Human plasma kallikrein inhibitor

Abstract

To provide novel compounds being inhibitors of plasma kallikrein that can act on an occluding thrombus to tilt the balance of fibrinolysis / thrombosis in favor of fibrinolysis, thereby promoting reperfusion and also attenuating the hypercoagulable state, thus preventing the thrombus from reforming and re-occluding the vessel.SOLUTION: The invention provides compounds represented by formula I or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

Related applications

[0001] This application claims the benefit of priority from U.S. Provisional Patent Application No. 61 / 949,808, filed on 7 March 2014, and U.S. Provisional Patent Application No. 61 / 981,515, filed on 18 April 2014, both of which are incorporated herein by reference. [Background technology]

[0002] Serine proteases constitute the largest and most widely studied group of proteolytic enzymes. The crucial roles of serine proteases in physiological processes extend to diverse areas, including blood coagulation, fibrinolysis, complement activation, reproductive function, digestive function, and the release of bioactive peptides. Many of these life processes begin with the cleavage of a single peptide bond or several peptide bonds in a precursor protein or peptide. Sequential and limited proteolytic reactions or cascades are involved in blood coagulation, fibrinolysis, and complement activation. The biological signals that initiate these cascades can be controlled and, as well as amplified. Similarly, controlled proteolysis can be stopped or inactivated by the cleavage of a single bond in a protein or peptide.

[0003] Kallikreins are a subgroup of serine proteases. In humans, plasma kallikrein (KLKB1) has no known homologs, while tissue kallikrein-associated peptidases (KLK) encode a family of 15 closely related serine proteases. Plasma kallikreins are involved in several pathways related to coagulation, inflammation, and the endogenous pathways of the complement system.

[0004] Coagulation is the process by which blood forms a clot, for example, to stop bleeding. The physiological function of coagulation is somewhat complex insofar as it involves two distinct initial pathways that converge on a final common pathway leading to clot formation. In the final common pathway, prothrombin is converted to thrombin, which in turn converts fibrinogen to fibrin, the latter of which is the main component of the cross-linked fibrin polymer that forms the hemostatic plug. Of the two initial pathways upstream of the final common pathway, one is known as the contact-activated pathway or endogenous pathway, and the other is known as the tissue factor pathway or exogenous pathway.

[0005] The endogenous pathway begins with the formation of a primary complex on collagen by high molecular weight kininogen (HMWK), prekallikrein, and FXII (factor XII, Hagemann factor). Prekallikrein is converted to kallikrein, and FXII is activated to become FXIIa. Next, FXIIa converts factor XI (FXI) to FXIa, which in turn activates factor IX (FIX). This FIX, together with its cofactor FVIIIa, forms a "tenase" complex, which in turn activates factor X (FX) to FXa. In the final common pathway, FXa is responsible for the conversion of prothrombin to thrombin.

[0006] Prekallikrein, an inactive precursor of plasma kallikrein, is synthesized in the liver and circulates in the plasma either bound to HMWK or as free zymogen. Prekallikrein is cleaved by activated factor XII (FXIIa) to release activated plasma kallikrein (PK). Activated plasma kallikrein exhibits endopeptidase activity toward peptide bonds following arginine (preferably) and lysine. PK then generates further FXIIa in a feedback loop, which in turn activates factor XI (FXI) to FXIa, connecting to the common pathway. Initial activation of the endogenous pathway is by a small amount of FXIIa activating a small amount of PK, but it is the subsequent feedback activation of FXII by PK that controls the degree of activation of the endogenous pathway and thus controls downstream coagulation. Non-patent document 1.

[0007] Activated plasma kallikrein also cleaves HMWK, releasing bradykinin, a potent vasodilator peptide. Activated plasma kallikrein can also cleave several inactive precursor proteins to produce active products such as plasmin (from plasminogen) and urokinase (from prourokinase). Plasmin, a coagulation regulator, proteolytically cleaves fibrin into fibrin degradation products, inhibiting excessive fibrin formation.

[0008] Clinical evidence indicates that patients with acute myocardial infarction (MI) are in a hypercoagulable (hypoclotogenic) state. Paradoxically, this hypercoagulation is further exacerbated in those receiving fibrinolytic therapy. In such patients, increased thrombin production, measured by thrombin-antithrombin III (TAT) levels, is observed, even compared to the already high levels seen in those receiving heparin monotherapy. Non-patent document 2. It has been suggested that the increase in thrombin is due to plasmin-mediated activation of the endogenous pathway, specifically direct activation of FXII by plasmin.

[0009] The increased coagulation induced by fibrinolysis not only leads to an increased rate of reocclusion, but is also at least partially involved in the failure to achieve complete fibrinolysis of blood clots (thrombi), a major drawback of fibrinolytic therapy (Non-Patent Literature 3). Another problem with fibrinolytic therapy is the associated increased risk of intracranial hemorrhage (Non-Patent Literature 4, Non-Patent Literature 5). Therefore, an adjunct anticoagulant therapy that inhibits the formation of new thrombin without increasing the risk of bleeding would be highly beneficial. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Hathaway, WE, et al. (1965) Blood 26:521-32 [Non-Patent Document 2] Hoffmeister,HMet al.(1998)Circulation 98:2527-33 [Non-Patent Document 3] Keeley, EC et al. (2003) Lancet 361:13-20 [Non-Patent Document 4] Menon, V. et al. (2004) Chest 126:549S-575S [Non-Patent Document 5] Fibrinolytic Therapy Trialists' Collaborative Group (1994) Lancet 343:311-22 [Overview of the project] [Problems that the invention aims to solve]

[0011] Therefore, there is a need to develop PK inhibitors that can act to dissolve the fibrinolysis / thrombus formation balance in occluded thrombi, thereby promoting reperfusion and weakening the hypercoagulable state, and thus preventing thrombus reformation and re-occlusion of blood vessels. [Means for solving the problem]

[0012] Compounds, pharmaceutical compositions containing these compounds, inhibition of plasma kallikrein, and methods useful for the treatment or prevention of diseases and conditions associated with plasma kallikrein are provided. The compounds and their pharmaceutically acceptable salts are useful as inhibitors of human plasma kallikrein.

[0013] In certain embodiments, the present invention provides a compound represented by Formula I, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0014] In a particular embodiment, the compound is represented by formula II. [ka]

[0015] In a particular embodiment, the compound is represented by formula III, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0016] In a particular embodiment, the compound is represented by formula IV. [ka]

[0017] In a particular embodiment, the compound is represented by formula V, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0018] In a particular embodiment, the compound is represented by formula VI. [ka]

[0019] In a particular embodiment, the compound is represented by formula VII, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0020] In a particular embodiment, the compound is represented by formula VIII. [ka]

[0021] In a particular embodiment, the compound is represented by formula IX, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0022] In a particular embodiment, the compound is represented by formula X. [ka]

[0023] In a particular embodiment, the compound is represented by formula XI, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0024] In a particular embodiment, the compound is represented by formula XII. [ka]

[0025] In a particular embodiment, the compound is represented by formula XIII, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0026] In a particular embodiment, the compound is represented by formula XIV. [ka]

[0027] In a particular embodiment, the compound is represented by formula XV, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0028] In a particular embodiment, the compound is represented by formula XVI. [ka]

[0029] In a particular embodiment, the compound is represented by formula XVII, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this. The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0030] In a particular embodiment, the compound is represented by formula XVIII. [ka]

[0031] In a particular embodiment, the compound is represented by formula XIX, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0032] In a particular embodiment, the compound is represented by formula XX. [ka]

[0033] In a particular embodiment, the compound is represented by formula XXI, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0034] In a particular embodiment, the compound is represented by formula XXII. [ka]

[0035] In a particular embodiment, the compound is represented by formula XXIII, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0036] In a particular embodiment, the compound is represented by formula XXIV. [ka]

[0037] In a particular embodiment, the compound is represented by formula XXV, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-. -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent this.

[0038] In other embodiments, the compound is represented by formula XXVI, [ka] During the ceremony, X is CH, C(OH), -C(NH2), or -C(NR a R b ) represents, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c is represented by halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, -NH2, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If X is phenyl, it can represent an -NH- group that condenses at the ortho position with respect to X on that phenyl.

[0039] In a particular embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0040] In a particular embodiment, the present invention provides a method for treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. The method comprises the step of administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. In one embodiment, the disease or condition characterized by undesirable plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post-fibrinolytic therapy conditions, tonsillitis, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss in cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, cerebral edema, increased albumin excretion, overt albuminuria, and nephropathy. [Modes for carrying out the invention]

[0041] Plasma kallikrein inhibitors have been reported and are useful in therapeutic methods and compositions suitable for use in eliminating or reducing various forms of ischemia, including, but not limited to, intraoperative blood loss, cerebral ischemia, the development of systemic inflammatory responses, and / or reperfusion injury, e.g., reperfusion injury associated with cerebral ischemia or focal cerebral ischemia. Intraoperative blood loss is caused by invasive surgical procedures, which lead to contact activation of complement components and the coagulation / fibrinolytic system. Kallikrein inhibitors can be used to reduce or prevent intraoperative blood loss and systemic inflammatory responses in patients undergoing invasive surgical procedures, particularly cardiothoracic surgery. Kallikrein inhibitors can also be used to reduce or prevent cerebral ischemia and stroke, and / or reperfusion injury associated with cerebral ischemia. Kallikrein inhibitors can also prevent neurological and cognitive impairments associated with stroke, blood loss, and cerebral ischemia, e.g., events not associated with surgical intervention. Further examples of applications for kallikrein inhibitors include pediatric cardiac surgery, lung transplantation, total hip replacement, and orthotopic liver transplantation, as well as reducing or preventing stroke during these procedures, and reducing or preventing stroke during coronary artery bypass grafting (CABG) and extracorporeal membrane oxygenation (ECMO). definition

[0042] As used herein, the term "alkyl" is a technical term and refers to saturated aliphatic groups, including linear alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a linear or branched alkyl group has about 30 or fewer carbon atoms in its main chain (for example, C1-C in the case of a linear group). 30 In the case of a branched chain, C3-C 30 Alternatively, it has about 20 or fewer carbon atoms. In one embodiment, the term "alkyl" means C1-C 10 This refers to a linear alkyl group. In one embodiment, the term "alkyl" refers to a C1-C6 linear alkyl group. In one embodiment, the term "alkyl" refers to a C3-C 12This refers to a branched alkyl group. In one embodiment, the term "alkyl" refers to a C3-C8 branched alkyl group. Cycloalkyls have about 3 to about 10 carbon atoms in their ring structure, and alternatively, about 5, 6, or 7 carbon atoms in their ring structure.

[0043] As used herein, the term “heterocyclyl” refers to, but is not limited to, a monocyclic, bicyclic, and tricyclic ring having 3 to 12 atoms, including at least one heteroatom such as nitrogen, oxygen, or sulfur, and may be fully saturated or contain one or more unsaturated units (for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring). For illustrative purposes only and not to be construed as a limitation of the present invention, the following are examples of heterocyclic rings: azilidinyl, azilinyl, oxylanyl, thyranyl, thyrenyl, dioxylanyl, diazilinyl, azetyl, oxetanyl, oxetyl, thietanyl, thiethyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithiethyl, furyl, dioxalanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl, tetrazo Ryl, pyridyl, pyridadinil, pyrimidinil, pyrazinil, triazinil, tetradinil, quinolinil, isoquinolinil, quinoxalinil, quinazolinil, pyridopyradinil, benzoxazolyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, indolyl, benzotriazolyl, naphthilidinil, azepine, azetidinil, morpholinil, oxopiperidinil, oxopyrrolidinil, piperazinil, piperidinil, pyrrolidinil, quiniculdinil, thiomorpholinil, tetrahydropyranil, and tetrahydrofuranil.

[0044] The term "heteroatom" is recognized in the field and includes atoms of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur, and selenium, with alternatives being oxygen, nitrogen, or sulfur.

[0045] As used herein, the term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups.

[0046] As used herein, the term “heterocycloalkylalkyl” refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.

[0047] As used herein, the term “alkenyl” means a linear or branched hydrocarbon radical containing 2 to 10 carbon atoms and at least one carbon-carbon double bond formed by the removal of two hydrogen atoms. Representative examples of alkenyls include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

[0048] As used herein, the term "alkynyl" means a linear or branched hydrocarbon radical containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond. Representative examples of alkynyls include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0049] The term "alkylene" is recognized in the art and, as used herein, refers to a diradical obtained by removing two hydrogen atoms from an alkyl group as defined above. In one embodiment, alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as halogens, azides, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, alkoxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, fluoroalkyls (such as trifluromethyl), cyanos, etc. That is, in one embodiment, "substituted alkyl" is "alkylene".

[0050] The term "amino" is a technical term and, as used herein, refers to both unsubstituted and substituted amines, for example, the general formula: [ka] This refers to the part that can be represented by, In the formula, R a , R b , and R c These are, independently, hydrogen, alkyl, alkenyl, and -(CH2) x -R d It represents, or R a and R b Together with the N atoms to which they bond, they complete a heterocycle with 4 to 8 atoms in the ring structure, R d x represents an aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl, and x is an integer in the range of 0 to 8. In certain embodiments, R a or R b Only one of them can be a carbonyl, for example, R a , R b , and nitrogen do not form an imide together. In other embodiments, R aand R b (and optionally R c ) are each independently hydrogen, alkyl, alkenyl, or -(CH2) x -R d This represents [something]. In one embodiment, the term "amino" refers to -NH2.

[0051] The term "acyl" is a technical term and, as used herein, refers to any group or radical of the form RCO-, where R is any organic group, such as alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0052] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. In one embodiment, the term "aminoalkyl" refers to an aminomethyl group.

[0053] The term "aminoacyl" is a technical term and, as used herein, refers to an acyl group substituted with one or more amino groups.

[0054] As used herein, the term "aminothionyl" refers to an aminoacyl analogue in which the oxygen atom of RC(O)- is replaced by sulfur, and thus the form RC(S)-.

[0055] The term "phosphoryl" is a technical term and, as used herein, refers to the formula: [ka] It can generally be expressed as follows, where Q50 represents S or O, and R59 represents hydrogen, a lower alkyl, or an aryl, such as -P(O)(OMe)- or -P(O)(OH)2. For example, when used to substitute alkyl, the phosphoryl group of phosphorylalkyl is represented by the general formula: [ka] It can be expressed as follows, where Q50 and R59 are defined independently above, and Q51 represents O, S, or N, for example, -OP(O)(OH)OMe or -NH-P(O)(OH)2. When Q50 is S, the phosphoryl portion is "phosphorothioate".

[0056] As used herein, the term "aminophosphoryl" means a phosphoryl group substituted with at least one amino group as defined herein, e.g., -P(O)(OH)NMe2.

[0057] As used herein, the term "carbonyl" refers to -C(O)-.

[0058] As used herein, the term "thiocarbonyl" refers to -C(S)-.

[0059] As used herein, the term "alkylphosphoryl" means a phosphoryl group substituted with at least one alkyl group as defined herein, e.g., -P(O)(OH)Me.

[0060] As used herein, the term "alkylthio" refers to alkyl-S-.

[0061] The term "aryl" is a technical term and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic hydrocarbon groups, such as benzene, naphthalene, anthracene, and pyrene. The aromatic ring may be substituted at the position of one or more rings with one or more substituents, such as halogens, azides, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, alkoxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, fluoroalkyls (such as trifluromethyl), cyanos, etc. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings (these rings are “fused rings”), at least one of which rings is an aromatic hydrocarbon, and for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. In one embodiment, the term “aryl” refers to a phenyl group.

[0062] The term "heteroaryl" is a technical term and, as used herein, refers to monocyclic, bicyclic, and polycyclic aromatic groups having one or more heteroatoms in their ring structure, such as pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. "Heteroaryl" may be substituted at the position of one or more rings with one or more substituents such as halogens, azides, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, alkoxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphonates, phosphinates, carbonyls, carboxyls, silyls, ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, fluoroalkyls (such as trifluromethyl), cyanos, etc. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings (these rings are “fused rings”), at least one of which rings is an aromatic group having one or more heteroatoms in the ring structure, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl.

[0063] The terms "aralkyl" or "arylalkyl" are technical terms and, as used herein, refer to alkyl groups substituted with an aryl group.

[0064] The terms "heteroaralkyl" or "heteroarylalkyl" are technical terms and, as used herein, refer to alkyl groups substituted with heteroaryl groups.

[0065] As used herein, the term "alkoxy" means an alkyl group as defined herein, which is added to the parent molecule via an oxygen atom. Representative examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0066] As used herein, the term “aryloxy” means an aryl group as defined herein, which is attached to the parent molecule via an oxygen atom.

[0067] As used herein, the term “heteroaryloxy” means a heteroaryl group, as defined herein, that is attached to the parent molecule via an oxygen atom.

[0068] As used herein, the term "carbocyrill" means a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing 3 to 12 carbon atoms, which is either fully saturated or has one or more unsaturated bonds (to avoid doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl)). Examples of carbocyrill groups include 1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl, and 2-cyclopentenylmethyl.

[0069] The term "cyano" is a technical term and, as used herein, refers to -CN.

[0070] As used herein, the term "fluoroalkyl" refers to an alkyl group as defined herein, in which some or all of the hydrogen atoms are replaced by fluorine.

[0071] The term "halo" is a technical term and, as used herein, refers to -F, -Cl, -Br, or -I.

[0072] The term "hydroxy" is a technical term and, as used herein, refers to the -OH group.

[0073] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the compounds of the present invention may also be optically active. The present invention intends that all such compounds, including cis and trans isomers, (R) and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, fall within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, and mixtures thereof, are intended to be included in the present invention.

[0074] For example, if a specific enantiomer of the compound of the present invention is desired, this enantiomer can be prepared by asymmetric synthesis or by derivation with a chiral auxiliary agent, where the resulting mixture of diastereoisomers is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereoisomerous salt is formed with a suitable optically active acid or base, and then the diastereoisomer formed is resolved by fractional crystallization or chromatographic means known in the art, followed by the recovery of the pure enantiomer.

[0075] It will be understood that the terms "substitution" or "substituted with" implicitly include the condition that such substitution results in a stable compound, subject to the permissible valencies of the atom and substituent being substituted, and that the substitution does not spontaneously undergo transformation by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reactions.

[0076] The term “substituted” is also intended to include all permissible substituents of an organic compound. In a broader sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Illustrative substituents are, for example, those listed herein. There may be one or more permissible substituents, and they may be the same or different for a given organic compound. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any permissible substituent of the organic compound described herein that satisfies the valence of the heteroatom. The present invention is not intended to be limited in any way by permissible substituents of an organic compound.

[0077] For the purposes of this invention, the chemical elements are identified according to the back cover of the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0078] Other chemical terms used herein are used in accordance with their prior art usage, as illustrated by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco (incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art relating to the present invention.

[0079] As used herein, the term “pharmaceutically acceptable salt” includes, for example, salts derived from inorganic or organic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2-sulfonic acid, and other acids. A pharmaceutically acceptable salt may include forms in which the ratio of molecules constituting the salt is not 1:1. For example, a salt may contain two or more molecules of inorganic or organic acid per base molecule, such as two molecules of hydrochloric acid per molecule of compound I. Alternatively, a salt may contain less than one molecule of inorganic or organic acid per base molecule, such as two molecules of compound I per molecule of tartaric acid.

[0080] As used herein, the terms “carrier” and “pharmaceutically acceptable carrier” refer to diluents, adjuvants, excipients, or vehicles to which a compound is administered or formulated together for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids such as water, saline, and oils, and solids such as rubber acacia, gelatin, starch paste, talc, keratin, colloidal silica, and urea. In addition, auxiliaries, stabilizers, thickeners, lubricants, flavorings, and colorants may be used. Other examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences by EW Martin, which is incorporated herein by reference in its entirety.

[0081] As used herein, the term “to treat” means to prevent, halt, or delay the progression of a disease or condition in a subject, or to eliminate it. In one embodiment, “to treat” means to halt or delay the progression of a disease or condition in a subject, or to eliminate it. In one embodiment, “to treat” means to reduce at least one objective sign of a disease or condition in a subject.

[0082] As used herein, the term “effective dose” refers to an amount sufficient to produce the desired biological effect.

[0083] As used herein, the term "therapeutic dose" refers to an amount sufficient to produce the desired therapeutic effect.

[0084] As used herein, the term “inhibit” means to reduce by an objectively measurable amount or degree. In various embodiments, “inhibit” means to reduce by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to a relevant control. In one embodiment, “inhibit” means to reduce by 100 percent, i.e., to stop or eliminate.

