPO Patent Application No. WO / 2010 / 020602). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the prevention of coagulation in patients undergoing percutaneous coronary intervention. While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the prevention of coagulation in patients undergoing percutaneous coronary intervention. While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the prevention of coagulation in patients undergoing percutaneous coronary intervention. While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the prevention of coagulation in patients undergoing percutaneous coronary intervention.

[0134] Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. The selective thrombin inhibitor dabigatran has been disclosed as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful as a therapeutic agent for (i) pulmonary hypertension caused by left heart failure, (ii) pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or pulmonary hypertension associated with hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic disease (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. The selective thrombin inhibitor dabigatran has been disclosed as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful as a therapeutic agent for (i) pulmonary hypertension caused by left heart failure, (ii) pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or pulmonary hypertension associated with hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic disease (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. The selective thrombin inhibitor dabigatran has been disclosed as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful as a therapeutic agent for (i) pulmonary hypertension caused by left heart failure, (ii) pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or pulmonary hypertension associated with hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic disease (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. The selective thrombin inhibitor dabigatran has been disclosed as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful as a therapeutic agent for (i) pulmonary hypertension caused by left heart failure, (ii) pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or pulmonary hypertension associated with hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic disease (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. The selective thrombin inhibitor dabigatran has been disclosed as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful as a therapeutic agent for (i) pulmonary hypertension caused by left heart failure, (ii) pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or pulmonary hypertension associated with hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic disease (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. The selective thrombin inhibitor dabigatran has been disclosed as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful as a therapeutic agent for (i) pulmonary hypertension caused by left heart failure, (ii) pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or pulmonary hypertension associated with hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic disease (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. The selective thrombin inhibitor dabigatran has been disclosed as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful as a therapeutic agent for (i) pulmonary hypertension caused by left heart failure, (ii) pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or pulmonary hypertension associated with hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic disease (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. The selective thrombin inhibitor dabigatran has been disclosed as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful as a therapeutic agent for (i) pulmonary hypertension caused by left heart failure, (ii) pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or pulmonary hypertension associated with hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic disease (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. The selective thrombin inhibitor dabigatran has been disclosed as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful as a therapeutic agent for (i) pulmonary hypertension caused by left heart failure, (ii) pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or pulmonary hypertension associated with hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic disease (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension.

[0135] Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension caused by left heart failure (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension caused by left heart failure. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension caused by left heart failure (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension caused by left heart failure. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension caused by left heart failure (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension caused by left heart failure. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension caused by left heart failure (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension caused by left heart failure. Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension caused by left heart failure (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). While not wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension caused by left heart failure.

[0136] Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or or hypoxia-related pulmonary arterial hypertension (Feu Ring, M. WIPO Patent Application No. WO / 2010 / 020600. Without wishing to be further bound, thrombin inhibition is generally associated with pulmonary disease. It is reasonable to assume that these compounds may be useful in treating pulmonary arterial hypertension, which is associated with

[0137] Known thrombin inhibitors are useful for the treatment of pulmonary hypertension caused by chronic thromboembolic disease. It has been reported that the compound is useful in the treatment of cancer (Feuring, M. WIPO Patent Application No. WO / 2013). Without wishing to be bound by any theory, In particular, thrombin inhibition is a potential treatment for pulmonary hypertension, which is commonly caused by chronic thromboembolic disease. It is reasonable to assume that it may be therapeutically useful.

[0138] Non-valvular atrial fibrillation is a persistent heart disorder that is often associated with heart disease. Known thrombin inhibitors such as gadolinium inhibit stroke in patients with nonvalvular atrial fibrillation It has been reported that it is useful for preventing c Dis 2006;21:279-293). Without wishing to be bound by any theory, Although not desirable for many, thrombin inhibition is generally beneficial for patients with non-valvular atrial fibrillation. It is reasonable to assume that this could be useful in preventing stroke in patients with cerebral infarction.

[0139] A transient ischemic attack (TIA) is a temporary neurological event that typically lasts less than an hour. It is an acute onset of brain dysfunction resulting from focal cerebral, spinal cord, or retinal ischemia and is associated with acute tissue infarction. In people who have had a TIA, the incidence of subsequent strokes is That is 11%, and it is as high as 24 - 29% over the next five years. The short - term risk of stroke after TIA Considering the high level, many physicians believe that antithrombotic therapy should be initiated as soon as the possibility of intracranial hemorrhage is excluded. The stroke preventive drugs typically recommended for cardiogenic embolism TIA are as follows: For patients with atrial fibrillation after TIA, warfarin; for patients unable to take oral anticoagulants, long - term anticoagulation with aspirin 325 mg / day); for acute myocardial infarction (MI) with left ventricular thrombus, oral anticoagulation with warfarin; for ischemic coronary artery disease [CAD], combined aspirin up to 162 mg / day); for dilated cardiomyopathy, oral anticoagulation with warfarin or antiplatelet therapy; for rheumatic mitral valve disease, oral anticoagulation with warfarin. For patients with cardio - embolic TIA and ischemic stroke due to atrial fibrillation, vitamin K antagonists (VKAs) are very effective in preventing recurrent ischemic stroke, but have important limitations and are therefore not used sufficiently. Antiplatelet therapy is much less effective than VKAs. The direct thrombin inhibitor dabigatran etexilate has shown greater effectiveness than warfarin in recent trials. Other new anticoagulants such as the oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, the parenteral factor Xa inhibitor idraparinux, and the new VKA, tecarfarin, etc. have been evaluated in 2010 (Hankey, G.J.; Eikelboom, J.W. ‘Ant ithrombotic Drugs for Patients with Isch Events.’ The Lancet Neurology 2010, 9(3), 2 73 - 284).

[0140] Known thrombin inhibitors have been reported to be useful for the treatment of venous thromboembolism resulting from the formation of venous thrombi (venous thrombosis) associated with acquired (long - term bed rest, surgery, injury, malignant tumors, pregnancy, and the post - partum state) or genetic (deficiency of natural coagulation inhibitors) risk factors (Marsic, L.P. et al. WIPO Patent Application No. WO / 200 3 / 048155). Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of venous thromboembolism resulting from the formation of venous thrombi in the peripheral veins associated with acquired or genetic risk factors and / or thrombus detachment. An example of an acquired risk factor is a history of venous thromboembolism and / or peripheral venous embolism caused by thrombus detachment. An example of an acquired risk factor is a history of venous thromboembolism.

[0141]

[0141] Known thrombin inhibitors have been reported to be useful for the treatment of cardiogenic thromboembolism resulting from the formation of intracardiac thrombi associated with peripheral arterial embolism generally caused by thrombus detachment in the brain (ischemic stroke), cardiac arrhythmias, heart valve defects, artificial heart valves or heart diseases. See Marsic, L.P. et al. WIPO Patent Application No. WO / 2003 / 048155. Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of cardiogenic thromboembolism.

[0142]

[0142] ​ Known thrombin inhibitors have been reported to be useful in the treatment of arterial thrombosis resulting from atherosclerotic processes that occlude or close arteries, cause myocardial ischemia (angina pectoris, acute coronary syndrome group), or myocardial infarction, occlude or close peripheral arteries (ischemic peripheral arterial disease), and occlude or close arteries after vascular procedures (reocclusion or restenosis after percutaneous coronary angioplasty, reocclusion or restenosis after percutaneous transluminal angioplasty of peripheral arteries). See Marsic, L.P. et al., WIPO Patent Application No. WO / 2003 / 048155. Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of arterial thrombosis. See Marsic, L.P. et al., WIPO Patent Application No. WO / 2003 / 048155. Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of arterial thrombosis. rsic, L.P. et al., WIPO Patent Application No. WO / 2003 / 048155 for reference. Without further wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of arterial thrombosis. See Marsic, L.P. et al., WIPO Patent Application No. WO / 2003 / 048155. Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of arterial thrombosis.

[0143] Known thrombin inhibitors have been reported to be useful in the treatment of disseminated intravascular coagulation in some conditions (e.g., pregnancy complications, metastatic malignancies, after large-scale injury, septicemia) when thrombus formation activation causes both widespread thrombosis in the vascular system and coagulation dysfunction. See Marsic, L.P. et al., WIPO Patent Application No. WO / 20 03 / 048155 for reference. Without further wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of disseminated intravascular coagulation. See Marsic, L.P. et al., WIPO Patent Application No. WO / 20 03 / 048155 for reference. Without further wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of disseminated intravascular coagulation. Without further wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of disseminated intravascular coagulation. See Marsic, L.P. et al., WIPO Patent Application No. WO / 2003 / 048155. Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of disseminated intravascular coagulation.

[0144] Known thrombin inhibitors, in combination with aspirin in patients with unstable angina designed to undergo percutaneous transluminal angioplasty in parallel with thrombolytic therapy in subacute myocardial infarction, and as a supplement in the treatment of patients with thrombosis and heparin-induced thrombocytopenia. See Marsic, L.P. et al., WIPO Patent Application No. WO / 2003 / 048155. Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of arterial thrombosis. See Marsic, L.P. et al., WIPO Patent Application No. WO / 2003 / 048155. Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of arterial thrombosis. It has been reported to be useful as adjuvant therapy (Marsic, L.P. et al. WIP Patent Application No. WO / 2003 / 048155). Although not wishing to be bound by any theory it is reasonable to consider that thrombin inhibition may generally be useful as an adjuvant therapy to other antithrombotic therapies.

[0145] Known thrombin inhibitors have been reported to be useful in the treatment of inflammation (Kirk, I. WIPO Patent Application No. WO / 2000 / 041716), type I diabetes (Korsgren, O., Nillson, B. WI PO Patent Application No. WO / 2003 / 061682), cancer (Kakkar, A.K. et al. J Clin Oncol 2004, 22, (10), 1944 - 8, Hua, Y. et al. Acta Neurochir Suppl 2005, 95, 403 -6, Nieman, M.T. et al. J Thromb Haemost, 6(2 008), 837 - 845, Van Ryn, J., Clemens, A. WIPO Patent Application No. WO / 2010 / 020601), fibrosis (Duplantier, J.G. e t al. Gut, 2004, 53:1682 - 1687, Seijo, S. et al . J Hepatol, 2007, 46:286 - 294, Assy, N. et al. Dig Dis Sci, 2007, 52:1187 - 1193, Bogatkevic h, G.S. et al. Arthritis Rheum, 2009, 60:3455 -3464), and pain (Garcia, P.S. et al. Thromb Haem ost, 103:1145 - 1151, Narita, M. et al. J Neuro sci, 2005, 25:10000 - 10009). There is a meta-analysis of clinical trials that studied the use of anticoagulants in cancer patients, showing that low molecular weight heparin (LMWH), a selective thrombin inhibitor, improves the overall survival rate of a subgroup of cancer patients. This finding was confirmed in subsequent clinical trials that specifically measured the survival rate of cancer patients, specifically, the FAMOUS clinical trial.

[0146] Although not further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment of thrombotic diseases or disorders with or without the formation of blood clot thrombi and / or associated with stroke and / or one or more transient ischemic attacks (TIAs) and / or pulmonary hypertension. Such conditions include, for example, acute coronary syndrome, thromboembolism, thrombosis, inflammation, diabetes, cancer, fibrosis, Alzheimer's disease, multiple sclerosis, pain, recurrent cardiac events after myocardial infarction, etc.

[0147] Kallikrein-related diseases and conditions. Kallikrein-related diseases or disorders are biological states related to or alleviated by kallikrein. These include, but are not limited to, states related to biological pathways alleviated by plasma kallikrein. An example of such a pathway is the kallikrein-kinin system (More au, M.E. 2005, Journal of Pharmacological S ciences, 99, 6). Kallikrein-related diseases or disorders include fibrosis, inflammation, thrombosis, hereditary angioedema, skin disorders, cancer, and ophthalmic diseases, but are not limited to these. ​​will not occur. Ophthalmic diseases include, but are not limited to, diabetic macular edema, diabetic retinopathy, and age-related macular degeneration Examples include, but are not limited to, these diseases

[0148] Diabetic macular edema. In a rodent model, activation of KLKB1 in the eye increases retinal vascular permeability, while inhibition of the kallikrein-kinin system has been shown to reduce retinal leakage induced by diabetes and hypertension These findings suggest that intraocular activation of the KLKB1 pathway may contribute to excessive retinal vascular permeability that can lead to diabetic macular edema Therefore, the evidence suggests that KLKB1 inhibitors may provide a new therapeutic opportunity to reduce retinal vascular permeability (Feener, E.P. 2010, Curr Diab Rep 10,270). Diab Rep 10,270).