[0085] As used herein, the term “subject” refers to a mammal. In various embodiments, the subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cattle, or non-human primate. In one embodiment, the subject is a human. compound

[0086] In some embodiments, the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, V is an aryl or heteroaryl that has been optionally substituted. W is an aryl or heteroaryl that has been optionally substituted. X is CH, C(OH), C(O(C1-C6)alkyl), -C(NH2), -C(NR a R b ), -C(N3), -C(CN), -C(NO2), -C(S(O) n R a ), -C[-C(=O)R c ], -C[-C(=O)R c ], -C[-C(=O)NR c R d], -C[-C(=O)SR c ], -C[-S(O)R c ], -C[-S(O)2R c ], -C[S(O)(OR c )], -C[-S(O)2(OR c )], -C[-SO2NR c R d ], -C(halogen), -C[(C1-C8)alkyl], -C[(C4-C8)carbocyrylalkyl], -C[(C1-C8)substituted alkyl], -C[(C2-C8)alkenyl], -C[(C2-C8)substituted alkenyl], -C[(C2-C8)alkynyl], -C[(C2-C8)substituted alkynyl], -C[aryl(C1-C8)alkyl], C(O)N, CH2N, N, C(O), P(O), -O-, S(O)N, or S(O)2N, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, X is C(OH), C(O(C1-C6)alkyl), -C(NH2), -C(NR a R b ), -C(N3), -C(CN), -C(NO2), -C(S(O) n R a ), -C[-C(=O)R c ], -C[-C(=O)R c ], -C[-C(=O)NR c R d ], -C[-C(=O)SR c ], -C[-S(O)R c ], -C[-S(O)2R c ], -C[S(O)(OR c )], -C[-S(O)2(OR c )], -C[-SO2NR c R d-YR is used when representing -C (halogen), -C[(C1-C8) alkyl], -C[(C4-C8) carbocylyl alkyl], -C[(C1-C8) substituted alkyl], -C[(C2-C8) alkenyl], -C[(C2-C8) substituted alkenyl], -C[(C2-C8) alkynyl], -C[(C2-C8) substituted alkynyl], or -C[aryl(C1-C8) alkyl]. 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR aR b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is absent, or halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, (C3-C8)cycloalkyl, (CH2) r Ure a NO2, (CH2) r NR a R b , (CH2) r C(O)R a , NR a C(O)R b , C(O)NR c R d , NR a C(O)NR c R d -C(=NR a )NR c R d , NHC(=NR a )NR c R d , NR a R b SO2NR c R d , NR a SO2NR c R d , NR a SO2-(C1-C6)alkyl, NR a SO2R a , S(O) p R a (CF2) r CF3, NHCH2R a OCH2R a SCH2R a NH(CH2)2(CH2) r R a O(CH2)2(CH2) r R a, and S(CH2)2(CH2) r R a Z represents one or more substituents independently selected from the group consisting of, or alternatively, Z is a 5 or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S. R 1c These are halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -C(=NH)NH2, and -CONR a R b -(C1-C6)alkylCONR a R b -SO2CH3, formyl, acyl, -NH2, -C(=NH)NH(OH), -C(=NH)NH(C(O)O-(C1-C6)alkyl), -C(=NH)NH(C(O)O-(C1-C6)haloalkyl), -C(=NH)NH(C(O)S-(C1-C6)alkyl), -C(=NH)NH(C(O)(OCH(C1-C6)alkyl)OC(O)(C1-C6)alkyl), optionally substituted aryl, or optionally substituted heteroaryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3a Either does not exist, or halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, (C3-C8)cycloalkyl, (CH2) r Ure a NO2, (CH2) r NR a R b , (CH2) rC(O)R a , NR a C(O)R b , C(O)NR c R d , NR a C(O)NR c R d -C(=NR a )NR c R d , NHC(=NR a )NR c R d , NR a R b SO2NR c R d , NR a SO2NR c R d , NR a SO2-(C1-C6)alkyl, NR a SO2R a , S(O) p R a (CF2) r CF3, NHCH2R a OCH2R a SCH2R a NH(CH2)2(CH2) r R a O(CH2)2(CH2) r R a , or S(CH2)2(CH2) r R a Represents one or more substituents independently selected from the group consisting of, or alternatively, R 3a It is a 5 or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S. R 4-(CR a R b ) r (CR a R b ) p - represents, or R 3 If it is phenyl, then -NR condenses at the ortho position with respect to X on that phenyl. a - can represent, Each R a and R b These are independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C3-C8)carbocykylalkyl, and -C(=O)R c , -C(=O)OR c -C(=O)NR c R d -C(=O)SR c ,-S(O)R c -S(O)2R c -S(O)(OR c ), or -SO2NR c R d And, Each R c and R d These are independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocykylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O) n(C1-C8)alkyl, or aryl(C1-C8)alkyl, or R c and R d If they are bonded to a common nitrogen atom, they can form a 3- to 7-membered heterocyclic ring, and optionally, the carbon atoms of the heterocyclic ring may be -O-, -S-, or -NR a - can be replaced, [ka] teeth, [ka] It can represent, n is either 2 or 3. r is 0, 1, 2, or 3 independently for each occurrence. p is 0, 1, or 2 independently for each occurrence. The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0087] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0088] In a particular embodiment, -XY- represents -CHNHCH2-.

[0089] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0090] In a particular embodiment, -XY- represents -CHOCH2-.

[0091] In a particular embodiment, R 3 is phenylene-R 3a It represents.

[0092] In a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0093] In a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0094] In a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0095] In a particular embodiment, R 3a It does not exist.

[0096] In a particular embodiment, R 4 It is cyclopropyl.

[0097] In a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0098] In a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0099] In a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0100] In a particular embodiment, Z does not exist.

[0101] In a particular embodiment, Z represents fluoro.

[0102] In a particular embodiment, Z represents chloro.

[0103] In certain embodiments, Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0104] In a particular embodiment, Z represents 6-F.

[0105] In a particular embodiment, R 1c This represents aminomethyl.

[0106] In a particular embodiment, R 1c This represents cyano.

[0107] In a particular embodiment, R 1c This represents -SO2CH3.

[0108] In a particular embodiment, R 2 It is either -CH3 or -CF3.

[0109] In a particular embodiment, R 2 It is -CF3.

[0110] In a particular embodiment, R 2 It is tert-butyl.

[0111] In a particular embodiment, R 2 It is cyclopropyl.

[0112] In a particular embodiment, R 2 It is -OCH3.

[0113] In a particular embodiment, R 2 It is -Si(CH3)3.

[0114] In a particular embodiment, R 2 It is -CONH2.

[0115] In a particular embodiment, R2 It is cyano.

[0116] In a particular embodiment, R 2 It is phenyl.

[0117] In a particular embodiment, the compound is represented by formula II. [ka]

[0118] In a particular embodiment, the compound is represented by formula IV. [ka]

[0119] In a particular embodiment, the compound is represented by formula VI. [ka]

[0120] In a particular embodiment, the compound is represented by formula VIII. [ka]

[0121] In a particular embodiment, the compound is represented by formula X. [ka]

[0122] In a particular embodiment, the compound is represented by formula XII. [ka]

[0123] In a particular embodiment, the compound is represented by formula XIV. [ka]

[0124] In a particular embodiment, the compound is represented by formula XVI. [ka]

[0125] In a particular embodiment, the compound is represented by formula XVIII. [ka]

[0126] In a particular embodiment, the compound is represented by formula XX. [ka]

[0127] In a particular embodiment, the compound is represented by formula XXII. [ka]

[0128] In a particular embodiment, the compound is represented by formula XXIV. [ka]

[0129] In a particular embodiment, the present invention provides a compound represented by formula III, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4-OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4-CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0130] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0131] In a particular embodiment, -XY- represents -CHNHCH2-.

[0132] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0133] In a particular embodiment, -XY- represents -CHOCH2-.

[0134] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0135] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0136] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0137] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0138] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0139] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0140] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0141] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0142] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0143] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0144] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0145] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0146] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0147] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0148] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0149] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents cyano.

[0150] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0151] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0152] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0153] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0154] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0155] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0156] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0157] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0158] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0159] According to any one of the embodiments described above, in a particular embodiment, R 2 It is phenyl.

[0160] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0161] In a particular embodiment, the compound [ka] It is selected from the group consisting of the following.

[0162] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0163] In a particular embodiment, the present invention provides a compound represented by formula V, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0164] In certain embodiments, X represents CH, and both Y and R 4 are present.

[0165] In certain embodiments, -X-Y- represents -CHNHCH2-.

[0166] In certain embodiments, -X-Y- represents -C(OH)CH2CH2-.

[0167] In certain embodiments, -X-Y- represents -CHOCH2-.

[0168] According to any one of the foregoing embodiments, in certain embodiments, R 3 represents phenylene-R 3a .

[0169] According to any one of the foregoing embodiments, in certain embodiments, -R 3 -R 3a is

Chemical formula

[0170] According to any one of the foregoing embodiments, in certain embodiments, -R 3 -R 3a is

Chemical formula

[0171] According to any one of the foregoing embodiments, in certain embodiments, -R 3 -R 3a is

Chemical formula

[0172] According to any one of the foregoing embodiments, in a certain specific embodiment, R 3a does not exist.

[0173] According to any one of the foregoing embodiments, in a certain specific embodiment, R 4 is cyclopropyl.

[0174] According to any one of the foregoing embodiments, in a certain specific embodiment, R 3 is phenyl, and R 3a is ortho, meta, or para-OH.

[0175] According to any one of the foregoing embodiments, in a certain specific embodiment, R 3 is phenyl, and R 3a is ortho, meta, or para-NH2.

[0176] According to any one of the foregoing embodiments, in a certain specific embodiment, R 3 is phenyl, and R 3a is ortho, meta, or para-CN.

[0177] According to any one of the foregoing embodiments, in a certain specific embodiment, Z does not exist.

[0178] According to any one of the foregoing embodiments, in a certain specific embodiment, Z represents fluoro.

[0179] According to any one of the foregoing embodiments, in a certain specific embodiment, Z represents chloro.

[0180] According to any one of the foregoing embodiments, in a certain specific embodiment, Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8) cycloalkyl.

[0181] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0182] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0183] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents cyano.

[0184] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0185] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0186] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0187] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0188] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0189] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0190] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0191] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0192] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0193] According to any one of the embodiments described above, in a particular embodiment, R 2 It is phenyl.

[0194] In another embodiment, the present invention provides compounds represented by formula VII, or pharmaceutically acceptable salts thereof. [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0195] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0196] In certain embodiments, -X-Y- represents -CHNHCH2-.

[0197] In certain embodiments, -X-Y- represents -C(OH)CH2CH2-.

[0198] In certain embodiments, -X-Y- represents -CHOCH2-.

[0199] According to any one of the foregoing embodiments, in certain embodiments, R 3 represents phenylene-R 3a .

[0200] According to any one of the foregoing embodiments, in certain embodiments, -R 3 -R 3a represents

Chemical formula

[0201] According to any one of the foregoing embodiments, in certain embodiments, -R 3 -R 3a represents

Chemical formula

[0202] According to any one of the foregoing embodiments, in certain embodiments, -R 3 -R 3a represents

Chemical formula

[0203] According to any one of the foregoing embodiments, in certain embodiments, R 3a is absent.

[0204] According to any one of the foregoing embodiments, in certain embodiments, R4 It is cyclopropyl.

[0205] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0206] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0207] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0208] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0209] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0210] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0211] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0212] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0213] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0214] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents cyano.

[0215] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0216] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0217] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0218] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0219] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0220] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0221] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0222] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0223] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0224] According to any one of the embodiments described above, in a particular embodiment, R 2 It is phenyl.

[0225] In other embodiments, the present invention provides compounds represented by formula IX, or pharmaceutically acceptable salts thereof. [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3aIt is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0226] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0227] In a particular embodiment, -XY- represents -CHNHCH2-.

[0228] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0229] In a particular embodiment, -XY- represents -CHOCH2-.

[0230] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0231] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0232] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0233] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0234] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0235] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0236] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0237] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0238] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0239] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0240] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0241] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0242] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0243] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0244] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0245] According to any one of the embodiments described above, in a particular embodiment, R 1cThis represents cyano.

[0246] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0247] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0248] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0249] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0250] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0251] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0252] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0253] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0254] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0255] According to any one of the embodiments described above, in a particular embodiment, R 2It is phenyl.

[0256] In a particular embodiment, the present invention provides a compound represented by formula XI, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4-N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3aIt is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0257] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0258] In a particular embodiment, -XY- represents -CHNHCH2-.

[0259] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0260] In a particular embodiment, -XY- represents -CHOCH2-.

[0261] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0262] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0263] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0264] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0265] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0266] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0267] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0268] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0269] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0270] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0271] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0272] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0273] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0274] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0275] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0276] According to any one of the embodiments described above, in a particular embodiment, R 1cThis represents cyano.

[0277] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0278] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0279] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0280] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0281] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0282] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0283] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0284] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0285] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0286] According to any one of the embodiments described above, in a particular embodiment, R 2It is phenyl.

[0287] In a particular embodiment, the present invention provides a compound represented by formula XIII, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4-N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3aIt is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0288] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0289] In a particular embodiment, -XY- represents -CHNHCH2-.

[0290] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0291] In a particular embodiment, -XY- represents -CHOCH2-.

[0292] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0293] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0294] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0295] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0296] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0297] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0298] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0299] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0300] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0301] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0302] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0303] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0304] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0305] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0306] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0307] According to any one of the embodiments described above, in a particular embodiment, R 1cThis represents cyano.

[0308] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0309] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0310] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0311] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0312] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0313] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0314] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0315] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0316] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0317] According to any one of the embodiments described above, in a particular embodiment, R 2It is phenyl.

[0318] In some embodiments, the present invention provides compounds represented by formula XV, or pharmaceutically acceptable salts thereof. [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4-N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3aIt is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0319] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0320] In a particular embodiment, -XY- represents -CHNHCH2-.

[0321] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0322] In a particular embodiment, -XY- represents -CHOCH2-.

[0323] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0324] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0325] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0326] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0327] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0328] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0329] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0330] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0331] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0332] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0333] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0334] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0335] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0336] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0337] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0338] According to any one of the embodiments described above, in a particular embodiment, R 1cThis represents cyano.

[0339] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0340] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0341] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0342] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0343] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0344] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0345] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0346] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0347] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0348] According to any one of the embodiments described above, in a particular embodiment, R 2It is phenyl.

[0349] In a particular embodiment, the present invention provides a compound represented by formula XVII, or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4-N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3aIt is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0350] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0351] In a particular embodiment, -XY- represents -CHNHCH2-.

[0352] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0353] In a particular embodiment, -XY- represents -CHOCH2-.

[0354] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0355] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0356] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0357] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0358] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0359] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0360] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0361] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0362] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0363] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0364] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0365] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0366] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0367] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0368] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0369] According to any one of the embodiments described above, in a particular embodiment, R 1cThis represents cyano.

[0370] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0371] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0372] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0373] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0374] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0375] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0376] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0377] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0378] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0379] According to any one of the embodiments described above, in a particular embodiment, R 2It is phenyl.

[0380] In a particular embodiment, the present invention provides a compound represented by formula XIX, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4-N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3aIt is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0381] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0382] In a particular embodiment, -XY- represents -CHNHCH2-.

[0383] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0384] In a particular embodiment, -XY- represents -CHOCH2-.

[0385] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0386] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0387] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0388] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0389] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0390] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0391] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0392] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0393] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0394] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0395] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0396] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0397] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0398] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0399] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0400] According to any one of the embodiments described above, in a particular embodiment, R 1cThis represents cyano.

[0401] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0402] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0403] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0404] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0405] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0406] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0407] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0408] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0409] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0410] According to any one of the embodiments described above, in a particular embodiment, R 2It is phenyl.

[0411] In a particular embodiment, the present invention provides a compound represented by formula XXI, or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4-N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3aIt is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0412] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0413] In a particular embodiment, -XY- represents -CHNHCH2-.

[0414] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0415] In a particular embodiment, -XY- represents -CHOCH2-.

[0416] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0417] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0418] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0419] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0420] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0421] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0422] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0423] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0424] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0425] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0426] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0427] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0428] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0429] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0430] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0431] According to any one of the embodiments described above, in a particular embodiment, R 1cThis represents cyano.

[0432] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0433] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0434] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0435] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0436] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0437] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0438] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0439] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0440] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0441] According to any one of the embodiments described above, in a particular embodiment, R 2It is phenyl.

[0442] In a particular embodiment, the present invention provides a compound represented by formula XXIII, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4-N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3aIt is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0443] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0444] In a particular embodiment, -XY- represents -CHNHCH2-.

[0445] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0446] In a particular embodiment, -XY- represents -CHOCH2-.

[0447] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0448] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0449] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0450] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0451] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0452] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0453] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0454] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0455] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0456] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0457] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0458] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0459] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0460] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0461] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0462] According to any one of the embodiments described above, in a particular embodiment, R 1cThis represents cyano.

[0463] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0464] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0465] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0466] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0467] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0468] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0469] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0470] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0471] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0472] According to any one of the embodiments described above, in a particular embodiment, R 2It is phenyl.

[0473] In a particular embodiment, the present invention provides a compound represented by formula XXV, or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X represents CH, C(OH), C(O(C1-C6)alkyl), C(O)N, CH2N, N, C(O), or -O-, however, If X represents CH, then -YR 4 represents -H or -OH, or Y and R 4 Both exist, If X represents C(OH) or C(O(C1-C6)alkyl), then -YR 4 There exists, If X represents C(O)N, then -YR 4 This represents H, or -YR 4 This represents H, and -R 3 -R 3a This represents H, If X represents CH2N, then -YR 4 This represents (C1-C6) alkyl, If X represents N, then -YR 4 This represents H, or Y and R 4 Both exist, If X represents C(O) or -O-, then -YR 4 Assuming that it does not exist, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4-N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c This represents a halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, or optionally substituted aryl. R 2 This represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, -OCH3, -Si(CH3)3, -CONH2, -C(O)OH, cyano, or phenyl. R 3 If present, represents -NH-, -O-, optionally substituted aryl, heteroaryl, phenyl, carbocykrill, or heterocyclyl. R 3aIt is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If it is phenyl, it can represent -NH- which condenses at the ortho position with respect to X on that phenyl, [ka] teeth, [ka] It can represent, The stereochemical structure of any chiral center is R, S, or a mixture of R and S.

[0474] In a particular embodiment, X represents CH, Y and R 4 Both exist.

[0475] In a particular embodiment, -XY- represents -CHNHCH2-.

[0476] In a particular embodiment, -XY- represents -C(OH)CH2CH2-.

[0477] In a particular embodiment, -XY- represents -CHOCH2-.

[0478] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenylene-R 3a It represents.

[0479] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0480] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0481] According to any one of the embodiments described above, in a particular embodiment, -R 3 -R 3a teeth, [ka] It represents.

[0482] According to any one of the embodiments described above, in a particular embodiment, R 3a It does not exist.

[0483] According to any one of the embodiments described above, in a particular embodiment, R 4 It is cyclopropyl.

[0484] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-OH.

[0485] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a It is ortho, meta, or para-NH2.

[0486] According to any one of the embodiments described above, in a particular embodiment, R 3 is phenyl, and R 3a This is ortho, meta, or para-CN.

[0487] According to any one of the embodiments described above, in a particular embodiment, Z does not exist.

[0488] According to any one of the embodiments described above, in a particular embodiment, Z represents fluoro.

[0489] According to any one of the embodiments described above, in a particular embodiment, Z represents chloro.

[0490] According to any one of the embodiments described above, in a particular embodiment, Z represents 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C3-C8)cycloalkyl.

[0491] According to any one of the embodiments described above, in a particular embodiment, Z represents 6-F.

[0492] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents aminomethyl.

[0493] According to any one of the embodiments described above, in a particular embodiment, R 1cThis represents cyano.

[0494] According to any one of the embodiments described above, in a particular embodiment, R 1c This represents -SO2CH3.

[0495] According to any one of the embodiments described above, in a particular embodiment, R 2 It is either -CH3 or -CF3.

[0496] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CF3.

[0497] According to any one of the embodiments described above, in a particular embodiment, R 2 It is tert-butyl.

[0498] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyclopropyl.

[0499] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -OCH3.

[0500] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -Si(CH3)3.

[0501] According to any one of the embodiments described above, in a particular embodiment, R 2 It is -CONH2.

[0502] According to any one of the embodiments described above, in a particular embodiment, R 2 It is cyano.

[0503] According to any one of the embodiments described above, in a particular embodiment, R 2It is phenyl.

[0504] In a particular embodiment, the present invention provides a compound represented by formula (XXVI), or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, X is CH, C(OH), -C(NH2), or -C(NR a R b ) represents, -YR 4 If present, -((C1-C6)alkyl)-R 4 -CH2C(O)-R 4 , -CH2NH-R 4 -CH2N((C1-C6)alkyl)-R 4 ,-CR a R b -R 4 , -NH-R 4 , -NHCH2-R 4 ,-NHC(O)-R 4 ,-N((C1-C6)alkyl)-R 4 -N((C1-C6)alkyl)CH2-R 4 ,-N((CH2)2OH)-R 4 ,-N[(C3-C8)cycloalkyl(C1-C6)alkyl]R 4 ,-heterocyclyl-R 4 , -OR 4 , -OCH2-R 4 -OC(O)-R 4 -OC(O)NR a R b , -SCH2R 4 , or -SR 4 Represents -((C1-C6)alkyl)-R 4 The (C1-C6) alkyl portion is optionally substituted. Z is either absent or represents halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, -SO2NH2, or (C3-C8)cycloalkyl. R 1c is represented by halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, -SO2CH3, formyl, acyl, -NH2, or optionally substituted aryl. R 3a It is either absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, -CF3, -OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, -C(O)NH2, cyano, -NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and -SO2NH2. R 4 -CH2- represents a 5- to 7-membered heterocyclic ring with optional substituents, formed by condensation at the 4-position of a ring supporting hydrogen, hydroxyl, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, -CH2OH, -CH((C1-C6)alkyl)OH, -CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, -CH2S(C1-C6)alkyl, amino, or cyano, or Z, or R. 3 If X is phenyl, it can represent an -NH- group that condenses at the ortho position with respect to X on that phenyl.

[0505] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0506] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0507] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0508] In a particular embodiment, the compound [ka] It is selected from the group consisting of the following.

[0509] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0510] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0511] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0512] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0513] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0514] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0515] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0516] In a particular embodiment, the compound [ka] [ka] It is selected from the group consisting of the following.

[0517] In a particular embodiment, the compound [ka] It is selected from the group consisting of the following. Pharmaceutical composition

[0518] The present invention provides pharmaceutical compositions, each comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises one compound of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention and a pharmaceutically acceptable carrier.

[0519] In certain embodiments, the pharmaceutical composition of the present invention further comprises at least one additional pharmaceutically active agent in addition to the compound of the present invention. This at least one additional pharmaceutically active agent may be a useful agent in the treatment of a disease or condition characterized by undesirable plasma kallikrein activity. For example, this at least one additional pharmaceutically active agent may be an anticoagulant, an antiplatelet agent, or a thrombolytic agent.

[0520] Anticoagulants prevent the coagulation of blood components and therefore prevent blood clot formation, for example, in atrial fibrillation. Examples of anticoagulants, though not limited to them, include heparin, warfarin, coumadin, dicumarol, fenprocumone, asenocumarol, ethylbiscum acetate, hirudin, bivalarutin, direct thrombin inhibitors, and indanedione derivatives.

[0521] Antiplatelet agents inhibit platelet aggregation and are often used to prevent thromboembolic stroke in patients who have experienced transient ischemic attacks, stroke, or atrial fibrillation. Examples of antiplatelet agents, though not limited to them, include aspirin, thienopyridine derivatives such as ticlopodine and clopidogrel, dipyridamole, sulfinpyrazone, and RGD mimetic.

[0522] Thrombolytic agents dissolve blood clots that cause thromboembolic events such as stroke, myocardial infarction, and pulmonary thromboembolism. Examples of thrombolytic agents, though not limited to them, include plasminogen, α2-antiplasmin, streptokinase, antistreplase, TNK, tissue plasminogen activator (tPA), and urokinase. Tissue plasminogen activators include natural tPA and recombinant tPA, as well as modified forms of tPA that retain the enzymatic or fibrinolytic activity of natural tPA.

[0523] The pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0524] In certain embodiments, the present invention provides a pharmaceutical composition formulated for prophylactic or therapeutic treatment of a disease or condition characterized by undesirable plasma kallikrein activity. How to use

[0525] The present invention provides compounds that inhibit thrombin formation via the intrinsic pathway, thereby reducing the risk of new thrombus formation (vascular occlusion or reocclusion), and improving fibrinolytic-induced reperfusion when administered as adjunctive therapy with fibrinolytic regimens. Diseases and conditions that can be treated with the compounds of the present invention include, but are not limited to, stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post-fibrinolytic treatment conditions, tonsillitis, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss in cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, cerebral edema, increased albumin excretion, overt albuminuria, and nephropathy.

[0526] For example, in patients with angioedema, the small polypeptide PK inhibitor DX-88 (ecalantide) alleviates edema in patients with hereditary angioedema (HAE). Williams, A. et al. (2003) Transfus. Apher. Sci. 29:255-8, Schneider, L. et al. (2007) J Allergy Clin Immunol. 120:416-22, and Levy, J. Het al. (2006) Expert Opin. Invest. Drugs 15:1077-90. Icatibant, a bradykinin B2 receptor antagonist, is also effective in treating HAE. Bork, K. et al. (2007) J. Allergy Clin. Immunol. 119:1497-1503. Since plasma kallikrein produces bradykinin, inhibition of plasma kallikrein is expected to inhibit bradykinin production.

[0527] For example, in coagulation caused by fibrinolytic therapy (e.g., treatment with tissue plasminogen activator or streptokinase), higher levels of plasma kallikrein are observed in patients undergoing fibrinolysis. Hoffmeister, HMet al. (1998) J. Cardiovasc. Pharmacol. 31:764-72. Plasmin-mediated activation of the endogenous pathway has been shown to occur in plasma and blood, and was significantly attenuated in plasma from individuals deficient in any of the components of the endogenous pathway. Ewald, GA et al. (1995) Circulation 91:28-36.

[0528] Individuals with acute myocardial infarction (MI) showed elevated levels of activated plasma kallikrein and thrombin. Hoffmeister, HM, et al. (1998) Circulation 98:2527-33.

[0529] DX-88 reduced cerebral edema, infarct volume, and neuropathy in an animal model of ischemic stroke. Storini, C. et al. (2006) J. Pharm. Exp. Ther. 318:849-854. C1-inhibitors reduced infarct size in a mouse model of middle cerebral artery occlusion (MCAO). De Simoni, M. Get al. (2004) Am. J. Pathol. 164:1857-1863, and Akita, N. et al. (2003) Neurosurgery 52:395-400). B2 receptor antagonists were shown to reduce infarct volume, cerebral swelling, and neutrophil accumulation, and were neuroprotective in an MCAO animal model. Zausinger, S. et al. (2003) Acta Neurochir.Suppl.86:205-7, Lumenta, DBet al. (2006) Brain Res.1069:227-34, Ding-Zhou, L. et al. (2003) Br.J Pharmacol.139:1539-47.

[0530] Regarding blood loss during cardiopulmonary bypass (CPB), it is known that the kallikrein-kinin (i.e., contact) system is activated during CABG. Wachtfogel, YT (1989) Blood 73:468. Activation of the contact system during CPB results in up to a 20-fold increase in plasma bradykinin. Cugno, M. et al. (2006) Chest 120:1776-82, and Campbell, D.J et al. (2001) Am.J. Physiol. Reg. Integr. Comp. Physiol. 281:1059-70.

[0531] Plasma kallikrein inhibitors, P8720 and PKSI-527, have also been shown to reduce joint swelling in rat models of arthritis. De La Cadena, RA et al. (1995) FASEB J.9:446-52, Fujimori, Y. (1993) Agents Action 39:42-8. Furthermore, inflammation in animal models of arthritis has been shown to be accompanied by activation of the contact system. Blais, C. Jr. et al. (1997) Arthritis Rheum. 40:1327-33.

[0532] In addition, the plasma kallikrein inhibitor P8720 has been shown to reduce inflammation in acute and chronic rat models of inflammatory bowel disease (IBD). Stadnicki, A. et al. (1998) FASEB J.12:325-33, Stadnicki, A. et al. (1996) Dig.Dis.Sci.41:912-20, and De La Cadena, RA, et al. (1995) FASEB J.9:446-52. The contact system is activated during acute and chronic small intestinal inflammation. Sartor, R.B et al. (1996) Gastroenterology 110:1467-81. B2 receptor antagonists, antibodies against high molecular weight kininogen, or reductions in kininogen levels have been shown to reduce clinicopathology in animal models of IBD. Ibid., Arai, Y. et al. (1999) Dig.Dis.Sci.44:845-51, and Keith, JCet al. (2005) Arthritis Res.Therapy 7:R769-76.

[0533] HD-Pro-Phe-Arg-chloromethyl ketone (CMK), a PK and FXII inhibitor and a physiological inhibitor (C1-inhibitor), has been shown to reduce vascular permeability in multiple organs and to reduce lesions in lipopolysaccharide (LPS)-induced or bacterial-induced sepsis in animals. Liu, D. et al. (2005) Blood 105:2350-5, Persson, K. et al. (2000) J. Exp. Med. 192:1415-24. Clinical improvement was observed in sepsis patients treated with C1-inhibitors. Zeerleder, S. et al. (2003) Clin. Diagnost. Lab. Immunol. 10:529-35, Caliezi, C., et al. (2002) Crit. Care Med. 30:1722-8, and Marx, G. et al. (1999) Intensive Care Med. 25:1017-20. Cases of sepsis mortality have been shown to have a higher degree of contact activation. Martinez-Brotons, F. et al. (1987) Thromb. Haemost. 58:709-713, and Kalter, E. et al. (1985) J. Infect. Dis. 151:1019-27.

[0534] Pre-PK levels are higher in diabetic patients, particularly those with proliferative retinopathy, and have been shown to correlate with fructosamine levels. (Gao, B.-B., et al. (2007) Nature Med. 13:181-8, and Kedzierska, K. et al. (2005) Archives Med. Res. 36:539-43). Pre-PK is also highest in patients with sensorimotor neuropathy. (Christie, M. et al. (1984) Thromb. Haemostas. (Stuttgart) 52:221-3). Pre-PK levels are elevated in diabetic patients and are associated with elevated blood pressure. Pre-PK levels correlate independently with albumin excretion rate and are elevated in diabetic patients with overt albuminuria, suggesting that pre-PK may be a marker of progressive nephropathy. Jaffa, AA et al. (2003) Diabetes 52:1215-21. B1 receptor antagonists have been shown to reduce plasma leakage in rats treated with streptozotocin. Lawson, SR et al. (2005) Eur. J. Pharmacol. 514:69-78. B1 receptor antagonists also prevent the development of hyperglycemia and renal failure in mice treated with streptozotocin. Zuccollo, A. et al. (1996) Can. J. Physiol. Pharmacol. 74:586-9.

[0535] In certain embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use as pharmaceuticals.

[0536] In a particular embodiment, the present invention provides a method for treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. The method comprises the step of administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby treating or preventing a disease or condition characterized by undesirable plasma kallikrein activity. The disease or condition characterized by undesirable plasma kallikrein activity is treated by reducing the plasma kallikrein activity of the subject.

[0537] Alternatively, in certain embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of diseases or conditions characterized by undesirable plasma kallikrein activity.

[0538] Alternatively, in certain embodiments, the present invention provides a method of using the compound or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for use in the treatment of a disease or condition characterized by undesirable plasma kallikrein activity.

[0539] As used herein, “a disease or condition characterized by undesirable plasma kallikrein activity” refers to any disease or condition in which a reduction in plasma kallikrein activity is desirable. For example, in a hypercoagulable state, a reduction in plasma kallikrein activity may be desirable. Another example is a situation of tissue ischemia associated with the presence or formation of a thrombus, in which a reduction in plasma kallikrein activity may be desirable.

[0540] In certain embodiments, diseases or conditions characterized by undesirable plasma kallikrein activity are selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post-fibrinolytic therapy conditions, tonsillitis, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss in cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, cerebral edema, increased albumin excretion, overt albuminuria, and nephropathy.

[0541] In a particular embodiment, the disease or condition characterized by undesirable plasma kallikrein activity is angioedema.

[0542] In a particular embodiment, a disease or condition characterized by undesirable plasma kallikrein activity is hereditary angioedema (HAE).

[0543] In a particular embodiment, the disease or condition characterized by undesirable plasma kallikrein activity is stroke.

[0544] In certain embodiments, the disease or condition characterized by undesirable plasma kallikrein activity is reperfusion injury.

[0545] In a particular embodiment, the disease or condition characterized by undesirable plasma kallikrein activity is acute myocardial infarction.

[0546] In certain embodiments, the disease or condition characterized by undesirable plasma kallikrein activity is bleeding.

[0547] In certain embodiments, the disease or condition characterized by undesirable plasma kallikrein activity is blood loss in the cardiopulmonary bypass.

[0548] In a particular embodiment, the disease or condition characterized by undesirable plasma kallikrein activity is selected from the group consisting of retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, and proliferative retinopathy. Formulation, route of administration, and drug administration

[0549] The compounds of the present invention can be formulated as pharmaceutical compositions and administered to mammalian hosts such as human patients in various forms suitable for selected routes of administration, such as orally or parenterally, intravenously, intraperitoneally, intramuscularly, topically, or subcutaneously. Further routes of administration are also envisioned by the present invention.

[0550] Therefore, the compound can be administered systemically, for example, orally, with a pharmaceutically acceptable vehicle or absorbable edible carrier, such as an inert diluent. These may be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly combined with the patient's diet. For therapeutic oral administration, the active compound may be combined with one or more excipients and may be used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. Such compositions and preparations should contain at least 0.1% of the active compound. The proportion of the compositions and preparations may, of course, vary and, for convenience, may be between about 2% and about 60% of the weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions is such that an effective dose level is obtained.

[0551] Tablets, lozenges, pills, capsules, etc. may also contain the following diluents and carriers: binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, wintergreen oil, or cherry flavoring. If the unit dosage form is a capsule, it may contain a liquid carrier such as vegetable oil or polyethylene glycol in addition to the above types of materials. Various other materials may be present as coatings or otherwise to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar. The syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methylparaben and propylparaben as preservatives, colorants, and flavorings such as cherry or orange flavoring. Of course, any materials used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts used. In addition, the active compound may be incorporated into sustained-release preparations and apparatus.

[0552] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water or a physiologically acceptable aqueous solution, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, as well as in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0553] Suitable pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions, or sterile powders containing the active ingredient, optionally encapsulated in liposomes, adapted for the immediate preparation of sterile injectable or injectable solutions or dispersions. In all cases, the final dosage form should be sterile, fluid, and stable under manufacturing and storage conditions. The liquid carrier or vehicle may be a solvent or liquid dispersion medium, for example, containing water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by liposome formation, maintenance of the required particle size in the case of dispersions, or the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. The extension of absorption of an injectable composition can be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0554] Sterile injectable solutions are prepared by combining the required amount of active compound with the various other components listed above in a suitable solvent, and then sterilizing by filtration as necessary. In the case of sterile powders for the preparation of sterile injectable solutions, preparation methods include vacuum drying and freeze-drying, which yield a powder of the active ingredient with any desired additional components present in a pre-sterilized filtered solution.

[0555] For topical administration, the compound can be applied in its pure form (i.e., when the compound is a liquid). However, it is generally preferable to administer the compound to the skin as a composition or formulation with a dermatologically acceptable carrier, which may be in solid or liquid form.

[0556] Useful solid carriers include fine powders such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohol, glycol, or a water-alcohol / glycol blend, in which the compound can be effectively dissolved or dispersed with the optional aid of a non-toxic surfactant. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resulting liquid composition may be applied from an absorbent pad, used to impregnate bandages and other bandaging materials, or sprayed onto the affected area using a pump or aerosol sprayer.

[0557] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified mineral materials can also be used together with liquid carriers for direct application to the user's skin to form applicable adhesives, gels, ointments, soaps, etc.

[0558] Examples of useful skin compositions that can be used to deliver the compounds of the present invention to the skin are known in the art, see, for example, Jacquet et al. (U.S. Patent No. 4,608,392, incorporated herein by reference), Geria (U.S. Patent No. 4,992,478, incorporated herein by reference), Smith et al. (U.S. Patent No. 4,559,157, incorporated herein by reference), and Wortzman (U.S. Patent No. 4,820,508, incorporated herein by reference).

[0559] Useful dosages of the compounds of the present invention can be determined, at least initially, by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949 (incorporated herein by reference).

[0560] The amount of compound or its activated salt required for therapeutic use varies not only depending on the specific compound or salt selected, but also on the route of administration, the nature of the condition being treated, and the patient's age and condition, and is ultimately at the discretion of the attending physician or clinician.

[0561] However, generally speaking, the preferred dose is in the range of approximately 0.5 to 100 mg per kg of body weight per day, for example, approximately 3 to 90 mg per kg of body weight per day, approximately 6 to 75 mg per kg of body weight per day, approximately 10 to 60 mg per kg of body weight per day, or approximately 15 to 50 mg per kg of body weight per day.

[0562] The compounds of the present invention can be conveniently formulated in unit dosage forms, for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of the active ingredient per unit dosage form. In one embodiment, the present invention provides a composition comprising the compounds of the present invention formulated in such unit dosage forms. The desired dose may be conveniently presented as a single dose, or as divided doses administered at appropriate intervals, for example, as sub-dose two, three, four or more times per day. The sub-dose itself may also be separated into several portions and further divided into doses with roughly spaced intervals.

[0563] The compounds of the present invention may also be administered together with other therapeutic agents, such as other agents useful for the treatment or prevention of ischemia, blood loss, or reperfusion injury.

[0564] Other delivery systems may include time-release, delayed-release, or sustained-release delivery systems, such as those well known in the art. Such delivery systems can avoid repeated administration of the active compound, improving convenience for both the patient and the physician. Many types of delivery systems are available to and known to those skilled in the art. The use of long-term sustained-release implants may be desirable. As used herein, long-term release means that the delivery system or implant is configured and positioned to deliver therapeutic levels of the active ingredient over a period of at least 30 days, preferably 60 days.

[0565] In certain embodiments, the compounds of the present invention are formulated for intraocular administration, for example, within an intraocular medical device, or for direct injection or insertion associated therewith.

[0566] The compounds of the present invention can be formulated for attachment to medical devices, which may include any of the following: various conventional grafts, stent grafts and other stents, catheters, balloons, baskets, or other devices that can be placed or permanently implanted in a body lumen. In certain specific examples, it may be desirable to have devices and methods that can deliver the compounds of the present invention to a body area being treated by interventional techniques.

[0567] In exemplary embodiments, the compounds of the present invention can be attached to medical devices such as stents and delivered to a treatment site for the treatment of a part of the body.

[0568] Stents are used as delivery vehicles for therapeutic agents (i.e., drugs). Intravascular stents are generally permanently implanted in coronary or peripheral blood vessels. Examples of stent designs include those specified in U.S. Patent No. 4,733,655 (Palmaz), U.S. Patent No. 4,800,882 (Gianturco), or U.S. Patent No. 4,886,062 (Wiktor). Such designs include both metallic and polymer stents, as well as self-expanding and balloon-expanding stents. Stents can also be used to deliver drugs at the site of contact with the vascular system, as disclosed, for example, in U.S. Patent No. 5,102,417 (Palmaz), U.S. Patent No. 5,419,760 (Narciso, Jr.), U.S. Patent No. 5,429,634 (Narciso, Jr.), and International Publication No. 91 / 12779 (Medtronic, Inc.) and International Publication No. 90 / 13332 (Cedars-Sanai Medical Center).

[0569] The term “adhered” means that the compound is coated, adsorbed, positioned, or otherwise incorporated into a device by methods known in the art. For example, the compound may be embedded in a polymer material coating or spreading over a medical device and released from there (“matrix type”), or it may be surrounded by a polymer material and released through there (“reservoir type”). In the latter example, the compound may be encapsulated within or bonded to a polymer material using one or more techniques known in the art for producing such a polymer material. In other formulations, the compound may be bonded to the surface of a medical device, for example, by a detachable bond, without the need for coating, and released over time, or removed by an active mechanical or chemical process. In other formulations, the compound may be in a permanently immobilized form that provides the compound at the implantation site.

[0570] In certain embodiments, the compound may be incorporated together with a polymer composition during the formation of biocompatible coatings for medical devices such as stents. The coatings resulting from these components are typically homogeneous and useful for coating many devices designed for implantation.

[0571] The polymer may be either a biostable polymer or a bioabsorbable polymer, depending on the desired release rate or degree of polymer stability. However, bioabsorbable polymers are often preferred in this embodiment because, unlike biostable polymers, they do not persist for a long time after implantation and do not cause any harmful, chronic local reactions. While not limited to these, the bioabsorbable polymers that can be used include poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyacid anhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D,L-lactic acid), poly(D,L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS), and polyphosphoric acid. Examples include sterols, polyphosphoesterurethanes, poly(amino acids), cyanoacrylates, poly(trimethylene carbonates), poly(iminocarbonates), copolymers (ether-esters) (e.g., PEO / PLA), polyalkylene oxalates, polyphosphazenes, as well as biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, crosslinkable or amphiphilic block copolymers of hydrogels, and other suitable bioabsorbable poplymers known in the art.Furthermore, biostable polymers with relatively low chronic tissue reactivity, such as polyurethane, silicone, and polyester, can also be used, provided they can be dissolved and cured or polymerized on the medical device. Examples include polyolefins, polyisobutylene, and ethylene-α-olefin copolymers; acrylic polymers and copolymers, halogenated vinyl polymers and copolymers such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers such as polyvinyl methyl ether; polyhalogenated vinylides such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics such as polystyrene, polyvinyl esters such as polyvinyl acetate; ethylene-methyl methacrylate copolymer, acrylonitrile-styrene copolymer, ABS resin, etc. Other polymers may also be used, such as copolymers of vinyl monomers, including ethylene-vinyl acetate copolymers, copolymers of vinyl monomers with olefins, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamide-phenol, polyethylene oxide-polylysine substituted with palmitoyl residues, polyamides such as nylon 66 and polycaprolactam, alkyd resins, polycarbonates, polyoxymethylene, polyimides, polyethers, epoxy resins, polyurethanes, rayons, rayon triacetates, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate-butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethylcellulose.

[0572] The polymer and semipermeable polymer matrix may be formed into molded articles such as valves, stents, tubing, and prosthetics.

[0573] In certain embodiments of the present invention, the compound of the present invention is linked to a polymer or semipermeable polymer matrix formed as a stent or stent-graft device.

[0574] Typically, polymers are applied to the surface of implantable devices by spin coating, dipping, or spraying. Additional methods known in the art can also be utilized for this purpose. Spraying methods include conventional methods as well as microdeposition techniques using inkjet-type dispensers. In addition, polymers can also be deposited onto implantable devices using optical patterning, which places the polymer only on specific parts of the device. This coating of the device provides a uniform layer around the device, which allows for improved diffusion of various analytes through the coating of the device.

[0575] In certain embodiments of the present invention, the compound is formulated for release from a polymer coating into the environment in which a medical device is placed. Preferably, the compound is released in a controlled manner over a long time frame (e.g., several months) using at least one of several known techniques involving a polymer carrier or layer to control the elution. Some of these techniques are described in U.S. Patent Application Publication No. 2004 / 0243225A1, and all of this disclosure is incorporated herein in whole.

[0576] Furthermore, the reaction conditions of the reagents and polymer compositions can be manipulated so that the release of the compound from the polymer coatings can be controlled, for example, as described in U.S. Patent No. 6,770,729, which is entirely incorporated herein. For example, the diffusion coefficients of one or more polymer coatings can be adjusted to control the release of the compound from the polymer coatings. In some variants of this subject, the diffusion coefficients of one or more polymer coatings can be adjusted to adjust the ability of analytes present in the environment in which the medical device is placed (e.g., analytes that promote the breakdown or hydrolysis of a portion of the polymer) to access one or more components in the polymer composition (and, for example, the ability to adjust the release of the compound from the polymer coatings). Yet another embodiment of the present invention includes a device having multiple polymer coatings, each having a plurality of diffusion coefficients. In such embodiments of the present invention, the release of the compound from the polymer coatings can be adjusted by those multiple polymer coatings.