[0149] Hereditary angioedema. Ecallantide (carbitol) is a recombinant protein consisting of 60 amino acids that acts as a potent reversible inhibitor of KLKB1 (Schneider L, et al. 2007, J Allergy Clin Immunol, 120 ,416), and has been approved by the FDA for the treatment of acute attacks of hereditary angioedema (HAE) Therefore, plasma kallikrein inhibition may be a useful treatment for HAE, and there is great interest in the development of plasma kallikrein inhibitors as a therapy for HAE

[0150] Hyperglycemic and diabetic individuals are at high risk of bleeding during thrombolytic therapy. In a rodent model with intracerebral hemorrhage (ICH ), KLKB1 inhibition or knockout has been shown to reduce this effect Although this mechanism is not fully understood, this evidence suggests that plasma kallikrein ​​​Suggesting that kallikrein inhibitors may be useful for the treatment of cerebral hemorrhage (Feener, E. P.Curr Diab Rep 2010, 10, 270).

[0151] Plasma kallikrein and factor XIIa inhibitors have neuroprotective effects in animal models with acute ischemic stroke and traumatic brain injury, and reduce edema formation, inflammation, and thrombosis (Albert-Weißenberger C, Siren AL , Kleinschnitz C. Prog Neurobiol. 2013, 101- 102, 65-82). Therefore, the evidence suggests that plasma kallikrein inhibitors may be useful for the treatment of acute ischemic stroke and traumatic brain injury.

[0152] Plasma kallikrein can also cleave glucagon-like peptide 1 (GLP-1) and neuropeptide Y (N PY), both of which are substrates for dipeptidyl peptidase-4 (DPP-4), a validated diabetes drug target. In the case of GLP-1, cleavage by KLKB1 reduces both its potency and plasma stability. In the case of NPY, cleavage by KLKB 1 reduces its affinity for Y2 and Y5. Therefore, the evidence suggests that plasma kallikrein inhibitors may be useful for the regulation of energy homeostasis and the treatment of diabetes (Feener, E. P. Curr Diab Rep 2010, 1 0, Feener, E. P. et al., Biol. Chem. 2013, 394, 3 19).

[0153] The kallikrein-kinin system is involved in vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase and are involved in the regulation of fibroblast growth factor 2, all of which are involved in angiogenesis (Ba der M. 2009, Arteriosclerosis, Thrombosis, and Vascular Biology, 29:617). Tissue kallikrein (KLK 1) is associated with vascular enlargement (Miura S., 2003, Hypertens ion, 41, 1118). Therapies that mitigate angiogenesis have been proposed for the treatment of both diabetic macular edema (DME) and age-related macular degeneration (AMD) (Syed, B.A.; E vans, J.B.; Bielory, L., 2012, Nature Reviews Drug Discovery, 11, 827). Without wishing to be bound by any theory, it is therefore reasonable to conclude that KLK1 inhibitors may be useful for the treatment of diabetic retinopathy, DME, and AMD.

[0154] Studies have shown that inflammation plays an important role in the origin and development of AMD, and treatment often includes anti-inflammatory drugs such as corticosteroids (Telander, D. , 2011, Seminars in Ophthalmology, 26(3), 19 2). The association between the kallikrein-kinin system and inflammation has also been well established (Duchen e, 2011, “Kallikrein-kinin kystem in infla mmatory diseases”. Kinins. De Gruyter. 261) . Without wishing to be bound by any theory, it is reasonable to conclude that the anti-inflammatory properties of kallikrein (e.g., KLK1 and KLKB1) inhibitors may be useful for the treatment of AMD.

[0155] PF-04886847 is an inhibitor of plasma kallikrein and lipopolysaccharide (LPS). 6-Keto-PGF in treated rats 1α It has been shown to be effective in reducing plasma levels (Kolte, D et al. Cardiovascular & Hem Atological agents in Medicinal Chemistry ,2012,10,154-166). I would prefer not to be bound by any theory. Although not the only treatment, plasma kallikrein inhibitors have been shown to be useful in treating hypotensive shock during sepsis. It is reasonable to think that this is possible.

[0156] Daiichi Seiyaku Co Ltd sells a drug for gastritis and peptic ulcers in Japan. The company received approval to market cetraxate, a plasma kallikrein inhibitor. (WIPO Patent Application No. WO / 2006 / 108643). Without wishing to be bound by any theory, it is believed that plasma kallikrein inhibition is a common In particular, it is reasonable to believe that it may be useful in the treatment of gastritis and peptic ulcers.

[0157] Fibrosis. Kallikrein is divided into plasma kallikrein (KLKB1) and tissue kallikrein. KLKB1 is a subgroup of serine proteases that regulates blood pressure and inflammation. Releases kinins (bradykinin and kallidin) from kininogen, a peptide involved in oxidization. In the contact activation pathway of the coagulation cascade, KLKB1 inhibits factor XII and factor XIIa. (Keel, M.; Trentz, O. Injury 2005, 36,691-709). Factor XIIa converts factor XI to factor XIa, which then In this process, it activates factor IX, and together with its cofactor, factor VIIIa, it forms a tenase complex, which ultimately activates factor X to factor Xa. In the fibrinolytic part of the coagulation cascade, KLKB1 functions to convert plasminogen to plasmin. Therefore, it has been proposed that KLKB1 inhibitors may be useful for the treatment of thrombotic and fibrinolytic diseases and disease states (U.S. Patent No. 7,625,944; Bird et al., Thrombosis and Hemostasis 2012 , 107, 1141). In the fibrinolytic part of the coagulation cascade, KLKB1 functions to convert plasminogen to plasmin. Therefore, it has been proposed that KLKB1 inhibitors may be useful for the treatment of thrombotic and fibrinolytic diseases and disease states (U.S. Patent No. 7,625,944; Bird et al., Thrombosis and Hemostasis 2012 , 107, 1141). Some studies have shown the usefulness of anticoagulant therapy in fibrotic diseases. For example, in a rat model with CCl4-induced chronic liver injury, DTI SSR182289 significantly reduced hepatic fibrosis 7 weeks after administration. The same has been observed in other studies using low molecular weight heparins such as nadroparin, tinzaparin, enoxaparin, and dalteparin sodium. See, for example, Duplantier, J.G., et al., 2 004, Gut, 53:1682 - 1687; Abdel - Salam, O.M., et al., 2005, Pharmacol Res, 51:59 - 67; Assy, N.

[0158] , et al., 2007, Dig Dis Sci, 52:1187 - 1193; Abe, W., et al., 2007, J Hepatol, 46:286 - 294. Therefore, thrombin inhibitors as anticoagulants may be useful for the treatment of fibrinolytic diseases. In another example, the DTI melagatran reduced ischemia in a renal transplantation model in large white pigs For example, see Duplantier, J.G., et al., 2 004, Gut, 53:1682 - 1687; Abdel - Salam, O.M., et al., 2005, Pharmacol Res, 51:59 - 67; Assy, N. , et al., 2007, Dig Dis Sci, 52:1187 - 1193; Abe, W., et al., 2007, J Hepatol, 46:286 - 294. Therefore, thrombin inhibitors as anticoagulants may be useful for the treatment of fibrinolytic diseases. In another example, the DTI melagatran reduced ischemia in a renal transplantation model in large white pigs

[0159] In another example, the DTI melagatran reduced ischemia Significantly reduced reperfusion injury. As a result, the survival rate of kidney transplantation at the 3-month time point was significantly improved. See, for example, Favreau, F., et al., 2010, Am J Trans plant, 10:30-39.

[0160] In a recent study, in a bleomycin-induced mouse model with pulmonary fibrosis, treatment with dabigatran etexilate has been shown to reduce important fibrosis progression events in lung fibroblasts, including the production of collagen and connective tissue growth factor. See, for example, Silv er, R.M., et al., 2010, Am.J.Respir.Crit.Car e Med., 181:A6780, Bogatkevich, G.S., et al. , 2009, Arthritis Rheum, 60:3455-3464. See also.

[0161] The above experimental evidence points to a close relationship between thrombin and fibrosis and suggests a new therapeutic opportunity for fibrosis using thrombin inhibitors. See, for example, Calvaruso, V. , et al., 2008, Gut, 57:1722-1727, Chambers, R .C., 2008, Br J Pharmacol, 153 Suppl 1:S367 -378, Chambers, R.C. & Laurent, G.J., 2002, Bi ochem Soc Trans, 30:194-200, Howell, D.C., e t al., 2001, Am J Pathol, 159:1383-1395. See also.

[0162] Inflammation. Kallikrein has long been implicated in inflammation (Clements ,J.A.The Molecular Biology of the Kallik reins and Their Roles in Inflammation,Ac ademic Press:San Diego,CA,1997;Vol.5).KL There is experimental evidence that KLKB1 is associated with sepsis and inflammatory arthritis (Colman ,R.W.,1998,Clinical Reviews in Allergy a nd Immunology,16:365).Therefore,KLKB1 inhibitors may be useful in the treatment of kallikrein-ki nin system-related inflammatory conditions such as systemic inflammatory response syndrome,sepsis,rheumatoid arthritis,and inflammatory bowel disease.

[0163] While not wishing to be bound by any theory,it is reasonable to consider that kallikrein inhibition is generally useful in the treatment of kallikrein-related diseases or disorders and / or diseases or disorders. Such conditions include,for example,thrombotic diseases,fibrinolytic diseases,fibrotic diseases,cancer,inflammatory conditions,dermatological conditions,and the like.

[0164] Accordingly,in a further aspect,a method for treating a disease or disorder in a subject in need thereof is provided.The method comprises administering to the subject in need thereof an effective amount of a compound of formula ( Ia),(Ib),(II),(III),(IV),or (V) herein,a compound described in Table A,Table B,Table C,or Table D,a pharmaceutically acceptable salt,ester,solvate,or prodrug thereof,or a pharmaceutical composition thereof for treating the disease or disorder. "Treatment" Terms such as "therapeutically effective amount", "amount effective to treat", "amount effective to prevent", etc. are those sought by researchers , veterinarians, physicians, or other clinicians, to induce a biological or medical response in a tissue, system, animal, or human drug or pharmaceutical agent (e.g., a compound or pharmaceutical composition disclosed herein ).

[0165] Compounds useful in the methods disclosed herein include those described by formula (Ia), (Ib), (II) , (III), (IV), or (V), and compounds described in Table A, Table B, Table C , or Table D above.

[0166] In some embodiments of the methods described herein, the disease or disorder being treated may include one or more thrombotic diseases or disorders and / or may be associated with the formation of a thrombus or thrombi. In some embodiments, the thrombotic disease or disorder may be an acute coronary syndrome, a pulmonary embolism, and / or thrombosis. In some embodiments, the pulmonary embolism may be a venous thromboembolism, an arterial thromboembolism, and / or a cardiogenic thromboembolism. In some embodiments, the venous thromboembolism may include deep vein thrombosis and / or pulmonary embolism. In some embodiments, the deep vein thrombosis and / or pulmonary embolism may occur after a medical procedure. In some embodiments, the thrombotic disease or disorder may be associated with coagulation dysfunction or disseminated intravascular coagulation. In some embodiments, a subject with coagulation dysfunction may be undergoing percutaneous coronary intervention (PCI). In some embodiments, the thrombotic disease or disorder may be associated with the formation of a thrombus or thrombi and may include a stroke and / or In some embodiments, the thrombotic disease or disorder may be associated with the formation of a thrombus or thrombi and may include a stroke and / or In some embodiments, the thrombotic disease or disorder may be associated with the formation of a thrombus or thrombi and may include a stroke and / or In some embodiments, the thrombotic disease or disorder may be associated with the formation of a thrombus or thrombi and may include a stroke and / or may further be accompanied by one or more transient ischemic attacks (TIAs). In some embodiments, a thrombotic disease or disorder associated with a blood clot thrombus or the potential for a blood clot thrombus may further be accompanied by a stroke, and the subject may have non-valvular atrial fibrillation. In some embodiments, the thrombotic disease or disorder may be associated with a blood clot thrombus or the potential for a blood clot thrombus and may further be accompanied by pulmonary hypertension. In some embodiments, pulmonary hypertension may be caused by one or more left heart disorders and / or chronic thromboembolic disease. In some embodiments, pulmonary hypertension may be associated with one or more pulmonary diseases and / or hypoxia, including idiopathic or other pulmonary fibrosis. In some embodiments, venous thromboembolism may be associated with the formation of a thrombus within a vein related to one or more acquired or genetic risk factors and / or peripheral venous embolism caused by thrombus detachment. In some embodiments, one or more risk factors may include a history of venous thromboembolism

[0167] In some embodiments, cardiogenic thromboembolism may be due to the formation of a thrombus within the heart related to arrhythmia, heart valve defect s, artificial heart valves or heart disease, and / or peripheral arterial embolism caused by thrombus detachment. In some embodiments, thrombus detachment may be within the brain (ischemic stroke). In some embodiments, thrombus detachment may cause a transient ischemic attack (TIA). In some embodiments, cardiogenic thromboembolism may be due to non-valvular atrial fibrillation. In some embodiments, the thrombotic disorder may be arterial thrombosis . In some embodiments, arterial thrombosis may be due to one or more underlying atherosclerotic processes within the artery. In some embodiments, one or more underlying processes within the artery may be due to atherosclerotic processes within the artery. In some embodiments, thrombus detachment may cause a transient ischemic attack (TIA). In some embodiments, cardiogenic thromboembolism may be due to non-valvular atrial fibrillation. In some embodiments, the thrombotic disorder may be arterial thrombosis . In some embodiments, arterial thrombosis may be due to one or more underlying atherosclerotic processes within the artery. In some embodiments, one or more underlying atherosclerotic processes within the artery The atherosclerotic process that forms can occlude or close arteries, can cause myocardial ischemia (angina pectoris, acute coronary syndrome), can cause myocardial infarction, can occlude or close peripheral arteries (ischemic peripheral artery disease), and / or can occlude or close arteries after a vascular procedure (reocclusion or restenosis after percutaneous coronary angioplasty, reocclusion or restenosis after percutaneous transluminal angioplasty of peripheral arteries). In some embodiments, the disease or disorder can include fibrosis, Alzheimer's disease, multiple sclerosis, pain, cancer, inflammation, and / or type I diabetes. In some embodiments, the disease or disorder can be accompanied by recurrent cardiac events after myocardial infarction. In some embodiments, the treatment or prevention can include adjuvant therapy. In some embodiments, the subject can have myocardial infarction, and the adjuvant therapy can be concurrent with thrombolytic therapy. In some embodiments, the subject can have unstable angina, thrombosis, and / or heparin-induced thrombocytopenia, and the adjuvant therapy can be used in combination with antiplatelet therapy. In some embodiments, the subject can have non-valvular atrial fibrillation, and the adjuvant therapy can be concurrent with one or more other therapies. In some embodiments of the methods described herein, the disease or disorder can be a kallikrein-related disease. In some embodiments, the kallikrein-related disease can be a thrombotic disease, a fibrinolytic disease, a fibrotic disease, certain cancers, an inflammatory condition, or a dermatological condition. In some embodiments, the kallikrein-related disease can be an ophthalmic disease.

[0168] In some embodiments, the disease or disorder can include fibrosis, Alzheimer's disease, multiple sclerosis, pain, cancer, inflammation, and / or type I diabetes. In some embodiments, the disease or disorder can be accompanied by recurrent cardiac events after myocardial infarction. In some embodiments, the treatment or prevention can include adjuvant therapy. In some embodiments, the subject can have myocardial infarction, and the adjuvant therapy can be concurrent with thrombolytic therapy. In some embodiments, the subject can have unstable angina, thrombosis, and / or heparin-induced thrombocytopenia, and the adjuvant therapy can be used in combination with antiplatelet therapy. In some embodiments, the subject can have non-valvular atrial fibrillation, and the adjuvant therapy can be concurrent with one or more other therapies. In some embodiments of the methods described herein, the disease or disorder can be a kallikrein-related disease. In some embodiments, the kallikrein-related disease can be a thrombotic disease, a fibrinolytic disease, a fibrotic disease, certain cancers, an inflammatory condition, or a dermatological condition.

[0169] In some embodiments, the treatment or prevention can include adjuvant therapy. In some embodiments, the subject can have myocardial infarction, and the adjuvant therapy can be concurrent with thrombolytic therapy. In some embodiments, the subject can have unstable angina, thrombosis, and / or heparin-induced thrombocytopenia, and the adjuvant therapy can be used in combination with antiplatelet therapy. In some embodiments, the subject can have non-valvular atrial fibrillation, and the adjuvant therapy can be concurrent with one or more other therapies. In some embodiments, the subject can have myocardial infarction, and the adjuvant therapy can be concurrent with thrombolytic therapy. In some embodiments, the subject can have unstable angina, thrombosis, and / or heparin-induced thrombocytopenia, and the adjuvant therapy can be used in combination with antiplatelet therapy. In some embodiments, the subject can have non-valvular atrial fibrillation, and the adjuvant therapy can be concurrent with one or more other therapies. In some embodiments, the subject can have unstable angina, thrombosis, and / or heparin-induced thrombocytopenia, and the adjuvant therapy can be used in combination with antiplatelet therapy. In some embodiments, the subject can have non-valvular atrial fibrillation, and the adjuvant therapy can be concurrent with one or more other therapies. In some embodiments, the subject can have non-valvular atrial fibrillation, and the adjuvant therapy can be concurrent with one or more other therapies. In some embodiments of the methods described herein, the disease or disorder can be a kallikrein-related disease. In some embodiments, the kallikrein-related disease can be a thrombotic disease, a fibrinolytic disease, a fibrotic disease, certain cancers, an inflammatory condition, or a dermatological condition. In some embodiments, the kallikrein-related disease can be an ophthalmic disease.

[0170] In some embodiments of the methods described herein, the disease or disorder can be a kallikrein-related disease. In some embodiments, the kallikrein-related disease can be a thrombotic disease, a fibrinolytic disease, a fibrotic disease, certain cancers, an inflammatory condition, or a dermatological condition. In some embodiments, the kallikrein-related disease can be a thrombotic disease, a fibrinolytic disease, a fibrotic disease, certain cancers, an inflammatory condition, or a dermatological condition. In some embodiments, the kallikrein-related disease can be an ophthalmic disease. In some embodiments, the kallikrein-related disease can be an ophthalmic disease.

[0171] In some embodiments, the kallikrein-related disease can be an ophthalmic disease. In some embodiments, In an embodiment, the present compound or the present pharmaceutical composition is in the form of an ophthalmic composition for topical application to the eye and can be administered. In some embodiments, the ophthalmic composition can be in the form of eye drops. In some embodiments, the present compound or the present pharmaceutical composition can be administered in the form of an ophthalmic composition by intravitreal injection . In some embodiments, the ophthalmic disease can be diabetic macular edema, hereditary angioedema, age-related macular degeneration, or diabetic retinopathy

[0172] In some embodiments where the disease or disorder can be a certain type of cancer, the certain type of cancer can be cervical cancer, testicular cancer, or non-small cell lung adenocarcinoma. In some embodiments, the cancer can be limited small cell lung cancer. In some embodiments, the cancer can be glioma. In some embodiments, the cancer can be breast cancer. In some embodiments, the cancer can be micrometastasis. In some embodiments, the micrometastasis can be blood or liver micrometastasis . In some embodiments, the cancer can be lung metastasis. In some embodiments, the cancer can be prostate cancer

[0173] In some embodiments where the disease or disorder can be an inflammatory condition, the inflammatory condition can be sepsis , inflammatory bowel disease, systemic inflammatory response syndrome, inflammatory arthritis, or rheumatoid arthritis .

[0174] In some embodiments where the disease or disorder can be a dermatological condition, the dermatological condition can be atopic dermatitis, psoriasis, or Netherton syndrome

[0175] In another aspect, a method for preventing a disease or disorder in a subject is provided. The method The method comprises administering to a subject in need thereof, an effective amount of a compound of any of formulae (Ia), (Ib), (II), (III), (IV), or (V), a compound described in any of Tables A, B, C, or D of the present specification, a pharmaceutically acceptable salt, ester, solvate thereof, or a prodrug, or a pharmaceutical composition thereof, for preventing a disease or disorder.

[0176] V. ASSAY The compounds described herein are known in the art and can be assayed for biological activity against various proteins, such as thrombin and KLKB1, e.g., inhibition of protease activity, by the various methods described herein.

[0177] The thrombin activity reported herein (e.g., in Table A) was obtained as follows. Human thrombin was obtained from Haematologic Technologies Inc. Chromogenic substrate S-2238 was obtained from DiaPharma. Thrombin was assayed in a buffer containing 0.05 M Tris (pH 7.4), 0.015 M NaCl, and 0.01% PEG-800. The final concentration of the enzyme used was 3 nM (thrombin). The final concentration of the substrate used was 125 μM (thrombin S-2238). All assays were performed at room temperature (RT) on a 96-well microtiter plate. The enzyme and inhibitor were pre-incubated for 10 minutes, then the substrate was added and read at 405 nm using a SpectraMax Plus spectrophotometer (Molecular Devices). The IC value of the inhibitor was determined as known in the art. 50 ​​​​​​​ The compound was added as 10 points and determined by serial three-fold dilution in a buffer solution. The plate was read at 10 minutes after substrate addition. The IC 50 was determined as known in the art by plotting the percent inhibition (%) against the compound concentration and fitting the data to a constrained four-parameter Sigmoidal curve.

[0178] The KLKB1 kallikrein activity reported in this specification (e.g., Table B) was obtained as follows Human KLKB1 protein was obtained from Enzyme Research Labs. The chromogenic substrate S-2302 was assayed with KLKB1 obtained from DiaPharma in a buffer containing 0 .05 M Tris (pH 7.4), 0.01 M NaCl, and 0.2 w / v% PEG-8 000. The final concentration of the enzyme used was 3 nM (KLK B1). The final concentration of the substrate used was 250 μM (KLKB1 S-2302) . All assays were performed at room temperature (RT) on a 96-well microtiter plate . The enzyme and inhibitor were pre-incubated for 10 minutes, then the substrate was added, and read at 405 nm using a SpectraMax Plus spectrophotometer (Molecular Devices) . The IC of the inhibitor 50 value was determined as known in the art by adding the test compound as 10 points and performing serial three-fold dilution in a buffer solution . The plate was read at 10 minutes after substrate addition. The IC 50 was determined as known in the art by plotting the percent inhibition (%) against the compound concentration and fitting the data to a constrained four-parameter Sigmoidal curve.

[0179] The chymotrypsin activity reported in this specification (e.g., Table D) was obtained as follows. Human pancreatic a-chymotrypsin was obtained from Sigma. The chromogenic substrate S-7388 was obtained from Sigma. The final concentration of the substrate used was 250 μM (chymotrypsin). All assays were performed at room temperature (RT) on a 96-well microtiter plate. The enzyme and inhibitor were pre-incubated for 10 minutes, after which the substrate was added and read at 405 nm using a SpectraMax Plus spectrophotometer (Molecular Devices). The IC 50 value of the inhibitor was determined by adding the test compound at 10 points and serially diluting it 3-fold in buffer solution. The rate was read at 5 minutes after substrate addition. The IC 50 was calculated as known in the art by plotting the percent inhibition (%) against the compound concentration and fitting the data to a constrained 4-parameter Sigmoidal curve.

[0180] The factor XIa activity reported in this specification (e.g., Table D) was obtained as follows. Human factor XIa was obtained from Enzyme Research. The chromogenic substrate S-236 6 was obtained from DiaPharma. The final concentration of the substrate used was 10 mM (factor XI a). All assays were performed at room temperature (RT) on a 96-well microtiter plate. The enzyme and inhibitor were pre-incubated for 10 minutes, after which the substrate was added and read at 405 nm using a SpectraMax Plus spectrophotometer (Molecular Devic es). The IC 50The value was determined by adding the test compound as 10 points and performing three-fold serial dilutions in a buffer solution, as is known in the art. The plate was read at 10 minutes after substrate addition. The IC was calculated by plotting the percent inhibition (%) against the compound concentration and fitting the data to a constrained four-parameter sigmoidal curve, as is known in the art. 50 in the art In another aspect, a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient is provided. The compound is any one of the compounds of formula (Ia), (Ib), (I I), (III), (IV), or (V) disclosed herein, a compound described in Table

[0181] VI. Pharmaceutical Compositions A, Table B, Table C, or Table D herein, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof. In some embodiments, the compound is described in Table A, Table B, Table C, or Table D herein. The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively non-toxic acids or bases depending on the particular substituents found on the compounds described herein. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. The compounds disclosed herein

[0182] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively non-toxic acids or bases depending on the particular substituents found on the compounds described herein. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. The compounds disclosed herein contain relatively acidic functional groups, and base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. The compounds disclosed herein are obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. The compounds disclosed herein contain relatively acidic functional groups, and base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, When it contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such a compound with any sufficient amount of a desired acid, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid, or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, camphoric acid, methanesulfonic acid, etc. Salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid are also included ( for example, see Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 6 6, 1-19). Certain compounds disclosed herein contain both basic and acidic functional groups, which allows the compound to be converted into either a base addition salt or an acid addition salt. Journal of Pharmaceutical Science, 1977, 6 6, 1-19). Certain compounds disclosed herein contain both basic and acidic functional groups, which allows the compound to be converted into either a base addition salt or an acid addition salt. The compounds disclosed herein can exist as salts such as salts having a pharmaceutically acceptable acid. Accordingly, the compounds contemplated herein include such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate,

[0183] citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof including racemic mixtures), succinate, benzoate, and gluconate The compounds disclosed herein can exist as salts such as salts having a pharmaceutically acceptable acid. Accordingly, the compounds contemplated herein include such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof including racemic mixtures), succinate, benzoate, and gluconate salt, etc. Salts having amino acids such as minoic acid can be mentioned. These salts can be prepared by methods known to those skilled in the art.