[0577] In yet another embodiment of the present invention, the release of the compound from the polymer coating is controlled by the presence of one or more endogenous or exogenous compounds, or alternatively, by adjusting one or more properties of the polymer composition, such as the pH of the polymer composition. For example, a particular polymer composition may be designed to release the compound in response to a decrease in the pH of the polymer composition. kit

[0578] The present invention also provides a kit comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of the present invention or a pharmaceutically acceptable salt thereof, and the other therapeutic agent (may be more than one) to a mammal to treat or prevent ischemia, blood loss, or reperfusion injury in that mammal. In one embodiment, the mammal is a human. [Examples]

[0579] The present invention is further illustrated by the following embodiments, which should not be construed in any way as further limitations. The entire contents of all references cited herein (including references to documents, granted patents, published patent applications, and concurrently pending patent applications) are expressly incorporated herein by reference. [ka]

[0580] Appropriately substituted pyrazole carboxylic acids can be prepared by various methods reported in the following references. 1. Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an SO2-containing group as vanilloid receptor ligands; Frank, Robert et al; International Publication No. 2013 / 068464, May 16, 2013 (incorporated by reference) 2.Design, synthesis and biological activity of E-β-farnesene analogues containing pyrazole-carboxamide;Sun, Yufeng et al;Youji Huaxue,31(9),1425-1432;2011 3. Preparation of heterocyclic urea derivatives as kinase inhibitors useful for the treatment of myeloproliferative diseases and other proliferative diseases; Flynn, Daniel L. et al; International Publication No. 2013 / 036232 (incorporated by reference) 4. Substituted phenylureas and phenylamides as vanilloid receptor ligands and their preparation; By Frank, Robert et al; U.S. Patent Application Publication No. 2012 / 0258946 (incorporated by reference) 5. Substituted cyclic carboxamide and urea derivatives as ligands of the vanilloid receptor; Frank, Robert et al; International Publication No. 2012 / 022487 (incorporated by reference) 6. Preparation of heterocyclic urea derivatives as kinase inhibitors useful for the treatment of hyperproliferative and other diseases; Flynn, Daniel L. and Kaufman, Michael D; U.S. Patent Application Publication No. 2012 / 0225057 (incorporated by reference) 7. Preparation of pyrazolylpyrimidine derivatives for use as protein kinase modulators; Casuscelli, Francesco et al; International Publication No. 2012 / 139930 (incorporated by reference) 8. 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Novel N-heterocyclic phosphonates and phosphinates as glucokinase activators for treatment of Type II diabetes; Ryono, Dennis E. et al; International Publication No. 2008 / 005964 (incorporated by reference) 24. 抗凝剂瑞扎西班的还原性异恶唑环开环是大鼠和犬体内主要的代谢清除途径;Zhang, Donglu等人;《药物代谢与处置》,36(2),303 - 315;2008年 25. 5 - 酮基吡唑因子Xa抑制剂的构效关系和药代动力学概况;Varnes, Jeffrey G.等人;《生物有机与药物化学快报》,18(2),749 - 754;2008年 26. 作为杀虫剂和杀真菌剂的(吡唑羰基氨基)苯甲酰胺衍生物的制备;Li, Bin等人;国际公开第2008 / 134969号(通过引用并入) 27. 共激活因子相关精氨酸甲基转移酶1(CARM1)的吡唑抑制剂;Purandare, Ashok V.等人;《生物有机与药物化学快报》,18(15),4438 - 4441;2008年 28. 麻疹病毒RNA依赖性RNA聚合酶复合物的强效非核苷抑制剂;Sun, Aiming等人;《药物化学杂志》,51(13),3731 - (此处原文有误,应为3741)3741;2008年 29.Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor 30. Preparation of pyrazoles for the treatment of obesity and other CNS disorders; Bennani, Youseff L. et al; International Publication No. 2007 / 094962 (incorporated by reference) 31. Preparation of ureidopyrazoles as kinase inhibitors, particularly as p38 kinase inhibitors; Bastian, Jolie Anne et al; International Publication No. 2007 / 053394, May 10, 2007. 32. Hydrazide compounds and their preparation, formulation, and pesticidal use; Ikegami, Hiroshi et al; International Publication No. 2007 / 043677 (incorporated by reference) 33.Trimethylsilylpyrazoles as novel inhibitors of p38 MAP kinase:A new use of silicon bioisosteres in medicinal chemistry;Barnes,Matthew J.et al;Bioorganic & Medicinal Chemistry Letters,17(2),354-357;2007 34. Preparation of anthranilamide derivative insecticides and acaricides; Lahm, George Philip et al; International Publication No. 2006 / 055922 (incorporated by reference) 35. Preparation of amino acid derivatives as inhibitors of protein arginine methyl transferases; Purandare, Ashok Vinayak and Chen, Zhong; International Publication No. 2006 / 069155 (incorporated by reference) 36. Preparation of azole carboxamides as inhibitors of bacterial type III protein secretion systems; Li, Xiaobing et al; International Publication No. 2005 / 113522 (incorporated by reference) 37. Preparation of pyrazolylbenzamides and pyrazolopyridinylbenzamides as factor Xa inhibitors for the treatment of thromboembolic disorders; Lam, Patrick Y. et al; U.S. Patent Application Publication No. 2006 / 0089496 (incorporated by reference) 38. Preparation of pyrazolylcarbonyl anthranilamides as insecticides; Lahm, George Philip and Selby, Thomas Paul; International Publication No. 2005 / 118552 (incorporated by reference) 39.Insecticidal anthranilic diamides:A new class of potent ryanodine receptor activators;Lahm,George P.et al;Bioorganic & Medicinal Chemistry Letters,15(22),4898-4906;2005 40. Process for the preparation of 1,3,5-trisubstituted pyrazoles via [3+2]cycloaddition; Shapiro, Rafael et al; U.S. Patent Application Publication No. 2006 / 0069270 (incorporated by reference) 41. 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Preparation of novel guanidine mimics as factor Xa inhibitors; Lam, Patrick Y. et al; International Publication No. 98 / 57951 (incorporated by reference) 61.Some reactions of β-aroylacrylic acid epoxide;By El-Sawy,AAet al;Journal of the Serbian Chemical Society,56(10),587-94;1991 62. 1,3 - 二苯基吡唑羧酸衍生物对肝细胞色素P - 450系统的影响;赫洛普希娜,T.G.等人;《化学制药杂志》,25(11),10 - 13;1991 63. 作为植物生长调节剂和保护剂的苯基吡唑羧酸盐的制备与测试;索恩,埃里希等人;德国专利公开号,3633840 64. 氮亲核试剂对β - 芳酰基丙烯酸环氧乙烷的作用;奥姆兰,S.A.等人;《埃及化学杂志》,28(5),399 - 410;1986 65. 1 - 苯基吡唑的顺序锂化反应;米切蒂奇,罗纳德·G.等人;《杂环化合物》,23(4),943 - 51;1985 [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [ka] [ka] Preparation of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) Step 1: Preparation of 3-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (9f)

[0581] A suspension of 3-bromoaniline (9a) (30.8 mL, 283 mmol) in 12N hydrochloric acid (85 mL, 1017 mmol) was slowly added to a solution of sodium nitrite (23.39 g, 339 mmol) in water (160 mL) at 0°C. After stirring for 1 hour, tin(II) chloride dihydrate (127 g, 565 mmol), pre-dissolved in 12N hydrochloric acid (85 mL, 1017 mmol), was added to the mixture at a rate that did not exceed 5°C. After stirring for 2 hours, a solution of 1,1,1-trifluoropentane-2,4-dione (9c) (39.4 mL, 325 mmol) in ethanol (650 mL) was added to the crude reaction mixture containing (3-bromophenyl)hydrazine (9b), and the mixture was heated overnight at 60°C. After cooling to room temperature, the solvent was removed, the aqueous solution was basicized with solid NaHCO3, diluted with water (300 mL), and partitioned with ethyl acetate (3 times × 500 mL). The organic phase was dried over MgSO4 and concentrated to produce a crude mixture of 1-(3-bromophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (9d) and 1-(3-bromophenyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazole (9e) (81.6 g, yield 94.6%). The reaction mixture was used directly in the next step.

[0582] A mixture of 1-(3-bromophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (9d) and 1-(3-bromophenyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazole (9e) (6.1 g, 20 mmol) in DMF (15 mL) was mixed with copper cyanide (2.24 g, 25 mmol) and heated overnight under reflux. TLC (ethyl acetate / hexane, 20%) indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was washed with water (200 mL) and brine (100 mL) and dried. The crude mixture was purified using ethyl acetate / hexane, 0-50% as the eluent via an 80 g silica gel flash column to obtain the following results. 1,3-(3-methyl-5-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (9g) (0.5g, yield 20%, higher electrophoresis spot) was obtained as yellow oil. 1 H NMR(300MHz,DMSO-d6)δ8.10-8.02(m,2H),7.92-7.76(m,2H),7.03(s,1H),2.32(s,3H);IR(KBr)31 Analysis, C 12 Calculated values ​​for H8F3N3: C, 57.37; H, 3.21; N, 16.73; Measured values: C, 57.58; H, 3.35; N, 16.83. 2.3-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (9f) (1.2 g, 4.78 mmol, yield 48%, lower electrophoresis spot) was obtained as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.17(t,J=1.7Hz,1H),8.06-7.92(m,2H),7.79(t,J=8.0Hz,1H),6.83(s,1H),2.40(d,J=0 Analysis, C 12Calculated values ​​for H8F3N3: C, 57.37; H, 3.21; N, 16.73; Measured values: C, 57.58; H, 3.35; N, 16.83. Step 2: Preparation of 3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (9H)

[0583] To a solution of 3-(5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (9f) (2.66 g, 10.59 mmol) in carbon tetrachloride (80 mL), 1-bromopyrrolidone-2,5-dione (NBS, 1.98 g, 11.12 mmol) and benzoyl peroxide (0.077 g, 0.318 mmol) were added. The reaction mixture was refluxed for 4 hours, cooled, filtered, and concentrated to obtain a crude bromide. The crude bromide was dissolved in a mixture of dioxane (40 mL) and water (40 mL), and calcium carbonate (1.91 g, 19.06 mmol) was added. The solution was heated overnight at 60°C with constant stirring. The reaction mixture was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated to remove volatile solvents, and the aqueous solution was extracted with ethyl acetate (2 times × 150 mL). The organic layers were combined, dried over MgSO4, and concentrated to obtain crude 3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (9h). The crude product was purified by flash column chromatography (40g silica gel, eluted with 0-50% ethyl acetate / hexane) to obtain 3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (9h) (520mg, 1.946 mmol, yield 18.38%) as a white solid. 1H NMR(300MHz,CDCl3)δ8.06(t,J=1.7Hz,1H),7.99(ddd,J=8.1,2.1,1.2Hz,1H),7.75(dt,J= 7.7,1.3Hz,1H),7.65(t,J=7.9Hz,1H),6.76(s,1H),4.72(t,J=9.8Hz,2H),2.13(t,J=5.5Hz 1H);IR(KBr)3370,3076,2946,2235,1484,1463,1256,1192,1127,1019,805,691,503cm -1 ;Analysis, C 12 Calculated values ​​for H8F3N3O: C, 53.94; H, 3.02; N, 15.73; Measured values: C, 53.96; H, 3.07; N, 15.48 Step 3: Preparation of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)

[0584] 3-(5-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (9h) (20.21 g, 76 mmol) was added to acetonitrile (100 mL), to which sodium periodate (32.4 g, 151 mmol), water (100 mL), and ruthenium(III) chloride hydrate (0.341 g, 1.513 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and concentrated to remove acetonitrile. The aqueous layer was basicized with 1 N NaOH and then washed with ether (twice × 100 mL) to remove organic impurities. The basic aqueous layer was acidified with 1 N HCl and extracted with ether (twice × 150 mL). The ether layer was concentrated to approximately 75 mL, then hexane was added until turbidity was observed, and the mixture was stirred overnight at room temperature. The obtained solid was collected by filtration and dried in a vacuum to obtain 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (7.48 g, yield 35%) as a pale yellow solid. 1H NMR(300MHz,DMSO-d6)δ13.84(bs,1H),8.22(t,J=1.7Hz,1H),8.06-8.00(m,1H) ,7.96(ddd,J=8.2,2.1,1.1Hz,1H),7.74(t,J=8.0Hz,1H),7.57(d,J=0.4Hz,1H); 19 F NMR(282MHz,DMSO)δ-60.96(s);Analysis, C 12 Calculated values ​​for H6F3N3O2: C, 51.26; H, 2.15; N, 14.94; Measured values: C, 51.19; H, 2.14; N, 14.58 [ka] Preparation of 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) Step 1: Preparation of 3-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (10c)

[0585] A 1.0 L three-necked flask containing a suspension of 3-aminobenzonitrile (5 g, 42.3 mmol) in 12 N HCl (12.70 mL, 152 mmol) was slowly added at 0°C to an aqueous solution of sodium nitrite (3.50 g, 50.8 mmol) in water (15 mL). After stirring the solid suspension for 1 hour, a solution of tin(II) chloride dihydrate (19.10 g, 85 mmol), pre-dissolved in 12 N HCl (12.70 mL, 152 mmol), was added at a rate such that the internal temperature did not exceed 5°C. After stirring at 0-5°C for 2 hours, a solution of 4,4,4-trifluoro-1-(furan-2-yl)butan-1,3-dione (10b) (10.47 g, 50.8 mmol) in ethanol (61 mL) was added to the mixture, and the mixture was heated overnight at 60°C. The reaction mixture was cooled to room temperature, concentrated under vacuum to remove ethanol, basicized with NaHCO3 aqueous solution (25 g in 250 mL), diluted with water (250 mL), and extracted with ethyl acetate (3 times × 50 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under vacuum until dry. The resulting residue was purified by flash column chromatography [120 g silica gel, eluted with ethyl acetate in hexane, 0-100%] to obtain 3-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (10c) (8.91 g, yield 69.4%) as a white solid. Step 2: Preparation of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i)

[0586] A solution of 3-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzonitrile (10c) (4.15 g, 13.69 mmol) in acetone (75 mL) was mixed with an aqueous solution of potassium permanganate (15.14 g, 96 mmol) in water (75 mL). This mixture was heated at 60 °C for 2 hours and then cooled to room temperature. The reaction mixture was stopped with 2-propanol (75 mL) and stirred overnight at room temperature. The reaction mixture was filtered through Celite, and the solid cake was washed with an acetone / water mixture (2 times × 50 mL) and methanol (2 times × 50 mL). The filtrate was evaporated under reduced pressure to remove the organic solvent. The aqueous solution was basicized with 1 N NaOH and washed with ether (2 times × 100 mL). The aqueous layer was poured onto crushed ice and very carefully acidified with 2 N HCl aqueous solution under constant stirring. The obtained solid was collected by filtration, washed with hexane (twice in 50 mL solutions), and dried over P2O5 to obtain 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (2.68 g, yield 69.6%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ14.01(s,1H),8.22(t,J=1.8Hz,1H),8.03(dt,J=7.7,1.3Hz, 1H),7.96(ddd,J=8.2,2.2,1.1Hz,1H),7.75(t,J=7.9Hz,1H),7.58(d,J=0.7Hz,1H); 19 F NMR (282MHz, DMSO-d6) δ-60.95. Step 3: Preparation of 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d)

[0587] To a stirred solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (100 g, 356 mmol) in anhydrous methanol (1000 mL) cooled to 0°C, nickel(II) chloride hexahydrate (8.45 g, 35.6 mmol) was added. Then, while maintaining the internal temperature at 0-5°C, sodium borohydride (53.8 g, 1423 mmol) was added in small amounts over 70 minutes. The reaction mixture was stirred for a further 15 minutes. A cold solution of NaOH (28.4 g, 711 mmol) in water (250 mL), di-tert-butyl dicarbonate (124 g, 569 mmol), and THF (500 mL) were added at 0°C. After 2 hours, di-tert-butyl dicarbonate (15.52 g, 71.1 mmol) was added to THF (100 mL), and stirring was continued for 10 hours. The reaction was stopped with N1-(2-aminoethyl)ethane-1,2-diamine (38 mL, 356 mmol), stirred for 30 minutes, and concentrated under vacuum. The resulting solid was dissolved in water (3000 mL), and insoluble substances were removed by filtration using a Celite pad. The filtrate was acidified by dropwise addition of 1N potassium bicarbonate (2134 mL, 2134 mmol, pH approximately 2) over 1 hour, while maintaining the internal temperature at 0-5°C. The separated solid was collected by filtration, washed with water (500 mL), and dissolved in dichloromethane (4000 mL). The dichloromethane layer was washed with water (1000 mL) and brine (1000 mL), dried, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography {2 kg of silica gel, CMA80 in chloroform (0%, 5%, and 10% [4000 mL each], 20%, 30%, and 40% [2000 mL each], 50% 10,000 mL, and 60% 4000 mL)} to obtain 1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (97 g, 252 mmol, yield 70.8%) as a pale green solid. 1 H NMR(300MHz,DMSO-d6)δ7.49(t,J=6.3Hz,1H),7.36(m,5H),4.20(d,J=6.0Hz,2H),1.38(s,9H);19 F NMR (282MHz, DMSO-d6) δ-60.75. [ka] Preparation of 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (11c) Step 1: Preparation of 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (11b)

[0588] A suspension of 4-methoxyaniline (3.08 g, 25 mmol) in hydrochloric acid (7.50 mL, 90 mmol) was to be added dropwise to a solution of sodium nitrite (2.070 g, 30.0 mmol) in water (13 mL) at 0°C. After stirring for 1 hour, tin(II) chloride dihydrate (11.28 g, 50.0 mmol), which had been pre-dissolved in hydrochloric acid (7.50 mL, 90 mmol), was added to the mixture at a rate that did not exceed 5°C. After stirring for 2 hours, a solution of 4,4,4-trifluoro-1-(furan-2-yl)butan-1,3-dione (10b) (5.67 g, 27.5 mmol) in ethanol (52 mL) was added to the mixture, and the mixture was heated overnight at 60°C. After cooling to room temperature, the resulting solid was collected by filtration, washed with water, and dried under vacuum to obtain 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (11b) (5.93 g, 19.22 mmol, yield 77%) as a gray solid. MP: 81.1℃; 1 H NMR(300MHz,DMSO-d6)δ7.78(dd,J=1.8,0.7Hz,1H),7.46-7.42(m,2H),7.22(s,1H),7. 12-7.08(m,2H),6.54(dd,J=3.5,1.8Hz,1H),6.12(dd,J=3.5,0.7Hz,1H),3.85(s,3H); 19 F NMR (300MHz, DMSO-d6) δ-60.39; MS (ES+) 309.0. Step 2: Preparation of 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (11c)

[0589] A solution of 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (11b) (5 g, 16.22 mmol) dissolved in acetone (180 mL) was mixed with a solution of KMnO4 (17.94 g, 114 mmol) in water (200 mL). The reaction mixture was heated at 60 °C for 3 hours and then cooled to room temperature. The reaction mixture was stopped with IPA (180 mL) and stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad and washed with acetone and water. The filtrate was concentrated to remove the organic solvent. The aqueous solution was acidified with acetic acid to pH 4-5 and extracted with ether. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum to obtain 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (11c) (3.965 g, 13.85 mmol, yield 85%) as a pale yellow solid. The analytical sample was obtained by column purification of a small amount of the crude product. 1 H NMR (300MHz, DMSO-d6) δ 13.34 (s, 1H), 7.50-7.38 (m, 3H), 7.10-6.99 (m, 2H), 3.83 (s, 3H); MS (ES+) 287.0 (M+1). [ka] Preparation of 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (12c) Step 1: Preparation of 1-(4-chlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (12b)

[0590] A suspension of 4-chloroaniline (12a) (3.19 g, 25 mmol) in hydrochloric acid (7.50 mL, 90 mmol) was met with a solution of sodium nitrite (2.070 g, 30.0 mmol) in water (13 mL) added dropwise at 0°C. After stirring for 1 hour, tin(II) chloride dihydrate (11.28 g, 50.0 mmol), pre-dissolved in hydrochloric acid (7.50 mL, 90 mmol), was added to the mixture at a rate that did not exceed 5°C. After stirring for 2 hours, a solution of 4,4,4-trifluoro-1-(furan-2-yl)butan-1,3-dione (10b) (5.67 g, 27.5 mmol) in ethanol (52 mL) was added to the mixture, and the mixture was heated overnight at 60°C. After cooling to room temperature, the reaction mixture was neutralized to pH=4 using 18 mL of 10 N NaOH and 1 N NaOH. The reaction mixture was concentrated under vacuum to remove ethanol. The resulting solid was collected by filtration, washed with water, and dried under vacuum. The residue was placed in 100 mL of saturated NaHCO3 aqueous solution and extracted with ethyl acetate (300 mL). The organic layer was dried and concentrated under vacuum. The resulting residue was purified by flash column chromatography (eluted with 40 g of silica gel and 0-50% ethyl acetate in hexane) to obtain 1-(4-chlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (12b) (6.238 g, 19.95 mmol, yield 80%) as a white solid. MP 62℃; 1 H NMR(300MHz,DMSO-d6)δ7.79(dd,J=1.9,0.7Hz,1H),7.68-7.61(m,2H),7.59-7.52(m ,2H),7.31(d,J=0.6Hz,1H),6.58(dd,J=3.5,1.8Hz,1H),6.40(dd,J=3.5,0.7Hz,1H); 19 F NMR (300MHz, DMSO-d6) δ-60.90; MS (ES+) 314.9 (M+1). Step 2: Preparation of 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (12c)

[0591] A solution of 1-(4-chlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (12b) (6.23 g, 19.92 mmol) dissolved in acetone (200 mL) was mixed with a solution of KMnO4 (22.04 g, 139 mmol) in water (220 mL). The reaction mixture was stirred at 60 °C for 3 hours and then cooled to room temperature. The reaction mixture was stopped with IPA (200 mL) and stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad and washed with acetone and water. The filtrate was concentrated to remove the organic solvent. The aqueous solution was acidified with acetic acid to pH 4-5 and extracted with ether. The organic layer was dried, filtered, and concentrated under vacuum to obtain 6.7 g of crude material. This crude material was purified by flash column chromatography (elution with methanol in chloroform on 80 g of silica gel) to obtain 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (12c) (2.5 g, 8.60 mmol, yield 43.2%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 14.06 (bs, 1H), 7.61-7.56 (m, 3H), 7.53-7.48 (m, 1H), 7.42 (d, J = 3.2Hz, 1H); MS (ES+) 328.8 (M + K). [ka] Preparation of 1-(5-chloropyridine-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (13d) Step 1: Preparation of 5-chloro-2-hydrazinylpyridine (13b)

[0592] A solution of 2,5-dichloropyridine (13a) (7.4 g, 50.0 mmol) and hydrazine hydrate (101 mL, 3250 mmol) in pyridine (100 mL) was heated under reflux for 6 hours and concentrated in vacuum until dry. The resulting residue was dissolved in DCM (500 mL) and washed with 1 N NaOH aqueous solution (500 mL) and water (3 times × 500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuum until dry to obtain 5-chloro-2-hydrazinylpyridine (13b) (2.95 g, 20.55 mmol, yield 41%) as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6) δ7.97(d,J=2.5Hz,1H),7.67(s,1H),7.50(dd,J=9.0,2.6Hz,1H),6.73(dd,J=9.0,0.6Hz,1H),4.17(s,2H);MS(ES+)144.2(M+1). Step 2: Preparation of 5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)pyridine (13c)

[0593] To a solution of 5-chloro-2-hydrazinylpyridine (13b) (717.87 mg, 5.00 mmol) in EtOH (12 mL), 4,4,4-trifluoro-1-(furan-2-yl)butan-1,3-dione (10b) (1134 mg, 5.50 mmol), water (3 mL), and hydrochloric acid (concentrated HCl, 1.667 mL, 20.00 mmol) were added. The reaction mixture was stirred overnight under reflux and concentrated in vacuum to remove the organic solvent. The aqueous solution was basicized with 1 N NaOH, and then partitioned twice with ethyl acetate. The organic layers were combined, dried, filtered, and concentrated in vacuum until dry. The obtained residue was purified by flash column chromatography (elution with 12g silica gel and 0-50% ethyl acetate in hexane) to obtain 5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)pyridine(13c). (795 mg, 2.53 mmol, yield 50.7%) was obtained as a pale yellow solid, 1¹H NMR showed a mixture of two compounds in a 2:1 ratio: MS(ES+)314.0(M+1),335.9(M+Na). Step 3: Preparation of 1-(5-chloropyridine-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (13d)