[0184] The neutral form of the present compound is preferably regenerated by contacting the salt with a base or an acid and isolating the affinity compound in a conventional manner. The parent form of the present compound is different from various salt forms in terms of certain physical properties such as solubility in polar solvents.

[0185] The pharmaceutically acceptable salts of the present compound in which a basic group or an acidic group is present in the structure are also included within the scope of the compounds contemplated herein. When acidic substituents such as -NHSO3H, -COOH, and -P(O)(OH)2 are present, ammonium, sodium, potassium, calcium salts, etc. can be formed for use as a dosage form. Basic groups, for example, amino or basic heteroaryl radicals or pyridyl, and acidic salts, for example, hydrochloride salts, hydrobromide salts, acetate salts, maleate salts, pamoate salts, methanesulfonate salts, p-toluenesulfonate salts, etc. can be used as a dosage form.

[0186] In embodiments where R-COOH is present, pharmaceutically acceptable esters, for example, methyl, ethyl, tert-butyl, pivaloyloxymethyl, etc., and esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations can also be used.

[0187] A. Formulations The compounds disclosed herein can be prepared and administered in a wide variety of ophthalmic, oral, parenteral, and topical dosage forms. The compounds described herein can be administered by eye drops. Also, the present ​The compounds described in the specification can be administered by injection (e.g., intravenous, intramuscular, intravitreal, intradermal, subcutaneous, duodenal, or intraperitoneal). Thus, the compounds described in the specification can also be administered by intravitreal injection. Further, the compounds described in the specification can be administered by inhalation, e.g., intranasally. Additionally, the compounds disclosed herein can be administered transdermally. It is also envisioned that the compounds disclosed herein can be administered using multiple routes of administration (e.g., intramuscular, oral, ocular). In some embodiments, the compounds disclosed herein can be formulated in a liquid pharmaceutical composition for intraocular administration. Compositions for intraocular use can contain one or more agents selected from the group consisting of buffers, solubilizers, colorants, viscosity enhancers, and preservatives to produce a pharmaceutically elegant and convenient formulation. In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components. In some embodiments, the compounds disclosed herein are tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups, or In some embodiments, the compounds disclosed herein can be formulated in a liquid pharmaceutical composition for intraocular administration. Compositions for intraocular use can contain one or more agents selected from the group consisting of buffers, solubilizers, colorants, viscosity enhancers, and preservatives to produce a pharmaceutically elegant and convenient formulation. In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components.

[0188] In some embodiments, the compounds disclosed herein can be formulated in a liquid pharmaceutical composition for intraocular administration. Compositions for intraocular use can contain one or more agents selected from the group consisting of buffers, solubilizers, colorants, viscosity enhancers, and preservatives to produce a pharmaceutically elegant and convenient formulation. In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components. In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components. In some embodiments, the compounds disclosed herein can be formulated in a liquid pharmaceutical composition for intraocular administration. Compositions for intraocular use can contain one or more agents selected from the group consisting of buffers, solubilizers, colorants, viscosity enhancers, and preservatives to produce a pharmaceutically elegant and convenient formulation.

[0189] In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components. In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components. In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components. In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components. In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components. In some embodiments, the composition for intraocular use can contain a preservative, such as benzalkonium chloride and / or EDTA, but is not limited thereto, to protect against microbial contamination. Other possible preservatives include, but are not limited to, benzyl alcohol, methylparaben, propylparaben, and chlorobutanol. Preferably, a preservative, or a combination of preservatives, is used to provide microbiological protection in addition to protection from oxidation of the components.

[0190] In some embodiments, the compounds disclosed herein are tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups, or In some embodiments, the compounds disclosed herein can be formulated in a liquid pharmaceutical composition for intraocular administration. Compositions for intraocular use can contain one or more agents selected from the group consisting of buffers, solubilizers, colorants, viscosity enhancers, and preservatives to produce a pharmaceutically elegant and convenient formulation. The composition may be administered orally as an elixir. Compositions for oral use may be prepared using pharma- ceutical refinements. In order to produce a palatable preparation, sweeteners, flavoring agents, coloring agents, and preservatives are selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. The composition may contain one or more agents selected from the following: Pharmaceutical compositions comprising an excipient and one or more compounds disclosed herein are also provided.

[0191] In some embodiments, tablets are prepared using non-toxic pharma- ceutically acceptable excipients suitable for the manufacture of tablets. It contains the active ingredient mixed with an excipient. These excipients can be, for example, (1) an inert diluent, For example, calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or or alginic acid, (3) a binder, such as starch, gelatin, or acacia, and ( 4) Lubricants, which may be, for example, magnesium stearate, stearic acid, or talc These tablets, even without coating, delay disintegration and absorption in the gastrointestinal tract. , by known techniques to provide a sustained effect over a longer period of time. It may be coated with, for example, glyceryl monostearate or glyceryl distearate. A time delay material such as glyceryl phosphate can be used.

[0192] To prepare pharmaceutical compositions from the compounds disclosed herein, pharma- ceutically acceptable The carrier may be either a solid or liquid. Solid form preparations include powders, tablets, etc. Solid carriers include tablets, pills, capsules, cachets, suppositories, and dispersible granules. may also act as a diluent, flavoring agent, binder, preservative, tableting, disintegrating agent, or encapsulating material. The substance may be one or more substances.

[0193] A free compound, or a pharmaceutically acceptable prodrug, metabolite, analogue, derivative, solvent The compounds disclosed herein in the form of a complex, or a salt, can be administered parenterally for in vivo applications by injection or by prolonged stepwise perfusion. Administration can be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavitary, or transdermal. For in vitro studies, the compound can be added or dissolved in a suitable biologically acceptable buffer and added to cells or tissues .

[0194] In powders, the carrier is a micronized solid in a mixture having the micronized active ingredient being. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in a suitable ratio and compressed into the desired shape and size.

[0195] Powders and tablets preferably contain 5% - 70% of the active compound. Suitable carriers are , magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, de xtrose, starch, gelatin, tragacanth, methylcellulose, carboxymethyl cellulose sodium, low melting wax, cocoa butter, etc. The term "preparation" refers to a formulation of the active compound with an encapsulating material as a carrier that provides a capsule agent associated therewith, thus surrounding the active ingredient with the carrier with or without other carriers and is therefore intended to include. Similarly, cachet agents and lozenge agents are included. Tablets, powders , capsules, pills, cachet agents, and lozenge agents can be used as solid dosage forms suitable for oral administration .

[0196] For preparing suppositories, low melting point waxes such as mixtures of fatty acid glycerides or cocoa butter are first melted, and the active ingredient is homogeneously dispersed therein by stirring. Thereafter, the melted homogeneous mixture is poured into a mold of a convenient size and cooled, thereby solidifying it. The melted wax is first melted, and the active ingredient is homogeneously dispersed therein by stirring. Thereafter, the melted homogeneous mixture is poured into a mold of a convenient size and cooled, thereby solidifying it.

[0197] Preparations in liquid form include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. In the case of parenteral injection, the liquid preparation can be formulated in a solution in an aqueous polyethylene glycol solution. For parenteral injection, the liquid preparation can be formulated in a solution in an aqueous polyethylene glycol solution. Thereafter, the melted homogeneous mixture is poured into a mold of a convenient size and cooled, thereby solidifying it.

[0198] If parenteral application is required or desired, particularly suitable mixtures for the compounds disclosed herein are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions, or implants including suppositories. Specifically, carriers for parenteral administration include aqueous glucose solutions, physiological saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, and the like. Ampoules are a convenient unit dosage form. The compounds disclosed herein may be incorporated into liposomes or administered by transdermal pumps or patches. Suitable pharmaceutical mixtures for use in the pharmaceutical compositions and methods disclosed herein include, for example, those described in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO96 / 05309, the teachings of both of which are incorporated herein by reference. Particularly suitable mixtures for the compounds disclosed herein are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions, or implants including suppositories. Specifically, carriers for parenteral administration include aqueous glucose solutions, physiological saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, and the like. For parenteral injection, the liquid preparation can be formulated in a solution in an aqueous polyethylene glycol solution. Thereafter, the melted homogeneous mixture is poured into a mold of a convenient size and cooled, thereby solidifying it. Ampoules are a convenient unit dosage form. The compounds disclosed herein may be incorporated into liposomes or administered by transdermal pumps or patches. Suitable pharmaceutical mixtures for use in the pharmaceutical compositions and methods disclosed herein include, for example, those described in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO96 / 05309, the teachings of both of which are incorporated herein by reference. In some embodiments, preparations for parenteral administration include sterile aqueous or non-aqueous solutions. For example, PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub.Co.,Easton,PA) and WO96 / 05309, the teachings of both of which are incorporated herein by reference. Thereafter, the melted homogeneous mixture is poured into a mold of a convenient size and cooled, thereby solidifying it.

[0199] In some embodiments, preparations for parenteral administration include sterile aqueous or non-aqueous solutions. Examples include solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, poly ethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcohol / aqueous solutions, emulsions or suspensions, e.g., physiological saline, and buffer media. Parenteral vehicles include sodium chloride solutions, Ringer's glucose, glucose, and sodium chloride, and lactated Ringer's Intravenous vehicles include water and nutrient supplements, electrolyte supplements (such as those based on Ringer's glucose etc.), etc. For example, preservatives such as antibacterial agents, antioxidants, chelating agents, growth factors, and inert gases and other additives may also be present.

[0200] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use are prepared by dispersing the micronized active ingredient in water using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. in water.

[0201] Solid-form preparations intended to be converted to a liquid-form preparation immediately before use for oral administration are also included. Such liquid-form preparations include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0202] Pharmaceutical preparations may preferably be in unit dosage form. In such form, the preparation is ​​It is subdivided into unit doses containing an amount of the active ingredient. The unit dosage form is a package containing discrete amounts of the preparation such as encapsulated tablets, capsules, and powders in vials or ampoules. It can be a packaged preparation. Also, the unit dosage form can be itself a capsule, tablet, cachet, or lozenge, or can be an appropriate number of any of these in packaged form.

[0203] The amount of the active ingredient in the unit dose preparation can vary or be adjusted within the range of 0.1 mg to 10,000 mg, more typically 1.0 mg to 1000 mg, and most typically 10 mg to 500 mg, according to the particular application and the potency of the active ingredient. The composition can also contain other compatible therapeutic agents, if desired.

[0204] Some compounds can have limited solubility in water and, therefore, may require a surfactant or other suitable co-solvent in the composition. Such co-solvents include Polyso rbate 20, 60, and 80, Pluronic F-68, F-84, and P- 103, cyclodextrin, and polyoxyl 35 castor oil. Such co-solvents are typically used at a concentration of about 0.01 wt% to about 2 wt%.

[0205] To reduce dispensing variability of the formulation, reduce physical separation of the components of a suspension or emulsion of the formulation, and / or otherwise improve the formulation, a viscosity greater than that of a simple aqueous solution may be desirable and achievable. Such viscosity increasing agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethyl Cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, chondroi tin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing are included Typically, such viscosity increasing agents are used at concentrations of about 0.01 wt% and about 2 wt% .

[0206] The compositions disclosed herein further include components that provide sustained release and / or comfort . Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides , and micronized drug carrier matrices. These components are described in more detail in U.S. Patent Nos. 4,91 1,920, 5,403,841, 5,212,162, and 4,8 61,760. The entire contents of these patents are hereby incorporated by reference herein in their entirety for all purposes .

[0207] Thereby, methods are provided for alleviating wound healing and mediating tissue repair (including, but not limited to, the treatment of peripheral and coronary vascular diseases ). In accordance with these methods, a subject having a wound or in need of tissue repair is treated with a free compound or a pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt of a compound disclosed herein, either at the wound site or damaged tissue site or systemically . Generally, the terms "treating", "treatment", etc. are used herein to mean acting on a subject, tissue, or cell so as to obtain a desired pharmacological and / or physiological effect . The effect is to completely or partially prevent a disease or disorder or its signs or symptoms .

[0208] Typically, the terms "treating", "treatment", etc. are used herein to mean acting on a subject, tissue, or cell so as to obtain a desired pharmacological and / or physiological effect . The effect is to completely or partially prevent a disease or disorder or its signs or symptoms . In terms of prevention, it can be preventive and / or therapeutic in terms of partially or completely curing, for example, pulmonary embolism after medical treatment, and / or complications and / or side effects resulting therefrom. It can be therapeutic. As used herein, "treating" encompasses any treatment or prevention of a disease or disorder in a vertebrate, mammal, particularly a human, and includes (a) preventing the onset of a disease or disorder in a subject who may be predisposed to having the disease or disorder but has not yet been diagnosed as having it; (b) suppressing, i.e., halting the onset of, a disease or disorder; or (c) alleviating or ameliorating, i.e., causing regression of, a disease or disorder.