[0594] To a solution of 5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)pyridine (13c) (750 mg, 2.39 mmol) in acetone (25 mL) and water (27.5 mL), KMnO4 (2645 mg, 16.74 mmol) was added. The reaction mixture was heated at 60 °C for 3 hours. The reaction mixture was allowed to cool to room temperature, the reaction was stopped with isopropanol (25 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad, and the filter cake was washed with 50 mL of acetone-water (1:1). The filtrate was concentrated to remove the organic solvent, and the resulting aqueous solution was acidified with 1 N HCl to pH 2-3. The solution was cloudy, and the resulting solid was collected by filtration, washed with some further water and hexane, and dried under vacuum to obtain 5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)pyridine (13c) (345 mg, 1.183 mmol, yield 49.5%) as a grayish-white solid. 1 H NMR(300MHz,DMSO-d6)δ13.67(s,1H),8.68(d,J=2.5Hz,1H),8.26(dd,J=8.7,2.6Hz,1H),7.94(d,J=8.8Hz,1H),7.54(s,1H); 19 F NMR (282MHz, DMSO-d6) δ-56; MS (ES+) 292.0 (M+1), 313.9 (M+Na), 329.9 (M+K). [ka] Preparation of 1-(6-chloronaphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (14d) Step 1: Preparation of 1-(6-bromonaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (14b)

[0595] A suspension of 6-bromonaphthalene-2-amine (14a) (2.6 g, 11.71 mmol) in hydrochloric acid (7.02 mL, 84 mmol) was slowly added to a solution of sodium nitrite (0.969 g, 14.05 mmol) in water (12 mL) at 0°C. After stirring for 1 hour, tin(II) chloride dihydrate (5.28 g, 23.41 mmol), which had been pre-dissolved in hydrochloric acid (7.02 mL, 84 mmol), was added to the mixture at a rate that did not exceed 5°C. After stirring for 2 hours, a solution of 4,4,4-trifluoro-1-(furan-2-yl)butan-1,3-dione (10b) (2.65 g, 12.88 mmol) in ethanol (24 mL) was added to the mixture, and the mixture was heated overnight at 60°C. After cooling to room temperature, the reaction mixture was basicized to pH=8 using 15 mL of 10 N NaOH aqueous solution and saturated NaHCO3. The reaction mixture was diluted with ethyl acetate and filtered through a Celite pad. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, dried, filtered, and concentrated under vacuum to obtain a crude residue. This crude residue was purified by flash column chromatography (eluting with 0-100% ethyl acetate in hexane using 12 g of silica gel) to obtain 1-(6-bromonaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (14b) (1.3 g, 3.19 mmol, yield 27.3%) as a semi-solid. 1 H NMR(300MHz,DMSO-d6)δ8.39(d,J=2.0Hz,1H),8.22(d,J=2.1Hz,1H),8.10(d,J=8.8Hz,1H),8.02(d,J=8.8Hz,1H),7.78(dd,J=8.8,2.0 Hz,1H),7.75(dd,J=1.8,0.8Hz,1H),7.64(dd,J=8.8,2.2Hz,1H),7.35(s,1H),6.53(dd,J=3.5,1.8Hz,1H),6.32(dd,J=3.5,0.7Hz,1H); 19F NMR (300MHz, DMSO-d6) δ-60.85; MS (ES+) 406.9, 408.8 (M+1). Step 2: Preparation of 1-(6-chloronaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (14c)

[0596] To a solution of 1-(6-bromonaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14b) (1.73 g, 4.25 mmol) in DMF (25 mL), copper(I) iodide (0.809 g, 4.25 mmol) and copper(I) chloride (4.21 g, 42.5 mmol) were added, and the mixture was heated overnight under reflux. The mixture was allowed to cool to room temperature, diluted with water (35 mL), and stirred for 1 hour. The precipitated solid was collected by filtration, washed several times with water, and dried under vacuum to obtain 1-(6-chloronaphthalene-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14c) (22 g) contaminated with copper salts. This solid was suspended in ethyl acetate (100 mL) and filtered. The filtrate was concentrated under vacuum until dry, and after purification by column chromatography (elution with 40 g of silica gel and 0-100% ethyl acetate in hexane), 1-(6-chloronaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole(14c) (1.2 g, 3.31 mmol, yield 78%) was obtained as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ8.23(t,J=1.6Hz,2H),8.10(dd,J=9.0,1.5Hz,2H),7.75(dd,J=1.9,0.7Hz,1H),7. 66(ddd,J=8.7,6.6,2.2Hz,2H),7.35(s,1H),6.53(dd,J=3.5,1.8Hz,1H),6.32(dd,J=3.5,0.8Hz,1H);Analysis, C 18 H 10 Calculated values ​​for ClF3N2O: C, 59.60; H, 2.78; N, 7.72; Cl, ​​9.77; Measured values: C, 59.34; H, 2.60; N, 7.70; Cl, ​​9.96 Step 3: Preparation of 1-(6-chloronaphthalene-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (14d)

[0597] A solution of 1-(6-chloronaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (14c) (4.42 g, 12.19 mmol) in acetone (120 mL) was mixed with a solution of KMnO4 (13.48 g, 85 mmol) in water (120 mL). The reaction mixture was stirred at 60 °C for 3 hours, cooled to room temperature, stopped with isopropanol (120 mL), and stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad and washed with acetone and water. The filtrate was concentrated under vacuum to remove the organic solvent. The aqueous solution was washed with ether and then acidified to pH 4 with 1N aqueous HCl. The aqueous layer was extracted, partitioned with ethyl acetate, dried, filtered, and concentrated under vacuum to obtain 1-(6-chloronaphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (14d) (0.86 g, 2.52 mmol, yield 21%) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ13.95(s,1H),8.22(dd,J=8.0,2.1Hz,2H),8.08(dd,J=13.5,8.9Hz,2H),7.7 5(dd,J=8.8,2.2Hz,1H),7.66(dd,J=8.8,2.1Hz,1H),7.58(s,1H);MS(ES+)340.9(M+1);338.7(M-1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15g) Step 1: Preparation of (4-amino-3-fluorophenyl)methanol (15b)

[0598] A suspension of lithium aluminum hydride (1.835 g, 48.3 mmol) in THF (20 mL) was added dropwise to a solution of 4-amino-3-fluorobenzoic acid (5 g, 32.2 mmol) in THF (20 mL) at 0°C. The reaction mixture was stirred overnight at room temperature. The mixture was then cooled to 0°C and the reaction was stopped with ethyl acetate (30 mL) and water (10 mL). The resulting slurry was filtered through Celite and washed with ethyl acetate (50 mL). The aqueous layer was separated, the organic layer was dried, filtered, and concentrated under vacuum until dry to obtain the crude product. The crude product was purified by flash column chromatography (elution with 0-100% ethyl acetate in hexane over 80 g of silica gel) to obtain (4-amino-3-fluorophenyl)methanol (15b) (2.2 g, yield 48.4%) as a yellowish-brown solid. 1 H NMR(300MHz,DMSO-d6)δ6.91(dd,J=12.5,1.8Hz,1H),6.81(dd,J=8.1,1.8Hz,1H),6.70(dd,J=9. 3,8.0Hz,1H),5.03-4.93(m,3H),4.31(d,J=5.5Hz,2H);MS(ES+)142.0(M+1);(ES-)140.0(M-1). Step 2: Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15c)

[0599] A 100 mL one-necked flask was loaded with 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (1.99 g, 7.09 mmol), (4-amino-3-fluorophenyl)methanol (15b) (1 g, 7.09 mmol), and bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (3.3 g, 7.09 mmol). This was then continuously treated with N,N-dimethylformamide (42.8 mL, 553 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.17 mL, 35.4 mmol) under a positive flow of nitrogen at room temperature. The resulting reaction mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction mixture was diluted with water (150 mL), extracted with ethyl acetate (twice × 150 mL), washed with brine (75 mL), and the combined organic layer was dried over anhydrous MgSO4, filtered, and evaporated until dry. The residue was purified by flash column chromatography [40 g silica gel, eluted with ethyl acetate in hexane at 0-100%] to obtain 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15c) (1.151 g, 2.85 mmol, yield 40.2%) as a pale yellow solid. MS(ES) + ):MS(ES+)405.2(M+1),MS(ES-)403.2(M-1). Step 3: Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15d)

[0600] To a stirred solution of 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15c) (1.106 g, 2.74 mmol) in dichloromethane (20 mL), sodium bicarbonate (1.149 g, 13.68 mmol) and Dess-Martin periodinane (1.74 g, 4.10 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Further Dess-Martin periodinane (1.74 g, 4.10 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes. Excess solvent was removed under reduced pressure. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (twice in 75 mL batches). The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated until dry. The obtained residue was purified by flash column chromatography (eluting with 25 g silica gel and 0-100% ethyl acetate / hexane) to obtain 1-(3-cyanophenyl)-N-(2-fluoro-4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15d) (0.418 g, yield 38.0%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.85(s,1H,exchanged with D2O),9.95(d,J=1.7Hz,1H),8.18(t,J=1.8Hz ,1H),8.04-7.98(m,1H),7.97-7.90(m,2H),7.85-7.78(m,3H),7.74(t,J=8.0Hz,1H); 19 F NMR(282MHz,DMSO-d6)δ-60.97,-120.36;MS(ES + ):MS(ES+)425.08(M+Na),MS(ES-)401.1(M-1). Step 4: Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15e)

[0601] Phenylmagnesium bromide (2.018 mL, 2.018 mmol) was added to a solution of 1-(3-cyanophenyl)-N-(2-fluoro-4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15d) (0.4 g, 0.994 mmol) in THF (10 mL) cooled to 0°C. The reaction mixture was stirred at room temperature for 16 hours and the reaction was stopped with saturated NH4Cl aqueous solution (60 mL). The product was extracted twice with ethyl acetate (100 mL, 75 mL). The combined organic extract was dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash column chromatography (eluting with ethyl acetate in hexane at 0-100% silica gel, 25 g) to obtain 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15e) (0.377 g, 0.785 mmol, yield 79%) as a waxy solid. 1 H NMR(300MHz,DMSO-d6)δ10.54(s,1H,exchanged with D2O),8.12(t,J=1.8Hz,1H),7.99(dt,J=7.7 ,1.4Hz,1H),7.89(ddd,J=8.2,2.2,1.1Hz,1H),7.77-7.67(m,2H),7.47(t,J=8.1Hz, 1H),7.39(d,J=1.8Hz,1H),7.36(d,J=1.3Hz,1H),7.34-7.28(m,2H),7.27-7.22(m,1 H),7.20(dt,J=8.6,2.4Hz,2H),6.06(d,J=4.0Hz,1H,replaced with D2O),5.71(d,J=4.0Hz,1H); 19 F NMR(282MHz,DMSO-d6)δ-60.98,-121.26;IR(KBr,cm -1 ): 2236cm -1 (CN stretching); MS(ES + ):MS(ES+)503.15(M+Na),MS(ES-)479.24(M-1). Step 5: Preparation of 1-(3-cyanophenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15f)

[0602] To a solution of 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15e) (0.453 g, 0.943 mmol) in cyclopropyl methanol (6.77 mL, 94 mmol), ytterbium(III) trifluoromethanesulfonate (1.170 g, 1.886 mmol) was added and the mixture was heated at 80°C for 16 hours. The reaction mixture was concentrated under vacuum until dry, and the resulting residue was diluted with chloroform (2 times × 50 mL) and filtered through a small Celite pad. The filtrate was concentrated until dried under vacuum, and the resulting residue was purified by flash column chromatography [elution with ethyl acetate in hexane at 0-100% silica gel (25 g)] to obtain 1-(3-cyanophenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15f) (0.076 g, yield 15%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.55(s,1H,exchanged with D2O),8.11(t,J=1.8Hz,1H),7.99(dt,J= 7.7,1.3Hz,1H),7.89(dd,J=8.5,1.8Hz,1H),7.77-7.68(m,2H),7.51(t,J=8.0Hz, 1H),7.40-7.32(m,4H),7.32-7.24(m,2H),7.19(dd,J=8.3,1.9Hz,1H),5.49(s,1H) ),3.24(d,J=6.8Hz,2H),1.11-1.02(m,1H),0.53-0.41(m,2H),0.20-0.12(m,2H); 19 F NMR(282MHz,DMSO-d6)δ-60.98,-120.92;MS(ES +):MS(ES+)557.1(M+1),MS(ES-)533.1(M-1). Step 6: Preparation of 1-(3-(aminomethyl)phenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15g)

[0603] To a stirred solution of 1-(3-cyanophenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15f) (0.071 g, 0.133 mmol) in anhydrous methanol (10 mL) at 0°C, nickel(II) chloride hexahydrate (0.047 g, 0.199 mmol) and sodium borohydride (0.060 g, 1.594 mmol) were added in small amounts over 5 minutes. The reaction mixture was stirred for 10 minutes, the reaction was stopped with N1-(2-aminoethyl)ethane-1,2-diamine (0.143 mL, 1.328 mmol), and the mixture was stirred for a further 30 minutes. Excess methanol was removed under reduced pressure. The reaction mixture was treated with saturated NH4Cl (50 mL), and the product was extracted with chloroform (twice × 50 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated until dry. The residue was purified by flash column chromatography (eluted with methanol in 0-50% chloroform on 12 g of silica gel) to obtain 1-(3-(aminomethyl)phenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15 g) (48 mg, yield 67%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ10.58(s,1H),7.55(d,J=4.6Hz,2H),7.51(d,J=3.8Hz,1H),7.45-7.40(m,2H),7.39-7.28(m,6H),7.26(dd,J=6.0,2.1 Hz,1H),7.19(dd,J=8.3,1.8Hz,1H),5.49(s,1H),3.76(s,2H),3.24(d, J=6.7Hz,2H),1.13-1.00(m,1H),0.53-0.41(m,2H),0.21-0.11(m,2H); 1 H NMR(300MHz,DMSO-d6D2O)δ7.55(s,2H),7.53-7.48(m,1H),7.45-7.40(m,2H),7.39-7.28(m,6H),7.27-7.23(m,1H),7.19( dd,J=8.3,1.9Hz,1H),5.49(s,1H),3.75(s,2H),3.24(d,J=6.7Hz,2H),1.06(m,1H),0.56-0.41(m,2H),0.20-0.11(m,2H); 19 F NMR(282MHz,DMSO-d6)δ-60.74,-121.19;MS(ES + ):MS(ES+)539.2(M+1),MS(ES-)537.2(M-1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (16b) Step 1: Preparation of 3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(16a)

[0604] To a stirred solution of 1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (15e) (0.284 g, 0.59 mmol) in anhydrous methanol (5 mL) cooled to 0°C, di-tert-butyl dicarbonate (0.258 g, 1.182 mmol) and nickel(II) chloride (0.035 g, 0.148 mmol) were added. Sodium borohydride (0.134 g, 3.55 mmol) was then added to the reaction mixture in small amounts over 15 minutes. The reaction mixture was stirred at 0°C for 15 minutes. TLC (50% ethyl hexane) indicates that all starting materials have been consumed. The reaction mixture was stopped with N1-(2-aminoethyl)ethane-1,2-diamine (0.128 mL, 1.182 mmol), stirred for 30 minutes, and concentrated under vacuum until dry. The resulting residue was dissolved in dichloromethane (20 mL) and water (20 mL). The organic layer was separated, dried, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography (eluted with 12 g of silica gel and 0-100% ethyl acetate in hexane) to obtain 3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl (16a) (0.185 g, 0.316 mmol, yield 53.5%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.55(s,1H),7.57(s,1H),7.50(q,J=7.7Hz,2H),7.44-7.37(m,3H),7.37-7.31(m,4H),7.29(dt ,J=6.3,0.8Hz,2H),7.25-7.15(m,2H),6.04(d,J=4.0Hz,1H),5.70(d,J=4.1Hz,1H),4.18(d,J=6.2Hz,2H),1.36(s,9H); 19 F NMR(282MHz,DMSO-d6)δ-60.82,-121.61;MS(ES+)607.3(M+Na);(ES-)583.2(M-1). Step 2: Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (16b)

[0605] To a stirred solution of tert-butyl (16a) (0.17 g, 0.291 mmol) of 3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate in acetonitrile (5 mL) at room temperature, concentrated HCl (1.212 mL, 14.54 mmol) and water (1.25 mL) were added. The reaction mixture was stirred overnight at room temperature and concentrated under vacuum until dry. The obtained residue was purified by flash column chromatography (elution with 0-100% ethyl acetate in hexane using 12 g of silica gel) to obtain 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-4-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (16c) (0.040 g, 0.080 mmol, yield 27.6%) as a white solid, which contained impurities of 1-(3-(aminomethyl)phenyl)-N-(4-(chloro(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (16d). Further elution yielded 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (16b) (0.022 g, 0.045 mmol, yield 15.62%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.64(s,1H),8.34(s,3H),7.71(d,J=2.0Hz,1H),7.67(s,1H),7.59(td,J=5.4,2.6Hz,1H),7. 55-7.46(m,3H),7.40-7.35(m,2H),7.34-7.27(m,2H),7.26-7.16(m,3H),6.07(d,J=4.0Hz,1H),5.71(d,J=4.0Hz,1H); 19F NMR(282MHz,DMSO-d6)δ-60.82,-121.23;MS(ES+)485.1(M+1);(ES-)483.2(M-1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17d) Step 1: Preparation of 1-(3-cyanophenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17b)

[0606] To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (400 mg, 1.423 mmol) in DMF (10 mL), N1-phenylbenzene-1,3-diamine (17a) (262 mg, 1.423 mmol), N-ethyl-N-isopropylpropan-2-amine (2.0 mL, 11.48 mmol), and hexafluorophosphate (V) bromotripyrrolidine-1-ylphosphonium (PyBrOP, 682 mg, 1.434 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2 times × 75 mL) and brine (75 mL), dried, filtered, and concentrated under vacuum until dry. The obtained residue was purified by flash column chromatography [eluted with silica gel, hexane / ethyl acetate (1:0~3:1)] to obtain 1-(3-cyanophenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17b) (316 mg, 50%) as brown rubber. 1 H NMR (300MHz, DMSO-d6) δ 10.57 (s, 1H), 8.31-6.73 (m, 14H); MS (ES+) 448.3 (M+1). Step 2: Preparation of 3-(5-((3-(phenylamino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(17c)

[0607] A solution of 1-(3-cyanophenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17b) (200 mg, 0.447 mmol) in methanol (4 mL) was cooled with ice / water, treated with di-tert-butyl dicarbonate (296 mg, 1.341 mmol) and nickel(II) chloride (21.85 mg, 0.092 mmol), then sodium borohydride (104 mg, 2.68 mmol) was slowly added over 5 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was stopped with N1-(2-aminoethyl)ethane-1,2-diamine (0.104 mL, 0.952 mmol), and then stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under vacuum until dry. The resulting residue was treated with ethyl acetate (100 mL) and washed with water (50 mL). The aqueous phase was extracted again with ethyl acetate (50 mL). The combined extracts were washed with brine (60 mL), dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography [eluted with silica gel, hexane / ethyl acetate (1:0~3:1)] to obtain 3-(5-((3-(phenylamino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl (17c) (160 mg, 65%) as a brown solid. 1 H NMR (300MHz, DMSO-d6) δ10.63(s,1H),8.24(s,1H),7.67-6.51(m,14H),4.20(d,J=6.3Hz,2H),1.37(s,9H);MS(ES+)552.4(M+1). Step 3: Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17d)

[0608] A solution of tert-butyl 3-(5-((3-(phenylamino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (17c) (127 mg, 0.230 mmol) in 1,4-dioxane (12 mL) was treated by dropwise addition of hydrochloric acid (2.4 mL, 9.60 mmol, 4 M in 1,4-dioxane), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with hexane, decanted, washed with hexane, and decanted again. The insoluble portion was purified by flash column chromatography [elution with 4 g silica gel, chloroform / CMA80 (1:0~2:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(phenylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (17d) (23 mg, 22%) as a white solid. mp: 73.8℃; 1 H NMR(300MHz,DMSO-d6)δ10.62(s,1H),8.25(s,1H),7.55(s,1H),7.53(s,1H),7.48(t,J=2.1Hz,1H),7.45-7.41(m,2H),7.35- 7.29(m,1H),7.23(t,J=7.9Hz,2H),7.16(d,J=8.0Hz,1H),7.08(d,J=2.2Hz,2H),7.05(s,1H),6.87-6.78(m,2H),3.78(s,2H); 19 F NMR (282MHz, DMSO-d6) δ-60.70; MS (ES+) 452.3 (M+1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18f) Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18g) Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18h) Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(isobutoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18i) Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(butoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18j) Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18k) Step 1: Preparation of N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18b)

[0609] To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (5.42 g, 19.27 mmol) in DMF (100 mL), 3-aminobenzophenone (18a) (3.8 g, 19.27 mmol), N-ethyl-N-isopropylpropan-2-amine (27 mL, 155 mmol), and bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (9.24 g, 19.42 mmol) were added at room temperature. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 39 hours. The reaction product was diluted with ethyl acetate (600 mL), washed with water (2 times × 300 mL) and brine (200 mL), dried, filtered, and evaporated until dry. The obtained residue was purified by flash column chromatography [elution with ethyl acetate in hexane at 0-25% silica gel, 120 g] to obtain N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18b) (5.633 g, yield 63%) as a white solid.1 H NMR(300MHz,DMSO-d6)δ10.89(s,1H),8.19(t,J=1.8Hz,1H),8.07-7.98(m,3H),7.93(ddd, J=8.2,2.2,1.1Hz,1H),7.79-7.67(m,6H),7.61-7.55(m,2H),7.50(dt,J=7.7,1.5Hz,1H); 19 F NMR(282MHz,DMSO-d6)δ-60.98;MS(ES+)461.162(M+1),483.134(M+Na) Step 2: Preparation of 3-(5-((3-(hydroxy(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(18c)

[0610] To a stirred solution of N-(3-benzoylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18b) (4.704 g, 10.22 mmol) in anhydrous methanol (100 mL) cooled to 0°C, di-tert-butyl dicarbonate (6.76 g, 30.7 mmol) and nickel(II) chloride hexahydrate (0.5 g, 2.103 mmol) were added, followed by the addition of sodium borohydride (2.367 g, 61.3 mmol) in small amounts over 5 minutes. The reaction mixture was stirred at room temperature for 30 minutes, the reaction was stopped with N1-(2-aminoethyl)ethane-1,2-diamine (2.3 mL, 21.08 mmol), stirred for 30 minutes, and concentrated under vacuum until dry. The residue was dissolved in ethyl acetate (400 mL), washed with water (200 mL) and brine (200 mL), dried, filtered, and concentrated under vacuum. The obtained residue was purified by flash column chromatography (80 g silica gel, eluted with 0-50% ethyl acetate / hexane) to obtain 3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(18c) (2.71 g, yield 46.8%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ10.70(s,1H),7.62(t,J=1.8Hz,1H),7.59-7.46(m,3H),7.45-7.40(m,2H),7.38-7.25(m,7H),7.23 -7.20(m,1H),7.13(dt,J=7.7,1.3Hz,1H),5.94(d,J=3.9Hz,1H),5.66(d,J=3.8Hz,1H),4.19(d,J=6.2Hz,2H),1.37(s,9H); 19 F NMR (282MHz, DMSO-d6) δ-60.80; MS (ES+) 589.3 (M+1), (ES-) 565.3 (M-1). Step 3: Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d)