[0209] Various pharmaceutical compositions useful for the remission of certain diseases and disorders are provided. The pharmaceutical composition according to one embodiment is prepared by formulating the compounds disclosed herein in the form of the free compound or a pharmaceutically acceptable prodrug, metabolite, analog, derivative, solvate, or salt, either alone or together with other pharmaceutical agents suitable for administration to a subject using carriers, excipients, and additives or adjuvants. Frequently used carriers or adjuvants include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk proteins, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol, and solvents such as sterile water, alcohol, glycerol, and polyhydric alcohols. Intravenous vehicles include water and nutrient supplements.

[0210] ​​​​​​​​​​​​​​​Examples of preservatives include antibacterial agents, antioxidants, chelating agents, and inert gases. Other Examples of pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients such as those described in Remington ’s Pharmaceutical Sciences, 15th ed. Easton : Mack Publishing Co., 1405-1412, 1461-148 7 (1975), and The National Formulary XIV., 14 th ed. Washington: American Pharmaceutical Association (1975), such as salts, preservatives, buffers, etc. The contents of these are incorporated herein by reference. The pH and exact concentrations of the various components of the pharmaceutical composition are adjusted according to routine techniques in the art. See, for example, Goodman and Gilman (eds.), 1990, THE PHARMACOLOG ICAL BASIS FOR THERAPEUTICS (7th ed.). See also .

[0211] The pharmaceutical composition is preferably prepared and administered in dosage units. Solid dosage units are tablets, capsules, and suppositories. Different daily dosages are used depending on the activity of the compound, the mode of administration, the nature and severity of the disease or disorder, and the age and weight of the subject. This can be obtained.

[0212] However, in certain circumstances, higher or lower daily dosages may be appropriate and can be obtained. Administration of the daily dosage can be by single administration in the form of an individual dosage unit or several smaller dosage units, or by multiple administrations of divided dosages at specific intervals. This can be done either way. This can be achieved. ​

[0213] The pharmaceutical compositions contemplated herein can be administered locally or systemically at therapeutically effective doses. The amount effective for this use will, of course, depend on the severity of the disease or disorder as well as the weight and general condition of the subject. Typically, dosages used in vitro can provide useful guidance regarding the amounts useful for in situ administration of the pharmaceutical composition, and the dosage effective for the treatment of a particular disorder can be determined using animal models.

[0214] For example, various considerations are described in Langer, 1990, Science, 249:1527, Goodman and Gilman’s (eds.), 1990 (ibid.), each of which is hereby incorporated by reference herein for all purposes. The dosage for parenteral administration of an active pharmaceutical agent can be converted to the corresponding oral dosage by multiplying by an appropriate conversion factor for parenteral dosage. For general application, multiplying the parenteral dosage (mg / mL) by 1.8 gives the corresponding oral dosage (milligrams (“mg” ). For oncological applications, multiplying the parenteral dosage (mg / mL) by 1.6 gives the corresponding oral dosage (mg). The average adult body weight is about 70 kg. For example, see Miller-Keane, 1992, ENCYCLOPEDIA & DICTION ARY OF MEDICINE, NURSING & ALLIED HEALTH, 5th Ed., (W.B. Saunders Co.), pp. 1708 and 1651 for reference.

[0215] The methods by which the compounds disclosed herein can be administered for oral use include, for example, those in which the active ingredient is A hard gelatin capsule agent mixed with an active solid diluent, or a soft gelatin capsule agent mixed with a co-solvent mixture such as PEG 400 containing Tween-20 can be. The compounds disclosed herein can also be administered in the form of an injectable sterile aqueous or fatty solution or suspension . Generally, the compounds can be administered intravenously or, for example, as an oral dose of 0.1 μg to 20 mg / kg administered every 3 to 24 hours . Preparations for oral use can be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate

[0216] , calcium phosphate, or kaolin . They can also be in the form of soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium such as peanut oil, liquid paraffin , or olive oil . Aqueous suspensions usually contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions

[0217] . Such excipients are (1) suspending agents such as sodium carboxymethyl cellulose , methylcellulose, hydroxypropylmethylcellulose, sodium alginate, poly vinylpyrrolidone, tragacanth gum, and acacia gum, (2) dispersing or wetting agents which can be, and the dispersing or wetting agents are (a) naturally occurring phosphatides such as lecithin,( b) condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate,( c) condensation products of ethylene oxide and long-chain aliphatic alcohols such as heptadecaethyleneoxy cetanol, (d) condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitol monooleate . substances, or (e) partial esters derived from ethylene oxide, fatty acids, and hexitol anhydrides and can be, for example, condensation products with polyoxyethylene sorbitan monooleate.

[0218] The pharmaceutical composition can be in the form of an injectable sterile aqueous or fatty suspension. This suspension can be formulated according to known methods using the above-mentioned suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations can be injectable sterile solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conveniently used as solvents or suspending media. For this purpose, any non-irritating fixed oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectable substances.

[0219] The compounds disclosed herein can also be administered in the form of an ophthalmic composition for topical application to the eye, preferably in the form of eye drops. The compounds disclosed herein can also be administered in the form of intravitreal injection.

[0220] The compounds disclosed herein can also be administered in the form of suppositories for rectal administration of drugs. These compositions are prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0221] ​​​​​​​​​​The compounds disclosed herein for use in the methods disclosed herein can also be administered in the form of a liposomal delivery system, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine, or phosphatidylcholine. For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds disclosed herein can be used. In addition, some of the compounds disclosed herein can form solvates with water or common organic solvents. Such solvates are included within the scope of the methods contemplated herein.

[0222] For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds disclosed herein can be used. In addition, some of the compounds disclosed herein can form solvates with water or common organic solvents. Such solvates are included within the scope of the methods contemplated herein.

[0223] In addition, some of the compounds disclosed herein can form solvates with water or common organic solvents. Such solvates are included within the scope of the methods contemplated herein. In addition, some of the compounds disclosed herein can form solvates with water or common organic solvents. Such solvates are included within the scope of the methods contemplated herein. In addition, some of the compounds disclosed herein can form solvates with water or common organic solvents. Such solvates are included within the scope of the methods contemplated herein.

[0224] B. Effective Dosage The pharmaceutical compositions provided herein include compositions in which the active ingredient is present in a therapeutically effective amount, i.e., an amount effective to achieve the intended purpose. The actual amount effective for a particular application depends, inter alia, on the condition being treated. The dosage and frequency (single or multiple doses) of the compound administered will vary depending on a variety of factors, such as the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature of the disease being treated (e.g., a disease responsive to thrombin and / or KLKB1 inhibition) and the degree of its symptoms; the presence of other diseases or other health-related problems; the type of concomitant therapy; and any complications or treatment regimens resulting from any disease. The dosage and frequency (single or multiple doses) of the compound administered will vary depending on a variety of factors, such as the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature of the disease being treated (e.g., a disease responsive to thrombin and / or KLKB1 inhibition) and the degree of its symptoms; the presence of other diseases or other health-related problems; the type of concomitant therapy; and any complications or treatment regimens resulting from any disease.

[0225] The dosage and frequency (single or multiple doses) of the compound administered will vary depending on a variety of factors, such as the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature of the disease being treated (e.g., a disease responsive to thrombin and / or KLKB1 inhibition) and the degree of its symptoms; the presence of other diseases or other health-related problems; the type of concomitant therapy; and any complications or treatment regimens resulting from any disease. The dosage and frequency (single or multiple doses) of the compound administered will vary depending on a variety of factors, such as the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature of the disease being treated (e.g., a disease responsive to thrombin and / or KLKB1 inhibition) and the degree of its symptoms; the presence of other diseases or other health-related problems; the type of concomitant therapy; and any complications or treatment regimens resulting from any disease. The dosage and frequency (single or multiple doses) of the compound administered will vary depending on a variety of factors, such as the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature of the disease being treated (e.g., a disease responsive to thrombin and / or KLKB1 inhibition) and the degree of its symptoms; the presence of other diseases or other health-related problems; the type of concomitant therapy; and any complications or treatment regimens resulting from any disease. The dosage and frequency (single or multiple doses) of the compound administered will vary depending on a variety of factors, such as the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature of the disease being treated (e.g., a disease responsive to thrombin and / or KLKB1 inhibition) and the degree of its symptoms; the presence of other diseases or other health-related problems; the type of concomitant therapy; and any complications or treatment regimens resulting from any disease. The dosage and frequency (single or multiple doses) of the compound administered will vary depending on a variety of factors, such as the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature of the disease being treated (e.g., a disease responsive to thrombin and / or KLKB1 inhibition) and the degree of its symptoms; the presence of other diseases or other health-related problems; the type of concomitant therapy; and any complications or treatment regimens resulting from any disease. The dosage and frequency (single or multiple doses) of the compound administered will vary depending on a variety of factors, such as the route of administration; the size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature of the disease being treated (e.g., a disease responsive to thrombin and / or KLKB1 inhibition) and the degree of its symptoms; the presence of other diseases or other health-related problems; the type of concomitant therapy; and any complications or treatment regimens resulting from any disease. Other treatment regimens or therapeutic agents can be used in parallel with the methods and compounds disclosed herein.

[0226] For any compound described herein, a therapeutically effective amount can be initially determined by various techniques known in the art, such as biochemical characterization of enzyme (thrombin or KLKB1) inhibition, cell culture assays, etc. The target concentration is, for example, the concentration of the active compound(s) that can reduce the enzyme activity measured using the described method.

[0227] A therapeutically effective amount for use in humans can be determined from animal models. For example, a human dosage can be devised to achieve the concentration found to be effective in animals. The dosage in humans can be adjusted, as described above, by monitoring enzyme inhibition and adjusting the dosage up or down.

[0228] The dosage can vary depending on the requirements of the patient and the compound used. The dosage administered to a patient should be sufficient to affect a beneficial therapeutic response in the patient over a long period of time in the context of the methods disclosed herein. The magnitude of the dosage is also determined by the presence, nature, and extent of any adverse side effects. Generally, treatment is initiated at a lower dosage, which is less than the optimal dosage of the compound. Thereafter, the dosage is increased gradually until the optimal effect is achieved under the circumstances. In some embodiments of the methods disclosed herein, the dosage range is from 0.001 w / v% to 10 w / v%. In some embodiments, the dosage range is from 0.1 w / v% to 5 w / v%. embodiments, the dosage range is from 0.1 w / v% to 5 w / v%.

[0229] The amount and interval of dosing are adjusted individually to provide an effective administered dosage for the particular clinical indication being treated. The concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. A treatment regimen is provided.

[0230] Using the teachings provided herein, an effective prophylactic or therapeutic treatment regimen that does not cause significant toxicity but is fully effective in treating the clinical symptoms exhibited by a particular patient can be planned. This planning should involve a careful selection of the active compound by considering factors such as the potency of the compound, relative bioavailability, patient weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity profile of the selected agent. A treatment regimen is provided. The concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. The concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. The concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. Accordingly, in some embodiments, the dosage levels of the compounds disclosed herein used in the method are, for example, on the order of about 0.1 mg to about 1 mg, about 1 mg to about 10 mg, about 0.5 mg to about 20 mg per 1 kg of body weight (average adult body weight 70 kg), and the preferred dosage range is about 0.1 mg to about 20 mg per 1 kg of body weight per day (about 7.0 mg to about 1.4 g per patient per day). The amount of the compounds disclosed herein that can be combined with a carrier material to provide a single dosage will vary depending on the host being treated and the particular mode of administration. For example, formulations for oral administration to humans can contain from about 5 μg to 1 g of the compounds disclosed herein, together with a suitable and convenient amount of carrier material that can vary in the range of about 5 to 95 percent of the total composition. Unit dosage forms can generally contain from about 0.1 mg to 500 mg of the compounds disclosed herein.

[0231] However, the specific dosage level for any particular patient will depend on a variety of factors, including the specific compound being used, the concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. the concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. the concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. the concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. the concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. the concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. the concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. the concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual. the concentration of the compound can be provided, thereby providing a treatment regimen appropriate to the severity of the disease state of the individual.

[0232] However, the specific dosage level for any particular patient will depend on a variety of factors, including the specific compound being used, The activity, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination drugs, and severity of the particular disease being treated depend on a variety of factors, including the above. It is understood that it depends on various factors including the above. It is understood.

[0233] C. Toxicity The ratio between the toxicity and the therapeutic effect of a particular compound is its therapeutic index, which can be expressed as the ratio between the LD 50 (the amount of the compound that is lethal in 50% of the population ) and the ED 50 (the amount of the compound that is effective in 50% of the population ). Compounds with a high therapeutic index are preferred. Therapeutic index data obtained from in vitro assays, cell culture assays, and / or animal studies can be used in devising the dosage range for human use. The dosage of such a compound is preferably within the plasma concentration range that includes little or no toxic ED . The dosage can vary within this range depending on the dosage form used and the route of administration utilized. For example, see Fingl et al., The Pharmacological Basis 50 of Therapeutics, Ch. 1, p. 1, 1975. . The exact formulation, route of administration, and dosage can be selected by the individual practitioner taking into account the patient's condition and the particular method in which the compound is to be used. In the case of in vitro formulations, the exact formulation and dosage can be selected by the practitioner taking into account the patient's condition and the particular method in which the compound is to be used. For example, see Fingl et al., The Pharmacological Basis of Therapeutics, Ch. 1, p. 1, 1975. The exact formulation, route of administration, and dosage can be selected by the individual practitioner considering the patient's condition and the particular way the compound is to be used. In the case of in vitro formulations, the exact formulation and dosage can be selected by the practitioner considering the patient's condition and the particular way the compound is to be used. It can be selected by the practitioner considering the patient's condition and the particular way the compound is to be used. It can be selected.

[0234] VII. Examples The following examples are intended to illustrate certain embodiments of the invention and are not intended to limit the scope of the invention. Abbreviations used herein are otherwise indicated. The abbreviations used herein are otherwise indicated. Unless otherwise indicated, they have their conventional meanings in the relevant art. Specific abbreviations include the following: Å = angstrom, Ac2O = acetic anhydride, AcOH = acetic acid, aq = aqueous, Bt = benzotriazole, BOC = N-tert-butoxycarbonyl , br = broad, t-BuOH = tert-butanol, °C = Celsius temperature, d = doublet , DABCO = 1,4-diazabicyclo[2.2.2]octane, DCE = 1,2-dichloro ethane, DCM = dichloromethane, dd = doublet of doublets, DIEA = diisopropylethylamine , DMAP = 4-dimethylaminopyridine, DMF = N,N-dimethylformamide , DMSO = dimethyl sulfoxide, δ = chemical shift (in ppm unless otherwise indicated ), EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide , eq = equivalent, Et2O = diethyl ether, Et3N = triethylamine , EtOAc = ethyl acetate, EtOH = ethanol, g = gram, h (or hr) = hour , HOBt = hydroxybenzotriazole, HPLC = high performance liquid chromatography , Hz = Hertz, IC 50 = inhibitory concentration at 50% inhibition, J = coupling constant (in Hz unless otherwise indicated ), LC = liquid chromatography, LHMDS = lithium hexamethyldisilazide , m = multiplet, M = mole, [M+H] + = parent mass spectrum peak + H + , MS = mass spectrum, ms = molecular sieve, MP = melting point, Me2NH = dimethylamine, MeOH = methanol, mg = milligram, mL = milliliter, mM = millimole, mmol = millimole, min = minute, μL = microliter, μM = micromole, ng = Nanogram, nM = nanomole, NMR = nuclear magnetic resonance, ppm = one millionth, q = quartet Line, R f = Retention factor, RT = room temperature, s = singlet, t = triplet, TFA = trifluoroacetic acid , THF = tetrahydrofuran, TLC = thin layer chromatography. List of general procedures

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0235] Synthesis Example Example 1: Preparation of Intermediate 1 The synthesis of Intermediate 1 was carried out according to the following General Procedure 1.

Chem.

[0236] Example 2: Preparation of Intermediate 2 The synthesis of Intermediate 2 followed the procedure of General Procedure 2 below.

Chemical formula

[0237] Example 3: Preparation of Compound 1 The synthesis of Compound 1 followed the procedure of General Procedure 3 below.

Chemical Structure

[0238] Example 4: Preparation of Compound 2 The synthesis of Compound 2 was carried out according to the procedure of General Procedure 4 below.

Chemical formula

[0239] Example 5: Preparation of Compound 3 The synthesis of Compound 3 was carried out according to the procedure of General Procedure 5a below.

Chemical formula

[0240] Example 6: Preparation of Compound 4 The synthesis of Compound 4 was carried out according to the procedure of General Procedure 5b below.

Chemical formula

[0241] Example 7: Preparation of Compound 5 The synthesis of Compound 5 was carried out according to the procedure of General Procedure 6a below. [Chemical formula] ​ In ethyl acetate (600 mL), a cold (0 °C) solution of tert-butyl 3-(5-(((5-chlorothiophen- 2-yl)methyl)amino)-1-(3-hydroxy-2,2-dimethylpropanoyl) -1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate (Compound 4, 0.4 g, 0.78 mmol, 1.0 equiv) was added dropwise with iodotrimethyl silane (0.5 mL). The reaction mixture was allowed to warm to room temperature and stirred for 30 h. The reaction was monitored by LC-MS and TLC. After completion, the reaction mixture was washed with sodium bicarbonate solution (20%, 150 mL), water (150 mL), and subsequently brine (150 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC using ammonia-water as the mobile phase to give 1-(5-(((5-chlorothio phen-2-yl)methyl)amino)-3-(3-methylpiperidin-3-yl)-1H -pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one (Compound 5, 0.030 g, 9.3% yield). m / z 410.90 [M+1]+ 1H NMR (400 MHz, DMSO) δ 7.71 (s, 1H), 7.00 (s, 2H), 5.57 (s, 1H), 4.89 - 4.75 (m, 1H), 4.44 (s, 2H), 3. 85 (s, 2H), 2.89 (s, 4H), 2.02 - 1.99 (m, 1H), 1.62 (s, 3H), 1.32 (s, 6H), 1.19 (s, 3H) ppm. Example 8: Preparation of Compound 6

[0242] The synthesis of Compound 6 was carried out according to the procedure of General Procedure 5a below.

Chemical formula

[0243] Example 9: Preparation of Compound 7 The synthesis of Compound 7 was carried out according to the procedure of General Procedure 6b below.

Chemical formula

[0244] Example 10: Preparation of Compound 8 The synthesis of Compound 8 was carried out according to the procedure of General Procedure 5a below.

Chemical Structure

[0245] Example 11: Preparation of Compound 9 The synthesis of Compound 9 was carried out according to the procedure of General Procedure 6b below.

Chemical formula

[0246] Example 12: Preparation of Compound 10 The synthesis of Compound 10 was carried out according to the procedure of General Procedure 5a below.

Chemical Structure

[0247] Example 13: Preparation of Compound 11 The synthesis of Compound 11 was carried out according to the procedure of General Procedure 6b below.

Chemical Structure

[0248] Example 14: Preparation of Compound 12 The synthesis of Compound 12 was carried out according to the procedure of General Procedure 5a below.

Chemical Structure

[0249] Example 15: Preparation of Compound 13 The synthesis of Compound 13 was carried out according to the procedure of General Procedure 6b below.

Chemical Structure

[0250] Example 16: Preparation of Intermediate 3 The synthesis of Intermediate 3 was carried out according to the procedure of General Procedure 2 below.

Chemical formula

[0251] Example 17: Preparation of Compound 14 The synthesis of compound 14 followed the procedure of General Procedure 3 below. [ka] tert-Butyl 4-(2-cyanoacetyl)piperidine in isopropanol (210 mL) azine-1-carboxylate) (Intermediate 3, 7.0 g, 27.6 mmol, 1.0 equiv.) To the solution, add hydrazine monohydrate (1.65 mL, 33.2 mmol, 1.2 equiv.) dropwise. This was followed by the addition of acetic acid (1.65 mL, 27.6 mmol, 1.0 equiv). The mixture was stirred at 85° C. for 4-5 hours. After completion, the reaction mixture was evaporated under reduced pressure. The residue was Using silica gel (60-120 mesh), 10-15% methanol in dichloromethane was used. The compound was purified by column chromatography eluting with tert-butyl 4-(5- Amino-1H-pyrazol-3-yl)piperidine-1-carboxylate (Compound 14 6.2 g, 84% yield, m / z 266.17. 11H NMR (DMSO-d 6, 400 MHz) δ 5.182 (1H, s), 3.935 - 3.965 (2H, d), 3.172 (2H, s), 2.791 (1H, m), 1.747 - 1.802 (2H, d ), 1.424 (9H, s), 1.361 - 1.402 (2H, d), 1.341 - 1. 351 (1H, d) ppm.

[0252] Example 18: Preparation of Compound 15 The synthesis of Compound 15 was carried out according to the procedure of General Procedure 4 below.

Chemical Structure

[0253] Example 19: Preparation of Compound 16 The synthesis of Compound 16 was carried out according to the procedure of General Procedure 5a below.

Chemical formula

[0254] Example 20: Preparation of Compound 17 The synthesis of Compound 17 was carried out according to the procedure of General Procedure 6a below.

Chemical formula

[0255] Example 21: Preparation of Intermediate 4 The synthesis of Intermediate 4 was carried out according to the procedure of General Procedure 7 below.

Chemical formula

[0256] Example 22: Preparation of Intermediate 5 The synthesis of Intermediate 5 was carried out according to the procedure of General Procedure 2 below.

Chemical Structure

[0257] Example 23: Preparation of Compound 18 The synthesis of Compound 18 was carried out according to the procedure of General Procedure 3 below.

Chemical formula

[0258] Example 24: Preparation of Compound 19 The synthesis of compound 19 followed the procedure of General Procedure 4 below. [ka] Allyl 4-(5-amino-1H-pyrazol-3-yl)piperidine in MeOH (140 mL) Lysine-1-carboxylate (compound 18, 7.0 g, 28 mmol, 1.0 equiv.) To the cooled solution (0 °C) was added acetic acid (2.52 mL, 42 mmol, 1.5 equiv.), followed by 5- Chlorothiophene-2-carbaldehyde (4.9 g, 33.6 mmol, 1.2 equiv.) The reaction mixture was stirred at room temperature for 4-5 hours. Sodium borohydride (3.5 g, 56 mmol, 2.0 equiv.) was added in small portions to 4 The reaction mixture was added over a period of 5 minutes and stirred for an additional 4-5 hours. The mixture was concentrated under reduced pressure and the residual mass was poured into ice-cold water with stirring. The product was then extracted with acetic acid. Extract with ethyl acetate, dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure. The residue was eluted with 2 - 4% methanol in dichloromethane using neutral silica gel in a column and purified by chromatography to obtain pure allyl 4 - (5 - (((5 - chlorothiophen -2 - yl)methyl)amino)-1H - pyrazol - 3 - yl)piperidine - 1 - car boxylate (Compound 19, 4.5 g, yield 45%). m / z [M + H]+ 380 .11 1H NMR (400 MHz, DMSO) δ11.41 (s, 1H), 6.88 (dd, J = 30.0, 3.7 Hz, 2H), 5.94 (ddd, J = 22.4, 10. 5, 5.2 Hz, 1H), 5.68 (d, J = 6.2 Hz, 1H), 5.28 (dd, J = 16.4, 2.5 Hz, 2H), 5.19 (dd, J = 10.5, 1.5 Hz, 1H) , 4.60 - 4.46 (m, 2H), 4.28 (d, J = 6.1 Hz, 2H), 4.12 (d, J = 4.8 Hz, 1H), 4.02 (d, J = 13.2 Hz, 2H), 3.17 ( d, J = 4.0 Hz, 2H), 2.90 (s, 2H), 2.69 (t, J = 11.6 Hz , 1H) ppm.

[0259] Example 25: Preparation of Compound 20 The synthesis of Compound 20 was carried out according to the procedure of General Procedure 5a below.

Chemical formula

[0260] Example 26: Preparation of Compound 21 The synthesis of Compound 21 was carried out according to the procedure of General Procedure 8a below.

Chemical formula

[0261] Example 27: Preparation of Intermediate 6 The synthesis of Intermediate 6 was carried out according to the procedure of General Procedure 9 below. [Chemical formula] A cooled solution (-78 °C) of diisopropylamine (8.74 g, 86.4 mmol, 1.6 equivalents) in THF (200 mL) was added with n-BuLi (34.5 mL, 86.4 mmol, 1. 6 equivalents), and the mixture was stirred at 0 °C for 1 hour. The mixture was cooled to -78 °C, and to this was added tert-butyl 2-oxopiperidine-1-carboxylate (10.0 g, 54.0 mmol, 1.0 equivalent). The mixture was stirred for 1 hour, and methyl chloroformate (6.1 2 g, 64.8 mmol, 1.2 equivalents) was added. The reaction mixture was warmed to room temperature overnight and monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ammonium chloride and evaporated under reduced pressure. The residue was extracted with ethyl acetate (2 × 150 mL), and the combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography using silica gel (60 - 120 mesh) and eluting with 4 0% ethyl acetate in n-hexane to give 1-(tert (tert-Butyl)-3-methyl-2-oxopiperidine-1,3-dicarboxylate (Intermediate 6, 9.2 g, yield 70%) was obtained. m / z 202.13 [M-56] + ; 1 H N MR (400 MHz, DMSO) δ 3.70 (s, 1H), 3.62 - 3.50 (m, 3 H), 2.10 - 1.89 (m, 2H), 1.88 - 1.72 (m, 2H), 1.42( s, 9H) ppm.