[0611] To a solution of tert-butyl 3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (18c) (65 mg, 0.115 mmol) in 1,4-dioxane (6 mL), hydrochloric acid (1.2 mL, 4.80 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with hexane and decanted. The residue was triturated with hexane and decanted to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d) as a white solid. Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18f)

[0612] A solution of 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d) in chloroform / methanol (40 mL / 15 mL) was mixed with 2 g of silica gel and concentrated under vacuum to obtain a slurry. This slurry was purified by flash column chromatography [elution with 2 × 4 g silica gel, chloroform / CMA80 (1:0~2:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18f) (26 mg, 47%) as a white solid at mp: 89.5℃. 1 H NMR(300MHz,DMSO-d6)δ10.71(s,1H),7.65-7.62(m,1H),7.60-7.49(m,3H),7.46-7.38(m,2H),7.3 3(d,J=4.3Hz,5H),7.31-7.23(m,2H),7.12(d,J=7.7Hz,1H),5.30(s,1H),3.78(s,2H),3.26(s,3H); 19 F NMR(282MHz,DMSO-d6)δ-60.74.MS(ES+)481.3(M+1) Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18g)

[0613] To a solution of tert-butyl(18c)(18c) (193 mg, 0.341 mmol) of 3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate in 1,4-dioxane (18 mL), hydrochloric acid (3.60 mL, 14.39 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 21 hours. The reaction mixture was diluted with hexane, decanted, and the resulting residue was washed with hexane while decanting. 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d) dissolved in chloroform / ethanol (40 mL / 15 mL) was mixed with 2 g of silica gel and concentrated under vacuum to obtain a slurry. This slurry was purified by flash column chromatography (eluting with 2 × 4 g of silica gel and chloroform / CMA80 (1:0~2:1)) to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(ethoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18 g) as a white solid (24 mg, 14%). 1 H NMR(300MHz,DMSO-d6)δ7.61(s,1H),7.57(s,2H),7.52(s,1H),7.42(d,J=6.2Hz,2H),7.35-7.31(m,5H),7.2 7(d,J=7.9Hz,2H),7.12(d,J=7.8Hz,1H),5.41(s,1H),3.76(s,2H),3.47-3.37(m,2H),1.17(t,J=7.0Hz,3H); 19 F NMR(282MHz,DMSO-d6)δ-60.73.MS(ES+)495.3(M+1). Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18h)

[0614] To a solution of tert-butyl (18c) (18c) (80 mg, 0.141 mmol) of 3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate in 1,4-dioxane (8 mL), hydrochloric acid (1.5 mL, 6 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with hexane, decanted, and the resulting residue was washed with hexane while decanting. 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d) residue dissolved in chloroform / 1-propanol (40 mL / 15 mL) was mixed with 2 g of silica gel and concentrated under vacuum to obtain a slurry. This slurry was purified by flash column chromatography (eluting with 2 × 4 g of silica gel and chloroform / CMA80 (1:0~2:1)) to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18h) (31 mg, 43%) as a colorless oil. 1 H NMR(300MHz,DMSO-d6)δ10.71(s,1H),7.61(t,J=1.8Hz,1H),7.59-7.51(m,3H),7.45-7.38(m,2H),7.36-7.28(m,6H),7.27 -7.22(m,1H),7.12(d,J=7.6Hz,1H),5.39(s,1H),3.77(s,2H),3.47-3.39(m,2H),1.64-1.50(m,2H),0.89(t,J=7.4Hz,3H); 1 H NMR (300MHz, methanol-d4) δ7.57(t,J=1.9Hz,1H),7.53(s,1H),7.52-7.45(m,3H),7.40(dt,J=4.5,2.4Hz,1H),7.35-7.22(m,7H),7. 17-7.11(m,1H),5.34(s,1H),3.86(s,2H),3.40(td,J=6.4,1.0Hz,2H),1.64(dtd,J=13.8,7.4,6.5Hz,2H),0.95(t,J=7.4Hz,3H);19 F NMR (282 MHz, methanol-d4): δ-63.73; MS (ES+): 509.3 (M+1); (ES-): 507.3 (M-1). Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(isobutoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18i)

[0615] To a solution of tert-butyl (18c) (18c) (80 mg, 0.141 mmol) of 3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate in 1,4-dioxane (8 mL), hydrochloric acid (1.5 mL, 6 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with hexane, decanted, and the resulting residue was washed with hexane while decanting. 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d) residue dissolved in chloroform / isobutanol (40 mL / 15 mL) was mixed with 2 g of silica gel and concentrated under vacuum to obtain a slurry. This slurry was purified by flash column chromatography (eluting with 2 × 4 g of silica gel and chloroform / CMA80 (1:0~2:1)) to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(isobutoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18i) (14 mg, 19%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ10.71(s,1H),7.61(d,J=1.9Hz,1H),7.59-7.50(m,3H),7.42(d,J=6.7Hz,2H),7.32(t,J=6.4Hz,5H),7.27-7.21( 19F NMR (282MHz, DMSO-d6) δ-60.71.; MS (ES+) 523.3 (M+1); (ES-) 521.4 (M-1). Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(butoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18j)

[0616] To a solution of tert-butyl (18c) (18c) (80 mg, 0.141 mmol) of 3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate in 1,4-dioxane (8 mL), hydrochloric acid (1.5 mL, 6 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with hexane, decanted, and the resulting residue was washed with hexane while decanting. 1-(3-(aminomethyl)phenyl)-N-(3-(chloro(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18d) residue dissolved in chloroform / 1-butanol (40 mL / 15 mL) was mixed with 2 g of silica gel and concentrated under vacuum to obtain a slurry. This slurry was purified by flash column chromatography (eluting with 2 × 4 g of silica gel and chloroform / CMA80 (1:0~2:1)) to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(butoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18j) (14 mg, 19%) as a colorless semi-solid. 1H NMR(300MHz,DMSO-d6)δ10.72(s,1H),7.64-7.49(m,4H),7.44-7.37(m,2H),7.36-7.20(m,7H),7.12(d,J=8.0Hz,1H),5.3 9(s,1H),3.77(s,2H),3.43-3.34(m,2H),1.54(dq,J=8.3,6.3Hz,2H),1.36(dq,J=9.4,7.2Hz,2H),0.85(t,J=7.3Hz,3H); 19 F NMR(282MHz,DMSO-d6)δ-60.73.MS(ES+):523.4(M+1). Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18k)

[0617] To a solution of tert-butyl(18c)(18c)(18c)(1.765 mmol) of 3-(5-(3-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate in 1,4-dioxane (90 mL), a solution of 4 M hydrochloric acid (19.00 mL, 76 mmol) in dioxane was added. The reaction mixture was stirred at room temperature for 16 hours and diluted with hexane. The organic solution was decanted, and the residue was washed with hexane. The residue was dissolved in chloroform / cyclopropanemethanol (120 mL / 7 mL) and stirred at room temperature for 68 hours. Silica gel (3 g) was added to the reaction mixture, and the mixture was concentrated under vacuum until dry. The slurry was purified twice by combiflash column chromatography (eluting with 12 g silica gel and 0-25% chloroform / CMA80) to obtain 1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (18k) (124 mg, 13.5%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ10.72(s,1H),7.64-7.50(m,4H),7.46-7.38(m,2H),7.36-7.27(m,6H),7.27-7.20(m,1H),7.13(d,J=7 .7Hz,1H),5.44(s,1H),3.77(s,2H),3.23(dd,J=6.7,1.3Hz,2H),1.14-0.97(m,1H),0.50-0.42(m,2H),0.19-0.10(m,2H);19F NMR (300MHz, DMSO-d6) δ-60.73; MS (ES+) 521.3 (M+1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-benzylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (19d) Step 1: Preparation of N-(3-benzylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (19b)

[0618] To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (400 mg, 1.423 mmol) in DMF (10 mL), 3-benzylaniline (19a) (261 mg, 1.423 mmol), N-ethyl-N-isopropylpropan-2-amine (2.0 mL, 11.48 mmol), and hexafluorophosphate (V) bromotripyrrolidine-1-ylphosphonium (PyBrOP, 682 mg, 1.434 mmol) were added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2 times × 75 mL) and brine (75 mL), dried over MgSO4, filtered, and concentrated under vacuum until dry. The obtained residue was purified by flash column chromatography [eluted with silica gel, hexane / ethyl acetate (1:0~3:1)] to obtain N-(3-benzylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (19b) (330 mg) as yellow rubber, which was used directly in the next step. MS(ES+) 469.3(M+23). Step 2: Preparation of 3-(5-((3-benzylphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(19c)

[0619] To a solution of N-(3-benzylphenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (19b) (200 mg, 0.448 mmol) in methanol (4 mL) cooled with ice / water, di-tert-butyl dicarbonate (296 mg, 1.344 mmol) and nickel(II) chloride hexahydrate (22.00 mg, 0.093 mmol) were added, followed by the addition of sodium borohydride (104 mg, 2.69 mmol) in small amounts over 5 minutes. The reaction mixture was stirred at room temperature for 1 hour, stopped with N1-(2-aminoethyl)ethane-1,2-diamine (0.100 mL, 0.914 mmol), stirred at room temperature for 0.5 hours, and concentrated under vacuum until dry. The residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL). The aqueous phase was extracted again with ethyl acetate (50 mL). The combined extract was washed with brine (60 mL), dried over MgSO4, filtered, and concentrated under vacuum until dry. The resulting crude product was purified by flash column chromatography [12 g silica gel, eluted with hexane / ethyl acetate (1:0~4:1)] to obtain 3-(5-(3-benzylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl (19c) (121 mg, 26% in two steps) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.68(s,1H),7.72-6.87(m,15H),4.19(d,J=6.4Hz,2H),3.91(s,2H),1.37(s,9H);MS(ES+)473.4(M+23). Step 3: Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-benzylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (19d)

[0620] To a solution of tert-butyl 3-(5-(3-benzylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (19c) (105 mg, 0.191 mmol) in 1,4-dioxane (9 mL), hydrochloric acid (2.0 mL, 8.0 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with hexane, decanted, washed with hexane, and decanted again. The insoluble portion was purified by flash column chromatography using [4 g silica gel, chloroform / CMA80 (1:0~2:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(3-benzylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (19d) (33 mg, 38%) as a grayish-white solid. MP 69.9℃; 1 H NMR(300MHz,DMSO-d6)δ10.66(s,1H),7.56-7.41(m,6H),7.33-7.25(m,4H),7.24-7.17(m,3H),7.01(d,J=7.6Hz,1H),3.91(s,2H),3.77(s,2H); 19 F NMR(282MHz,DMSO-d6)δ-60.73;MS(ES+)451.3(M+1) [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (20d) Step 1: Preparation of 1-(3-cyanophenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (20b)

[0621] To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (400 mg, 1.423 mmol) in DMF (10 mL), 3-phenoxyaniline (20a) (263 mg, 1.423 mmol), N-ethyl-N-isopropylpropan-2-amine (2.0 mL, 11.48 mmol), and hexafluorophosphate (V) bromotripyrrolidine-1-ylphosphonium (PyBrOP, 682 mg, 1.434 mmol) were added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2 times × 75 mL) and brine (75 mL), dried over MgSO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash column chromatography [eluted with silica gel, hexane / ethyl acetate (1:0~3:1)] to obtain 1-(3-cyanophenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (20b) (296 mg, 46%) as a grayish-white solid. 1 H NMR(300MHz,DMSO-d6)δ10.73(s,1H),8.17(t,J=1.9Hz,1H),8.00(dt,J=7.7,1.3Hz,1H),7.94-7.87(m,1H),7.78 -7.64(m,2H),7.51-7.27(m,5H),7.22-7.11(m,1H),7.08-6.99(m,2H),6.83-6.78(m,1H);MS(ES+)471.2(M+23). Step 2: Preparation of 3-(5-((3-phenoxyphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(20c)

[0622] To a solution of 1-(3-cyanophenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (20b) (200 mg, 0.446 mmol) in methanol (4 mL) cooled with ice / water, di-tert-butyl dicarbonate (295 mg, 1.338 mmol) and nickel(II) chloride hexahydrate (22.00 mg, 0.093 mmol) were added, followed by the slow addition of sodium borohydride (103 mg, 2.68 mmol) in small amounts over 5 minutes. The reaction mixture was stirred at room temperature for 1 hour, stopped with N1-(2-aminoethyl)ethane-1,2-diamine (0.100 mL, 0.912 mmol), stirred at room temperature for 0.5 hours, and concentrated under vacuum until dry. The residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL). The aqueous phase was extracted again with ethyl acetate (50 mL). The combined extract was washed with brine (60 mL), dried over MgSO4, filtered, and concentrated under vacuum until dry. The crude product was purified by flash column chromatography [12 g silica gel, eluted with hexane / ethyl acetate (1:0~3:1)] to obtain 3-(5-(3-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl (20c) (173 mg, 70%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ10.78(s,1H),7.57(s,1H),7.53-6.75(m,14H),4.19(d,J=6.3Hz,2H),1.37(s,9H);MS(ES+)475.4(M+23). Step 3: Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (20d)

[0623] To a solution of tert-butyl 3-(5-(3-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (20c) (115 mg, 0.208 mmol) in 1,4-dioxane (9 mL), hydrochloric acid (2.2 mL, 8.8 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with hexane, decanted, washed with hexane, and decanted again. The insoluble portion was purified by flash column chromatography [elution with 4 g silica gel, chloroform / CMA80 (1:0~2:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (20d) (70 mg, 74%) as a grayish-white solid. MP 89.0℃; 1 H NMR(300MHz,DMSO-d6)δ10.80(s,1H),7.60(s,2H),7.52-7.48(m,2H),7.46-7.32(m,6H) ,7.16(t,J=7.4Hz,1H),7.06-7.01(m,2H),6.82-6.77(m,1H),5.71(s,2H),3.95(s,2H); 19 F NMR (282MHz, DMSO-d6) δ-60.78; MS (ES+) 453.3 (M+1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenylcarbamoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (21e) Step 1: Preparation of 3-nitro-N-phenylbenzamide (21b)

[0624] To a solution of aniline (2.94 mL, 32.2 mmol) in ethyl acetate (30 mL), triethylamine (5.39 mL, 38.7 mmol) was added at room temperature, followed by the addition of a solution of 3-nitrobenzoyl chloride (5.98 g, 32.2 mmol) in ethyl acetate (30 mL). The reaction mixture was stirred at room temperature for 20 hours and the reaction was stopped with water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (twice × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum until dry. The resulting residue was purified by flash column chromatography (eluted with ethyl acetate in hexane, 0-100% silica gel, 25 g) to obtain 3-nitro-N-phenylbenzamide (21b) (2.93 g, 12.1 mmol, yield 37.5%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.60(s,1H,exchanged with D2O),8.79(t,J=2.0Hz,1H),8.43(dddd,J=12.0,7.8,2 .1,1.1Hz,2H),7.85(t,J=8.0Hz,1H),7.82-7.75(m,2H),7.44-7.35(m,2H),7.20-7.10(m,1H). Step 2: Preparation of 3-amino-N-phenylbenzamide (21c)

[0625] To a suspension of palladium-carbon (5%) (0.149 g, 1.404 mmol) in ethanol (120 mL), 3-nitro-N-phenylbenzamide (3.4 g, 14.04 mmol) was added and hydrogenated in a Parr apparatus at 45 psi for 3 hours. The reaction mixture was filtered through Celite and concentrated under vacuum. The residue was dried to obtain the compound, 3-amino-N-phenylbenzamide (21c) (2.872 g, 13.53 mmol, yield 96%), as a colorless solid. 1H NMR(300MHz,DMSO-d6)δ10.09(s,1H),7.84-7.71(m,2H),7.43-7.25(m,2H),7.15(t,J= 7.7Hz, 1H), 7.12-7.04 (m, 3H), 6.75 (ddd, J=7.9, 2.3, 1.1Hz, 1H), 5.35 (replaced with s, 2H, D2O). Step 3: Preparation of 3-(5-((3-(phenylcarbamoyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(21d)

[0626] To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (0.1 g, 0.26 mmol) in N,N-dimethylformamide (2 mL), 3-amino-N-phenylbenzamide (0.066 g, 0.311 mmol), N-ethyl-N-isopropylpropan-2-amine (0.362 mL, 2.076 mmol), and bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP, 0.133 g, 0.285 mmol) were added at room temperature. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 times × 20 mL). The organic layers were combined, washed with water (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure until dry. The obtained residue was purified by flash column chromatography (elution with ethyl acetate / hexane in hexane, 0-100% silica gel, 12 g) to obtain tert-butyl 3-(5-(3-(phenylcarbamoyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (21d) (77 mg, 0.133 mmol, yield 51.2%). 1 H NMR(300MHz,DMSO-d6)δ10.92(s,1H),10.29(s,1H),8.17(t,J=1.9Hz,1H),7.87(d,J=7.9Hz,1H),7.79-7.69(m,3H),7.65(s,1H) ,7.56-7.31(m,8H),7.16-7.06(m,1H),4.20(d,J=6.2Hz,2H),1.37(s,9H);MS(ES+)580.3(M+1),602.3(M+23),(ES-)578.3(M-1). Step 4: Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenylcarbamoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (21e)

[0627] To a stirred solution of tert-butyl(21d)(21d) (50 mg, 0.086 mmol) 3-(5-(3-(phenylcarbamoyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate in methanol (5 mL), concentrated hydrochloric acid (0.052 mL, 1.725 mmol) was added, and the reaction mixture was stirred overnight. Further 20 equivalents of HCl were added, and the mixture was stirred under reflux for 30 minutes. The reaction mixture was concentrated under vacuum until dry. The residue was dried under vacuum overnight, suspended in ether (25 mL), heated under reflux for 30 minutes, and stirred overnight at room temperature. The separated solid was collected by filtration and dried to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(phenylcarbamoyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide dihydrochloride (21e) (45 mg, 0.081 mmol, yield 94%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.99(s,1H,exchanged with D2O),10.32(s,1H,exchanged with D2O),8.34(s,3H,exchanged with D2O),8.23(t,J=1.9Hz,1H),7.92-7.82(m,1H),7.80-7. analysis, C 25 H 20 Calculated values ​​for F3N5O2(HCl)2: C, 54.43; H, 4.02; N, 12.72; Measured values: C, 54.59; H, 4.55; N, 12.52. [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-benzoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (22b) Step 1: Preparation of 3-(5-((3-benzoylphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(22a)

[0628] To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (200 mg, 0.519 mmol) in DMF (5 mL), (3-aminophenyl)(phenyl)methanone (18a) (102 mg, 0.518 mmol), N-ethyl-N-isopropylpropan-2-amine (0.730 mL, 4.19 mmol), and hexafluorophosphate (V) bromotripyrrolidine-1-ylphosphonium (PyBrOP, 248 mg, 0.522 mmol) were added and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (100 mL, 75 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash column chromatography [eluted with silica gel, hexane / ethyl acetate (1:0~2:1)] to obtain tert-butyl 3-(5-(3-benzoylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (22a) (182 mg, 62%) as a pale yellow rubber. 1 H NMR(300MHz,DMSO-d6)δ10.95(s,1H),8.04(t,J=1.8Hz,1H),7.99(d,J=8.0Hz,1H ),7.78-7.28(m,13H),4.19(d,J=6.2Hz,2H),1.36(s,9H);MS(ES+)587.3(M+23). Step 2: Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-benzoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (22b)

[0629] To a solution of tert-butyl (22a) (22a) (0.15 g, 0.266 mmol) of 3-(5-(3-benzoylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (14 mL) in 1,4-dioxane, hydrochloric acid (2.80 mL, 11.21 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with hexane, and the resulting solid was collected by filtration. The pale yellow solid was purified by flash column chromatography using 2 × 4 g of silica gel [eluted with chloroform / CMA80 (1:0~2:1)] to obtain tert-butyl (22b) (75 mg, 61%) 3-(5-(3-benzoylphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate as a grayish-white solid. 1 H NMR(300MHz,DMSO-d6)δ10.92(s,1H),8.04(t,J=1.8Hz,1H),7.97(d,J=7.9Hz,1H),7.75(d,J=1.7Hz,1H),7.73(d,J=1.6Hz,1H),7.71-7.65(m, 1H),7.61(s,1H),7.60(s,1H),7.57(s,1H),7.56-7.52(m,2H),7.51-7. 47(m,1H),7.45-7.41(m,2H),7.33(dt,J=5.3,2.5Hz,1H),3.78(s,2H); 19 F NMR (282MHz, DMSO-d6) δ-60.75; MS (ES+) 465.2 (M+1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(23c) Step 1: Preparation of 3-(5-((2-fluoro-3-phenoxyphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(23b)

[0630] To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (200 mg, 0.519 mmol) in DMF (5 mL), 2-fluoro-3-phenoxyaniline (23a) (105 mg, 0.519 mmol), N-ethyl-N-isopropylpropan-2-amine (0.730 mL, 4.19 mmol), and hexafluorophosphate (V) bromotripyrrolidine-1-ylphosphonium (PyBrOP, 249 mg, 0.523 mmol) were added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (2 times × 75 mL) and brine (750 mL), dried over MgSO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash column chromatography [eluted with silica gel, hexane / ethyl acetate (1:0~2:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(3-benzoylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (23b) (72 mg, 24%) as a colorless rubber. 1 H NMR (300MHz, DMSO-d6) δ7.80-6.72 (m, 13H), 3.78 (s, 2H); MS (ES+): 593.2 (M+23). Step 2: Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(23c)

[0631] To a solution of tert-butyl 3-(5-(2-fluoro-3-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (23b) (70 mg, 0.123 mmol) in 1,4-dioxane (5 mL), hydrochloric acid (1.3 mL, 5.2 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with hexane, and the resulting solid was collected by filtration. The pale yellow solid was purified by flash column chromatography using [silica gel 2 × 4 g, eluted with chloroform / CMA80 (1:0~2:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (23c) (32 mg, 55%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ7.60(s,1H),7.53(s,1H),7.48-7.32(m,6H),7.24-7.11(m,2H),7.06-6.97(m,3H),3.78(s,2H); 19 F NMR (282MHz, DMSO-d6) δ -60.76, -139.25; MS (ES+), 471.2 (M+1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (24c) Step 1: Preparation of 3-(5-((2-fluoro-5-phenoxyphenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(24b)

[0632] A solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (152 mg, 0.394 mmol) in DMF (3.5 mL) was treated with 2-fluoro-5-phenoxyaniline (24a) (80 mg, 0.394 mmol), N-ethyl-N-isopropylpropan-2-amine (0.550 mL, 3.16 mmol), and hexafluorophosphate (V) bromotripyrrolidine-1-ylphosphonium (PyBrOP, 189 mg, 0.398 mmol), and stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2 times × 50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash column chromatography [eluted with silica gel, hexane / ethyl acetate (1:0~3:1)] to obtain tert-butyl 3-(5-(2-fluoro-5-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (24b) (57 mg, 25%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.65(s,1H),7.58(s,1H),7.53-6.86(m,13H),4.18(d,J=6.3Hz,2H),1.37(s,9H);(ES+)593.3(M+23) Step 2: Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (24c)

[0633] To a solution of tert-butyl 3-(5-(2-fluoro-5-phenoxyphenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (24b) (55 mg, 0.096 mmol) in 1,4-dioxane (4 mL), hydrochloric acid (1.0 mL, 4.0 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with hexane, and the resulting solid was collected by filtration. The obtained solid was purified by flash column chromatography [elution with 4 g silica gel, chloroform / CMA80 (1:0~2:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-phenoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (24c) (20 mg, 44%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.68(s,1H),7.65-7.55(m,2H),7.52-7.30(m,7H),7 .15(tt,J=6.9,1.2Hz,1H),7.03-6.98(m,2H),6.96-6.89(m,1H),3.95(s,2H); 19 F NMR(282MHz,DMSO-d6)δ-60.80,-127.85;MS(ES+)471.2(M+1);(ES-)469.1(M-1) [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(ethoxy(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25b) and 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25c) Step 1: Preparation of 3-(5-((2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(25a)

[0634] To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (284 mg, 0.737 mmol) in DMF (6.5 mL), (3-amino-4-fluorophenyl)(phenyl)methanol (26c) (160 mg, 0.737 mmol), N-ethyl-N-isopropylpropan-2-amine (1.05 mL, 6.03 mmol), and hexafluorophosphate (V) bromotripyrrolidine-1-ylphosphonium (PyBrOP, 353 mg, 0.742 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (2 times × 75 mL), brine (60 mL), dried over MgSO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash column chromatography [eluted with silica gel, hexane / ethyl acetate (1:0~1:1)] to obtain tert-butyl 3-(5-(2-fluoro-5-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (25a) (196 mg, 46%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.56(s,1H),7.64-7.14(m,14H),6.00(d,J=3.9Hz,1H), 5.69(d,J=4.0Hz,1H),4.19(d,J=6.2Hz,2H),1.38(s,9H);MS(ES+)607.3(M+23). Step 2: Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-(ethoxy(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25b) and 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25c)

[0635] To a solution of tert-butyl (25a) (25a) (0.18 g, 0.308 mmol) of 3-(5-((2-fluoro-5-(hydroxy(phenyl)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (25a) (16 mL) in 1,4-dioxane, hydrochloric acid (3.2 mL, 12.81 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 26 hours. The reaction mixture was diluted with hexane (approximately 80 mL) and decanted to obtain a yellow oil. A portion of the insoluble yellow oil was dissolved in ethanol and converted into a silica gel slurry. The slurry was purified by flash column chromatography [elution with 4g silica gel, chloroform / CMA80 (1:0~3:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(5-(ethoxy(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25b) (61 mg, 39%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.57(s,1H),7.54(d,J=18.4Hz,3H),7.45-7.38(m,2H),7.33(M,5H) ),7.27-7.22(m,3H),5.45(s,1H),3.77(s,2H),3.42(q,J=7.0Hz,2H),1.16(t,J=7.0Hz,3H); 19 F NMR(282MHz,DMSO-d6)δ-60.76,-122.95;MS(ES+)513.3(M+1);(ES-)511.2(M-1).

[0636] Another portion of the insoluble yellow oil was dissolved in methanol and converted to silica gel. The slurry was purified by flash column chromatography [elution with 4 g silica gel, chloroform / CMA80 (1:0~1:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-5-(methoxy(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (25c) (11 mg, 7.2%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ10.58(s,1H),7.61-7.52(m,3H),7.52-7.34(m,2H), 7.40-7.29(m,6H),7.29-7.21(m,4H),5.34(s,1H),3.80(s,2H),3.25(s,3H); 19 F NMR(282MHz,DMSO-d6)δ-60.77,-122.99;MS(ES+)499.3(M+1);(ES-)497.3(M-1);533.3(M+Cl). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-benzyl-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (26f) Step 1: Preparation of (4-fluoro-3-nitrophenyl)(phenyl)methanol (26b)

[0637] A solution of 4-fluoro-3-nitrobenzaldehyde (26a) (4g, 23.65 mmol) in THF (60 mL) cooled to 0°C was met with dropwise addition of phenylmagnesium bromide (48.0 mL, 48.0 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was stopped with saturated aqueous NH4Cl solution (240 mL) and extracted with ethyl acetate (300 mL, 150 mL). The combined extract was washed with brine (150 mL), dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash column chromatography [elution with 80 g silica gel, hexane / ethyl acetate (1:0~2:1)] to obtain (4-fluoro-3-nitrophenyl)(phenyl)methanol (26b) (3.265 g, 56%) as brown rubber. 1 H NMR (300MHz, DMSO-d6) δ10.63(s,1H),8.24(s,1H),7.67-6.51(m,14H),4.20(d,J=6.3Hz,2H),1.37(s,9H);MS(ES+)270.1(M+1). Step 2: Preparation of (3-amino-4-fluorophenyl)(phenyl)methanol (26c) and 5-benzyl-2-fluoroaniline (26d)

[0638] To a solution of (4-fluoro-3-nitrophenyl)(phenyl)methanol (26b) (2g, 8.09 mmol) in ethanol (70 mL) and ethyl acetate (35 mL), Pd / C 10% (0.440 g, 0.413 mmol) was added and then hydrogenated for 4.5 hours (approximately 50 Psi). The reaction mixture was filtered through a Celite pad, and the filtrate was treated with 4 M HCl and 4 N HCl (aqueous solution, approximately 0.2 mL) in 1,4-dioxane (approximately 0.2 mL) to pH = approximately 5. The filtrate was concentrated under vacuum, and the resulting residue was purified by flash column chromatography [elution with hexane / ethyl acetate (1:0~3:1) on 25 g silica gel]. 1. (3-amino-4-fluorophenyl)(phenyl)methanol (26c) (175 mg, 10%) was obtained as light brown rubber. 1 H NMR(300MHz,DMSO-d6)δ7.37-7.14(m,5H),6.87(dd,J=11.5,8.3Hz,1H),6.76(dd,J=9.0,2.2Hz,1H) ,6.50(177dd,J=8.3,4.6,2.2,0.6Hz,1H),5.75(d,J=3.9Hz,1H),5.52(d,J=3.9Hz,1H),5.06(s,2H); 19 F NMR (282MHz, DMSO-d6) δ-137.89; MS (ES+): 218.2 (M+1). 2,5-benzyl-2-fluoroaniline (26d) (1.084 g, 67%) was obtained as brown rubber. 1 H NMR(300MHz,DMSO-d6)δ7.34-7.11(m,5H),6.86(dd,J=11.6,8.2Hz,1H),6.57(dd ,J=8.9,2.2Hz,1H),6.36(ddd,J=8.2,4.5,2.2Hz,1H),5.04(s,2H),3.76(s,2H); 19 F NMR (282MHz, DMSO-d6) δ-139.01; MS (ES+): 202.1 (M+1). Step 3: Preparation of 3-(5-(5-benzyl-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(26e)

[0639] To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (303 mg, 0.786 mmol) in DMF (7 mL), 5-benzyl-2-fluoroaniline (26d) (158 mg, 0.786 mmol), N-ethyl-N-isopropylpropan-2-amine (1.1 mL, 6.31 mmol), and hexafluorophosphate (V) bromotripyrrolidine-1-ylphosphonium (PyBrOP, 377 mg, 0.793 mmol) were added and the mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (2 times × 75 mL) and brine (60 mL), dried over MgSO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash column chromatography [eluted with silica gel, hexane / ethyl acetate (1:0~3:1)] to obtain 3-(5-(5-benzyl-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(26e) (228 mg) as a white solid, which was used directly in the next step. MS(ES+) 591.3(M+23). Step 4: Preparation of 1-(3-(aminomethyl)phenyl)-N-(5-benzyl-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (26f)

[0640] To a solution of tert-butyl (26e) (0.202 g, 0.355 mmol) of 3-(5-(5-benzyl-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (26e) in 18 mL of 1,4-dioxane, hydrochloric acid (3.7 mL, 14.78 mmol, 4 M in 1,4-dioxane) was added dropwise, and the mixture was stirred at room temperature for 21 hours. The reaction mixture was diluted with hexane, and the resulting yellow solid was collected by filtration. The yellow solid was purified by flash column chromatography [elution with 12 g of silica gel and chloroform / methanol (1:0~9:1)] to obtain 1-(3-(aminomethyl)phenyl)-N-(5-benzyl-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (26f) (99 mg) as a colorless rubber. 1 H NMR(300MHz,DMSO-d6)δ10.54(s,1H),7.56(s,1H),7.51(s,1H),7.47-7.40(m,3H),7.35-7 .25(m,3H),7.27-7.15(m,4H),7.13(ddt,J=8.5,5.0,2.2Hz,1H),3.92(s,2H),3.78(s,2H); 19 F NMR(282MHz,DMSO-d6)δ-60.75,-125.06;MS(ES+)469.3(M+1);(ES-)467.2(M-1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (27f) Step 1: Preparation of 3-nitro-N-phenyl-N-propylaniline (27c)

[0641] To a solution of 1-bromo-3-nitrobenzene (27a) (3 g, 14.85 mmol) and N-propylaniline (27b) (2.41 g, 17.82 mmol) in toluene (15 mL), sodium 2-methylpropane-2-oleate (1.142 g, 11.88 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.859 g, 1.485 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.408 g, 0.446 mmol) were added. The reaction mixture was stirred at 110 °C for 16 hours under a positive nitrogen flow. The reaction mixture was cooled to room temperature, stopped with water (75 mL), and extracted with ethyl acetate (twice × 100 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated until dry. The resulting residue was purified by flash column chromatography (eluting with ethyl acetate in hexane at 0-100% silica gel, 80 g) to obtain 3-nitro-N-phenyl-N-propylaniline (27c) (2.931 g, 11.44 mmol, yield 77%) as a yellowish-brown oil. The purity of the isolated product was not extremely high, but it was good enough to be used directly in the next step. MS(ES+) 257.2(M+1). Step 2: Preparation of N1-phenyl-N1-propylbenzene-1,3-diamine (27d)

[0642] To a solution of 3-nitro-N-phenyl-N-propylaniline (27c) (2.9 g, 11.31 mmol) in methanol (30 mL), palladium (10% Pd carbon, 0.241 g) was added. The mixture was hydrogenated for 2 hours, filtered through a Celite pad, and the filtrate was concentrated until dry under vacuum. The residue was purified by flash column chromatography (eluted with ethyl acetate in hexane, 0-100% silica gel, 80 g) to obtain N1-phenyl-N1-propylbenzene-1,3-diamine (27d) (1.195 g, 5.28 mmol, yield 46.7%) as a dark green oil. MS(ES+) 227.2(M+1). Step 3: Preparation of 3-(5-((3-(phenyl(propyl)amino)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(27e)

[0643] To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (0.19 g, 0.493 mmol) in DMF (3 mL), N1-phenyl-N1-propylbenzene-1,3-diamine (27d) (0.134 g, 0.592 mmol), N-ethyl-N-isopropylpropan-2-amine (0.687 mL, 3.94 mmol), and bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBrop, 0.253 g, 0.542 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 17 hours and concentrated under vacuum until dry. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (50, 20 mL). The organic layers were combined, dried, filtered, and evaporated until dry. The obtained residue was purified by flash column chromatography [elution with ethyl acetate in hexane at 0-25% silica gel (12 g)] to obtain tert-butyl(27e) 3-(5-(3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (0.199 g, 0.335 mmol, yield 68.0%) as a white solid. MS(ES+)616.3(M+Na),(ES-)592.3(M-1). Step 4: Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (27f)

[0644] To a solution of tert-butyl(27e)(27e) (0.183 g, 0.308 mmol) of 3-(5-(3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate in dioxane (4 mL), hydrochloric acid (4 M in dioxane, 4.32 mL, 17.26 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under vacuum until dry, and the resulting residue was purified by flash column chromatography (eluted with methanol in chloroform at 0-100% silica gel, 25 g) to obtain 1-(3-(aminomethyl)phenyl)-N-(3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide(27f) (0.086 g, 0.174 mmol, yield 56.5%) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ10.61(s,1H,exchanged with D2O),7.53(s,2H),7.49-7.42(m,2H),7.34-7.23(m,4H),7.22-7.17(m,2H) ,7.05-6.93(m,3H),6.71-6.67(m,1H),3.81(s,2H),3.68-3.54(m,2H),1.57(h,J=7.5Hz,2H),0.88(t,J=7.4Hz,3H); 19 F NMR(282MHz, DMSO-d6)δ-60.73; MS(ES+)494.3(M+1),(ES-)492.2(M-1),528.2(M+Cl). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((methyl(phenyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (28f) Step 1: Preparation of N-methyl-N-(3-nitrobenzyl)aniline (28c)

[0645] To a solution of 1-(chloromethyl)-3-nitrobenzene (28a) (4 g, 23.31 mmol) in DMF (50 mL), N-methylaniline (28b) (2.53 mL, 23.31 mmol) was added, followed by the addition of potassium carbonate (20.94 g, 152 mmol). The reaction mixture was stirred at room temperature for 20 hours, poured into water (200 mL), and extracted with ethyl acetate (twice × 50 mL). The organic layers were combined, washed with water (100 mL) and brine (50 mL), dried, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by flash column chromatography (eluting with 0-100% ethyl acetate in hexane over 40 g of silica gel) to obtain N-methyl-N-(3-nitrobenzyl)aniline (28c), which was pure enough to be used in the next step. MS(ES+) 243.2(M+1). Step 2: Preparation of N-(3-aminobenzyl)-N-methylaniline (28d)

[0646] To a stirred solution of N-methyl-N-(3-nitrobenzyl)aniline (28c) (1.5 g, 6.19 mmol) in acetic acid (20 mL), iron powder (1.729 g, 31.0 mmol) was added, and the mixture was heated to 60°C and stirred for 30 minutes. The reaction was stopped by adding water (100 mL), and the mixture was filtered. The filtrate was extracted with ethyl acetate (twice × 100 mL). The ethyl acetate layers were combined, washed with water (twice × 100 mL) and brine (50 mL), dried, and concentrated under vacuum. The resulting residue was purified by flash column chromatography to obtain N-(3-aminobenzyl)-N-methylaniline (28d) (533 mg, 2.51 mmol, yield 40.6%). 1 H NMR(300MHz,DMSO-d6)δ7.19-7.06(m,2H),7.02-6.92(m,1H),6.73-6.64(m,2H),6.58(tt,J=7.2,1 .0Hz,1H),6.49-6.36(m,3H),5.46(s,2H,replaced with D2O),4.39(s,2H),2.98(s,3H);MS(ES+)213.2(M+1). Step 3: Preparation of 3-(5-((3-((methyl(phenyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(28e)

[0647] To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (193 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL), N-ethyl-N-isopropylpropan-2-amine (0.697 mL, 4.00 mmol), N-ethyl-N-isopropylpropan-2-amine (0.697 mL, 4.00 mmol), and bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP, 256 mg, 0.55 mmol) were added at room temperature. The reaction mixture was stirred at 25°C for 16 hours, diluted with water (20 mL), and extracted with ethyl acetate (twice in 50 mL batches). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure until dry. The obtained residue was purified by flash column chromatography (elution with hexane in ethyl acetate / hexane at 0-100% concentration, using 12 g of silica gel) to obtain tert-butyl(28e) (110 mg, 0.190 mmol, yield 37.9%) as a colorless, viscous substance. 1 H NMR (300MHz, DMSO-d6) δ10.71 (s, 1H, exchanged with D2O), 7.59-7.45 (m, 4H), 7.45-7.38 (m, 2H ),7.34(d,J=7.7Hz,2H),7.27(t,J=7.9Hz,1H),7.20-7.07(m,2H),6.97(d,J=7.7Hz ,1H),6.69(d,J=8.1Hz,2H),6.60(t,J=7.2Hz,1H),4.52(s,2H),4.19(d,J=6.2Hz,2 H),3.01(s,3H),1.37(s,9H);MS(ES+)580.4(M+1),602.4(M+23),(ES-)578.4(M-1) Step 4: Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-((methyl(phenyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (28f)

[0648] To a stirred solution of tert-butyl(28e)(28e) (100 mg, 0.173 mmol) of 3-(5-((3-((methyl(phenyl)amino)methyl)phenyl)carbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate in methanol (10 mL), HCl (0.575 mL, 6.90 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was heated under reflux for 30 minutes and concentrated in vacuum until dry. The residue was dried overnight in vacuum, suspended in ether (25 mL), heated for 30 minutes, and stirred overnight at room temperature. The separated solid was collected by filtration and dried to obtain 1-(3-(aminomethyl)phenyl)-N-(3-((methyl(phenyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide hydrochloride (28f) (75 mg, 0.145 mmol, yield 84%). 1H NMR(300MHz,DMSO-d6)δ10.79(s,1H),8.38(s,3H),7.72(s,1H),7.66(s,1H),7.61( d,J=7.5Hz,1H),7.58-7.54(m,1H),7.54-7.47(m,2H),7.28(t,J=7.8Hz,1H),7.16( t,J=7.7Hz,2H),7.00(d,J=7.5Hz,1H),6.70(d,J=25.7Hz,3H),4.54(s,2H),4.13(d ,J=5.7Hz,3H),3.02(s,3H);MS(ES+)480.3(M+1);(ES-)478.2(M-1),514.2(M+35). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (29e) Step 1: Preparation of 2-fluoro-3-nitro-N-phenyl-N-propylaniline (29b)

[0649] To a solution of 1-bromo-2-fluoro-3-nitrobenzene (29a) (3 g, 13.64 mmol) and N-propylaniline (27b) (2.213 g, 16.36 mmol) in toluene (80 mL), sodium 2-methylpropane-2-oleate (1.048 g, 10.91 mmol), biphenyl-2-yldi-tert-butylphosphine (0.407 g, 1.364 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.375 g, 0.409 mmol) were added. The reaction mixture was stirred at 110 °C for 16 hours under a positive nitrogen flow. The reaction was stopped with water (75 mL) and extracted with ethyl acetate (twice × 100 mL). The combined organic matter was dried over MgSO4, filtered, and evaporated until dry. The residue was purified by flash column chromatography (eluting with ethyl acetate in hexane at 0-100% silica gel, 80 g) to obtain 2-fluoro-3-nitro-N-phenyl-N-propylaniline (29b) (3.451 g, 12.58 mmol, 92% yield) as a yellowish-brown oil, which was pure enough to be used in the next step. MS(ES+)275.2(M+1) Step 2: Preparation of 2-fluoro-N1-phenyl-N1-propylbenzene-1,3-diamine(29c)

[0650] To a solution of 2-fluoro-3-nitro-N-phenyl-N-propylaniline (29b) (3.4 g, 12.40 mmol) in methanol (30 mL), palladium (10% Pd carbon, 0.264 g, 2.479 mmol) was added. The mixture was hydrogenated for 2.5 hours, filtered through a Celite pad, and concentrated until dry. The residue was purified by flash column chromatography (eluted with ethyl acetate in hexane, 0-100% silica gel, 80 g) to obtain 2-fluoro-N1-phenyl-N1-propylbenzene-1,3-diamine (29c) (0.295 g, 1.207 mmol, yield 9.74%) as a brown oil. MS(ES+)245.2(M+1);(ES-)243.2(M-1) Step 3: Preparation of 3-(5-(2-fluoro-3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(29d)

[0651] To a solution of 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (0.190 g, 0.493 mmol) in N,N-dimethylformamide (2.98 mL, 38.5 mmol), 2-fluoro-N1-phenyl-N1-propylbenzene-1,3-diamine (29c) (0.145 g, 0.592 mmol), N-ethyl-N-isopropylpropan-2-amine (0.687 mL, 3.94 mmol), and bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP, 0.253 g, 0.542 mmol) were added at room temperature. The resulting reaction mixture was stirred at 25°C for 17 hours. Excess DMF was removed under reduced pressure. The reaction mixture was extracted with ethyl acetate (50 mL, 20 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure until dry. The residue was purified by flash column chromatography (eluted with hexane in ethyl acetate / hexane at 120 g silica gel, 0-100%) to obtain tert-butyl 3-(5-(2-fluoro-3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl (29d) (0.182 g, 0.298 mmol, yield 60.3%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.54(s,1H,exchanged with D2O),7.57(s,1H),7.53-7.31(m,4H),7.28-7.15(m,4H),6.94-6.83 (m,4H),4.18(d,J=6.2Hz,2H),3.68-3.51(m,2H),1.55(q,J=7.5Hz,2H),1.37(s,9H),0.87(t,J=7.4Hz,3H); 19 F NMR (282MHz, DMSO-d6) δ-60.82, -129.49; MS (ES+) 634.33 (M+Na), MS (ES-) 610.31 (M-1). Step 4: Preparation of 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (29e)