[0262] Example 28: Preparation of Intermediate 7 The synthesis of Intermediate 7 was carried out according to the procedure of General Procedure 1 below.

Chemical Structure

[0263] Example 29: Preparation of Intermediate 8 The synthesis of Intermediate 8 followed the procedure of General Procedure 6b below.

Chemical formula

[0264] Example 30: Preparation of Intermediate 9 The synthesis of Intermediate 9 followed the procedure of General Procedure 2 below.

Chemical formula

[0265] Example 31: Preparation of Compound 22 The synthesis of Compound 22 was carried out according to the procedure of General Procedure 3 below.

Chemical formula

[0266] The synthesis of Compound 23 was carried out according to the procedure of General Procedure 4 below. To a cooled solution (0 °C) of 3-(5-amino-1H-pyrazol-3-yl)-3-methylpiperidin-2-one (Compound 22, 1.0 g, 5.15 mmol, 1.0 equivalent) in methanol (20 mL) was added dropwise acetic acid (0.3 g, 5.15 mmol, 1.0 equivalent).

Chemical formula

[0267] Example 33: Preparation of Compound 24 The synthesis of Compound 24 was carried out according to the procedure of General Procedure 5a below.

Chemical formula

[0268] Example 34: Preparation of Compound 25 The synthesis of Compound 25 was carried out according to the procedure of General Procedure 5c below. [Chemical formula] To a cooled solution (0 °C) of 3 - hydroxy - 2,2 - dimethylpropanoic acid (0.13 0 g, 1.1 mmol, 1.2 equiv) in THF (10 mL) under nitrogen, N, N,N’,N’ - tetramethyl - O - (benzotriazol - 1 - yl)uronium tetrafluoroborate (T BTU, 0.320 g, 1.0 mmol, 1.1 equiv) and diisopropylethylamine (DIEA, 0.280 g, 2.9 mmol, 3.0 equiv) were added. The reaction mixture was stirred at 3​​ Stirred for 0 minutes, and 3-(5-(((5-chlorothiophen-2-yl)methyl)amino )-1H-pyrazol-3-yl)-3-methylpiperidin-2-one (Compound 23, 0.3 g, 0.9 mmol, 1.0 equivalent) was added. The reaction was monitored by LC-MS , and after completion, the mixture was poured into water (40 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile-water as the mobile phase to give the desired product 3-(5-(((5-chlorothiophen-2-yl)methyl )amino)-1-(3-hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol -3-yl)-3-methylpiperidin-2-one (Compound 25, 0.0129 g, yield 3%). m / z 425.30 [M+1] + ; 1 H NMR (400 MHz, CD 3CN) δ 7.48 (s, 1H), 6.88 (q, J = 3.8 Hz, 2H), 6.10 ( s, 1H), 5.44 (s, 1H), 4.45 (d, J = 6.2 Hz, 2H), 3.89 (d, J = 6.2 Hz, 2H), 3.43 (t, J = 6.2 Hz, 1H), 3.27 (d , J = 6.6 Hz, 2H), 2.34 - 2.23 (m, 1H), 1.91 - 1.70 (m , 3H), 1.49 - 1.34 (m, 3H), 1.30 (s, 6H) ppm.

[0269] Example 35: Preparation of Compound 26 The synthesis of Compound 26 was carried out according to the procedure of General Procedure 5c below.

Chemical formula

[0270] Example 36: Preparation of Compound 27 The synthesis of Compound 27 was carried out according to the procedure of General Procedure 5a below.

Chemical Structure

[0271] Example 37: Preparation of Compound 28 The synthesis of Compound 28 was carried out according to the procedure of General Procedure 5a below. [Chemical Structure] To a cooled solution (0 °C) of 3 - thiophenecarboxylic acid (0.177 g, 1.38 mmol, 1.5 eq) in THF (15 mL) under nitrogen, 1 - (3 - dimethylaminopropyl)-3 - ethylcarbodiimide hydrochloride (EDCI·HCl, 0.264 g, 1.38 mmol, 1 .5 eq), and then triethylamine (TEA, 0.28 g, 2.77 mmol, 3. 0 eq) were added. The reaction mixture was stirred for 30 minutes, to which hydroxybenzotriazole (HOBt, 0.024 g, 0.18 mmol, 0.2 eq) was added, followed by 3-(5 - ( ((5 - chlorothiophen - 2 - yl)methyl)amino)-1H - pyrazol - 3 - yl )-3 - methylpiperidin - 2 - one (Compound 23, 0.3 g, 0.92 mmol, 1. )-3 - methylpiperidin - 2 - one (Compound 23, 0.3 g, 0.92 mmol, 1. 0 eq) was added. The reaction was monitored by LC - MS and after completion, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with water, brine , dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was Purified by preparative HPLC using ammonia-water as the mobile phase to obtain the desired product 3- (5 - (((5-chlorothiophen-2-yl)methyl)amino)-1-(thiophen- 3-carbonyl)-1H-pyrazol-3-yl)-3-methylpiperidin-2-one( Compound 28, 0.12 g, yield 30%). m / z 436.06 [M+1] + ; 1 H NMR (400 MHz, DMSO) δ 8.90 (d, J = 2.4 Hz, 1H), 7. 90 - 7.49 (m, 4H), 6.98 (s, 2H), 5.55 (s, 1H), 4.49 (d, J = 6.2 Hz, 2H), 3.18 (s, 2H), 2.23 (d, J = 10.4 H z, 1H), 1.75 (d, J = 10.8 Hz, 3H), 1.42 (s, 3H) ppm.

[0272] Example 38: Preparation of Compound 29 The synthesis of Compound 29 was carried out according to the procedure of General Procedure 5a below.

Chemical formula

[0273] Example 39: Preparation of Intermediate 10 The synthesis of Intermediate 10 was carried out according to the procedure of General Procedure 9 below.

Chemical formula

[0274] Example 40: Preparation of intermediate 11 The synthesis of intermediate 11 followed the procedure of General Procedure 1 below. [Chemical] 1-(tert-Butyl)-3-methyl-2-oxopyrrolidine in DMF (100 mL) -1,3-dicarboxylate (Intermediate 10, 10.0 g, 41.1 mmol, 1.0 equiv) A cooled solution (0 °C) of potassium carbonate (28.4 g, 205.5 mmol, 5.0 equiv) was added. After stirring at 0 °C for 1 hour, methyl iodide (7.02 g, 49.3 mmol, 1.2 equiv) was added. The reaction mixture was allowed to come to room temperature and stirred overnight. This was monitored by TLC and LC-MS. After completion, the reaction mixture was poured into ice-cooled water and filtered to obtain 1- (tert-Butyl)-3-methyl-3-methyl-2-oxopyrrolidine-1,3-dicarboxylate (Intermediate 11, 7.3 g, yield 69%). m / z 202.13 M-56] + 1 H NMR (400 MHz, CDCl3) δ 1 H NMR (400 MHz, CDCl3) δ 3.78 (d, J = 6.0 Hz, 5H), 2.54 (ddd, J = 1 3.0, 7.4, 4.3 Hz, 1H), 1.91 (dt, J = 13.1, 8.2 Hz, 1 H), 1.54 (d, J = 11.7 Hz, 9H), 1.49 (d, J = 11.6 Hz, 3 H) ppm. z, CDCl3) δ 3.78 (d, J = 6.0 Hz, 5H), 2.54 (ddd, J = 1 3.0, 7.4, 4.3 Hz, 1H), 1.91 (dt, J = 13.1, 8.2 Hz, 1 H), 1.54 (d, J = 11.7 Hz, 9H), 1.49 (d, J = 11.6 Hz, 3 H) ppm.

[0275] Example 41: Preparation of Intermediate 12 The synthesis of Intermediate 12 was carried out according to the procedure of General Procedure 6b below. [Chemical] 1-(tert-Butyl)-3-methyl-3-methyl-2-oxopiperidine-1,3-dicarboxylate (Intermediate 11, 5.0 g, 19.4 mmol) in dichloromethane (50 mL) -1,3-dicarboxylate (Intermediate 11, 5.0 g, 19.4 mmol, 1.0 equiv) To a cooled solution (0 °C) of acetonitrile (1.2 g, 26.5 mmol, 1.6 eq) in anhydrous tetrahydrofuran (30 mL), n-BuLi (2.5 M in hexanes, 10.6 mL, 26.5 mmol, 1.6 eq) was added dropwise over 20 minutes. After stirring for 1 hour, methyl 3-methyl-2-oxopyrrolidine-3-carboxylate (Intermediate 12, 2.6 g, 16.5 mmol, 1.0 eq) was added portionwise and the reaction mixture was stirred at -78 °C for 3 hours. The reaction was quenched with saturated ammonium chloride solution and the product was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl 3-methyl-2-oxopyrrolidine-3-carboxylate (Intermediate 12, 2.26 g, 74% yield). m / z 158.04 was added trifluoroacetic acid (2.5 mL). After stirring for 1 hour, the mixture was allowed to warm to room temperature overnight. This was monitored by TLC and LC-MS. After completion, the reaction mixture was treated with saturated NaHCO3 solution and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl 3-methyl-2-oxopyrrolidine-3-carboxylate (Intermediate 12, 2.26 g, 74% yield). m / z 158.04 with saturated NaHCO3 solution and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl 3-methyl-2-oxopyrrolidine-3-carboxylate (Intermediate 12, 2.26 g, 74% yield). m / z 158.04 (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl 3-methyl-2-oxopyrrolidine-3-carboxylate (Intermediate 12, 2.26 g, 74% yield). m / z 158.04 M+1] H NMR (400 MHz, DMSO) δ H NMR (400 MHz, + 1 DMSO) δ 7.94 (s, 1H), 3.63 (s, 3H), 3.32 - 3.14 (m, 1 DMSO) δ 7.94 (s, 1H), 3.63 (s, 3H), 3.32 - 3.14 (m, 2H), 2.58 - 2.37 (m, 1H), 2.04 - 1.86 (m, 1H), 1.26 2H), 2.58 - 2.37 (m, 1H), 2.04 - 1.86 (m, 1H), 1.26 (s, 3H) ppm.

[0276] Example 42: Preparation of Intermediate 13 The synthesis of Intermediate 13 was carried out according to the procedure of General Procedure 2 below.

Chemical formula

[0277] Example 43: Preparation of Compound 30 The synthesis of Compound 30 was carried out according to the procedure of General Procedure 3 below.

Chemical formula

[0278] Example 44: Preparation of Compound 31 The synthesis of Compound 31 was carried out according to the procedure of General Procedure 4 below. [Chemical formula] 3-(5-Amino-1H-pyrazol-3-yl)-3-methyl in methanol (20 mL), pyrrolidin-2-one (Compound 30, 1.0 g, 5.5 mmol, 1.0 equivalent) was cooled solution (0 °C), acetic acid (0.3 g, 5.5 mmol, 1.0 equivalent) was added dropwise, followed by 5 -chlorothiophene-2-carbaldehyde (0.92 g, 6.6 mmol, 1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 30 - 45 minutes. Then, sodium cyanoborohydride (0.65 g, 11.0 mmol, 2.0 equivalents) was added portionwise over 15 minutes and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure . The residue was purified by column chromatography using silica gel (60 - 100 mesh) and eluting with 0 - 5% methanol in dichloromethane to give 3-(5-((( (5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)- 3-methylpyrrolidin-2-one (Compound 31, 0.21 g, yield 12%). m / z 311.3 [M+1] + ; 1 H NMR (400 MHz, DMSO) δ 11.43( s, 1H), 7.70 (s, 1H), 6.89 (dd, J = 29.1, 3.5 Hz, 2H ), 5.77 (s, 1H), 5.35 (s, 1H), 4.29 (s, 2H), 3.20( t, J = 6.5 Hz, 2H), 2.33 (s, 1H), 2.01 (d, J = 11.9 Hz , 1H), 1.32 (s, 3H) ppm。

[0279] Example 45: Preparation of Compound 32 The synthesis of Compound 32 was carried out according to the procedure of General Procedure 5a below.

Chemical Structure

[0280] Example 46: Preparation of Compound 33 The synthesis of Compound 33 was carried out according to the procedure of General Procedure 5a below.

Chemical formula

Claims

1. A compound having the following structure: 【Chemical 1】 During the ceremony, L 1 is —NH; L 2 is a bond or —C(O), with the proviso that when L 2 is a bond, R 2 is hydrogen; L 4 is a bond; R 1 is —CH 2 —(5-chlorothiophen-2-yl); R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl; R 4 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; V is hydrogen or substituted or unsubstituted alkyl; W is absent, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, —C(O)R 6 , —C(O)NR 6 R 7 , —SO 2 R 6 , or —SO 2 NR 6 R 7 , where R 6 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R 7 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and when both R 6 and R 7 are present, they may combine to form substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; wherein W is substituted alkyl or substituted heteroalkyl, and the optional substituents for said substituted alkyl or substituted heteroalkyl group are selected from the group consisting of -OH, -NH 2 , -SH, -CN, -CF 3 , -NO 2 , halogen, -COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; X is a bond, substituted or unsubstituted alkylene, —O—, or —NR 8 —; Y is a bond, substituted or unsubstituted alkylene, —O—, or —N—, provided that when Y is —O—, W is absent; Z is a bond, —C(O)—, substituted or unsubstituted alkylene, —O—, or —NR 9 —; wherein R 8 and R 9 are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)R 6 , —C(O)NR 6 R 7 , —SR 6 , —SOR 6 , —SO 2 R 6 , —SO 2 NR 6 R 7 , —OR 6 , —NHSO 2 R 6 , or —NR 6 R 7 , wherein R 6 and R 7 are as defined above; The compound, or a pharmaceutically acceptable salt or solvate thereof, is provided that at least one of X is —NR 8 —, Y is —N—, or Z is —NR 9 —.

2. The compound of claim 1, wherein X is a bond or a substituted or unsubstituted alkylene.

3. The compound of claim 2, wherein Z is a bond or a substituted or unsubstituted alkylene.

4. The compound of claim 3, wherein Y is -N- and W is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, -C(O)R 6 , -C(O)NR 6 R 7 , -SO 2 R 6 , or -SO 2 NR 6 R 7 , wherein R 6 and R 7 may independently be substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or, when both R 6 and R 7 are present, they may combine to form substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

5. The compound of claim 4, wherein X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is a bond.

6. The compound of claim 4, wherein X is a bond and Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene.

7. The compound of claim 4, wherein X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene.

8. The compound of claim 7, wherein X and Z are both branched alkylene, and X and Z are covalently bonded.

9. A compound described in any one of claims 6 to 8, wherein Z is selected from the group consisting of substituted methylene, substituted ethylene, substituted propylene, substituted butylene, and substituted pentylene, having one or more substituents selected from the group consisting of -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

10. The compound of claim 4, wherein X is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene, and Z is -C(O)-.

11. The compound of claim 4, wherein W is hydrogen.

12. The compound of any one of claims 4 to 10, wherein W is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, -C(O)R 6 , -C(O)NR 6 R 7 , -SO 2 R 6 , and -SO 2 NR 6 R 7 .

13. The compound described in claim 12, wherein W is a substituted alkyl, substituted heteroalkyl, substituted alkenyl, or substituted heteroalkenyl having one or more substituents selected from the group consisting of -OH, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, -COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

14. The compound of claim 12, wherein W is C(O)R 6 , —C(O)NR 6 R 7 , —SO 2 R 6 , —SO 2 NR 6 R 7 , wherein R 6 and R 7 are substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 6 and R 7 combined to form substituted or unsubstituted alkylene, or substituted or unsubstituted alkylene.

15. The compound of claim 1, wherein W is absent, X is —NR 8 —, Y is a bond or substituted or unsubstituted alkylene, and Z is —NR 9 —.

16. The compound of claim 15, wherein Y is selected from the group consisting of substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, and substituted or unsubstituted pentylene.

17. The compound of claim 16, wherein R 8 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted heteroalkenyl, -COR 6 , -C(O)NR 6 R 7 , -SO 2 R 6 , and -SO 2 NR 6 R 7 , and R 9 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted heteroalkenyl, -COR 6 , -C(O)NR 6 R 7 , -SO 2 R 6 , and -SO 2 NR 6 R 7 .

18. The compound of claim 1, wherein V is hydrogen or substituted or unsubstituted methyl.

19. The compound of any one of claims 1 to 18, wherein R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused-ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.

20. The compound of claim 19, wherein L 2 is a bond and R 2 is hydrogen.

21. The compound of claim 19, wherein L 2 is —C(O)—, and R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused-ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.

22. The compound of claim 21, wherein R 2 is substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl.

23. The compound of claim 22, wherein R 2 is substituted or unsubstituted phenyl.

24. The compound of claim 23, wherein R 2 is a substituted phenyl having at least one halogen and one carboxylic acid substituent.

25. The compound of claim 24, wherein the halogen is selected from the group consisting of chlorine or fluorine.

26. The compound of claim 25, wherein the halogen is chlorine.

27. The compound of any one of claims 1 to 26, wherein L 4 is a bond and R 4 is hydrogen.

28. The compound of any one of claims 1 to 26, wherein L 4 is a bond and R 4 is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

29. The compound of claim 28, wherein R 4 is selected from the group consisting of methyl, cyano, or methoxy.

30. The compound 30. The compound of any one of claims 1 to 29, selected from the group consisting of:

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30.

32. The pharmaceutical composition of claim 31 for treating a disease or disorder in a subject, wherein the disease or disorder responds to inhibition of thrombin and / or inhibition of kallikrein.

33. The pharmaceutical composition of claim 32, wherein the disease or disorder is a thrombotic disease or disorder and / or involves the potential formation of a blood clotting thrombus or a blood clotting thrombus.

34. The pharmaceutical composition of claim 33, wherein the thrombotic disease or disorder is coronary syndrome, thromboembolism, and / or thrombosis.

35. The pharmaceutical composition described in claim 34, wherein the thromboembolism is venous thromboembolism, arterial thromboembolism, and / or cardiogenic thromboembolism.

36. The pharmaceutical composition described in claim 35, wherein the venous thromboembolism includes deep vein thrombosis and / or pulmonary embolism.

37. The pharmaceutical composition described in claim 36, wherein venous thromboembolism and / or pulmonary embolism occurs after medical treatment.

38. The pharmaceutical composition of claim 33, wherein the thrombotic disease or disorder is associated with dysfunctional coagulation or disseminated intravascular coagulation.

39. The pharmaceutical composition described in claim 38, wherein the subject is undergoing percutaneous coronary intervention (PCI).

40. The pharmaceutical composition of claim 33, wherein the thrombotic disease or disorder is associated with the potential formation of a blood clot or a blood clot and is further associated with a stroke and / or one or more transient ischemic attacks (TIAs).

41. The pharmaceutical composition of claim 40, wherein the thrombotic disease or disorder associated with the potential formation of a blood clot thrombus or a blood clot thrombus is further associated with stroke, and wherein the subject has non-valvular atrial fibrillation.

42. The pharmaceutical composition of claim 33, wherein the thrombotic disease or disorder is associated with the potential formation of a blood clot thrombus or a blood clot thrombus, and is further associated with pulmonary hypertension.

43. The pharmaceutical composition described in claim 42, wherein the pulmonary hypertension is caused by one or more left heart disorders and / or chronic thrombotic occlusive diseases.

44. The pharmaceutical composition of claim 42, wherein the pulmonary hypertension is associated with one or more lung diseases, including pulmonary fibrosis (idiopathic or otherwise) and / or hypoxia.

45. The pharmaceutical composition of claim 32, wherein the disease or disorder comprises fibrosis, Alzheimer's disease, multiple sclerosis, pain, cancer, inflammation, and / or type 1 diabetes.

46. The pharmaceutical composition described in claim 32, wherein the disease or disorder is associated with recurrent cardiac events after myocardial infarction.

47. The pharmaceutical composition described in claim 35, wherein the venous thromboembolism is associated with peripheral venous embolism due to venous thrombus formation and / or detached thrombus associated with one or more acquired or genetic risk factors.

48. The pharmaceutical composition described in claim 47, wherein the one or more risk factors include previous venous thromboembolism.

49. The pharmaceutical composition described in claim 35, wherein the cardiogenic thromboembolism is caused by intracardiac thrombus formation associated with cardiac arrhythmia, cardiac valve abnormality, artificial heart valve, or heart disease, and / or peripheral arterial embolism caused by detached thrombus.

50. The pharmaceutical composition described in claim 49, wherein the detached thrombus is in the brain (ischemic cerebral infarction).

51. The pharmaceutical composition described in claim 50, wherein the detached thrombus causes a transient ischemic attack (TIA).

52. The pharmaceutical composition described in claim 49, wherein the cardiogenic thromboembolism is caused by non-valvular atrial fibrillation.

53. The pharmaceutical composition described in claim 34, wherein the thrombosis is arterial thrombosis.

54. The pharmaceutical composition described in claim 53, wherein the arterial thrombosis is caused by one or more underlying atherosclerotic processes in the arteries.

55. The pharmaceutical composition of claim 54, wherein one or more underlying atherosclerotic processes in the arteries cause arteries to become blocked or occlude, leading to myocardial ischemia (angina, acute coronary syndrome), and causing myocardial infarction. Occlusion or occlusion of peripheral arteries (ischemic peripheral arterial disease), and / or occlusion or occlusion of arteries after vascular procedures (reocclusion or restenosis after transluminal coronary angioplasty, reocclusion or restenosis after percutaneous transluminal coronary angioplasty of peripheral arteries).

56. The pharmaceutical composition of claim 32, wherein the treatment includes adjuvant therapy.

57. The pharmaceutical composition described in claim 56, wherein the subject has a myocardial infarction and the adjunctive therapy is used in combination with thrombolytic therapy.

58. The pharmaceutical composition described in claim 56, wherein the subject has unstable angina, thrombosis, and / or heparin-induced thrombocytopenia, and the adjunctive therapy is used in combination with antiplatelet therapy.

59. The pharmaceutical composition described in claim 56, wherein the subject has non-valvular atrial fibrillation and the adjunctive therapy is used in combination with one or more other therapies.

60. The pharmaceutical composition described in claim 32, wherein the disease or disorder is a kallikrein-associated disorder.

61. The pharmaceutical composition described in claim 60, wherein the kallikrein-related disease is a thrombotic disease, a fibrinolytic disease, a fibrotic disease, a type of cancer, an inflammatory disease, or a dermatological disease.

62. The pharmaceutical composition described in claim 60, wherein the kallikrein-related disease is an ophthalmic disease.

63. The pharmaceutical composition of claim 62, wherein the compound or pharmaceutical composition is administered in the form of an ophthalmic composition that is applied topically to the eye.

64. The pharmaceutical composition described in claim 63, wherein the ophthalmic composition is in the form of eye drops.

65. The pharmaceutical composition of claim 62, wherein the compound or pharmaceutical composition is administered by intraorbital injection in the form of an ophthalmic composition.

66. The pharmaceutical composition described in claim 62, wherein the ophthalmic disease is diabetic macular edema, age-related macular degeneration, or diabetic retinopathy.

67. The pharmaceutical composition of claim 61, wherein the type of cancer is selected from the group consisting of cervical cancer, testicular cancer, or non-small cell lung adenocarcinoma, limited small cell lung cancer, glioma, malignant breast cancer, micrometastasis (e.g., micrometastasis in the blood or liver), lung metastasis, and prostate cancer.

68. The pharmaceutical composition of claim 61, wherein the inflammatory condition is sepsis, inflammatory bowel disease, inflammatory arthritis, systemic inflammatory response syndrome, hereditary angioedema, or rheumatoid arthritis.

69. The pharmaceutical composition described in claim 61, wherein the dermatological disease is atopic dermatitis, psoriasis, or Netherton syndrome.

70. A pharmaceutical composition according to any one of claims 32 to 69, wherein the compound acts by inhibiting thrombin and / or kallikrein.

71. The pharmaceutical composition of claim 70, wherein the compound acts by inhibiting tissue kallikrein and / or plasma kallikrein.

72. The pharmaceutical composition of claim 32, wherein the amount of compound administered is a therapeutically effective dose sufficient to achieve an initial concentration of the compound or its active metabolite in plasma within the range of 1 to 10 nM, 10 to 100 nM, 0.1 to 1 μM, 1 to 10 μM, 10 to 100 μM, 100 to 200 μM, 200 to 500 μM, or 500 to 1000 μM, or more.

73. The pharmaceutical composition of claim 72, wherein after intravenous injection, more than 50% of the initial compound concentration persists in the plasma for 1 hour, 3 hours, or more.

74. A pharmaceutical composition described in claim 31 for use in a method according to any one of claims 34 to 75.

75. The pharmaceutical composition of claim 31, wherein the compound has inhibitory activity against thrombin and / or plasma kallikrein within the range of 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or 500-1000 μM or more.

76. A pharmaceutical product comprising a pharmaceutical composition described in any one of claims 31 to 75.

Images