[0652] To a solution of tert-butyl (29d) (0.166 g, 0.271 mmol) of 3-(5-(2-fluoro-3-(phenyl(propyl)amino)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (29d) (0.166 g, 0.271 mmol) in dioxane (4 mL), hydrochloric acid (4 N in dioxane) (3.80 mL, 15.20 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 hours. TLC analysis (CHCl3 / MeOH, 8 / 2, v / v) indicated completion of the reaction. The excess solvent was discharged under reduced pressure, and the residue was purified by flash column chromatography (elution with methanol in chloroform at 0-100% concentration, using 25 g of silica gel) to obtain 1-(3-(aminomethyl)phenyl)-N-(2-fluoro-3-(phenyl(propyl)amino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (29e) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ7.57(s,1H),7.52(s,1H),7.48-7.40(m,2H),7.37-7.30(m,1H),7.29-7.16(m ,4H),6.95-6.82(m,4H),3.79(s,2H),3.65-3.51(m,2H),1.54(h,J=7.3Hz,2H),0.87(t,J=7.3Hz,3H); 19 F NMR(282MHz,DMSO-d6)δ-60.75,-129.55;MS(ES + ):MS(ES+)512.3(M+1),(ES-)510.3(M-1),546.2(M+Cl). [ka] Preparation of N-(5-((1H-imidazole-1-yl)methyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30g) Step 1: Preparation of (3-amino-4-fluorophenyl)methanol (30b)

[0653] To a solution of (4-fluoro-3-nitrophenyl)methanol (30a) (3.81 g, 22.24 mmol) in methanol (30 mL), palladium carbon (10%) (0.39 g, 3.67 mmol) was added and hydrogenated at 60 PSI for 1 hour. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under vacuum. The resulting residue was purified by flash column chromatography [elution with 0-100% ethyl acetate / methanol (9:1) in hexane over 40 g of silica gel] to obtain (3-amino-4-fluorophenyl)methanol (30b) (3.05 g, 21.61 mmol, yield 97%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ6.89(dd,J=11.6,8.2Hz,1H),6.73(dd,J=9.1,2.1Hz,1H),6.52-6.33(m,1H),5.20-4.91(m,3H),4.32(dd,J=5.8,0.9Hz,2H); 19 F NMR(282MHz,DMSO-d6)δ-138.13. Step 2: Preparation of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30c)

[0654] To a solution of 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (9i) (5.67 g, 20.15 mmol) in DMF (50 mL), (3-amino-4-fluorophenyl)methanol (30b) (2.37 g, 16.79 mmol), N-ethyl-N-isopropylpropan-2-amine (14.62 mL, 84 mmol), and bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (8.61 g, 18.47 mmol) were added at room temperature. The resulting reaction mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction mixture, diluted with water (25 mL), was extracted with ethyl acetate (twice × 50 mL), washed with brine (25 mL), and the combined organic layer was dried over anhydrous MgSO4, filtered, and evaporated until dry. The obtained residue was purified by flash column chromatography [elution with 40 g silica gel and 0-100% ethyl acetate / methanol (9 / 1) in hexane] to obtain 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30c) (1.66 g, 4.11 mmol, yield 24.45%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.57(s,1H),8.18-8.09(m,1H),8.00(dt,J=7.8,1.3Hz,1H),7.91(ddd,J=8.1,2.3,1. 1Hz,1H),7.78-7.69(m,2H),7.57-7.45(m,1H),7.33-7.15(m,2H),5.30(t,J=5.7Hz,1H),4.46(d,J=5.7Hz,2H); 19 F NMR(282MHz,DMSO-d6)δ-60.98,-124.32.;MS(ES+)427.2(M+Na),(ES-)403.2(M-1). Step 3: Preparation of N-(5-(chloromethyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30d)

[0655] To a solution of 1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30c) (1.66 g, 4.11 mmol) in dichloromethane (30 mL), thionyl chloride (1.798 mL, 24.63 mmol) was added at 0°C and the mixture was stirred for 2.5 hours. The reaction mixture was concentrated under vacuum to obtain a white residue. The residue was dissolved in CHCl3 and treated with silica gel (2 g). The resulting slurry was purified by flash column chromatography (eluted with ethyl acetate in hexane with 40 g of silica gel, 0-50%) to obtain N-(5-(chloromethyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30d) (1.353 g, yield 78%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.63(s,1H),8.18-8.11(m,1H),8.01(dt,J=7.7,1.3Hz,1H), 7.91(ddd,J=8.1,2.2,1.1Hz,1H),7.80-7.65(m,3H),7.43-7.22(m,2H),4.77(s,2H); 19 F NMR(282MHz,DMSO-d6)δ-60.98(d,J=6.8Hz),-121.36. Step 4: Preparation of N-(5-((1H-imidazole-1-yl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30e)

[0656] To a stirred solution of N-(5-(chloromethyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30d) (0.15 g, 0.355 mmol) in N,N-dimethylformamide (4 mL), imidazole (0.121 g, 1.774 mmol) and potassium carbonate (0.343 g, 2.484 mmol) were added, and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated under vacuum, and the resulting residue was dissolved in methanol and filtered through a Celite® pad. The filtrate was evaporated until dry, and the resulting crude residue was purified by flash column chromatography (elution with 0-100% methanol in chloroform using 12 g of silica gel) to obtain N-(5-((1H-imidazole-1-yl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30e) (0.107 g, yield 66.4%) as a white foamy solid. 1 H NMR(300MHz,DMSO-d6)δ10.59(s,1H),8.13(t,J=1.8Hz,1H),8.00(dt,J=7.7,1.3Hz,1H),7.94-7.86(m,1H),7.77-7. 71(m,3H),7.43(d,J=7.1Hz,1H),7.31(dd,J=10.4,8.5Hz,1H),7.23-7.14(m,2H),6.90(t,J=1.1Hz,1H),5.19(s,2H); 19 F NMR (282MHz, DMSO-d6) δ-60.98(d,J=5.4Hz),-122.18; MS(ES+)455.2(M+1),(ES-)453.2(M-1). Step 5: Preparation of 3-(5-(5-((1H-imidazole-1-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(30f)

[0657] To a stirred solution of N-(5-((1H-imidazole-1-yl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30e) (0.1 g, 0.22 mmol) in anhydrous methanol (10 mL) cooled to 0°C, di-tert-butyl[(Boc)2O)] (0.144 g, 0.66 mmol) and nickel(II) chloride hexahydrate (10.46 mg, 0.044 mmol) were added, followed by the addition of sodium borohydride (0.050 g, 1.320 mmol) in small amounts over 5 minutes. The reaction mixture was stopped with N1-(2-aminoethyl)ethane-1,2-diamine (0.048 mL, 0.440 mmol), stirred at room temperature for 30 minutes, and concentrated under vacuum until dry. The residue was dissolved in water / ethyl acetate (1:1, 25 mL each). The organic layer was separated and concentrated until dry under vacuum. The resulting residue was purified by flash column chromatography (eluting 12 g silica gel with 0-50% ethyl acetate / hexane) to obtain 3-(5-(5-((1H-imidazole-1-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl (30f) (0.042 g, 0.075 mmol, yield 34.2%) as a white solid. MS(ES+)559.3(M+1),(ES-)557.2(M-1). Step 6: Preparation of N-(5-((1H-imidazole-1-yl)methyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30g)

[0658] To a solution of tert-butyl (30f) (0.022 g, 0.039 mmol) of 3-(5-(5-((1H-imidazole-1-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (30f) (0.022 g, 0.039 mmol) in dioxane (4 mL), hydrochloric acid (4 N in dioxane, 0.551 mL, 2.206 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under vacuum until dry, and the resulting residue was purified by flash column chromatography (elution with 0-100% methanol in chloroform using 12 g of silica gel) to obtain N-(5-((1H-imidazole-1-yl)methyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (30 g) (0.016 g, 0.035 mmol, yield 89%) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ14.58(s,1H,exchanged with D2O),10.77(s,1H,exchanged with D2O),9.21(s,1H),8.37(s,3H,exchanged with D2O),7.75(t,J=1.6Hz,1H),7 .69(ddd,J=11.3,3.6,1.7Hz,4H),7.64-7.54(m,2H),7.54-7.48(m,1H),7.40-7.33(m,2H),5.42(s,2H),4.12(d,J=5.7Hz,2H); 19 F NMR(282MHz,DMSO-d6)δ-60.82,-121.10;MS(ES + ):MS(ES+)459.3(M+1),(ES-)457.3(M-1),493.2(M+Cl). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(hydroxy(pyridine-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (31f) Step 1: Preparation of (3-nitrophenyl)(pyridine-3-yl)methanol(31c)

[0659] To a solution of 3-bromopyridine (31b) (2.89 mL, 30.0 mmol) in ether (20 mL) at -78°C, n-BuLi (15.94 mL, 25.5 mmol) was added dropwise, and the mixture was stirred at -78°C for 30 minutes. To the 3-lithium pyridine, a solution of 3-nitrobenzaldehyde (31a) (4.53 g, 30 mmol) in THF (30 mL) at -78°C was added dropwise, and the mixture was stirred at -78°C for 2 hours, followed by stirring at room temperature for 2 hours. The reaction mixture was stopped with saturated ammonium chloride (50 mL). The organic layer was separated, dried, filtered, and concentrated under vacuum until dry. The obtained residue was purified by flash column chromatography (elution with 0-100% ethyl acetate in hexane over 80 g of silica gel) to obtain (3-nitrophenyl)(pyridine-3-yl)methanol (31c) (2.842 g, 12.34 mmol, yield 41.1%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ8.66(d,J=2.2Hz,1H),8.47(dd,J=4.8,1.7Hz,1H),8.30( t,J=2.0Hz,1H),8.12(ddd,J=8.2,2.5,1.1Hz,1H),7.85(d,J=7.5Hz,1H),7.78(dt ,J=7.9,2.0Hz,1H),7.64(t,J=7.9Hz,1H),7.36(ddd,J=7.9,4.7,0.9Hz,1H),6.45 (d,J=4.2Hz,1H),5.99(d,J=4.0Hz,1H);MS(ES+)231.1(M+1),(ES-)459.4(2M-1). Step 2: Preparation of (3-aminophenyl)(pyridine-3-yl)methanol (31d)

[0660] To a solution of (3-nitrophenyl)(pyridine-3-yl)methanol (31c) (1 g, 4.34 mmol) in ethanol (36 mL) and ethyl acetate (18 mL), 0.1 g of Pd / C 10% was added and hydrogenated at approximately 50 Psi for 2 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography [elution with 2 × 12 g silica gel and chloroform / methanol (1:0 to 9:1)] to obtain (3-aminophenyl)(pyridine-3-yl)methanol (31d) (209 mg, 24%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ8.55(dt,J=2.2,0.7Hz,1H),8.40(dd,J=4.8,1.7Hz,1H),7 .68(dddd,J=7.8,2.3,1.7,0.6Hz,1H),7.31(ddd,J=7.8,4.7,0.9Hz,1H),6.94(t,J =7.7Hz,1H),6.61-6.56(m,1H),6.55-6.48(m,1H),6.40(ddd,J=8.0,2.3,1.1Hz,1 H),5.89(d,J=3.9Hz,1H),5.58(d,J=3.9Hz,1H),5.05(s,2H);MS(ES+)201.1(M+1). Step 3: Preparation of 3-(5-(3-(hydroxy(pyridine-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate tert-butyl(31e)

[0661] To a solution of (3-aminophenyl)(pyridine-3-yl)methanol (31d) (80 mg, 0.400 mmol) in N,N-dimethylformamide (4 mL), 1-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (10d) (154 mg, 0.400 mmol), N-ethyl-N-isopropylpropan-2-amine (0.560 mL, 3.22 mmol), and hexafluorophosphate (V) bromotripyrroridine-1-ylphosphonium (PyBroP, 192 mg, 0.403 mmol) were added at room temperature. The reaction mixture was stirred at 25°C for 22 hours and diluted with ethyl acetate (120 mL). The reaction mixture was washed with water (60 mL twice) and brine (60 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum until dry. The resulting residue was purified by flash column chromatography [eluted with 12 g silica gel and chloroform / methanol (1:0 to 9:1)] to obtain tert-butyl(31e) 3-(5-(3-(hydroxy(pyridine-3-yl)methyl)phenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl)benzylcarbamate (31e) (153 mg, 68%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.71(s,1H),8.58(d,J=2.2Hz,1H),8.43(dd,J=4.8,1.7Hz,1H),7.70(dt,J=8.1,2.1Hz,1H),7. 64(t,J=1.9Hz,1H),7.60-7.11(m,10H),6.14(d,J=4.0Hz,1H),5.76(d,J=4.0Hz,1H),4.19(d,J=6.2Hz,2H),1.36(s,9H); 19 F NMR (282MHz, DMSO-d6) δ-60.80; MS (ES+) 568.3 (M+1). Step 4: Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(hydroxy(pyridine-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (31f)

[0662] To a stirred solution of tert-butyl(31e) The slurry was purified by flash column chromatography [elution with silica gel, chloroform / CMA80 (1:0~1:1)] to obtain 1-(3-cyanophenyl)-N-(3-(hydroxy(pyridine-4-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (31f) (93 mg, 84%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ10.70(s,1H),8.57(d,J=2.2Hz,1H),8.43(dd,J=4.8,1.7Hz,1H),7.70(dt,J=8.0,2.0Hz,1H),7.66(t,J=1.8Hz,1H),7.56 (d,J=3.2Hz,1H),7.55-7.49(m,2H),7.46-7.38(m,2H),7.37-7.26(m,3H ),7.16(d,J=7.6Hz,1H),6.15(d,J=4.0Hz,1H),5.76(s,1H),3.77(s,2H); 19 F NMR (282MHz, DMSO-d6) δ-60.73; MS (ES+) 468.3 (M+1). [ka] Preparation of 1-(3-(aminomethyl)phenyl)-N-(3-(1-phenylpentyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (32f) Step 1: Preparation of 1-(3-aminophenyl)-1-phenylpentan-1-ol (32a)

[0663] To a stirred solution of (3-aminophenyl)(phenyl)methanone (18a) (2 g, 10.14 mmol) in tetrahydrofuran (40 mL), n-BuLi (19.01 mL, 30.4 mmol, 1.6 M in hexane) was added at 0°C. The react...

Claims

1. A compound represented by formula II or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, X is CH, C(OH), C(O(C １ -C ６ ) alkyl), —C(NH ２ ), -C(NR ａ R ｂ ), or N, -Y-R ４ is -((C １ -C ６ ) alkyl)-R ４ , -CH ２ C(O)-R ４ , -CH ２ NH-R ４ , -CH ２ N ((C １ -C ６ ) alkyl)-R ４ , -CR ａ R ｂ -R ４ , -NH-R ４ , -NHCH ２ -R ４ , -NHC(O)-R ４ , -N((C １ -C ６ ) alkyl)-R ４ , -N((C １ -C ６ ) alkyl) CH ２ -R ４ , -N((CH ２ ) ２ OH)-R ４ , -N[(C ３ -C ８ ) cycloalkyl (C １ -C ６ ) alkyl]R ４ , -heterocyclyl-R ４ , -OR ４ , -OCH ２ -R ４ or —OC(O)—R ４ and the -((C １ -C ６ ) alkyl)-R ４ (C １ -C ６ ) the alkyl portion is optionally substituted; Z is absent or is selected from halo and (C ３ -C ８ ) represents one or more substituents independently selected from the group consisting of cycloalkyl; R １ｃ is amino (C １ -C ６ ) alkyl, —C(═NH)NH ２ , -CONR ａ R ｂ , -C(=NH)NH(OH), -C(=NH)NH(C(O)O-(C １ -C ６ ) alkyl), —C(═NH)NH(C(O)O—(C １ -C ６ ) haloalkyl), —C(═NH)NH(C(O)S—(C １ -C ６ ) alkyl), or —C(═NH)NH(C(O)(OCH(C １ -C ６ ) alkyl)OC(O)(C １ -C ６ ) alkyl), R ２ is (C １ -C ６ ) alkyl, (C １ -C ６ ) Fluoroalkyl, —CONH ２ , —C(O)OH, or cyano; R ３ represents an optionally substituted arylene, an optionally substituted heteroarylene, or an optionally substituted heterocyclylene; R ３ａ is hydrogen or halo, hydroxy, (C １ -C ６ ) alkyl, —CF ３ , -OCF ３ , (C １ -C ６ ) alkoxy, aryl, aryloxy, amino, amino (C １ -C ６ ) alkyl, —C(O)NH ２ , cyano, -NHC(O)(C １ -C ６ ) alkyl, —SO ２ (C １ -C ６ ) alkyl, —SO ２ NH ２ , (CH ２ ) ｒ OR ａ , (CH ２ ) ｒ NR ａ R ｂ , N.R. ａ C(O)R ｂ , C(O)NR ｃ R ｄ , N.R. ａ R ｂ and OCH ２ R ａ or alternatively, R ３ａ is a 5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S; R ４ is hydrogen, hydroxy, optionally substituted (C １ -C ６ ) alkyl, optionally substituted (C ３ -C ８ ) cycloalkyl, heterocyclyl (C １ -C ６ ) alkyl, optionally substituted (C ３ -C ８ ) cycloalkyl (C １ -C ６ ) alkyl, —CH ２ OH, -CH((C １ -C ６ ) alkyl)OH, —CH(NH ２ ) CH((C １ -C ６ ) alkyl) ２ , optionally substituted aryl, heteroaryl, optionally substituted heteroaryl (C １ -C ６ ) alkyl, —CH ２ S (C １ -C ６ ) alkyl, amino, or cyano, or R ３ is phenylene, R ４ is further fused to the phenylene at the ortho position relative to X, -NR ａ - can be represented, Each R ａ and R ｂ are independently H, (C １ -C ８ ) alkyl, (aryl (C １ -C ８ ) alkyl, —C(═O)R ｃ , -S(O)R ｃ , or -S(O) ２ R ｃ and Each R ｃ and R ｄ are independently H or (C １ -C ８ ) alkyl, r is, independently for each occurrence, 0, 1, 2, or 3; and the stereochemistry of any chiral center is R, S, or a mixture of R and S; Additionally, any of the optional substituents may be halogen, (C １ -C ８ ) alkyl, aryl (C １ -C ８ ) alkyl, hydroxy, (C １ -C ８ ) selected from alkoxy, amino, oxo (=O) and cyano; The compound or a pharmaceutically acceptable salt thereof.

2. In the formula II, X is CH, C(OH) or —C(NH ２ ) and -Y-R ４ is -((C １ -C ６ ) alkyl)-R ４ , -NH-R ４ , -NHCH ２ -R ４ , -OR ４ or -OCH ２ -R ４ represents Z is absent or represents a halo; R １ｃ is amino (C １ -C ６ ) represents alkyl, R ２ is (C １ -C ６ ) represents fluoroalkyl; R ３ represents an optionally substituted arylene or an optionally substituted heteroarylene; R ３ａ is hydrogen or hydroxy, (C １ -C ６ ) represents one or more substituents independently selected from the group consisting of alkoxy, amino, and cyano; R ４ is optionally substituted (C ３ -C ８ ) cycloalkyl, or optionally substituted (C ３ -C ８ ) cycloalkyl (C １ -C ６ ) alkyl, or R ３ is phenylene, R ４ is further fused to the phenylene at the ortho position relative to X, -NR ａ - can represent, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. In the formula II, X is CH, C(OH) or —C(NH ２ ) and -Y-R ４ is -((C １ -C ６ ) alkyl)-R ４ , -NH-R ４ , -NHCH ２ -R ４ , or -OCH ２ -R ４ represents Z is absent or represents a halo; R １ｃ is amino (C １ -C ６ ) alkyl, or —C(═NH)NH ２ represents R ２ is (C １ -C ６ ) Fluoroalkyl, —CONH ２ , or cyano, R ３ represents an optionally substituted arylene or an optionally substituted heteroarylene; R ３ａ is hydrogen or halo, hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, amino, —C(O)NH ２ , cyano, -NHC(O)(C １ -C ６ ) alkyl, and —SO ２ NH ２ represents one or more substituents independently selected from the group consisting of R ４ is optionally substituted (C ３ -C ８ ) cycloalkyl, or (C ３ -C ８ ) cycloalkyl (C １ -C ６ ) alkyl, or R ３ is phenylene, R ４ is further fused to the phenylene at the ortho position relative to X, -NR ａ - can represent, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X represents CH.

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X represents -C(NH 2 ).

6. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X represents C(OH).

7. -XY- is -CHNHCH ２ --, --CHCH ２ CH ２ -, -C(OH)CH ２ CH ２ -or-CHOCH ２ 4. The compound according to claim 1, wherein R represents - or a pharmaceutically acceptable salt thereof.

8. R ３ -R 3a is phenylene -R ３ａ The compound according to any one of claims 1 to 7, wherein the compound represents: or a pharmaceutically acceptable salt thereof.

9. -R ３ -R ３ａ but, 【Chemistry 2】 The compound according to any one of claims 1 and 4 to 7, wherein the compound represents: or a pharmaceutically acceptable salt thereof.

10. R ３ａ 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

11. R ３ is phenylene, and R ３ａ is ortho-, meta-, or para-OH, or R ３ is phenylene, and R ３ａ is ortho, meta, or para-NH ２ or R ３ is phenylene, and R ３ａ 11. The compound of any one of claims 1 to 8 and 10, or a pharmaceutically acceptable salt thereof, wherein is ortho-, meta-, or para-CN.

12. Z is absent, fluoro, chloro, or 2-F, 3-F, 5-F, 6-F, 6-Cl, or 5-(C ３ -C ８ 12. The compound of any one of claims 1 and 3 to 11, or a pharmaceutically acceptable salt thereof, wherein Z represents 6-F.

13. R １ｃ 13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein represents aminomethyl.

14. R ２ But, -CF ３ , -CONH ２ 14. The compound of any one of claims 1 and 3 to 13, or a pharmaceutically acceptable salt thereof, wherein:

15. R ４ is cyclopropyl, or R ３ is phenylene, R ４ is further fused to the phenylene at the ortho position relative to X, -NR ａ - or a pharmaceutically acceptable salt thereof.

16. R ３ is phenylene, and R ４ is fused at the ortho position to X on the phenylene -NR ａ 2. The compound of claim 1, wherein R represents - or a pharmaceutically acceptable salt thereof.

17. -Y-R ４ But -OC(O)-R ４ 17. The compound of claim 16, wherein:

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, the composition being formulated for parenteral or oral administration.

19. 20. A pharmaceutical composition comprising the compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition characterized by unwanted plasma kallikrein activity.

20. 20. The pharmaceutical composition of claim 19, wherein the disease or condition characterized by unwanted plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, conditions after fibrinolytic therapy, tonsillitis, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, cerebral edema, increased albumin excretion, overt albuminuria, and nephropathy.

21. 20. The pharmaceutical composition of claim 19, wherein the disease or condition characterized by unwanted plasma kallikrein activity is angioedema.

22. 20. The pharmaceutical composition of claim 19, wherein the disease or condition characterized by unwanted plasma kallikrein activity is hereditary angioedema.

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